Title of Invention

A PROCESS FOR THE EFFICIENT SYNTHESIS OF (2S, 3R)-2-0-BENZYL-3, 4-O-ISOPROPYLIDENE-D-ERYTHRITOL

Abstract

A process for the efficient synthesis of (2S, 3R),2-O-BENZYL-3,4-O-ISOPROPYLIEDENE-D-ERYTHRITOL, comprising the steps of stirring a solution of D-erythronolnctone and a secondary amine (N,N'-dimethyl amine, morpholine, pyrrolidene) in methanol; removing the methanol end suspending the residue in acetone and a chemical selected from (i) 2,2'-dimethoxy propane along with. anhydrous para-toluene sulphonic acid (ii) a catalytic amount of concentrated sulphuric acid, stirring the same until the reaction is complete; evaporating acetone completely and taking the residue in ethyl acetate;successively washing the ethyl acetate layer with saturated sodium bicarbonate solution and water; drying the ethyl acetate Iayer over anhydrous sodium sulphate and evaporating to obtain a solid; crystallising the same from benzenehexane mixture to give compound 3 (Mp 79 -8 1 °C); adding a suspension of NaH in dry DMF to a solution of compound 3 in dry DMF, stirring the mixture; adding benzyl bromide and thereafter adding saturated anunoniurn chloride solution; extracting the product with ethyl acetate, drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating to obtain a solid, crystallising the same from benzehe-hexene mixture to yield compound A as u while crystalline solid (Mp 83°C); adding sodium borohydride to a solution of the. Compound in distilledand heating the reaction mixture evaporating the ethanol completely and adding water extracting the aqucous layer with ethyl acetate and drying the combined organic layer over anhydrous sodium sulphate removing the solvent and purifying the residue by silica gel column ohromalography to obtain compound I as a colourless oil the said compounds 3,4 and 1 having the respective structure as given under wherein R<SUP>1</SUP>,R<SUP>1</SUP> is alkyl (represented by ,methyl,ethyl and the combinations);-CH<SUB>2</SUB>(CH<SUB>2</SUB>)2CH-;CH<SUB>2</SUB>(CH<SUB>2</SUB>)3CH<SUB>2</SUB>-;CH<SUB>2</SUB>CH<SUB>2</SUB>OCH<SUB>2</SUB>CH<SUB>2</SUB> and OBn =OCH<SUB>2</SUB> phenyl;-OCH<SUB>2</SUB>-substituted-phenyl(substitutent:alkyl,halogen,alkoxy,azido)

Full Text

This invention relates to a process for the efficient synthesis of (2S, 3R)-2-0-BENZYL-3,4TO-ISOPROPYLIDENE-D-ERYTHRITOL. This invention proposes a process for the preparation of 1, Fig. 1, which is enantiospecific, since this is based on chiron approach, starting from D-erythronolactone as a chiral pool starting material. The said process also involves the reduction of a-alkoxy amide to an alcohol using sodium borohydride. The advantage of the process proposed herein are that the nimiber of steps involved in the synthesis are less; the chemical reagents used are not hazardous or poisonous; all the reactions are clean and therefore do not necessitate tedious work-up procedures to isolate the compounds; and the reactions can be carried out on multigram scale. Various other features of this invention will be apparent from the following further description thereof given hereunder. Fig-2 represents the complete synthesis to arrive at 1 from D-erythronolactone 2 as starting substrate. Following is the description of the process from start to finish. It includes the conversion of 2 -> 3^ 4 -> 1. The process according to this invention, for the efficient synthesis of (2S, 3R)-2-0-BENZYL-3,4-0-ISOPROPYLIDENE-D-ERYTHRITOL 1, comprises the steps of stirring a solution of D-erythronolactone 2 and a secondary amine (N,N"-dimethyl amine, morpholine, pyrrolidene) in methanol and suspending the residue in acetone and a chemical selected from (i) 2,2"-dimethoxy propane along with anhydrous para-toluene sulphonic acid (ii) a catalytic amount of concentrated sulphuric acid, stirring the same until the reaction was complete; evaporating acetone completely and taking the residue in ethyl acetate; successively washing the ethyl acetate layer with saturated sodium bicarbonate solution and water; drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating the same to obtain a solid; crystallizing the same from benzene-hexane mixture to give compound 3 (Mp 79-81°C); adding a suspension of NaH in dry DMF to a solution of compound 3 in dry DMF, stirring the mixture; adding benzyl bromide and thereafter adding saturated ammonium chloride solution; extracting the of concentrated sulphuric acid, and stirring the same at 15°C - 60°C for Ih - 6h until the reaction was complete. 3. Evaporating acetone completely and taking the residue in ethyl acetate and successively washing the ethyl acetate layer with saturated sodium bicarbonate solution and water. 4. Drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating the same to obtain a solid. 5. Crystallising the same from benzene-hexane mixture to give compound 3 (Mp79°C-81°C). 6. Adding a suspension of 60% NaH (200 mg - 940 mg) in dry DMF (5 ml - 10 ml) to a solution of compound 3 (2 g - 6 g) in dry DMF (15 ml - 30 ml), stirring the mixture at -10°C - 0°C for 15min - Ih. 7. Adding benzyl bromide (0.55 ml - 2.65 ml) and after Ih - 6h adding saturated ammonium chloride solution. 8. Extracting the product with ethyl acetate, drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating to obtain a solid. 9. Crystallising the same from benzene-hexane mixture to yield compound 4 as a white crystalline solid (Mp 83 °C). 10. Adding sodium borohydride (60 mg - 350 mg) to a solution of the compound 4 (1 g -4 g) in distilled ethanol (2 ml -15 ml), and heating the reaction mixture (20°C -60°C for 6 h -18 h), evaporating the ethanol completely and adding water. 11. Extracting the aqueous layer with ethyl acetate and drying the combined organic layer over sodium sulphate, removing the solvent and purifying the residue by silica gel column chromatography to obtain compound 1 as a colourless oil. By way of further illustration of the process proposed herein and not by way of limitation. Examples of carrying out the said process with specific values of parameters are set out herein below: SPECIFIC EXAMPLE 1 Synthesis of compound 3 [Conversion 2 -> 3] A solution of D-erythronolactone (4.00 g, 33.89 mmol) and distilled morpholine (3.25 ml, 37.28 mmol) in methanol (25ml) was stirred for 8 h at 32°C. Methanol was removed and the residue was suspended in acetone (30 ml) and 2,2"-dimethoxy propane (8.44 ml, 68.82 nmiol) along with anhydrous j^ara-toluene sulphonic acid (150 mg - 2.03 g) and stirred at 32°C for 1.5 h. Acetone was completely evaporated and the residue was taken in ethyl acetate. The ethyl acetate layer was successively washed with saturated sodium bicarbonate solution and water. The ethyl acetate layer was dried over anhydrous sodium sulphate and evaporated to get a solid which was crystallized from benzene - hexane mixture to give compound 3 (6.8 g, 28.09 mmol, 83%) as a white solid Mp 79-81°C. Synthesis of compound 4 [Conversion 3 -> 4] To a suspension of 60% NaH (940 mg, 24.48 mmol) in dry DMF (5 ml) was added a solution of compound 3 (5 g, 20.40 mmol) in dry DMF (15 ml) and allowed the mixture to stir at 0°C for 15 min and added benzyl bromide (2.65 ml, 22.45 mmol). After Ih added saturated ammoniimi chloride solution, and extracted the product with ethyl acetate. Dried the ethyl acetate layer over anhydrous sodium sulphate and evaporated to obtain a solid which was crystallized from benzene-hexane mixture to afford compound 4 (5.60 g, 16.73 mmol; 82%) as a white crystalline solid Mp 83°C. Synthesis of compound 1 [Conversion 4 -> 1] To a solution of compound 4 (3g, 8.95 mmol) in distilled ethanol (12 ml) was added sodium borohydride (386 mg, 10.74 mmol) and heated the reaction mixture at 60°C. After 18 hours, evaporated ethanol completely and added water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over sodium sulphate. The solvent was removed and the residue was purified by silica gel column chromatography (hexane: EtOAc, 7.5:2.5) affording compound 1 (1.69 g, 6.71 mmol, 75%) as a colorless oil. SPECIFIC EXAMPLE 2 Synthesis of compound 3 by an alternative procedure [Conversion 2 -> 3] A solution of D-erythronolactone (4.00 g, 33.89 mmol) and distilled morpholine (3.25 ml, 37.28 mmol) in methanol (25ml) was stirred for 8 h at 32°C. Methanol was removed and the residue was suspended in acetone (30 ml) along with catalytic amount of concentrated .sulphuric acid and stirred at 32°C for 1.5 hours. Acetone was completely removed under vacuum and the residue was taken in ethyl acetate. The ethyl acetate layer was successively washed with saturated sodium bicarbonate solution and water. The ethyl acetate layer was dried over anhydrous sodium sulphate and evaporated to get a solid which was crystallized from benzene- hexane mixture to give compound 3 (6.8 g, 28.09 mmol, 78%) as a white solid Mp 79-81 °C. In the above Example, Acetone along with acid can be replaced with 2,2"-diniethoxy propane for isopropylidenation [ketal protection] in the conversion of compound 2 to compound 3. Also the benzylation in conversion 3 to 4 can be done using benzyl bromide/silver oxide mixture, We claim: 1. A process for the efficient synthesis of (25, 3/R)-2-C>-BENZYL-3,4-6>-iSOPROPYLIEDENE-D-ERYTHRITOL, comprising the steps of stirring a solution of D-erythronoIactone and a secondary amine (N,N"-dimethyl amine, morpholine, pyrrolidene) in methanol; removing the methanol and suspending the residue in acetone and a chemical selected from (i) 2,2"-dimethoxy propane along with anhydrous para-toluene sulphonic acid (ii) a catalytic amount of concentrated sulphuric acid, stirring the same until the reaction is complete; evaporating acetone completely and taking the residue in ethyl acetate; successively washing the ethyl acetate layer with saturated sodium bicarbonate solution and water; drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating to obtain a solid; crystallising the same from benzene-hexane mixture to give compound 3 (Mp 79 -81°C); adding a suspension of NaH in dry DMF to a solution of compound 3 in dry DMF, stirring the mixture; adding benzyl bromide and thereafter adding saturated ammonium chloride solution; extracting the product with ethyl acetate, drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating to obtain a solid; crystallzing the same from benzehe-hexaiie mixture to yield, compound ,4 as a white crystalline solid (Mp 83°C); adding sodium borohydride to a solution of (he compound 4 in distilled elhanol, and heating the reaction mixture, evaporating the ethanol completely and adding water; extracting the aqueous layer with ethyl acetate and drying the oombined organic layer over anhydrous sodium sulphate, "removing the solvent and purifying the residue by silica gel column ,chroomatography to obtain compound I us a colourless oil the said compounds under substituted- Phenyl (substituent: alkyl, halogen, alkoxy, azido) 2. A process as claimed in claim 1 comprising tile stirring of a solution of D- erylhronolactone (1,00 g - 5,00 g) and secondary amine (N.N"-dimethylamine, morphollne, pyrollidene) (0,80 ml - 4,00 ml) in methanol (5 mJ - 25 ml) for 5h -20hat20°C-50"C, 3. A process as claimed in claim 1 or claim 2 comprising removing the methanol and suspending the residue in acetone (5 ml 30 ml) and a chemical selected from (i) 2,2"-dimethoxy propane (1 ml - 8 ml) along with anhydrous para- toluene sulphonic acid (150 mg - 2;03 g) (i) a catalytic amount of concentrated sulphuric acid, and stirring the same" at 15C- 60C for 1 h - 6h until the reaction was completely over. 4. A process as claimed in claim 3 claims comprising evaporating acetone and taking the residue in ethyl acetate and successively washing the ethyl acetate layer with saturated sodium bicarbonate solution and water. 5. A process as claimed in claim 4 comprising drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating the same to obtain a solid. 6. A process as claimed in claim 5 comprising crystallising the same from benzene-hexane mixture to giv^ compound 3 (Mp 79°C - 81°C). 7. A process as claimed in claim 6 comprising adding a suspension of 60% NaH (200 mg - 940 mg) in dry DMF (5 ml - 10 ml) to a solution of compound 3 (2 g - 6 g) in dry DMF (15 ml - 30 ml), stirring the mixture at -10°C - 0°C for 15 min- Ih. 8. A process as claimed in claim 7 comprising adding benzyl bromide (0.55 ml -2.65 ml) and after Ih - 6h adding saturated ammonium chloride solution. 9. A process as claimed in claim 8 comprising extracting the product with ethyl acetate, drying the ethyl acetate layer over anhydrous sodium sulphate and evaporating to obtain a solid. 10. A process as claimed in claim 9 comprising crystallising the same from benzene - hexane mixture to yield compound 4 as a white crystalline solid (Mp 83°C). 11. A process as claimed in claim 10 comprising adding sodium borohydride (60 mg - 350 mg) to a solution of the compound 4 (Ig - 4 g) in distilled ethanol (2ml - 15 ml), and heating the reaction mixture (20°C - 60°C for 6h - 18h), evaporating the ethanol completely and adding water. 12. A process as claimed in claim 11 comprising extracting the aqueous layer with ethyl acetate and drying the combined organic layer over sodium sulphate, removing the solvent and purifying the residue by silica gel column chromatography to obtain compound 1 as a colourless oil. 13. A process for the efficient synthesis of (25, 3R)-2-0-BENZYL-3,4-0- ISOPROLPYLIDENE-D-ERYTHRITOL substantially as herein described and as illustrated by the Examples. 14. (25,3iR)-2-0-BENZYL-3,4-0-ISOPROLPYLIDENE-D-ERYTHRITOL, whenever synthesized by a process as claimed in any one of the preceding claims.

Documents:

0543-mas-2002 claims-duplicate.pdf

0543-mas-2002 claims.pdf

0543-mas-2002 correspondence-others.pdf

0543-mas-2002 correspondence-po.pdf

0543-mas-2002 description(complete)-duplicate.pdf

0543-mas-2002 description(complete).pdf

0543-mas-2002 form-1.pdf

0543-mas-2002 form-19.pdf

0543-mas-2002 form-26.pdf

543-mas-2002 abstract.pdf

abs-543-mas-2002.pdf