Processes for preparing morphinans and intermediates thereof

一种烷基、去甲二氢蒂巴因酮的技术，应用在有机化学等方向，能够解决产率和效率降低等问题

Inactive Publication Date: 2008-03-26
MALLINCKRODT INC
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since many steps are required to synthesize the starting material β, γ-hexahydroisoquinolinone (starting from 3-methoxyphenethylamine, for example, as described by Rice in U.S. Patent No. 4,368,326), such manipulations lead to Significantly lower productivity and efficiency

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
  • Processes for preparing morphinans and intermediates thereof
  • Processes for preparing morphinans and intermediates thereof
  • Processes for preparing morphinans and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0246] Conversion of α,β-Hexahydroisoquinolones to Protected β,γ-Hexahydroisoquinolones

[0247]

[0248] The isomer 1-(2′-bromo-4′-methoxy-5′-hydroxybenzyl)-2-formyl-1,3,4,7,8-hexahydroisoquinoline-6- Ketone and 1-(2'-bromo-4'-methoxy-5'-hydroxybenzyl)-2-formyl-1,3,4,5-hexahydroisoquinolin-6-one in chloroform solvent The solution in is added to ethylene glycol (such as a keto-protected compound) within 1 hour to form 1-(2'-bromo-4'-methoxy-5'-hydroxybenzyl)-2-formyl-6 - Ketal - 1,3,4,5,7,8-Hexahydroisoquinoline solution (>90% area / area by HPLC analysis). solution was added to 5% NH 4 OH (200 mL), a suspension formed and extracted with chloroform (3 x 40 mL). The combined organic layers were washed with water (3 x 100 mL) and placed under vacuum until dry to give the product as a white solid (1.03 g, 80% area / area and 70% w / w by HPLC).

Embodiment 2

[0250] Hydrolysis of protected β, γ-hexahydroisoquinolones to give unprotected β, γ-hexahydroisoquinolones

[0251]

[0252] 1-(2'-Bromo-4'-methoxy-5'-hydroxybenzyl)-2-formyl-6-ketal-1,3,4,5,7,8-hexahydroisoquinone A sample of morphine (0.97 g) was dissolved in 10 mL of 88% acetic acid. The resulting solution was stirred at room temperature for 1 hour. After the solution was stirred for 1 hour, the solution was washed with 50 mL H 2 Dilute with 0 and 40mL chloroform, swirl, and then pour into a 500mL separatory funnel. After the mixture was combined and separated, the organic layer was separated. An additional 40 mL of chloroform was added to the aqueous layer. The solution was repeatedly mixed and separated, and the organic layer was separated again to obtain an aqueous layer in a separatory funnel. Another 40 mL of chloroform was added to the aqueous layer. The solution was swirled again, and after the organic layer was separated again, an aqueous layer was obtained...

Embodiment 3

[0254] Grewe cyclization step

[0255]

[0256] A mixture of 270 mL of 98% triflic acid and 60 mL of 99% triflic anhydride was added to a 2 L round bottom flask. The mixture was heated to reflux, and the steam temperature reached 88°C-130°C. solution in N 2 Cool down to 5°C-10°C. Dissolve 100 g in 750 mL of CHCl 3 1-(2′-bromo-4′-methoxy-5′-hydroxybenzyl)-2-formyl-1,3,4,5,7,8-hexahydroisoquinoline-6- The ketone (eg, β,γ-hexahydroisoquinolinone) was placed in a 1 L round bottom flask under nitrogen. The β,γ-hexahydroisoquinolinone solution was added to the triflic acid solution at a constant rate over 30 minutes with constant stirring. The trifluoromethanesulfonic acid solution was surrounded by an ice bath to maintain the solution temperature at 15°C during the addition of the β,γ-hexahydroisoquinolinone. After the combined solutions were complete, the reaction was warmed to room temperature and stirred for approximately 12 hours. After stirring at room temperature, t...

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

The present invention is directed to processes for the synthesis of morphinans. In particular, a process for cyclizing a ss,bicyclic ketone compound to form a nordihydrothebainone product using the Grewe cyclization reaction is improved by forming a reaction mixture comprising a ss,bicyclic ketone compound, a cyclizing acid and a water scavenging cyclization additive. In one embodiment, the Grewe transformation occurs in the presence of an acid anhydride as the cyclization additive. Further, the present invention is directed to processes for converting a,ss-bicyclic ketone compounds (e.g., by-products of the Grewe cyclization reaction) to ss,bicyclic ketone compounds, wherein the ss,bicyclic ketone compounds may be recovered to further undergo Grewe cyclization and form the nordihydrothebainone product.

Description

Background of the invention [0001] In general, the present invention relates to methods for the synthesis of morphinans, and more particularly to nordihydrothebainone and its analogs. [0002] Nordihydrothebainone and its derivatives are important synthetic intermediates of many morphinane compounds, including buprenorphine, codeine, etorphine, hydrocodone, hydromorphone, morphine, Nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. These compounds are generally analgesics and are widely used in the pharmaceutical field to reduce pain due to their opioid receptor agonist effects. However, nalmefene, naloxone, and naltrexone are opioid receptor antagonists; they are used to reverse anesthesia / respiratory depression caused by opioid receptor agonists. [0003] Various methods for synthesizing nordihydrothebainone and its analogs are known. Nordihydrothebainone is typically obtained using a Grewe cyclization reaction. In U.S. Pat. No. 4,368,326, Rice disc...

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): C07D221/28C07D489/02C07D217/20C07D491/10
CPCC07D491/10C07D221/28C07D217/20C07D489/02
Inventor 王先棋弗兰克·W·莫泽加里·L·坎特雷尔鲍健
Owner MALLINCKRODT INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap