CN107857709A - A kind of preparation method of antiepileptic Pregabalin - Google Patents
A kind of preparation method of antiepileptic Pregabalin Download PDFInfo
- Publication number
- CN107857709A CN107857709A CN201711177783.0A CN201711177783A CN107857709A CN 107857709 A CN107857709 A CN 107857709A CN 201711177783 A CN201711177783 A CN 201711177783A CN 107857709 A CN107857709 A CN 107857709A
- Authority
- CN
- China
- Prior art keywords
- compound
- pregabalin
- preparation
- antiepileptic
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation method of antiepileptic Pregabalin, belong to pharmaceutical synthesis field.It is raw material with compound 2, reacting into the synthesis steps such as salt, recrystallization by decarbonylation base and compound 4 is prepared into Pregabalin.Compared to the method for existing literature report, synthesis step is reduced, and is split equivalent and is halved, and technology stability is higher, simple to operate, and reaction condition is gentle, is adapted to large-scale production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of antiepileptic Pregabalin.
Background technology
Entitled (S) -3- aminomethyl -5- methylhexanoic acids [(the 3S) -3- of Pregabalin [Pregabalin, (S) -1] chemistry
Aminomethyl-5-methylhex-anoic acid], it is the γ-aminobutyric acid developed by Pfizer Inc.
(GABA) receptor antagonist, European Union's approval has been obtained in July, 2004 and in Britain's Initial Public Offering, suffered from as partial seizure
The attached of person helps epilepsy therapy medicine.Compared with the Gabapentin (gabapentin) clinically used, the anticonvulsant action of this product
Stronger, adverse reaction is smaller, has the advantages that dosage is low, it is few to take number, has angst resistance effect concurrently, is the replacement of Gabapentin
Product, wide market.Pregabalin is chipal compounds, and S- type isomers has pharmacological activity.Document report condition is severe
Carve, route is longer, and cost is high, complex operation.
Structure：
China is increasing to the demand share of antiepileptic, is particularly liked deeply by many patients and doctor new
Type pharmaceutical pregabaline, therefore, one economy of exploitation, environment-friendly, the synthesis technique for the Pregabalin that can be mass produced
Route is of great practical significance.
Therefore, on the basis of with reference to existing synthetic route, one process conditions of research are gentle well, production efficiency is high,
Low in input cost, operation is simple, environmental pollution is small, it is just very necessary to be easy to industrial synthetic route, is Puri
Important data and technique preparation are added in the developing target market of Bahrain at home, make can produce at a low price at home its future, extensively
Using.
The content of the invention
In order to solve the deficiencies in the prior art, the invention provides a kind of preparation method of antiepileptic Pregabalin.
A kind of preparation method of antiepileptic Pregabalin, it is characterised in that comprise the following steps：It is original with compound 2
Material, by decarbonylation base, split into salt, be prepared into Pregabalin 1 after re-crystallization step.
Reaction equation is as follows：
Further, the de-carbonyl reaction step is that compound 2 and bromine and sodium hydroxide are reacted to obtain into compound 3.
Further, it is described to be into salt resolution reaction step, by compound 3 and (the S- almonds of 0.5-0.55eq compounds 4
Acid) into salt compound 5 is obtained, obtain compound 1 after adding aqueous slkali free.
Further, the re-crystallization step is that product 1 is passed through into isopropanol：Water=2：1 (mass ratio) is recrystallized to give
The sterling 1 of purity more than 99.5%.
The beneficial effect of invention：
1st, the toxic reagents such as contaminative heavy metal, toluene are avoided compared to the method for existing literature report, synthesis step
Use, it is more green using chemical chiral resolution, integrated artistic.
2nd, crude product 1 passes through isopropanol：After water recrystallization, the product of purity more than 99.5%, structure and text can be obtained
Report is offered to be consistent.
3rd, synthesis step of the present invention is few, and technology stability is higher, is more suitable for large-scale production.The synthetic route operation side
Just, cost is low, is adapted to industrialized production, has wide market prospects.
Embodiment
Embodiment 1
Water (8mL) is added in the three-neck flask that 50mL is dried, is slowly added to sodium hydroxide (0.12g, 3mmol), is stirred
Dissolving, it is cooled to 15-25 DEG C and adds starting material compound 2 (0.561g, 3mol), stirring and dissolving 30min, initiation material is made
Solution, it is standby to be pumped into gravity tank.
Water (2g) is added in the three-neck flask that 50mL is dried, is slowly added to sodium hydroxide (0.28g, 7mmol), stirring is molten
Solution.0 ± 5 DEG C is cooled to, bromine (0.56g, 3.5mmol) is added dropwise into solution at this temperature.After dripping at this temperature
Insulation reaction 0.5h, sodium hypobromite solution is made.It is molten that the starting material solution prepared is added dropwise to sodium hypobromite at 0 ± 5 DEG C
In liquid, drop finishes insulation reaction 0.5h at this temperature, is warming up to 65 ± 5 DEG C, at this temperature insulation reaction 30min.It is cooled to
Less than 30 DEG C, release reaction solution.
Concentrated hydrochloric acid (1.1g) is added in the three-neck flask that 50mL is dried, reaction solution is added dropwise to concentrated hydrochloric acid in less than 30 DEG C
In, 30min (now pH=1~3) is stirred after dripping.Less than 30 DEG C adjust pH=7~8 with 40%NaOH.It is cold after having neutralized
But, crystallization 2h at 10 ± 5 DEG C, centrifugation (each centrifugal material with 2mL0-5 DEG C of water washing), obtains racemic pregabalin wet product about
1.05g。
Water (1.5g), racemic pregabalin wet product (0.477g, 3mmol) are added in the three-neck flask that 50mL is dried, is stirred
Mix and be heated to 65 ± 5 DEG C, add S-MA (0.228g, 1.5mmol), insulation dissolving 30min.Cool, added at 50 ± 3 DEG C
Crystal seed (0.04g), continue to be cooled to 15 ± 5 DEG C of insulation 1h, centrifugation, obtain S-MA salt crude product wet product.
Water, the S-MA salt crude product of 2.7 times of crude product wet product weight of middle addition are wet in the three-neck flask that 100mL is dried
Product, 75 ± 5 DEG C are heated with stirring to, insulation dissolving 30min.15 ± 5 DEG C are cooled to, is incubated 2h, centrifugation, 70 ± 5 DEG C of forced air dryings
10~16h, obtain the about 0.53g of compound 5.
Middle addition tetrahydrofuran (20g), water (0.1g), compound 5-S- mandelic acids in the three-neck flask that 100mL is dried
Salt (0.530g), agitating and heating, 62 ± 3 DEG C of insulation 1h (reflux state).Cool, 2h is incubated at 20 ± 5 DEG C, centrifuge, 55 ± 5 DEG C
6~10h of forced air drying, Pregabalin crude product about 0.269g after must dissociating.
Middle addition isopropanol 5g, water 1g and above-mentioned Pregabalin crude product, agitating and heating in the three-neck flask that 50mL is dried
To 80 ± 5 DEG C of dissolved clarifications, 0.39g activated carbons are added, are incubated 30min.50L crystallization kettles, the filtrate between refining of press filtration while hot are slow
Cool (2.5~3.5h is down to 5 DEG C), 2h is incubated at 0 ± 5 DEG C, centrifuge, 60 ± 5 DEG C of 16~24h of vacuum drying, obtain white crystals 1
(2.65g, yield 55.4%), HPLC measure contents more than 99.6%, fusing point:187-189 DEG C, structure and document (The Merck
Index, 13th, 7813) report be consistent.(document:186.0~188 DEG C of mp).1H-NMR(400MHz,D2O)δ:0.85~0.91
(m, 6H), 1.14~1.25 (t, 2H), 1.63~1.68 (m, 2H), 2.00~2.24 (m, 3H), 2.45~2.68 (m, 2H).13C-NMR(400MHz,D 2O)δ:23.6、23.7、31.5、40.1、41.2、45.3、179.6。
Embodiment 2
Water (8mL) is added in the three-neck flask that 100mL is dried, is slowly added to sodium hydroxide (1.2g, 30mmol), is stirred
Dissolving, it is cooled to 15-25 DEG C and adds starting material compound 2 (5.61g, 30mol), stirring and dissolving 30min, initiation material is made
Solution, it is standby to be pumped into gravity tank.
