Title of Invention	NOVEL SUBSTITUTED 1,2,4-TRIOXANES USEFUL AS ANTI MALARIAL AGENTS AND A PROCESS FOR THE PREPARATION OF THE SAME
Abstract	Novel substituted 1,2,4 trioxanes useful as antimalarial agent and a process for the preparation of the same by reacting hydroxyacetophenones with α-haloesters in the presence of a base optionally in an organic solvent at a temperature in the range of room temperature of refluxing temperature to give keto-esters, reacting keto-esters under Reformatsky condition in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß-hydroxyesters; dehydrating ß-hydroxyesters ; dehydrating ß-hydroxyesters using a catalyst in an organic solvent at a temperature in the range of room temperature to refluxing temperature to give α,ß-unsaturated esters ; reducing ß-hydroxyesters esters with a complex metal hydride such as LiAIH4 in an ether solvent at a temperature in the range of 0°C to room temperature to give allylic alcohols ; oxygenation of allylic alcohols in presence of a sensitizer in an organic solvent at a temperature in the range of -10°C to room temperature to give ß-hydroxyhydroperoxides ; isolating and then reacting or reaction in situ ß-hydroxyhydroperoxides with compounds containing aldehyde or ketone group in presence of an acid catalyst in an organic solvent at a temperature in the range of 0°C to room temperature to give hydroxyl-functionalized 1,2,4-trioxanes with an acid chloride or anhydrides in presence of a base in an organic solvent at a temperature in the range of 0°C to room temperature to give trioxane esters.

Title of Invention

NOVEL SUBSTITUTED 1,2,4-TRIOXANES USEFUL AS ANTI MALARIAL AGENTS AND A PROCESS FOR THE PREPARATION OF THE SAME

Abstract

Novel substituted 1,2,4 trioxanes useful as antimalarial agent and a process for the preparation of the same by reacting hydroxyacetophenones with α-haloesters in the presence of a base optionally in an organic solvent at a temperature in the range of room temperature of refluxing temperature to give keto-esters, reacting keto-esters under Reformatsky condition in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß-hydroxyesters; dehydrating ß-hydroxyesters ; dehydrating ß-hydroxyesters using a catalyst in an organic solvent at a temperature in the range of room temperature to refluxing temperature to give α,ß-unsaturated esters ; reducing ß-hydroxyesters esters with a complex metal hydride such as LiAIH4 in an ether solvent at a temperature in the range of 0°C to room temperature to give allylic alcohols ; oxygenation of allylic alcohols in presence of a sensitizer in an organic solvent at a temperature in the range of -10°C to room temperature to give ß-hydroxyhydroperoxides ; isolating and then reacting or reaction in situ ß-hydroxyhydroperoxides with compounds containing aldehyde or ketone group in presence of an acid catalyst in an organic solvent at a temperature in the range of 0°C to room temperature to give hydroxyl-functionalized 1,2,4-trioxanes with an acid chloride or anhydrides in presence of a base in an organic solvent at a temperature in the range of 0°C to room temperature to give trioxane esters.

Full Text	This invention relates to novel substituted 1,2,4 trioxanes useful as anti malarial agents and a process for the preparation of the same. This invention also relates to a process for the preparation of novel substituted 1,2,4,- trioxanes. This invention particularly relates to a process for the preparation of 6-[α-(hydroxyalkoxy substituted aryl)vinyl]-1,2,4-trioxanes and their esters as new antimalarial agents. More particularly the present invention provides a process for the preparation of hydroxyl- functionalized trioxanes and their esters of general formula 1, wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl; R3 and R4 represent (Formula Removed) Formula 1 hydrogen, alkyl group such as methyl, ethyl, aryl such as phenyl, naphthyl or part of a cyclic system; R5 represents hydrogen, alkyl group such as methyl, ethyl, propyl, aryl such as phenyl or a carboxy alkyl group such as CH2CH2CO2H; X represents hydrogen or lower alkoxy such as Ome, Z represents O or OCO. These compounds have been tested against multi-drug resistant P. yoelii in mice and several of them show promising antimalarial activity. Some of these compound with promising antimalarial activity have been tested against P. cynomolgi in monkeys and have been found effective. The invention thus relates to pharmaceutical industry. The trioxanes of general formula 1 are new chemical entities and they have not been prepared earlier. Trioxanes of general formula 1 are oil-soluble and can be administered as solution in oil such as groundnut oil. Some of the compounds of formula 1 are hemisuccinate derivates and are soluble both in oil and aqueous NaHCO3 solution and can be administered as a solution in groundnut oil or aqueous NaHCO3. The mode of administration can be oral, intramuscular, subscutaneous or intravenous. The main objective of this invention is to provide novel substituted 1,2,4-trioxanes useful as antimalarials. The objective of the present invention is also to provide a process for the preparation of novel substituted 1,2,4-trioxanes. The another objective of the present invention is to provide a process for the preparation of hydroxyl-functionalized trioxanes and their esters of general formula 1, a new series of antimalarial agents. Accordingly, the present invention provides novel substituted 1,2,4-trioxanes useful as anti malarial agent of formula 1 wherein R1, R2 are hydrogen, alkyl group such as methyl, ethyl, propyl; R3, R4 are hydrogen, alkyl group such as methyl, ethyl, aryl such as phenyl, naphthyl, R5 is hydrogen, alkyl group such as methyl, ethyl, propyl, aryl such as phenyl, or carboxyalkyl group such as CH2CH2CO2H ; Z is O or OCO. (Formula Removed) Formula 1 Accordingly, the present invention proves a process for the preparation of novel substituted 1,2,4-trioxanes and their esters of general formula 1 which comprises reacting hydroxyacetophenones of formula 2 wherein X represents hydrogen or lower alkoxy such as Ome, with α-haloesters of formula 3 wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl and Y represents halogen such as Cl or Br, in the presence of a base optionally in an organic solvent at a temperature in the range of room temperature of refluxing temperature to give keto-esters of general formula 4, wherein R1, R2 and X have the same meaning as above; reacting keto-esters of general formula 4 under Reformatsky condition in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß-hydroxyesters of general formula 5, wherein R1, R2 and X have the same meaning as above; dehydrating ß-hydroxyesters of general formula 5, wherein R1, R2 and X have the same meaning as above; dehydrating ß-hydroxyesters of formula 5 using a catalyst in an organic solvent at a temperature in the range of room temperature to refluxing temperature to give α,ß-unsaturated esters of general formula 6, wherein R1, R2 and X have the same meaning as above; reducing ß-hydroxyesters esters of general formula 6 with a complex metal hydride such as LiAIH4 in an ether solvent at a temperature in the range of 0°C to room temperature to give allylic alcohols of formula 7 wherein R1, R2, X have the same meaning as above; oxygenation of allylic alcohols of formula 7 in presence of a sensitizer in an organic solvent at a temperature in the range of -10°C to room temperature to give ß-hydroxyhydroperoxides of general formula 8 wherein R1, R2, X have the same meaning above; isolating and then reacting or reaction in situ ß-hydroxyhydroperoxides of formula 8 with compounds containing aldehyde or ketone group in presence of an acid catalyst in an organic solvent at a temperature in the range of 0°C to room temperature to give hydroxyl-functionalized 1,2,4-trioxanes of general formula 1, wherein R1,R2 and X have the same meaning as above, R3, R4 are hydrogen, alkyl group such as methyl, propyl, aryl group such as phenyl, naphthyl or part of a cyclic system, R5 is H and Z is 0; reacting hydroxyl-functionalized trioxanes of general formula 1 wherein R is H and Z is 0 with an acid chloride or anhydrides in presence of a base in an organic solvent at a temperature in the range of 0°C to room temperature to give trioxane esters of general formula 1, wherein R1, R2, R3, R4 and X have the same meaning as above, R5 is alkyl group such as methyl, ethyl, propyl, aryl group such as phenyl, carboxyalkyl such as CH2CH2CO2H; Z is O-CO. In the process hydroxyacetophenones of formula 2 are reacted with α-haloesters of formula 3 in presence of a base such as Na2CO3, K2CO3, KHCO3 in an organic solvent such as acetone, dimethylformamide, dimethylsulfoxide or without solvent, to give ketoesters of general formula 4. These ketoesters can be isolated and purified by standard laboratory methods such as crystallization or chromatography using an adsorbent such as silica gel. All ketoesters of general formula 4 except lla (formula 11, R1 = R2 = X = H), 11c(formula 11, R1 = H, R2 = Me, X = H) and 12a (formula 12, R1 = R2 = H) are new compounds and they have not been prepared earlier. Ketoesters lla, 11c and 12a are known compounds, [(a) Chin Ther., 8, 574 (1973), Indian J. Chem., 24, 119 (1985), Chen Abstracts, 124, 8616e (1996)]. In the process ketoesters of general formula 4 are reacted with ethyl bromoacetate and Zn in an aprotic solvent such as benzene, diethyl ether, to give ß-hydroxyesters of general formula 5. These ß-hydroxyesters can be isolated and purified by standard laboratory methods such as column chromatography using an adsorbent such as silica gel and a hydrocarbon solvent in combination with ethyl acetate as eluent or can be used without purification in the next step,ß-hydroxyesters of general formula 5 are new compounds and they have not been prepared earlier. These hydroxy esters of general formula 5 have an additional ester group as part of substitution in the aromatic ring. In the process dehydration of ß-hydroxyesters of geneal formula 5 is accomplished in an hydrocarbon solvent such as benzene, toluene, CH2C12, in the presence of a catalyst such as I2, ß-toluenesulfonic acid, P2O3, or acidic resin such as Amberlyst-15 to give α,ß-unsaturated esters of general formula 6. These unsaturated esters can be isolated and purified by standard laboratory methods such as chromatography using an adsorbent such as silica gel. α,ß-Unsaturated esters of general formula 6 have an addition ester group as part of substitution in the aromatic ring. These esters of general formula 6 are new compounds and they have not been prepared earlier. In the process reduction of α,ß-unsaturated esters of general formula 6 is done by reacting the compound with a complex metal hydride such as LiAlH, in an ether solvent such as diethyl ether, THF, to give allylic alcohols of general formula 7. These allylic alcohols of general formula 7 have an addition hydroxyl group as hydroxyalkoxy substitution in the aromatic ring. These allylic alcohols of general formula 7 can be isolated and purified by standard laboratory methods such as chromatography using an adsorbent such as silica gel and a hydrocarbon solvent in combination with ethyl acetate as eluant. Compounds of general formula 7 are new chemical entities and they have not been prepared earlier. In the process allylic alcohols of general formula 7 are converted to p-hydroxyhydroperoxides of formula 8 by passing oxygen gas in the solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light. The dye which acts as a sensitizer i.e. converts triplet oxygen to highly reactive singlet oxygen, may be such as methylene blue, Rose Bengal, tetraphenylporphine. Organic sol vent used may be such as CH2C12, CH3CN, acetone, methanol, benzene. These p-hydroxyhydroperoxides of general formula 8 can be isolated and purified by known laboratory methods or can be used in situ, without purification and isolation, inthe next step. These p-hydroxyhydroperoxides of formula 8 are new chemical entities and they have not been prepared earlier. Furthermore, these p-hydroxyhydroperoxides have an extra hydroxyl group in the form of hydroxyalkoxy substitution in the aromatic ring. The novel feature of these p-hydroxyhydroperoxides is that this extra hydroxyl group which is present as a hydroxyalkoxy substituent in the aromatic ring, does not take part in the next reaction i.e. condensation of hydroperoxides with aldehyde and ketones and thus provide 1,2,4-trioxanes which carry a hydroxy group suitable for further derivatization. In the process 0-hydroxyhydroperoxides of general formula 8 are converted to hydroxy-functionalized 1,2,4-trioxanes of general formula 1 (R5 = H, Z = O) by reacting these hydroperoxides with carbonyl compounds of formula 21-22 in presence of an acid catalyst in an aprotic organic solvent. The carbonyl compounds used may be such as benzaldehyde, naphthaldehyde, acetone, ethyl methyl ketone, methyl propyl ketone, methyl isobutyl ketone, 4-heptanone, 5-nonanone, 6-undecanone, dibenzyl ketone and the such as, cyclic ketone such as cyclopentanone, cyclohexanone, cycloheptanone, bicyolic ketone such as norcomphor (22a) and tricyclic ketone such as 2-adamantanone (22b). The acid catalyst used may be HC1, H2S04, p-toluene sulfornic acid, BF3.OEt2, acidic resin such as Amberlyst-15. The organic solvent used may be CH2Cl2, CHC13, benzene, CH3CN. These trioxanes of general formula 1 (R5= H, Z = O) are stable compounds and can be isolated and purified by standard chromatographic techniques using an adsorbent such as silica gel and a hydrocarbon solvent in combination with polar organic solvent as eluant. These trioxanes of general formula 1 (R3 = H, Z = O) are new chemical entities and they have not been prepared earlier. The novel feature of these trioxanes is that they are equipped with a primary hydroxyl group suitable for making derivatives of these trioxanes. This hydroxyl group is part of alkoxy substituent in the aromatic ring. These trioxanes of general formula 1 (R3 = H, Z = 0) have been tested against malarial parasites in animal models and several of them show very promising antimalarial activity, both against chloroquine sensitive and chloroquine resistant malaria These trioxanes are oil-soluble and can be administered as solution in oil such as groundnut oil. Some of these trioxanes have shown significant gamatocidal activity. In the process reaction of trioxanes of general formula 1 (R5 = H, Z = 0) with acid chlorides of formula 29 or acid anhydrides of formula 30 wherein R3 is alkyl group such as methyl, ethyl, propyl, aryl group such as phenyl, is done in an aprotic organic solvent in the presence of a base to give trioxane esters of general formula 1 wherein R3 is alkyl group such as methyl, ethyl, propyl, aryl group such as phenyl, Z is OCO. In the reaction hydroxyl group of trioxanes of formula 1 (R5 = H, Z = O) is esterified. The acid chlorides and acid anhydrides used may be such as acetyl chloride, beazoyl chloride, prop ionic anhydride, butyric anhydride, heptanoic anhdride. The base can be such as EfeN, pyridine, with or without the catalyst such as 4-dimethylaminopyridine (DMAP). The organic solvent used may be such as CH2C12, CHC13, THF, CH3CN. These trioxanes of general formula 1 (R5 = alkyl, aryl, Z = OCO) can be isolated and purified by known laboratory methods such as crystallization or chromatography using an adsorbent such as silica gel and hydrocarbon solvent in combination with polar organic solvents as eluant. The trioxanes are new chemical entities and they have not been prepared earlier. These trioxanes are oil-soluble and can be administered as solution in edible oil such as groundnut oil. Some of the trioxanes of general formula 1 (Rj = alkyl, aryl, Z = OCO) have shown promising antimalarial activity in animal models. In the process trioxanes of formula 1 (R5 = H, Z = 0) are reacted with succinic anhydride in an aprotic solvent in presence of tertiary amine with or without the presence of 4-dimethylaminopyridine (DMAP) to give carboxy fimctionalized trioxanes of general formula 1 (R5 = CH3CH2CO2H, Z = OCO). The tertiary amine may be such as Et3N, pyridine. Aprotic organic solvent may be such as CH2C12, CHC13, CH3CN, toluene, THF. In the reaction, the hydroxyl group of me trioxanes 1(R5 = H,Z = 0)is esterified. The trioxanes of general formula 1 (R5 = CH2CH2CO2H, Z = OCO) have a carboxyl group and are soluble in aqueous bicarbonate or carbonate solutions. Thus they can be administered both as solution in oil or aqueous bicarbonate/carbonate solutions. Trioxanes of general formula 1 (R3 = CH2CH2CO2H, Z = OCO) can be isolated and purified by known laboratory methods such as given above. Trioxanes of general formula 1 (R5 == CH2CH2C02H, Z = OCO) are new chemical entities and they have not been prepared earlier. Some of these trioxanes have shown promising antimalarial activity against both chloroquine-sensitive and resistant malaria in animal models. Some of these trioxanes also show significant gamatocidal activity. The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention. Example 1 Ethyl (4-acetylphenoxy)acetate (compound lla, fonuula 11, R1 = R3- X = H) A mixture of p-hydroxyacetophenone (50 g), ethyl chloroacetate (60 ml), K2CO3 (120 g) in acetone (450 ml) was refluxed with stirring for 24 h. The reaction mixture was filtered and the residue was washed with acetone. The combined fi:lterate was concentrated and the residue was redissolved in ether, the ether extract was washed with aqueous NaOH, and then with water, dried, concentrated and purified by chromatography on silica gel using hexane - ethylacetate as eluant to give 63.3 g (77% yield) of lla, m.p.64-68°C. Compound lla was also prepared using the conditions as given in table 1. Table 1 (Table Removed) ß- Hydroxyester I3a (formula 13. Rl = R2 = X = H) To a mixture of ketoester lla (20 g) zinc metal (12 g), I2(20 mg) in benzene was added ethyl bromoacetate (10 ml) dropwise. The reaction mixture was refluxed for another 7 hr, cooled, acidified with aqueous HC1, benzene layer was separated and the aqueous layer was extracted with benzene. Combined organic extract was washed with water and then aqueous NaHC03, dried and concentrated. The crude product was purified by column chromatography on silica gel using mixture of hexane and ethylacetate as eluant to furnish 13a (63% yield) of ß-hydroxyester as an oil. Compound 13a was also prepared using the conditions given in table 2. Table 2 (Table Removed) α,ß-Unsaturated ester 15a (formula 15, R1= R2 = X - H) A mixture of ß-hydroxyester 13a (10 g) and P2O5 (4 g) in benzene (150 ml) was refluxed for 2.5 h. The reaction mixture was filtered and the filtrate was concentrated to give 10 g of crude product which was purified by column chromatography on silica gel using hexane - ethylacetate as eluant to give 5.13 g (56% yield) of α,ß-unsaturated ester 15a as an oil. Allylic alcohol 17a (formula 17, R1 = R2 = X = H) To a stirred and ice-cooled mixture of LiAlH4 (6 g) in dry ether (400 ml) was added dropwise a solution of α,ß-unsaturated ester 15a (12 g) in ether. The reaction mixture was stirred in ice-bath for 5 h. and then quenched with water and 10% NaOH. The organic layer was separated, dried on Na2S04 and concentrated to give 8.84 g of crude product which was purified by column chromatography to furnish 5.67 g (59%) of allylic alcohol 17a; m.p. 83-86°C. 3-[4-(2-Hydroxyethoxy)phenyl]-l-hydroxy-but-3-en-2-hydroperoxide (compound 19a, general formula 19, R1 = R2 - H, X - H) (1) A solution of allylic alcohol 17a and methylene blue (15 mg) in ethanol (60 ml) was irradition with a 250 watt tungston-halogen lamp at -10°C while a slow stream oxygen was passed through the reaction mixture for 9.5 h. The reaction mixture was diluted with water and extracted with ether. The ether extract was concentrated and the crude product was chromatographed on silica gel using CH2Cl2 - ether as eluant to give 650 mg (28% yield) of ß-hydroxyhydroperoxide 19a. (2) A solution of allylic alcohol 17a (1 g), tetraphenylporphine (50 mg) in CHC13 (60 ml) wag photooxygenated at r.t. for 6 h. ß-Hydroxyhydroperoxide 19a separated as a solid. It was washed with ether to give 500 mg (44% yield) of tic pure 19a. Trioxane 23al (formula 23, R1= R2 = X = H, R3, R4 = -CH2CH2CH2CH2) (1) Two-pot procedure : A mixture of p-hydroxyhydroperoxide 19a (900 mg), cyclopentanone (2 ml) and p-toluene sulfonic acid (50 mg) in acetonitrile (10 ml) was stirred at room temperature for 3.5 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with ether. The ether extract was concentrated and the crude product was purified by chromatography (elution with ethylacetate-hexane ; 1 : 9) to furnish 310 mg (44% yield) oftrioxane 23al. (2) One-pot procedure : A solution of alcohol 17a (3.5 g) and methylene blue (10 mg) in CH3CN (65 ml) was irradiation with a tangston halogen lamp at 0°C for 7.5 h when a slow stream of oxygen was passed through the reaction mixture to give p-hydroxyhydroperoxide 19a as indicated by.TLC. To the reaction mixture were added cyclopentanone (6 ml) and p-toluenesulfonic acid (50 mg) and the reaction mixture was stirred at r.t. for 2 days. Workup and purification by chromatography furnished 1.14 g (23% yield based on alcohol 17a) oftrioxane 23al. Acetate oftrioxane 23 a 1 [compound 31al, formula 31, R1= R2 = H ; R3, R4= CH2CH2CH2CH2 ; RS = CH3;X = H] A solution oftrioxane 23al (200 mg) in pyridine (6 ml) was treated with acetic anhydride (0.5 ml) and the resulting mixture was left in refrigerator (~ 5°C) overnight. The reaction mixture was diluted with water and extracted with ether. Ether extract was washed sequencially with water, 10% HC1, water, and then dried (Na2S04) and concentrated. The crude product was purified by column chromatography on silica gel to give 180 mg (91% yield) compound 26al as an oil. Example 2 Benzoate oftrioxane 23 a 1 [compound 31a5. formula 31, R1= R2 = H ; R3, R4= CH2CH2CH2CH2 ; R5=Ph;X = H] A solution oftrioxane 23al (180 mg) and benzoyl chloride (0.5 ml) in pyridine (3 ml) was left at r.t. overnigllt. The reaction mixture was diluted with water, extracted with ether, Ether extract on usual processing followed by column chromatography on silica gel using hexane - ethylacetate as eluant furnished 100 mg (42% yield) of benzoate 31a5 as an oil. Example 3 Trioxane 23a2 (formula 23, R1, = R2 = X = H, R3, R4 = -CH2CH2CH2CH2CH2-) A solution of allylic alcohol 17a (1 g) and methylene blue (15 mg) in acetonitrile was photooxygenated at 0°C for 6.5 h. as above and then reacted with cyclohexanone (2 ml) using p-toluenesulfonic acid as catalyst at r.t. for 5 h. The crude product obtained after workup as above was purified by chromatography to give 0.86 g (57% yield based on the alcohol 17a) to furnish 1,2,4-trioxane 23a2. Example 4 Trioxane 23a3 (formula 23, R1 = R2 - X = H ; R3 = R4 = Me) (1) From P-hydroxyhydroperoxide 19a To a solution of p-hydroxyhydroperoxide 19a (100 mg) in a acetone (5 ml) was added one drop of cone. HCI and the reaction mixture was stirred at r.t. for 30 minutes. The reaction mixture was concentrated under vacuum and the crude product was purified by chromatography on silica gel using hexane - ethylacetate as eluant to give 60 mg (52% yield) of trioxane 23a3. (2) From allyiic alcohol 17a A sv'sition of allyiic alcohol 17a (1 g) and Rose Bengal (5 mg) in acetone (40 ml) was photooxygenated at -8°C for 6h To this reaction mixture were added 3 drops of cone. HCI and the reaction mixture was left overnight at r.t. The solvent was removed under vacuum and the crude product was chromatographed on silica gel as above to furnish 340 mg (26% yield based on allyiic alcohol 17a) of trioxane 23a3. Example 5 Trioxane 27a (formula 27, R! = R2 = X « H) A solution of allyiic alcohol 17a (2 g) and methylene blue (5 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 6 h to give p-hydroxyhydroperoxide 19a as indicated by TLC. To this reaction mixture 2-adamantanone (2 g) was added and the reaction mixture was stirred for 1 h when p-toluenesulfonic acid (10 mg) was added and the reaction mixture was stirred for another 6 h at room temperature. The reaction was quenched with aqueous NaHC03, diluted with water and extracted with ether. Ether extract was washed with water, dried (Na2SO4) concentrated and the crude product was purified by chromatography on silica gel to furnish 1.9 g (57% yield based on alcohol 17a) of trioxane 27a as an oil. Acetate of trioxane 27a [compound 35al, formula 35, RI= Ra = H ; Rs = CH3 ; X = H] A mixture of trioxane 27a (200 mg), acetic anhydride (1 ml) in pyridine (4 ml) was left at r.t. overnight. The reaction mixture was diluted with water and extracted with ether. Ether extract was washed with water, 10% aqueous HCI, water, dried (Na2SO4) and concentrated to give 200 mg of crude product which was purified by chromatography on silica gel (8 g, elution with 50% EtoAc in CH2C12) to give 178 mg (80% yield) of acetate 35al as an oil. Hemisuccinate of trioxane 27a [compound 4 la, formula 41, R1 = R2 = H ; X = H] A mixture of trioxane 27a (2 g) and succinic anhydride (3 g) in pyridine (20 ml) was left at r.t. overnight. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, 10% HC1, water, dried (Na2SO4) and concentrated to give 2.3 g of crude product which was purified by chromatography on silica gel (25 g, eluted with 50% ether in CH2C12) to give 1.5 g (60% yield) of hemisuccinate 41a as a highly viscous material. Example 6 Trioxane 23al3 (formula 23, R1 = R2 = X = H ; R3, R4 = H, 1-naphthyl) A solution of allylic alcohol 17a (1.0 g) and methylene blue (70 mg) in CH3CN (50 ml) was photooxygenated at -10 to 0°C for 6 h. To one-half of this reaction mixture were added 1-naphthaldehyde (1 ml) and p-toluene sulfonic acid (20 mg) and the reaction mixture was kept at 5°C overnight. Usual workup followed by purification by chromatography furnished trioxane 17al3) in 32% yield. Hemisuccinate of trioxane 23al3 [compound 37a4, formula 37, R1= R2 = H; R3, R4 = H, 1-naphthyl; X = H] To an ice-cooled mixture of 23al3 (120 mg) and succinic anhydride (200 mg) in CH2C12 (20 ml) were added triethylamine (0.2 ml) and 4-dimethylaminopyridine (30 mg) and the reaction mixture was left overnight at r.t. Workup as above followed by column chromatography on silica gel using CH2C12 - ether as eluant furnished hemisuccinate 37a4 as an oil (100 mg ; 67% yield). Example 7 Ethyl 2-(4-acetylphenoxy)isobutyrate (compound11b Formula 11, Rl = R2 = Me ; X = H) A mixture of p-hydroxyacetophenone (14 g), ethyl 2-bromoisobutyrate (21 g) and K2CO3 (40 g) in acetone (260 ml) was refluxed with stirring for 19 h. The reaction mixture was diluted with water and extracted with benzene. Usual processing of the benzene extract furnished 10.5 g (41% yield) of keto ester 11b as an oil. Compound 11b was also prepared using the conditions as given in table 3. Table 3 (Table Removed) ß-Hydroxyester 13b (formula 13, R1 = R2 - Me, X = H) To arefluxing mixture ofketoester llb(12g), zinc (6 g), I2 (70 mg) in benzene (200 ml) was added dropwise ethyl bromoacetate (7 ml) and the reaction mixture was refluxed for 7 hr. Work up and purification by chromatography on silica gel (hexane - EtoAc on eluant) furnished 45% yield of ß-hydroxyester 13b. α,ß-Unsaturated ester 15b (formula 15, R1 = R2 = Me, X = X) To a refluxing mixture of ketoester 11b (10.5 g), zinc (5 g), I2 (40 mg) in benzene (200 ml) was added, dropwise a solution of ethyl bromoacetate (5 ml) in benzene (50 ml) and the reaction mixture was refluxed for 7 h. The reaction mixture was cooled and acidified with 10% aqueous HCI. Benzene layer was separated and the aqueous layer was extracted with benzene (2 x 150 ml). The combined organic extract was washed with water and aqueous NaHCO3 solution, dried (Na2SO4) and concentrated to give ß-hydroxyester 13b which was used in the next without isolation and purification. The crude 13b as obtained above was dissolved in benzene (200 ml), I2 (50 mg) was added the reaction mixture was refluxed for 1.75 h. The reaction mixture was cooled, washed with aqueous sodium thiosulphate and then with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography to furnish 6.80 g (51% yield) of α,ß-unsaturated ester 15b. Allylic alcohol 17b (formula 17, R1 = R2 = Me ; X - H) To a stirred and ice-cooled mixture of LiAlH4, (5 g) in dry ether (450 ml) was added dropwise a solution of α,ß-unsaturated ester 15b (6.2 g) in dry ether. The reaction mixture was stirred for 5 h. and then quenched with water and 10% aqueous NaOH. The organic layer was separated. The residue was washed with ether and the combined organic extract was dried (Na2SO4), concentrated and the crude product was purified to give 3.0 g (66% yield) of allylic alcohol 17b, as an oil. 3-[4-(2-Hydroxy-1,l-dimethyl-ethoxy)phenyl]-l-hydroxy-but-3-en-2-hydroperoxide (compound 19b, formula 19, R1 = R2 = Me, X = H) A solution of aJlylic alcohol 17b( 1.40 g) and methylene blue (100 mg) in CH3CN (45 ml) was irradiated with a 500 watt tungsten-halogen lamp at 0°C for 5 h while a slow stream of oxygen was passed through the reaction mixture. The reaction mixture was concentrated to 20 ml and men diluted with water (20 ml) and extracted with ether (3 x 25 ml). The combined ether extract was washed with water, dried (Na2S04), concentrated and purified by chromatography on silica gel to furnish 860 mg (61% yield) of ß-hydroxyhydroperoxide 19b as an oil. Trioxane 23bl (formula 23, R1 = R2 = Me, X = H ; R3, R, = -CH2-CH2-CH2-CH2-) A slution of allylic alcohol 17b (680 mg) and methylene blue (15 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 3.25 h to give p-hydroxyhydroperoxide 19b as indicated by TLC. This reaction mixture was divided into two equal parts. To one part were added cyclopentanone (2 ml) and PTSA (25 mg) and stirred at r.t. for 2.75 h. Usual workup followed by chromatography on silic gel furnished 240 mg (63% yield based on allylic alcohol 17b) of trioxane 23bl. Hemisuccinate of trioxane 23bl [compound 37bl, formula 37, R1 = R2 = Me ; R3, R4 = CH2CH2CH2CH2;X=H] A solution trioxane 23bl (1 g) in CH2C12 (40 ml) was reacted with succinic anhydride as above and the product was purified by chromatography as above to furnish 1.23 g (93% yield) of hemisuccinate 37bl. Example 8 Trioxane 23b2 (formula 23, R1= R2 = Me, X = H ; R3, R4= -CH2-(CH2)3-CH2-) To one half of the photooxygenated mixture from the above example were added cyclohexanone (2 ml) and PTSA (25 mg) and the reaction mixture was stirred at r.t. for 2.75 h. Normal workup followed by purification by chromatography on silica gel column gave 230 mg (46% yield based on the allylic alcohol 17b used) of trioxane 23b2. Example 9 Trioxane 27b (formula 27, R1= R2 = Me, X - H) A mixture of allylic alcohol 17b (2.0 g) and methylene blue (100 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 6.5 h. To this reaction mixture were added 2-adamantanone (3.0 g) and p- toluenesulfonic acid (100 mg) and the reaction mixture was left at room temperature overnight. The reaction mixture was quenched with aqueous NaHC03, diluted with water and extracted with ether. The ether extract was washed with water, dried (Na2S04) and concentrated. The crude product was purified by chromatography on silica gel column to give 1.61 g (59% yield based on allylic alcohol 17b) of 1,2,4-trioxane 27b, m.p. 100-102°C. Trioxane 27b was obtained in 44% yield when the condensation with 2-adamantanone was done using Amberlyst-15 as catalyst. Acetate of trioxane 27b [compound 35bl, formula 35, R1 = R2 = Me ; R5 = CH3; X = H] A solution of trioxane 27b (200 mg) and acetic anhydride (1 ml) in pyridine (4 ml) was reacted at r.t overnight. Workup as above followed by column chromatography on silica gel furnished 0.21 g of acetate 35bl as a viscous material. Example 10 Propionate of trioxane 27b [compound 35b2, formula 35, R1= R2 = Me ; R5 = Et; X = H] To an ice-cooled mixture of 27b (300 mg) and propionic anhydride (1.3 ml) in CH2C12 (10 ml) were added triethylamine (0.8 ml) and 4-dimethylaminopyridine (20 mg) and a left overnight at r.t. Usual workup as above followed by column chromatography on silica gel furnished 310 mg (91% yield) of propionate 35b2 as a colourless oil. Example 11 Hexanoate of trioxane 27b [compound 35b4, formula 35, R1= R2 - Me ; Rs = n-pentyl; X = H] A mixture of trioxane 27b (300 mg) and hexanoic anhydride (1 ml) in CH2C12 (15 ml) was reacted in presence of triethylamine (0.5 ml) and 4-dimethylamino pyridine (20 mg) at r.t for 1 h. Workup as above followed by column chromatography on silica gel furnished 330 mg (89% yield) of hexanoate 35b4 as an oil. Example 12 Hemisuccinate of trioxane 27b [compound 41b, formula 41, R1 = R2 = Me ; X = H] To a stirred and ice-cooled mixture of trioxane 27b (2.3 g) and succinic anhydride (2.5 g) in CH2C12 (100 ml) were added triethylamine (2.5 ml) and 4-dimethylamino pyridine (50 mg) and the reaction mixture was stirred at r.t. for 2 h, concentrated under reduced pressure, acidified (50 ml of 10% HC1) and extracted with ether (3 x 150 ml). Ether extract was washed with water (3 x 100 ml), dried (Na2S04) and concentrated under reduced pessure to give 3.1 g of crude material which was chromatographed on silica gel (50 g, eluted with 50% ether in hexane) to give 2.3 g solid which was crystallized from ether-hexae to give 1.91 g (68% yield) of hemisuccinate 41b as while crystals, rap. 96-99°C. Similar yields of 41b were obtained when the reaction was done in absence of 4-dimethylaminopyridine. Example 13 Ketoester 1 If (formula 11, R1 = R2 = H, X = Ome) Compound llf was prepared from 3-methoxy-4-hydroxyacetophenone (formula 9, X = Ome) in 84% yield following the procedure used for the preparation of compound lla as given in example 1. ß-Hydroxy ester 13f (formula 13, R1= R2 = H, X = OMe) To a refluxing mixture of ketoester llg (21 g), zinc (6 g), and catalytic amount of iodine in benzene (400 ml) was added dropwise ethyl bromoacetate (15 ml) and the reaction mixture was refluxed for 8 hr. Work up and purification as given in example 1 furnished 20 g (71% yield) of ß-hydroxyester 13f. α,ß-Unsaturated ester 15f (formula 15, R1 = R2 = H, X = OMe) ß-Hydroxyester 13f (20 g) was dehydrated with P205 in refluxing benzene as above and the crude product was purified by column chromatography on silica gel to furnish 10.5 g (55%) of α,ß-unsaturated ester 15f. Allylic alcohol 17f (formula 17, R1 = R2 = H ; X = OMe) α,ß-Unsaturated ester 15f (1.2 g) was reduced with LiAlH4, (240 mg) in dry ether (25 ml) at 0°C. Work and purification was done according to the procedure as given above to give 260 mg (29% yield) of allylic alcohol 17f. Trioxane 27f (formula 27, R1=R2 =H ; X = OMe) A solution of allylic alcohol 17f (550 mg), adamantanone (540 mg) and methylene blue (15 mg) in CH3CN (40 ml) was photooxygenated as above for 6 h. to give ß-hydroxyhydroperoxide 19f (formula 19, R1 = R2 = H, X = OMe) as indicated by TLC. To this reaction mixture was added p-toluenesulfonic acid (20 mg) and was left at room temperature overnight. Workup as above followed by chromatography on silica gel furnished 180 mg (19% yield based on the allylic alcohol 17f used) of 1,2,3-trioxane 27f. Hemisuccinate for trioxane 27f (compound 4 If, formula 41, R1 = R2 = H, X = OMe) Hemisuccinate 41f was prepared from trioxane 27f in 80% yield following the procedure used for preparation of compound 41a as given in example 5. Example 14 Ketoester llg (formula 11, R1 = R2 = Me, X = OMe) A mixture of 4-hydroxy-3-methoxyaeetophenone (15 g) ethyl 2-bromoisobutyrate (22 ml) and K2CO3 (45 g) in acetone (450 ml) was refluxed for 27 h. Most of the solvent was distilled off and the reminder was diluted with water and extracted with ether, ether extract dried on Na2S04 and concentrated. The crude product was chromatographyed on silica gel (elution with 5% ethylacetate in hexane) to furnish 4.41 g (18% yield) of ketoester llg as an oil. ß-Hydroxyester 13g (formula 13, R1 ,= R2 =Me, X = OMe) A mixture of ketoester llg (4.4 g), zinc (3 g) and ethyl bromoacetate (2.5 g) in benzene was refluxed for 7 hr. Work up as above to give 6.0 g of crude product which was used in the next step without purification. α,ß-Unsaturated ester 15g (formula 15, R1= R2 = Me, X = OMe) ß-Hydroxyester 13g (crude product 6.0 g as obtained above) was dissolved in benzene (100 ml), I2 (40 mg) was added the reaction mixture was refluxed for 6 hr. Workup and purification effected as above furnished 2.7 g (49% yield, based on ketoester llg) of α,ß-unsaturated ester 15g as an oil. Allylic alcohol 17g (formula 17, R1 = R2 = Me ; X = OMe) α,ß-Unsaturated ester 15g ( 1.9 g) was reduced with LiAlH4(1.8 g) in dry ether at 0°C as above. Normal workup followed by chromatography furnished 1.1 g (76% yield) of allylic alcohol 17g as an oil. Trioxane 27g (formula 27, R1= R2 = Me ; X - OMe) A solution of allylic alcohol 17g (1.1 g) and memylene blue (20 mg) in acetonitrile (50 ml) was photooxygenated as above at 0°C for 7 h. to give p-hydroxyhydroperoxide 19g (formula 19, R1= R2 = Me, X = OMe) as indicated by TLC. The reaction mixture was divided into two equal parts. One part was reacted with 2-adamantanone (500 mg) in presence of cone. HC1 (4 drops) at room temperature overnight. Usual workup followed by chromatography furnished 300 mg (34% yield based on the alcohol 17g used) of trioxane 27g as thick oil. Example 15 Trioxane 23gl (formula 23, R1= R2 = Me ; X = OMe ; R3, R4 = -CH2CH2CH2CH2-) The other half of the reaction mixture as obtained in the above experiment was reacted with cyclopentanone (1 ml) in presence of cone. HC1 (5 drops) at r.t. overnight. Usual workup followed by purification furnished 210 mg (28% yield based on alcohol 17g) of trioxane 