Title of Invention

"PROCESS FOR THE SYNTHESIS OF ENANTIOMERICALLY PURE ALKYS (S)- 4-BROMO-3-HYDROXYBUTANOATE"

Abstract

The present invention provides an improved synthesis of enantiomerically pure Alkyl (Methyl or Ethyl) (S)-4-Bromo-3-hydroxybutanoate has been achieved. The synthetic strategy features use of D-erythronolactone as the starting substrate. Its ready conversion to Alkyl 2,4-dibromo-3-hydroxybutanoate and selective C-2 debromination affords optically pure Alkyl (,S')-4-Bromo-3-hydroxybutanoate. The title compound is a key intermediate in arriving at the substrates for HMG-coA reductase inhibitors.

Full Text

PROCESS FOR THE SYNTHESIS OF ENANTIOMERICALLY PURE ALKYL (S)-4-BROMO-3-HYDROXYBUTANOATE Field of the invention The present invention relates to a process for the synthesis of enantiomerically pure Alkyl (S)-4-bromo-3-hydroxybutanoate. (Formula Removed) Formula 1 wherein R is Alkyl (methyl, ethyl, propyl or butyl). More particularly the present invention relates to one pot conversion of D-Erythronolactone to Alkyl (S)-4-bromo-3-hydroxybutanoate. Background of the invention Alkyl (S)-4-bromo-3-hydroxybutanoate is an important intermediate for the synthesis HMG-coA reductase inhibitors. Another very valuable, synthetic intermediate, (R) -4-cyano-3-hydroxybutyric acid ester, required in the synthesis of HMG-coA reductase inhibitors is obtained using Alkyl (.S)-4-bromo-3-hydroxybutanoate as a starting substrate. It is also needed in the synthesis of L-carnitine and GABOB, molecules of medical significance in lipid biosynthesis, [(a) Karanewsky, D. S.; Biller, S. A.; Gordon, E. M.; 1988, Ger. Offen DE 3817375; (b) Sletzinger, M; Verhoeven, T. R.; Volante, R.P.; McNamara, J. M.; Corley, E. G.; Liu, T.M.H. Tetrahedron Letters. 1985, 26, 2951; (c) Brower, P. L; Butler, D. E.; Deering, C. F.; Ee, T. V.; Millar, A.; Nanninga, T. N.; Roth, B.D. Tetrahedron Betters. 1992, 33, 2279; (d) Hollingsworth, R. I.; Wang, G. Tetrahedron Asymmetry. 1999,10, 1895]. In the prior-art, the synthesis of Alkyl (5)-4-bromo-3-hydroxybutanoate has been accomplished employing various synthetic strategies. A commonly used strategy for the synthesis of Alkyl (S)-4-bromo-3-hydroxybutanoate is to employ the use of (S)-3-Hydroxybutyrolactone as a starting point. (S^-3-Hydroxybutyrolactone is first reacted with hydrogen bromide in acetic acid, followed by quenching in ethyl alcohol affords the Ethyl (5)-4-bromo-3-hydroxybutanoate. (Jacks, T; Elliot, B; Donald, E, WO 98/04543, PCT/US97/11654. 1997; Hollingsworth, R. I.; Wang, G. Tetrahedron Asymmetry. 1999, 10,1895). In another prior art method, Alkyl (5)-4-halo-3-hydroxybutanoate can be obtained by the reaction of epichlorohydrin with CO and an aliphatic alcohol in presence of cobalt carbonyl catalyst (Kobayashi, 1. et al JP56068644 1981). In yet another prior-art method, Alkyl (5)-4-halo-3-hydroxybutanoate was obtained by treatment of y-haloacetoacetic ester with fungus selected from the group consisting of Trichosporon, Rhodotorula, Debaryomyces, Cryptococcus, Torulopsis and Candida (Hasegawa, M. et al JP60251890 1985). In still another prior art method, Alkyl (S)-4-halo-3-hydroxybutanoate was obtained by stereo specific asymmetric reduction of the p-carbonyl group in y-halo-acetoacetic esters, using microbial reduction procedures. The yeast selected from the group Candida genus, Debaryomyces genus, Endomyces genus, Geotricum genus was the preference (Takahashi, S. et al JP61146191 1986). In another prior-art method, Alkyl (5)-4-halo-3-hydroxybutanoate needed as a raw material for the synthesis of L-'carnitine was once again obtained by stereospecific asymmetric reduction of the p-carbonyl group in y-halo-acetoacetic esters. However this time the microorganism used belonged to Sporobolomyces genus (Yamada, H.etalJP621952901987). In yet another