Title of Invention	AN IMPROVED PROCESS FOR RACEMIZATION OF (1S, 2S-(+)-2 AMINO-1-(4-NITRO PHENYL) -1, 3-PROPANEDIOL
Abstract	An improved process of racemization of 1S,2S-(+)-2-amino-1- (4-nitrophenyl )-1,3-propanediol (d base) by reacting d- base with acetamidine or benzamidine hydrochloride in presence of triethylamine by a known process to obtain 4S , 5S- 4- hydroxymethyl-5-(4-nitrophenyl )-1,3- oxazoline derivative, oxidizing oxazoline compound in presence of dimethylsulfoxide, an acid activator in an aprotic solvent at a temperature in the range of -80 to 0°C for a period in the range of 1 to 2 hrs to get formyl derivative, reducing the formyl derivative in presence of a reducing agent in aprotic solvent and an inorganic salt selected from metallic chloride at a temperature ranging between -10 to 40°C to give compound and isomerizing and hydroiyzing the above said compound to obtain threo dl base ( 2- amino-1-(4- nitrophenyl)- propane-1,3-diol

Title of Invention

AN IMPROVED PROCESS FOR RACEMIZATION OF (1S, 2S-(+)-2 AMINO-1-(4-NITRO PHENYL) -1, 3-PROPANEDIOL

Abstract

An improved process of racemization of 1S,2S-(+)-2-amino-1- (4-nitrophenyl )-1,3-propanediol (d base) by reacting d- base with acetamidine or benzamidine hydrochloride in presence of triethylamine by a known process to obtain 4S , 5S- 4- hydroxymethyl-5-(4-nitrophenyl )-1,3- oxazoline derivative, oxidizing oxazoline compound in presence of dimethylsulfoxide, an acid activator in an aprotic solvent at a temperature in the range of -80 to 0°C for a period in the range of 1 to 2 hrs to get formyl derivative, reducing the formyl derivative in presence of a reducing agent in aprotic solvent and an inorganic salt selected from metallic chloride at a temperature ranging between -10 to 40°C to give compound and isomerizing and hydroiyzing the above said compound to obtain threo dl base ( 2- amino-1-(4- nitrophenyl)- propane-1,3-diol

