CN106278915A

CN106278915A - A kind of method preparing tapentadol hydrochloride intermediate

Info

Publication number: CN106278915A
Application number: CN201510255379.5A
Authority: CN
Inventors: 李子清
Original assignee: CHONGQING CHANGJIE MEDICAL CHEMICAL Co Ltd; Chongqing Shenghuaxi Pharmaceutical Co Ltd
Current assignee: CHONGQING CHANGJIE MEDICAL CHEMICAL Co Ltd; Chongqing Shenghuaxi Pharmaceutical Co Ltd
Priority date: 2015-05-19
Filing date: 2015-05-19
Publication date: 2017-01-04

Abstract

The invention discloses a kind of enantioselective synthesis method of tapentadol hydrochloride key intermediate.The present invention is with meta-methoxy propiophenone as initiation material, under the catalysis of chiral catalyst L-PROLINE, asymmetric mannich is occurred to react, generating (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methyl acetone, this compound is the key intermediate of synthetic hydrochloric acid tapentadol hydrochloride.The present invention has the advantages such as raw material availability is high, reaction condition is gentle, garbage is few.

Description

A kind of method preparing tapentadol hydrochloride intermediate

Technical field

The present invention relates to medication chemistry technology, prepare tapentadol hydrochloride key intermediate 2S-3-dimethylamino-1-(3-methoxyphenyl more specifically to one) synthesis technique of-2-methyl isophthalic acid-acetone.

Background technology

Tapentadol hydrochloride (tapentadol), chemistry entitled (-)-(1R, 2R)-3-(3-dimethylamino-1-Ethyl-2-Methyl propyl group) phenol hydrochloride, is by Gruenenthal company of Germany and Johson & Johnson (Johnson & Johnson) joint research and development exploitation central analgesia medicine, there is opiate receptor agonist and adrenergic transmitter uptake inhibitor dual function, obtain FDA (Food and Drug Adminstration) (FDA) approval listing on November 21st, 2008, be clinically used for releasing in adult to severe acute pain.This product is better tolerance compared with other opium kind analgesics such as morphine (morphine) and tramadol (tramado1), and untoward reaction (such as nausea and vomiting) is lighter.

Universal Chinese character name: tapentadol hydrochloride；

English common name: tapentadol hydrochloride

No. CAS: 175591-09-0

Structural formula:

Tapentadol hydrochloride is the oral analgesic thing acting on central nervous system of a kind of novelty, it has two kinds of mechanism of action: one is to act on opium μ 2 receptor, by improving pain perception and emotional factor, inhibition of pain transmission in spinal cord, thus the activity of the cerebral cortical sites of impact and control perception pain；Another kind is the inhibitory action to norepinephrine reuptake, suppresses its heavy neurocyte that is absorbed into, thus improves the noradrenaline levels in brain, also functions to analgesic activity equally.Tapentadol hydrochloride is independent of metabolism activation effect, does not has metabolism activation product, and various acute inflammations and neuralgia are respectively provided with potent effect, and intravenous injection all can obtain higher blood drug level with oral, is less susceptible to produce analgesic tolerance and dependency compared with morphine.

It has been reported that tapentadol hydrochloride chemical synthesis process have following several.

The synthesis technique (route is as follows) of compound patent EP0693475 report, it is with 3-bromoanisole as initiation material, with 1-(dimethylamino)-2-methyl-3-carbonyl pentane reacts, generate compound 2, the chiral fractionation of compound 2 obtains (1S, 2R)-3-(dimethylamino)-2-methyl isophthalic acid-ethyl-1-(3-methoxyphenyl) propanol (compound 3), compound 3 is through step synthetic hydrochloric acid tapentadol hydrochlorides such as halo, reduction, demethylation, one-tenth salt.The shortcomings such as this process selectivity is poor, and chiral separation yield is low, and atom is uneconomical.Processing step and the above-mentioned technique of patent WO2012023147 report are essentially the same, simply with 2R-1-(dimethylamino)-2-methyl-3-carbonyl pentane reacts with 3-bromoanisole, the isomer of compound 2 reduces 2, splits and becomes simple to operation, but uses R type side chain cost high.

Patent WO2008012047 is with meta-methoxy propiophenone as initiation material, through mannich reaction, fractionation, grignard addition, it is dehydrated, reduces fractionation, demethylation and become salt etc. that tapentadol hydrochloride is synthesized, patent WO2004108658, WO2005000788 all use this technique, compound 3 is esterified by WO2008012283, WO2011067714 by trifluoroacetic anhydride, then reduce, obtain compound 5, it is to avoid partial racemization in compound 3 dehydration, improve yield.This technique initiation material is cheap and easily-available, but during synthesis compound 1, stereo selectivity is poor, needs to improve.Patent WO2008012046 utilizes benzyl protection phenolic hydroxyl group, sloughs protection group simultaneously, eliminate demethylation steps when compound 8 reduces.

