Process for the synthesis of enantiomerically pure...

Details Process for the synthesis of enantiomerically pure... Process for the synthesis of enantiomerically pure...

2003-03-28

2004-11-30

Desai, Rita (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

C562S470000, C562S491000

Reexamination Certificate

active

06825378

ABSTRACT:

FIELD OF INVENTION
The present invention relates to a improved process for the synthesis of enantiomerically pure cyclohexylphenyl glycolic acid of formula (1). The present invention more particularly relates to a process using cyclohexylphenyl ketone for the synthesis of enantiomerically pure cyclohexylphenyl glycolic acid of formula (1)
BACKGROUND ART
Tertiary hydroxy acids/esters are highly important intermediates in the synthesis of a variety of medicinal agents [(a) Carter, P. J.; Blob, L; Audia, V. A.; Dupont, A. C.; Mcpherson, D. W.; NataleJr, K J.; Reszotarski, W. 1.: Spadguolo, C. J.; Waid, P P.; Kaicer, C. Med. Chem. 1991, 34, 3065; (b) Tambutc, A.; Collet, A. Butll De La Chimi. Fr. 19&4, −2,11-77; (c) Kiesewetter, D. O. Tetrahedron: Asymmetry 19.93, 4, 2183; (d)McPherson, D. W.; Knapp, F. F. J. Org. Chem. 1996, 61, 8335] and natural products [(a) Caldwell, C. G.; Riupprecht, K. M; Bondy, S. S.; Pavis, A. A. J. Org. Chemt. 1990, 55, 2355; (b) Kada4 Y.; Fukuyamai T. J. Am. Chem. Soc. 1993, 115, 8451]. Cyclbhexylphenyl glycolic acid is an important intermediate for the synthesis of oxybutynin (Ditropan), which is a widely prescribed muscaronic receptor antagonist for the treatment of urinary frequency; urgency and urge incontinence Yarker. Y. E.; Goa, K. L.; Fitton, A. Drug Aging, 1995, 6, 243.
In the prior-art the synthesis of cyclohexylphenyl glycolic acid segment of oxybutynin and related tertiary hydroxy esters has been accomplished employing various synthetic strategies.
An early synthesis utilizes carbohydrate systems containing an asymmetric benzylic center of known absolute configuration, which on degradation give tertiary hydroxy acids in enantiomerically pure form [Inch, T. D.; Ley, R Rich, P. J. Chem. Soc. ©, 1968, 1693.
In another prior art method, cis-aminoindanol or related constrained amino alcohols are used as a highly defined chiral handle for the preparation of enantiopure tertiary &agr;-hydroxy acids via appropriate metal coordinated 1,1-dicarbonyl systems in the Grignard reaction to give tertiary hydroxy acids in 99% enantiomeric purity [Senanayake, C. H.; Fang, K; Grover, P.; Bakale, R. P.; Vandenbossche, C. P.; Wald, S. A. Tetrahedron Lett. 0.1999, 40, 819].
In yet another prior art method chiral mandelic acid has been used as a template to generate the tertiary hydroxy acid by Aldol process to give cyclohexylphenyl glycolic acid it greater than 99.9% diasteromeric purity [Grover, P. T.; BHongle, Nr. N.; Wald, S. A.; Senamayake, C. H. J. Org Chem. 2000, 65, 6283]
In still another prior art method the racemic cyclohexylphenyl glycolic acid is resolves via the tyrosine methyl ester to further obtain the cyclohexylphenyl glycolic acid in 99% enantiomeric purity [(a) Bakale, et al. US 6140529, 2000; (b) US S973182, 1998]. Some of the major drawbacks of the methods known in the prior-art are such as follows:
(i) Multi-step synthesis
(ii) High cost of chiral materials employed
(iii) Complicated reagents and longer reaction time:
(iv) Difficulties involved in work-up procedure:
(v) Overall low yield of the desired compound;
(vi) Lack of reusability of expensive reagents
OBJECTS OF THE INVENTION
The main object of the present invention is to develop an improved, efficient and enantio selective process for the synthesis of cyclohexylphenyl glycolic acid.
An object of the present invention is, to provide a process for the synthesis of enantiomerically pure cyclohexylphenyl glycolic acid, which overcomes the drawbacks of the prior-art processes employing the sharpless asymmetric dihydroxylation and selective oxidation of primary hydroxyl to an acid.


REFERENCES:
patent: 6025177 (2000-02-01), Senanayake et al.
patent: 6140529 (2000-10-01), Bakale et al.

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