Process for preparing optically active &agr;-hydroxy acids...

Details Process for preparing optically active &agr;-hydroxy acids... Process for preparing optically active &agr;-hydroxy acids...

2002-10-08

2003-10-28

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S179000, C560S183000, C562S465000, C562S529000, C564S080000, C568S339000, C568S591000, C568S820000, C549S265000

Reexamination Certificate

active

06639095

ABSTRACT:

This application is a 371 of PCT/US99/28440 filed Dec. 2, 1999.
FIELD OF THE INVENTION
The present invention relates to a process for preparing optically active &agr;-hydroxy acids and derivatives thereof. &agr;-Hydroxy acids are important intermediates for synthesis of organic compounds in pharmaceutical and industrial applications. More particularly, the present invention relates to an enantioselective synthesis for &agr;-hydroxy acids by employing 10-camphorsulfonamide as a chiral auxiliary through 1,3-dioxolanones.
BACKGROUND OF THE INVENTION
Optically active &agr;-hydroxy acids are structural subunits of many natural products, such as motuportin, integerrimine, monocrotaline, and eremantholide A. &agr;-Hydroxy acids and their derivatives are important intermediates for the synthesis of organic compounds in pharmaceutical and industrial applications. A number of useful synthetic methods for the preparation of enantiomertically pure &agr;-branched &agr;-hydroxy acids have been developed. Generally, optically active &agr;-hydroxy acids are obtained through microbial methods, enzymatic syntheses and enantioselective syntheses using chiral auxiliaries.
Microbial methods utilizes microorganism to convert the precursors of &agr;-hydroxy acids, such as oxo- or hydroxy-containing compounds, to produce &agr;-hydroxy acids and derivatives thereof. For example, U.S. Pat. No. 5,326,702 discloses a process for biologically producing an &agr;-hydroxyamide or an &agr;-hydroxy acid, comprising reacting an &agr;-hydroxynitrile or an aldehyde with a microorganism which produces an amide or acid from the corresponding &agr;-hydroxynitrile, in the presence of a sulfite ion, a disulfite ion or a dithionite ion. The related prior art such as U.S. Pat. Nos. 5,371,014, 5,508,181, 5,756,306 and 5,273,895 can also be incorporated herein for reference. However, when using microbial methods, it is difficult to isolate the product from the fermentation broth. The purification for the product is complex and very expensive. Also, the fermentation process usually generates a large amount of waste effluent which harm the environment. An additional treatment process is required and it is not economical.
U.S. Pat. No. 5,098,841 discloses a process for the preparation of the enantiomers of 2-hydroxy-4-phenylbutyric acid, comprising reducing 2-oxo-4-phenyl-butyric acid with the enzyme lactate dehydroaenases in the presence of an electron donor and an enzyme/substrate system. The related prior art utilizing enzymatic syntheses, such as U.S. Pat. Nos. 5,273,895, 5,523,223, 5,686,275 and 5,770,410, can also be incorporated herein for reference. However, purified enzymes are expensive. Therefore, enzymatic syntheses need a stoichiometric amount of expensive cofactors. In addition, the optical purity of an enantioselective product obtained from enzymatic synthesis is highly substrate dependent.
U.S. Pat. Nos. 5,488,131 discloses a method for synthesis of compounds of predetermined chirality that are useful in asymmetric synthesis, comprising the acylation of an enantiomer of pseudoephedrine and then the alkylation of the &agr;-carbon of the adduct, wherein the alkylation proceeds in a stereoselective manner and is directed by the chiral auxiliary pseudoephedrine. The related prior art utilizing enantioselective syntheses using chiral auxiliary, such as U.S. Pat. Nos. 4,983,766, 5,512,682, 5,512,688, 5,516,930, 5,578,730, 5,760,237 and 5,919,949 can also be incorporated therein for reference. There are still some disadvantages when utilizing those enantioselective syntheses. For example, the enantioselectivity of the product is low; chiral auxiliary is very expensive and is not available for large scale production; and the recovery of chiral auxiliary is difficult. Therefore, there remains some room for the development of more efficient methods to produce an optically active compound.