Water (20.9g) is added in the three-neck flask that 100mL is dried, sodium hydroxide (2.8g, 70mmol) is slowly added to, stirs
Mix dissolving.0 ± 5 DEG C is cooled to, bromine (5.6g, 35mmol) is added dropwise into solution at this temperature.In this temperature after dripping
Lower insulation reaction 1h, sodium hypobromite solution is made.It is molten that the starting material solution prepared is added dropwise to sodium hypobromite at 0 ± 5 DEG C
In liquid, drop finishes insulation reaction 1h at this temperature, is warming up to 65 ± 5 DEG C, at this temperature insulation reaction 30min.It is cooled to 30
Below DEG C, reaction solution is released.
Concentrated hydrochloric acid (11g) is added in the three-neck flask that 100mL is dried, reaction solution is added dropwise to concentrated hydrochloric acid in less than 30 DEG C
In, 30min (now pH=1~3) is stirred after dripping.Less than 30 DEG C adjust pH=7~8 with 40%NaOH.It is cold after having neutralized
But, crystallization 2h at 10 ± 5 DEG C, centrifugation (each centrifugal material with 5L0-5 DEG C of water washing), obtains racemic pregabalin wet product about
10.50g。
Water (15g), racemic pregabalin wet product (4.77g, 30mmol) are added in the three-neck flask that 100mL is dried, is stirred
Mix and be heated to 65 ± 5 DEG C, add S-MA (2.28g, 15mmol), insulation dissolving 30min.Cool, added at 50 ± 3 DEG C brilliant
Kind (0.04g), continue to be cooled to 15 ± 5 DEG C of insulation 2h, centrifugation, obtain S-MA salt crude product wet product.
Water, the S-MA salt crude product of 2.7 times of crude product wet product weight of middle addition are wet in the three-neck flask that 100mL is dried
Product, 75 ± 5 DEG C are heated with stirring to, insulation dissolving 30min.15 ± 5 DEG C are cooled to, is incubated 2h, centrifugation, 70 ± 5 DEG C of forced air dryings
10~16h, obtain the about 5.30g of compound 5.
Middle addition tetrahydrofuran (200g), water (1g), compound 5-S- mandelates in the three-neck flask that 100mL is dried
(5.30g), agitating and heating, 62 ± 3 DEG C of insulation 1h (reflux state).Cool, 2h is incubated at 20 ± 5 DEG C, centrifuge, 55 ± 5 DEG C of drums
Air-dry dry 6~10h, Pregabalin crude product about 2.69g after must dissociating.
Middle addition isopropanol (10g), water (5g), Pregabalin crude product, agitating and heating in the three-neck flask that 100mL is dried
To 80 ± 5 DEG C of dissolved clarifications, 0.39g activated carbons are added, are incubated 30min.50L crystallization kettles, the filtrate between refining of press filtration while hot are slow
Cool (2.5~3.5h is down to 5 DEG C), 2h is incubated at 0 ± 5 DEG C, centrifuge, 60 ± 5 DEG C of 16~24h of vacuum drying, obtain white crystals 1
(2.65g, yield 55.4%), HPLC measure contents more than 99.6%, fusing point:187-189 DEG C, structure is consistent with document report.
Embodiment 3
Water (8L) is added in 20L reactors, sodium hydroxide (1.2Kg, 30mol) is slowly added to, stirring and dissolving, is cooled to
15-25 DEG C adds starting material compound 2 (5.61Kg, 30mol), stirring and dissolving 30min, starting material solution is made, is pumped into
Gravity tank is standby.