Full Text	The present invention relates to an improved process for racemization of [1S, 2S-(+)-2- amino-1-(4- nitro phenyl)-1,3-propanediol] Chloramphenicol [(1 R,2R)-2-Dichloroacetamino-1-(4-nitrophenyl)-1,3- propanediol ] of formula 1 shown in the drawing accompanying the specification processes a fairly wide spectrum of anti- microbial activity against gram-negative bacteria while it's threo 1S.2S diastereomer is devoid of anti bacterial activity. It's precursor i.e. I base (1R, 2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol of formula 3 is obtained in large scale from racemic dl-base of formula 2 by entertainment resolution [J.Jacques, A. Collet, S.H. Willem" Enantiomers, racemetes and resolution "John wiley and sons 1987, p 223] . The d-base of formula 4 obtained in same chemical and optical purity, as I- base of formula 3_has no antibacterial activity and hence discarded having no industrial applications. The present invention relates to an improved process of racemization of d-base, an undesired product to d l-base i.e. dl-thero-2-amino-1-(4-nitrophenyl) 1,3-propanediol of the formula 2, the starting material for l-base of the formula 3. The invention relates to drug and pharmaceutical industry. Prior Art: In principal two strategies exist for conversion of 1S,2S (+)2- amino-1- (4- nitrophenyl )-1,3-propanediol 4 in to l-base 3_[ (1R, 2R ) (-)2- amino-1-(4- nitrophenyl )-1,3- propanediol]. The first involves a recemization of d-base to dl- base, the precursor of l-base and second deals with direct conversion of d- base 4 to l-base 3. The processes have been studied which allow the racemization of 2S, 3S- 2- amino-1-(4-nitrophenyl )-1,3-propanediol of formula 4 to 2-amino-(4- nitrophenyl)-1,3-propanediol (racemic, threo base) of formula 2 ,a 1:1 mixture (1R,2R ) (-) isomer 3 and (1S.2S ) (+)isomer of formula 4 is described in Tetrahedron letters 29, 5561 (1988) and references cited therein ; & V. Hozak ; F. Moezie ; R. F. X. Klein ; C. Giordeno ; Synthesis , 1984, 839 ; G. Jommi ; D. Dellabella ;D. Chiarino; M. Fantucci; Italian pat. Applied 20968 (1985; Italian pat. 1186716, (1987) followed by entertainment resolution [L.M. Long, U.S. pat. 2, 767, 313(1956)]. In above process, the 2-amino and 3- hydroxy functionally of amino propanediol of formula 4_is protected and the free benzylic alcohol function is oxidized to the keto compound. The racemized keto compound is reduced to obtain a mixture of threo and erthro propanediol in a ratio of 90:10, thus erythro isomer remains a contaminant in the production of racemic threo base of formula 2 .In the second strategy involving the direct conversion of one enantiomer i.e. d- base to I-base with out recemization has been developed by Zambon group of Italy . 4 or d-base of thiamphenicol is converted directly to I - base i. e. (1R.2R ) (-)-2- amino-1-aryl- 3-propanediol by a process based upon dynamic kinetic resolution [C.Giodano , S. Cavicchioli , S. Levi , M. Villa; J. Organic chemistry , 1991, 56; 6114-6118 ; M.Villa, C.Giordano.S.Cavicchioli, and S.Levi ;U.S.patent 5,401,852 (1995) ] . In large-scale operation such process is usually cost prohibititive. . For both the strategies, presence of three functionalities i.e. one amino and two hydroxyl groups complicates the problems of chemo- selectivity. The latter strategy though elegant requires large number of steps i.e. at least 9 steps and the industrially less feasible than the former strategy. As racemic threo base of formula 2 can be easily separated to I- base of formula 3 and d- base of formula 4 by entrainment resolution, racemization of 4 to obtain 2 is economical for utilization of undesired isomer and minimization of waste disposal. In the drawing accompanying the specification formula 1 represents Chloramphenicol. Racemic threo base (2-amino-(4-nitrophenyl)-1,3- propanediol), I base [1R.2R-1- (4-nitrophenyl)-2- amino- 1,3 - propanediol], d-base [1S, 2S (+)2- amino-1-(4-nitrophenyl ) 1,3- propanediol] are represented by formulae 2, 3.and ,4 respectively. Formulae 5 a represents 4S, 5S-(+)- 2-methyl-4- hydroxymethyl-5- (4- nitrophenyl)-1,3 oxazoline and 5b represents 4S, 5S-(+)- 2-phenyl-4- hydroxymethyl-5- (4- nitrophenyl)-1,3 oxazoline. 4S,5S/R-2-Methyl-4- formyl-5- (4- nitrophenyl)-1,3 oxazoline and 4S.5S/R-2- phenyl-4-formyl-5- (4- nitrophenyl)-1,3 oxazoline are represented by formulae 6a and 6b respectively. 4S,5R/S-2-Methyl-4- hydroxymethyl-5- (4- nitrophenyl)-1,3 oxazoline and 4S,5S/R-2- phenyl-4- hydroxymethyl -5-(4- nitrophenyl)-1,3 oxazoline are represented by formulae 7a and 7b respectively Objectives : It is the object of present invention to provide a new and commercially useful process for racemization of d- base of chloramphenicol (1S, 2S )-(+)-2- ammo-(4-nitrophenyl )-1,2-propanediol of figure 4 to racemic threo base i.e. (+) 2- amino-1-(4-nitrophenyl )-1, -propanediol of figure 2 , (a 1:1 mixture of I- base of figure 3 . and d-base of figure 4) , which involves racemization at the both stereogenic centers at C^ and C3of figure 4_. Accordingly, the present invention provides an improved process of racemization of 1S,2S-(+)-2-amino-1- (4-nitrophenyl )-1,3-propanediol (d base) of formula 2 which comprises of (i) reacting d- base of formula 4 with acetamidine or benzamidine hydrochloride in presence of triethylamine by a known process to obtain 4S , 5S- 4-hydroxymethyl-5-(4- nitrophenyl )-1,3- oxazoline derivative of formula 5 ; (ii) oxidizing oxazoline compound of formula 5 in presence of dimethylsulfoxide, an acid activator in an aprotic solvent at a temperature in the range of -80 to 0°C for a period in the range of 1 to 2 hrs to get formyl derivative of formula 6, (iii) reducing the formyl derivative of formula 6 in presence of a reducing agent such as herein described in aprotic solvent and an inorganic salt selected from metallic chloride at a temperature ranging between -10 to 40°C to give compound of formula 7, (iv) isomerizing and hydrolyzing compound of formula 7 to obtain threo dl base ( 2- amino-1- (4- nitrophenyl )- propane-1,3-dioi ) of formula 2_ by the method such as herein described. In an embodiment of the present invention the acid activator used is selected from oxalyl chloride, trifluoroacetic anahydride, bis-trichloromethyl carbonate, cyanouryl chloride, phosphorous pentaoxide and the similar. In another embodiment of the present invention the oxidation of compound 5 to 6 is carried out in an aprotic solvent selected from group consisting of dichloromethane, dichloroethane, THF. In yet another embodiment of the present invention the oxidation of compound 5 to 6 is carried out at a temperature preferably between -40°c and-20°C for a period of 1 to 2 hrs. In still another embodiment of the present invention during preparation of oxazoline of formula 6, it spontaneously racemises at C4 during work up to obtain 1: 1 mixture of erythro isomer [4S.5S- 4-formyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] and threo isomer [4R.5S- 4-formyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] of formula 6. In still another embodiment of the present invention the reducing agent is selected from group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, Red Al, lithium aluminum hydride. In still another embodiment of the present invention the reducing agent used is preferably sodium borohydride. In still another embodiment of the present invention the reduction of compound 6 to compound 7 is carried out in a protic solvent selected from methanol, ethanol, propanol .butanol, isopropanol etc. In still another embodiment of the present invention the reduction of compound 6 to compound 7 is carried out in presence of an inorganic salt such as calcium chloride, aluminum chloride, zinc chloride preferably calcium chloride . In still another embodiment of the present invention the reduction of compound 6 to compound 7 is carried out at temperature preferably between 5 to 10° C for a period of 1/2 to 2 hrs and then warming to higher temperature. In still another embodiment of the present invention the oxazoline alcohol 7 composed of 1:1 mixture of erythro isomer [4R,5S- 4- hydroxy methyl-5-(4- nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] and the threo isomer [4S.5S- 4- hydroxymethyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] is heated in acidic medium to effect solvolysis of oxazoline to open chain amide and isomerization of erthro isomer to more stable threo isomer, the crude amido diol with out purification is hydrolyzed in