Title of Invention

A PROCESS FOR PREPARING ENANTIOMERICALLY PURE (S)-3-HYDROXY-γ-BUTYROLACTONE.

Abstract

A process for the preparation of enantiomerically pure (5)-3-hydroxy-y-butyrolactone by dissolving D-hexose source an aqueous alkali solution, heating the solution to a temperature in the range of 40°C to 50°C for a period of 1 to 4 hours to obtain a dark yellow to dark red colour solution; adding a peroxide reagent to the solution obtained, raising the temperature of the reaction mixture upto 70°C, maintaining it for further 8 to 24 hours to obtain a mixture of 3,4-dihydroxybutyric acid glycolic acid, cooling the reaction mixture to 25°C and acidifying to about pH 1.0, evoporating the acidified solution to dryness to remove water and glycolic acid to obtain a yellow syrup, neutralizing the yellow syrup with solid alkali carbonate, extracting with aliphatic organic solvent, drying the organic layer over anhydrous sodium sulphate, evaporating the filtrate to obtain a residue, and purifying the residue of over silica gel column using a mixture of aliphatic organic solvent to obtain the pure compound (5)-3-hydroxy-y-butyrolactone.

Full Text

The present invention relates to a process for the synthesis of optically pure (-S)-hydroxy-y-butyrolactone (Formula-1) from a D-hexose source.(Formula Removed) More particularly the present invention relates to the said process from a glucose source containing 1,4-linked glucose as substituent. (5)-3-Hydroxy-y-butyrolactone is an important synthetic intermediate for variety of chiral compounds. They are key intermediate for preparing neuromediater (R)-GABOB (Tetrahedron 1990, 46, 4277), L-carnitine, a health supported agent (WO 99, 05092), atorvastatin, HMG-CoA reductase inhibitor, a cholesterol lowering drug (Tetrahedron Lett., 1992, 33, 2279) , (5)-3-tetrahydrofuran, an intermediate for AIDS drug (J. Am. Chem. Soc. 1995, 117, 1181; WO 94, 05, 639). (5)-3-Hydroxy-y-butyrolactone has been reported as a satiety agent (Okukado et al. Bull. Chem. Soc. Jpn 1988. 61, 2025) as well as a potentiating agent to neuroleptic drugs (Fuxe et al, US Patent No. 4. 138.484. They are also useful intermediate in synthetic efforts towards natural products. (J. Org. Chem. 1985, 50, 1144, Can. J. Chem. 1987, 65, 195, Tetrahedron Lett.1992, 507.) The literature search on the present invention has been carried out which reveals that the proposed work is quite feasible and would open up a new methodology for the production of secondary chiral feedstock, (5)-3-hydroxy-y-butyrolactone (HGB) from lactose, maltose and maltodextrin. This approach would have its further application in the efficient synthesis of large family of chiral intermediate without the need to design custom chiral synthesis for each new compound. Besides, the method developed would be able to reduce the cost of enantiomerically pure (5)-3-hydroxy-y-butyrolactone at the process level and can influence related industry in a positive manner. In the prior-art, the synthesis of (S)-3-hydroxy-y-butyrolactone has been accomplished employing various synthetic strategies. A commonly used strategy for the synthesis of title compound-[l] and its intermediate (5)-3-hydroxybutyric acid derivatives is from the enzymatic or catalytic reduction of (3-keto ester (EP 452, 143A2, Tetrahedron Lett. 1990, 31, 267; J. Am. Chem. Soc. 1983,105, 5935). In another prior-art method, (5)-3-hydroxy-y-butyrolactone can be obtained from the selective reduction of (I)-malic acid ester (USP, 5,808,107, Chem. Lett. 1984, 1389). In yet another prior-art method, the tretment of a carbohydrate containing glucose substituent in the 4-position, such as cellobiose (p-l,4-linked glucose disaccharide), maltose (the a-1,4 linked isomer, amylose and cellulose with alkali has been shown to produce low yield of the desired material along with D, L-2, 4-dihydroxybutyric acid, glycolic acid isosaccharinic acid, ketones, diketones, glycolic acid and a plethora of other degradation and condensation products (Corbett etal. J. Chem. Soc. 1995, 1431; Green, J. W. J. Am. Chem. Soc. 1956, 78, 1894, Rowell, R. M. et al Carbohydrate Res. 1969, 11,17). In still another prior-art method, the (5)-3,4-dihydroxybutyric acid was obtained as a major product by alkaline degradation of carbohydrates to give the dicarbonyl compound and subsequent reaction with hydrogen peroxide (J. Chem. Soc. 1960, 1932). In another prior-art method, the (5)-3,4-dihydroxybutyric acid was obtained from lactose using base and oxidant. The acid obtained was cyclised to (5)-3-hydroxy-y-butyrolactone under the reaction condition and purified by protection of the two hydroxyl groups to acetonide ester compound, methyl (S)-3,4-O-isopropylidene-3, 4-dihydroxybutanoate which was recyclised to (5)-3-hydroxy-y-butyrolactone under acidic media (WO 98, 04543). In yet another prior-art method, a large number of methods have been developed to make (5)-3,4-dihydroxybutyric acid by alkaline oxidation of carbohydrate containing glucose substituent at the 4-position (USP 5,292,939, 5,319,110 & 5,374,773 (1994). In these methods the dicarbonyl compounds formed is oxidized to f5)-3,4-dihydroxybutyric acid and glycolic acid. In still another prior-art (5)-3,4-dihydroxybutyric acid is prepared from carbohydrate either using base only or using oxygen in base. The yield reported of the desired compound is very low (30%) due the formation of large number of by-products (J. Am. Chem. Soc. 1953, 2245, J. Am. Chem. Soc. 1955, 1431, Carbohydrate Res. 1969, 11, 17, J. Chromatography 1991,549,113). In another prior-art method the target compound has been prepared by alkaline oxidative degradation of polysaccharides such as maltodextrin, starch and cellulose with (1,4) and /or (1,6) linked glucose units. The reaction leads to the complex mixture containing formic acid, oxalic acid, glycolic acid and erythronic acid (J. Am. Chem. Soc.1959, 81, 3136, Synthesis 1997, 597). In yet another prior-art method, the (S)-3,4-dihydroxybutyric acid derivatives has been prepared by oxidation of a-(l,4) linked oligosaccharides with a basic anion exchange resin with an oxidants to give (5)-3,4-dihydroxybutyric acid anion exchange resin complex dissociating the (5)-3,4-dihydroxybutyric acid from anion exchange resin complex. Chiral dihydroxybutyric acids and the corresponding esters, lactones and derivatives have proven to be valuable chemical entities. (5)-3-Hydroxy-y-butyrolactone (HGB) is an important building block to produce other chiral intermediates using classical chemistry methodology. Defunctionalisation of carbohydrate has been attracting much attention as a vibrant synthetic tool for the enantioselective synthesis of a wide variety of compounds. The synthesis of a chiral compound with desired number of chiral center could be achieved by eliminating the unneeded chiral centers quickly from carbohydrate precursors. A large number of a small-scale complex synthesis of (5)-3- hydroxy-y- butyrolactone have been reported demonstrating the value of this compound. Therefore, there is a genuine need for simple and inexpensive method for the large-scale preparation (S)-3- hydroxy-y-butyrolactone and its derivatives. In this project, it is proposed to synthesis (5)-3- hydroxy-y-butyrolactone by using inexpensive readily available carbohydrate material such as maltose, maltodextrin and lactose. A carbohydrate source is treated in a solvent with cumene hydroperoxide in the presence of a base, which leads to the formation of (S)-3,4 -dihydroxybutyric acid and glycolic acid. The subsequent acidification with an acid and removal of solvent affords the desired (5)-3-hydroxy-y- butyrolactone in optically active form. Thus employing the secondary chiral feedstock strategy, the readily available natural raw material could be used to manufacture (5)-3-hydroxy-y- butyrolactone (HGB) which act as a building block for a wide range of products. The new technology offers a practical and cost-effective route and would have advantage since it avoids use of expensive starting material to make the (S)-3- hydroxyl-y- butyrolactone. Some of the major drawback of the method known in the prior-art is such as 1. Expensive metal catalyst used for the reduction of prochiral center e.g. enzymatic or catalytic reduction of p-keto ester. 2. Selective reduction to only one of the two functional groups. 3. Low yields of (S)-3,4-dihydroxybutyric acid and (5)-3-hydroxy-y-butyrolactone 4. The over oxidation of (S)-3,4-dihydroxybutyric acid to formic acid and glycolic acid. 5. Many methods are not suitable as low yield of the desired product is obtained due to the formation of large number of side product such as glycolic acid, isosaccharinic acid, formic acid, ketone, diketone and glycolic acid. 6. The optical purity of the compound is low (poor enantioselectivity). 