Chinese patent CN102002065 reports with under R-proline effect, m-methoxybenzaldehyde and propionic aldehyde occur Andorra to react, one-step synthesis (2R, 3S)-3-hydroxy-2-methyl-3-(3-methoxyphenyl) propionic aldehyde (compound 9), one step builds 2 chiral centres, chiral purity is the highest, have impact on purification yield.

4 diastereomers of method one chiral separation, split difficulty big, and condition requires harshness, and yield is low.Method two uses the method that substep forms chiral centre, needs to split twice, resolution yield about 50% for the first time, and raw material availability is low, uneconomical, needs to improve.Method three occurs Andorra to react under the catalysis of organic micromolecule catalyst L-PROLINE, and a step forms two chiral centres, chiral fractionation, is refining to obtain highly purified (2R, 3R) product, splits 4 isomers 1 time, and yield is substantially reduced.

Asymmetric mannich reaction is the effective means preparing chiral beta-amino acids and amino alcohol and derivant thereof, along with deepening continuously of asymmetric mannich repercussion study, various metallic catalysts and organic micromolecule catalyst are constantly found, and proline is exactly wherein to apply wide organic micromolecule catalyst.Studied L-PROLINE currently without people and be catalyzed asymmetric mannich reaction preparation 2S-3-dimethylamino-1-(3-methoxyphenyl)-2-methyl isophthalic acid-acetone (hereinafter referred to as compound 1), this compound is the key intermediate preparing tapentadol hydrochloride, enantioselective synthesis compound 1 does not only have the highest economic worth, and environmental benefit is also apparent from.

Summary of the invention

The problems such as compound 1 synthesis of selective is low, raw material availability is the highest, three waste discharge is high are present invention mainly solves.

It is an object of the invention to provide the new technology of a kind of enantioselective synthesis compound 1.

Present invention employs following technical proposal:

The invention provides a kind of enantioselective synthesis compound 1 new technology, technical scheme is as follows:

1) with meta-methoxy propiophenone as initiation material, occur asymmetric mannich to react under the catalysis of L-PROLINE, generate compound 1；

2) compound 1 becomes salt refining with L-dibenzoyl tartaric acid, and then dissociating under the conditions of alkalescence obtains high-purity compound 1；

Reaction equation is as follows:

In step 1), meta-methoxy propiophenone, under the catalysis of organic micromolecule catalyst L-PROLINE, occurs asymmetric mannich to react with paraformaldehyde, dimethyl amine, generates compound 1.A kind of in water, methanol, ethanol, oxolane, acetonitrile, the isopropanol of reaction dissolvent or their mixture, preferred solvent is ethanol；Reaction temperature 50-85 DEG C；The rate of charge of L-PROLINE is 0.5～2 equivalents.

Selection process data statistics:

In step 2) in, compound 1 becomes salt refining with L-dibenzoyl tartaric acid, dissociates the most in the basic conditions.Reaction dissolvent is selected from methanol, ethanol, acetone and their mixture, preferably acetone；The rate of charge of L-dibenzoyl tartaric acid is 0.8～1.1.

Selection process data statistics:

。

Compared to the prior art, the present invention has a following Advantageous Effects:

1) yield is greatly improved, by the technique synthesis compound 1 of document WO2008012047 report, resolution yield about 50%, the lower enantioselective synthesis compound 1 of L-PROLINE catalysis, before refined, ee value reaches more than 92%, after refined, ee value reaches more than 99%, and yield improves to more than 80%, and cost is substantially reduced；

2) according to document it has been reported that process, compound 7 splits in acid condition, and configuration can overturn, be conducive to S anomeric product to generate, but have the product close to half to work as waste material, and the addition of chiral catalyst substantially increases raw material availability, garbage greatly reduces, and environmental benefit is obvious；

3) avoiding the caustic acid such as use concentrated hydrochloric acid, use L-PROLINE to make catalyst, equipment corrosion is few, production operation improvement of environment.

Detailed description of the invention

Further describing technical scheme below by embodiment, for the ordinary skill in the art, the following example does not constitute the restriction to protection scope of the present invention.