presence of aqueous alkali to obtain threo racemic aminodiol of formula 2. In still another embodiment of the present invention the acidic medium employed is a mixture acetic anhydride and acetic acid or methane sulfonic acid in dichloroethane. In still another embodiment of the present invention the threo isomer does not isomerize during heating which is carried for 1 to 10 hrs preferably for 4 hrs and undergoes only solvolysis during heating process. In still another embodiment of the present invention the amidodiol without purification is directly hydrolyzed by heating in presence aqueous metal hydroxide selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide In still another embodiment of the present invention the aqueous metal hydroxide used is preferably sodium hydroxide of strength 1 to 20 % preferably 5 % for(period) of 1- 20 hrs preferably for 6-8 hrs, the racemic threo aminodiol 2, which is isolated by filtration and recrystallization. In an embodiment of improved process, the oxidation of oxazoline of formula 5 is carried out with dimethyl sufoxide and an acidic activator such as oxalyl chloride, trifuoroacetic anhydride, bis-trichloromethyl carbonate (triphosgene), cyanouryl chloride, phosphorous pent oxide etc. The oxidation is carried between-72° to-10° C preferably between-40° to-30°C. The oxazoline aldehyde undergoes racemisation at C4- position during work up. In other embodiment of the improved process the reduction of partially racemized oxazoline aldehyde of formula 6 is mediated by sodium borohydride, sodium triactoxyborohydride, Red-AI, lithium aluminum hydride preferably sodium borohydride in aprotic solvent such as methanol, ethanol, isopropanol to obtain oxazoline alcohol of formula 7 . In other embodiment of the improved process acidic medium used in heating the partially racemized alcohol is acetic anhydride-acetic acid, methane sulphonic acid in dichloroethane. In another embodiment of the process the aqueous alkali used is from lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide preferably sodium hydroxide and the mixture heated between 60 °c and 100 °c, preferably at 90 ° c for a period of 4- 20 hrs, preferably for 8 hrs. The product is isolated by filtration and finally recrstallized from either water or an organic solvent such as toluene. Conversion of d-base 4 to dl- base 2 requires recemization at both C1 and C2 stereoogenic centers with threo disposition of Ci- OH between C2-NH2 functionalities. The aim of oxidizing the primary hydroxyl group of d- base 4 is o facilitate the racemization at C2 stereogenic center of 4.Derivatization cehmical were to oxazoline 5 protects C1- OH and C2-NH2 and allows regio-selective oxidation of C3- OH. Facile abstraction of C4- H of oxazoline aldehyde paves away the racemization at C4 of aldehyde 6 leading to formation 1: 1 mixture threo (4R, 5S) and erythro (4S, 5S) stereomers of 6. We recall that according to nomenclature convention, the replacement of CH2OH group by CHO group modifies the denomination of configuration of the carbon atom position C4 of oxazoline 6 but this does not mean that absolute configuration is changed. Subsequent reduction of aldehyde 6 furnishes a 1:1 mixture of oxazoline alcohol 7 having configuration 4R, 5S (erythro ) and 4S,5S (threo). Heating this mixture in acidic medium leads to epimerisation of only erythro stereomer (4R, 5S) to thermodynamically more stable threo stereomer (4R, 5R) whereas the threo stereomer (4S,5S) does not epimerize. The oxazoline ring undergo hydrolysis under reaction condition to obtain corresponding amido alcohol which without isolation and purification directly hydrolyzed to racemic dl- base (1:1 mixture of l-base 3 and d- base 4) by treatment with alkali. The product is isolated by filtration and recrystallization. The examples given here should not be construed to limit the scope of the present invention. Example 1 To a stirred slurry of 1S, 2S- 1- (4- nitrophenyl )- 2- aminopropane- 1, 3- diol (d-base of chloroamphenicol ) (10.00g, 50 m. mol ) in dry dichioroethane (300ml ) methyl acetimidate hydrochloride (6.6g , 60 m. mol ),( prepared from acetonitrile and methanol), triethylamine 10.0 ml is added drop wise with stirring . The mixture is stirred at same temperature for three hrs and ambient temperature for 6 hrs. The product mixture is washed with water, dil. HCI (1N), 3x50ml) and sodium bi carbonate (5%, 3x50 ml) brine (1x30 ml). It is dried over sodium sulfate and evaporated to obtain 13.0 g of 3 as crude solid product which is recrystallized from ethyl acetate- hexane. Yield: 9.2 (81 %) MP. 123-125°C[α] = + 28° Example 20 To a stirred slurry d- base 2 (10.0g in 50 ml ) in anhydrous ethylene glycol (150 ml), benzonitrile (12.0 , 60 m. mol) and powdered potassium carbonate (6.0g ) is added and heated at 150°" 160° c for a period of 8 hrs. The mixture is cooled to ambient temperature and poured in to ice cold water (300 ml) and extracted with chloroform (3x 60 ml ) . The combined chloroform extracts is washed with brine, dried, evaporated. The crude product is recrystallized from ethyl alcohol- hexane to yield 10.6 g of 5b(77%) MP. 148- 150° C [α] = +31° (c = 0.3, CHCI3). Example 3 To suspended slurry of d- base 2 (20.g) in dichloroethane (500 ml) ethy benzamidine hydrochloride (20 g) [prepared from benzonitrile and ethanol] is added at 0°C followed by drop wise of triethylamine (16.5ml). The mixture is stirred ambient temperature for two hrs and heated to refluxed for 1hr. It is cooled to ambient temperature and washed with dil. HCI (2x50 ml, 1N); sodium bicarbonate (2x100 ml, 5%) and brine (1x300 ml). The dichloroethane solution is evaporated to dryness. The crude product is crystallized from isopropyl acetate to obtain pure 5b (yield: 21.5 g)(78 % ) MP. 148-150°, [α] = +30.5 °(c=0.3,CHCI3) Example 4 To a solution of 3a (8.0, 0.04 mol ) in dichloromethane (100ml ) dimethylsulfoxide (4.0 ml ) diluted with dichloromethane (10 ml ) is added drop wise at-30°C . After stirring the mixture for 1/2. at same temperature a solution of oxalyl chloride(4.0g in 20 ml of DCM) is added drop wise over 30 minutes . The reaction mixture is continued to stirred 1/4 hr at same temperature and then a solution of triethylamine (6.0 ml ) in DCM (30ml) is added drop wise . The reaction mixture is allowed to warm to room temperature and washed with dil. HCI (0.5 N), sodium bicarbonate ( 1x30 ml , 5% ) and saturated brine (1x20 ml ) . The dichloromethane solution is dried over sodium sulfate, filtered and evaporated to yield crude 6a, which is, recrystallized from isopropyl acetate- pet. Ether. Yield = 5.5 g(69 %); MP. = 61-3°C [α] =+2° (c=1,CHCI3) Example 5 To a solution of 3a (8.0, 0.04 mol) in dichloromethane (100ml) dimethylsulfoxide (4.0 ml) diluted with dichloromethane (10 ml ) is added drop wise at-30°C . After stirring the mixture for 1/4 hr. at same temperature a solution of BTC (bistrichloromethyl carbonate (5.0g in 20 ml of DCM) is added drop wise over 30 minutes. The reaction mixture is continued to stirred 1/4 hr at same temperature and then a solution of triethylamine (6.0 ml) in DCM (30ml) is added drop wise. The reaction mixture is allowed to warm to room temperature and washed with dil. HCI (0.5 N ), sodium bicarbonate (1x30 ml, 5% ) and saturated brine (1x20 ml). The dichloromethane solution is dried over sodium sulfate, filtered and evaporated to yield crude 6a, which is recrystallized, from isopropyl acetate- pet. Ether. Yield = 5.6 g (70 %) MP. = 61-3°C [α] = +2 ° (c = 1 ,CHCI3) Example 6 A solution of DMSO (4.03 g, 0.05 mol) in dichloromethane (10 ml ) is added to stirred solution of trifluoroacetic anhydride (0.021 mol) in dichloromethane (10 ml 0 over 30 minutes at-30 °C under anhydrous condition and the solution is stirred for 1/2 hr and a solution of 4S , 5S-2-phenyl- 4- hydroxymethyl-5-(4-nitrophenyl)- 1,3-oxazine 5b (3.46g , 0.012 mol ) in dichloromethane (30 ml ) is added drop wise over 30 minutes at-30°C The reaction mixture is stirred at-30°C for 15 minutes and then warmed to-20°C . Triethylamine (14.0ml, 0.1 mol) is added to the solution at same temperature drop wise over 20 minutes . The reaction mixture is warmed to 0°C over 2hrs and poured in to 10% aqueous NH4CI solution (50 ml). The organic phase is separated and aqueous phase is extracted with 20 ml with dichloromethane. The combined organic phase is washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to yield crude 6 b (4.2 g). This is dissolved in methanol (30 ml) and chilled to 