7. Purification of target compound is very difficult due to the formation of the complex mixture, containing formic acid, oxalic acid, glycolic acid and erythronic acid. 8. Multi-step synthesis. 9. Longer reaction time and high reaction temperature. 10. Overall low yield of the desired compound. In view of the above-mentioned drawbacks and disadvantages of the prior-art procedures, it is desirable to develop an efficient and enatioselective process for the synthesis of (-S)-hydroxy-y-butyrolactone, which overcomes the drawbacks of the prior-art process employing the oxidation of a D-hexose source under basic condition.(Table Removed) Objects of the invention The main object of the present invention is to provide a process for preparing enantiomerically pure (5)-3-hydroxy-y-butyrolactone. Another object of the invention is to provide a simple, inexpensive and economical process of preparing enantiomerically pure (5)-3-hydroxy-y-butyrolactone. The significant feature of the present invention is: i) The process is simple, inexpensive and economical, It is a single step process. The process leads to moderate to good yields of the desired compound, iv) The process gives high enantioselectivity of the product. Summary of the Invention Accordingly, the present invention provides a process for the preparation of enantiomerically pure (5)-3-hydroxy-y-butyrolactone said process comprising steps of: i) dissolving D-hexose source such as herein described in an aqueous alkali solution, ii) heating the solution of step (i) to a temperature in the range of 40°C to 50°C for a period of 1 to 4 hours to obtain a dark yellow to dark red colour solution; iii) adding a peroxide reagent such as herein described to the solution obtained from step (ii), raising the temperature of the reaction mixture upto 70°C, maintaining it for further 8 to 24 hours to obtain a mixture of 3,4-dihydroxybutyric acid of the formula 2 as described in specification and glycolic acid of formula 3 as described, iv) cooling the reaction mixture to 25°C and acidifying to about pH 1.0, v) evoporating the acidified solution of step (v) to dryness to remove water and glycolic acid to obtain a yellow syrup, vi) neutralizing the yellow syrup of step (vi) with solid alkali carbonate, extracting with aliphatic organic solvent, drying the organic layer over anhydrous sodium sulphate, evaporating the filtrate to obtain a residue, and vii) purifying the residue of step (vi) over silica gel column using a mixture of aliphatic organic solvent to obtain the pure compound (5)-3-hydroxy-y-butyrolactone. One of the embodiment of the invention provides a process, in which the base used in step (i) is derived from alkali or alkaline earth metal preferably the alkali metal hydroxide. Another embodiment of the invention, the oxidizing agents used in step (i) is selected from the group consisting of cumene hydroperoxide, tertiary butyl hydroperoxide, and preferably cumene hydroperoxide. Still another embodiment, the molar concentration of base used is in the range of 0.005M - 0.2M and the oxidizing agent used is in the range between 0.05M and 0.2M. Yet another embodiment, the D-hexose source used in step (i) is a glucose source is selected from group consisting of glucose, galactose attached to the glucose substituents in the 4-position and preferably glucose or galactose. Yet another embodiment, the reaction temperature in step (iii) is preferably between 25°C and 70°C for 10-24 hours. Yet another embodiment, the base used in step (vi) for neutralization is selected from a group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate and preferably sodium bicarbonate. Still another embodiment, the solvent used in step (vi) for the extraction is selected from ethyl acetate, chloroform and ether, preferably ethyl acetate. Yet another embodiment, the eluent used in step (vii) for purification is mixture of solvent selected from a group consisting of pet ether, ethyl acetate, chloroform, and methanol, preferably a mixture of ethyl acetate and pet ether. Yet another embodiment, the acid used for cyclisation of the 3,4 dihydroxybutyric acid is a protic acid selected from a group consisting of HC1, H2SO4, methanesulfonic acid, trifluoromethanesulfonic acid, and preferably HC1 or H2SO4. In yet another embodiment, the 3-hydroxy-y-butyrolactone obtained in step (vii) is (S)-3 -hy droxy-y-buty ro lactone. The process of the present invention is described in schematic diagram herein below.(Formula Removed) One more embodiment of the present invention provides an improved, efficient and practical process for the synthesis of (S)-3-hydroxy-y-butyrolactone, which comprises 1) Treating the D-hexose source with a base and peroxide as oxidizing agent at 25°C to 70°C temperature to obtain 3,4-dihydroxybutyric acid of formula-[2] and glycolic acid of formula- [3], respectively. ii) Treating 3, 4-dihydroxybutyric acid with an acid, removing water and glycolic acid under rotary evaporation and extracting the residue with an organic solvent after neutralization with a base and purifying it by column chromatography using mixture of organic solvents as eluent to obtain compound of formula- [1]. In one of the embodiments of the present invention the D-hexose source used in (i) may be maltose, lactose, and maltodextrin, preferably maltose and maltodextrin. In yet another embodiment, the D-hexose source used in (i) may be a glucose source containing glucose as substituent and another sugar e.g. glucose or galactose attached to the glucose substituent in the 4-position, preferably glucose or galactose. Novelty and non-obviousness of the invention 1. It is a single step process 2. The carbohydrate source used in the process is cheap and readily available making the process economical 3. The method gives optically pure compound 4. Unlike other conventional oxidizing agents, the cumune hydroperoxide used in the reaction is stable under alkaline medium for longer duration of time, thus making the process efficient. The present invention relates to an efficient non-obvious process for the synthesis of enantiomerically pure 3-hydroxy-y-butyrolactone. The novelty of the method lies in the fact that the process is simple, inexpensive and economical. Another noteworthy feature of the present invention is that both the enantiomer could be prepared using this process. The process involves less number of steps and leads to good yield and high enantioselectivity of the product. Another salient feature of this process is that starting from a cheap carbohydrate source; the desired compound can be synthesized in enantiomerically pure form and in less number of steps as compared to the prior- art methods. (5)-3-Hydroxy-y-butyrolactone (HGB) is an important synthetic intermediate for a variety of chiral compounds. They are key intermediate for preparing neuromediater (R)-GABOB, L-carnitine, a health supported agent. HGB is an important intermediate in the synthesis of a range of Pharmaceuticals including a product for reducing cholesterol i.e. atorvastatin, a new HMG- CoA reductase inhibitor, a cancer treatment, a dietary supplement, an analgesic, an AIDS treatments and an antibiotic. HGB serves, as an important precursor not only in the synthesis of a variety of natural products but it is also useful in a number of clinical applications. For example, it has been reported as a satiety agent as well as potentiating agent to neuroleptic drug. The process of the present invention is further illustrated by the following examples, which may not however be construed to limit the scope of present invention. EXAMPLE-1 In a two-necked l00mL round bottom flask with thermo well and reflux condenser, was added maltose monohydrate (1.0 g, 2.77mmol) dissolved in 0.16 M NaOH solution (0.32g in 50mL water, 7.93mmol, 2.86eq.). The reaction mixture was heated at 40°C, for 2h. The color of the reaction mixture became dark yellowish to dark red. To this solution, was added slowly 80% cumene hydroperoxide (0.68mL~1.0mL, 3.66mmol, 1.32eq.). The reaction temperature was increased slowly to 70°C and heated at this temperature for another 8 hours. The reaction mixture was cooled to 25°C and then to 0°C temperature. The cooled reaction mixture was acidified with cone. H2SO4 to pH 1 using pH-meter. The acidified solution was concentrated to dryness at 50°C, on rotavapour in order to remove glycolic acid and water. To yellow colored syrup formed, was added 5 g of ice and neutralized with solid sodium bicarbonate, extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue obtained was purified by silica gel column using eluent EtOAc : Pet ether (4:6) to give the pure product with optical purity of 94% (0.153g) i.e. 54% yield. EXAMPLE- 2 In a two-necked l00mL round bottom flask with thermo well and reflux condenser, was added maltodextrin (l.0g, 2.77mmol) dissolved in 0.16 M KOH solution (0.32g in 50mL water, 7.93mmol, 2.86eq.). The reaction mixture was heated at 40°C for 2h. The color of the reaction mixture became dark yellowish to dark red. To this solution, was added slowly 80% cumene hydroperoxide (0.68mL~1.0mL, 3.66mmol, 1.32eq). The reaction temperature was increased slowly to 70°C and heated for another 8h. The reaction mixture was cooled to 25°C, and then to 0°C temperature. The cooled reaction mixture was acidified with cone. H2SO4 to pH 1 using pH-meter. The acidified solution was concentrated to dryness at 55°C, on rotavapour in order to remove glycolic acid and water. To yellow colored syrup formed, was added l0g of ice and neutralized with solid sodium bicarbonate, extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue obtained was purified by silica gel column using eluent EtOAc : Pet ether (4:6) to give the pure product with optical purity of 90% (0.16g)i.e.56%yield. EXAMPLE- 3 In a two necked 100ml round bottom flask with thermowell and reflux condenser, was added lactose (1.0 gm, 2.77mmol) dissolved in 0.16 M NaOH solution (0.32 gm in 50 ml water, 7.93mmols, 2.86eq.). The reaction mixture was heated at 40°C for 2 h. The colour of the reaction mixture became dark yellowish to dark red. To this solution, was added slowly 80% cumene hydroperoxide (0.68ml~1.0mL. 3.66mmol, 1.32eq.). The reaction temperature was increased slowly to 70°C and heated for another 10 h. The reaction mixture was cooled to 25°C, and then to 0°C temperature. The cooled reaction mixture was acidified with cone. HC1 to pH 1 using pH-meter. The acidified solution was concentrated to dryness at 60°C on rotavapour in order to remove glycolic acid and water. To yellow coloured syrup formed, was added l0g of ice and neutralized with solid sodium bicarbonate, extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue obtained was purified by silica gel column using eluent EtOAc :Pet ether (4:6) to give the pure product with optical purity of 88% (0.107g) i.e. 38 % yield. EXAMPLE- 4 In a two-necked 100ml round bottom flask with thermo well and reflux condenser, was added maltose (l0g, 2.77mmols) dissolved in 0.16 M NaOH solution (0.32g in 50mL water, 7.93mmol, 2.86eq.). The reaction mixture was heated at 40°C for 2 h. The colour of the reaction mixture became dark yellowish to dark red. To this solution, was added slowly 70% tertiary butyl hydrogen peroxide (TBHP) (0.68mL~1.0mL., 3.66mmols, 1.32eq.). The reaction temperature was increased slowly to 70°C and heated for another 8h. The reaction mixture was cooled to 25°C, and then to 0°C temperature. The cooled reaction mixture was acidified with cone. H2SO4 to pH 1 using pH-meter. The acidified solution was concentrated to dryness at 60°C on rotavapour in order to remove glycolic acid and water. To yellow coloured syrup formed, was added lOg of ice and neutralized with solid sodium bicarbonate, extracted with chloroform and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue obtained was purified by silica gel column using eluent EtOAc :Pet ether (4:6) to give the pure product with optical purity of 92% (.098g) i.e. 35% yield. EXAMPLE- 5 In a two-necked 100ml round bottom flask with thermowell and reflux condenser, was added maltose (l.Og, 2.77mmol) dissolved in 0.16M NaOH solution (0.32g in 50mL water, 7.93mmols, 2.86eq.). The reaction mixture was heated at 40°C for 2 h. The colour of the reaction mixture became dark yellowish to dark red. To this solution, was added slowly 5-6 M t-butyl hydroperoxide in decane (5.5mL., 2.77mmol, leq.). The reaction temperature was increased slowly to 70°C and heated for another 24 h. The reaction mixture was cooled to 25°C, and then to 0°C temperature. The cooled reaction mixture was acidified with cone. HC1 to pH 1 using pH-meter. The acidified solution was concentrated to dryness at 60°C on rotavapour in order to remove glycolic acid and water. To yellow coloured syrup formed, was added l0g of ice and neutralized with solid sodium carbonate, extracted with chloroform and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue obtained was purified by silica gel column using eluent CHCl3: MeOH (9: 1) to give the pure product with optical purity of 94% (0.112g) i.e. 39% yield. (Formula Removed)The advantages of the present invention are as follows. i) The process uses a cheap and readily available starting material. ii) It is a one step process. iii) The reaction could be carried out at lower temperature. iv) Both the enantiomer could be prepared using this process. v) The process gives the high enantio selectivity of the product. v) The process does not involve any sophisticated reagent. vi) The work-up procedure is simple and method developed is economical. We claim : 1. A process for the preparation of enantiomerically pure (5)-3-hydroxy-y-butyrolactone said process comprising steps of: i) dissolving D-hexose source such as herein described in an aqueous alkali solution, ii) heating the solution of step (i) to a temperature in the range of 40°C to 50°C for a period of 1 to 4 hours to obtain a dark yellow to dark red colour solution; iii) adding a peroxide reagent such as herein described to the solution obtained from step (ii), raising the temperature of the reaction mixture upto 70°C, maintaining it for further 8 to 24 hours to obtain a mixture of 3,4-dihydroxybutyric acid of the formula 2 as described in specification and glycolic acid of formula 3 as described, iv) cooling the reaction mixture to 25°C and acidifying to about pH 1.0, v) evoporating the acidified solution of step (v) to dryness to remove water and glycolic acid to obtain a yellow syrup, vi) neutralizing the yellow syrup of step (vi) with solid alkali carbonate, extracting with aliphatic organic solvent, drying the organic layer over anhydrous sodium sulphate, evaporating the filtrate to obtain a residue, and vii) purifying the residue of step (vi) over silica gel column using a mixture of aliphatic organic solvent to obtain the pure compound (5)-3-hydroxy-y-butyrolactone. 2. A process as claimed in claim 1, wherein the base used in step (i) is derived from alkali or alkaline earth metal . 3. A process as claimed in claims 1&2, wherein the oxidizing agents used in step (i) is selected from the group consisting of cumene hydroperoxide, tertiary butyl hydroperoxide, 4. A process as claimed in claims 1-3, wherein the molar concentration of base used is in the range of 0.005M - 0.2M and the oxidizing agent used is in the range between 0.05M and 0.2M. 5. A process as claimed in claims 1-4, wherein the D-hexose source used in step (i) is a glucose source. 6. A process as claimed in claims 1-5, wherein the D-hexose source used in step (i) is selected from a group consisting of maltose, lactose, and maltodextrin, preferably maltose and maltodextrin. 7. A process as claimed in claims 1-6, wherein the glucose source is selected from group consisting of glucose, galactose attached to the glucose substituent in the 4-position 8. A process as claimed in claims 1-7, wherein the reaction temperature in step (iii) is preferably between 25°C and 70°C for 10-24 hours. 9. A process as claimed in claims 1-8, wherein in step (vi) the base used for neutralization is selected from a group consisting of sodium hydroxide, sodium bicarbonate and sodium carbonate 10.A process as claimed in claims 1-9, wherein in step (vi) the solvent used for the extraction is selected from ethyl acetate, chloroform and ether, preferably ethyl acetate. 11. A process as claimed in claim 1 wherein in step (vii) the eluent used for purification is mixture of solvent selected from a group consisting of pet ether, ethyl acetate, chloroform and methanol, 12. A process as claimed in claim 1, wherein the acid used for cyclisation of the 3,4 dihydroxybutyric acid is a protic acid selected from a group consisting of HCI, H2SO4, methanesulfonic acid and trifluoromethanesulfonic acid, 13. A process for the preparation of enantiomerically pure (,S)-3-hydroxy- y-butyrolactone, substantially as herein described with reference to the examples.

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