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Preparation method of alvimopan

A technology for crude products of Avimopan and Vimopan, which is applied in the field of pharmaceutical chemical preparation, can solve the problems of harsh alkaline hydrolysis reaction conditions, unsuitable for industrial production, and difficult separation and purification, and achieve high reaction yield and stable configuration , the effect of cost reduction

Inactive Publication Date: 2013-01-30
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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Problems solved by technology

[0004] Chinese Patent No. ZL 92102213.1 discloses a preparation method of piperidine derivatives, which uses 3R, 4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine, 2-benzyl Ethyl acrylate is used as the starting material, and the target compound is prepared by five steps of Michael addition, hydrolysis, condensation, chiral column chromatography, and hydrolysis. The advantage of this method is that the reaction steps are relatively short and the conditions of each step are relatively short. It is not harsh, and its disadvantage is that the products of each step of the reaction are slurry, which is not easy to separate and purify. The separation, purification, and separation of chiral enantiomers of the intermediates all need to be prepared by column chromatography. Low efficiency, cumbersome operation, high cost, not suitable for industrial production
However, this method has a potential safety hazard of explosion during the hydrogenolysis production process of Avibenzyl Ester, and its alkaline hydrolysis reaction conditions are relatively harsh, which is not suitable for industrial production.

Method used

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  • Preparation method of alvimopan
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  • Preparation method of alvimopan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of Alvimopan Crude

[0031] (3R,4R)-3-(3,4-Dimethyl-4-piperidinyl)phenol 60g (0.292mol), (S)-2-methylsulfonylmethylphenylpropionyl-glycine isobutyl ester Add 144g (0.388mol), 180ml of triethylamine, and 3000ml of toluene into a three-necked flask, heat and reflux for 6 hours, after the reaction is complete, cool to room temperature, add 1200ml of water and stir, separate the organic layer, dry over anhydrous sodium sulfate, filter, and reduce Concentrate under pressure to exhaust the solvent to obtain 88 g of Avibutyrate, properties: pale yellow oil, yield: 63.8%. After nuclear magnetic resonance, the data are as follows:

[0032] 1 HNMR (300MHZ, DMSO): 0.68~0.71(d, 3H), 0.86~0.89(m, 6H), 1.02~1.05(d, 2H), 1.31(d, 3H), 1.60~1.82(s, 1H), 1.82~1.95(s, 1H), 2.20~2.40(m, 2H), 2.67~2.98(m, 3H), 3.00~3.30(dd, 4H), 3.75~3.95(dd, 4H), 6.61~6.63(m , 3H), 7.11 (m, 1H), 7.23-7.30 (m, 5H), 9.00-9.05 (s, 1H), 9.33 (s, 1H).

[0033]Take 88g of Evitamin isobutyl ester...

Embodiment 2

[0035] Preparation of Alvimopan Crude

[0036] (3R,4R)-3-(3,4-Dimethyl-4-piperidinyl)phenol 30g (0.146mol), (S)-2-methylsulfonylmethylphenylpropionyl-glycine isobutyl ester Add 55g (0.148mol), 150ml of diethylamine, and 1500ml of toluene into a three-necked flask, heat and reflux for 6 hours, after the reaction is complete, cool to room temperature, add 600ml of water and stir, separate the organic layer, dry over anhydrous sodium sulfate, filter, reduce Concentrate under pressure to exhaust the solvent to obtain 34 g of Avibutyrate, properties: pale yellow oil, yield: 48.4%. Take 34g of Evitamin Isobutyl Ester and add it to a 2000ml three-necked flask, add 850ml of ethanol and 100ml of water, add 210ml of 1N sodium hydroxide solution dropwise under stirring at room temperature, drop it in 20 minutes, stir at room temperature for 3 hours, concentrate under reduced pressure to remove ethanol, and the residual Add 200ml of absolute ethanol to the mixture, add 6N hydrochloric ac...

Embodiment 3

[0038] Preparation of Alvimopan Crude

[0039] (3R,4R)-3-(3,4-Dimethyl-4-piperidinyl)phenol 30g (0.146mol), (S)-2-methylsulfonylmethylphenylpropionyl-glycine isobutyl ester Add 81g (0.218mol), 300ml of triethylamine, and 1200ml of toluene into a three-neck flask, heat and reflux for 6 hours, after the reaction is complete, cool to room temperature, add 600ml of water and stir, separate the organic layer, dry over anhydrous sodium sulfate, filter, reduce Concentrate under pressure to exhaust the solvent to obtain 42 g of Avibutyrate, properties: pale yellow oil, yield: 59.8%. Take 42g of Evitamin Isobutyl Ester and add it to a 2000ml three-neck flask, add 850ml of ethanol and 100ml of water, add 90ml of 1N sodium hydroxide solution dropwise under stirring at room temperature, drop it in 20 minutes, stir at room temperature for 3 hours, concentrate under reduced pressure to remove ethanol, and the residual Add 200ml of absolute ethanol to the mixture, add 6N hydrochloric acid d...

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Abstract

The invention provides a preparation method of alvimopan and an intermediate for synthesizing the alvimopan. The preparation method comprises the following steps of: designing a process route through a two-chain method, respectively synthesizing initial raw materials, then condensing and hydrolyzing to obtain the alvimopan. The method can be used for directionally synthesizing a single optical isomer through N-alkylation reaction under an alkaline condition, the configuration change of the chiral centers of the raw materials and the product can not be generated both in reaction conditions and a post-processing method, and the obtained product can be hydrolyzed into the alvimopan under the mild alkaline condition.

Description

technical field [0001] The present invention relates to the field of medicinal chemical preparation, in particular to the structural formula [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R), 4-dimethyl-1-piperidine Base] methyl] -1-oxo-3-phenylpropyl] amino] acetic acid, the preparation method of general name love Wei Mopan (alvimopan). Background technique [0002] Alvimopan (alvimopan) is the world's first drug for the prevention and treatment of postoperative gastrointestinal dysfunction. It acts on the mu opioid receptors in the gastrointestinal tract and competitively antagonizes the effects of endogenous and exogenous opioids on the stomach. Effects of intestinal inhibition. The chemical name of alvimopan is: [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R), 4-dimethyl-1-piperidinyl ]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid, its structural formula is: [0003] Formula 4 [0004] Chinese Patent No. ZL 92102213.1 discloses a preparation method of piperidine derivatives, which uses 3...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/22
Inventor 王颖袁明旭李智
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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