0-5 °c. While stirring sodium borohydride (0.5 g) is added. The reaction mixture is stirred at same temperature for 1/2 hr, warmed to room temperature and heated to reflux for 1 hr, evaporated to dryness The residual solid is extracted with dichloromethane (2x30 ml). The resulting solid extracted with dichloromethane andis washed with water, dried over sodium sulfate, evaporated to obtain crude 7b 4R/S, 5S-2-phenyl- 4- hydoxymethyl-5- (4-nitrophenyl)-1,3-oxazine, which is recrystallized from ethyl acetate-hexane. yield 3.0 g ((87 %) MP. = 148-150 g [α] = + 5° (C = 1, CHCI 3) Example 7 To a methanolic solution of crude 6_b is cooled to 0°C, sodium borohydride (0.5 g ) is added in portions over !4 hr and the mixture is stirred at same temperature for 1 hr. and warmed to room temperature over 2hrs. and evaporated . The residual solid is extracted with dichloromethane (2x30 ml). The resulting solid is washed with water, dried over sodium sulfate, evaporated to obtain crude 7b 4R/S, 5S-2-phenyl-4- hydoxymethyl-5- (4-nitrophenyl)-1,3- oxazine which is recrystallized from ethyl acetate- Hexane. Yield = 2.8 g, 81 % MP. = 148-150 g [α] = + 5° (C = 1, CHCI 3) Example 8 To a solution of 7a (4.59 g, 0.02 mol) in 100 ml of chloroform, acetic anhydride (2ml ) is added and mixture is heated to reflux for 3 hrs. The solution is cooled to 10°C and 3 ml of triethylamine added with stirring. The resulting solution poured in to ice-cold water , the chloroform layer is separated washed with water , dried (anhydrous Na2SO4) and evaporated . The resulting crude solid is dissolved in dioxane (10 ml) , and sodium hydroxide (1.5 g in 15 ml of water ) is added . The resulting mixture is heated to reflux with stirring for 8 hrs , cooled and rotavapored to remove dioxane. Water 20 ml is added and cooled to 15°C for 1 hr. The precipitated solid is filtered under suction. The residue is washed with water (2x10 ml ) under suction , and dried under vacuum to obtained threo-racemic 2- amino- (l-4-nitrophenyl)-l,3- propandiol 2. Yield = 3.0 g (74 %) M.P. = 162-4 °C [α =0° (C = 2.4 % in 1.0 (N) HC1). Example 9 To a solution of 4-(R/S), 5 S-2- phenyl-4- hydroxymethyl-5-(4- nitrophenyl)- 1,3- oxazine 7b (11.5 g , 0.04 mol) in acetic acid (80 ml), acetic anhydride (4ml) is added. The mixture is heated to reflux with stirring for 1 hr. The solution is evaporated under suction. To the resulting residual crude product, aqueous sodium hydroxide (4 g in 50 ml water) is added. The resulting suspension is heated to reflux for 8 hrs. The mixture is cooled and diluted with 20 ml of water and stored at 10- 15° for 4 hrs. The precipitated product is filtered under suction. The residue is washed with ice cold water and finally recrystallized from water to yield 8.3 g of threo- (+)- 2- amino-1- (4- nitrophenyl)- 1,3- propanediol. 2 Yield =6.5 g (74 % ) M.P. =162-4 °C [α] = 0° (C = 2.4 % in 1.0 (N) HCI Advantage : Chlorophenicol, a broad spectrum antibiotics is produced from 1R, 2R- 2- amino-1- aryl- 1 ,3- propandiol 3 which obtained by entrainment resolution of threo racemic 1- aryl-2- amino- propane-1,2- diol 2 . The parallel processing of undesired 1S, 2R- 1- aryl-2- amino propane-1, 2-diol 4 or d- base as the source of I- base offers an opportunity to develop a practical route with maximizing the utilization of raw material and minimizing waste disposal. Recemization of d- base 4 to obtain threo recemic base 2 requires less number of steps then to the direct conversion to I- base 3 In the known of racemization of d- base 4. A mixture of racemic threo 2and it's enthreo isomers are obtained in a ratio of 9:1 due to involvement of oxidation of benzylic alcohol function of 2,3-protected derivative of 4 and diastereoselective reduction of the resulting ketone in the subsequent step . In the present invention 3- hydroxyl group of 5 is oxidized to aldehyde 6 and reduction of the aldehyde furnished only threo alcohol 6 hence formation of erythro isomer does not arise. . Thus 1S, 2R isomer (d-base) is racemised by a process with high yield, low cost and less number of steps with out formation of erythro isomer in the present invention. Following similar process, the d- base of fluorfenicol, thiamphenicol can be racemized to threo dl- base. We claim 1. An improved process of racemization of 1_S,2S-(+)-2-amino-1- (4-nitrophenyl )-l,3- propanediol (d base) of formula 2 which comprises of (i) reacting d- base of formula 4 with acetamidine or benzamidine hydrochloride in presence of triethylamine by a known process to obtain 4S , 5S- 4- hydroxymethyl-5-(4- nitrophenyl )-1,3- oxazoline derivative of formula 5 ; (ii) oxidizing oxazoline compound of formula 5 in presence of dimethylsulfoxide, an acid activator in an aprotic solvent at a temperature in the range of -80 to 0°C for a period in the range of 1 to 2 hrs to get formyl derivative of formula 6, (iii) reducing the formyl derivative of formula 6 in presence of a reducing agent such as herein described in aprotic solvent and an inorganic salt selected from metallic chloride at a temperature ranging between -10 to 40°C to give compound of formula 7, (iv) isomerizing and hydrolyzing compound of formula 7 to obtain threo dl base ( 2- amino-1- (4- nitrophenyl)- propane-1,3-diol ) of formula 2_ by the method such as herein described. 2. An improved process of racemization as claimed in claim(1) wherein the acid activator used is selected from oxalyl chloride, trifluoroacetic anahydride, bis-trichloromethyl carbonate, cyanouryl chloride, phosphorous pentaoxide. 3. An improved process of racemization as claimed in claims 1 & 2 wherein the oxidation of compound of formula 5 to compound of formula 6 is carried out in an aprotic solvent selected from group consisting of dichloromethane, dichloroethane, Tetrahydrofuran. 4. A process as claimed in claims 1 & 3 wherein the oxidation of compound of formula 5 is carried out at a temperature preferably between -40°c and-20°C for a period of 1 to 2 hrs. 5. An improved process as claimed in claims 1 to 4, wherein the reducing agent is selected from group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, Red Al, lithium aluminum hydride. 6. An improved process as claimed in claims 1 to 5, wherein the reducing agent used is preferably sodium borohydride, 7. An improved process as claimed in claims 1 to 6, wherein the reduction of compound of formula 6 to compound of formula 7 is carried out in a protic solvent selected from methanol, ethanol, propanol ,butanol, isopropanol. 8. A process as claimed in claims 1 to 7, wherein the reduction of compound of formula 6 to compound of formula 7 is carried out in presence of an inorganic salt such as calcium chloride, aluminum chloride, zinc chloride preferably calcium chloride. 9. A process as claimed in claims 1 to 8, wherein the reduction of compound of formula 6 to compound of formula 7 is carried out at temperature preferably between 5 to 10° C for a period of 1/2 to 2 hrs and then warming to higher temperature. 10. An improved process as claimed in claims 1 to 9, where the oxazoline alcohol of formula 7 composed of 1:1 mixture of erythro isomer [4R,5S- 4- hydroxymethyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] and the threo isomer [4S,5S- 4-hydroxymethyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] is heated in acidic medium to effect solvolysis of oxazoline to open chain amide and isomerization of erthro isomer to more stable threo isomer, the crude amido diol with out purification is hydrolyzed in presence of aqueous alkali to obtain threo racemic ammodiol of formula 2 11. A process as claimed in claims 1 to 10 wherein the acidic medium employed is a mixture acetic anhydride and acetic acid or methane sulfonic acid in dichloroethane. 12. A process as claimed in claims 1 to 11 wherein the aminodiol without purification is directly hydrolyzed by heating in presence aqueous metal hydroxide selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide. 13. A process as claimed in claims 1 to 12 wherein the aqueous metal hydroxide used is preferably sodium hydroxide of strength 1 to 20 % preferably 5 % for period of 1-20 hrs preferably for 6-8 hrs, the racemic threo aminodiol 2, which is isolated by filtration and recrystallization. 14. An improved process of racemization of 1S,2S-(+)-2-amino-1- (4-nitrophenyl )-1,3-propanediol (d base ) of formula 2 of the drawing accompanying this specification substantially as herein described with reference to the examples and drawing accompanying this specification.

Full Text

The present invention relates to an improved process for racemization of [1S, 2S-(+)-2- amino-1-(4- nitro phenyl)-1,3-propanediol]
Chloramphenicol [(1 R,2R)-2-Dichloroacetamino-1-(4-nitrophenyl)-1,3-
propanediol ] of formula 1 shown in the drawing accompanying the specification processes a fairly wide spectrum of anti- microbial activity against gram-negative bacteria while it's threo 1S.2S diastereomer is devoid of anti bacterial activity. It's precursor i.e. I base (1R, 2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol of formula 3 is obtained in large scale from racemic dl-base of formula 2 by entertainment resolution [J.Jacques, A. Collet, S.H. Willem" Enantiomers, racemetes and resolution "John wiley and sons 1987, p 223] . The d-base of formula 4 obtained in same chemical and optical purity, as I- base of formula 3_has no antibacterial activity and hence discarded having no industrial applications. The present invention relates to an improved process of racemization of d-base, an undesired product to d l-base i.e. dl-thero-2-amino-1-(4-nitrophenyl) 1,3-propanediol of the formula 2, the starting material for l-base of the formula 3. The invention relates to drug and pharmaceutical industry.
Prior Art: In principal two strategies exist for conversion of 1S,2S (+)2- amino-1-
(4- nitrophenyl )-1,3-propanediol 4 in to l-base 3_[ (1R, 2R ) (-)2- amino-1-(4-
nitrophenyl )-1,3- propanediol]. The first involves a recemization of d-base to dl-
base, the precursor of l-base and second deals with direct conversion of d- base 4
to l-base 3. The processes have been studied which allow the racemization of 2S,
3S- 2- amino-1-(4-nitrophenyl )-1,3-propanediol of formula 4 to 2-amino-(4-
nitrophenyl)-1,3-propanediol (racemic, threo base) of formula 2 ,a 1:1 mixture
(1R,2R ) (-) isomer 3 and (1S.2S ) (+)isomer of formula 4 is described in Tetrahedron letters 29, 5561 (1988) and references cited therein ; & V. Hozak ; F. Moezie ; R. F. X. Klein ; C. Giordeno ; Synthesis , 1984, 839 ; G. Jommi ; D. Dellabella ;D. Chiarino; M. Fantucci; Italian pat. Applied 20968 (1985; Italian pat. 1186716, (1987) followed by entertainment resolution [L.M. Long, U.S. pat. 2, 767, 313(1956)]. In above process, the 2-amino and 3- hydroxy functionally of amino propanediol of formula 4_is protected and the free benzylic alcohol function is oxidized to the keto compound. The racemized keto compound is reduced to obtain a mixture of threo and erthro propanediol in a ratio of 90:10, thus erythro isomer remains a contaminant in the production of racemic threo base of formula 2 .In the second strategy involving the direct conversion of one enantiomer i.e. d- base to I-base with out recemization has been developed by Zambon group of Italy . 4 or d-base of thiamphenicol is converted directly to I - base i. e. (1R.2R ) (-)-2- amino-1-aryl- 3-propanediol by a process based upon dynamic kinetic resolution [C.Giodano , S. Cavicchioli , S. Levi , M. Villa; J. Organic chemistry , 1991, 56; 6114-6118 ; M.Villa, C.Giordano.S.Cavicchioli, and S.Levi ;U.S.patent 5,401,852 (1995) ] . In large-scale operation such process is usually cost prohibititive. . For both the strategies, presence of three functionalities i.e. one amino and two hydroxyl groups complicates the problems of chemo- selectivity. The latter strategy though elegant requires large number of steps i.e. at least 9 steps and the industrially less feasible than the former strategy. As racemic threo base of formula 2 can be easily separated to I- base of formula 3 and d- base of formula 4 by
entrainment resolution, racemization of 4 to obtain 2 is economical for utilization of undesired isomer and minimization of waste disposal.
In the drawing accompanying the specification formula 1 represents Chloramphenicol. Racemic threo base (2-amino-(4-nitrophenyl)-1,3- propanediol), I base [1R.2R-1- (4-nitrophenyl)-2- amino- 1,3 - propanediol], d-base [1S, 2S (+)2- amino-1-(4-nitrophenyl ) 1,3- propanediol] are represented by formulae 2, 3.and ,4 respectively. Formulae 5 a represents 4S, 5S-(+)- 2-methyl-4- hydroxymethyl-5- (4- nitrophenyl)-1,3 oxazoline and 5b represents 4S, 5S-(+)- 2-phenyl-4- hydroxymethyl-5- (4- nitrophenyl)-1,3 oxazoline. 4S,5S/R-2-Methyl-4- formyl-5- (4- nitrophenyl)-1,3 oxazoline and 4S.5S/R-2- phenyl-4-formyl-5- (4- nitrophenyl)-1,3 oxazoline are represented by formulae 6a and 6b respectively. 4S,5R/S-2-Methyl-4- hydroxymethyl-5- (4- nitrophenyl)-1,3 oxazoline and 4S,5S/R-2- phenyl-4- hydroxymethyl -5-(4- nitrophenyl)-1,3 oxazoline are represented by formulae 7a and 7b respectively
Objectives : It is the object of present invention to provide a new and commercially useful process for racemization of d- base of chloramphenicol (1S, 2S )-(+)-2- ammo-(4-nitrophenyl )-1,2-propanediol of figure 4 to racemic threo base i.e. (+) 2- amino-1-(4-nitrophenyl )-1, -propanediol of figure 2 , (a 1:1 mixture of I- base of figure 3 . and d-base of figure 4) , which involves racemization at the both stereogenic centers at C^ and C3of figure 4_.
Accordingly, the present invention provides an improved process of racemization of 1S,2S-(+)-2-amino-1- (4-nitrophenyl )-1,3-propanediol (d base) of formula 2 which comprises of (i) reacting d- base of formula 4 with acetamidine or benzamidine
hydrochloride in presence of triethylamine by a known process to obtain 4S , 5S- 4-hydroxymethyl-5-(4- nitrophenyl )-1,3- oxazoline derivative of formula 5 ; (ii) oxidizing oxazoline compound of formula 5 in presence of dimethylsulfoxide, an acid activator in an aprotic solvent at a temperature in the range of -80 to 0°C for a period in the range of 1 to 2 hrs to get formyl derivative of formula 6, (iii) reducing the formyl derivative of formula 6 in presence of a reducing agent such as herein described in aprotic solvent and an inorganic salt selected from metallic chloride at a temperature ranging between -10 to 40°C to give compound of formula 7, (iv) isomerizing and hydrolyzing compound of formula 7 to obtain threo dl base ( 2- amino-1- (4- nitrophenyl )- propane-1,3-dioi ) of formula 2_ by the method such as herein described.
In an embodiment of the present invention the acid activator used is selected from oxalyl chloride, trifluoroacetic anahydride, bis-trichloromethyl carbonate, cyanouryl chloride, phosphorous pentaoxide and the similar.
In another embodiment of the present invention the oxidation of compound 5 to 6 is carried out in an aprotic solvent selected from group consisting of dichloromethane, dichloroethane, THF.
In yet another embodiment of the present invention the oxidation of compound 5 to 6 is carried out at a temperature preferably between -40°c and-20°C for a period of 1 to 2 hrs.
In still another embodiment of the present invention during preparation of oxazoline of formula 6, it spontaneously racemises at C4 during work up to obtain 1: 1 mixture of erythro isomer [4S.5S- 4-formyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] and threo isomer [4R.5S- 4-formyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] of formula 6.
In still another embodiment of the present invention the reducing agent is selected
from group consisting of sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, Red Al, lithium aluminum hydride.
In still another embodiment of the present invention the reducing agent used is
preferably sodium borohydride.
In still another embodiment of the present invention the reduction of compound 6 to
compound 7 is carried out in a protic solvent selected from methanol, ethanol,
propanol .butanol, isopropanol etc.
In still another embodiment of the present invention the reduction of compound 6 to
compound 7 is carried out in presence of an inorganic salt such as calcium chloride,
aluminum chloride, zinc chloride preferably calcium chloride .
In still another embodiment of the present invention the reduction of compound 6 to
compound 7 is carried out at temperature preferably between 5 to 10° C for a
period of 1/2 to 2 hrs and then warming to higher temperature.
In still another embodiment of the present invention the oxazoline alcohol 7
composed of 1:1 mixture of erythro isomer [4R,5S- 4- hydroxy methyl-5-(4-
nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] and the threo isomer [4S.5S- 4-
hydroxymethyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] is heated in acidic
medium to effect solvolysis of oxazoline to open chain amide and isomerization
of erthro isomer to more stable threo isomer, the crude amido diol with out
purification is hydrolyzed in presence of aqueous alkali to obtain threo racemic
aminodiol of formula 2.
In still another embodiment of the present invention the acidic medium employed is
a mixture acetic anhydride and acetic acid or methane sulfonic acid in
dichloroethane.
In still another embodiment of the present invention the threo isomer does not
isomerize during heating which is carried for 1 to 10 hrs preferably for 4 hrs and
undergoes only solvolysis during heating process.
In still another embodiment of the present invention the amidodiol without
purification is directly hydrolyzed by heating in presence aqueous metal hydroxide
selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium
hydroxide
In still another embodiment of the present invention the aqueous metal hydroxide
used is preferably sodium hydroxide of strength 1 to 20 % preferably 5 % for(period)
of 1- 20 hrs preferably for 6-8 hrs, the racemic threo aminodiol 2, which is
isolated by filtration and recrystallization.
In an embodiment of improved process, the oxidation of oxazoline of formula 5 is carried out with dimethyl sufoxide and an acidic activator such as oxalyl chloride, trifuoroacetic anhydride, bis-trichloromethyl carbonate (triphosgene), cyanouryl chloride, phosphorous pent oxide etc. The oxidation is carried between-72° to-10° C preferably between-40° to-30°C. The oxazoline aldehyde undergoes racemisation at C4- position during work up. In other embodiment of the improved process the reduction of partially racemized oxazoline aldehyde of formula 6 is mediated by sodium borohydride, sodium triactoxyborohydride, Red-AI, lithium aluminum
hydride preferably sodium borohydride in aprotic solvent such as methanol, ethanol, isopropanol to obtain oxazoline alcohol of formula 7 . In other embodiment of the improved process acidic medium used in heating the partially racemized alcohol is acetic anhydride-acetic acid, methane sulphonic acid in dichloroethane. In another embodiment of the process the aqueous alkali used is from lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide preferably sodium hydroxide and the mixture heated between 60 °c and 100 °c, preferably at 90 ° c for a period of 4- 20 hrs, preferably for 8 hrs. The product is isolated by filtration and finally recrstallized from either water or an organic solvent such as toluene.
Conversion of d-base 4 to dl- base 2 requires recemization at both C1 and C2 stereoogenic centers with threo disposition of Ci- OH between C2-NH2 functionalities. The aim of oxidizing the primary hydroxyl group of d- base 4 is o facilitate the racemization at C2 stereogenic center of 4.Derivatization cehmical were
to oxazoline 5 protects C1- OH and C2-NH2 and allows regio-selective oxidation of C3- OH. Facile abstraction of C4- H of oxazoline aldehyde paves away the racemization at C4 of aldehyde 6 leading to formation 1: 1 mixture threo (4R, 5S) and erythro (4S, 5S) stereomers of 6. We recall that according to nomenclature convention, the replacement of CH2OH group by CHO group modifies the denomination of configuration of the carbon atom position C4 of oxazoline 6 but this does not mean that absolute configuration is changed. Subsequent reduction of aldehyde 6 furnishes a 1:1 mixture of oxazoline alcohol 7 having configuration 4R, 5S (erythro ) and 4S,5S (threo). Heating this mixture in acidic medium leads to epimerisation of only erythro stereomer (4R, 5S) to thermodynamically more stable
threo stereomer (4R, 5R) whereas the threo stereomer (4S,5S) does not epimerize. The oxazoline ring undergo hydrolysis under reaction condition to obtain corresponding amido alcohol which without isolation and purification directly hydrolyzed to racemic dl- base (1:1 mixture of l-base 3 and d- base 4) by treatment with alkali. The product is isolated by filtration and recrystallization. The examples given here should not be construed to limit the scope of the present invention. Example 1
To a stirred slurry of 1S, 2S- 1- (4- nitrophenyl )- 2- aminopropane- 1, 3- diol (d-base of chloroamphenicol ) (10.00g, 50 m. mol ) in dry dichioroethane (300ml ) methyl acetimidate hydrochloride (6.6g , 60 m. mol ),( prepared from acetonitrile and methanol), triethylamine 10.0 ml is added drop wise with stirring . The mixture is stirred at same temperature for three hrs and ambient temperature for 6 hrs. The product mixture is washed with water, dil. HCI (1N), 3x50ml) and sodium bi carbonate (5%, 3x50 ml) brine (1x30 ml). It is dried over sodium sulfate and evaporated to obtain 13.0 g of 3 as crude solid product which is recrystallized from ethyl acetate- hexane. Yield: 9.2 (81 %) MP. 123-125°C[α] = + 28° Example 20
To a stirred slurry d- base 2 (10.0g in 50 ml ) in anhydrous ethylene glycol (150 ml), benzonitrile (12.0 , 60 m. mol) and powdered potassium carbonate (6.0g ) is added and heated at 150°" 160° c for a period of 8 hrs. The mixture is cooled to ambient temperature and poured in to ice cold water (300 ml) and extracted with
chloroform (3x 60 ml ) . The combined chloroform extracts is washed with brine, dried, evaporated. The crude product is recrystallized from ethyl alcohol- hexane to yield 10.6 g of 5b(77%)
MP. 148- 150° C [α] = +31° (c = 0.3, CHCI3). Example 3
To suspended slurry of d- base 2 (20.g) in dichloroethane (500 ml) ethy benzamidine hydrochloride (20 g) [prepared from benzonitrile and ethanol] is added at 0°C followed by drop wise of triethylamine (16.5ml). The mixture is stirred ambient temperature for two hrs and heated to refluxed for 1hr. It is cooled to ambient temperature and washed with dil. HCI (2x50 ml, 1N); sodium bicarbonate (2x100 ml, 5%) and brine (1x300 ml). The dichloroethane solution is evaporated to dryness. The crude product is crystallized from isopropyl acetate to obtain pure 5b (yield: 21.5 g)(78 % ) MP. 148-150°, [α] = +30.5 °(c=0.3,CHCI3) Example 4
