Process for preparing entacapone substantially free of z-isomer, synthesis intermediates thereof and a new crystalline form

A technology of entacapone and isomers, applied in the preparation of carboxylic acid nitrile, organic chemistry methods, chemical instruments and methods, etc., can solve problems such as instability

Inactive Publication Date: 2009-12-30
凯默伊比利亚公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, the authors of this patent discovered that entacapone (E-isomer) exists in two polymorphic forms A and B; the (Z)-isomer and crystalline form B exhibit instability

Method used

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  • Process for preparing entacapone substantially free of z-isomer, synthesis intermediates thereof and a new crystalline form
  • Process for preparing entacapone substantially free of z-isomer, synthesis intermediates thereof and a new crystalline form
  • Process for preparing entacapone substantially free of z-isomer, synthesis intermediates thereof and a new crystalline form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1. Entacapone provided as a synthetic intermediate by using the organic base piperidine From 3,4-dihydroxy-5-nitrobenzoic acid (V) and N,N-dimethylcyanoacetamide (VI) Method for preparing entacapone substantially free of Z-isomer

[0077] a) method for obtaining entacapone piperidine salt (IIIa)

[0078] 3,4-Dihydroxy-5-nitrobenzaldehyde (70g; 382mmol), N,N-diethylhydroxyacetamide (107g; 764mmol), piperidine (56.6ml; 573mmol) and acetic acid (32.8ml; 573 mmol) in isopropanol (700 mL) was heated to reflux for about 3 hours. The resulting solution was cooled to room temperature, and the resulting precipitate was stirred at this temperature overnight. Finally, it was cooled to 0-5°C, filtered and washed with isopropanol (140ml). The resulting product was dried in a vacuum oven at 40°C, yielding 119 g (79.7% yield) of an organic solid (melting point = 152-4°C: HPLC purity = 98.0% (Z-isomer = 0.94%)).

[0079] IR (cm -1 ): 3190, 3038, 2975, 2828, 2723, 254...

Embodiment 2

[0084] Example 2. Entacapone provided as a synthetic intermediate by using the organic base piperidine Piperidinium salt and from crude entacapone (Z / E) to prepare Entacapone substantially free of Z-isomer Methods

[0085] a) method for obtaining entacapone piperidine salt (IIIa)

[0086] Piperidine (6.26g; 73.5mmol) was added to entacapone (E-isomer=75%; Z-isomer=25%) (12.5g; 40.9mmol) in isopropanol (150ml) at room temperature in suspension. The mixture was stirred for about 2 hours and a large precipitate formed. Finally, it was cooled at 0-5° C. for about 2 hours, and the resulting precipitate was filtered and washed with cold isopropanol (20 ml). The resulting product was dried in a vacuum oven at 40°C, yielding 14.2 g (yield = 88.8%) of an organic solid (melting point = 152-4°C (decomposition); (Z-isomer = 1.3%)).

[0087] b) Obtained from entacapone piperidine salt (entacapone crystal form G) substantially free of Z-isomer Entacapone method

[0088] Enta...

Embodiment 3

[0089] Example 3. Provision of Enta as Synthetic Intermediate by Using Inorganic Base Sodium Hydroxide Entacapone sodium salt and prepare Entacapone substantially free of Z-isomer from crude Entacapone (Z / E) Peng's method

[0090] a) method for obtaining entacapone sodium salt (IIIb)

[0091] Add 30% NaOH aqueous solution at room temperature to a suspension of entacapone (E-isomer=69%; Z-isomer=31%) (15.15g; 40.9mmol) in ethanol (100ml) (8.73g ; 65.5 mmol). The mixture was stirred at room temperature, and the resulting precipitate was stirred at this temperature overnight. Finally, it was cooled at 0-5°C for about 2 hours, and the resulting precipitate was filtered and washed with cold ethanol (20 ml). The resulting product was dried in a vacuum oven at 40°C to give 14.13 g (yield = 87.1%) of a red solid (melting point = 260-4°C (decomposition); (Z-isomer = 1.80%)).

[0092] IR (cm -1 ): 3317, 2990, 2201, 1641, 1592, 1538, 1475, 1460, 1443, 1390, 1350, 1265, 1213, ...

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Abstract

The present invention relates to a new process for preparing Entacapone substantially free of Z-isomer from 3, 4-dihydroxy-5-Nitrobenzaldehyde and N, N-Dimethylcyano acetamide, or directly from a mixture of (E) - and (Z) - isomers of Entacapone, by formation of organic or inorganic salts, specially piperidine and sodium ones. A new crystalline form G of Entacapone can be obtained from this method in a fast, efficient, and simple way and substantially free of Z-isomer. Another object of the invention is a pharmaceutical composition comprising it.

Description

technical field [0001] The present invention relates to a novel process for the preparation of Entacapone substantially free of the Z-isomer by forming organic or inorganic salts as reaction intermediates. [0002] The invention also relates to novel reaction intermediates formed in said process, in particular entacapone salts substantially free of the Z-isomer. [0003] The present invention also relates to a new crystal form G, and a pharmaceutical composition comprising the crystal form. Background technique [0004] Entacapone is a COMT (catechol-oxo-methyltransferase) inhibitor indicated for the treatment of Parkinson's disease. The pure E-isomer is used for therapeutic purposes. The chemical name of entacapone is (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-acrylamide, and its structure As follows: [0005] [0006] Entacapone was first disclosed in the patent US 4,963,590 as a regioisomeric mixture of (E)- and (Z)-two geometric isomers. There is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/34C07C253/30C07C255/41A61K31/277A61P25/16
CPCC07C253/30C07B2200/13C07C253/34C07C255/41A61P25/16A61K31/277C07C235/34C07C255/44
Inventor F·E·帕罗莫尼古拉A·莫利纳庞塞J·贝尼特-布赫霍尔茨L·索拉卡拉登
Owner 凯默伊比利亚公司
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