CN105037248B - A kind of synthetic method of Aiweimopan - Google Patents
A kind of synthetic method of Aiweimopan Download PDFInfo
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- CN105037248B CN105037248B CN201510486944.9A CN201510486944A CN105037248B CN 105037248 B CN105037248 B CN 105037248B CN 201510486944 A CN201510486944 A CN 201510486944A CN 105037248 B CN105037248 B CN 105037248B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Abstract
The present invention relates to a kind of synthetic method of Aiweimopan; it is to protect the compound A of piperidines fragment to be raw material and (S) ethyl 2 (the third ammonia of methyl sulphur epoxide of 2 benzyl 3) acetic acidreaction with acetyl group, then carries out a step basic hydrolysis and prepare Aiweimopan.Technical scheme has the advantages that gentle working condition, simple production process, few side reaction, product yield and purity are high, is adapted to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to a kind of synthetic method of Aiweimopan.
Background technology
Aiweimopan (Alvimopan) is a kind of peripheral mu type opiate receptor antagonist of high selectivity, by GlaxoSmithKline PLC
Company (GSK) develops jointly with A Daoluo (Adolor) company.Opium and opiate receptor have emphatically in regulation intestines and stomach function
The effect wanted, in operation, particularly abdominal operation, due to using opioid analgesic medicine so that intestines and stomach malfunction, table
It is now apocleisis, nausea, flatulence, abdominal distension, defecation reduction and intestinal obstruction etc..Opiate receptor antagonistic using selectivity can have
The alleviation above-mentioned symptom of effect.Pharmacological research shows that Aiweimopan has good affinity to opiate receptor, especially to μ types
Acceptor has the selectivity of height.Aiweimopan is on May 20th, 2008 in FDA (Food and Drug Adminstration) (FDA) approval
City, the gastrointestinal function early recovery of postoperative patient, trade name Entereg are cut off for enteron aisle.The chemical name of Aiweimopan
Title is：[[(2S) -2- [[(3R, 4R) -4- (3- hydroxyphenyls) -3,4- lupetidine -1- bases] methyl] -3- phenylpropyl alcohols acyl] amino]
Acetic acid dihydrate, molecular formula is C25H32N2O4·2H2O, molecular weight 442.53, its structural formula is：
In terms of the structure of Aiweimopan.It is spliced by following 2 modules：
Module 1 generally will be prepared first due to chirality；Module 2 can be prepared first, then be spelled again with module 1
Connect；Based on the preparation just preparation comprising module 1 and module 2 so related generally to, module l and the connection of module 2, module 1,
Then cascade reaction prepares Aiweimopan.Then on the basis of module l, it can also lay bricks one as head after module 1 prepared
Walk module 2 " to be taken " on the basis of module 1 and come out.
Route one：On the basis of module 1, progressively build module 2 and prepare Aiweimopan；
As Chinese patent ZL92102213.1 is disclosed with 3R, 4R- (3- hydroxy phenyls) -3,4 lupetidines, 2- benzyls
Ethyl acrylate is starting material, and through Michael's addition, hydrolysis, condensation, chiral column chromatography, hydrolysis, prepared by the reaction of totally five steps successively
Target compound.
JAVemer disclosed a kind of preparation method of Aiweimopan (JOC, 61 (2), 587-97,1996) equal to 1996,
This method is with 3R, 4R- (3- hydroxy phenyls) -3, and 4 lupetidines, methyl acrylate are starting material, successively addition, hydrolysis,
Six-step process prepares target compound altogether for condensation, hydrolysis.
The maximum shortcoming of above-mentioned this kind of method is split again after putting up molecular bulk structure, and loss of material is big, no
Meet atom economy, cause high cost and environmental pollution.
Route two：All individually complete to prepare in advance in module 1 and module 2, then to being connected in Aiweimopan；
Chinese patent ZL200610013255.7 discloses a kind of preparation method of Aiweimopan, and the technique is with 3R, 4R-
(3- hydroxy phenyls) -3,4 lupetidines be initiation material, then with (S)-bromomethyl benzene Propionylglycine substituted benzyl or
(S)-sulfonvlmethvl benzene Propionylglycine substituted benzyl carries out N- alkylations, and two chiral optical isomers are anti-through alkyl
Obtained (+)-(3R, 4R)-[[2S- [4- (3- hydroxy phenyl -3,4 dimethyl -1- piperidyls)-methyl] -1- oxos -3- should be synthesized
Phenylpropyl] amino] acetic acid substituted benzyl, then obtain target compound through hydrogenolysis or the method for hydrolysis.
A kind of preparation method of Aiweimopan disclosed in CN101985433,
This method is with (S) -2- ((lupetidine -1- bases of (3R, 4R) -4- (3- isopropyl phenyls) -3,4) methyl) -3-
Phenylpropionate is initiation material, and target compound is prepared by hydrolysis, condensation, the method hydrolyzed again.
CN102127005 sets chirality using two fragments and docks to obtain finished product, and course of reaction is as follows：
But due to piperidines fragment, solubility is low in acetonitrile in reaction, need to could be with sulphonic acid ester piece through long-time back flow reaction
Duan Fanying completely, but for a long time must flow back, sulphonic acid ester fragment can occur elimination reaction generation alkene, then again with piperidines fragment
Addition reaction occurs for amine, into product and a diastereomer of product, causes chiral purity to reduce, and excessive sulphonic acid ester
Fragment is difficult to eliminate clean, causes accessory substance to increase, yield, purity decline.
It is raw material and (S)-ethyl -2- (2- benzene that patent 201210081078.1, which is reported with TMS protection piperidines fragments (I),
The third ammonia of methyl -3- methyl sulphur epoxides)-acetic acidreaction, then carry out sour water solution removal TMS protection groups and the basic hydrolysis removing step of ester group two
Hydrolysis obtains Aiweimopan.
This method technique is simple, high income, but employs toxic organic solvent acetonitrile and two-step hydrolysis technique, is not inconsistent cyclization
The requirement of guarantor.
The content of the invention
An object of the present invention is to provide that a kind of working condition gentle, simple production process, side reaction be few, product yield
The synthetic method of high Aiweimopan with purity.
The present invention is realized using following technical scheme：
A kind of synthetic method of Aiweimopan, it is characterised in that comprise the following steps：
1) under catalyst and triethylamine effect, compound A and compound B is reacted in solvent acetone and form compound
C；
2) by step 1) the compound C for preparing is dissolved in alcohols aqueous solvent and carries out basic hydrolysis, neutralize, and crystallization is washed
Wash, dry obtained Aiweimopan；Its synthetic route is as follows：
It is preferred that, step 1) in, the catalyst is sodium iodide；Compound A, compound B, triethylamine and catalyst rub
You are than being 1.0-1.2：1：1.0-1.4：0.01-0.03.
It is preferred that, step 1) in, in 20-25 DEG C of stirring reaction 1-3 hours.
It is preferred that, step 2) in, the volume ratio of alcohol and water is 4-6 in the alcohols aqueous solvent：1；The preferred second of alcohol
Alcohol.
Relative to prior art, the invention has the advantages that：
1) present invention is using the compound A of acetyl group protection piperidines fragment as raw material, and compound A is molten in reaction dissolvent acetone
Solution property is very good, sulphonic acid ester fragment fast reaction that can be with compound B, it is to avoid because return time is long, compound B occurs
Generation alkene is eliminated, so that the problem of influenceing the chiral purity of finished product.The patent 201210081078.1 that compares simultaneously for,
The present invention can be such that reaction quickly carries out at room temperature by adding the sodium iodide of catalytic amount in step 1, and no longer need to add
The probability of elimination reaction occurs for heat backflow, the sulphonic acid ester fragment that reduce further compound B, improves the chiral purity of finished product
Degree, it is energy-saving, it is adapted to industrialized production.Simultaneously as the dissolubilities of compound A in acetone are good, compound A is fitted in reaction
Amount is excessive so that compound B reactions are complete, it is to avoid excessive compound B residuals are difficult to the problem removed.
2) present invention can only be led in step 2 from acetyl group as the blocking group of phenolic hydroxyl group in compound A fragments
Parlkaline is hydrolyzed, so that it may which a step is by two hydrolysis of ester group, it is to avoid first acidic hydrolysis removing TMS in patent 201210081078.1
Protection group, then basic hydrolysis remove the relatively cumbersome operation of ester group, simplify operating procedure.
Embodiment
Technical scheme is further described with embodiment below, it will help to the technical side of the present invention
Advantage, the effect of case, which have, further to be understood, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determined.
Embodiment 1：
(1) compound C preparation：
Compound A 24.73g and compound B 34.34g are added in 250ml acetone, add 12.12g triethylamines and
0.30g sodium iodides, stirring reaction 2 hours at 20-25 DEG C.Be concentrated under reduced pressure removing acetone, adds 250ml ethyl acetate, 150ml
Twice, organic phase anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtains compound C 47.28g, yield 95.6% for washing.