By use of the enantioselectivity of 10-camphorsulfonamide, we have found an enantioselective synthetic method for &agr;-hydroxy acids and derivative thereof through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary. The process of the present invention does not have the disadvantages encountered in the prior art and has several advantages such as high enantioselectivity of products and high chemical yields. Moreover, both (S) form and (R) form of 10-camphorsulfonamide chiral auxiliaries are commercially available for large scale production and such chiral auxiliaries can be easily recovered in high yield in the process per se. Therefore, the process of the present invention is highly enantioselective, efficient, economic, and easy to do.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing optically active &agr;-hydroxy acids and derivatives thereof through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary. The 1,3-dioxolanones are prepared by the catalyzed condensation of a dialkoxy acetal which is derived from the chiral auxiliary, 10-camphorsulfonamide, by treating with &agr;-hydroxy acids. The 1,3-dioxolanones are enantioselective and therefore can be further used to produce optically active compounds such as &agr;-hydroxy acids and derivatives thereof. The 1,3-dioxolanones are subjected to alkylation and then either to alcoholysis or to hydrolysis to produce mono- and disubstituted &agr;-hydroxy acids and derivatives thereof and 10-camphorsulfonamide. 10-camphorsulfonamide can be easily recovered.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an enantioselective synthesis for &agr;-hydroxy acids through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary.
Generally, the process of the present invention for preparing optically active &agr;-hydroxy acids comprises steps of
(a) reacting 10-camphorsulfonamide of formula I
wherein R
1
and R
2
are the same or different and are each independently H or C
1-6
alkyl,
with alkoxy-substituted alkane to form dialkoxy acetal of formula II
wherein R
1
and R
2
are the same or different and are each independently H or C
1-6
alkyl, R
3
and R
4
are the same or different and are each independently C
1-4
alkyl;
(b) reacting the dialkoxy acetal of formula II with an &agr;-hydroxy acid having the formula
wherein R
5
is H, C
1-16
alkyl, or unsubstituted or substituted phenyl, to form 1,3-dioxolanones of formula III
wherein R
1
and R
2
are the same or different and are each independently H or C
1-6
alkyl, and R
5
is H, C
1-16
alkyl, or unsubstituted or substituted phenyl;
(c) reacting the 1,3-dioxolanones of formula III with alkylation reagents to form alkylated 1,3-dioxolanones of formula IV
wherein R
1
and R
2
are the same or different and are each independently H or C
1-6
alkyl, R
5
is H, C
1-16
alkyl, or unsubstituted or substituted phenyl, and R
6
is C
1-8
alkyl, C
2-7
alkenyl or unsubstituted or substituted benzyl;
(d) subjecting the alkylated 1,3-dioxolanones of formula IV to either
(i) alcoholysis, when R
5
is H, to form 10-camphorsulfonamide and &agr;-hydroxy acids derivatives of formula V
wherein R
7
is C
1-6
alkyl, and R
6
is C
1-8
alkyl, C
2-7
alkenyl or unsubstituted or substituted benzyl, or
(ii) hydrolysis, when R
5
is C
1-16
alkyl or unsubstituted or substituted phenyl, to form 10-camphorsulfonamide and &agr;-hydroxy acids of formula VI
wherein R
5
is H, C
1-16
alkyl, or unsubstituted or substituted phenyl, and R
6
is C
1-8
alkyl, C
2-7
alkenyl or unsubstituted or substituted benzyl.
The starting material, 10-camphorsulfonamide of formula I, for the process of the present invention is generally known and available in the art. In step (a), the 10-camphorsulfonamide of formula I reacts with alkoxy-substituted alkane to form a dialkoxy acetal of formula II. The reaction can be conducted in the absence or presence of catalysts and solvents known to persons skilled in the art. Catalysts such as p-toluene sulfonic acid (p-TSA) and solvents such as alcohols, for example, methanol, are commonly used. In the preferred embodiment of

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