CN101260111A - Method for preparing buprenorphine hydrochloride intermediate - Google Patents
Method for preparing buprenorphine hydrochloride intermediate Download PDFInfo
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- CN101260111A CN101260111A CNA2007100568946A CN200710056894A CN101260111A CN 101260111 A CN101260111 A CN 101260111A CN A2007100568946 A CNA2007100568946 A CN A2007100568946A CN 200710056894 A CN200710056894 A CN 200710056894A CN 101260111 A CN101260111 A CN 101260111A
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- buprenorphine hcl
- oripavine
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Abstract
The invention provides a preparation method for an intermediate of buprenorphine hydrochloride, wherein an N-methyl group at 17 position and an O-methyl group at the 6 position of the N-cyan group-7alpha(1-(S)-1-hydroxy group-1, 2, 2- trimethyl propyl)-3- methoxyl group-6, 14-inner bridge ethyl group-6, 7, 8, 14- tetrahydro oripavine(I) are simultaneously removed under the alkaline condition, and thus the intermediate, namely N- norabieta-7alpha(1-(S)-1-hydroxy group-1, 2, 2- trimethyl propyl)-6, 14- inner bridge ethyl group-6, 7, 8, 14- tetrahydro oripavine(II) is obtained. Compared with a conventional synthetic technology, the novel preparation method is greatly improved in aspects of improving yield, simplifying operation and saving reaction period, so that the preparation method is suitable for industrialized mass production.
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 14.5%.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 new preparation method of suitability for industrialized production Buprenorphine hcl that is suitable for is provided.This technological reaction cycle is short, the yield height.
Preparation scheme of the present invention is as follows:
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.
The described hydrochloric acid fourth third promise intermediate hydrolysis preparation method is characterized in that the mineral alkali that adds is NaOH, KOH, CsOH, Ba (OH) in solution
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, Cs
2CO
3
The described hydrochloric acid fourth third promise intermediate hydrolysis preparation method, the quality proportioning that it is characterized in that mineral alkali and reactant are 1.5-4 times.
The described hydrochloric acid fourth third promise intermediate hydrolysis preparation method is characterized in that temperature of reaction is 190 ℃-240 ℃.
The described hydrochloric acid fourth third promise intermediate hydrolysis preparation method is characterized in that used reaction solvent is a glycol ether, ethylene glycol phenyl ether, triethylene glycol.
Adopt new synthetic process, with 17 N-methyl of compound (I) and 6 O-methyl while demethylating, hydrolysate N-demethyl-7 α that makes (1-(S)-1-hydroxyl-1,2,2-trimethylammonium propyl group)-6, bridge ethyl-6 in the 14-, 7,8,14-tetrahydrochysene oripavine (II) carries out alkylated reaction, make buprenorphine, salify promptly gets product.The success of novel process shortens to two hydrolysis, alkylation two-step reaction to hydrolysis in the former synthesis technique, condensation, reduction and demethylation four-step reaction.
Chemical equation of the present invention:
In the four-hole bottle that stirring, condenser, thermometer are housed, add compound (I), mineral alkali (NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, Cs
2CO
3) and organic solvent (glycol ether, ethylene glycol phenyl ether, triethylene glycol).Stir, be heated to 190 ℃-240 ℃ (preferred 200 ℃-220 ℃) reaction to obtaining intermediate (II) fully.Pour in the frozen water and the cyclopropylmethyl bromide methane reaction, firmly stir, add hydrochloric acid, be neutralized to pH2-3, cooling.Filter drying.Get the Buprenorphine hcl crude product, yield 70%.
Characteristics of the present invention:
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
Adopt new synthetic process, with 17 N-methyl of compound (I) and 6 O-methyl while demethylating, hydrolysate N-demethyl-7 α that makes (1-(S)-1-hydroxyl-1,2,2-trimethylammonium propyl group)-6, bridge ethyl-6 in the 14-, 7,8,14-tetrahydrochysene oripavine (II) carries out alkylated reaction, make buprenorphine, salify promptly gets product.The success of novel process shortens to two hydrolysis, alkylation two-step reaction to hydrolysis in the former synthesis technique, condensation, reduction and demethylation four-step reaction.The invention will be further described below in conjunction with embodiment, but do not limit the present invention.
