USRE38324E1 - Process for the preparation of hydroxy substituted gamma butyrolactones - Google Patents

Process for the preparation of hydroxy substituted gamma butyrolactones Download PDF

Info

Publication number
USRE38324E1
USRE38324E1 US10109487 US10948702A USRE38324E US RE38324 E1 USRE38324 E1 US RE38324E1 US 10109487 US10109487 US 10109487 US 10948702 A US10948702 A US 10948702A US RE38324 E USRE38324 E US RE38324E
Authority
US
Grant status
Grant
Patent type
Prior art keywords
acid
process
ester
hydroxy
ml
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US10109487
Inventor
Rawle I. Hollingworth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Michigan State University
Original Assignee
Michigan State University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date
Family has litigation

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D315/00Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups C07D303/00 - C07D313/00

Abstract

Preparation of 4-hydroxy substituted butyrolactones is described. A process for the preparation of 3-hydroxybutyrolactone, 1.2.4-trihydroxybutane and 3,4-dihydroxy acid methyl ester from malic acid is particularly described. The preparation of 4-hydroxymethyl-4-hydroxybutyric acid -1-methyl ester and 4-hydroxymethyl butyrolactone is particularly described. The compounds are intermediates to various pharmaceutical and agricultural products.

Description

BACKGROUND OF THE INVENTION

(1) Summary of the Invention

The present invention relates to the preparation of hydroxy substituted gamma butyrolactones. In particular, the present invention relates to a process for the preparation of isomers, in the (R) or (S) form. Further, the present invention relates to the preparation of 3 hydroxybutyrolactone and derivatives thereof such as 1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid-1-methyl ester from malic acid. Further still, the present invention relates particularly to the preparation of 4-hydroxy methyl butyrolactone from 4-hydroxybutane dicarboxylic acid dimethyl ester. The compounds as the isomers are particularly useful as intermediates for pharmaceuticals, agrochemicals favors and fragrances.

(2) Description of Related Art

U.S. Pat. Nos. 4,994.597 and 5,087,751 to Inone et al describe derivatives of 3,4-dihydroxybutyric acid. The pro ass for preparing the acid is different from the present invention involving a reaction of metal cyanide and a 3,4-dihydroxy butyl chloride and then hydrolyzing. The acid is an intermediate to 3-hydroxybutyrolactone.

(S)-3-Hydroxybutyrolactone is a key 4-carbon intermediate for the preparation of various drug intermediates including cholesterol lowering drugs. (S)-carnitine, and HIV protease inhibitor drugs, broad spectrum antibiotics.

(R)-3-Hydroxybutyrolactone or (R)-3,4-dihydroxybutyric acid gamma lactose is a key 4-carbon intermediate for the preparation of various drug intermediates. It can also be converted to 1-carnitine, a naturally occurring vitamin and ingredient used in several applications including treatment of various nervous system and metabolic disorders, as an additive in health foods and as a supplement in tonics. The world wide market for carnitine is estimated to be in the hundreds of metric tons. It is currently made by fermentation and by resolution of the d and 1 forms. There is no direct chemical route of any commercial value.

(S)-3-hydroxybutyrolactone can be prepared by the process of Hollingsworth (U.S. Pat. No. 5,374,773). (R)-3-Hydroxybutyrolactone cannot be prepared by the process since this would require the use of a starting material with a 4-linked L-hexane. No such material is known.

1-Malic acid (1-hydroxybutanedioic acid) is a 4-carbon dicarboxylic acid that la obtained in quantity, from apple juice and wine among other fruit juices. R can also be obtained by the hydraulics of fumaric acid and by the fermentation of sugars by some yeasts either as the free acid or as the polyester (polymalic acid). It is relatively inexpensive in isomeric forms.

There are rationally two major commercial routes to (S)-3-hydroxybutyrolactone involving enzymatic resolution. (1) One route to (S)-3-hydroxybutyrolactone involves the reduction of the dimethyl ester of malic acid to (S)-1,2,4-butanetriol, the preparation of a dioxolane intermediate to protect the 1 and 2 hydroxyl groups followed by oxidation of the 4-hydroxyl group to an aldehyde and then to an acid. The acid is then deprotected and the dihydroxy compound cyclized to (S)-3-hydroxybutyrolactone. This is shown by the following reaction (Scheme (I)).

Figure USRE038324-20031118-C00001

This is a very involved process and has no commercial value. It is complicated by the fan that the dioxolane is contaminated with about 10% of the dioxane. This is difficult to remove and results in the formation of contaminating 2-hydroxybutyrolactone. The process is described in Corey, et al., (E. J. Corey, H. Niwa and I. Knolle. “Total Synthesis of (S)-12-Hydroxy-5,8,14-cis-10-transeicosatetraenoic Acid”. J. Amer. Chem Soc. 100 1942-1943(1978)).

(2) Another route involves a process for the direct reduction of malic acid to (S)-3-hydroxybutyric acid and the transformation to (S)-3-hydroxybutyrolactone. This reaction employs the dimethyl sulfide complex of borane and a catalytic amount of sodium borohydride as the reducing system Borane dimethyl sulfide requires specialized equipment to handle and an oxygen free and moisture free environment. It is very toxic and dimethyl sulfide is a very noxious gas. The reducing system is very expensive. The process is described in Saito et al., (S. Saito, T. Hasegawa, M. Inaba, R. Nishida, T. Fujii, S. Nomizu, and T. Moriwaki. “Combination of borane-dimethyl sulfide complex with catalytic sodium tetrahydroborate as a selective reducing agent of a-hydroxy esters, versatile chiral building block from (S)-(−)-malic acid” Chem Letts. 1389-1392 (1984)).

Other references which are pertinent to the present invention are: Arth et al., Liebigs Ann. 2037-2042 (1995) who describe the production of 1,2,4-butanetriol from malic acid using a borane reduction. Tandon, V., et al., J. Org. Chem. 48:767-2769 (1983) who describe the cyclization of 1.2.4-triol to tetrahydrofuran. Boger a al., 46 1208-1210 (1981) who describe a process for producing chiral derivatives from malic acid. Herradon, Asymmetry 2 191-194 (1991) who describes the use of a borane-dimethyl sulfide complex reduction to 1,2,4 butanetriol. This is a difficult process to practice because of problems in handling the butane, Hanessian et al., 199 2146-2147 (1984) describe triol derivatives produced from malic acid using boranes.

The use of alkali metal borohydrides, particularly lithium borohydride, as a reducing and hydrogenerating agent are generally known in the prior art. They are described in U.S. Pat No. 2,683,721 to Schlesinger et al. These are not known for use in preparing hydroxy substituted gamma butyrolactones.

The preparation of la lactones in general is described for instance in Advanced Organic Chemistry 1977, page 363. U.S. Pat. Nos. 3,024,250 to Klein et al., 3,868,370 to Smith, 3,997,569 to Powell, 4,105,674 to De Thomas et al., 4,155,919 to Ratatouille et al., 4,772.729 to Rao, 4,940,805 to Fisher et al., 5,292,939 to Hollingsworth, 5,319,110 to Hollingsworth, 5,374,773 to Hollingsworth, and 5,502,217 to Fuchikami et al. These patents describe diverse processes for the preparation of lactones. They particularly do not describe the use of malic acid as a starting material. The processes described are also relatively complex.

There is a need for an improved process for the preparation of hydroxy butyrolactones and related alcohols and acid derivatives, particularly 4-hydroxy methyl butyrolactone, 3-hydroxybutyrolactone, 1,2,4-butanetriol and 3,4-dihydroxy acid, methyl ester in high yield.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1, 2 and 3 are NMR spectra of (S)-3,4-dihydroxybutyric acid methyl ester (FIG. 1); (S)-1,2,4-butanetriol (FIG. 2) and (S)-3-hydroxy gamma butyric acid lactone (FIG. 3). The asterisk is used to designate impurities. In each instance, the produce are as isolated without further purification. The formulas are shown in FIGS. 1A, 2A and 3A, respectively.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to a process for producing a hydroxy substituted compound which comprises: reacting in a reaction mixture a 2-hydroxy substituted alkane diacid lower alkyl diester, wherein the diacid contains 4 to 8 carbon atoms and alkyl contains 1 to 4 carbon atoms, with an alkali metal borohydride in a non-reactive solvent to produce the hydroxy substituted compound.

The present invention relates to a process for the preparation of a hydroxy substituted gamma butyrolactone which comprises: reacting in a reaction mixture a 2-hydroxy substituted alkane diacid lower alkyl diester, wherein the acid contains 4 to 5 carbon atoms and alkyl contains 1 to 4 carbon atoms, with an alkali metal borohydride in a non-reactive solvent at a temperature between about −10° and 60° C. to produce the hydroxy substituted butyrolactone and an alcohol as a by-product.

In the process of the present invention, the preferred lithium borohydride is generated in situ from sodium borohydride and lithium chloride in a solvent, preferably in a mixture of tetrahydrofuran and methanol. This reducing agent is safe to handle without special precaution. It is cheap and readily available. The lithium borohydride is one-tenth the cost of the dimethyl sulfide butane complex of the prior art which is dangerous. The product of the process is isolated by a simple acidification, concentration and extraction. The yields of the process of the present invention are very good. Other alkali metal borohydrides are described in U.S. Pat. No. 2,683,721 to Schlesinger, et al.

The present invention particularly relates to a process for the preparation of a compound selected from the group consisting of 1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid -1-methyl ester and mixtures thereof which comprises: reacting in a reaction mixture malic acid with a molar excess (preferably more than 100%) of anhydrous methanol in the presence of a catalytic amount of hydrogen ion and at a temperature between about 40° C. and reflux to produce hydroxy butane dioic acid dimethyl ester (2-hydroxy-succinic acid dimethyl ester); and (b) reducing the hydroxy butane dioic acid dimethyl ester with an alkali metal, preferably lithium borohydride in the reaction mixture to produce the compound. The 3-hydroxy gamma butyrolactone can be produced by hydrolyzing the ester.

The ratio of the preferred lithium borohydride to the hydroxy butanedioic acid dimethyl ester determines the predominant product from malic acid which is produced as is shown as follows by Scheme II for the (S) isomer and in Examples 1 to 4:

Figure USRE038324-20031118-C00002

At one equivalent (eq.) the product is essentially the lactone in the presence of added acid. With two (2) equivalents of the lithium borohydride, the product is essentially the (S)1, 2,4-trihydroxybutane. This can be seen from the following examples. The NMR spectra am shown in FIGS. 1 to 3 with the formulas shown in FIGS. 1A, 2A and 3A.

The Process of the present invention has the advantage that the steps are performed in the same reaction vessel. The yields are 88% a better of the 3-hydroxybutyrolactone. The yield of the 1.2,4-trihydroxybutane is generally greater than 96% with a molar excess of the lithium borohydride. The preferred reaction temperature is between −10° and 60° C.

The reaction after the formation of 3.4-dihydroxybutyric acid-1-methyl ester as shown is Scheme II, as a result of the reduction reaction, is heated with acid or methanol to form the 3-hydroxybutyrolactone. Preferably a strong acid is used for the acidification, such as phosphoric acid or hydrochloric acid. After adding water and extracting the 3-hydroxybutyrolactone with a solvent such as ethyl acetate, the 1,2,4-trihydroxybutane is left to the water layer.

It will be appreciated that the 3.4-hydroxybutyric acid methyl ester can be converted to the acid or to a metal salt (preferably alkali metal salt). There is no advantage to this step if the final product is the 3-hydroxybutyrolactone.

Example 5 shows the preparation of (S)-4-hydroxymethyl gamma butyrolactone. The reaction Scheme III is as follows.

Figure USRE038324-20031118-C00003

Various solvents can be used to extract the reaction products from the reaction mixture. The 3-hydroxybutane and 4-hydroxy methyl butyrolactone are soluble in ethyl acetate. The 1,2,4-trihydroxybutane is soluble in water. Other isolation techniques can be used. If the product is an intermediate to a further product the reaction mixture may be used without isolating the product.

EXAMPLE 1

Direct Reduction of Malic Acid to Lactone (S)-Isomer

L-Malic acid (50 grams, 0.37 moles) was refluxed for 3 hours with 500 ml of anhydrous methanol containing 1% hydrogen chloride to form the dimethyl ester (Scheme II). The solution was concentrated to a syrup and dissolved in 200 ml of tetrahydrofuran. Anhydrous lithium chloride (32 grams, 0.74 moles) was added followed by sodium borohydride (16 grams, 0.42 moles) and methanol (80 ml) to provide the reducing agent. The mixture was stirred at room temperature (25° C.) for 6 hours, filtered, concentrated to dryness, treated with methanol (500 ml) containing hydrochloric acid (50 ml) and concentrated to dryness on a rotary evaporator at a bath temperature of 35° C. A-further 500 ml of methanol was added and the solution concentrated again. The process was repeated twice again and the final syrup partitioned between ethyl acetate and water 20 ml: 400 ml. The ethyl acetate layer was recovered, dried and concentrated to yield (S)-3-hydroxybutyrolactone (34 grams, 90%).

EXAMPLE 2

Direct Reduction of Malic Acid to Lactone (R)-Isomer

D-Malic acid (1 gram, 0.0075 moles) was refluxed for 3 hours with 10 ml of anhydrous methanol containing 1% hydrogen chloride to form the dimethyl ester (Scheme II). The solution was concentrated to a syrup and dissolved in 4 ml of tetrahydrofuran. Anhydrous lithium chloride (0.6 grams. 0.014 moles) was added followed by sodium borohydride (0.32 grams, 0.0084 moles) and methanol (2 ml) to provide the reducing agent. The mixture was stirred at room temperature(25° C.) for 6 hours, filtered, concentrated to dryness, treated with methanol (10 ml) containing hydrochloric acid (1 ml) and concentrated b dryness on a rotary evaporator at a bath temperature of 35° C. A further 10 ml of methanol was added and the solution concentrated again. The process was repeated twice again and the final syrup partitioned between ethyl acetate and water, 0.4 of: 8 ml. The ethyl acetate layer was recovered, dried and concentrated to yield (R)-3-hydroxybutyrolactone (0.6 grams, 88%).

EXAMPLE 3

Direct Reduction of L-Malic Acid to (S)1,2,4-Trihydroxybutane

L-Malic acid (134 grams. 1 mole) was dissolved in methanol (1,200 ml) and concentrate hydrochloric acid (12 ml) was added The solution was heated under reflux in a 3 liter flask equipped with a calcium chloride drying tube for 4 hours to provide the dimethyl ester (Scheme II) and then concentrated to a syrup under vacuum (water aspirator). More methanol (200 ml) was added and the solution concentrated again to remove tracts of acid. The syrup was then dissolved in tetrahydrofuran (800 ml) and sodium borohydride (80 grams, 2.1 moles) and lithium chloride (126 grams. 3 moles) added. The sodium borohydride was added first carefully over a period of 10 minutes. There should be very little effervescence if all of the acid was removed earlier. The deals was cooled to 30° C. and the mixture was stirred for 15 minutes and then methanol (600 ml) was added over a period such that the temperature does not exceed 30° C. Concentrated (88%) phosphoric acid (1 mole) was carefully added to destroy excess reagent (cooling if necessary). The mixture was then filtered through Whatman #1 paper and concentrated to a syrup to yield 130 grams of crude 1.2.4-trihydroxybutane.

EXAMPLE 4

Direct Reduction of L-Malic Acid to (S)-1,2.4-Trihydroxybutane

L-Malic acid (134 grams, 1 mole) was dissolved in methanol (1,200 ml) and concentrate hydrochloric acid (12 ml) was added The solution was heated under reflux in a 3 liter flask equipped with a calcium chloride drying tube for 4 hours and then concentrated to a syrup under vacuum (water aspirator) to provide the dimethyl ester (Scheme II). More methanol (200 ml) was added and the solution concentrated again to remove trams of acid. The syrup was then dissolved in tetrahydrofuran (800 ml) and lithium chloride (126 grams, 3 moles) and sodium borohydride (80 grams. 2.1 moles) added. The sodium borohydride was added carefully. There should be very little effervescence if all of the acid was removed earlier. The flask was fitted with a condenser and drying robe and the mixture was stirred for 15 minutes and then methanol (600 ml) was added over a 5 minute period. The first 400 ml was added at once and the remaining 200 ml was then added There is an increase in temperature of the mixture to 52°-54° C. resulting in a gentle reflux with a steady release of hydrogen especially as the last 200 ml of methanol was added. The reaction mixture was tut cooled ova this period. The temperature drops back to room temperature after 1 hour and the reaction mixture wan then refluxed for 4 hours and cooled. It was diluted with 400 ml of methanol and concentrated HCl (200 ml) was carefully added to destroy excess reagent (cooling if necessary). The mixture was then filtered through Whatman #1 paper, concentrated to a syrup and desalted through A cation exchange (DOWEX 50WX4-50, Made by Dow Chemical Midland Mich.) and concentrated to a syrup which was concentrated 4 times from methanol (500 ml) an equal vol of water added and extracted twice with 500 ml of ethyl acetate (to remove lactone if there is under-reduction) and the water fraction concentrated. Yields of crude product at end of ethyl acetate extract: 3-hydroxybutyrolactone, 37 grams; 1,2,4-trihydroxybutane 126 grams.

EXAMPLE 5

Selective Reduction of (S)-4-Carboxy-γ-Butyrolactone to (S)4-Hydroxymethyl-γ-Butyrolactone. (Scheme III)

(S)-4-carboxy-γ-butyrolactone (130 grams, 1 mole) was dissolved in methanol (1,200 ml) and concentrated hydrochloric acid (12-ml) was added. The solution was heated under reflux in a 3 liter flask equipped with a calcium chloride drying tube for 4 hours to form the dimethyl ester (Scheme III). The mixture was then treated with calcium carbonate (20 grams) to remove acid and then concentrated to ˜300 ml under vacuum (water aspirator). The syrup was then dissolved in tetrahydrofuran (800 ml) and sodium borohydride (20 grams, 1.05 moles) and lithium chloride (63 grams, 1.5 moles) added as the reducing agent. The sodium borohydride was added first carefully over a period of 10 minutes. Very little effervescence was observed if all of the acid was removed earlier. The flask was cooled to 30° C. and the mixture stirred for 15 minutes and then methanol (300 ml) was added over a period such that the temperature does not exceed 30° C. Concentrated (88%) phosphoric acid (½ mole) was carefully added to destroy excess reagent cooling if necessary). The mixture was then filtered through Whatman #1 paper and concentrated to a syrup. The syrup was taken up in ethyl acetate and filtered the filtrate concentrated and redissolved in water (400 ml). The solution was passed over a mixed bed ion exchange resin to remove salts. On concentration it yielded 100 grams (87%) of the desired product

In a similar manner, other hydroxy alkyl substituted butyrolactones can be prepared with 6 to 8 carbon atoms.

It is intended that the foregoing description be only illustrative of the present invention and that the present invention be limited only by the hereinafter appended claims.

Claims (34)

I claim:
1. A process for producing a hydroxy substituted compound which comprises: reacting in a reaction mixture a 2-hydroxy substituted alkane diacid lower alkyl diester wherein the diacid contains 4 to 8 carbon atoms and alkyl contains 1 to 4 carbon atoms, with an alkali metal borohydride in a non-reactive solvent to produce the hydroxy substituted compound.
2. A process for the preparation of a hydroxy substituted gamma butyrolactone which comprises:
reading in a reaction mixture a 2-hydroxy substituted alkane diacid lower alkyl diester, wherein the diacid contains 4 in 5 carbon atoms and alkyl contains 1 to 4 carbon atoms, with an alkali metal borohydride in a non-reactive solvent at a temperature between about −10° and 60° C. to produce the hydroxy substituted gamma butyrolactone and an alcohol as a by-product.
3. The process of claim 2 wherein the diester is 4-carboxymethyl-4-hydroxybutyric acid-1-methyl ester and wherein the hydroxy substituted gamma butyrolactone is 4-hydroxymethyl butyrolactone.
4. The process of any one of claims 2 or 3 wherein the ester and the hydroxy substituted gamma butyrolactone are isomers.
5. The process of any me of claims 2 or 3 wherein one ester and the hydroxy substituted gamma butyrolactone are isomers, and wherein the isomers are (S) isomers.
6. The process is any one of claims 2 or 3 wherein the ester and the hydroxy substituted gamma butyrolactone are isomers and wherein the isomer are (R) isomers.
7. The process of any one of claims 2 or 3 wherein as an additional step the reaction mixture is acidified and heated to volatilize the alcohol from the vendors mixture and the hydroxy substituted gamma, butyrolactone.
8. The process of claim 2 wherein the hydroxy substituted gamma butyrolactone is extracted from the reaction mixture with ethyl acetate.
9. The process of claim 2 wherein in the ester the lower alkyl is methyl, wherein the alkylene contains five carbon atoms and wherein the butyrolactone is 4-hydroxymethyl gamma butyrolactone.
10. A process for the preparation of a compound selected from the group consisting of 1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid -1-methyl ester and mixtures thereof which comprises:
(a) reacting in a reaction mixture malic acid with a molar excess of anhydrous methanol in the presence of a catalytic mount of hydrogen ion end at a temperature between about 40° and reflux to produce hydroxybutane dioic acid di methyl ester; and
(b) reducing the hydroxybutane dioic acid dimethyl ester with an alkali metal borohydride to produce the compound.
11. The process of claim 10 27wherein about one equivalent of the alkali metal borohydride is reacted with the hydroxybutane dioic acid dimethyl ester andto produce wherein the compound is substantially the 3.4-hydroxybutyric acid methyl ester.
12. The process of claim 10 wherein about three equivalents of the alkali metal borohydride is reacted with the hydroxy butane dioic acid dimethyl ester and the compound is substantially the 1,2,4-trihydroxybutane.
13. The process of any one of claims 10, 11 or 12 wherein the malic acid is an isomer.
14. The process of any one of claims 11 or 12 wherein the malic acid is an isomer and the humid is the (S) isomer.
15. The process of any one of claim 11 or 12 wherein the malic acid is an isomer and the isomer is the (R) isomer.
16. The process of claim 10 wherein the 3.4-dihydroxybutyric acid methyl ester is extracted from the reaction mixture with ethylacetate.
17. The process of claim 10 wherein the reaction mixture in step (a) is refluxed.
18. The process of claim 11 wherein as an additional step the 3,4-dihydroxy butyric acid -1-methyl ester is acidified and heated to volatilize the methanol from the reaction mixture from step (a) and to produce the hydroxylactone 4-hydroxymethyl butyrolactone.
19. The process of claim 18 wherein about one equivalent of the alkali metal borohydride which is lithium borohydride is reacted with the hydroxy butane dioic acid dimethyl ester to produce the 3,4-dihydroxybutyric acid -1-methyl ester.
20. The process of claim 10 wherein the 1,2,4-trihydroxybutane is extracted from the reaction mixture using water.
21. The process of claim 19 wherein the malic acid is as the (R) isomer and the compound 3,4 dihydroxybutyric acid- 1 -methyl ester produced is the (R) isomer.
22. The process of claim 19 wherein the malic acid is as the (S) isomer and the compound 3,4-dihydroxy butyric acid- 1 -methyl ester produced is the (S) isomer.
23. The process of claim 10 wherein in addition the 3,4-hydroxy butyric acid -1-methyl ester is separated and reacted with an acid to form 3-hydroxy gamma butyrolactone.
24. The process of claim 1 wherein the alkali metal borohydride is lithium borohydride.
25. The process of claim 2 wherein the alkali metal borohydride is lithium borohydride.
26. The process of claim 10 wherein the alkali metal borohydride is lithium borohydride.
27. A process for the preparation of 3,4-dihydroxybutyric acid- 1 -methyl ester which comprises:
(a) reacting in a reaction mixture malic acid with a molar excess of anhydrous methanol in the presence of a catalytic amount of hydrogen ion and at a temperature between about 40° and reflux to produce hydroxybutane dioic acid dimethyl ester; and
(b) reducing the hydroxybutane dioic acid dimethyl ester with an alkali metal borohydride to produce the 3,4 -dihydroxybutyric acid- 1 -methyl ester.
28. The process of any one of claims 11 or 27 wherein the malic acid is an isomer.
29. The process of claim 11 wherein the malic acid is an isomer and the isomer is the (S) isomer.
30. The process of claim 11 wherein the malic acid is an isomer and the isomer is the (R) isomer.
31. The process of claim 27 wherein the 3,4-dihydroxybutyric acid methyl ester is extracted from the reaction mixture with ethylacetate.
32. The process of claim 27 wherein the reaction mixture in step (a) is refluxed.
33. The process of claim 27 wherein in addition the 3,4-hydroxy butyric acid- 1 -methyl ester is separated and reacted with an acid to form 3 -hydioxy gamma butyrolactone.
34. The process of claim 27 wherein the alkali metal borohydride is lithium borohydride.
US10109487 1997-10-31 2002-03-28 Process for the preparation of hydroxy substituted gamma butyrolactones Expired - Lifetime USRE38324E1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08962365 US5808107A (en) 1997-10-31 1997-10-31 Process for the preparation of hydroxy substituted gamma butyrolactones
US10109487 USRE38324E1 (en) 1997-10-31 2002-03-28 Process for the preparation of hydroxy substituted gamma butyrolactones

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10109487 USRE38324E1 (en) 1997-10-31 2002-03-28 Process for the preparation of hydroxy substituted gamma butyrolactones

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08962365 Reissue US5808107A (en) 1997-10-31 1997-10-31 Process for the preparation of hydroxy substituted gamma butyrolactones

Publications (1)

Publication Number Publication Date
USRE38324E1 true USRE38324E1 (en) 2003-11-18

Family

ID=25505755

Family Applications (2)

Application Number Title Priority Date Filing Date
US08962365 Expired - Lifetime US5808107A (en) 1997-10-31 1997-10-31 Process for the preparation of hydroxy substituted gamma butyrolactones
US10109487 Expired - Lifetime USRE38324E1 (en) 1997-10-31 2002-03-28 Process for the preparation of hydroxy substituted gamma butyrolactones

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US08962365 Expired - Lifetime US5808107A (en) 1997-10-31 1997-10-31 Process for the preparation of hydroxy substituted gamma butyrolactones

Country Status (9)

Country Link
US (2) US5808107A (en)
EP (1) EP1027343B2 (en)
JP (1) JP3527706B2 (en)
KR (1) KR100369857B1 (en)
CA (1) CA2304809C (en)
DE (2) DE69809962D1 (en)
DK (1) DK1027343T3 (en)
ES (1) ES2188017T5 (en)
WO (1) WO1999023086A1 (en)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9618099D0 (en) 1996-08-30 1996-10-09 Zeneca Ltd Process
DK0924206T3 (en) * 1997-12-16 2003-07-28 Sigma Tau Ind Farmaceuti A process for the preparation of (R) -3-hydroxy-4-butyrolactone useful for preparing (R) -carnitine
DE69923163D1 (en) * 1998-03-03 2005-02-17 Daiso Co Ltd A process for the preparation of 1,2,4-butanetriol
US6949684B2 (en) 1998-03-03 2005-09-27 Daiso Co., Ltd. Process for preparing 1,2,4-butanetriol
US6040464A (en) * 1998-06-01 2000-03-21 Board Of Trustees Operating Michigan State University Process for the preparation of protected 3-amino-1,2-dihydroxypropane acetal and derivatives thereof
US6084131A (en) * 1998-06-01 2000-07-04 Board Of Trustees Operating Michigan State University Process for the preparation of protected dihydroxypropyl trialkylammonium salts and derivatives thereof
US6713290B2 (en) * 1998-07-24 2004-03-30 Samsung Fine Chemicals Co., Ltd. Process for preparing optically pure (S)-3-hydroxy-γ-butyrolactone
US6221639B1 (en) 1998-07-24 2001-04-24 Samsung Fine Chemicals Co., Ltd. Process for preparing optically pure(S)-3,4-dihydroxybutyric acid derivatives
US6423850B1 (en) * 1999-06-18 2002-07-23 E.I. Du Pont De Nemours And Company Preparation and use of gamma-butyrolactones as cross-linking agents
KR100645665B1 (en) * 2000-07-27 2006-11-13 에스케이 주식회사 Continuous Process for the Production of S-?-hydroxy-?-butyrolactone
US6288238B1 (en) 2000-09-19 2001-09-11 Board Of Trustees Operating Michigan State University Process for the preparation of 5-hydroxymethyl 2-oxazolidinone and novel intermediate
US6288239B1 (en) 2000-09-19 2001-09-11 Board Of Trustees Operating Michigan State University 5-trityloxymethyl-oxazolidinones and process for the preparation thereof
JP4824874B2 (en) 2001-07-19 2011-11-30 高砂香料工業株式会社 Method for producing optically active γ- butyrolactone
EP1398312A1 (en) * 2002-09-13 2004-03-17 Hong-Sun Uh Beta-substituted-gamma-butyrolactones and a process for preparation thereof
WO2004026223A3 (en) * 2002-09-18 2005-06-09 Ki-Nam Chung CONTINUOUS PROCESS FOR THE PRODUCTION OF OPTICALLY PURE (S)-β HYDROXY-Ϝ-BUTYROLACTONE
US20110165641A1 (en) * 2006-03-31 2011-07-07 The Board Of Trustees Of Michigan State University Synthesis of 1,2,4-Butanetriol Enantiomers from Carbohydrates
WO2005068642A3 (en) 2003-10-01 2005-12-15 John W Frost Bacterial synthesis of 1,2,4-butanetriol enantiomers
WO2007100227A1 (en) * 2006-03-02 2007-09-07 Lg Chem, Ltd. Method for preparing (s)-3-hydroxy-gamma-butyrolactone using hydrolase
US20110076730A1 (en) * 2006-07-19 2011-03-31 Board Of Trustees Of Michigan State University Microbial synthesis of d-1,2,4-butanetriol
CN100441573C (en) 2006-07-20 2008-12-10 厦门大学 Synthesis of S-(3)-hydroxy tetrahydrofuran
WO2010101651A1 (en) * 2009-03-06 2010-09-10 Massachusetts Institute Of Technology Microbial production of 3-hydroxyacids from glucose and glycolate
WO2012116307A1 (en) 2011-02-25 2012-08-30 Massachusetts Institute Of Technology Microbial production of 3,4-dihydroxybutyrate (3,4-dhba), 2,3-dihydroxybutyrate (2,3-dhba) and 3-hydroxybutyrolactone (3-hbl)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2683721A (en) * 1952-01-17 1954-07-13 Hermann I Schlesinger Method of reducing and hydrogenating chemical compounds by reacting with alkali metal borohydrides
US3024250A (en) * 1962-03-06 Certificate of correction
US3868370A (en) * 1973-02-09 1975-02-25 Gen Electric Process for making 4-butyrolactone
US3997569A (en) * 1972-11-08 1976-12-14 Texaco Inc. Method for preparing a lactone reaction product
US4105674A (en) * 1976-08-20 1978-08-08 Gaf Corporation Production of gamma-butyrolactone from maleic anhydride with a hydrogenation catalyst
US4155919A (en) * 1976-11-23 1979-05-22 U C B Societe Anonyme Process for the production of 1,4-butanediol and tetrahydrofuran
US4772729A (en) * 1987-01-23 1988-09-20 E. I. Du Pont De Nemours And Company Hydrogenation of citric acid and substituted citric acids to 3-substituted tetrahydrofuran, 3- and 4-substituted butyrolactones and mixtures thereof
US4940805A (en) * 1987-08-08 1990-07-10 Basf Aktiengesellschaft Preparation of 1,4-butanediol or tetrahydrofuran or both
US4994597A (en) * 1988-04-27 1991-02-19 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Method for preparing optically active 3,4-dihydroxy butyric acid derivatives
US5087751A (en) * 1988-04-27 1992-02-11 Kanegafuchi Kagaku Kogyo K.K. Method of preparing optically active 3,4-dihydroxy butyric acid derivatives
US5292939A (en) * 1991-05-13 1994-03-08 Board Of Trustees Operating Michigan State University Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof
US5502217A (en) * 1991-11-18 1996-03-26 Tosoh Corporation Process for preparing lactones

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9618099D0 (en) 1996-08-30 1996-10-09 Zeneca Ltd Process

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3024250A (en) * 1962-03-06 Certificate of correction
US2683721A (en) * 1952-01-17 1954-07-13 Hermann I Schlesinger Method of reducing and hydrogenating chemical compounds by reacting with alkali metal borohydrides
US3997569A (en) * 1972-11-08 1976-12-14 Texaco Inc. Method for preparing a lactone reaction product
US3868370A (en) * 1973-02-09 1975-02-25 Gen Electric Process for making 4-butyrolactone
US4105674A (en) * 1976-08-20 1978-08-08 Gaf Corporation Production of gamma-butyrolactone from maleic anhydride with a hydrogenation catalyst
US4155919A (en) * 1976-11-23 1979-05-22 U C B Societe Anonyme Process for the production of 1,4-butanediol and tetrahydrofuran
US4772729A (en) * 1987-01-23 1988-09-20 E. I. Du Pont De Nemours And Company Hydrogenation of citric acid and substituted citric acids to 3-substituted tetrahydrofuran, 3- and 4-substituted butyrolactones and mixtures thereof
US4940805A (en) * 1987-08-08 1990-07-10 Basf Aktiengesellschaft Preparation of 1,4-butanediol or tetrahydrofuran or both
US4994597A (en) * 1988-04-27 1991-02-19 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Method for preparing optically active 3,4-dihydroxy butyric acid derivatives
US5087751A (en) * 1988-04-27 1992-02-11 Kanegafuchi Kagaku Kogyo K.K. Method of preparing optically active 3,4-dihydroxy butyric acid derivatives
US5292939A (en) * 1991-05-13 1994-03-08 Board Of Trustees Operating Michigan State University Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof
US5319110A (en) * 1991-05-13 1994-06-07 Board Of Trustees Operating Michigan State University Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof
US5374773A (en) * 1991-05-13 1994-12-20 Board Of Trustees Operating Michigan State University Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof
US5502217A (en) * 1991-11-18 1996-03-26 Tosoh Corporation Process for preparing lactones

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Arth et al., Liebigs Ann., pp. 2037-2042, 1995.* *
Boger et al., J. Org. Chem., 46, pp. 1208-1210, 1981.* *
Hanessian et al., Can J. Chem., pp. 2146-2147, 1984. *
Herradon, Tetrahedron: Asymmetry, 2(3), pp. 191-194, 1991.* *
Tandon et al., J. Org. Chem., 48, pp. 2767-2769, 1983.* *

Also Published As

Publication number Publication date Type
DE69809962T2 (en) 2003-04-24 grant
EP1027343B2 (en) 2006-01-11 grant
JP2001521931A (en) 2001-11-13 application
ES2188017T5 (en) 2006-07-16 grant
DE69809962T3 (en) 2006-12-14 grant
KR100369857B1 (en) 2003-02-05 grant
WO1999023086A1 (en) 1999-05-14 application
EP1027343B1 (en) 2002-12-04 grant
ES2188017T3 (en) 2003-06-16 grant
EP1027343A4 (en) 2001-08-22 application
DE69809962D1 (en) 2003-01-16 grant
CA2304809C (en) 2006-08-01 grant
CA2304809A1 (en) 1999-05-14 application
JP3527706B2 (en) 2004-05-17 grant
EP1027343A1 (en) 2000-08-16 application
US5808107A (en) 1998-09-15 grant
DK1027343T3 (en) 2003-03-31 grant

Similar Documents

Publication Publication Date Title
US6403844B1 (en) Condensed phase catalytic hydrogenation of lactic acid to propylene glycol
US5292939A (en) Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof
US4730040A (en) Preparation of caprolactam
Lemieux et al. BIOCHEMISTRY OF THE USTILAGINALES: IV. THE CONFIGURATIONS OF SOME β–HYDROXYACIDS AND THE BIOREDUCTION OF β–KETOACIDS
US5430171A (en) T-butyl (R)-(-)-4-cyano-3-hydroxybutyrate and process for preparing the same
US20090137825A1 (en) Method of producing a carboxylic alkyl ester
US6066763A (en) Process for preparing free α-hydroxy acids from ammonium salts thereof
WO1998004543A1 (en) Improved process for the synthesis of protected esters of (s)-3,4-dihydroxybutyric acid
Nishikori et al. A short-step synthesis of trans-whisky lactone by an asymmetric Michael reaction
WO1997031883A1 (en) Process for preparing 1,6 hexane diol and caprolacton
WO2000034221A1 (en) Nitric acid removal from oxidation products
US20030029711A1 (en) Process for obtaining an organic acid from an organic acid ammonium salt, an organic acid amide, or an alkylamine organic acid complex
US4994597A (en) Method for preparing optically active 3,4-dihydroxy butyric acid derivatives
US5292891A (en) Optically active 2,2-dimethyl-1,3-dioxin-4-ones and method for preparing same and method for preparing optically active compound for synthesis of physiologically active substance and optically active intermediate compound
EP0033537A2 (en) Hydrogenation products of mevinolin and dihydromevinolin, a process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same
Solladié et al. Stereoselective synthesis towards the C8–C18 subunit of pamamycin-607 induced by a chiral sulfoxide group
JPH06172256A (en) Production of 3-hydroxybutyric acid derivative
US5808107A (en) Process for the preparation of hydroxy substituted gamma butyrolactones
WO2004110972A1 (en) Process for producing (2r)-2-propyloctanoic acid and intermediate therefor
US3403170A (en) Process for the preparation of hexahydrophthalic acid and anhydride
US5091595A (en) Reduction of diethyl phenylmalonate to 2-phenyl-1,3-propanediol
US8084626B1 (en) Processes for the production of hydrogenated products
Ferraboschi et al. Baker's yeast-mediated preparation of optically active aryl alcohols and diols for the synthesis of chiral hydroxy acids
JPH05308977A (en) Production of optically active 3,5-dihydroxyfatty acid ester derivative
WO2011123268A1 (en) Processes for producing succinic acid from fermentation broths containing diammonium succinate

Legal Events

Date Code Title Description
CC Certificate of correction
AS Assignment

Owner name: NATIONAL SCIENCE FOUNDATION, VIRGINIA

Free format text: CONFIRMATORY LICENSE;ASSIGNOR:MICHIGAN STATE UNIVERSITY;REEL/FRAME:017035/0476

Effective date: 20051129

SULP Surcharge for late payment

Year of fee payment: 7

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
SULP Surcharge for late payment

Year of fee payment: 11

FPAY Fee payment

Year of fee payment: 12