20.9kg water is added in 50L reactors, is slowly added to sodium hydroxide (2.8Kg, 70mol), stirring and dissolving.Cooling
To 0 ± 5 DEG C, bromine (5.6Kg, 35mol) is added dropwise into solution at this temperature, insulation reaction at this temperature after dripping
1h, sodium hypobromite solution is made.The starting material solution prepared is added dropwise in sodium hypobromite solution at 0 ± 5 DEG C, drop finishes
Insulation reaction 1h at a temperature of this, 65 ± 5 DEG C are warming up to, at this temperature insulation reaction 30min.Less than 30 DEG C are cooled to, is released
Reaction solution.
Concentrated hydrochloric acid (11.00Kg) is added in 50L reactors, reaction solution is added dropwise in concentrated hydrochloric acid in less than 30 DEG C, is dripped
30min (now pH=1~3) is stirred after adding.Less than 30 DEG C adjust pH=7~8 with 40%NaOH.Cooling after having neutralized, 10
Crystallization 2h at ± 5 DEG C, centrifugation (each centrifugal material with 5L0-5 DEG C of water washing), obtains racemic pregabalin wet product about
10.50Kg。
Water (15Kg), racemic pregabalin wet product (4.77Kg, 30mol) are added in 50L reactors, is heated with stirring to 65
± 5 DEG C, add S-MA (2.28Kg, 15mol), insulation dissolving 30min.Cool, crystal seed (0.4g) added at 50 ± 3 DEG C,
Continue to be cooled to 15 ± 5 DEG C of insulation 2h, centrifugation, obtain S-MA salt crude product wet product.
Water, the S-MA salt crude product wet product of 2.7 times of crude product wet product weight are added in 50L reactors, is heated with stirring to
75 ± 5 DEG C, insulation dissolving 30min.15 ± 5 DEG C are cooled to, 2h is incubated, centrifugation, 70 ± 5 DEG C of 10~16h of forced air drying, obtains chemical combination
The about 5.30Kg of thing 5.
Tetrahydrofuran (200Kg) is added in 50L reactors, water (1Kg), compound 5S- mandelates (5.30Kg), is stirred
Mix heating, 62 ± 3 DEG C of insulation 1h (reflux state).Cool, 2h is incubated at 20 ± 5 DEG C, centrifuge, 55 ± 5 DEG C of forced air dryings 6~
10h, Pregabalin crude product about 2.69Kg after must dissociating.
Isopropanol (10Kg) is added in 50L reactors, water (5Kg), Pregabalin crude product, is heated with stirring to 80 ± 5 DEG C
Dissolved clarification, 39.0g activated carbons are added, be incubated 30min.The 50L crystallization kettles between refining of press filtration while hot, filtrate slow cooling (2.5~
3.5h is down to 5 DEG C), 2h is incubated at 0 ± 5 DEG C, is centrifuged, and 60 ± 5 DEG C of 16~24h of vacuum drying, is obtained white crystals 1 and (2.64kg, is received
Rate 55.3%), HPLC contents more than 99.5%, fusing point:187-189 DEG C, structure is consistent with document report.
Embodiment above describes the general principle of the present invention, main features and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (5)
1. a kind of preparation method of antiepileptic medicine Pregabalin, it is characterised in that reaction equation is as follows：
Comprise the following steps：It is raw material with compound 2, by decarbonylation base, splits into salt, is prepared into Puri bar after re-crystallization step
Woods 1.
2. according to a kind of preparation method of antiepileptic Pregabalin in claim 1, it is characterised in that：The de-carbonyl reaction
Step is that will obtain compound 3 after compound 2 and bromine and sodium hydroxide reaction decarbonylation base.
3. according to a kind of preparation method of antiepileptic medicine Pregabalin in claim 1, it is characterised in that：It is described to be split into salt
Step is that compound 3 and compound 4 are reacted into salt obtains compound 5, and compound 1 is obtained after adding aqueous slkali free.
4. according to a kind of preparation method of antiepileptic medicine Pregabalin in claim 1, it is characterised in that：The compound 3
Equivalent proportion with compound 4 is 1：0.5-0.55.
5. according to a kind of preparation method of antiepileptic Pregabalin in claim 3 or 4, it is characterised in that：The recrystallization
Step is that compound 1 is passed through into isopropanol：Water=2：1 (mass ratio) is recrystallized to give the sterling 1 of purity more than 99.5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711177783.0A CN107857709A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of antiepileptic Pregabalin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711177783.0A CN107857709A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of antiepileptic Pregabalin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107857709A true CN107857709A (en) | 2018-03-30 |
Family
ID=61702332
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711177783.0A Pending CN107857709A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of antiepileptic Pregabalin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107857709A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109867609A (en) * | 2019-03-21 | 2019-06-11 | 常州工程职业技术学院 | A method of preparing Pregabalin raceme |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011077463A1 (en) * | 2009-12-24 | 2011-06-30 | Msn Laboratories Limited | Process for preparing pregabalin and its intermediate |
| CN104193635A (en) * | 2014-08-28 | 2014-12-10 | 太仓运通生物化工有限公司 | Synthesis method of pregabalin |
-
2017
- 2017-11-23 CN CN201711177783.0A patent/CN107857709A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011077463A1 (en) * | 2009-12-24 | 2011-06-30 | Msn Laboratories Limited | Process for preparing pregabalin and its intermediate |
| CN104193635A (en) * | 2014-08-28 | 2014-12-10 | 太仓运通生物化工有限公司 | Synthesis method of pregabalin |
Non-Patent Citations (1)
| Title |
|---|
| 刘春霞: "普瑞巴林的合成工艺研究", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109867609A (en) * | 2019-03-21 | 2019-06-11 | 常州工程职业技术学院 | A method of preparing Pregabalin raceme |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106278861B (en) | A method of preparing substituted phenylacetic acid | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN102993044A (en) | Preparation method of 4-chlorophenylhydrazine hydrochloride | |
| CN107857709A (en) | A kind of preparation method of antiepileptic Pregabalin | |
| CN105037139A (en) | Preparation method for 2-phenylpropionic acid | |
| CN112321552A (en) | Synthesis method of delta-caprolactone spice | |
| CN101781248B (en) | Method for synthesizing N-methylhexahydroazepin-4-one hydrochloride, azelastine hydrochloride intermediate | |
| CN104326975A (en) | Preparation method of high-purity milrinone | |
| CN103508934A (en) | Preparation method of gliclazide | |
| CN100494187C (en) | Method for synthesizing Ranolazine | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN102050702B (en) | Method for promoting synthesis of resveratrol by micro waves | |
| CN100355717C (en) | Method for synthesizing diphenyl-2-carboxylic acid | |
| CN101481334B (en) | Rivastigmine preparation suitable for industrial production | |
| CN103923003A (en) | Preparation method of 4-bromomethylquinoline-2(H)-ketone | |
| CN102432524A (en) | Method for preparing indole-2-carboxylic acid | |
| CN107857710A (en) | A kind of preparation method of antiepileptic Pregabalin | |
| CN104098540B (en) | A kind of method preparing Zaltoprofen | |
| CN103102327A (en) | Preparation method of rubber accelerator DZ (N,N-Dicyclohexyl-2-benzothiazolsulfene amide) | |
| CN102295568B (en) | Preparation method of dopexamine hydrochloride | |
| CN102199154A (en) | Novel synthesis method for pyrrole derivatives | |
| CN111056997A (en) | Synthetic method of benzamide compound | |
| CN102086147B (en) | Preparation method of substituted phenol | |
| CN101665417B (en) | One-pot process for synthesizing 1,2,3-trimethoxy-benzene by using o-vanillin | |
| CN111087319A (en) | Method for continuously preparing glycine in alcohol phase |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180330 |