Embodiment one: add compound (I) 50g, and potassium hydroxide 75g, glycol ether 550ml is heated to 200 ℃-210 ℃, reacts 2.0 hours.Obtain solid after the processing.
Embodiment two: add compound (I) 50g, and potassium hydroxide 200g, glycol ether 550ml is heated to 200 ℃-210 ℃, reacts 2.0 hours.Obtain solid after the processing.Yield 54%.
Embodiment three: add compound (I) 50g, and potassium hydroxide 125g, glycol ether 600ml is heated to 200 ℃-210 ℃, reacts 2.0 hours.Obtain solid after the processing.Yield 75%.HPLC90％。
Embodiment four: add compound (I) 50g, and potassium hydroxide 125g, glycol ether 600ml is heated to 220 ℃-230 ℃, reacts 2.0 hours.Obtain solid after the processing.Yield 62%.HPLC75％。
Embodiment five: add compound (I) 50g, and potassium hydroxide 125g, glycol ether 600ml is heated to 190 ℃-200 ℃, reacts 2.0 hours.Obtain solid after the processing.Yield 56%.HPLC69％。
Claims (5)
1. the preparation method that the Buprenorphine hcl intermediate is new 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 in the 14-, 7,8,17 N-methyl of 14-tetrahydrochysene oripavine (I) and 6 O-methyl be the while demethylating under alkaline condition, the hydrolysate intermediate (II) that makes.
2. according to the described hydrochloric acid fourth third promise intermediate hydrolysis preparation method of claim 1, it is characterized in that the mineral alkali that adds is NaOH in solution, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KHCO
3, K
2CO
3, Na
2CO
3, Cs
2CO
3
3. the new preparation method of Buprenorphine hcl intermediate according to claim 1, the quality proportioning that it is characterized in that mineral alkali and reactant are 1.5-4 times.
4. the new preparation method of Buprenorphine hcl intermediate according to claim 1 is characterized in that temperature of reaction is 190 ℃-240 ℃.
5. the new preparation method of Buprenorphine hcl intermediate according to claim 1 is characterized in that used reaction solvent is a glycol ether, ethylene glycol phenyl ether, triethylene glycol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100568946A CN101260111A (en) | 2007-03-09 | 2007-03-09 | Method for preparing buprenorphine hydrochloride intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100568946A CN101260111A (en) | 2007-03-09 | 2007-03-09 | Method for preparing buprenorphine hydrochloride intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101260111A true CN101260111A (en) | 2008-09-10 |
Family
ID=39960841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100568946A Pending CN101260111A (en) | 2007-03-09 | 2007-03-09 | Method for preparing buprenorphine hydrochloride intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101260111A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010039214A1 (en) * | 2008-09-30 | 2010-04-08 | Mallinckrodt Inc. | Processes for increasing the yield of the hydrolysis of the 3-0-methyl and 17-n-nitrile group in the preparation of opiate alkaloid derivatives |
| GB2591302A (en) * | 2020-01-27 | 2021-07-28 | Azad Pharma Ag | Process for the synthesis of buprenorphine |
-
2007
- 2007-03-09 CN CNA2007100568946A patent/CN101260111A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010039214A1 (en) * | 2008-09-30 | 2010-04-08 | Mallinckrodt Inc. | Processes for increasing the yield of the hydrolysis of the 3-0-methyl and 17-n-nitrile group in the preparation of opiate alkaloid derivatives |
| US8227608B2 (en) | 2008-09-30 | 2012-07-24 | Mallinckrodt Llc | Processes for increasing the yield of opiate alkaloid derivatives |
| AU2009300384B2 (en) * | 2008-09-30 | 2014-10-02 | SpecGx LLC | Processes for increasing the yield of opiate alkaloid derivatives |
| EP2344507B1 (en) | 2008-09-30 | 2015-11-11 | Mallinckrodt LLC | Processes for increasing the yield of the hydrolysis of the 3-o-methyl and 17-n-nitrile group in the preparation of opiate alkaloid derivatives |
| GB2591302A (en) * | 2020-01-27 | 2021-07-28 | Azad Pharma Ag | Process for the synthesis of buprenorphine |
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Open date: 20080910 |