To a solution of 3a (8.0, 0.04 mol ) in dichloromethane (100ml ) dimethylsulfoxide (4.0 ml ) diluted with dichloromethane (10 ml ) is added drop wise at-30°C . After stirring the mixture for 1/2. at same temperature a solution of oxalyl chloride(4.0g in 20 ml of DCM) is added drop wise over 30 minutes . The reaction mixture is continued to stirred 1/4 hr at same temperature and then a solution of triethylamine (6.0 ml ) in DCM (30ml) is added drop wise . The reaction mixture is allowed to warm to room temperature and washed with dil. HCI (0.5 N), sodium bicarbonate ( 1x30 ml , 5% ) and saturated brine (1x20 ml ) . The dichloromethane solution is dried over sodium sulfate, filtered and evaporated to yield crude 6a, which is,
recrystallized from isopropyl acetate- pet. Ether. Yield = 5.5 g(69 %); MP. = 61-3°C [α] =+2° (c=1,CHCI3) Example 5
To a solution of 3a (8.0, 0.04 mol) in dichloromethane (100ml) dimethylsulfoxide (4.0 ml) diluted with dichloromethane (10 ml ) is added drop wise at-30°C . After stirring the mixture for 1/4 hr. at same temperature a solution of BTC (bistrichloromethyl carbonate (5.0g in 20 ml of DCM) is added drop wise over 30 minutes. The reaction mixture is continued to stirred 1/4 hr at same temperature and then a solution of triethylamine (6.0 ml) in DCM (30ml) is added drop wise. The reaction mixture is allowed to warm to room temperature and washed with dil. HCI (0.5 N ), sodium bicarbonate (1x30 ml, 5% ) and saturated brine (1x20 ml). The dichloromethane solution is dried over sodium sulfate, filtered and evaporated to yield crude 6a, which is recrystallized, from isopropyl acetate- pet. Ether. Yield = 5.6 g (70 %) MP. = 61-3°C [α] = +2 ° (c = 1 ,CHCI3)
Example 6
A solution of DMSO (4.03 g, 0.05 mol) in dichloromethane (10 ml ) is added to stirred solution of trifluoroacetic anhydride (0.021 mol) in dichloromethane (10 ml 0 over 30 minutes at-30 °C under anhydrous condition and the solution is stirred for 1/2 hr and a solution of 4S , 5S-2-phenyl- 4- hydroxymethyl-5-(4-nitrophenyl)- 1,3-oxazine 5b (3.46g , 0.012 mol ) in dichloromethane (30 ml ) is added drop wise over 30 minutes at-30°C The reaction mixture is stirred at-30°C for 15 minutes and then warmed to-20°C . Triethylamine (14.0ml, 0.1 mol) is added to the solution at
same temperature drop wise over 20 minutes . The reaction mixture is warmed to 0°C over 2hrs and poured in to 10% aqueous NH4CI solution (50 ml). The organic phase is separated and aqueous phase is extracted with 20 ml with dichloromethane. The combined organic phase is washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to yield crude 6 b (4.2 g). This is dissolved in methanol (30 ml) and chilled to 0-5 °c. While stirring sodium borohydride (0.5 g) is added. The reaction mixture is stirred at same temperature for 1/2 hr, warmed to room temperature and heated to reflux for 1 hr, evaporated to dryness The residual solid is extracted with dichloromethane (2x30 ml). The resulting solid extracted with dichloromethane andis washed with water, dried over sodium sulfate, evaporated to obtain crude 7b 4R/S, 5S-2-phenyl- 4- hydoxymethyl-5- (4-nitrophenyl)-1,3-oxazine, which is recrystallized from ethyl acetate-hexane. yield 3.0 g ((87 %) MP. = 148-150 g [α] = + 5° (C = 1, CHCI 3) Example 7
To a methanolic solution of crude 6_b is cooled to 0°C, sodium borohydride (0.5 g ) is added in portions over !4 hr and the mixture is stirred at same temperature for 1 hr. and warmed to room temperature over 2hrs. and evaporated . The residual solid is extracted with dichloromethane (2x30 ml). The resulting solid is washed with water, dried over sodium sulfate, evaporated to obtain crude 7b 4R/S, 5S-2-phenyl-4- hydoxymethyl-5- (4-nitrophenyl)-1,3- oxazine which is recrystallized from ethyl acetate- Hexane. Yield = 2.8 g, 81 % MP. = 148-150 g [α] = + 5° (C = 1, CHCI 3)
Example 8
To a solution of 7a (4.59 g, 0.02 mol) in 100 ml of chloroform, acetic anhydride (2ml ) is added and mixture is heated to reflux for 3 hrs. The solution is cooled to 10°C and 3 ml of triethylamine added with stirring. The resulting solution poured in to ice-cold water , the chloroform layer is separated washed with water , dried (anhydrous Na2SO4) and evaporated . The resulting crude solid is dissolved in dioxane (10 ml) , and sodium hydroxide (1.5 g in 15 ml of water ) is added . The resulting mixture is heated to reflux with stirring for 8 hrs , cooled and rotavapored to remove dioxane. Water 20 ml is added and cooled to 15°C for 1 hr. The precipitated solid is filtered under suction. The residue is washed with water (2x10 ml ) under suction , and dried under vacuum to obtained threo-racemic 2- amino- (l-4-nitrophenyl)-l,3- propandiol 2. Yield = 3.0 g (74 %) M.P. = 162-4 °C [α =0° (C = 2.4 % in 1.0 (N) HC1). Example 9
To a solution of 4-(R/S), 5 S-2- phenyl-4- hydroxymethyl-5-(4- nitrophenyl)- 1,3- oxazine 7b (11.5 g , 0.04 mol) in acetic acid (80 ml), acetic anhydride (4ml) is added. The mixture is heated to reflux with stirring for 1 hr. The solution is evaporated under suction. To the resulting residual crude product, aqueous sodium hydroxide (4 g in 50 ml water) is added. The resulting suspension is heated to reflux for 8 hrs. The mixture is cooled and diluted with 20 ml of water and stored at 10- 15° for 4 hrs. The precipitated product is filtered under suction. The residue is washed with ice cold water and finally recrystallized from water to yield 8.3 g of threo- (+)- 2- amino-1- (4- nitrophenyl)- 1,3- propanediol. 2 Yield =6.5 g (74 % ) M.P. =162-4 °C [α] = 0° (C = 2.4 % in 1.0 (N) HCI
Advantage :
Chlorophenicol, a broad spectrum antibiotics is produced from 1R, 2R- 2- amino-1-
aryl- 1 ,3- propandiol 3 which obtained by entrainment resolution of threo racemic
1- aryl-2- amino- propane-1,2- diol 2 . The parallel processing of undesired 1S, 2R-
1- aryl-2- amino propane-1, 2-diol 4 or d- base as the source of I- base offers an
opportunity to develop a practical route with maximizing the utilization of raw
material and minimizing waste disposal. Recemization of d- base 4 to obtain threo
recemic base 2 requires less number of steps then to the direct conversion to I-
base 3 In the known of racemization of d- base 4. A mixture of racemic threo 2and
it's enthreo isomers are obtained in a ratio of 9:1 due to involvement of oxidation of
benzylic alcohol function of 2,3-protected derivative of 4 and diastereoselective
reduction of the resulting ketone in the subsequent step . In the present invention
3- hydroxyl group of 5 is oxidized to aldehyde 6 and reduction of the aldehyde
furnished only threo alcohol 6 hence formation of erythro isomer does not arise. .
Thus 1S, 2R isomer (d-base) is racemised by a process with high yield, low cost
and less number of steps with out formation of erythro isomer in the present
invention. Following similar process, the d- base of fluorfenicol, thiamphenicol can
be racemized to threo dl- base.