23gl. Example 16 Ketoester 12a (formula 12, R1 = R2 = H) A mixture of 3-hydroxyacetophenone (5 g), ethyl chloroacetate (5.6 ml) and K2C03 (7.5 g) was heated at 65°C with stirring for 13 h. It was cooled to room temperature, diluted with water (50 ml) and extracted with ether (2 x 100 ml). Ether extract was washed with water (3 x 50 ml), dried (Na2SO4), concentrated and chromatographyed on silica gel using 50% ethylacetate - hexane as eluant to give 4.52 g (49% yield) of ketoester 12a as an oil. α,ß-Unsaturated ester 16a (formula 16, R1 = R2 = H) To a refluxing mixture of ketoester 12a (15 g), zinc (6 g), iodine (70 mg) in benzene (350 ml) was added dropwise ethyl bromoacetate (8 ml) and the reaction mixture was refluxed for 9 hr. The reaction mixture was cooled, acidified with aqueous 10% HC1, benzene layer was separated and the aqueous layer was extracted with benzene. The combined benzene extract was washed with water, aqueous NaHC03, dried (Na2SO4) and concentrated to give 14a which was dehydrated with P203 (5 g) using the procedure as given in example 7, and the final product was purified by column chromatography on silica gel (hexane - ethylacetate as eiuant) to furnish 14.75 g (45% based on 12a) of 16a as an oil. Allylic alcohol 18a (formula 18, R1= R2 = H) To a stirred and ice-cooled mixture of LiAlH4 (8 g) in dry ether (400 ml) was added dropwise a solution of a,p-unsaturated ester 16a (11 g) in dry ether and stirred the reaction mixture in ice bath for 6 h. It was quenched with H2O and 10% NaOH. The organic layer was separated and the residue was washed with ether. The combined ether extract was dried (Na2SO4), concentrated and purified by column chromatography on silica gel using hexane - ethylacetate as eluant to give 5.8 g (74% yield) of allylic alcohol 18a. Trioxane 24a 1 (formula 24, R1= R2 - H ; R3, R4= CH2CH2CH2CH2) A solution of allylic alcohol 18a (1.0 g) and Rose Bengal (5 mg) in acetonitrile (65 mg) was photooxygenated at 0°C for 7 h. to give p-hydroxyhydroperoxide 20a (formula 20, R1 = R2 = H) as indicated by TLC. To this reaction mixture were added cyclopentanone (1.5 ml) and p-toluenesulfonicacid (15 mg) and the reaction mixture was stirred at room temperature for 4 h. Workup as above followed by chromatography on silica gel column furnished 600 mg (43% yield based on allylic alcohol 18a) of trioxane 24al. Hemisuccinate of trioxane 24al (compound 38al, formula 38, R1 = R2 = H ; R3 = R4 = CH2CH2CH2CH2) A solution trioxane 24al (600 mg) and succinic anhydride (2.0 g) in pyridine (5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ether. The ether extract was washed with water, 10% aqueous HC1, water, dried (Na2S04) anc concentrated. The crude product on purified by chromatography on silica gel using CH2C12 - ether as eluant furnished 780 mg (98% yield) of hemisuccinate 38al. Example 17 Trioxane 28a (formula 28, R1= R2= H) A solution of allylic alcohol 18a (1.0 g) and methylene blue (5 mg) in CH2CI2 (65 mg) was photooxygenated as above at 0°C for 10 h. To the reaction mixture were added 2-adamantanone (1 g) and p-toiuenesulfonic acid (15 mg) and the reaction mixture was kept at room temperature overnight. Usual workup as above followed by purification by chromatography on silica gel column furnished 350 mg (21% yield based on allylic alcohol 18a) of trioxane 28a as a thick oil. Hemisuccinate for trioxane 28a (compound 42a, formula 42, R1 = R2 = H) Hemisuccinate 42a was prepared in 91% yield by reacting trioxane 28a with succinic anhydride following procedure as given in the above example. Example 18 Ketoester 12b (formula 12, R1 = R2 = Me) A mixture of 3-hydroxyacetophenone (5 g) ethyl 2-bromoisobutyrate (5.4 ml) and K2CO3 (7.5 g) was heated at 120°C for 6 h. The reaction mixture was diluted with water, extracted with ether. Ether extract was washed with water, dried, concentrated and chromatographyed on silica gel to furnish 1.82 g (22% yield) of ketoester 12b as an oil. α,ß-Unsaturated ester 16b (formula 16, R1 = R2 = Me) To arefluxing mixture of ketoester 12b (14.6 g), zinc (7.3 g) and iodine (50 mg) in benzene (400 ml) was added dropwise a solution of ethyl bromoacetate (7.3 ml) in benzene (50 ml) and the reaction mixture was refluxed for 14.5 hr. when it was cooled, acidified with 10% aqueous HC1. Benzene layer was separated, washed with aqueous NaHCO3, dried and concentrated to give -hydroxy ester 14b which was used in the next step without purification. The crude p-hydroxyester 14b as obtained above was dissolved in benzene (500 ml), P2O5(10 g) was added and the mixture was refluxed for 3 h. Usual workup followed by chromatography furnished α,ß-unsaturated ester 16b (7 g, 42% yield based on 12b). Allyttc alcohol 18b (formula 18, R1 = R2 = Me) To a stirred and ice-cooled mixture of LiAltit (3.2 g) in dry ether (450 ml) was added a solution of α,ß-unsaturated 16b (3.6 g). The reaction mixture was stirred for 2.5 h. in ice bath. It was quenched with water and 10% aqueous NaOH. Ether layer was separated and concentrated to give 2.6 g of residue which was chromatographed on silica gel to give 2.3 g (86% yield) of allylic alcohol 18b. Trioxane 24bl (formula 24, R1 = R2 - Me ; R3, R4 = CH2CH2CH2CH2) A mixture of allylic alcohol 18b (300 mg) and methylene blue (20 mg) in CH3CN (40 ml) was photooxygenated at 0°C for 5.5 h. to give ß-hydroxyhydroperoxide 20b (formula 26, R1 = R2 = Me) as indicated by TLC. The reaction mixture was divided in two equal parts. To one-half of this reraction were added cyclopentanone of (1 ml) and FTSA (40 mg) and the reaction mixture was stirred at room temperature for 5 h. Usual workup followed by chromatography on silica gel furnished 170 mg (81% yield based on alcohol 18b) of trioxane 24bl. Hemisuccinate for trioxane 24bl (compound 38bl, formula 38, R1 = R2 = Me ; R3, R4 = CH2CH2CH2CH2) To an ice-cooled solution of trioxane 24bl (200 mg) and succinc anhydride (400 mg) in CH2C12 (20 ml) were added Et3N (1 ml) and 4-dimethylamino-pyridine (DMAP, 20 mg) and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under vacuum, acidified with 10% aq. HC1 and extracted with ether. Ether extract was washed with water, concentrated and purified by chromatography on silica gel to give 230 mg (92% yield) of compound 38bl as an oil. Trioxane 24b2 (formula 24, R1 = R2 - Me, R3, R4 = CH2CH2CH2CH2CH2) To the other half of the photooxygenated mixture obtained as in the above experiment were added cyclohexanone (1 ml) and PTSA (40 mg) and the reaction mixture was stirred at r.t. for 5 h. Workup and chromatography on silica gel column as above furnished 110 mg (50% yield based on alcohol 18b) of trioxane 24b2. Hemisuccinate for trioxane 24b2 (compound 38b2, formula 38, R1 = R2 = Me ; R3, R4 = CH2CH2CH2CH2 CH2) Trioxane 24b2 (250 mg) was reacted with succinc anhydride (350 mg) in CH2C12 (20 ml) as above and the crude product was purified by chromatography on silica gel using 25% ether in CH2C12 as eluant to give 280 mg (87% yield) of compound 38b2 as an oil. Example 19 Trioxane 28b (formula 28, R1= R2 = Me) A solution of allylic alcohol 18b (300 mg) and methylene blue (70 mg) in CH3CN (30 ml) was photooxygenated at -8°C for 6 h. To the reaction mixture were added 2-adamantanone (300 mg) and p-toluenesulibnic acid (50 mg) and left at room temperature overnight. The solvent was removed under vacuum and the residue was diluted with aq. NaHC03 and water and extracted with ether. The ether -extract was washed with water, dried, concentrated and chromatographed on silica gel to furnish 310 mg (62% yield) of trioxane 28b as an oil. Hemisuccinate of trioxane 28b [compound 42b, formula 42, R1 = R2 = Me] To a stirred ice-cooled mixture of trioxane 28b (100 mg) and succinic anhydride (200 mg) in CH2C12 (10 ml) were added triethylamine (0.5 ml) and 4-dimethylamino pyridine (20 mg) and the reaction mixture was stirred at r.t. for 3 hr. The reaction mixture was concentrated under reduced pressure, acidified with 10% aquoeus HC1 and extracted with ether (2 x 20 ml). The ether extract was washed with water dried (Na2S04), concentrated and purified by column chromatography on silica gel to give 100 mg (80% yield) of hemisuccinate 42b as a thick oil. Example 20 Ketoester 11c (formula 11, R1 = H, R2 = Me, X = H) A mixture of 4-hydroxyacetophenone (5 g), ethyl 2-bromopropionate (5 ml) and K2CO3 (7.5 g) was heated at 120°C for 7.5 h. The reaction mixture was extracted with ether, washed with water, dried, concentrated and chromatographed on silica gel to furnish 1.8 g (21% yield) of l1c, m.p. 64-72°C. α,ß-Unsaturated ester 15c (formula 15, R1 = H, R2 = Me, X = H) To a refluxing mixture of ketoester lic (25 g), Zn (6.5 g) and iodine (50 mg) in benzene (250 ml) was added dropwise ethyl bormoacetate (12 ml) and the reaction mixture was refluxed for 7 h. The crude product (13c) obtained after usual workup was dehydrated with iodine (2 g) in benzene (100 ml) by refluxing for 4 h. The reaction mixture was washed with a slution of sodium thiosulphate, concentrated and purified by chromatography on silica gel to give 14.6 g (47% yield) of 15c as an oil. Allylic alcohol 17c (formula 17, R1 = H, R2 - Me, X = H) α,ß-Unsaturated ester 15c (5.0 g) was reduced with LiAlH4 (3 g) in dry ether (250 ml) as above to give 2.7 g allylic alcohol 17c. Trioxane 25c (formula 25, R1= Me. R2 = X = II) A solution of allylic alcohol 17c (1.5 g) and methylene blue (10 mg) in CH2CN (45 ml) was photooxygenated as above for 6 h. to give p-hydroxyhydroperoxide 19c (formula 19, R1= Me ; R2 - X = H). One third (corresponding to 500 mg of lOc) was taken and reacted with norcomphor (1.0 g) in presence of catalytic amount of p-toluenesulfonic acid at r.t. for 3 h. Usual workup followed by chromatography on silica gel column furnished 300 mg (38% yield based on the allylic alcohol 17c used) of trioxane 25c. Example 21 Ketoester 11d (formula 11, R1=H, R2 = Et, X =H) A mixture of 4-hydroxyacetophenone (5.0 g), ethyl 2-bromobutyrate (5 ml) and K2C03 (7.5 g) was heated at 120°C for 7.5 h, Workup followed by purification of the crude product as above (example 20) furnished 3.9 g (42% yield) of compound 11d as an oil. α,ß-Unsaturated ester 15d (formula 15, R1 = H, R2 = Et, X = H) To a refluxing mixture of ketoester lid (3.5 g), Zinc (2.0 g), iodine (50 mg) in benzene (50 ml) was added ethyl bormoacetate (1.5 ml) and the reaction mixture was refluxed for 5 h. It was acidified with 10% HC1, benzene layer was separated and concentrated and the crude product was purified by chromatography to give 2.45 g (52% yield) of 13d. Compound 13d (2.4 g) was dehydrated in refluxing benzene using P2O5 as catalyst Workup followed by column chromatography on silica gel as above furnished 2.0 g (88% yield) of ester 15d as an oil. Allylic alcohol 17d (formula 17, R1= H ; R2 = Et; X = H) α,ß-Unsaturated ester 15d (2.7 g) was reduced with LiAlH4 (1.5 g) in dry ether (150 ml) and the crude product was purified by chromatography on silica gel using hexane - ethylacetate as eluant to give 1.2 g of allylic alcohol 17d. Trioxane 27d (formula 27, R1= Et, R2 = X = H) A solution of allylic alcohol 17d (1.2 g) and methylene blue (10 mg) in CH3CN (40 ml) was photooxygenated as above for 7 h. to give ß-hydroxyhydroperoxide 19d (formula 19, R1 = Et; R2 = X = H) as indicated by TLC. To one half of this reaction mixture were added adamantanone (600 mg) and PTSA (10 mg) and the reaction mixture was stirred at r.t. for 2 h. Usual workup followed by chromatography on silica gel furnished 300 mg (30% yield based on the allylic alcohol 17d used) of trioxane 27d as oil. Example 22 Ketoester 11e (formula 11, R1= H, R2 = n-pentyl, X = H) A mixture of 4-hydroxyacetophenone (5.0 g), ethyl 2-bromoheptanoate (8.3 g) and K2CO3 was heated at 120°C for 7.5 h. The reaction mixture was extracted with ether. Ether extract was washed with water, dried, concentrated and chromatographed on silica gel to furnish 9.1 g (89% yield) of compound 11e, as an oil. α,ß-Unsaturated ester 15e (formula 15, R1 = H, R2 = n-pentyl, X = H) To a refluxing mixture of ketoester He (25 g), Zn (7.5 g), iodine (100 mg) in benzene (450 ml) was added ethyl bormoacetate (9 ml) dropwise and the resulting mixture was refluxed for 5.5 h. It was acidified with 10% HC1, benzene layer was separated, washed with aq. NaHC03 solution, dried and concentrated to give ß-hydroxy-ester 13e which was used without purification in the next step. Crude product 13e as obtained above was dissolved in benzene (350 ml), iodine (100 mg) was added and the mixture was refluxed for 2.5 h. The reaction mixture was washed with a solution of sodium thiosulphate, dried, concentrated and chromatographed on silica gel (elution with 5% ethyl acetate -hexane) to give 22.1 g (71% yield) of α,ß-unsaturated ester 15e as an oil. Allylic alcohol 17e (formula 17, R1 = H ; R2 = n-pentyl; X = H) α,ß-Unsaturated ester 15e (12 g) was reduced with LiAlH, (10 g) in dry ether (600 ml) at 0°C as above to give 8.3 g of crude product which was purified by chromatography on silica gel to furnish 6.5 g (71% yield) of allylic alcohol 17e. Trioxane 23el (formula 23, R1 = CH2CH2CH2CH2CH3 ; R2 = X = H, R3, R4 = -CH2CH2CH2CH2-) A solution of alcohol 17e (2 g) and methylene blue (100 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 4.5 h. to give p-hydroxyhydroperoxide 19e (formula 19, RI = CH2CH2CH2CH2CH3; R2 = X = H) as indicated by TLC. One half this photooxygenated reaction mixture was reacted with cyclopentanone (2 ml) in presence of PTSA (50 mg) at r.t. for 5.5 h. Usual workup and chromatography on silica gel column to furnish 610 mg (45% yield based on allylic alcohol 17e used) of trioxane 23el. Trioxane 27e (formula 27, R1= CH2CH2CH2CH2CH3 ; R2 = X = H) To the other half of the photooxygenated mixture as obtained in the above example were added 2-adamantanone (1 g) and PTSA (50 mg) and the reaction mixuture was stirred at r.t. for 5 h. Usual workup followed by chromatography on silica gel column using hexane - ethylacetate as eluant furnished 780 mg (76% yield based on allylic alcohol 17e used) of trioxane 27e as a thick oil. Hemisuccinate of trioxane 27e [compound 41e, formula 41, R\| = H, R2 - n-pentyl; X * H] To a stirred and ice-cooled mixture of trioxane 27 e (200 mg) and succinic anhydride (200 mg) in CH2C12 (20 ml) were added triethylamine (0.5 ml) and 4-dimethylamino pyridine (20 mg) and the reaction mixture was stirred at r.t. for 1.5 h. Workup as above followed by purification by column chromatography on silica gel furnished 200 mg (82% yield) of hemisuccinate 41eas a colourless oil. Using the above procedures the following hydroxy-fiinctionalized trioxane and their esters were also prepared. Trioxane 23a4 (formula 23, R1 = R2 = X = H; R3, R4 = Me, Et) ; 36% yield Trioxane 23aS (formula 23, R1 = R2 = X = H, R3,R4 = Me, CH2CH2CH3); 43% yield Trioxane 23a6 (fonnula 23R1 = R2 = X = H, R3, R4 = Me, CH2CHMe2); 29% yield Trioxane 23a7 (formula 23, R1 = R2 = X = H, R3 = R4= n-propyl); 21% yield Trioxane 23a8 (formula 23, R1 = R2 = X = H, R3 = R4= n-butyl) ; 11% yield Trioxane 23a9 (formula 23, R1 = R2 = X = H, R3 = R4 = n-pentyl); 16% yield Trioxane 23alO (formula 23, R1 = R2 = X = H, R3, R4= -CH3(CH2)9-CH2-); 16% yield Trioxane 23all (formula 23, R1 = R2 = X = H, R3,R4 = -CH2-CH2-CO-CH2-CH2); 6% yield Trioxane 23al2 (formula 23, R1 = R2 = X = H, R3, R4 = H, -C6H5); 45% yield Trioxane 23al3 (formula 23, R1 = R2 = X = H, R3, R4= H, 1-naphthyl); 38% yield Trioxane 23b3 (formula 23, R1 = R2 = Me, X = H, R3, R4= H, 1-naphthyl); 7% yield Trioxane 23b4 (formula 23, R1 = R2 = Me, X = H, R3, R4 = CH2(CH2)4-CH2); 15% yield Trioxane 23cl (formula 23, R1 R2 = H, Me ; X = H, R3, R4 = -CH2-CH2-CH2-CH2-); 42% yield Trioxane 23c2 (formula 23, R1 R2 = H, Me ; X = H, R3, R4 = -CH2-(CH2)3-CH2); 46% yield Trioxane 23dl (formula 23, R1 , R2 = H, Et; X = H, R3, R4= -CHrCH2-CH2-CH2-); 33% yield Trioxane 23e2 (formula 23,R1 R2 = H, n-pentyl; X = H, R3, R4 = -CHr(CH2)3-CH2); 54% yield Trioxane 23e3 (formula 23, R1 R2 = H, n-pentyl; X = H, R3, , R4 = -CH2-(CH2)4-CH2); 38% yield Trioxane 23e4 (formula 23, R1 R2 = H, n-pentyl; X = H, R3, , R4 = -CH2-(CH2)3-CH2); 15% yield Trioxane 23e5 (formula 23, R1 R2 = H, n-pentyl; X - H, R3, , R4 = Me); 54% yield Trioxane 23fl (formula 23,R1 = R2 = H; X = OMe ; R3, , R4 =-CH2-CH2-CH2-CH2); 27% yield Trioxane 23f2 (formula 23, R1 = R2 = H; X = OMe, R3,, R4 = -CH2-(CH2) 3-CH2); 16% yield Trioxane 23gl (formula 23, R1 = R2 = Me ; X = OMe, R3, R4 = -CH2-CH2-CH2-CHr); 28% yield Trioxane 24a2 (formula 24, R1 =R2 = H ; R3, R4 = -CH2(CH2)3CH2); 41% yield Trioxane 24a3 (formula 24, R1 = R2 = H; R3, R4=-CH2(CH2)4-CH2); 60% yield Trioxane 24b3 (formula 24, R1 - R2 = Me ; R3, R4 = H, 1-naphthyl); 24% yield Trioxane 25a (formula 25, R1 = R2 = H); 34% yield Trioxane 25c (formula 25, R1 R2 = H, Me); 39% yield Trioxane 25d (formula 25, R1 R2 = H, Et); 15% yield Trioxane 25e (formula 25, R1 R2 = H, n-pentyl); 35% yield Trioxane 26a (formula 26, R1 R2 = H); 23% yield Trioxane 26b (formula 26, R1 R2 = Me); 53% yield Trioxane 27c (formula 27, R1 R2 - H, Me); 39% yield Trioxane 28b (formula 28, R1 R2 = Me); 27% yield Compound 31a2 (formula 31; R1 = R2 - X = H; R3, R4 = -CH2-CH2-CH2-CH2-; R5 = Et); 80% yield Compound 31a3 (formula 31 ;R1 = R2 = X = H ; R3,R4 = -CHrCH2-CH2-CH2-; R5 = n-Pr); 78% yield Compound 31a4 (formula 31;R1 = R2 - X = H ; R3, R4 = -CH2-CH2-CH2-CH2- ; R3 = n-hexyl) ; 75% yield Compound 31a5 (formula 31; R1 = R2 = X = H ; R3, R4 = -CH2-CH2-CH2-CH2-; R5 = phenyl); 42% yield Compound 31a6 (formula 31;R1 = R2 = X = H; R3, R4 = H, 1-naphthyl; R5 = CH3); 36% yield Compound 31bl (formula 31; R1 = R2 = Me, X = H; R3, R4 = H, 1-naphthyl; R5 = CH3); 90% yield Compound 32bl (formula 32R1 = R2 = Me ; R3, R4 = -CH2-CH2-CH2-CHr ; R5 = Me); 89% yield Compound 32b2 (formula 32; R1 = R2 - Me ; R3, R4 = -CH2-(CH2)3-CH2-; R5 = Me); 86% yield Compound 32b3 (formula 32;R1 = R2 = Me ; R3, R4 = H, 1-naphthyl; R3 = Me); 73% yield Compound 33al (formula 33 ; R1 = R2 = X = H; R5 = Me); 82% yield Compound 33a2 (formula 33 ; R1 = R2 = X = H; R5 = Et); 76% yield Compound 33a3 (formula 33 ; R1 = R2 = X = H; R5 = n-hexyl); 83% yield Compound 34b (formula 34 ; R1 = R2 = Me, R3 = Me); 94% yield Compound 35b3 (formula 35; R1 = R2 = Me ; X = H; R5 = n-Pr) ; 57% yield Compound 35b5 (formula 35 ; R1 = R2 = Me ; X = H; R3 = n-hexyl); 95% yield Compound 36b (formula 36 ; R1 = R2 = R3 = Me); 91% yield Compound 37al (formula 37 ; R1 = R2 = X = H; R3, R4 = -CH2-CH2-CH2-CH2-); 87% yield Compound 37a2 (fonnula 37 ; R1 = R2 = X = H; R3,R4 = -CH2-(CH2)3-CH2-); 40% yield Compound 37a3 (fonnula 37 ; R1 = R2 = X = H; R3 = R4 = Me); 70% yield Compound 37a4 (formula 37 ; R1 = R2 = X = H; R3 = R4 = H, 1-naphtfiyl); 66% yield Compound 37b2 (formula 37 ; R1= R2 = Me, X = H; R3, R4 = -CH2-(CH2)3-CH2-); 86% yield Compound 37b3 (formula 37 ; R1= R2 = Me, X = H; R3, R4 = H, 1-naphthyl): 66% yield Compound 37el (formula 37 ; R1R2 = H, n-penthyl, X = H; R3,R4 = -CH2CH2CH2CH2-); 79% yield Compound 37fl (formula 37 R1 = R2 = H, X = OMe ; R3R4 = -CHrCHrCH2-CHr); 76% yield Compound 38a2 (formula 38; R1= R2 = H; R3, R4 = -CH2 (CH2)3-CH2-); 90% yield Compound 38bl (formula 38 ; R1= R2 = Me ; R3,R4 = -CHrCH2-CHrCH2-); 92% yield Compound 38b2 (formula 38 ; R1= R2 = Me ; R3, R4 = -CH2(CH2)3-CH2-); 88% yield Compound 38b3 (formula 38 ; R1= R2 = Me ; R3, R4 = H, 1-naphthyl); 87% yield Compound 39a (formula 39 ; R1 = R2 = X = H); 97% yield Compound 40b (formula 40 ;R1 = R2 = Me); 96% yield Compound 4 If (formula 41;R1=R2 = H;X = OMe); 80% yield Compound 41g (formula 41; R1 = R2 = Me, X = OMe) Compound 42a (formula 42; R1= R2 = H); 91% yield Antimalarial Activity The antimalariaJ activity of the test compounds was evaluated in rodent using multidrug resistant strain of lasmodiumyoeiii Nigeriensis in swiss mice. General Procedure : Random bred swiss mice of either sex (20 ± 2 gm) were inoculated intraperitoneally with 1 x 105 P. yoelil (MDR) parasites on day zero. The treatment with test compounds were administered to groups of 6 mice each at different dose levels ranging between 24-96 mg/kg/day. The trioxanes were dissolved in groundnut oil (or 50% sodium bicarbonate solutions in case of hemisuccinate derivatives) and were administered via intramuscular or oral route for 4 consecutive days (day 0-3). Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular interval till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. For determingthe curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been recorded as the curative dose. The antimalarial data is summarized in Table-4. Table 4 : Antimalarial activity of substituted trioxanes against multi drug resistant strain of Plasmodium yoelii Nigeriensis in swiss mice (Table Removed) Trioxane 27 a, 27b ande their hemisuccinates 4la and 41b were evaluated for blood schizontocidal activity against Plasmodium cynomolgi and Plasmodium knowlesi in Rhesus monkeys using the following protocol: For activity against P. cynomolgi, rhesus monkeys were inoculated intravenously with 1 x 103 parasitized RBC and the treatment was initiated when the parasitaemia level reached above 0.5%. For activity against P. knowlesi the rhesus monkeys were inoculated intravenously with 1 x 104 parasitized RBC and the treatment was initiated at 0.1% parasitaemia level. Compounds 27a and 27b were dissolved in groundnut oil and administered in various regimens for 3-5 days via oral or intramuscular (im) routes. Hemisuccinates 4la and 41b were dissolved in 5% bicarbonate solution and administered similarly by oral, im or iv routes. The blood smears from the treated monkeys were examined once daily to record parasitaemia clearance time and subsequent recurrence of parasitaemia. The animals in which no recrudescence was observed upto day 60 were recorded as cured. The antimalarial data is summerized in table 5 and table 6. Table 5 : Antimalarial activity of trioxanes against Plasmodium cynomolgi in rhesus monkey model (Table Removed) Table 6 : Antimalarial activity of trioxanes against P. knowlesi in rhesus monkey model (Table Removed) Gametocytocidal Activity Compounds 27a and 41a were also tested for gametocytocidal activity according to the following protocol: Different batches of 3 to 4 days old naive Anopheles stephensis mosquitoes are allowed to engorge blood from gametocyte carrying infected host (rhesus monkey infected with P. cynomolgi or hamster infected with P. yoelii) at different time intervals prior to and after administration with a single dose of the test compound. The blood fed mosquitoes were maintained for the next 7-10 days in an insectorium to allow development of oocysts. A comparison of mosquito infectively rate and oocyst numbers in pre-treatment versus post-treatment provided index for gametocytocidal potential of the test agent. Compound 27a and 4 la showed complete loss of infectivity in mosquito batches fed 24 h post-treatment with 50 mg/kg (im, single dose) in P. yoelii model and 20 mg/kg (im, single dose) or 30 mg/kg (oral, single dose) in P. cynomolgi model. We claim : 1, Novel substituted 1,2,4-trioxanes useful as anti malarial agent of formula 1 wherein R1, R2 are hydrogen, alkyl group such as methyl, ethyl, propyl; R3, R4 are hydrogen, alkyl group such as methyl, ethyl, aryl such as phenyl, naphthyl, R5 is hydrogen, alkyl group such as methyl, ethyl, propyl, aryl such as phenyl, or carboxyalkyl group such as CH2CH2CO2H ; Z is O or OCO. (Formula Removed) 2. Novel trioxanes as claimed in claim 1 wherein the said compounds having structural formulae 23a1-23a13, 23b1-23b3, 23c1-23c2, 23d1, 23e1-23e5, 23f 1-2312, 23g1 as shown below. (Formula Removed) 23a1 R1, R2 = H,H: X=H;X=H; R3, R4 =CH2CH2CH2CH2 23a2 R1, R2 =H,, H; X = H; R3 ,R4 = CH2CH2CH2CH2CH2 23a3 R1,R2 = H, H; X = H; R3,R4 =Me, Me 23a4 R1,R2 = H,H;X = H;R3,R4-Me,Et 23a5 R1,R2 = H, H ; X = H ; R3, R4 = Me, CH2CH2CH3 23a6 R1, R2 = H, H ; X = H ; R3l R4 - Me, CH2CHMe2 23a7 V R2 = H, H ; X = H ; R3, R4 = n-propyl, n-propyl 23a8 R1, R2 - H, H ; X = H; R3, R4 = n-butyl, n-butyl 23a9 R1, R2 = H, H ; X = H ; R3, R4 = n-pentyl, n-pentyl 23a10 R1, R2 - H, H; X = H; R3, R4 =CH2-(CH2)9-CH2- 23a11 R1, R2 = H, H; X = H; R3, R4 = CH2CH2-CO- CH2CH2 23a12 R1, R2-H,H;X = H; R3, R4 = H, phenyl 23a13 R1,R2 - H, H; X = H ; R3, R4, = H, 1-naphthyl 23b1 R1,R2 - Me, Me ; X = H; R3, R4 = CH2CH2CH2CH2 23b2 R1, R2 - Me, Me ; X = H; R3, R4 - CH2CH2CH2CH2CH2 23b3 R1,R2 = Me, Me ; X - H ; R3, R4 - H, 1-naphthyl 23c1 R1,R2 = H, Me; X - H; R3, R4 = CH2CH2CH2CH2 23c2 R1, R2 = H, Me ; X = H ; R3, R4 - CH2CH2CH2CH2CH2 23d1 R1, R2 - H, Et; X = H ; R3, R4 - CH2CH2CH2CH2 23e1 R1, R2 = H, n-pentyl; X = H ; R3, R4 = CH2CH2CH2CH2 23e2 R1, R2 = H, n-pentyl; X = H ; R3, R4, = CH2CH2CH2CH2CH2 23e3 R1,R2 - H, n-pentyl; X - H ; R3, R4, = - CH2(CH2)4CH2 23e4 V R2 = H, n-pentyl; X - H ; R3, R4 =- CH2(CH2)3CH2 23e5 R1, R2 - H, n-pentyi; X = H; R3, R4 = Me, Me 23f1,R1, R2 = H, H; X = OMe ; R3, R4 = - CH2CH2CH2CH2 23f2 R1,R2 - H, H ; X - OMe ; R3, R4 = CH2-(CH2) 3-CH2 23g1 RR1,R2 = Me, Me ; X = OMe ; R3, R4 = CH2CH2CH2CH2 3. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 24a1, 24b1, 24b3 as shown below. (Formula Removed) Formula 24 24a1 R1,R2 = H, H;R3, R4 = CH2CH2CH2CH2 24a2 R1,R2 = H,H; R3, R4 = CH2-(CH2)3-CH2 24a3 R1,R2 = H,H; R3, R4=CH2-(CH2)4-CH2 24b1 R1, R2=Me, Me; R3, R4-CH2CH2CH2CH2 (24b2 )R1,R2 =Me, Me; R3, R4 = CH2CH2CH2CH2CH2 24b3 R1,R2=Me, Me; R3, R4=H,1-naphthyl 4. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 25a, 25c, 25d, 25e as shown below. (Formula Removed) Formula 25 25a R1,R2 = H, H,X= H 25c R1,R2 =H, Me, X=H 25d R1,R2 = H, Et, X = H 25e R1, R2 = H, n-phenyl, X - H 5. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 26a, 26b as shown below. (Formula Removed) Formula 26 26a R1, R2 = H, H 26b R1,R2 =Me, Me 6. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 27a, 27b, 27c, 27d, 27e, 27f, 27g as shown below. (Formula Removed) Formula 27 27a R1, R2=H, H;X = H 27b R1,R2 = Me, Me; X = H 27c R1,R2= H,Me;X=H 27d R1,R2 = H,Et;X=H 27e R1,R2 = H,n-pentyl;X = H 27f R1,R2= H,H;X-OMe 27g R1,R2 = Me, Me;X = OMe 7. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 28a, 28b as shown below. (Formula Removed) Formula 28 28aR1,R2=H, H 28b R1,R2 =Me, Me 8. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 31a1-31a6, 31b1 as shown below, (Formula Removed) Formula 31 31 a1 R1, R2 =H, H; X= H; R3, R4 = CH2CH2CH2CH2; R3 = CH3 31a2 R1,R2= H,H;X = H; R3, R4 = CH2CH2CH2CH2; R5 = Et 31 a3 R1,R2 = H, H; X = H; R3, R4 = CH2CH2CH2CH2; R5 = n-propyl 31 a4 R1, R2 = H, H ; X = H ; R3, R4 = CH2CH2CH2CH2; R5 = n-hexyl 31 a5 R1, R2 =H, H; X = H; R3, R4 = CH2CH2CH2CH2; R5 = Ph 31 a6 R1,R2 = H, H ; X = H ; R3, R4 = H, l-naphthyl; R5 = CH3 31 bl R1, R2 = Me, Me;X-H;R3,R4 = H, 1-naphthyl; R5 = Me 9. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 32b1-32b3 as shown below. (Formula Removed) Formula 32 32b1 R1, R2 = Me, Me ; R3, R4 = CH2CH2CH2CH2; R3 = Me 32b2 R1, R2 = Me, Me ; R3, R4 = CH2CH2CH2CH2CH2; R5 = Me 32b3 R1,R2 = Me, Me ; R3, R4 = H, l-naphthyl; R5 = Me 10. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 33a1-33a3 as shown below. (Formula Removed) Formula 33 33a1 R1, R2 = H,H;X = H;R5=Me 33a2 R1,R2=H,H;X=H;R5=Et 33a3 R1,R2 = H, H; X - H ; R5 = n-hexyl 11. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 34b as shown below. (Formula Removed) Formula 34 34b R1,R2 = Me, Me;R5, = Me 12. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 35a1, 35b1-35b5 as shown below. (Formula Removed) Formula 35 35a1 R1,R2 = H, H; X = H; R5 =-Me 35b1 R1, R2 = Me, Me; X = H; R5 = Me 35b2 R1,R2 = Me,Me;X=H;R5 = Et 35b3 RR1,R2 = Me, Me; X = H ; R5 = n-propyl 35b4 R1,R2 = Me, Me; X = H; R5 = n-pentyl 35b5 R1,R2 = MelMe;X=H;R5 = n-hexyl 13. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 36b as shown below. (Formula Removed) Formula 36 36b R1, R2 = Me, Me ; R5 = Me 14. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 37a1-37a4, 37bl-37b3, 37el, 37fl as shown below. (Formula Removed) Formula 37 37a1 R1, R2 = H, H ; X = H ; R3, R4=CH2CH2CH2CH2 37a2 R1,R2 = H, H ; X = H ; R3, R4 = CH2CH2CH2CH2CH2 37a3 R1,R2 = H, H; X = H; R3, R4 = Me, Me 37a4 R1,R2 = H, H ; X = H; R3, R4 = H, 1-naphmyl 37b1 R1,R2=Me, Me;X=H ; R3, R4= CH2CH2CH2CH2 37b2 R1,R2=Me, Me;X= H ; R3, R4 = CH2CH2CH2CH2 37b3 R1,R2 = Me, Me ; X = H ; R3, R4, = H, 1-naphthyl 37e1 R1,R2=H,n-pentyl;X=H;R3,R4 = CH2CH2CH2CH2 37f1 R1,R2=H,H ; X = OMe ; R3, R4, = CH2CH2CH2CH2 15. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 38a1-38a2, 38b1-38b3 as shown below. (Formula Removed) Formula 38 38a1 R1,R2 = H, H; R3, R4, = CH2CH2CH2CH2 38a2 R1,R2 = H, H; R3, R4 = CH2CH2CH2CH2CH2 38b1 R1, R2 = Me, Me ; R3, R4 = CH2CH2CH2CH2 38b2 R1,R2 = Me, Me ; R3> R4 = CH2CH2CH2CH2CH2 38b3 R1, R2 = Me, Me ; R3, R4 = H, 1-naphthyl 16. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 39a as shown below. (Formula Removed) Formula 39a 39a R1,R2 = H, H;X = H 17. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 40b as shown below. (Formula Removed) 40bR1, R2 = Me, Me 18 Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 41 a, 41 b, 41 e, 41f, 41 g as shown below. (Formula Removed) Formula 41 41a R1,R2=H,H;X = H 41b R1,R2=Me, Me;X = H 41 e R1, R2 = H, n-pentyl; X = H 41f R1,R2 = H,H;X=OMe 41g R1,R2 = Me, Me;X = Ome Formula 42 19. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 42a, 42b as shown below. (Formula Removed) 42a R1,R2 = H, H 42b R1,R2 = Me, Me 20. A process for the preparation of novel substituted 1,2,4-trioxanes and their esters of general formula 1 which comprises 1) reacting hydroxyacetophenones of 2 wherein X represents hydrogen or lower alkoxy such as OMe, with α-haloesters of formula 3 wherein RI and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl and Y represents halogen such as Cl or Br, in the presence of a base optionally in an organic solvent at a temperature in the range range of room temperature to refluxing temperature to give keto-esters of general formula 4, wherein R1, R2 and X have the same meaning as above 2) reacting keto-esters of general formula 4 under Reformatsky condition in an aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß.-hiydroxyesters of general formula 5, wherein RI, R2 and X have the same meaning as above 3) dehydrating ß-hydroxyesters of formula 5 using a catalyst in an organic solvent at a temperature in the range of room temperature to refluxing temperature to give α,ß - unsaturated esters of general formula 6, wherein RI, R2 and X have the same meaning as above 4) reducing ap-unsatu rated esters of general formula 6 with a complex metal hydride such as LiAIH4 in an ether solvent at a temperature in the range of 0°C to room temperature to give allylic alcohols of formula 7 wherein RI, R2, X have the same meaning as above 5) oxygenation of allylic alcohols of formula 7 in presence of a sensitizer in an organic solvent at a temperature in the range of -10°C to room temperature to give p- hydroxyhydroperoxides of general formula 8 wherein RI, R2, X have the same meaning above, 6) isolating and then reacting or reacting in situ ß-hydroxyhydroperoxides of formula 8 with compounds containing aldehyde or ketone group in presence of an acid catalyst in an organic solvent at a temperature in the range of 0°C to room temperature to give hydroxy-functionalized 1,2,4-trioxanes of general formula 1, wherein RI, R2 and X have the same meaning as above, R3, R4 are hydrogen, alkyl group such as methyl, propyl, aryl group such as phenyl, naphthyl or part of a cyclic system, R5 is H and Z is 0; 7) reacting hydroxy-functionalized trioxanes of general formula 1, wherein R is H and Z is O with an acid chloride or anhydrides in presence of a base in an organic solvent at a temperature in the range of 0°C to room temperature to give trioxane esters of general formula 1, wherein RI, R2, R3, R4 and X have the same meaning as above, R3 is alkyi group such as methyl, ethyl, propyl, aryl group such as phenyl, carboxyalkyl such as CH2CH2CO2H ; 2 is O-CO. 21. A process as claimed in claim 20, wherein the substituted acetophenones of formula 2 are reacted with α-haloesters of formula 3 in presence of a base such as KaHC03, Na2CO3, K2C03, in an organic solvent such as acetone, DMSO, DMF. 22. A process as claimed in claims 20-21 wherein Reformatsky reaction is carried out by reacting ketoesters of formula 4 with ethyl bromoacetate and Zn in an aprotic organic solvent such benzene, diethylether, THF. 23. A process as claimed in claims 20-22 wherein dehydration of ß-hydroxyesters of formula 5 is effected in a hydrocarbon solvent such as benzene, toluene, CH2C12, using a catalyst such as I2, P2O5, p-toluene-sulfornic acid, acidic resin such as Amberlyst-15. 24. A process as claimed in claims 20-23 wherein the reduction of esters of formula 6 with LiAIH4, is carried out in an ether solvent such as diethyl ether, THF. 25. A process as claimed in claims 20-24 wherein the oxygenation is effected by photooxygenation of allylic alcohols of formula 7 in an organic solvent such as acetone, CH3CN, CH2CI2, methanol, ethanol, using a dye (sensitizer) such as methylene blue, Rose Bengal, tetraphenyl porphine. 26. A process as claimed in claims 20-25, wherein condensation of p- hydroxyhydroperoxides of formula 8 with aldehydes and ketones of formulae 21-22 is done in an organic solvent such as CH2CI2, CHCI3, benzene, CH3CN, using as acid catalyst such as HCI, H2SO4, 27. A process as claimed in claims 20-26, wherein esterification of hydroxy- functionalized trioxanes of formulae 23-28 with acid chlorides of formula 29 or an acid anhydride of formula 30 is done in an organic solvent such as CH2CI2, CHCI3, THF, CH3CN in presence of base such as Et3N, pyridine, dimethylaminopyridine. 28. A process as claimed in claims 20-27, wherein hemisuccinate derivatives of formulae 37-42 are prepared in an organic solvent such as CH2Cl2, CHCI3, CH3CN, toluene, THF, in presence of a base such as Et3N, pyridine, dimethylaminopyridine. 29. A process as claimed in claims 20-28, wherein the compounds containing aldehyde and ketonic group are of formulae 21-22 given in the drawing wherein R3 and R4 are hydrogen, alky! group such as methyl, ethyl, aryl such as phenyl, naphthyl, araalkyl such as benzyl, or part of a cyclic system. 30. A process as claimed in claims 20-29, wherein acid chlorides and acid anhydrides used are having the formulae 29 and 30 wherein R5 represent alkyl group such as methyl, ethyl, propyl, aryl such as phenyl. 31. Novel substituted 1,2,4 trioxanes useful as antimalarial agents and a process for the preparation of the same substantially as herein described with reference to the examples and the drawings accompanying this specification.

Full Text

This invention relates to novel substituted 1,2,4 trioxanes useful as anti malarial
agents and a process for the preparation of the same.
This invention also relates to a process for the preparation of novel substituted 1,2,4,-
trioxanes.
This invention particularly relates to a process for the preparation of 6-[α-(hydroxyalkoxy
substituted aryl)vinyl]-1,2,4-trioxanes and their esters as new antimalarial agents. More
particularly the present invention provides a process for the preparation of hydroxyl-
functionalized trioxanes and their esters of general formula 1, wherein R1 and R2
represent hydrogen, alkyl group such as methyl, ethyl, propyl; R3 and R4 represent
(Formula Removed)
Formula 1
hydrogen, alkyl group such as methyl, ethyl, aryl such as phenyl, naphthyl or part of a cyclic system; R5 represents hydrogen, alkyl group such as methyl, ethyl, propyl, aryl such as phenyl or a carboxy alkyl group such as CH2CH2CO2H; X represents hydrogen or lower alkoxy such as Ome, Z represents O or OCO. These compounds have been tested against multi-drug resistant P. yoelii in mice and several of them show promising antimalarial activity. Some of these compound with promising antimalarial activity have been tested against P. cynomolgi in monkeys and have been found effective. The invention thus relates to pharmaceutical industry. The trioxanes of general formula 1 are new chemical entities and they have not been prepared earlier. Trioxanes of general formula 1 are oil-soluble and can be administered as solution in oil such as groundnut oil. Some of the compounds of formula 1 are hemisuccinate derivates and are soluble both in oil and aqueous NaHCO3 solution and can be administered as a solution in groundnut oil or aqueous NaHCO3. The mode of administration can be oral, intramuscular, subscutaneous or

intravenous.
The main objective of this invention is to provide novel substituted 1,2,4-trioxanes
useful as antimalarials.
The objective of the present invention is also to provide a process for the
preparation of novel substituted 1,2,4-trioxanes.
The another objective of the present invention is to provide a process for the
preparation of hydroxyl-functionalized trioxanes and their esters of general formula
1, a new series of antimalarial agents.
Accordingly, the present invention provides novel substituted 1,2,4-trioxanes useful as
anti malarial agent of formula 1 wherein R1, R2 are hydrogen, alkyl group such as
methyl, ethyl, propyl; R3, R4 are hydrogen, alkyl group such as methyl, ethyl, aryl such
as phenyl, naphthyl, R5 is hydrogen, alkyl group such as methyl, ethyl, propyl, aryl
such as phenyl, or carboxyalkyl group such as CH2CH2CO2H ; Z is O or OCO.

(Formula Removed)
Formula 1
Accordingly, the present invention proves a process for the preparation of novel substituted 1,2,4-trioxanes and their esters of general formula 1 which comprises reacting hydroxyacetophenones of formula 2 wherein X represents hydrogen or lower alkoxy such as Ome, with α-haloesters of formula 3 wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl and Y represents halogen such as Cl or Br, in the presence of a base optionally in an organic solvent at a temperature in the range of room temperature of refluxing temperature to give keto-esters of general formula 4, wherein R1, R2 and X have the same meaning as above; reacting keto-esters of general formula 4 under Reformatsky condition in an

aprotic organic solvent in the temperature range of room temperature to refluxing temperature to give ß-hydroxyesters of general formula 5, wherein R1, R2 and X have the same meaning as above; dehydrating ß-hydroxyesters of general formula 5, wherein R1, R2 and X have the same meaning as above; dehydrating ß-hydroxyesters of formula 5 using a catalyst in an organic solvent at a temperature in the range of room temperature to refluxing temperature to give α,ß-unsaturated esters of general formula 6, wherein R1, R2 and X have the same meaning as above; reducing ß-hydroxyesters esters of general formula 6 with a complex metal hydride such as LiAIH4 in an ether solvent at a temperature in the range of 0°C to room temperature to give allylic alcohols of formula 7 wherein R1, R2, X have the same meaning as above; oxygenation of allylic alcohols of formula 7 in presence of a sensitizer in an organic solvent at a temperature in the range of -10°C to room temperature to give ß-hydroxyhydroperoxides of general formula 8 wherein R1, R2, X have the same meaning above; isolating and then reacting or reaction in situ ß-hydroxyhydroperoxides of formula 8 with compounds containing aldehyde or ketone group in presence of an acid catalyst in an organic solvent at a temperature in the range of 0°C to room temperature to give hydroxyl-functionalized 1,2,4-trioxanes of general formula 1, wherein R1,R2 and X have the same meaning as above, R3, R4 are hydrogen, alkyl group such as methyl, propyl, aryl group such as phenyl, naphthyl or part of a cyclic system, R5 is H and Z is 0; reacting hydroxyl-functionalized trioxanes of general formula 1 wherein R is H and Z is 0 with an acid chloride or anhydrides in presence of a base in an organic solvent at a temperature in the range of 0°C to room temperature to give trioxane esters of general formula 1, wherein R1, R2, R3, R4 and X have the same meaning as above, R5 is alkyl group such as methyl, ethyl, propyl, aryl group such as phenyl, carboxyalkyl such as CH2CH2CO2H; Z is O-CO.
In the process hydroxyacetophenones of formula 2 are reacted with α-haloesters of formula 3 in presence of a base such as Na2CO3, K2CO3, KHCO3 in an organic solvent such as acetone, dimethylformamide, dimethylsulfoxide or without solvent, to give ketoesters of general formula 4. These ketoesters can be isolated and purified by standard laboratory methods such as crystallization or

chromatography using an adsorbent such as silica gel. All ketoesters of general formula 4 except lla (formula 11, R1 = R2 = X = H), 11c(formula 11, R1 = H, R2 = Me, X = H) and 12a (formula 12, R1 = R2 = H) are new compounds and they have not been prepared earlier. Ketoesters lla, 11c and 12a are known compounds, [(a) Chin Ther., 8, 574 (1973), Indian J. Chem., 24, 119 (1985), Chen Abstracts, 124, 8616e (1996)].
In the process ketoesters of general formula 4 are reacted with ethyl bromoacetate and Zn in an aprotic solvent such as benzene, diethyl ether, to give ß-hydroxyesters of general formula 5. These ß-hydroxyesters can be isolated and purified by standard laboratory methods such as column chromatography using an adsorbent such as silica gel and a hydrocarbon solvent in combination with ethyl acetate as eluent or can be used without purification in the next step,ß-hydroxyesters of general formula 5 are new compounds and they have not been prepared earlier. These hydroxy esters of general formula 5 have an additional ester group as part of substitution in the aromatic ring.
In the process dehydration of ß-hydroxyesters of geneal formula 5 is accomplished in an hydrocarbon solvent such as benzene, toluene, CH2C12, in the presence of a catalyst such as I2, ß-toluenesulfonic acid, P2O3, or acidic resin such as Amberlyst-15 to give α,ß-unsaturated esters of general formula 6. These unsaturated esters can be isolated and purified by standard laboratory methods such as chromatography using an adsorbent such as silica gel. α,ß-Unsaturated esters of general formula 6 have an addition ester group as part of substitution in the aromatic ring. These esters of general formula 6 are new compounds and they have not been prepared earlier.
In the process reduction of α,ß-unsaturated esters of general formula 6 is done by reacting the compound with a complex metal hydride such as LiAlH, in an ether solvent such as diethyl ether, THF, to give allylic alcohols of general formula 7. These allylic alcohols of general formula 7 have an addition hydroxyl group as hydroxyalkoxy substitution in the aromatic ring. These allylic alcohols of general formula 7 can be isolated and purified by standard laboratory methods such as chromatography using an adsorbent such as silica gel and a hydrocarbon solvent in combination with ethyl acetate as eluant. Compounds of general formula 7 are new chemical entities and they have not been prepared earlier.
In the process allylic alcohols of general formula 7 are converted to p-hydroxyhydroperoxides of formula 8 by passing oxygen gas in the solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light. The dye which acts as a sensitizer i.e. converts triplet oxygen to highly reactive singlet oxygen, may be such as methylene blue, Rose Bengal,

tetraphenylporphine. Organic sol vent used may be such as CH2C12, CH3CN, acetone, methanol, benzene. These p-hydroxyhydroperoxides of general formula 8 can be isolated and purified by known laboratory methods or can be used in situ, without purification and isolation, inthe next step. These p-hydroxyhydroperoxides of formula 8 are new chemical entities and they have not been prepared earlier. Furthermore, these p-hydroxyhydroperoxides have an extra hydroxyl group in the form of hydroxyalkoxy substitution in the aromatic ring. The novel feature of these p-hydroxyhydroperoxides is that this extra hydroxyl group which is present as a hydroxyalkoxy substituent in the aromatic ring, does not take part in the next reaction i.e. condensation of hydroperoxides with aldehyde and ketones and thus provide 1,2,4-trioxanes which carry a hydroxy group suitable for further derivatization.
In the process 0-hydroxyhydroperoxides of general formula 8 are converted to hydroxy-functionalized 1,2,4-trioxanes of general formula 1 (R5 = H, Z = O) by reacting these hydroperoxides with carbonyl compounds of formula 21-22 in presence of an acid catalyst in an aprotic organic solvent. The carbonyl compounds used may be such as benzaldehyde, naphthaldehyde, acetone, ethyl methyl ketone, methyl propyl ketone, methyl isobutyl ketone, 4-heptanone, 5-nonanone, 6-undecanone, dibenzyl ketone and the such as, cyclic ketone such as cyclopentanone, cyclohexanone, cycloheptanone, bicyolic ketone such as norcomphor (22a) and tricyclic ketone such as 2-adamantanone (22b). The acid catalyst used may be HC1, H2S04, p-toluene sulfornic acid, BF3.OEt2, acidic resin such as Amberlyst-15. The organic solvent used may be CH2Cl2, CHC13, benzene, CH3CN. These trioxanes of general formula 1 (R5= H, Z = O) are stable compounds and can be isolated and purified by standard chromatographic techniques using an adsorbent such as silica gel and a hydrocarbon solvent in combination with polar organic solvent as eluant. These trioxanes of general formula 1 (R3 = H, Z = O) are new chemical entities and they have not been prepared earlier. The novel feature of these trioxanes is that they are equipped with a primary hydroxyl group suitable for making derivatives of these trioxanes. This hydroxyl group is part of alkoxy substituent in the aromatic ring. These trioxanes of general formula 1 (R3 = H, Z = 0) have been tested against malarial parasites in animal models and several of them show very promising antimalarial activity, both against chloroquine sensitive and chloroquine resistant malaria These trioxanes are oil-soluble and can be administered as solution in oil such as groundnut oil. Some of these trioxanes have shown significant gamatocidal activity.
In the process reaction of trioxanes of general formula 1 (R5 = H, Z = 0) with acid chlorides of formula 29 or acid anhydrides of formula 30 wherein R3 is alkyl group such as methyl, ethyl, propyl,

aryl group such as phenyl, is done in an aprotic organic solvent in the presence of a base to give trioxane esters of general formula 1 wherein R3 is alkyl group such as methyl, ethyl, propyl, aryl group such as phenyl, Z is OCO. In the reaction hydroxyl group of trioxanes of formula 1 (R5 = H, Z = O) is esterified. The acid chlorides and acid anhydrides used may be such as acetyl chloride, beazoyl chloride, prop ionic anhydride, butyric anhydride, heptanoic anhdride. The base can be such as EfeN, pyridine, with or without the catalyst such as 4-dimethylaminopyridine (DMAP). The organic solvent used may be such as CH2C12, CHC13, THF, CH3CN. These trioxanes of general formula 1 (R5 = alkyl, aryl, Z = OCO) can be isolated and purified by known laboratory methods such as crystallization or chromatography using an adsorbent such as silica gel and hydrocarbon solvent in combination with polar organic solvents as eluant. The trioxanes are new chemical entities and they have not been prepared earlier. These trioxanes are oil-soluble and can be administered as solution in edible oil such as groundnut oil. Some of the trioxanes of general formula 1 (Rj = alkyl, aryl, Z = OCO) have shown promising antimalarial activity in animal models.
In the process trioxanes of formula 1 (R5 = H, Z = 0) are reacted with succinic anhydride in an aprotic solvent in presence of tertiary amine with or without the presence of 4-dimethylaminopyridine (DMAP) to give carboxy fimctionalized trioxanes of general formula 1 (R5 = CH3CH2CO2H, Z = OCO). The tertiary amine may be such as Et3N, pyridine. Aprotic organic solvent may be such as CH2C12, CHC13, CH3CN, toluene, THF. In the reaction, the hydroxyl group of me trioxanes 1(R5 = H,Z = 0)is esterified. The trioxanes of general formula 1 (R5 = CH2CH2CO2H, Z = OCO) have a carboxyl group and are soluble in aqueous bicarbonate or carbonate solutions. Thus they can be administered both as solution in oil or aqueous bicarbonate/carbonate solutions. Trioxanes of general formula 1 (R3 = CH2CH2CO2H, Z = OCO) can be isolated and purified by known laboratory methods such as given above. Trioxanes of general formula 1 (R5 == CH2CH2C02H, Z = OCO) are new chemical entities and they have not been prepared earlier. Some of these trioxanes have shown promising antimalarial activity against both chloroquine-sensitive and resistant malaria in animal models. Some of these trioxanes also show significant gamatocidal activity.
The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention.

Example 1
Ethyl (4-acetylphenoxy)acetate (compound lla, fonuula 11, R1 = R3- X = H)
A mixture of p-hydroxyacetophenone (50 g), ethyl chloroacetate (60 ml), K2CO3 (120 g) in acetone (450 ml) was refluxed with stirring for 24 h. The reaction mixture was filtered and the residue was washed with acetone. The combined fi:lterate was concentrated and the residue was redissolved in ether, the ether extract was washed with aqueous NaOH, and then with water, dried, concentrated and purified by chromatography on silica gel using hexane - ethylacetate as eluant to give 63.3 g (77% yield) of lla, m.p.64-68°C.
Compound lla was also prepared using the conditions as given in table 1.
Table 1

(Table Removed)
ß- Hydroxyester I3a (formula 13. Rl = R2 = X = H)
To a mixture of ketoester lla (20 g) zinc metal (12 g), I2(20 mg) in benzene was added ethyl bromoacetate (10 ml) dropwise. The reaction mixture was refluxed for another 7 hr, cooled, acidified with aqueous HC1, benzene layer was separated and the aqueous layer was extracted with benzene. Combined organic extract was washed with water and then aqueous NaHC03, dried and concentrated. The crude product was purified by column chromatography on silica gel using mixture of hexane and ethylacetate as eluant to furnish 13a (63% yield) of ß-hydroxyester as an oil.
Compound 13a was also prepared using the conditions given in table 2.

Table 2
(Table Removed)
α,ß-Unsaturated ester 15a (formula 15, R1= R2 = X - H)
A mixture of ß-hydroxyester 13a (10 g) and P2O5 (4 g) in benzene (150 ml) was refluxed for 2.5 h. The reaction mixture was filtered and the filtrate was concentrated to give 10 g of crude product which was purified by column chromatography on silica gel using hexane - ethylacetate as eluant to give 5.13 g (56% yield) of α,ß-unsaturated ester 15a as an oil. Allylic alcohol 17a (formula 17, R1 = R2 = X = H)
To a stirred and ice-cooled mixture of LiAlH4 (6 g) in dry ether (400 ml) was added dropwise a solution of α,ß-unsaturated ester 15a (12 g) in ether. The reaction mixture was stirred in ice-bath for 5 h. and then quenched with water and 10% NaOH. The organic layer was separated, dried on Na2S04 and concentrated to give 8.84 g of crude product which was purified by column chromatography to furnish 5.67 g (59%) of allylic alcohol 17a; m.p. 83-86°C.
3-[4-(2-Hydroxyethoxy)phenyl]-l-hydroxy-but-3-en-2-hydroperoxide (compound 19a, general formula 19, R1 = R2 - H, X - H)
(1) A solution of allylic alcohol 17a and methylene blue (15 mg) in ethanol (60 ml) was irradition
with a 250 watt tungston-halogen lamp at -10°C while a slow stream oxygen was passed through the
reaction mixture for 9.5 h. The reaction mixture was diluted with water and extracted with ether. The
ether extract was concentrated and the crude product was chromatographed on silica gel using CH2Cl2
- ether as eluant to give 650 mg (28% yield) of ß-hydroxyhydroperoxide 19a.
(2) A solution of allylic alcohol 17a (1 g), tetraphenylporphine (50 mg) in CHC13 (60 ml) wag
photooxygenated at r.t. for 6 h. ß-Hydroxyhydroperoxide 19a separated as a solid. It was washed with
ether to give 500 mg (44% yield) of tic pure 19a.

Trioxane 23al (formula 23, R1= R2 = X = H, R3, R4 = -CH2CH2CH2CH2)
(1) Two-pot procedure : A mixture of p-hydroxyhydroperoxide 19a (900 mg), cyclopentanone (2 ml)
and p-toluene sulfonic acid (50 mg) in acetonitrile (10 ml) was stirred at room temperature for 3.5 h.
The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with ether. The
ether extract was concentrated and the crude product was purified by chromatography (elution with
ethylacetate-hexane ; 1 : 9) to furnish 310 mg (44% yield) oftrioxane 23al.
(2) One-pot procedure : A solution of alcohol 17a (3.5 g) and methylene blue (10 mg) in CH3CN (65
ml) was irradiation with a tangston halogen lamp at 0°C for 7.5 h when a slow stream of oxygen was
passed through the reaction mixture to give p-hydroxyhydroperoxide 19a as indicated by.TLC. To the
reaction mixture were added cyclopentanone (6 ml) and p-toluenesulfonic acid (50 mg) and the reaction
mixture was stirred at r.t. for 2 days. Workup and purification by chromatography furnished 1.14 g (23%
yield based on alcohol 17a) oftrioxane 23al.
Acetate oftrioxane 23 a 1 [compound 31al, formula 31, R1= R2 = H ; R3, R4= CH2CH2CH2CH2 ; RS = CH3;X = H]
A solution oftrioxane 23al (200 mg) in pyridine (6 ml) was treated with acetic anhydride (0.5 ml) and the resulting mixture was left in refrigerator (~ 5°C) overnight. The reaction mixture was diluted with water and extracted with ether. Ether extract was washed sequencially with water, 10% HC1, water, and then dried (Na2S04) and concentrated. The crude product was purified by column chromatography on silica gel to give 180 mg (91% yield) compound 26al as an oil. Example 2
Benzoate oftrioxane 23 a 1 [compound 31a5. formula 31, R1= R2 = H ; R3, R4= CH2CH2CH2CH2 ; R5=Ph;X = H]
A solution oftrioxane 23al (180 mg) and benzoyl chloride (0.5 ml) in pyridine (3 ml) was left at r.t. overnigllt. The reaction mixture was diluted with water, extracted with ether, Ether extract on usual processing followed by column chromatography on silica gel using hexane - ethylacetate as eluant furnished 100 mg (42% yield) of benzoate 31a5 as an oil. Example 3 Trioxane 23a2 (formula 23, R1, = R2 = X = H, R3, R4 = -CH2CH2CH2CH2CH2-)
A solution of allylic alcohol 17a (1 g) and methylene blue (15 mg) in acetonitrile was photooxygenated at 0°C for 6.5 h. as above and then reacted with cyclohexanone (2 ml) using p-toluenesulfonic acid as catalyst at r.t. for 5 h. The crude product obtained after workup as above

was purified by chromatography to give 0.86 g (57% yield based on the alcohol 17a) to furnish
1,2,4-trioxane 23a2.
Example 4
Trioxane 23a3 (formula 23, R1 = R2 - X = H ; R3 = R4 = Me)
(1) From P-hydroxyhydroperoxide 19a
To a solution of p-hydroxyhydroperoxide 19a (100 mg) in a acetone (5 ml) was added one drop of cone. HCI and the reaction mixture was stirred at r.t. for 30 minutes. The reaction mixture was concentrated under vacuum and the crude product was purified by chromatography on silica gel using hexane - ethylacetate as eluant to give 60 mg (52% yield) of trioxane 23a3.
(2) From allyiic alcohol 17a
A sv'sition of allyiic alcohol 17a (1 g) and Rose Bengal (5 mg) in acetone (40 ml) was photooxygenated at -8°C for 6h To this reaction mixture were added 3 drops of cone. HCI and the reaction mixture was left overnight at r.t. The solvent was removed under vacuum and the crude product was chromatographed on silica gel as above to furnish 340 mg (26% yield based on allyiic alcohol 17a) of trioxane 23a3. Example 5 Trioxane 27a (formula 27, R! = R2 = X « H)
A solution of allyiic alcohol 17a (2 g) and methylene blue (5 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 6 h to give p-hydroxyhydroperoxide 19a as indicated by TLC. To this reaction mixture 2-adamantanone (2 g) was added and the reaction mixture was stirred for 1 h when p-toluenesulfonic acid (10 mg) was added and the reaction mixture was stirred for another 6 h at room temperature. The reaction was quenched with aqueous NaHC03, diluted with water and extracted with ether. Ether extract was washed with water, dried (Na2SO4) concentrated and the crude product was purified by chromatography on silica gel to furnish 1.9 g (57% yield based on alcohol 17a) of trioxane 27a as an oil. Acetate of trioxane 27a [compound 35al, formula 35, RI= Ra = H ; Rs = CH3 ; X = H]
A mixture of trioxane 27a (200 mg), acetic anhydride (1 ml) in pyridine (4 ml) was left at r.t. overnight. The reaction mixture was diluted with water and extracted with ether. Ether extract was washed with water, 10% aqueous HCI, water, dried (Na2SO4) and concentrated to give 200 mg of crude product which was purified by chromatography on silica gel (8 g, elution with 50% EtoAc in CH2C12) to give 178 mg (80% yield) of acetate 35al as an oil.

