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Intermediate of alvimopan and synthesis method thereof

A kind of technology of avimopanate and intermediate, applied in the field of medicinal chemistry synthesis

Active Publication Date: 2011-07-20
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route improves the utilization rate of piperidine raw materials and reduces the production cost to a certain extent, the chiral center in this route still has to rely on resolution to obtain a single configuration, and the yield is low, which limits this route. Application of the method in actual production

Method used

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  • Intermediate of alvimopan and synthesis method thereof
  • Intermediate of alvimopan and synthesis method thereof
  • Intermediate of alvimopan and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 7

[0075] The preparation of embodiment 7 avimopandoxate hydrochloride

[0076]

[0077] Take (+)-(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine (synthesized with reference to the method disclosed in US5250542) 20.5g, VIII 1 Compound 37.7g was added to 200ml of acetonitrile, and then 10.1g of triethylamine was added, and heated to reflux for 10 hours. After cooling, concentrate to remove acetonitrile, add 200ml ethyl acetate, wash twice with 100ml water, dry the ethyl acetate layer with anhydrous sodium sulfate, filter to remove the desiccant, add 4M HCl ethyl acetate dropwise, adjust pH=3, stir and crystallize , filtered to get IX 1 The hydrochloride of avimopandoxate was 42.8g, the yield was 87.5%, and the HPLC purity was 99.6%.

[0078] 1 H NMR (CDCl 3 ( m, 4H), 2.825(s, 1H), 3.330-3.361(d, 1H), 3.794-3.837(d, 1H), 4.140-4.203(m, 3H), 6.634-6.659(m, 1H), 6.748( s, 1H), 6.803-6.823(d, 1H), 7.136-7.218(m, 4H), 7.258-7.301(m, 4H), 9.043(s, 1H)

Embodiment 8

[0079] Embodiment 8 Preparation of Avimopan

[0080]

[0081] Get according to the IX that the method shown in embodiment 7 makes 1 Add 48.9g of avimopandoxate hydrochloride, add 1L of ethanol, then add 250ml of water, adjust the pH to 13 with 50% sodium hydroxide, react for half an hour, adjust the pH to 6 with concentrated hydrochloric acid, stir and crystallize, filter, wash with water, After drying under reduced pressure at room temperature, 39.0 g of X avimopan was obtained, with a yield of 85.1% and a purity of 99.7% by HPLC.

[0082] 1H NMR (CDCl 3 ( m, 3H), 3.674-3.688(d, 1H), 6.528-6.552(m, 1H), 6.650-6.699(t, 1H), 7.051-7.091(t, 1H), 7.163-7.271(m, 5H), 8.326-8.354(t, 1H), 9.116(s, 1H)

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Abstract

The invention mainly relates to a synthesis method of alvimopan. A preparation method of the related alvimopan comprises the following steps of: condensing phenylpropionic acid and substituted oxazolidone; undergoing reaction with chloromethyl benzyl ether under the action of a catalyst to obtain a single configuration; hydrolyzing, and recycling oxazolidone to obtain carboxylic acid; condensing with glycinate; performing deprotection and undergoing reaction with a leaving group donor; butting with (+)-(3R,4R)-4-(3-hydroxy phenyl)-3,4-dimethyl piperidine to obtain alvimopan ester; and hydrolyzing to obtain the alvimopan. The invention also relates to a novel intermediate of the alvimopan and preparation methods of the alvimopan and the novel intermediate of the alvimopan. The technical scheme of the invention has the advantages of simple process, low cost and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a new avimopan intermediate and a synthesis method thereof. Background technique [0002] The chemical name of Alvimopan is: [[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1- Base] methyl] -3-phenylpropionyl] amino] acetic acid, the molecular formula is C 25 h 32 N 2 o 4 , molecular weight 424.53, has the following chemical structure: [0003] [0004] Avimopan is a highly selective peripheral mu opioid receptor antagonist jointly developed by GlaxoSmithKline (GSK) and Adolor. Opioids and opioid receptors play an important role in regulating gastrointestinal function. During surgery, especially abdominal surgery, the use of opioid analgesics can cause gastrointestinal dysfunction, manifested as anorexia, nausea, flatulence, and abdominal distension. , reduced defecation, and intestinal obstruction, the use of selective...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22C07D263/14C07C235/34C07C231/02C07C309/66C07C303/28
Inventor 袁建栋郁光亮
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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