Asymmetric synthesis of a key intermediate for making...

Details Asymmetric synthesis of a key intermediate for making... Asymmetric synthesis of a key intermediate for making...

2001-07-19

2003-04-15

Kifle, Bruck (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06548665

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of asymmetric synthesis of a chemical compound. More particularly, the present invention relates to a method of converting a intermediate compound in synthesizing benazepril from one diastereomer form R,S (hereinafter the “RS” form) to another diastereomer form S,S (hereinafter the “SS” form), which is a desired form for making benazepril.
2. Description of the Related Art
It is generally known in the art that, for certain chemical compounds when used as therapeutic drugs, only one specific stereoisomer is effective. The other stereoisomers of the same compound may be less effective or have no effect at all. As a general technique, crystallization has been used to induce asymmetric synthesis, see Marianne Langston, et. al,
Organic Process Research
&
Development,
4:530-533 (2000). The success of this method depends on a large solubility difference between the diastereomers and a condition that facilitates effective epimerization of the desired optical center. In a predetermined solvent, the desired diastereomer should have a low solubility and thus precipitates easily as crystals while the undesired diastereomer has a high solubility and thus largely remains in the solvent. As the more desired diastereomer forms crystals, its concentration in the solution becomes lower, a condition that helps further conversion from the undesired diastereomer to the desired one.
The synthesis of benazepril, an important angiotensin converting enzyme (ACE) inhibitor, is made difficult due to the need to prepare the SS form of the compound. The need to chemically resolve an early intermediate or to chemically synthesize a chiral intermediate adds much more expense to the synthesis. For example, Novartis Pharmaceuticals reported a method based on the crystallization technique, which converts one of the intermediate in the benazepril synthesis to the desired SS form. While this method produced a good yield of the desired SS chiral amide form, the necessary step of producing the homophenyl alanine portion is very expensive. In addition, the chiral S-phenylethyl amine used in the process is expensive and cannot be recovered, which further increases the costs. It would be much desired if (1) S-homophenyl alanine could be coupled with the benzlactam portion and (2) then induce chirality at the site alpha to the lactam. Our pending International Patent Application Serial Number PCT/1800/00478 disclosed a method of coupling between S-homophenyl alanine and benzlactam to accomplish the first step. To accomplish the second step in an efficient manner is one of the objects to be attained by the present invention.


REFERENCES:
Marianne Langston et al., “Racemisation of R-Bupivacaine: A Key Factor in the Integrated and Economic Process for the Production of Levobupivacaine”, Organic Process Research & Development 2000, pp. 530-533.
Wen-chung Shieh, et al., “Asymmetric Synthesis of N-Substitutedx-Aminobenzlactam via Crystallization-Induced Asymmetric Transformation of Covalent Diastereomer”, J. Org. Chem. 1997, 62, 8271-8272, pp. 8271-8272.
Von Stephen K. Boyer et al., “Note on the Synthesis of an Optically Active ACE Inhibitor with Amino-oxo-benzazepine-1-alkanoic-Acid Structure by Means of an Enantiocovergent Crystallization-Based Resolution”, pp. 337-343. Helvicta Chimica Acta - vol. 71 (1998).

Affiliated with

Also associated with

Rating

Asymmetric synthesis of a key intermediate for making... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Asymmetric synthesis of a key intermediate for making..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Asymmetric synthesis of a key intermediate for making... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3051297