Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Improved process for making apomorphine and apocodeine

A technology for apocodeine and apomorphine, which is applied in the field of preparing apomorphine and apocodeine, can solve the problems of cumbersome methods, poor product yield, high reaction temperature, etc., and achieves reduction of cumbersome operations and convenient The effect of reaction temperature

Inactive Publication Date: 2009-04-22
MALLINCKRODT INC
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this reaction is limited as it only gives yields in the range of 32% to 35%
[0006] Thus, disadvantages of all methods reported in the prior art for morphine / apomorphine type rearrangements include poor yields of products, high reaction temperatures (ranging from 125°C to 150°C), or both.
Moreover, these methods are cumbersome from the standpoint of unit operation in industrial scale process equipment

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Improved process for making apomorphine and apocodeine
  • Improved process for making apomorphine and apocodeine
  • Improved process for making apomorphine and apocodeine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of apomorphine

[0026] A mixture of morphine monohydrate (1.00 g), phosphoric acid (5.01 g) and phosphorus pentoxide (0.48 g) was gradually heated to 90°C to 100°C under an inert atmosphere. The resulting solution was stirred at this temperature for 2 hours to afford apomorphine (unisolated yield 63.22%). Pure apomorphine hydrochloride is isolated by hydrolysis of the reaction mixture, salting out, pH adjustment to liberate the free base, extraction of the free base and conversion to the hydrochloride salt. MS data: [M+H] = 268. The H1 and C13 NMR data demonstrated the structural arrangement of apomorphine and these spectra matched very well with reference spectra recorded in the Aldrich Library for NMR.

[0027] H-1NMR (DMSO-d 6 )δ 8.30ppm ( 2 J H，H d, 7.8Hz, 1Ar-H), 7.34ppm ( 2 J H，H t, 7.8Hz, 1Ar-H), 7.14ppm ( 2 J H，H d, 7.8Hz, 1Ar-H), 6.79ppm ( 2 J H，H d, 7.8Hz, 1Ar-H), 6.67ppm ( 2 J H，H d, 7.8Hz, 1Ar-H), δ 4.29-2.50 (multiplet, aliphatic-H,...

Embodiment 2

[0030] Preparation of apocodeine

[0031] Under an inert atmosphere, a mixture of codeine monohydrate (1.00 g), phosphoric acid (5.05 g) and phosphorus pentoxide (0.5 g) was gradually heated to 90°C to 100°C. The resulting solution was stirred at this temperature for 1 hour to afford apocodeine (73.45% unisolated yield). Pure apocodeine monoethanolate was isolated by hydrolysis of the reaction mixture, salting out, pH adjustment to release the free base, and recrystallization from ethanol. MS data: [M+H] = 282.

[0032] H-1 NMR (CDCl3) δ 8.25ppm ( 2 J H，H d, 7.8Hz, 1 Ar-H), 7.26ppm ( 2 J H，H t, 7.8Hz, 1 Ar-H), 7.05ppm ( 2 J H，Hd, 7.8Hz, 1 Ar-H), 6.75ppm (multiplet, 2 Ar-H), 6.5ppm (broad peak, phenolic hydroxyl proton), 3.68ppm (q, aliphatic 2H), 1.22(t, aliphatic 3H) δ3.75-2.35 (multiplet, aliphatic-H, 7H), 3.88 (singlet, O-CH 3 , 3H), δ 2.55ppm (single peak; N-CH 3 , 3H) and 2.19ppm (broad peak, 1H).

[0033] C-13 NMR (CDCl3) δ 146.0, 143.2, 134.5, 132.6, 131.6, 1...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Provided is an improved and convenient process for the synthesis of aporphines, such as apomorphine and apocodeine, by the rearrangement of the corresponding morphine or codeine derivatives. The use of a suitable water scavenger in an acid catalyzed rearrangement of the morphine derivatives unexpectedly results in a reaction temperature convenient for plant operation without sacrificing product. The method of the present invention also alleviates the cumbersome operations that were employed in the prior art to eliminate water from the reaction mixture at the elevated temperatures. This process is adaptable for the general preparation of other aporphines from the corresponding morphine congeners.

Description

Background of the invention [0001] Apomorphine, 5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol, and apocodeine, 5,6 , 6a,7-tetrahydro-10-methoxy-6-methyl-4H-dibenzo[de,g]quinolin-11-ol, are non-narcotic morphine / codeine derivatives, they can Used as pro-emetic agents in accidental poisoning. Apomorphine is a dopaminergic agonist used to treat off ("off") seizures in Parkinson's disease patients. Apomorphine is also marketed in 46 countries under the trade name , for the treatment of erectile dysfunction in men. Recently, other possible indications for apomorphine have been disclosed, such as female sexual dysfunction. [0002] Acid-catalyzed rearrangements of the morphine / apomorphine type are known in the prior art. In conventional synthetic reactions prior to 1970, suitable acid catalyst solutions included concentrated HCl, oxalic acid, glacial acetic acid, phosphoric acid, 85% phosphoric acid with anhydrous HCl stream, 85% phosphoric acid with nitrog...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/18
CPCC07D221/18
Inventor 纳拉亚纳萨米·格鲁萨米
Owner MALLINCKRODT INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com