Process for the synthesis of protected esters of (S)-3,4-dihydro

Details Process for the synthesis of protected esters of (S)-3,4-dihydro Process for the synthesis of protected esters of (S)-3,4-dihydro

1999-01-27

1999-12-07

McKane, Joseph K.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549454, C07C 5910, C07C 69675, C07D30720, C07D31712

Patent

active

059986336

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

(S)-3-Hydroxybutyrolactone and a derivative, methyl (S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate, are optically active starting materials in the preparation of [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin), a new HMG-CoA reductase inhibitor (Nanninga, et al., Tetrahedron Lett., 1992;33:2279).
Chiral dihydroxybutyric acids and the corresponding esters, lactones, and derivatives have proven to be valuable chemical entities. In addition to useful intermediates in synthetic efforts towards natural products (Cf Benezra, et al., J. Org. Chem., 1985;50:1144; Hanessian, et al., Can. J. Chem., 1987;65:195; Ahn, et al., Tetrahedron Lett., 1992:507), a number of clinical applications have been disclosed. (S)-3-Hydroxybutyrolactone 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., U.S. Pat. No. 4,138,484).
Clearly, there is a need for a simple and inexpensive method for the large scale preparation of (S)-3,4-dihydroxybutyric acid, (S)-3-hydroxybutyro-lactone, and derivatives of these chiral molecules. A large number of small scale complex syntheses have been reported demonstrating the value of these compounds.
Preparation of methyl (S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate has been reported in the literature. It is prepared by reduction of dimethyl malate with borane-dimethyl sulfide complex/NaBH.sub.4 followed by acid catalyzed reaction with dimethoxypropane to yield the acetonide (Saito, et al., Chem. lett., 1984:1389; Tetrahedron, 1992;48:4067).
The acetonide has been prepared from isoascorbic acid via a multi-step sequence, but the yield was quite low due to the instability of an intermediate in the synthetic strategy (Tanaka, et al., Synthesis, 1987:570). The ethyl ester of the acetonide can be prepared from D-isoascorbic acid (Abushanab, et al., Synth. Comm., 1989;19:3077) via a similar multi-step route. An enzymatic resolution starting with racemic dimethyl malate has also been employed to produce the acetonide methyl ester on a small scale (Benezra, et al., J. Org. Chem., 1985;50:1144).
An additional reported procedure (Williams, et al., Tetrahedron Lett., 1988;29:5087) involves the direct oxidation of the corresponding acetonide aldehyde with alcoholic bromine to give the acetonide methyl ester in good yield.
Although there are a variety of routes to this acetonide ester, they all involve either expensive starting materials, difficult to handle reagents, or multi-step sequences.
There are a number of procedures in the literature for the preparation of (S)-3,4-dihydroxybutyric acid and the corresponding internal ester, (S)-3-hydroxybutyrolactone. The oxidation of water soluble carbohydrates to (S)-3,4-dihydroxybutyric acid and the corresponding lactone, (S)-3-hydroxybutyrolactone, has been reported (Hollingsworth, U.S. Pat. Nos. 5,292,939; 5,319,110; and 5,374,773). However, there is no discussion on how to isolate the product, (S)-3-hydroxybutyrolactone, except by chromatography. This hydroxylactone is very difficult to isolate from the reaction mixture due to the high water solubility of the molecule and the ease of decomposition/dehydration at the high temperatures required for purification by distillation. The preparation discussed in these patents is performed at high dilution, presumably due to the highly exothermic nature of the oxidation. In addition, this preparation does not provide the hydroxylactone ((S)-3-hydroxybutyrolactone) in the yields reported. Thus, this process is not readily amenable to large scale, economical preparations of (S)-3-hydroxybutyrolactone. Further, the above patents do not discuss the preparation of esters of (S)-3,4-O-isopropylidene-3,4-dihydroxybutyrate directly from carbohydrate oxidation reaction mixtures.
Preparation of (S)-3-hydroxybutyrolactone has been reported in a multi-step procedure starting wi

REFERENCES:
patent: 5292939 (1994-03-01), Hollingsworth
Ahn et al., Tetrahedron Let. 33(4), 507-510, 1992.
Reese, Protective Groups in Org. Chem. p. 120-143, 1973.
Lee et al., J. Org. Chem. (1993) 58, 1887-94.
Tokunaga et al., J. Chem. Soc., Perkin Trans. 1 (1986) 581-4.
Lag Cheveque et al. Tetrahedron, 43(10), 2303-10, 1987.
Saito et al., Tetrahedron, 48(20), 4067-86, 1992.

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