Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-28
2004-03-30
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06713639
ABSTRACT:
The present invention relates to a process for the in situ preparation of optically pure (S)-3,4-dihydroxybutyric acid derivatives represented by Formula [2] below and more particularly, to a process which enables preparing optically pure (S)-3-hydroxy-&ggr;-butyrolactone represented by Formula [1] below by oxidation of an &agr;- or &bgr;-(1,4) linked disaccharide or oligosaccharide with an oxidant under basic conditions to give acid and cyclization sequentially under acidic condition to give (S)-3-hydroxy-&ggr;-butyrolactone.
BACKGROUND AND PRIOR ART OF THE PRESENT INVENTION
(S)-3-Hydroxy-&ggr;-butyrolactone (HGB) is an important synthetic intermediate for variety of chiral compounds. It is a key intermediate for preparing (R)-GABOB, gamma-amino beta-hydroxybutyric acid, a neuromediater (Tetrahedron 1990, 46, 4277); L-carnitine, a health supported agent (WO 99/05092); atorvastatin, a HMG-CoA reductase inhibitor which is used as a cholesterol lowering drug (Tetrahedron Lett., 1992, 33, 2279); and (S)-3-tetrahydrofuran, an AIDS drug intermediate (J. Am. Chem. Soc. 1995, 117, 1181; WO 94/05639). (S)-3-Hydroxy-&ggr;-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 (U.S. Pat. No. 4,138,484.) It is 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.) HGB serves as an important precursor for the production of a variety of natural and clinical products.
The present invention relates to a new method of producing secondary chiral feedstock, (S)-3-hydroxy-&ggr;-butyrolactone (HGB), from lactose, maltose and maltodextrin. This approach can be used in the efficient synthesis of members of a large family of chiral intermediates without the need to design custom chiral synthesis for each new compound. The method provides a cost-effective method of producing pure (S)-3-hydroxy-&ggr;-butyrolactone at the process level.
The prior art shows that synthesis of (S)-3-hydroxy-&ggr;-butyrolactone has been accomplished employing various strategies. A commonly used strategy for the synthesis of a compound-represented by Formula [1] and its intermediate (S)-3-hydroxybutyric acid derivatives is from the enzymatic or catalytic reduction of &bgr;-keto ester (EP452143A2, Tetrahedron Lett. 1990, 31, 267; J. Am. Chem. Soc. 1983, 105, 5935).
(S)-3-hydroxy-&ggr;-butyrolactone can also be obtained from the selective reduction of (L)-malic acid ester (U.S. Pat. No. 5,808,107, Chem. Lett. 1984, 1389).
The treatment of a carbohydrate containing a glucose substituent in the 4-position, such as cellobiose (&bgr;-1,4-linked glucose disaccharide), maltose (the &agr;-1,4 linked isomer, amylose and cellulose with alkali, has been shown to produce a 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 et al. 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).
(S)-3,4-dihydroxybutyric acid was also 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).
(S)-3,4-dihydroxybutyric acid was obtained from lactose using a base and an oxidant. The acid obtained was cyclized to (S)-3-hydroxy-&ggr;-butyrolactone and purified by protection of the two hydroxyl groups to acetonide ester compound, methyl (S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate which was recyclized to (S)-3-hydroxy-&ggr;-butyrolactone under acidic media (WO 98/04543).
A large number of methods have been developed to make (S)-3,4-dihydroxybutyric acid by alkaline oxidation of carbohydrate containing glucose substituent at the 4-position (U.S. Pat. Nos. 5,292,939, 5,319,110 and 5,374,773). In these methods, the dicarbonyl compounds formed is oxidized to (S)-3,4-dihydroxybutyric acid and glycolic acid.
(S)-3,4-dihydroxybutyric acid has also been prepared from carbohydrates 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).
(S)-3,4-dihydroxybutyric acid 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).
(S)-3,4-dihydroxybutyric acid derivatives has been prepared by oxidation of &agr;-(1,4) linked oligosaccharides with a basic anion exchange resin with an oxidants to give (S)-3,4-dihydroxybutyric acid anion exchange resin complex dissociating the (S)-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. (S)-3-Hydroxy-&ggr;-butyrolactone (HGB) is an important building block to produce other chiral intermediates using classical chemistry methodology. Defunctionalization of carbohydrate has been attracting much attention as a vibrant synthetic tool for the enantioselective synthesis of a variety of compounds. The synthesis of a chiral compound with desired number of chiral centers could be achieved by eliminating the unneeded chiral centers quickly from carbohydrate precursors. A large number of a small-scale complex synthesis of (S)-3-hydroxy-&ggr;-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 of (S)-3-hydroxy-&ggr;-butyrolactone and its derivatives.
The methods in the prior-art are described above and found in Table 1 below. These methods have shown that expensive metal catalysts are used for the reduction of the prochiral center, e.g. enzymatic or catalytic reduction of &bgr;-keto ester. Furthermore, selective reduction to only one of the two functional groups is achieved. In addition, the yields of (S)-3,4-dihydroxybutyric acid and (S)-3-hydroxy-&ggr;-butyrolactone produced have been low and (S)-3,4-dihydroxybutyric acid can be overoxidized to formic acid and glycolic acid.
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. The optical purity of the compound is low, having poor enantioselectivity.
Purification of the target compound, (S)-3-hydroxy-&ggr;-butyrolactone, can be difficult due to the formation of a complex mixture, containing formic acid, oxalic acid, glycolic acid and erythronic acid. The prior art methods require a multi-step synthesis, long reaction times, high reaction temperatures, and produce an overall low yield of the desired compound.
In view of the above-mentioned disadvantages of the prior-art procedures, it is desirable to develop an efficient and enantioselective process for the synthesis of (S)-3-hydroxy-&ggr;-butyrolactone, which overcomes the drawbacks of the prior art process employing the oxidation of a D-hexose source under basic condition.
TABLE 1
Comparison of Prior Art Methods
Starting
No. of
Optical purity
Process
material
steps
(ee)
Yield
U.S. Pat. No.
Amylopectin
Four
From
20.2 to
6,288,272
Method
steps
disaccharide
23.7 Wt. %
(enzymatic
Maltose (94%)
reaction)
From
oligosaccharide
(99.9%)
U.S. Pat. No.
Starch, Maltose
Two
Not mentioned
66-85%
5,292,939
(Oxidizing
agent, H
2
O
2
)
WO 04543
Lactose
Four
Not mentioned
Not
(1998)
steps
mentioned
Synthesis, 570,
D-isoascorbic
Seven
Not mentioned
88%
(19
Deshmukh Anis Naim
Gurjar Mukund Keshao
Kumar Pradeep
Upadhyay Puspesh Kumar
Upadhyay Rajesh Kumar
Council of Scientific and Industrial Research
Morris Patricia L.
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