Embodiment 1 :

2S-3-dimethylamino-1-(3-methoxyphenyl)-2-methyl isophthalic acid-acetone (compound 1):

In reaction bulb add meta-methoxy propiophenone 262.4g ( 1.6mol), paraformaldehyde 96g(3.2mol), L-PROLINE 92g(0.8mol), dimethylamine 144g(3.2mol), methanol 800ml, stirring and dissolving, is warming up to 65 DEG C of back flow reaction 48 hours, and TLC monitoring raw material is fully converted to product (developing solvent: ethyl acetate: normal hexane=1:3).React complete, be spin-dried for reaction dissolvent, add 10% hydrochloric acid 1300ml and dissolve, the 500ml that adds methylene chloride extracts three times, and organic layer reclaims raw material, and water layer regulates pH value to about 10 with 10% sodium hydroxide 1400ml, add 500mL dichloromethane extraction three times, merge organic layer, be washed to neutrality, anhydrous sodium sulfate is dried, filtering desiccant, filtrate reduced in volume, to without slipping out thing, obtains grease 323.2g, yield 91.4%, ee value 96%.ESI-MS (m/z ) :222 [M+1]⁺。

Refining of compound 1

By compound 1 323.2g (1.46mol), L-dibenzoyl tartaric acid 471.2g(1.32mol) it is dissolved in 2260ml methanol, it is warming up to about 40 DEG C stirring reactions 24 hours, about slow cooling to 5 DEG C, stirs growing the grain 4h, sucking filtration, obtain solid 711g.Solid is dissolved in 2000ml water, and 10% sodium hydroxide regulation pH value, to 9～10, adds dichloromethane 800ml and extracts three times, merge organic layer, be washed to neutrality, and anhydrous sodium sulfate is dried, sucking filtration, is spin-dried for solvent and obtains grease 268.4g, yield 83%.[α]=+ 28.8 ° (C=0.5, methanol), ee value 99.0%. ESI-MS (m/z ) :222 [M+1]⁺。

Embodiment 2 :

2S-3-dimethylamino-1-(3-methoxyphenyl)-2-methyl isophthalic acid-acetone (compound 8):

In reaction bulb add meta-methoxy propiophenone 262.4g ( 1.6mol), paraformaldehyde 96g(3.2mol), L-PROLINE 184g(1.6mol), dimethylamine 144g(3.2mol), ethanol 850ml, stirring and dissolving, is warming up to 77 DEG C of back flow reaction 36 hours, and TLC monitoring raw material is fully converted to product (developing solvent: ethyl acetate: normal hexane=1:3).React complete, be spin-dried for reaction dissolvent, add 10% hydrochloric acid 1300ml and dissolve, the 500ml that adds methylene chloride extracts three times, and organic layer reclaims raw material, and water layer regulates pH value to about 10 with 10% sodium hydroxide 1400ml, add 500mL dichloromethane extraction three times, merge organic layer, be washed to neutrality, anhydrous sodium sulfate is dried, filtering desiccant, filtrate reduced in volume, to without slipping out thing, obtains grease 329.5g, yield 93.2%, ee value 97%.ESI-MS (m/z ) :222 [M+1]⁺。

Refining of compound 1

By compound 1 329.5g (1.49mol), L-dibenzoyl tartaric acid 533.4g(1.49mol) it is dissolved in 2966ml acetone, it is warming up to about 40 DEG C stirring reactions 24 hours, about slow cooling to 5 DEG C, stirs growing the grain 4h, sucking filtration, obtains solid 810.9g.Solid is dissolved in 2500ml water, and 10% sodium hydroxide regulation pH value, to 9～10, adds dichloromethane 1000ml and extracts three times, merge organic layer, be washed to neutrality, and Matrii Sulfas Exsiccatus is dried, sucking filtration, is spin-dried for solvent and obtains grease 306.2g, yield 93%.[α]=+ 29.5 ° (C=0.5, methanol), ee value 99.5%.ESI-MS (m/z ) :222 [M+1]⁺。

Claims

1. a 2S-3-dimethylamino-1-(3-methoxyphenyl) synthesis technique of-2-methyl isophthalic acid-acetone (hereinafter referred to as compound 1), it is characterised in that this technique comprises the following steps:

(1) under the catalysis of L-PROLINE, meta-methoxy propiophenone occurs asymmetric mannich to react with paraformaldehyde, dimethylamine, generates compound 1；

(2) compound 1 becomes salt refining with L-dibenzoyl tartaric acid, the most in the basic conditions the compound 1 of free high chiral purity；

Process route is as follows:

Wherein: L-DBTA represents L-dibenzoyl tartaric acid, (HCHO) n represents paraformaldehyde.

2. according to the preparation method described in claim 1, it is characterized in that: in step 1), meta-methoxy propiophenone is under L-PROLINE is catalyzed, asymmetric Mannich reaction is occurred to generate compound 1, a kind of in water, methanol, ethanol, oxolane, acetonitrile, the isopropanol of reaction dissolvent or their mixture；Reaction temperature is 50-85 DEG C；Catalyst L-PROLINE is 0.5～2 equivalents with the rate of charge of meta-methoxy propiophenone.

3. according to the preparation method described in claim 1, it is characterised in that: in step 2) in, compound 1 and L-dibenzoyl tartaric acid generation salt-forming reaction, reaction dissolvent is selected from methanol, ethanol, acetone and their mixture；L-dibenzoyl tartaric acid is 0.8～1.1 with the rate of charge of compound 1.