Hemisuccinate of trioxane 27a [compound 4 la, formula 41, R1 = R2 = H ; X = H]
A mixture of trioxane 27a (2 g) and succinic anhydride (3 g) in pyridine (20 ml) was left at r.t. overnight. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, 10% HC1, water, dried (Na2SO4) and concentrated to give 2.3 g of crude product which was purified by chromatography on silica gel (25 g, eluted with 50% ether in CH2C12) to give 1.5 g (60% yield) of hemisuccinate 41a as a highly viscous material. Example 6 Trioxane 23al3 (formula 23, R1 = R2 = X = H ; R3, R4 = H, 1-naphthyl)
A solution of allylic alcohol 17a (1.0 g) and methylene blue (70 mg) in CH3CN (50 ml) was photooxygenated at -10 to 0°C for 6 h. To one-half of this reaction mixture were added 1-naphthaldehyde (1 ml) and p-toluene sulfonic acid (20 mg) and the reaction mixture was kept at 5°C overnight. Usual workup followed by purification by chromatography furnished trioxane 17al3) in 32% yield.
Hemisuccinate of trioxane 23al3 [compound 37a4, formula 37, R1= R2 = H; R3, R4 = H, 1-naphthyl; X = H]
To an ice-cooled mixture of 23al3 (120 mg) and succinic anhydride (200 mg) in CH2C12 (20 ml) were added triethylamine (0.2 ml) and 4-dimethylaminopyridine (30 mg) and the reaction mixture was left overnight at r.t. Workup as above followed by column chromatography on silica gel using CH2C12 - ether as eluant furnished hemisuccinate 37a4 as an oil (100 mg ; 67% yield). Example 7 Ethyl 2-(4-acetylphenoxy)isobutyrate (compound11b Formula 11, Rl = R2 = Me ; X = H)
A mixture of p-hydroxyacetophenone (14 g), ethyl 2-bromoisobutyrate (21 g) and K2CO3 (40 g) in acetone (260 ml) was refluxed with stirring for 19 h. The reaction mixture was diluted with water and extracted with benzene. Usual processing of the benzene extract furnished 10.5 g (41% yield) of keto ester 11b as an oil.
Compound 11b was also prepared using the conditions as given in table 3.

Table 3

(Table Removed)
ß-Hydroxyester 13b (formula 13, R1 = R2 - Me, X = H)
To arefluxing mixture ofketoester llb(12g), zinc (6 g), I2 (70 mg) in benzene (200 ml) was added dropwise ethyl bromoacetate (7 ml) and the reaction mixture was refluxed for 7 hr. Work up and purification by chromatography on silica gel (hexane - EtoAc on eluant) furnished 45% yield of ß-hydroxyester 13b. α,ß-Unsaturated ester 15b (formula 15, R1 = R2 = Me, X = X)
To a refluxing mixture of ketoester 11b (10.5 g), zinc (5 g), I2 (40 mg) in benzene (200 ml) was added, dropwise a solution of ethyl bromoacetate (5 ml) in benzene (50 ml) and the reaction mixture was refluxed for 7 h. The reaction mixture was cooled and acidified with 10% aqueous HCI. Benzene layer was separated and the aqueous layer was extracted with benzene (2 x 150 ml). The combined organic extract was washed with water and aqueous NaHCO3 solution, dried (Na2SO4) and concentrated to give ß-hydroxyester 13b which was used in the next without isolation and purification.
The crude 13b as obtained above was dissolved in benzene (200 ml), I2 (50 mg) was added the reaction mixture was refluxed for 1.75 h. The reaction mixture was cooled, washed with aqueous sodium thiosulphate and then with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography to furnish 6.80 g (51% yield) of α,ß-unsaturated ester 15b. Allylic alcohol 17b (formula 17, R1 = R2 = Me ; X - H)
To a stirred and ice-cooled mixture of LiAlH4, (5 g) in dry ether (450 ml) was added dropwise a solution of α,ß-unsaturated ester 15b (6.2 g) in dry ether. The reaction mixture was stirred for 5 h. and then quenched with water and 10% aqueous NaOH. The organic layer was separated. The residue was washed with ether and the combined organic extract was dried (Na2SO4), concentrated and the crude product was purified to give 3.0 g (66% yield) of allylic alcohol 17b, as an oil.

3-[4-(2-Hydroxy-1,l-dimethyl-ethoxy)phenyl]-l-hydroxy-but-3-en-2-hydroperoxide (compound 19b, formula 19, R1 = R2 = Me, X = H)
A solution of aJlylic alcohol 17b( 1.40 g) and methylene blue (100 mg) in CH3CN (45 ml) was irradiated with a 500 watt tungsten-halogen lamp at 0°C for 5 h while a slow stream of oxygen was passed through the reaction mixture. The reaction mixture was concentrated to 20 ml and men diluted with water (20 ml) and extracted with ether (3 x 25 ml). The combined ether extract was washed with water, dried (Na2S04), concentrated and purified by chromatography on silica gel to furnish 860 mg (61% yield) of ß-hydroxyhydroperoxide 19b as an oil. Trioxane 23bl (formula 23, R1 = R2 = Me, X = H ; R3, R, = -CH2-CH2-CH2-CH2-)
A slution of allylic alcohol 17b (680 mg) and methylene blue (15 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 3.25 h to give p-hydroxyhydroperoxide 19b as indicated by TLC. This reaction mixture was divided into two equal parts. To one part were added cyclopentanone (2 ml) and PTSA (25 mg) and stirred at r.t. for 2.75 h. Usual workup followed by chromatography on silic gel furnished 240 mg (63% yield based on allylic alcohol 17b) of trioxane 23bl.
Hemisuccinate of trioxane 23bl [compound 37bl, formula 37, R1 = R2 = Me ; R3, R4 = CH2CH2CH2CH2;X=H]
A solution trioxane 23bl (1 g) in CH2C12 (40 ml) was reacted with succinic anhydride as above and the product was purified by chromatography as above to furnish 1.23 g (93% yield) of hemisuccinate 37bl. Example 8 Trioxane 23b2 (formula 23, R1= R2 = Me, X = H ; R3, R4= -CH2-(CH2)3-CH2-)
To one half of the photooxygenated mixture from the above example were added cyclohexanone (2 ml) and PTSA (25 mg) and the reaction mixture was stirred at r.t. for 2.75 h. Normal workup followed by purification by chromatography on silica gel column gave 230 mg (46% yield based on the allylic alcohol 17b used) of trioxane 23b2. Example 9 Trioxane 27b (formula 27, R1= R2 = Me, X - H)
A mixture of allylic alcohol 17b (2.0 g) and methylene blue (100 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 6.5 h. To this reaction mixture were added 2-adamantanone (3.0 g) and p-

toluenesulfonic acid (100 mg) and the reaction mixture was left at room temperature overnight. The reaction mixture was quenched with aqueous NaHC03, diluted with water and extracted with ether. The ether extract was washed with water, dried (Na2S04) and concentrated. The crude product was purified by chromatography on silica gel column to give 1.61 g (59% yield based on allylic alcohol 17b) of 1,2,4-trioxane 27b, m.p. 100-102°C.
Trioxane 27b was obtained in 44% yield when the condensation with 2-adamantanone was done using Amberlyst-15 as catalyst. Acetate of trioxane 27b [compound 35bl, formula 35, R1 = R2 = Me ; R5 = CH3; X = H]
A solution of trioxane 27b (200 mg) and acetic anhydride (1 ml) in pyridine (4 ml) was reacted at r.t overnight. Workup as above followed by column chromatography on silica gel furnished 0.21 g of acetate 35bl as a viscous material. Example 10 Propionate of trioxane 27b [compound 35b2, formula 35, R1= R2 = Me ; R5 = Et; X = H]
To an ice-cooled mixture of 27b (300 mg) and propionic anhydride (1.3 ml) in CH2C12 (10 ml) were added triethylamine (0.8 ml) and 4-dimethylaminopyridine (20 mg) and a left overnight at r.t. Usual workup as above followed by column chromatography on silica gel furnished 310 mg (91% yield) of propionate 35b2 as a colourless oil. Example 11 Hexanoate of trioxane 27b [compound 35b4, formula 35, R1= R2 - Me ; Rs = n-pentyl; X = H]
A mixture of trioxane 27b (300 mg) and hexanoic anhydride (1 ml) in CH2C12 (15 ml) was reacted in presence of triethylamine (0.5 ml) and 4-dimethylamino pyridine (20 mg) at r.t for 1 h. Workup as above followed by column chromatography on silica gel furnished 330 mg (89% yield) of hexanoate 35b4 as an oil. Example 12 Hemisuccinate of trioxane 27b [compound 41b, formula 41, R1 = R2 = Me ; X = H]
To a stirred and ice-cooled mixture of trioxane 27b (2.3 g) and succinic anhydride (2.5 g) in CH2C12 (100 ml) were added triethylamine (2.5 ml) and 4-dimethylamino pyridine (50 mg) and the reaction mixture was stirred at r.t. for 2 h, concentrated under reduced pressure, acidified (50 ml of 10% HC1) and extracted with ether (3 x 150 ml). Ether extract was washed with water (3 x 100 ml), dried (Na2S04) and concentrated under reduced pessure to give 3.1 g of crude material which was chromatographed on silica gel (50 g, eluted with 50% ether in hexane) to give 2.3 g solid which was

crystallized from ether-hexae to give 1.91 g (68% yield) of hemisuccinate 41b as while crystals, rap. 96-99°C.
Similar yields of 41b were obtained when the reaction was done in absence of 4-dimethylaminopyridine. Example 13 Ketoester 1 If (formula 11, R1 = R2 = H, X = Ome)
Compound llf was prepared from 3-methoxy-4-hydroxyacetophenone (formula 9, X = Ome) in 84% yield following the procedure used for the preparation of compound lla as given in example 1. ß-Hydroxy ester 13f (formula 13, R1= R2 = H, X = OMe)
To a refluxing mixture of ketoester llg (21 g), zinc (6 g), and catalytic amount of iodine in benzene (400 ml) was added dropwise ethyl bromoacetate (15 ml) and the reaction mixture was refluxed for 8 hr. Work up and purification as given in example 1 furnished 20 g (71% yield) of ß-hydroxyester 13f. α,ß-Unsaturated ester 15f (formula 15, R1 = R2 = H, X = OMe)
ß-Hydroxyester 13f (20 g) was dehydrated with P205 in refluxing benzene as above and the crude product was purified by column chromatography on silica gel to furnish 10.5 g (55%) of α,ß-unsaturated ester 15f. Allylic alcohol 17f (formula 17, R1 = R2 = H ; X = OMe)
α,ß-Unsaturated ester 15f (1.2 g) was reduced with LiAlH4, (240 mg) in dry ether (25 ml) at 0°C. Work and purification was done according to the procedure as given above to give 260 mg (29% yield) of allylic alcohol 17f. Trioxane 27f (formula 27, R1=R2 =H ; X = OMe)
A solution of allylic alcohol 17f (550 mg), adamantanone (540 mg) and methylene blue (15 mg) in CH3CN (40 ml) was photooxygenated as above for 6 h. to give ß-hydroxyhydroperoxide 19f (formula 19, R1 = R2 = H, X = OMe) as indicated by TLC. To this reaction mixture was added p-toluenesulfonic acid (20 mg) and was left at room temperature overnight. Workup as above followed by chromatography on silica gel furnished 180 mg (19% yield based on the allylic alcohol 17f used) of 1,2,3-trioxane 27f. Hemisuccinate for trioxane 27f (compound 4 If, formula 41, R1 = R2 = H, X = OMe)
Hemisuccinate 41f was prepared from trioxane 27f in 80% yield following the procedure used for preparation of compound 41a as given in example 5.

Example 14
Ketoester llg (formula 11, R1 = R2 = Me, X = OMe)
A mixture of 4-hydroxy-3-methoxyaeetophenone (15 g) ethyl 2-bromoisobutyrate (22 ml) and K2CO3 (45 g) in acetone (450 ml) was refluxed for 27 h. Most of the solvent was distilled off and the reminder was diluted with water and extracted with ether, ether extract dried on Na2S04 and concentrated. The crude product was chromatographyed on silica gel (elution with 5% ethylacetate in hexane) to furnish 4.41 g (18% yield) of ketoester llg as an oil. ß-Hydroxyester 13g (formula 13, R1 ,= R2 =Me, X = OMe)
A mixture of ketoester llg (4.4 g), zinc (3 g) and ethyl bromoacetate (2.5 g) in benzene was refluxed for 7 hr. Work up as above to give 6.0 g of crude product which was used in the next step without purification. α,ß-Unsaturated ester 15g (formula 15, R1= R2 = Me, X = OMe)
ß-Hydroxyester 13g (crude product 6.0 g as obtained above) was dissolved in benzene (100 ml), I2 (40 mg) was added the reaction mixture was refluxed for 6 hr. Workup and purification effected as above furnished 2.7 g (49% yield, based on ketoester llg) of α,ß-unsaturated ester 15g as an oil. Allylic alcohol 17g (formula 17, R1 = R2 = Me ; X = OMe)
α,ß-Unsaturated ester 15g ( 1.9 g) was reduced with LiAlH4(1.8 g) in dry ether at 0°C as above. Normal workup followed by chromatography furnished 1.1 g (76% yield) of allylic alcohol 17g as an oil. Trioxane 27g (formula 27, R1= R2 = Me ; X - OMe)
A solution of allylic alcohol 17g (1.1 g) and memylene blue (20 mg) in acetonitrile (50 ml) was photooxygenated as above at 0°C for 7 h. to give p-hydroxyhydroperoxide 19g (formula 19, R1= R2 = Me, X = OMe) as indicated by TLC. The reaction mixture was divided into two equal parts. One part was reacted with 2-adamantanone (500 mg) in presence of cone. HC1 (4 drops) at room temperature overnight. Usual workup followed by chromatography furnished 300 mg (34% yield based on the alcohol 17g used) of trioxane 27g as thick oil. Example 15 Trioxane 23gl (formula 23, R1= R2 = Me ; X = OMe ; R3, R4 = -CH2CH2CH2CH2-)
The other half of the reaction mixture as obtained in the above experiment was reacted with cyclopentanone (1 ml) in presence of cone. HC1 (5 drops) at r.t. overnight. Usual workup followed by purification furnished 210 mg (28% yield based on alcohol 17g) of trioxane 23gl.

Example 16
Ketoester 12a (formula 12, R1 = R2 = H)
A mixture of 3-hydroxyacetophenone (5 g), ethyl chloroacetate (5.6 ml) and K2C03 (7.5 g) was heated at 65°C with stirring for 13 h. It was cooled to room temperature, diluted with water (50 ml) and extracted with ether (2 x 100 ml). Ether extract was washed with water (3 x 50 ml), dried (Na2SO4), concentrated and chromatographyed on silica gel using 50% ethylacetate - hexane as eluant to give 4.52 g (49% yield) of ketoester 12a as an oil. α,ß-Unsaturated ester 16a (formula 16, R1 = R2 = H)
To a refluxing mixture of ketoester 12a (15 g), zinc (6 g), iodine (70 mg) in benzene (350 ml) was added dropwise ethyl bromoacetate (8 ml) and the reaction mixture was refluxed for 9 hr. The reaction mixture was cooled, acidified with aqueous 10% HC1, benzene layer was separated and the aqueous layer was extracted with benzene. The combined benzene extract was washed with water, aqueous NaHC03, dried (Na2SO4) and concentrated to give 14a which was dehydrated with P203 (5 g) using the procedure as given in example 7, and the final product was purified by column chromatography on silica gel (hexane - ethylacetate as eiuant) to furnish 14.75 g (45% based on 12a) of 16a as an oil. Allylic alcohol 18a (formula 18, R1= R2 = H)
To a stirred and ice-cooled mixture of LiAlH4 (8 g) in dry ether (400 ml) was added dropwise a solution of a,p-unsaturated ester 16a (11 g) in dry ether and stirred the reaction mixture in ice bath for 6 h. It was quenched with H2O and 10% NaOH. The organic layer was separated and the residue was washed with ether. The combined ether extract was dried (Na2SO4), concentrated and purified by column chromatography on silica gel using hexane - ethylacetate as eluant to give 5.8 g (74% yield) of allylic alcohol 18a. Trioxane 24a 1 (formula 24, R1= R2 - H ; R3, R4= CH2CH2CH2CH2)
A solution of allylic alcohol 18a (1.0 g) and Rose Bengal (5 mg) in acetonitrile (65 mg) was photooxygenated at 0°C for 7 h. to give p-hydroxyhydroperoxide 20a (formula 20, R1 = R2 = H) as indicated by TLC. To this reaction mixture were added cyclopentanone (1.5 ml) and p-toluenesulfonicacid (15 mg) and the reaction mixture was stirred at room temperature for 4 h. Workup as above followed by chromatography on silica gel column furnished 600 mg (43% yield based on allylic alcohol 18a) of trioxane 24al.

Hemisuccinate of trioxane 24al (compound 38al, formula 38, R1 = R2 = H ; R3 = R4 = CH2CH2CH2CH2)
A solution trioxane 24al (600 mg) and succinic anhydride (2.0 g) in pyridine (5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ether. The ether extract was washed with water, 10% aqueous HC1, water, dried (Na2S04) anc concentrated. The crude product on purified by chromatography on silica gel using CH2C12 - ether as eluant furnished 780 mg (98% yield) of hemisuccinate 38al. Example 17 Trioxane 28a (formula 28, R1= R2= H)
A solution of allylic alcohol 18a (1.0 g) and methylene blue (5 mg) in CH2CI2 (65 mg) was photooxygenated as above at 0°C for 10 h. To the reaction mixture were added 2-adamantanone (1 g) and p-toiuenesulfonic acid (15 mg) and the reaction mixture was kept at room temperature overnight. Usual workup as above followed by purification by chromatography on silica gel column furnished 350 mg (21% yield based on allylic alcohol 18a) of trioxane 28a as a thick oil. Hemisuccinate for trioxane 28a (compound 42a, formula 42, R1 = R2 = H)
Hemisuccinate 42a was prepared in 91% yield by reacting trioxane 28a with succinic anhydride following procedure as given in the above example. Example 18 Ketoester 12b (formula 12, R1 = R2 = Me)
A mixture of 3-hydroxyacetophenone (5 g) ethyl 2-bromoisobutyrate (5.4 ml) and K2CO3 (7.5 g) was heated at 120°C for 6 h. The reaction mixture was diluted with water, extracted with ether. Ether extract was washed with water, dried, concentrated and chromatographyed on silica gel to furnish 1.82 g (22% yield) of ketoester 12b as an oil. α,ß-Unsaturated ester 16b (formula 16, R1 = R2 = Me)
To arefluxing mixture of ketoester 12b (14.6 g), zinc (7.3 g) and iodine (50 mg) in benzene (400 ml) was added dropwise a solution of ethyl bromoacetate (7.3 ml) in benzene (50 ml) and the reaction mixture was refluxed for 14.5 hr. when it was cooled, acidified with 10% aqueous HC1. Benzene layer was separated, washed with aqueous NaHCO3, dried and concentrated to give -hydroxy ester 14b which was used in the next step without purification.

The crude p-hydroxyester 14b as obtained above was dissolved in benzene (500 ml), P2O5(10 g) was added and the mixture was refluxed for 3 h. Usual workup followed by chromatography furnished α,ß-unsaturated ester 16b (7 g, 42% yield based on 12b). Allyttc alcohol 18b (formula 18, R1 = R2 = Me)
To a stirred and ice-cooled mixture of LiAltit (3.2 g) in dry ether (450 ml) was added a solution of α,ß-unsaturated 16b (3.6 g). The reaction mixture was stirred for 2.5 h. in ice bath. It was quenched with water and 10% aqueous NaOH. Ether layer was separated and concentrated to give 2.6 g of residue which was chromatographed on silica gel to give 2.3 g (86% yield) of allylic alcohol 18b. Trioxane 24bl (formula 24, R1 = R2 - Me ; R3, R4 = CH2CH2CH2CH2)
A mixture of allylic alcohol 18b (300 mg) and methylene blue (20 mg) in CH3CN (40 ml) was photooxygenated at 0°C for 5.5 h. to give ß-hydroxyhydroperoxide 20b (formula 26, R1 = R2 = Me) as indicated by TLC. The reaction mixture was divided in two equal parts. To one-half of this reraction were added cyclopentanone of (1 ml) and FTSA (40 mg) and the reaction mixture was stirred at room temperature for 5 h. Usual workup followed by chromatography on silica gel furnished 170 mg (81% yield based on alcohol 18b) of trioxane 24bl.
Hemisuccinate for trioxane 24bl (compound 38bl, formula 38, R1 = R2 = Me ; R3, R4 = CH2CH2CH2CH2)
To an ice-cooled solution of trioxane 24bl (200 mg) and succinc anhydride (400 mg) in CH2C12 (20 ml) were added Et3N (1 ml) and 4-dimethylamino-pyridine (DMAP, 20 mg) and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under vacuum, acidified with 10% aq. HC1 and extracted with ether. Ether extract was washed with water, concentrated and purified by chromatography on silica gel to give 230 mg (92% yield) of compound 38bl as an oil. Trioxane 24b2 (formula 24, R1 = R2 - Me, R3, R4 = CH2CH2CH2CH2CH2)
To the other half of the photooxygenated mixture obtained as in the above experiment were added cyclohexanone (1 ml) and PTSA (40 mg) and the reaction mixture was stirred at r.t. for 5 h. Workup and chromatography on silica gel column as above furnished 110 mg (50% yield based on alcohol 18b) of trioxane 24b2.

Hemisuccinate for trioxane 24b2 (compound 38b2, formula 38, R1 = R2 = Me ; R3, R4 = CH2CH2CH2CH2 CH2)
Trioxane 24b2 (250 mg) was reacted with succinc anhydride (350 mg) in CH2C12 (20 ml) as above and the crude product was purified by chromatography on silica gel using 25% ether in CH2C12 as eluant to give 280 mg (87% yield) of compound 38b2 as an oil. Example 19 Trioxane 28b (formula 28, R1= R2 = Me)
A solution of allylic alcohol 18b (300 mg) and methylene blue (70 mg) in CH3CN (30 ml) was photooxygenated at -8°C for 6 h. To the reaction mixture were added 2-adamantanone (300 mg) and p-toluenesulibnic acid (50 mg) and left at room temperature overnight. The solvent was removed under vacuum and the residue was diluted with aq. NaHC03 and water and extracted with ether. The ether -extract was washed with water, dried, concentrated and chromatographed on silica gel to furnish 310 mg (62% yield) of trioxane 28b as an oil. Hemisuccinate of trioxane 28b [compound 42b, formula 42, R1 = R2 = Me]
To a stirred ice-cooled mixture of trioxane 28b (100 mg) and succinic anhydride (200 mg) in CH2C12 (10 ml) were added triethylamine (0.5 ml) and 4-dimethylamino pyridine (20 mg) and the reaction mixture was stirred at r.t. for 3 hr. The reaction mixture was concentrated under reduced pressure, acidified with 10% aquoeus HC1 and extracted with ether (2 x 20 ml). The ether extract was washed with water dried (Na2S04), concentrated and purified by column chromatography on silica gel to give 100 mg (80% yield) of hemisuccinate 42b as a thick oil. Example 20 Ketoester 11c (formula 11, R1 = H, R2 = Me, X = H)
A mixture of 4-hydroxyacetophenone (5 g), ethyl 2-bromopropionate (5 ml) and K2CO3 (7.5 g) was heated at 120°C for 7.5 h. The reaction mixture was extracted with ether, washed with water, dried, concentrated and chromatographed on silica gel to furnish 1.8 g (21% yield) of l1c, m.p. 64-72°C. α,ß-Unsaturated ester 15c (formula 15, R1 = H, R2 = Me, X = H)
To a refluxing mixture of ketoester lic (25 g), Zn (6.5 g) and iodine (50 mg) in benzene (250 ml) was added dropwise ethyl bormoacetate (12 ml) and the reaction mixture was refluxed for 7 h. The crude product (13c) obtained after usual workup was dehydrated with iodine (2 g) in benzene (100 ml) by refluxing for 4 h. The reaction mixture was washed with a slution of sodium thiosulphate, concentrated and purified by chromatography on silica gel to give 14.6 g (47% yield) of 15c as an oil.

Allylic alcohol 17c (formula 17, R1 = H, R2 - Me, X = H)
α,ß-Unsaturated ester 15c (5.0 g) was reduced with LiAlH4 (3 g) in dry ether (250 ml) as above to give 2.7 g allylic alcohol 17c. Trioxane 25c (formula 25, R1= Me. R2 = X = II)
A solution of allylic alcohol 17c (1.5 g) and methylene blue (10 mg) in CH2CN (45 ml) was photooxygenated as above for 6 h. to give p-hydroxyhydroperoxide 19c (formula 19, R1= Me ; R2 - X = H). One third (corresponding to 500 mg of lOc) was taken and reacted with norcomphor (1.0 g) in presence of catalytic amount of p-toluenesulfonic acid at r.t. for 3 h. Usual workup followed by chromatography on silica gel column furnished 300 mg (38% yield based on the allylic alcohol 17c used) of trioxane 25c. Example 21 Ketoester 11d (formula 11, R1=H, R2 = Et, X =H)
A mixture of 4-hydroxyacetophenone (5.0 g), ethyl 2-bromobutyrate (5 ml) and K2C03 (7.5 g) was heated at 120°C for 7.5 h, Workup followed by purification of the crude product as above (example 20) furnished 3.9 g (42% yield) of compound 11d as an oil. α,ß-Unsaturated ester 15d (formula 15, R1 = H, R2 = Et, X = H)
To a refluxing mixture of ketoester lid (3.5 g), Zinc (2.0 g), iodine (50 mg) in benzene (50 ml) was added ethyl bormoacetate (1.5 ml) and the reaction mixture was refluxed for 5 h. It was acidified with 10% HC1, benzene layer was separated and concentrated and the crude product was purified by chromatography to give 2.45 g (52% yield) of 13d. Compound 13d (2.4 g) was dehydrated in refluxing benzene using P2O5 as catalyst Workup followed by column chromatography on silica gel as above furnished 2.0 g (88% yield) of ester 15d as an oil. Allylic alcohol 17d (formula 17, R1= H ; R2 = Et; X = H)
α,ß-Unsaturated ester 15d (2.7 g) was reduced with LiAlH4 (1.5 g) in dry ether (150 ml) and the crude product was purified by chromatography on silica gel using hexane - ethylacetate as eluant to give 1.2 g of allylic alcohol 17d. Trioxane 27d (formula 27, R1= Et, R2 = X = H)
A solution of allylic alcohol 17d (1.2 g) and methylene blue (10 mg) in CH3CN (40 ml) was photooxygenated as above for 7 h. to give ß-hydroxyhydroperoxide 19d (formula 19, R1 = Et; R2 = X = H) as indicated by TLC. To one half of this reaction mixture were added adamantanone (600 mg) and PTSA (10 mg) and the reaction mixture was stirred at r.t. for 2 h. Usual workup followed by

chromatography on silica gel furnished 300 mg (30% yield based on the allylic alcohol 17d used) of
trioxane 27d as oil.
Example 22
Ketoester 11e (formula 11, R1= H, R2 = n-pentyl, X = H)
A mixture of 4-hydroxyacetophenone (5.0 g), ethyl 2-bromoheptanoate (8.3 g) and K2CO3 was heated at 120°C for 7.5 h. The reaction mixture was extracted with ether. Ether extract was washed with water, dried, concentrated and chromatographed on silica gel to furnish 9.1 g (89% yield) of compound 11e, as an oil. α,ß-Unsaturated ester 15e (formula 15, R1 = H, R2 = n-pentyl, X = H)
To a refluxing mixture of ketoester He (25 g), Zn (7.5 g), iodine (100 mg) in benzene (450 ml) was added ethyl bormoacetate (9 ml) dropwise and the resulting mixture was refluxed for 5.5 h. It was acidified with 10% HC1, benzene layer was separated, washed with aq. NaHC03 solution, dried and concentrated to give ß-hydroxy-ester 13e which was used without purification in the next step.
Crude product 13e as obtained above was dissolved in benzene (350 ml), iodine (100 mg) was added and the mixture was refluxed for 2.5 h. The reaction mixture was washed with a solution of sodium thiosulphate, dried, concentrated and chromatographed on silica gel (elution with 5% ethyl acetate -hexane) to give 22.1 g (71% yield) of α,ß-unsaturated ester 15e as an oil. Allylic alcohol 17e (formula 17, R1 = H ; R2 = n-pentyl; X = H)
α,ß-Unsaturated ester 15e (12 g) was reduced with LiAlH, (10 g) in dry ether (600 ml) at 0°C as above to give 8.3 g of crude product which was purified by chromatography on silica gel to furnish 6.5 g (71% yield) of allylic alcohol 17e. Trioxane 23el (formula 23, R1 = CH2CH2CH2CH2CH3 ; R2 = X = H, R3, R4 = -CH2CH2CH2CH2-)
A solution of alcohol 17e (2 g) and methylene blue (100 mg) in CH3CN (60 ml) was photooxygenated at 0°C for 4.5 h. to give p-hydroxyhydroperoxide 19e (formula 19, RI = CH2CH2CH2CH2CH3; R2 = X = H) as indicated by TLC. One half this photooxygenated reaction mixture was reacted with cyclopentanone (2 ml) in presence of PTSA (50 mg) at r.t. for 5.5 h. Usual workup and chromatography on silica gel column to furnish 610 mg (45% yield based on allylic alcohol 17e used) of trioxane 23el. Trioxane 27e (formula 27, R1= CH2CH2CH2CH2CH3 ; R2 = X = H)
To the other half of the photooxygenated mixture as obtained in the above example were added 2-adamantanone (1 g) and PTSA (50 mg) and the reaction mixuture was stirred at r.t. for 5 h. Usual workup

followed by chromatography on silica gel column using hexane - ethylacetate as eluant furnished 780 mg (76% yield based on allylic alcohol 17e used) of trioxane 27e as a thick oil. Hemisuccinate of trioxane 27e [compound 41e, formula 41, R| = H, R2 - n-pentyl; X * H]
To a stirred and ice-cooled mixture of trioxane 27 e (200 mg) and succinic anhydride (200 mg) in CH2C12 (20 ml) were added triethylamine (0.5 ml) and 4-dimethylamino pyridine (20 mg) and the reaction mixture was stirred at r.t. for 1.5 h. Workup as above followed by purification by column chromatography on silica gel furnished 200 mg (82% yield) of hemisuccinate 41eas a colourless oil.
Using the above procedures the following hydroxy-fiinctionalized trioxane and their esters were also prepared.
Trioxane 23a4 (formula 23, R1 = R2 = X = H; R3, R4 = Me, Et) ; 36% yield Trioxane 23aS (formula 23, R1 = R2 = X = H, R3,R4 = Me, CH2CH2CH3); 43% yield Trioxane 23a6 (fonnula 23R1 = R2 = X = H, R3, R4 = Me, CH2CHMe2); 29% yield Trioxane 23a7 (formula 23, R1 = R2 = X = H, R3 = R4= n-propyl); 21% yield Trioxane 23a8 (formula 23, R1 = R2 = X = H, R3 = R4= n-butyl) ; 11% yield Trioxane 23a9 (formula 23, R1 = R2 = X = H, R3 = R4 = n-pentyl); 16% yield Trioxane 23alO (formula 23, R1 = R2 = X = H, R3, R4= -CH3(CH2)9-CH2-); 16% yield Trioxane 23all (formula 23, R1 = R2 = X = H, R3,R4 = -CH2-CH2-CO-CH2-CH2); 6% yield Trioxane 23al2 (formula 23, R1 = R2 = X = H, R3, R4 = H, -C6H5); 45% yield Trioxane 23al3 (formula 23, R1 = R2 = X = H, R3, R4= H, 1-naphthyl); 38% yield Trioxane 23b3 (formula 23, R1 = R2 = Me, X = H, R3, R4= H, 1-naphthyl); 7% yield Trioxane 23b4 (formula 23, R1 = R2 = Me, X = H, R3, R4 = CH2(CH2)4-CH2); 15% yield Trioxane 23cl (formula 23, R1 R2 = H, Me ; X = H, R3, R4 = -CH2-CH2-CH2-CH2-); 42% yield Trioxane 23c2 (formula 23, R1 R2 = H, Me ; X = H, R3, R4 = -CH2-(CH2)3-CH2); 46% yield Trioxane 23dl (formula 23, R1 , R2 = H, Et; X = H, R3, R4= -CHrCH2-CH2-CH2-); 33% yield Trioxane 23e2 (formula 23,R1 R2 = H, n-pentyl; X = H, R3, R4 = -CHr(CH2)3-CH2); 54% yield Trioxane 23e3 (formula 23, R1 R2 = H, n-pentyl; X = H, R3, , R4 = -CH2-(CH2)4-CH2); 38% yield Trioxane 23e4 (formula 23, R1 R2 = H, n-pentyl; X = H, R3, , R4 = -CH2-(CH2)3-CH2); 15% yield Trioxane 23e5 (formula 23, R1 R2 = H, n-pentyl; X - H, R3, , R4 = Me); 54% yield Trioxane 23fl (formula 23,R1 = R2 = H; X = OMe ; R3, , R4 =-CH2-CH2-CH2-CH2); 27% yield Trioxane 23f2 (formula 23, R1 = R2 = H; X = OMe, R3,, R4 = -CH2-(CH2) 3-CH2); 16% yield Trioxane 23gl (formula 23, R1 = R2 = Me ; X = OMe, R3, R4 = -CH2-CH2-CH2-CHr); 28% yield

Trioxane 24a2 (formula 24, R1 =R2 = H ; R3, R4 = -CH2(CH2)3CH2); 41% yield
Trioxane 24a3 (formula 24, R1 = R2 = H; R3, R4=-CH2(CH2)4-CH2); 60% yield
Trioxane 24b3 (formula 24, R1 - R2 = Me ; R3, R4 = H, 1-naphthyl); 24% yield
Trioxane 25a (formula 25, R1 = R2 = H); 34% yield
Trioxane 25c (formula 25, R1 R2 = H, Me); 39% yield
Trioxane 25d (formula 25, R1 R2 = H, Et); 15% yield
Trioxane 25e (formula 25, R1 R2 = H, n-pentyl); 35% yield
Trioxane 26a (formula 26, R1 R2 = H); 23% yield
Trioxane 26b (formula 26, R1 R2 = Me); 53% yield
Trioxane 27c (formula 27, R1 R2 - H, Me); 39% yield
Trioxane 28b (formula 28, R1 R2 = Me); 27% yield
Compound 31a2 (formula 31; R1 = R2 - X = H; R3, R4 = -CH2-CH2-CH2-CH2-; R5 = Et); 80% yield
Compound 31a3 (formula 31 ;R1 = R2 = X = H ; R3,R4 = -CHrCH2-CH2-CH2-; R5 = n-Pr); 78% yield
Compound 31a4 (formula 31;R1 = R2 - X = H ; R3, R4 = -CH2-CH2-CH2-CH2- ; R3 = n-hexyl) ; 75%
yield Compound 31a5 (formula 31; R1 = R2 = X = H ; R3, R4 = -CH2-CH2-CH2-CH2-; R5 = phenyl); 42%
yield
Compound 31a6 (formula 31;R1 = R2 = X = H; R3, R4 = H, 1-naphthyl; R5 = CH3); 36% yield Compound 31bl (formula 31; R1 = R2 = Me, X = H; R3, R4 = H, 1-naphthyl; R5 = CH3); 90% yield Compound 32bl (formula 32R1 = R2 = Me ; R3, R4 = -CH2-CH2-CH2-CHr ; R5 = Me); 89% yield Compound 32b2 (formula 32; R1 = R2 - Me ; R3, R4 = -CH2-(CH2)3-CH2-; R5 = Me); 86% yield Compound 32b3 (formula 32;R1 = R2 = Me ; R3, R4 = H, 1-naphthyl; R3 = Me); 73% yield Compound 33al (formula 33 ; R1 = R2 = X = H; R5 = Me); 82% yield Compound 33a2 (formula 33 ; R1 = R2 = X = H; R5 = Et); 76% yield Compound 33a3 (formula 33 ; R1 = R2 = X = H; R5 = n-hexyl); 83% yield Compound 34b (formula 34 ; R1 = R2 = Me, R3 = Me); 94% yield Compound 35b3 (formula 35; R1 = R2 = Me ; X = H; R5 = n-Pr) ; 57% yield Compound 35b5 (formula 35 ; R1 = R2 = Me ; X = H; R3 = n-hexyl); 95% yield Compound 36b (formula 36 ; R1 = R2 = R3 = Me); 91% yield
Compound 37al (formula 37 ; R1 = R2 = X = H; R3, R4 = -CH2-CH2-CH2-CH2-); 87% yield Compound 37a2 (fonnula 37 ; R1 = R2 = X = H; R3,R4 = -CH2-(CH2)3-CH2-); 40% yield

Compound 37a3 (fonnula 37 ; R1 = R2 = X = H; R3 = R4 = Me); 70% yield Compound 37a4 (formula 37 ; R1 = R2 = X = H; R3 = R4 = H, 1-naphtfiyl); 66% yield Compound 37b2 (formula 37 ; R1= R2 = Me, X = H; R3, R4 = -CH2-(CH2)3-CH2-); 86% yield Compound 37b3 (formula 37 ; R1= R2 = Me, X = H; R3, R4 = H, 1-naphthyl): 66% yield Compound 37el (formula 37 ; R1R2 = H, n-penthyl, X = H; R3,R4 = -CH2CH2CH2CH2-); 79% yield Compound 37fl (formula 37 R1 = R2 = H, X = OMe ; R3R4 = -CHrCHrCH2-CHr); 76% yield Compound 38a2 (formula 38; R1= R2 = H; R3, R4 = -CH2 (CH2)3-CH2-); 90% yield Compound 38bl (formula 38 ; R1= R2 = Me ; R3,R4 = -CHrCH2-CHrCH2-); 92% yield Compound 38b2 (formula 38 ; R1= R2 = Me ; R3, R4 = -CH2(CH2)3-CH2-); 88% yield Compound 38b3 (formula 38 ; R1= R2 = Me ; R3, R4 = H, 1-naphthyl); 87% yield Compound 39a (formula 39 ; R1 = R2 = X = H); 97% yield Compound 40b (formula 40 ;R1 = R2 = Me); 96% yield Compound 4 If (formula 41;R1=R2 = H;X = OMe); 80% yield Compound 41g (formula 41; R1 = R2 = Me, X = OMe) Compound 42a (formula 42; R1= R2 = H); 91% yield

Antimalarial Activity
The antimalariaJ activity of the test compounds was evaluated in rodent using multidrug resistant strain of lasmodiumyoeiii Nigeriensis in swiss mice.
General Procedure : Random bred swiss mice of either sex (20 ± 2 gm) were inoculated intraperitoneally with 1 x 105 P. yoelil (MDR) parasites on day zero. The treatment with test compounds were administered to groups of 6 mice each at different dose levels ranging between 24-96 mg/kg/day. The trioxanes were dissolved in groundnut oil (or 50% sodium bicarbonate solutions in case of hemisuccinate derivatives) and were administered via intramuscular or oral route for 4 consecutive days (day 0-3).
Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular interval till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the percent suppression of parasitaemia in treated groups was calculated.
For determingthe curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been recorded as the curative dose. The antimalarial data is summarized in Table-4.