We claim
1. An improved process of racemization of 1_S,2S-(+)-2-amino-1- (4-nitrophenyl )-l,3-
propanediol (d base) of formula 2 which comprises of (i) reacting d- base of formula
4 with acetamidine or benzamidine hydrochloride in presence of triethylamine by a
known process to obtain 4S , 5S- 4- hydroxymethyl-5-(4- nitrophenyl )-1,3-
oxazoline derivative of formula 5 ; (ii) oxidizing oxazoline compound of formula 5 in
presence of dimethylsulfoxide, an acid activator in an aprotic solvent at a
temperature in the range of -80 to 0°C for a period in the range of 1 to 2 hrs to get
formyl derivative of formula 6, (iii) reducing the formyl derivative of formula 6 in
presence of a reducing agent such as herein described in aprotic solvent and an
inorganic salt selected from metallic chloride at a temperature ranging between -10
to 40°C to give compound of formula 7, (iv) isomerizing and hydrolyzing compound
of formula 7 to obtain threo dl base ( 2- amino-1- (4- nitrophenyl)- propane-1,3-diol
) of formula 2_ by the method such as herein described.
2. An improved process of racemization as claimed in claim(1) wherein the acid activator used is selected from oxalyl chloride, trifluoroacetic anahydride, bis-trichloromethyl carbonate, cyanouryl chloride, phosphorous pentaoxide.
3. An improved process of racemization as claimed in claims 1 & 2 wherein the oxidation of compound of formula 5 to compound of formula 6 is carried out in an aprotic solvent selected from group consisting of dichloromethane, dichloroethane, Tetrahydrofuran.
4. A process as claimed in claims 1 & 3 wherein the oxidation of compound of formula
5 is carried out at a temperature preferably between -40°c and-20°C for a period of
1 to 2 hrs.
5. An improved process as claimed in claims 1 to 4, wherein the reducing agent is selected from group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, Red Al, lithium aluminum hydride.
6. An improved process as claimed in claims 1 to 5, wherein the reducing agent used is preferably sodium borohydride,
7. An improved process as claimed in claims 1 to 6, wherein the reduction of compound of formula 6 to compound of formula 7 is carried out in a protic solvent selected from methanol, ethanol, propanol ,butanol, isopropanol.
8. A process as claimed in claims 1 to 7, wherein the reduction of compound of formula 6 to compound of formula 7 is carried out in presence of an inorganic salt such as calcium chloride, aluminum chloride, zinc chloride preferably calcium chloride.
9. A process as claimed in claims 1 to 8, wherein the reduction of compound of formula 6 to compound of formula 7 is carried out at temperature preferably between 5 to 10° C for a period of 1/2 to 2 hrs and then warming to higher temperature.
10. An improved process as claimed in claims 1 to 9, where the oxazoline alcohol of formula 7 composed of 1:1 mixture of erythro isomer [4R,5S- 4- hydroxymethyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] and the threo isomer [4S,5S- 4-hydroxymethyl-5-(4-nitrophenyl)-2-methyl/phenyl-1,3-oxazoline ] is heated in acidic medium to effect solvolysis of oxazoline to open chain amide and isomerization of erthro isomer to more stable threo isomer, the crude amido diol with out purification is hydrolyzed in presence of aqueous alkali to obtain threo racemic ammodiol of formula 2
11. A process as claimed in claims 1 to 10 wherein the acidic medium employed is a mixture acetic anhydride and acetic acid or methane sulfonic acid in dichloroethane.
12. A process as claimed in claims 1 to 11 wherein the aminodiol without purification is directly hydrolyzed by heating in presence aqueous metal hydroxide selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide.
13. A process as claimed in claims 1 to 12 wherein the aqueous metal hydroxide used is preferably sodium hydroxide of strength 1 to 20 % preferably 5 % for period of 1-20 hrs preferably for 6-8 hrs, the racemic threo aminodiol 2, which is isolated by filtration and recrystallization.
14. An improved process of racemization of 1S,2S-(+)-2-amino-1- (4-nitrophenyl )-1,3-propanediol (d base ) of formula 2 of the drawing accompanying this specification substantially as herein described with reference to the examples and drawing accompanying this specification.

Documents:

992-del-2003-abstract.pdf

992-del-2003-claims.pdf

992-del-2003-complete specification (granted).pdf

992-del-2003-correspondence-others.pdf

992-del-2003-correspondence-po.pdf

992-del-2003-description (complete).pdf

992-del-2003-drawings.pdf

992-del-2003-form-1.pdf

992-del-2003-form-2.pdf

992-del-2003-form-3.pdf

« Previous Patent

Next Patent »

Patent Number

217523

Indian Patent Application Number

992/DEL/2003

PG Journal Number

38/2008

Publication Date

19-Sep-2008

Grant Date

27-Mar-2008

Date of Filing

12-Aug-2003

Name of Patentee

COUNCL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG NEW DELHI-110 001,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	DEVI PRASAD SAHU	CENTRAL DRUG RESARCH INSTITUTE CHATTAR MANZIL PALACE, LUCKNOW-226 001,INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA