Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives

a technology of oxopentanoic acid and derivatives, which is applied in the preparation of carboxylic acid nitrile, carboxylic compound preparation, organic chemistry, etc., can solve the problems of neither being a favorable process for commercial-scale production, and achieve the effect of easy preparation

Inactive Publication Date: 2006-10-10
KANEKA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prior art (1) requires an expensive starting material while the prior art (2) involves a very low reaction temperature of −78° C. to −40° C., so that neither is a favorable process for commercial-scale production.

Method used

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  • Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives
  • Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives
  • Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives

Examples

Experimental program
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Effect test

example 1

Tert-butyl 6-benzyloxy-5-hydroxy-3-oxohexanoate

[0044]Under argon gas, a solution composed of 5.01 g (49.5 mmol) of diisopropylamine and 5 mL of tetrahydrofuran was added dropwise to 30 mL (45 mmol) of n-butyllithium / hexane (1.5 mol / L) with stirring at 5° C. and the mixture was stirred for 1 hour to prepare: a lithium diisopropylamide solution.

[0045]In 8.0 ml of tetrahydrofuran were dissolved 2.38 g (10 mmol) of ethyl 4-benzyloxy-3-hydroxybutyrate and 2.32 g (20 mmol) of tert-butyl acetate, and the solution was stirred in an argon atmosphere at 0 to 5° C. To this solution, the lithium diisopropylamide solution prepared above was added dropwise over 30 minutes, and the mixture was further stirred at 5 to 20° C. for 16 hours.

[0046]In a separate vessel, 35 mL of 3 N-hydrochloric acid was mixed with 30 mL, of ethyl acetate under stirring and the above reaction mixture was poured. After standing, the organic layer was separated, washed with saturated aqueous sodium chloride solution, and ...

example 2

Tert-butyl 6-benzyloxy-5-hydroxy-3-oxohexanoate

[0050]Under argon gas, a solution composed of 3.90 g (38.5 mmol) of diisopropylamine and 3 mL of tetrahydrofuran was added dropwise to 22.9 ml-(35 mmol) of n-butyllithium / hexane (1.5 mol / L) with stirring at 5° C. and the mixture was stirred for 1 hour to prepare a lithium diisopropylamide solution.

[0051]In 3.0 ml of tetrahydrofuran were dissolved 2.38 g (10 mmol) of ethyl 4-benzyloxy-3-hydroxybutyrate and 2.32 g (20 mmol) of tert-butyl acetate, and the solution was stirred in an argon atmosphere at 0 to 5° C. To this solution was added 5.7 g (10 mmol) of a solution of tert-butylmagnesium chloride in toluene / tetrahydrofuran (1:2.5 by weight) (1.75 mol / kg) dropwise over 10 minutes, and the mixture was further stirred at 5° C. for 50 minutes. To this, the lithium diisopropylamide solution prepared above was added drop-wise over 30 minutes, and the mixture was further stirred at 5 to 20° C. for 16 hours.

[0052]In a separate vessel, 30 mL of ...

example 3

Tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate

[0054]Under argon gas, a solution composed of 2.67 g (26.4 mmol) of diisopropylamine and 5 mL of tetrahydrofuran was added dropwise to 15 mL (24 mmol) of n-butyl lithium / hexane (1.6 mol / L) with stirring at 5° C. and the mixture was stirred for 1 hour to prepare a lithium diisopropylamide solution.

[0055]In 5.0 ml of tetrahydrofuran were dissolved 1.0 g (6.0 mmol) of ethyl (3S)-4-chloro-3-hydroxybutyrate and 2.78 g (24 mmol) of tert-butyl acetate, and the solution was stirred in an argon atmosphere at 0 to 5° C. To this the lithium diisopropylamide solution prepared above was added drop-wise over 20 minutes and the mixture was further stirred at 5 to 20° C. for 16 hours.

[0056]In a separate: vessel, 6.31 g of concentrated hydrochloric acid, 20 g of water, and 20 mL of ethyl acetate were mixed together under stirring and the above reaction mixture was poured. After standing, the organic layer was separated, washed with saturated aqueous s...

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Abstract

This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low-temperature reactor.Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acidwhich comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C.Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acidwhich comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I),and permitting a lithium amide to act upon the mixture at a temperature not below −20° C.This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low temperature reactor. Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C.<?insert-end id="INS-S-00001" ?>

Description

[0001]This application is a 371 of PCT / JP 00 / 03574 filed Jun. 2, 2000.TECHNICAL FIELD[0002]The present invention relates to a process for producing a 5-hydroxy-3-oxopentanoic acid derivative which is of value as a pharmaceutical intermediate, particularly an intermediate of an HMG-COA reductase inhibitor.BACKGROUND ART[0003]The hitherto-known process for producing a 5-hydroxy-3-oxopentanoic acid derivative includes the following processes.[0004](1) The process in which 3-hydroxypropionic acid imidazolide prepared from 3-hydroxypropionic acid and diimidazoyl ketone is coupled to a malonic acid monoester monomagnesium salt (Synthesis, 1992, 4, 403-408).[0005](2) The process in which a lithium enolate prepared from tert-butyl acetate and lithium diisopropylamide is reacted with a 3-hydroxypropionic acid ester (Japanese Kokai Publication Hei-8-198832, Chem. Pharm. Bull., 1994, 42 (11), 2403-2405, Tetrahedron Lett., 1993, 49(10), 1997-2010, Tetrahedron, 1990, 46 (29), 7283-7288, Tetrahed...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07C69/66C07C59/185C07C67/343C07C253/30C07C255/21C07D319/06C12P7/62
CPCC07B2200/07C07C67/343C07C253/30C07D319/06C12P7/62C07C69/716C07C255/21C07C69/738C07C67/18
Inventor NISHIYAMA, AKIRAINOUE, KENJI
Owner KANEKA CORP
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