Table 4 : Antimalarial activity of substituted trioxanes against multi drug resistant strain of Plasmodium yoelii Nigeriensis in swiss mice

(Table Removed)

Trioxane 27 a, 27b ande their hemisuccinates 4la and 41b were evaluated for blood schizontocidal activity against Plasmodium cynomolgi and Plasmodium knowlesi in Rhesus monkeys using the following protocol:
For activity against P. cynomolgi, rhesus monkeys were inoculated intravenously with 1 x 103 parasitized RBC and the treatment was initiated when the parasitaemia level reached above 0.5%. For activity against P. knowlesi the rhesus monkeys were inoculated intravenously with 1 x 104 parasitized RBC and the treatment was initiated at 0.1% parasitaemia level.
Compounds 27a and 27b were dissolved in groundnut oil and administered in various regimens for 3-5 days via oral or intramuscular (im) routes. Hemisuccinates 4la and 41b were dissolved in 5% bicarbonate solution and administered similarly by oral, im or iv routes.
The blood smears from the treated monkeys were examined once daily to record parasitaemia clearance time and subsequent recurrence of parasitaemia. The animals in which no recrudescence was observed upto day 60 were recorded as cured. The antimalarial data is summerized in table 5 and table 6.
Table 5 : Antimalarial activity of trioxanes against Plasmodium cynomolgi in rhesus monkey model
(Table Removed)
Table 6 : Antimalarial activity of trioxanes against P. knowlesi in rhesus monkey model

(Table Removed)
Gametocytocidal Activity
Compounds 27a and 41a were also tested for gametocytocidal activity according to the following protocol:
Different batches of 3 to 4 days old naive Anopheles stephensis mosquitoes are allowed to engorge blood from gametocyte carrying infected host (rhesus monkey infected with P. cynomolgi or hamster infected with P. yoelii) at different time intervals prior to and after administration with a single dose of the test compound. The blood fed mosquitoes were maintained for the next 7-10 days in an insectorium to allow development of oocysts. A comparison of mosquito infectively rate and oocyst numbers in pre-treatment versus post-treatment provided index for gametocytocidal potential of the test agent.
Compound 27a and 4 la showed complete loss of infectivity in mosquito batches fed 24 h post-treatment with 50 mg/kg (im, single dose) in P. yoelii model and 20 mg/kg (im, single dose) or 30 mg/kg (oral, single dose) in P. cynomolgi model.

We claim :
1, Novel substituted 1,2,4-trioxanes useful as anti malarial agent of formula 1 wherein R1, R2 are hydrogen, alkyl group such as methyl, ethyl, propyl; R3, R4 are hydrogen, alkyl group such as methyl, ethyl, aryl such as phenyl, naphthyl, R5 is hydrogen, alkyl group such as methyl, ethyl, propyl, aryl such as phenyl, or carboxyalkyl group such as CH2CH2CO2H ; Z is O or OCO.
(Formula Removed)
2. Novel trioxanes as claimed in claim 1 wherein the said compounds having structural formulae 23a1-23a13, 23b1-23b3, 23c1-23c2, 23d1, 23e1-23e5, 23f 1-2312, 23g1 as shown below.
(Formula Removed)

23a1 R1, R2 = H,H: X=H;X=H; R3, R4 =CH2CH2CH2CH2
23a2 R1, R2 =H,, H; X = H; R3 ,R4 = CH2CH2CH2CH2CH2
23a3 R1,R2 = H, H; X = H; R3,R4 =Me, Me
23a4 R1,R2 = H,H;X = H;R3,R4-Me,Et
23a5 R1,R2 = H, H ; X = H ; R3, R4 = Me, CH2CH2CH3
23a6 R1, R2 = H, H ; X = H ; R3l R4 - Me, CH2CHMe2
23a7 V R2 = H, H ; X = H ; R3, R4 = n-propyl, n-propyl
23a8 R1, R2 - H, H ; X = H; R3, R4 = n-butyl, n-butyl
23a9 R1, R2 = H, H ; X = H ; R3, R4 = n-pentyl, n-pentyl
23a10 R1, R2 - H, H; X = H; R3, R4 =CH2-(CH2)9-CH2-
23a11 R1, R2 = H, H; X = H; R3, R4 = CH2CH2-CO- CH2CH2
23a12 R1, R2-H,H;X = H; R3, R4 = H, phenyl
23a13 R1,R2 - H, H; X = H ; R3, R4, = H, 1-naphthyl
23b1 R1,R2 - Me, Me ; X = H; R3, R4 = CH2CH2CH2CH2
23b2 R1, R2 - Me, Me ; X = H; R3, R4 - CH2CH2CH2CH2CH2
23b3 R1,R2 = Me, Me ; X - H ; R3, R4 - H, 1-naphthyl
23c1 R1,R2 = H, Me; X - H; R3, R4 = CH2CH2CH2CH2
23c2 R1, R2 = H, Me ; X = H ; R3, R4 - CH2CH2CH2CH2CH2
23d1 R1, R2 - H, Et; X = H ; R3, R4 - CH2CH2CH2CH2
23e1 R1, R2 = H, n-pentyl; X = H ; R3, R4 = CH2CH2CH2CH2
23e2 R1, R2 = H, n-pentyl; X = H ; R3, R4, = CH2CH2CH2CH2CH2
23e3 R1,R2 - H, n-pentyl; X - H ; R3, R4, = - CH2(CH2)4CH2
23e4 V R2 = H, n-pentyl; X - H ; R3, R4 =- CH2(CH2)3CH2
23e5 R1, R2 - H, n-pentyi; X = H; R3, R4 = Me, Me
23f1,R1, R2 = H, H; X = OMe ; R3, R4 = - CH2CH2CH2CH2
23f2 R1,R2 - H, H ; X - OMe ; R3, R4 = CH2-(CH2) 3-CH2
23g1 RR1,R2 = Me, Me ; X = OMe ; R3, R4 = CH2CH2CH2CH2
3. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 24a1, 24b1, 24b3 as shown below.

(Formula Removed)
Formula 24
24a1 R1,R2 = H, H;R3, R4 = CH2CH2CH2CH2 24a2 R1,R2 = H,H; R3, R4 = CH2-(CH2)3-CH2 24a3 R1,R2 = H,H; R3, R4=CH2-(CH2)4-CH2
24b1 R1, R2=Me, Me; R3, R4-CH2CH2CH2CH2 (24b2 )R1,R2 =Me, Me; R3, R4 = CH2CH2CH2CH2CH2
24b3 R1,R2=Me, Me; R3, R4=H,1-naphthyl
4. Novel trioxanes as claimed in claim 1 wherein the said compounds having the
structural formulae 25a, 25c, 25d, 25e as shown below.
(Formula Removed)
Formula 25
25a R1,R2 = H, H,X= H
25c R1,R2 =H, Me, X=H
25d R1,R2 = H, Et, X = H
25e R1, R2 = H, n-phenyl, X - H
5. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 26a, 26b as shown below.

(Formula Removed)
Formula 26
26a R1, R2 = H, H
26b R1,R2 =Me, Me
6. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 27a, 27b, 27c, 27d, 27e, 27f, 27g as shown below.
(Formula Removed)
Formula 27
27a R1, R2=H, H;X = H
27b R1,R2 = Me, Me; X = H
27c R1,R2= H,Me;X=H
27d R1,R2 = H,Et;X=H
27e R1,R2 = H,n-pentyl;X = H
27f R1,R2= H,H;X-OMe
27g R1,R2 = Me, Me;X = OMe
7. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 28a, 28b as shown below.

(Formula Removed)
Formula 28 28aR1,R2=H, H 28b R1,R2 =Me, Me
8. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 31a1-31a6, 31b1 as shown below,
(Formula Removed)
Formula 31
31 a1 R1, R2 =H, H; X= H; R3, R4 = CH2CH2CH2CH2; R3 = CH3 31a2 R1,R2= H,H;X = H; R3, R4 = CH2CH2CH2CH2; R5 = Et 31 a3 R1,R2 = H, H; X = H; R3, R4 = CH2CH2CH2CH2; R5 = n-propyl 31 a4 R1, R2 = H, H ; X = H ; R3, R4 = CH2CH2CH2CH2; R5 = n-hexyl 31 a5 R1, R2 =H, H; X = H; R3, R4 = CH2CH2CH2CH2; R5 = Ph 31 a6 R1,R2 = H, H ; X = H ; R3, R4 = H, l-naphthyl; R5 = CH3 31 bl R1, R2 = Me, Me;X-H;R3,R4 = H, 1-naphthyl; R5 = Me
9. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 32b1-32b3 as shown below.

(Formula Removed)
Formula 32
32b1 R1, R2 = Me, Me ; R3, R4 = CH2CH2CH2CH2; R3 = Me 32b2 R1, R2 = Me, Me ; R3, R4 = CH2CH2CH2CH2CH2; R5 = Me 32b3 R1,R2 = Me, Me ; R3, R4 = H, l-naphthyl; R5 = Me
10. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 33a1-33a3 as shown below.
(Formula Removed)
Formula 33
33a1 R1, R2 = H,H;X = H;R5=Me 33a2 R1,R2=H,H;X=H;R5=Et 33a3 R1,R2 = H, H; X - H ; R5 = n-hexyl
11. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 34b as shown below.

(Formula Removed)
Formula 34
34b R1,R2 = Me, Me;R5, = Me
12. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 35a1, 35b1-35b5 as shown below.
(Formula Removed)
Formula 35
35a1 R1,R2 = H, H; X = H; R5 =-Me 35b1 R1, R2 = Me, Me; X = H; R5 = Me 35b2 R1,R2 = Me,Me;X=H;R5 = Et 35b3 RR1,R2 = Me, Me; X = H ; R5 = n-propyl 35b4 R1,R2 = Me, Me; X = H; R5 = n-pentyl 35b5 R1,R2 = MelMe;X=H;R5 = n-hexyl
13. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 36b as shown below.

(Formula Removed)
Formula 36
36b R1, R2 = Me, Me ; R5 = Me
14. Novel trioxanes as claimed in claim 1 wherein the said compounds having the
structural formulae 37a1-37a4, 37bl-37b3, 37el, 37fl as shown below.
(Formula Removed)
Formula 37 37a1 R1, R2 = H, H ; X = H ; R3, R4=CH2CH2CH2CH2
37a2 R1,R2 = H, H ; X = H ; R3, R4 = CH2CH2CH2CH2CH2 37a3 R1,R2 = H, H; X = H; R3, R4 = Me, Me 37a4 R1,R2 = H, H ; X = H; R3, R4 = H, 1-naphmyl 37b1 R1,R2=Me, Me;X=H ; R3, R4= CH2CH2CH2CH2 37b2 R1,R2=Me, Me;X= H ; R3, R4 = CH2CH2CH2CH2 37b3 R1,R2 = Me, Me ; X = H ; R3, R4, = H, 1-naphthyl 37e1 R1,R2=H,n-pentyl;X=H;R3,R4 = CH2CH2CH2CH2 37f1 R1,R2=H,H ; X = OMe ; R3, R4, = CH2CH2CH2CH2
15. Novel trioxanes as claimed in claim 1 wherein the said compounds having the
structural formulae 38a1-38a2, 38b1-38b3 as shown below.

(Formula Removed)
Formula 38
38a1 R1,R2 = H, H; R3, R4, = CH2CH2CH2CH2 38a2 R1,R2 = H, H; R3, R4 = CH2CH2CH2CH2CH2 38b1 R1, R2 = Me, Me ; R3, R4 = CH2CH2CH2CH2 38b2 R1,R2 = Me, Me ; R3> R4 = CH2CH2CH2CH2CH2
38b3 R1, R2 = Me, Me ; R3, R4 = H, 1-naphthyl
16. Novel trioxanes as claimed in claim 1 wherein the said compounds having the
structural formulae 39a as shown below.
(Formula Removed)
Formula 39a 39a R1,R2 = H, H;X = H
17. Novel trioxanes as claimed in claim 1 wherein the said compounds having
the structural formulae 40b as shown below.
(Formula Removed)

40bR1, R2 = Me, Me
18 Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 41 a, 41 b, 41 e, 41f, 41 g as shown below.
(Formula Removed)
Formula 41
41a R1,R2=H,H;X = H 41b R1,R2=Me, Me;X = H 41 e R1, R2 = H, n-pentyl; X = H 41f R1,R2 = H,H;X=OMe 41g R1,R2 = Me, Me;X = Ome
Formula 42
19. Novel trioxanes as claimed in claim 1 wherein the said compounds having the structural formulae 42a, 42b as shown below.

(Formula Removed)

42a R1,R2 = H, H 42b R1,R2 = Me, Me
20. A process for the preparation of novel substituted 1,2,4-trioxanes and their esters of general formula 1 which comprises
1) reacting hydroxyacetophenones of 2 wherein X represents hydrogen or lower alkoxy
such as OMe, with α-haloesters of formula 3 wherein RI and R2 represent hydrogen,
alkyl group such as methyl, ethyl, propyl and Y represents halogen such as Cl or Br, in
the presence of a base optionally in an organic solvent at a temperature in the range
range of room temperature to refluxing temperature to give keto-esters of general formula
4, wherein R1, R2 and X have the same meaning as above
2) reacting keto-esters of general formula 4 under Reformatsky condition in an
aprotic organic solvent in the temperature range of room temperature to refluxing
temperature to give ß.-hiydroxyesters of general formula 5, wherein RI, R2 and X have
the same meaning as above
3) dehydrating ß-hydroxyesters of formula 5 using a catalyst in an organic solvent at a
temperature in the range of room temperature to refluxing temperature to give α,ß -
unsaturated esters of general formula 6, wherein RI, R2 and X have the same meaning as
above
4) reducing ap-unsatu rated esters of general formula 6 with a complex metal hydride
such as LiAIH4 in an ether solvent at a temperature in the range of 0°C to room
temperature to give allylic alcohols of formula 7 wherein RI, R2, X have the same meaning
as above
5) oxygenation of allylic alcohols of formula 7 in presence of a sensitizer in an organic
solvent at a temperature in the range of -10°C to room temperature to give p-
hydroxyhydroperoxides of general formula 8 wherein RI, R2, X have the same meaning
above,
6) isolating and then reacting or reacting in situ ß-hydroxyhydroperoxides of formula 8

with compounds containing aldehyde or ketone group in presence of an acid catalyst in an organic solvent at a temperature in the range of 0°C to room temperature to give hydroxy-functionalized 1,2,4-trioxanes of general formula 1, wherein RI, R2 and X have the same meaning as above, R3, R4 are hydrogen, alkyl group such as methyl, propyl, aryl group such as phenyl, naphthyl or part of a cyclic system, R5 is H and Z is 0;
7) reacting hydroxy-functionalized trioxanes of general formula 1, wherein R is H and Z is O with an acid chloride or anhydrides in presence of a base in an organic solvent at a temperature in the range of 0°C to room temperature to give trioxane esters of general formula 1, wherein RI, R2, R3, R4 and X have the same meaning as above, R3 is alkyi group such as methyl, ethyl, propyl, aryl group such as phenyl, carboxyalkyl such as CH2CH2CO2H ; 2 is O-CO.
21. A process as claimed in claim 20, wherein the substituted acetophenones of
formula 2 are reacted with α-haloesters of formula 3 in presence of a base such as
KaHC03, Na2CO3, K2C03, in an organic solvent such as acetone, DMSO, DMF.
22. A process as claimed in claims 20-21 wherein Reformatsky reaction is carried out
by reacting ketoesters of formula 4 with ethyl bromoacetate and Zn in an aprotic
organic solvent such benzene, diethylether, THF.
23. A process as claimed in claims 20-22 wherein dehydration of ß-hydroxyesters
of formula 5 is effected in a hydrocarbon solvent such as benzene, toluene,
CH2C12, using a catalyst such as I2, P2O5, p-toluene-sulfornic acid, acidic resin
such as Amberlyst-15.
24. A process as claimed in claims 20-23 wherein the reduction of esters of formula 6
with LiAIH4, is carried out in an ether solvent such as diethyl ether, THF.
25. A process as claimed in claims 20-24 wherein the oxygenation is effected by
photooxygenation of allylic alcohols of formula 7 in an organic solvent such as acetone, CH3CN, CH2CI2, methanol, ethanol, using a dye (sensitizer) such as methylene blue, Rose Bengal, tetraphenyl porphine.
26. A process as claimed in claims 20-25, wherein condensation of p-
hydroxyhydroperoxides of formula 8 with aldehydes and ketones of formulae
21-22 is done in an organic solvent such as CH2CI2, CHCI3, benzene, CH3CN,
using as acid catalyst such as HCI, H2SO4,

27. A process as claimed in claims 20-26, wherein esterification of hydroxy-
functionalized trioxanes of formulae 23-28 with acid chlorides of formula 29 or an
acid anhydride of formula 30 is done in an organic solvent such as CH2CI2, CHCI3,
THF, CH3CN in presence of base such as Et3N, pyridine, dimethylaminopyridine.
28. A process as claimed in claims 20-27, wherein hemisuccinate derivatives of
formulae 37-42 are prepared in an organic solvent such as CH2Cl2, CHCI3,
CH3CN, toluene, THF, in presence of a base such as Et3N, pyridine,
dimethylaminopyridine.
29. A process as claimed in claims 20-28, wherein the compounds containing
aldehyde and ketonic group are of formulae 21-22 given in the drawing wherein
R3 and R4 are hydrogen, alky! group such as methyl, ethyl, aryl such as phenyl,
naphthyl, araalkyl such as benzyl, or part of a cyclic system.
30. A process as claimed in claims 20-29, wherein acid chlorides and acid
anhydrides used are having the formulae 29 and 30 wherein R5 represent alkyl
group such as methyl, ethyl, propyl, aryl such as phenyl.
31. Novel substituted 1,2,4 trioxanes useful as antimalarial agents and a process for
the preparation of the same substantially as herein described with reference to the examples and the drawings accompanying this specification.

Documents:

1579-del-1999-abstract.pdf

1579-del-1999-claims.pdf

1579-del-1999-correspondence-others.pdf

1579-del-1999-correspondence-po.pdf

1579-del-1999-description (complete).pdf

1579-del-1999-drawings.pdf

1579-del-1999-form-1.pdf

1579-del-1999-form-18.pdf

1579-del-1999-form-19.pdf

1579-del-1999-form-2.pdf

1579-del-1999-form-3.pdf

1579-del-1999-petition-138.pdf

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Patent Number

232539

Indian Patent Application Number

1579/DEL/1999

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

18-Mar-2009

Date of Filing

28-Dec-1999

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHANDAN SINGH	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P),INDIA
2	SUNIL KUMAR PURI	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P),INDIA

PCT International Classification Number

A61K 31/4433

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA