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Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids

An aryl and alkyl technology, which is used in the field of preparation of highly functionalized γ-butyrolactam and γ-amino acid

Inactive Publication Date: 2005-08-03
WARNER-LAMBERT CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] A disadvantage of any of these approaches, especially on a large scale and in production, is that they require multiple steps and refining operations

Method used

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  • Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids
  • Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids
  • Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids

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preparation example Construction

[0100] The inventive process for preparing 3-substituted gamma-aminobutyric acids disclosed herein has a number of advantages. First, they obtain 3-substituted γ-aminobutyric acids such as furgabalin or its analogues such as 3-aminomethyl-5-methyl-octanoic acid with a minimum of steps and under mild conditions. Second, they use generally inexpensive and readily available reagents. Third, they exploited the synthetic possibility of viscohaloacids.

[0101] Mucic acid 1 (2,3-dichloro-4-oxo-2-butenoic acid) and mucbromic acid (2,3-dibromo-4-oxo-2-butenoic acid) are commercially available and Inexpensive starting material. Both molecules are characterized by a carbon-carbon double bond with a Z configuration, two halogen atoms and two carbonyl groups. This high degree of functionality makes both mucchloric acid and mucbromic acid particularly useful as building blocks for the synthesis of various biologically active heterocycles: such as substituted 1,5-dihydropyrrol-2-ones, py...

Embodiment

[0201] Route A, Option 2

[0202] Step A: 5-Benzyloxy-3,4-dihalo-5H-furan-2-one

[0203] In 1000 mL of toluene and in an apparatus equipped with a Dean-Stark trap (strap), mix viscohalic acid (0.4-0.6 mol, 1 eq), benzyl alcohol (1.5 eq), and p-toluenesulfonic acid (0.05 eq) . The mixture was heated at reflux until water collection in the Dean Stark trap ceased. The mixture was then cooled to room temperature. The toluene was removed in vacuo at 35-40 °C to leave the crude product as a very light amber oil. The crude product was purified by silica gel column chromatography eluting with 55% then 10% ethyl acetate in heptane.

[0204] 1. 5-Benzyloxy-3,4-dichloro-5H-furan-2-one. Prepared as provided in Procedure A. 95% yield. 1 HNMR (CDCl 3 , 300MHz) δ7.3(s, 5H), 5.92(s, 1H), 4.95(d, 1H), 4.89(d, 1H). C 10 h 8 Cl 2 o 3 The elemental analysis measured value (theoretical value): C, 51.12 (50.99); H, 2.93 (3.11); N, <0.05 (0.00); Cl, ​​27.19 (27.37).

[0205] 2. 5-Benzyl...

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Abstract

The invention relates to a process for preparing highly functionalized gamma- butyrolactams and gamma-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin or 3-aminomethyl-5-methyl octanoic acid, GABA analogs with desirable medicinal activity. (Formula I).

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Provisional Patent Application No. 60 / 376991, filed April 30,2002. field of invention [0003] The present invention relates to a process for the preparation of highly functionalized γ-butyrolactams and γ-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses the preparation of GABA analogues fugabalin with the desired pharmaceutical activity (pregabalin) method. Background of the invention [0004] Fugabalin (3-aminomethyl-5-methyl-hexanoic acid) is a 3-substituted analogue of gamma-aminobutyric acid (GABA) which exhibits an array of useful medical properties, as described in WO93 / 23383, and U.S. Patent As disclosed in No. 6306910 and WO 00 / 76958, the latter two documents are assigned to the same assignee as the present application. [0005] [0006] ric...

Claims

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Application Information

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IPC IPC(8): A61K31/198A61K31/405C07D207/38A61K31/4172C07B61/00C07C227/12C07C227/22C07C229/00C07C229/04C07C229/06C07C229/08C07C229/28C07C229/34C07C229/38C07D207/24C07D209/18C07D213/55C07D233/66
CPCC07C229/18C07C227/22C07D207/38C07C229/08C07D401/04
Inventor P·G·布拉泽卡J·G·戴维森三世张霁
Owner WARNER-LAMBERT CO
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