CN101768162A - Novel method for preparing partial agonist antagonist of opiate receptor - Google Patents
Novel method for preparing partial agonist antagonist of opiate receptor Download PDFInfo
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- CN101768162A CN101768162A CN200910067621A CN200910067621A CN101768162A CN 101768162 A CN101768162 A CN 101768162A CN 200910067621 A CN200910067621 A CN 200910067621A CN 200910067621 A CN200910067621 A CN 200910067621A CN 101768162 A CN101768162 A CN 101768162A
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- methyl
- partial agonist
- opiate receptor
- hydroxyl
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Abstract
The invention relates to a novel method for preparing a partial agonist antagonist of an opiate receptor, in particular to an intermediate of buprenorphine hydrochloride. The method comprises the following steps of: simultaneously removing methyl groups from the N-methyl at the seventieth bit and the O-methyl at the sixth bit of N-cyan-7alpha(1-(s)-1-hydroxyl-1,2,2-trimethyl propyl)-3-methoxyl-6, 14-inner-bridge ethyl-6,7,8,14-tetrahydro oripavine(I) under an alkali condition to prepare the intermediate of N-methyl removing-7alpha(1-(s)-1-hydroxyl-1,2,2-trimethyl propyl)-6,14-inner-bridge ethyl-6, 7,8,14-tetrahydro oripavine(II).
Description
Technical field
The present invention relates to the partial agonist antagonist Buprenorphine hcl intermediates preparation of opiate receptor.
Background technology
Buprenorphine hcl (Buprenorphine Hydrochloride) is the partial agonist antagonist of opiate receptor, have long action time, dosage is little and habituation may extremely low characteristics, it is medium and have an intense pain to be used to remove postoperative pain, chronic pain caused by cancer, burn pain, vasculitis acroaesthesia and Encelialgia etc.Simultaneously, the person's that can be used for the opiate addiction detoxification treatment is a promising analgesia and drug-breaking medicine.
Buprenorphine hcl, chemistry N-by name encircles third methyl-7 α (1-(S)-1-hydroxyl-1,2,2-trimethylammonium propyl group)-6, bridge ethyl-6,7,8 in the 14-, the 14-tetrahydrochysene removes first Ao Liebawen hydrochloride.
Former synthesis technique is with compound N-cyano group-7 α (1-(S)-1-hydroxyl-1,2,2-trimethylammonium propyl group)-3-methoxyl group-6, bridge ethyl-6 in the 14-, 7,8,14-tetrahydrochysene oripavine (I) forms N-through hydrolysis, condensation, reduction reaction and encircles third methyl, and totally 5 steps obtained Buprenorphine hcl to carry out 6 hydroxyls of demethylation reaction formation and salify at last.Total recovery is 10.5%.This technological reaction cycle is long, and yield is lower.
Summary of the invention
The present invention is intended to overcome deficiency of the prior art, and a kind of simple and convenient process for preparing that is suitable for the suitability for industrialized production Buprenorphine hcl is provided.
Preparation scheme of the present invention is as follows:
With the N-methyl of compound (I) and 6 O-methyl while demethylating, the hydrolysate N-demethyl-7 α (1-(S)-1-hydroxyl-1 that makes, 2,2-trimethylammonium propyl group)-6, bridge ethyl-6,7 in the 14-, 8,14-tetrahydrochysene oripavine (II) carries out alkylated reaction, makes buprenorphine, and salify promptly gets product.The success of novel process shortens to hydrolysis, alkylation two-step reaction to hydrolysis in the former synthesis technique, condensation, reduction and demethylation four-step reaction.
In the four-hole bottle that stirring, condenser, thermometer are housed, add compound (I), mineral alkali and organic solvent.Stir, be heated to 190 ℃ of-220 ℃ of reactions to obtaining intermediate (II) fully.Pour in the frozen water and the cyclopropylmethyl bromide methane reaction, firmly stir, add hydrochloric acid, be neutralized to pH2, cooling.Filter drying.Get the Buprenorphine hcl crude product, yield 60%.
At present novel process is compared with former synthesis technique, improving yield, simplify the operation, being significantly improved aspect saving reaction time, is suitable for large-scale industrialization production.
Embodiment
The invention will be further described below in conjunction with embodiment, but do not limit the present invention.
Embodiment one: add compound (I) 25g, and potassium hydroxide 150g, glycol ether 350ml is heated to 200 ℃, reacts 1.5 hours.Obtain solid after the processing.
Embodiment two: add compound (I) 30g, and potassium hydroxide 300g, glycol ether 400ml is heated to 210 ℃, reacts 2.0 hours.Obtain solid after the processing.Yield 40%.
Embodiment three: add compound (I) 50g, and potassium hydroxide 325g, glycol ether 550ml is heated to 200 ℃-210 ℃, reacts 2.0 hours.Obtain solid after the processing.Yield 60%.
Claims (1)
1. bridge ethyl-6,7,8 in Buprenorphine hcl intermediate N demethyl-7 α (1-(S)-1-hydroxyl-1,2,2-trimethylammonium propyl group)-6,14-, the new preparation method of 14-tetrahydrochysene oripavine (II) is characterized in that comprising the steps:
With compound N-cyano group-7 α (1-(S)-1-hydroxyl-1,2,2-trimethylammonium propyl group)-3-methoxyl group-6, bridge ethyl-6,7 in the 14-, 8,17 N-methyl of 14-tetrahydrochysene oripavine (I) and 6 O-methyl be the while demethylating under alkaline condition, the hydrolysate intermediate (II) that makes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910067621A CN101768162A (en) | 2009-01-06 | 2009-01-06 | Novel method for preparing partial agonist antagonist of opiate receptor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910067621A CN101768162A (en) | 2009-01-06 | 2009-01-06 | Novel method for preparing partial agonist antagonist of opiate receptor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101768162A true CN101768162A (en) | 2010-07-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN200910067621A Pending CN101768162A (en) | 2009-01-06 | 2009-01-06 | Novel method for preparing partial agonist antagonist of opiate receptor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101768162A (en) |
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2009
- 2009-01-06 CN CN200910067621A patent/CN101768162A/en active Pending
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| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100707 |