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Compound for preparing alvimopan and preparation process and application thereof

A technology of compound and methyl, which is applied in the field of preparation of avimopan compound and its preparation, can solve the problems of harsh reaction conditions, corrosiveness, and short reaction conditions in reaction steps, and achieve mild reaction conditions, easy operation, and yield high rate effect

Active Publication Date: 2012-10-03
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Patent CN1065455A discloses a preparation method of piperidine derivatives, which uses 3R, 4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine and ethyl 2-benzyl acrylate as Starting raw materials, the target compound is obtained through 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 reaction conditions of each step are relatively mild; the disadvantage is that each step The products are all slurry, and the separation and purification of intermediates and the separation of products need to be prepared by column chromatography, so it is not suitable for industrial production
[0005] The method of patent CN1988805A uses 3R,4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine and methyl acrylate as starting materials, and undergoes addition, alkylation, resolution, hydrolysis and condensation 1. Hydrolysis and total six-step reaction to prepare the target compound. This method solves the technical problem that industrial production cannot be realized in the patent CN1065455A, and the steps are shorter, but the disadvantage is that lithium diisopropylamide (LDA) must be used in the preparation process of the alkylation reaction. ) is an alkalizing reagent, and it needs to be carried out at low temperature (-50~-40°C) and under absolute anhydrous conditions. The reaction conditions are relatively harsh, and the compound is a strong base, which is corrosive. Airtight preservation, so this method is not conducive to industrial production

Method used

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  • Compound for preparing alvimopan and preparation process and application thereof
  • Compound for preparing alvimopan and preparation process and application thereof
  • Compound for preparing alvimopan and preparation process and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of 3-hydroxyl-2-methylene-3-phenylpropionic acid

[0042] At room temperature, a solution of KOH (11.0g, 0.2mol) in water (180mL) was added dropwise to 3-hydroxy-2-methylidene-3-phenylpropanoic acid methyl ester (29.0g, 0.15mol) in methanol (60mL ) solution, the dropwise addition was completed after about 1h, and then stirred at room temperature for 16h, and the methanol was distilled off under reduced pressure. Then add methyl tert-butyl ether (100mL×2) for extraction, adjust the aqueous phase to acidity with 6mol / L hydrochloric acid, then extract with methyl tert-butyl ether (100mL×3), combine the organic phases, wash with saturated salt water (100 mL) and washed with MgSO 4 dry. The solvent was distilled off by a rotary evaporator to obtain a colorless viscous liquid (25 g, 94%).

[0043] [M+H] + :179.

Embodiment 2

[0044] Embodiment 2: Preparation of [[3-hydroxyl-2-methylidene 1-oxo-3-phenylpropyl] amino] ethyl acetate

[0045] Triethylamine (3.75g, 0.027mol, 1.2eq) was added to glycine ethyl ester hydrochloride (3.44g, 0.024mol, 1.1eq) in dichloromethane (60mL) suspension, the mixture was stirred for 15min, then cooled to 0°C.

[0046]3-Hydroxy-2-methylene-3-phenylpropionic acid (4 g, 0.022 mol, 1.0 eq) and dicyclohexylcarbodiimide (5.09 g, 0.025 mol, 1.1 eq) were added to the mixture with stirring, The reaction was continued for 17 h, triethylamine hydrochloride and DCU were removed by filtration, and the filtrate was washed with 1 mol / L hydrochloric acid (60 mL) and saturated brine (60 mL) successively. Then it was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (hexane / EtOAc=2:1) ​​to obtain a yellow liquid (3.51 g, 60%).

[0047] 1 H NMR (CDCl3, 400MHz, TMS) δ1.26(t, J=7.2Hz,...

Embodiment 3

[0048] Embodiment 3: Preparation of [[3-acetoxy-2-methylidene 1-oxo-3-phenylpropyl]amino]ethyl acetate

[0049] Dissolve ethyl [[3-hydroxy-2-methylidene 1-oxo-3-phenylpropyl]amino]acetate and triethylamine in dichloromethane, then add DMAP and cool to 0°C.

[0050] Under stirring at 0°C, acetic anhydride was added dropwise, and the addition was completed in about 40 minutes. Return to room temperature and stir for 16 hours. Under cooling, add saturated aqueous sodium carbonate solution, stir evenly and then separate the liquids. The organic layer is dried over anhydrous magnesium sulfate and concentrated to obtain a deep red liquid, which is directly used for the reaction.

[0051] 1 H NMR (CDCl3, 400MHz, TMS) δ1.27(t, J=7.2Hz, 3H), 2.16(s, 3H), 4.02(dq, J=19.2, 4.8Hz, 2H), 4.20(q, J= 7.2Hz, 2H), 5.64(s, 1H), 6.06(s, 1H), 6.54(br s, 1H), 6.72(s, 1H), 7.31-7.37(m, 5H) ppm.

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Abstract

The invention discloses a compound for preparing alvimopan, and a preparation process and application thereof. The formula I of the compound is 2-[2-[[(3R,4R)-4-(3-hydroxycyclohexyl phenyl)-3,4-dimethyl piperidine-1-group] methyl]-3-phenyl acrylamid] acetate. Alvimopan is prepared by the compound with the formula I by steps of catalytic hydrogenation, resolution and hydrolyzation finally. The preparation process of the compound is simple and convenient and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a compound used for preparing avimopan, a preparation method and application thereof. Background technique [0002] The chemical name of alvimopan is (+)-2-[2(S)-benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4- Dimethyl-1-piperidinyl]propionamido]acetic acid, the drug was jointly developed by GSK and adolor, and was approved for marketing by the US Food and Drug Administration (FDA) on May 20, 2008. The product name is Entereg, which is used to accelerate the recovery time of gastrointestinal function after partial resection and anastomosis of the large intestine or small intestine. It is a highly selective peripheral mu opioid receptor antagonist. [0003] The preparation methods of avimopan publicly disclosed in China at present include: [0004] Patent CN1065455A discloses a preparation method of piperidine derivatives, which uses 3R, 4R-(3-hydroxyphenyl)-3,4-dimethylpiperidine and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
Inventor 张波张宇辰张桂森马彦琴杨相平
Owner NHWA PHARMA CORPORATION