(2) preparation of Aiweimopan：
Compound C 45.00g are added into 600ml second alcohol and water (5:1) in mixed solution, 6mol/L sodium hydroxides are added
Solution 120ml, stirring reaction 3 hours at 20-25 DEG C.Adjust pH value to 6 with concentrated hydrochloric acid, crystallization be stirred at room temperature 2 hours, filter,
Washing, dry Aiweimopan 36.63g, HPLC purity 99.8%, chiral purity is more than 99.7%.
Embodiment 2：
(1) compound C preparation：
Compound A 29.68g and compound B 34.34g are added in 250ml acetone, add 14.17g triethylamines and
0.45g sodium iodides, stirring reaction 1 hour at 20-25 DEG C.Be concentrated under reduced pressure removing acetone, adds 250ml ethyl acetate, 150ml
Twice, organic phase anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtains compound C 47.53g, yield 96.1% for washing.
(2) preparation of Aiweimopan：
Compound C 46.00g are added into 600ml second alcohol and water (4:1) in mixed solution, 6mol/L sodium hydroxides are added
Solution 120ml, stirring reaction 3 hours at 20-25 DEG C.Adjust pH value to 6 with concentrated hydrochloric acid, crystallization be stirred at room temperature 2 hours, filter,
Washing, dry Aiweimopan 37.86g, HPLC purity 99.6%, chiral purity is more than 99.7%.
Embodiment 3：
(1) compound C preparation：
Compound A 27.20g and compound B 34.34g are added in 250ml acetone, add 10.15g triethylamines and
0.15g sodium iodides, stirring reaction 2 hours at 20-25 DEG C.Be concentrated under reduced pressure removing acetone, adds 250ml ethyl acetate, 150ml
Twice, organic phase anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtains compound C 47.38g, yield 95.8% for washing.
(2) preparation of Aiweimopan：
Compound C 47.00g are added into 600ml second alcohol and water (6:1) in mixed solution, 6mol/L sodium hydroxides are added
Solution 120ml, stirring reaction 3 hours at 20-25 DEG C.Adjust pH value to 6 with concentrated hydrochloric acid, crystallization be stirred at room temperature 2 hours, filter,
Washing, dry Aiweimopan 39.15g, HPLC purity 99.5%, chiral purity is more than 99.8%.
Claims (3)
1. a kind of synthetic method of Aiweimopan dihydrate, it is characterised in that comprise the following steps：
1）Under catalyst sodium iodide and triethylamine effect, compound A and compound B are reacted in solvent acetone and form chemical combination
Thing C；Compound A, compound B, the mol ratio of triethylamine and catalyst are 1.0-1.2：1：1.0-1.4：0.01-0.03；Step
1）In, in 20-25 DEG C of stirring reaction 1-3 hours；
2）By step 1）The compound C prepared, which is dissolved in alcohols aqueous solvent, carries out basic hydrolysis, neutralizes, and crystallizes, washing,
Dry obtained Aiweimopan dihydrate；The alcohol is ethanol；Its synthetic route is as follows：
。
2. the synthetic method of Aiweimopan dihydrate according to claim 1, it is characterised in that：Step 2）In, it is described
The volume ratio of alcohol and water is 5-6 in alcohols aqueous solvent：1.
3. the synthetic method of Aiweimopan dihydrate according to claim 1, it is characterised in that：Step 2）In, it will change
Compound C adds ethanol:Water=5-6:In 1 mixed solution, 6mol/L sodium hydroxide solutions stirring reaction 3 at 20-25 DEG C is added
Hour；Adjust pH value to 6 with concentrated hydrochloric acid, crystallization is stirred at room temperature 2 hours, filters, washing, dry Aiweimopan dihydrate.
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| WO2011161646A2 (en) * | 2010-06-25 | 2011-12-29 | Ranbaxy Laboratories Limited | Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof |
| CN101967118B (en) * | 2010-10-14 | 2013-01-30 | 成都苑东药业有限公司 | Preparation method of alvimopan |
| CN102417463B (en) * | 2011-11-03 | 2016-12-21 | 北京华禧联合科技发展有限公司 | The preparation method of alvimopan |
| WO2013080221A2 (en) * | 2011-12-01 | 2013-06-06 | Hetero Research Foundation | Process for alvimopan |
| CN103360300B (en) * | 2012-03-26 | 2015-02-04 | 信泰制药（苏州）有限公司 | Synthesis method of alvimopan |
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Inventor after: Niu Hongfen Inventor after: Zhu Zhengchuan Inventor after: Wang Xingli Inventor before: Niu Hongfen Inventor before: Feng Chunxiang Inventor before: Wang Xingli |
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