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Method for preparing methylnaltrexone bromide

A technology of bromomethylnaltrexone and naltrexone, applied in the field of pharmaceutical engineering

Active Publication Date: 2010-09-29
NANJING CHENGONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method avoids the use of dimethyl sulfate, but the use of pressure vessels has brought unsafe factors to industrial production, and a large amount of low-temperature concentrated water is still unavoidable

Method used

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  • Method for preparing methylnaltrexone bromide
  • Method for preparing methylnaltrexone bromide
  • Method for preparing methylnaltrexone bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] This example illustrates the preparation of bromomethylnaltrexone.

[0063] In the dry reaction flask, add naltrexone hydrochloride (94.5g, 0.25mol), N,N-dimethylformamide 1000mL, then add triethylamine (50.6g, 0.5mol), and stir the mixture at 20°C for 0.5 hours, Dimethyl tert-butylchlorosilane (37.7 g, 0.25 mol) was added slowly, and the mixture was stirred at 25° C. for 18 hours. The reaction solution was poured into 500 mL of water, and the resulting product was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to dryness under reduced pressure to obtain 3-O-dimethyl tert-butylsilyl ether group-naltrexone (105 g, 0.23mol), yield 92%.

[0064] In the dry reaction flask, add 3-O-dimethyl tert-butylsilyl ether base-naltrexone (105g, 0.23mol), N,N-dimethylformamide 500mL, add dimethyl carbonate (62.2g , 0.69mol), stirred at 100°C for 8 hours, concentrated under reduced pressure to 100mL, filtered after cooling in an ice-water bath, and va...

Embodiment 2

[0067] This example illustrates the preparation of bromomethylnaltrexone.

[0068] In the dry reaction flask, add naltrexone hydrochloride (94.5g, 0.25mol), acetone 1000mL, then add pyridine (59.3g, 0.75mol), stir the mixture at 20°C for 0.5 hour, slowly add dimethyl tert-butyl chloride Silane (37.7 g, 0.25 mol), and the mixture was stirred at 30° C. for 12 hours. The reaction solution was poured into 500 mL of water, and the resulting product was extracted with ethyl acetate. The ethyl acetate layer was dried and then concentrated to dryness under reduced pressure to obtain 3-O-dimethyl tert-butylsilyl ether group-naltrexone (100 g, 0.22mol), the yield is 88%.

[0069] In the dry reaction flask, add 3-O-dimethyl tert-butylsilyl ether group-naltrexone (100g, 0.22mol), acetone 500mL, add dimethyl carbonate (99.2g, 1.1mol), stir at 105°C Concentrate under reduced pressure to 100 mL for 8 hours, filter after cooling in an ice-water bath, and dry the filter cake in vacuum at 35°...

Embodiment 3

[0072] This example illustrates the preparation of bromomethylnaltrexone.

[0073] In the dry reaction flask, add naltrexone hydrochloride (94.5g, 0.25mol), N-methylpyrrolidone 1000mL, then add N,N-dimethylaniline (75.7g, 0.625mol), and stir the mixture at 20°C for 0.5 hours , slowly added dimethyl tert-butylchlorosilane (37.7 g, 0.25 mol), and the mixture was stirred at 20° C. for 24 hours. The reaction solution was poured into 500 mL of water, and the resulting product was extracted with ethyl acetate. The ethyl acetate layer was dried and then concentrated to dryness under reduced pressure to obtain 3-O-dimethyl tert-butylsilyl-naltrexone (110 g, 0.23mol), yield 92%.

[0074] In the dry reaction bottle, add 3-O-dimethyl tert-butyl silyl ether base-naltrexone (110g, 0.23mol), N-methylpyrrolidone 500mL, add dimethyl carbonate (82.9g, 0.92mol) , stirred at 110°C for 6 hours, concentrated under reduced pressure to 100mL, filtered after cooling in an ice-water bath, and vacuum...

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Abstract

The invention discloses a method for preparing methylnaltrexone bromide and belongs to the technical field of pharmaceutical engineering. The method comprises the following steps of: generating 3-O-t-butyl dimethyl silyl-naltrexone by taking naltrexone hydrochloride as a raw material, t-butyl dimethyl chlorosilane as a protection group and a dipolar aprotic solvent as a medium in the presence of organic base; reacting dimethyl carbonate serving as a methylating agent and the dipolar aprotic solvent serving as the medium with the dimethyl carbonate; and finally, reacting with solution of hydrobromic acid in the water serving as a medium, and distilling at reduced pressure to obtain the methylnaltrexone bromide. The protection group t-butyl dimethyl chlorosilane of phenolic hydroxyl is white solid, has no pungent odor, can generate stable intermediate products at normal temperature, has simple removal step, and is an ideal hydroxyl protective agent. The methylating agent dimethyl carbonate makes reaction environment-friendly, reaction yield higher, and technology simpler; the methylnaltrexone bromide is generated during deprotection; the steps are shortened; and the industrialized production is convenient.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical engineering, and specifically relates to a method for preparing peripheral μ-opioid receptor antagonist bromomethylnaltrexone. Background technique [0002] Bromomethylnaltrexone (CAS number: 73232-52-7, English common name: Methylnaltrexone bromide, chemical name: (R)-N-(cyclopropylmethyl)noroxymorphone methobromide, Chinese chemical name: bromide-17-(cyclopropyl Methyl)-4.5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinan; molecular formula: C 21 h 26 NO 4 Br, molecular weight 436.36, abbreviated as (R)-MNTX, its chemical structure is as follows: [0003] [0004] Bromomethylnaltrexone was synthesized for the first time by scholars from the University of Chicago in the 1970s. They found that bromomethylnaltrexone has a good peripheral opioid receptor blocking effect in accidental experiments. Molecularly different from naltrexone, bromomethylnaltrexone contains a positive charge in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/08
CPCY02P20/55
Inventor 郭昭
Owner NANJING CHENGONG PHARM CO LTD
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