prior-art method, a bacterium stain [eg Ccllulomonas sq. AKU 672 strain (PERM P-9026), etc] was used for asymmetric reduction of the p-carbonyl group in y-halo-acetoacetic esters, to obtain y-halo-p-hydroxybutyric ester (Yamada, H. et al JP63123387 1988). In still another prior art method, NADPH-dependent reductase of the reduction type derived from the fungus belonging to the genus Sporobolomyces was used for the reduction of y-halo-acetoacetic esters, for obtaining the y-halo-p-hydroxybutyric ester (Yamada, H. et al JP63304991 1988). In yet another prior art method, an enzyme extracted from baker's yeast has been used for reduction of the p-carbonyl group in y-halo-acetoacetic esters, for the obtension of y-halo-p (^)-hydroxybutyric ester (Hasegawa. M, et al JP1060391 1989) In another prior-art method, specific microorganism belonging to the genus Stemphylium has been used for reduction of the [3-carbonyl group in y-halo-acetoacetic esters, for the obtension of y-halo-p (S^-hydroxy butyric ester (Onishi. I, et alJP6038776 1994). In another prior art method, microbial reduction has been used for the production of optically active 4-halo-3-hydroxybutyric acid esters (Kobayashi. Y, et al EP0606899 1994). In yet another prior art method, specific microorganism belonging to the genera Yarrowia, Filobasidium, Metschnikowia, Galactomyces, Ambrosiozyma, Trichosporonoides etc, has been used for reduction of the (3-carbonyl group in y-halo-acetoacetic esters, for the obtension of y-halo-p-hydroxybutyric ester (Takai. Y, et al EP0737751 1996). In still another prior art method, the (S)-4-halo-3-hydroxybutyric acid ester was prepared by reduction of 4-halo-acetic acid ester using (3-ketoacyl-acylcarrier protein reductase for stereospecificity (Yamamoto, H. EP 0955375, 1999). In yet another prior-art method, the optically active 4-chloro-3-hydroxy butanoic acid ester has been obtained by the acid hydrolysis of optically active 4-chloro-3-hydroxybutyronitrile. (Sakaguchi, J JP 4124157, 1992). In still another prior-art method, 4-halo-3-hydroxybutyronitrile has been hydrolysed using nitrile hydrolase derived from a bacterium belonging to the genus Arthobacter, Nocardia, Pseudonocardia, Rhodococcus or Caseobacter to produce 4-halo-3-hydroxybutyric acid (Fujio, T. JP 4360689, 1992). In another prior-art method, the optically active 4-chloro-3-hydroxy butanoic acid ester has been obtained by the hydrolysis of optically active 4-chloro-3-hydroxybutyronitrile using enzyme nitriiase from a bacterium belonging to the genus Bacillus, Brevibacterium, Cornybacterium, Escherichia, Pseudomonas, Cytophaga, Alcaligenes, etc. (Nakayama, K. JP 61173789, 1986). In still another prior art method, optically active 3,4-dihydroxy butyric acid derivative or 3-hydroxybutyrolactone is reacted with a brominating agent preferably hydrogen bromide to afford the title compound (Taoka, N. M. JP 4149151, 1992). In yet another prior art method, potassium salt of D-erythronate obtained from D-arabinose was treated with brominating agent (HBr) and subsequent hydrogenation using Pd/C afforded the title compound (Bock, K. Acta. Chemica. Scandinavica. B 37, 1983,341-344). Some of the major drawbacks of the methods known in the prior art are such as (i) Specificity of the micro-organism (ii) Lack of specificity in the reduction (iii) Difficulties involved in work-up procedure (iv) Difficulties associated in handling microbial cultures and cells (v) Overall low yield of the desired compound (vi) Low enantioselectivity and contamination of the undesired isomer. In view of the above drawbacks and disadvantages of prior art procedures, it is desirable to develop an improved, efficient and enantioselective process for the synthesis of Alkyl (,S)-4-bromo-3-hydroxybutanoate. Objects of the invention The main object of the present invention is to provide an improved and efficient process for the synthesis of enantiomerically pure Alkyl (5)-4-bromo-3-hydroxybutanoate, which overcomes the drawbacks of the prior art processes. Summary of the invention The present invention employs conversion of D-erythronolactone to dibromo derivative and subsequent selective C-2 denomination to afford the target. The significant feature of the present invention is: (i) The process involves only two steps and both the steps can be effected in one pot; (ii) The reaction involved in each step according to the present invention can be carried out at room temperature; (iii) The process leads to good yields of the desired compound; (iv) The process gives product of high optical purity; (v) The process is enantiospecific (vi) Both the enantiomers of Alkyl -4-bromo-3-hydroxybutanoate can be prepared using this process by using either D-erythronolactone or L-erythronolactone Accordingly, the present invention provides an improved, efficient and enantioselective process for the synthesis of Alkyl (S)-4-bromo-3-hydroxybutanoate of formula 1, which comprises: (i) treating D-erythronolactone of formula 2 with 33%HBr in acetic acid at room temperature for a period of 20 to 30 h and then with an alkyl alcohol to obtain a dibromo derivative of formula (3); (ii) treating the dibromo derivative of formula 3 with zinc in presence of a proton source, for a period of 4 to 8 h at room temperature to obtain the compound of formula (1). In one embodiment of the invention the alcohol used is selected from the group consisting of methyl, ethyl, propyl and butyl alcohol. In another embodiment of the invention the ratio of HBr to lactone of formula 2 is not more than 2.5. In another embodiment of the invention the ratio of zinc to the dibromo derivative of formula 3 is not more than 5.0. In yet another embodiment of the invention, the proton source is derived from the group consisting of weak acids, primary amine salts and secondary amine salts, and is preferably ammonium chloride. In still another embodiment the dibromo derivative of formula 3 does not require isolation. In another embodiment of the invention, both enantiomers of Alkyl-4-bromo-3-hydroxybutanoate are prepared by using both D to L erythronolactone as the starting substrate. Detailed description of the invention The present invention provides a process for the preparation of employs conversion of D-erythronolactone to dibromo derivative and subsequent selective C-2 debromination to afford the target. The significant feature of the present invention is: (i) The process involves only two steps and both the steps can be effected in one pot; (ii) The reaction involved in each step according to the present invention can be carried out at room temperature; (iii) The process leads to good yields of the desired compound; (i v) The process gives product of h igh optical purity; (v) The process is enantiospecific (vi) Both the enantiomers of Alkyl -4-bromo-3-hydroxybutanoate can be prepared using this process by using either D-erythronolactone or Z,-erythronolactone The process of the invention essentially comprises an improved, efficient and enantioselective and one pot process for the synthesis of Alkyl (S)-4-bromo-3-hydroxybutanoate, which comprises: (i) treating D-erythronolactone of formula 2 with 33%HBr in acetic acid at room temperature for a period of 20 to 30 h and then with an alkyl alcohol to obtain a dibromo derivative of formula (3); (ii) treating the dibromo derivative of formula 3 with zinc in presence of a proton source, for a period of 4 to 8 h at room temperature to obtain the compound of formula (1). (Formula Removed) Formula 1 The alcohol used is selected from the group consisting of methyl, ethyl, propyl and butyl alcohol. The ratio of HBr to lactone of formula 2 is not more than 2.5 and the ratio of zinc to the dibromo derivative of formula 3 is not more than 5.0. The proton source is derived from the group consisting of weak acids, primary amine salts and secondary amine salts, and is preferably ammonium chloride. The dibromo derivative of formula 3 does not require isolation. Both enantiomers of Alkyl-4-bromo-3-hydroxybutanoate can be prepared by using both D and L erythronolactone as the starting substrate. The process of the present invention is described in details in schematic diagram here in below (Formula Removed) Formula 1 (Formula Removed) Formula 2 (Formula Removed) Formula 3 The process of the present invention is described herein below with examples, which are illustrative and should not be construed to limit the scope of present invention in any manner. Example 1 To a 250 mL flask equipped with a magnetic stirrer bar was charged 8.0 g of D-erythronolactone (m.p. 108-110 °C), 40.0 mL of 33% HBr in acetic acid (w/v). The contents were stirred at room temperature (35°C to 38°C) for 18 h and TLC analysis indicated consumption of starting material. The contents of the flask were distilled to remove the acetic acid at laboratory vacuum and at a temperature of 45°C to 50°C to provide dark orange coloured oil of 2,4-dibromo-3-hydroxy butyric acid.To the same flask containing the above 2,4-dibromo-3-hydroxybutyric acid, is added 40 mL of methanol and stirring continued at room temperature (35°C to 38°C) for 16 h and TLC indicated consumption of starting material and formation of Methyl-2, 4-dibromo-3-hydroxy butanoate. Excess of methanol is distilled and the residual orange liquid is purified using silica-gel chromatography with Hexane: EtOAc (4 :1) as eluent, to afford 13.1 (70%) of Methyl 2,4-dibromo-3-hydroxybutanoate To a 100 mL flask containing 13.0 g of Methyl 2,4-dibromo-3-hydroxybutanoate in 40 mL of methanol is charged, 5.07 g of ammonium chloride and 15.4 g of zinc powder and stirring continued at room temperature (35°C to 38°C) for a period of 6 h and TLC indicated consumption of Methyl-2, 4-dibromo-3-hydroxy butanoate. The content of the flask is filtered through a pad of Celite to remove the suspended zinc and zinc salts, and the solid residue in the funnel washed with additional methanol. The filtrate along with the washings is distilled to remove methanol under vacuum at 35°C and the product obtained, Methyl (5)-4-bromo-3-hydroxybutanoate is purified using silica gel chromatography using Hexane: EtOAc (4 :1) as eluent or distilled at 78°C-80°C (1 mm of Hg) to afford 4.6 g (49.6 %). Example 2 To a 250 mL flask equipped with a magnetic stirrer bar was charged 8.0 g of D-erythronolactone (m.p. 108-110°C), 40.0 mL of 33% HBr in acetic acid (w/v) . The contents were stirred at room temperature (35°C to 38°C) for 18 h and TLC analysis indicated consumption of starting material. The contents of the flask were distilled to remove the acetic acid at laboratory vacuum and at a temperature of 45°C to 50°C to provide dark orange coloured oil of 2,4-dibromo-3-hydroxy butyric acid. To the same flask containing 2,4~dibromo-3-hydroxy-butyric acid, is added 40 mL of methanol and stirring continued at room temperature (35°C to 38°C) for 16 h and TLC indicated consumption of starting material and formation of Methyl-2, 4-dibromo-3-hydroxy butanoate. To the same flask is charged, 7.25 g of ammonium chloride and 22 g of zinc powder and stirring continued at room temperature (35°C to 38°C) for a period of 5 h and TLC indicated consumption of Methyl-2,4-dibromo-3-hydroxy butanoate. The content of the flask is filtered through a pad of Celite to remove the suspended zinc and zinc salts, and the solid residue in the funnel washed with additional methanol. The filtrate along with the washings is distilled to remove methanol under vacuum at 35°C and the product obtained, Methyl (5)-4-bromo-3-hydroxybutanoate is purified using silica gel chromatography using Hexane: EtOAc (4:1) as eluent or distilled at 78°C-80°C (1 mm of Hg) to afford 6.5 g (48,6%) [a]598 = -16.2(cl,CHCl3) Example 3 To a 250 mL flask equipped with a magnetic stirrer bar was charged 8.0 g of D-erythronolactone (m.p. 108-110°C), 40.0 mL of 33% HBr in acetic acid (w/v) . The contents were stirred at room temperature (35°C to 38°C) for 18 h and TLC analysis indicated consumption of starting material. The contents of the flask were distilled to remove the acetic acid at laboratory vacuum and at a temperature of 45°C to 50°C to provide dark orange coloured oil of 2,4-dibromo-3-hydroxy butyric acid. To the same flask containing 2,4-dibromo-3-hydroxy-butyric acid, is added 40 mL of ethanol, 0.lmL of concentrated sulphuric acid, and stirring continued at 60°C for 7 hrs and TLC indicated consumption of starting material and formation of Ethyl-2, 4-dibromo-3-hydroxy butanoate. To the same flask is charged, 7.25 g of ammonium chloride and 22 g of zinc powder and stirring continued at room temperature (35°C to 38°C) for a period of 5 h and TLC indicated consumption of Ethyl-2, 4-dibromo-3-hydroxy butanoate. The content of the flask is filtered through a pad of Celite to remove the suspended zinc and zinc salts, and the solid residue in the funnel washed with additional ethanol. The filtrate along with the washings is distilled to remove ethanol under vacuum at 40°C and the product obtained, Ethyl (S)-4-bromo-3-hydroxybutanoate is purified using silica gel chromatography using Hexane: EtOAc (4 :1) as eluent to afford 6.3 g (44.0%) [a]598 = -14.0(cl.l,CHCl3) The advantages of the present invention are as follows: (i) The two steps process can be carried out in one pot. (ii) The reactions involved in each step, according to the present invention could be carried at room temperature (35°C to 38°C). (iii) The process leads to good yields of the desired products. (iv) Both the enantiomers of the Methyl-4-bromo-3-hydroxybutanoate could be prepared using this process. (v) The process gives optically pure products. (vi) The alkyl part in the ester could be changed from methyl to other group by use of other alcohol. We Claim: 1. A process for the synthesis of Alkyl (S)-4-bromo-3-hydroxybutanoate of formula 1, which comprises: (i) treating D-erythronolactone of formula 2 with 33%HBr in acetic acid at room temperature for a period of 20 to 30 h and then with an alkyl alcohol to obtain a dibromo derivative of formula (3); (ii) treating the dibromo derivative of formula 3 with zinc in presence of a proton source, for a period of 4 to 8 h at room temperature to obtain the compound of formula (1). (Formula Removed) 2. A process as claimed in claim 1 wherein the alcohol used is selected from the group consisting of methyl, ethyl, propyl and butyl alcohol. 3. A process as claimed in claim 1 wherein the ratio of HBr to lactone of formula 2 is not more than 2.5. 4. A process as claimed in claim 1 wherein the ratio of zinc to the dibromo derivative of formula 3 is not more than 5.0. 5. A process as claimed in claim 1 wherein the proton source is derived from the group consisting of weak acids, primary amine salts and secondary amine salts. 6. A process as claimed in claim 1 wherein the proton source is ammonium chloride. 7. A process as claimed in claim 1 wherein the dibromo derivative of formula 3 does not require isolation. 8. A process as claimed in claim 1 wherein the starting substrate are both D and L erythronolactone to obtain both enantiomers of Alkyl-4-bromo-3-hydroxybutanoate. 9. A process for the synthesis of Alkyl (S)-4-bromo-3-hydroxybutanoate of formula 1 substantially as herein describe with reference to examples accompanying this specification.

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