CN109851543A - A method of preparing pregabalin lactams - Google Patents
A method of preparing pregabalin lactams Download PDFInfo
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- CN109851543A CN109851543A CN201910068340.0A CN201910068340A CN109851543A CN 109851543 A CN109851543 A CN 109851543A CN 201910068340 A CN201910068340 A CN 201910068340A CN 109851543 A CN109851543 A CN 109851543A
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- pregabalin
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Abstract
The present invention provides a kind of preparation methods of pregabalin lactams, the reaction promoter that reaction step is added is cheap and very easy acquisition, the water that water segregator separates the generation of Pregabalin molecule inner ring condensation is connected simultaneously, promote the thorough converted product pregabalin lactams of reaction substrate Pregabalin, the pregabalin lactams product purity made is up to 99% or more, 94% or more yield, while this preparation method is easy to operate, is easy in laboratory operation.
Description
Technical field
The present invention relates to medical manufacturing technology fields, in particular to a kind of rapidly and efficiently to prepare pregabalin lactams
Method.
Background technique
Pregabalin (pregabalin), chemical name: (S) -3- aminomethyl -5- methylhexanoic acid, molecular formula C8H17NO2, point
Son amount is 159.23, and structural formula is as follows:
Pregabalin trade name diazepamListed in the U.S. within 2004,2010 in Discussion on Chinese Listed, as
First to be authenticated jointly by US and European for treating 2 kinds of neuralgic drugs, principal indication is diabetic peripheral nerve
Bitterly, post-herpetic neuralgia, fibromyalgia, spinal cord injury neuralgia.
Pregabalin bulk pharmaceutical chemicals and Pregabalin piece find in stability study at us, acyl in pregabalin
Amine is main degradation impurity in Pregabalin bulk pharmaceutical chemicals and Pregabalin piece, especially Pregabalin bulk pharmaceutical chemicals or Puri bar
It also or is that product stability condition standing time is too long, impurity S- is general when woods preparation prescription preparation condition state modulator is bad
Auspicious Bahrain's lactam content can achieve 0.5% or more, more than the limit index that the single impurity of product is more than 0.20%, therefore close
Quality research is carried out to Pregabalin bulk pharmaceutical chemicals and its formulation products at the impurity reference substance just to have great importance.S- Puri
Bahrain's lactam structure formula is as follows:
It is more to the synthetic method of pregabalin lactams at present, wherein periodical literature Advanced Synthesis
And Catalysis, 360 (2018), the method for P768-778 report are to work as raw material using Pregabalin, and azo methyl three is added
Methyl-monosilane is that cyclizing agent synthesizes pregabalin lactams, and patent WO2016075082 is also to use identical synthetic strategy,
The azo methyltrimethylsilane reagent price used in these methods is expensive, while the reagent also has stronger toxicity,
Be not suitable in laboratory operation；Other periodical literature Tetrahedron, 67 (2001), P636-640 is using with 2-
Methoxycarbonyl-Pregabalin lactams works as raw material, and NaOH methoxycarbonyl handle is added and is hydrolyzed into carboxyl, then under heating condition
It sloughs a molecule carbon dioxide and obtains pregabalin lactams, raw material 2- methoxycarbonyl-Pregabalin that the method uses
Lactams is not easy to obtain, and simultaneously synthesizing step is also comparatively laborious；It is sub- using oxalyl chloride or dichloro in patent CN107641093 simultaneously
Sulfone activates the carboxyl of Pregabalin, and molecule inner ring condensation then occurs with amino and generates pregabalin lactams, the method uses
To high irritating oxalyl chloride or thionyl chloride, and many acid impurities and irritating smell can be generated, while reagent
It is also higher to save requirement；In addition, patent CN104829515 works as cyclizing agent using hydrochloric acid or acetic acid, make Puri bar under heating condition
The dehydration of woods molecule inner ring condensation generates pregabalin lactams, but the pregabalin lactam product generated under this preparation condition
Hydrolysis be will continue into raw material Pregabalin, cause reaction conversion ratio not high, product yield is lower.
Summary of the invention
The present invention provides a kind of method for preparing pregabalin lactams of simplicity, specific reaction equation is as follows:
The following steps are included:
(a) under reaction promoter effect, Pregabalin back flow reaction 1~36 hour in organic solvent, reflux course
The water generated in middle removing reaction process；
(b) it isolates and purifies and obtains target product pregabalin lactams.
Preferably, organic solvent described in step (a) is the solvent immiscible with water.Further preferred toluene, benzene,
Dimethylbenzene, n-hexane, hexamethylene, normal heptane etc..Still more preferably toluene or dimethylbenzene.
The volume mass of organic solvent and Pregabalin ratio is 3-30ml/g in step (a)；Preferred volume quality is 10-
20ml/g
Preferably, reaction promoter described in step (a) be selected from acidic metal oxide, silica gel or kaolin or it
The mixture that forms；Further preferred acidic alumina, acidic silica gel or acid kaolin.
Preferably, the mass ratio of step (a) reaction promoter and Pregabalin be 0.01~10:1, preferably 0.5
~1:1.
Preferably, step (a) return time is 4~20 hours.
The method provided by the invention for preparing pregabalin lactams following advantage as follows:
1. the reaction promoter that the present invention uses such as acidic alumina, acidic silica gel or acid kaolin are cheap, non-
Often it is easy to get.
2. for target product pregabalin lactam content up to 99% or more, remaining other components are main in reaction solution
It is easy to operate for the complete a small amount of Pregabalin of unreacted, acyl in the pregabalin of high-purity can be obtained without complex separations
Amine product, while yield is up to 94% or more.
Specific embodiment
The present invention is further elaborated below with reference to example, the present invention is not limited to following embodiments, any couple of present invention
Transformation and modification all belong to protection scope of the present invention.
Embodiment 1:
10g Pregabalin is added in 100mL toluene, 5g acidic alumina is subsequently added into, then connects water segregator again, add
Hot back flow reaction 12 hours, reaction process separates the water generated in reaction process in real time；After reaction, room is slowly cooled to
Temperature, filtering remove insoluble matter, and obtained filtrate boils off solvent with Rotary Evaporators again, and obtained solid uses ethyl acetate again: ring
Hexane (1:1) is recrystallized, and target product pregabalin lactams 8.42g, HPLC purity 99.4%, yield 95% are obtained.
Embodiment 2:
10g Pregabalin is added in 100mL dimethylbenzene, 5g acidic alumina is added, then connect water segregator, is heated to reflux
Reaction 6 hours, separates the water generated in reaction process in real time；After reaction, it is slowly cooled to room temperature, filters, remove insoluble
Object, obtained filtrate boil off solvent, and obtained solid is again with ethyl acetate: hexamethylene (2:3) is recrystallized, and target product is obtained
Pregabalin lactams 8.51g, HPLC purity 99.2%, yield 96%.
Embodiment 3
10g Pregabalin is added in 150mL toluene, is subsequently added into 9.5g acidic alumina, then connect water segregator, is heated
Back flow reaction 9 hours, the water generated in reaction process was separated in real time；After reaction, it is slowly cooled to room temperature, filters, remove
Insoluble matter, filtrate are evaporated, and obtained solid is again with ethyl acetate: hexamethylene (1:1) is recrystallized, and obtains target product S- Puri
Bahrain lactams 8.51g, HPLC purity 99.3%, yield 96%.
Embodiment 4
10g Pregabalin is added in 100mL toluene, 5g acidic silica gel is subsequently added into, connects water segregator, is heated to reflux anti-
It answers 15 hours, separates the water generated in reaction process in real time；After reaction, it is slowly cooled to room temperature, filters, filtrate rotation
Evaporimeter boils off solvent, and obtained solid is again with ethyl acetate: hexamethylene (1:1) is recrystallized, and obtains target product S- Puri
Bahrain lactams 8.34g, HPLC purity 99.5%, yield 94%.
Embodiment 5:
First 10g Pregabalin is added in 100mL hexamethylene, 5g acidic silica gel is added, connects water segregator, be heated to reflux
Reaction 5 hours, reaction process separates the water generated in reaction process in real time；After reaction, it is slowly cooled to room temperature, filters,
Insoluble matter is removed, obtained filtrate boils off solvent with Rotary Evaporators again, and obtained solid uses ethyl acetate again: hexamethylene (1:
1) it is crystallized, obtains target product pregabalin lactams 8.43g, HPLC purity 99.2%, yield 95%.
Embodiment 6:
10g Pregabalin is added in 100mL toluene, 5g acidity kaolin is subsequently added into, then connects water segregator again, add
Hot back flow reaction 16 hours, reaction process separates the water generated in reaction process in real time；After reaction, room is slowly cooled to
Temperature, filtering remove insoluble matter, and obtained filtrate boils off solvent with Rotary Evaporators again, and obtained solid uses ethyl acetate again: ring
Hexane (1:1) is crystallized, and target product pregabalin lactams 8.51g, HPLC purity 99.5%, yield 96% are obtained.
Embodiment 7:
10g Pregabalin is added in 100mL dimethylbenzene, 5g acidity kaolin is added, then connects water segregator again, is heated
Back flow reaction 6 hours, the water generated in reaction process was separated in real time；After reaction, it is slowly cooled to room temperature, filters, remove
Insoluble matter, obtained filtrate boil off solvent with Rotary Evaporators again, and obtained solid uses ethyl acetate again: hexamethylene (1:1) into
Row crystallization, obtains target product pregabalin lactams 8.60g, HPLC purity 99.3%, yield 97%.
Embodiment 8:
10g Pregabalin is added in 100mL normal heptane, 5g acidity kaolin is added, connects water segregator, is heated to reflux anti-
It answers 18 hours, separates the water generated in reaction process in real time；After reaction, it is slowly cooled to room temperature, filters, remove insoluble
Object, obtained filtrate boil off solvent with Rotary Evaporators again, and obtained solid is again with ethyl acetate: hexamethylene (1:1) is tied
Crystalline substance obtains target product pregabalin lactams 8.34g, HPLC purity 99.2%, yield 94%.
Claims (7)
1. a kind of preparation method of pregabalin lactams, reaction equation are as follows:
It is characterized in that the following steps are included:
(a) under reaction promoter effect, Pregabalin back flow reaction 1~36 hour in organic solvent is removed in reflux course
The water generated during dereaction；
(b) it isolates and purifies and obtains target product pregabalin lactams.
2. preparation method according to claim 1, it is characterised in that: organic solvent described in step (a) be with water mutually not
The solvent to mix.
It is described that toluene, benzene, dimethylbenzene, just are selected from the immiscible solvent of water 3. preparation method according to claim 2
Hexane, hexamethylene, normal heptane etc.；It is preferred that toluene or dimethylbenzene.
4. the volume mass ratio of preparation method according to claim 2 or 3, the organic solvent and Pregabalin is 3-
30ml/g；Preferred volume quality is 10-20ml/g.
5. preparation method according to claim 1, it is characterised in that: reaction promoter described in step (a) is selected from acidity
Metal oxide, silica gel or kaolin or the mixture that they are formed；Preferred acidic aluminium oxide, acidic silica gel or acid high
Ridge soil.
6. preparation method according to claim 1 or 5, it is characterised in that: step (a) reaction promoter and Puri bar
The mass ratio of woods is 0.01~10:1, preferably 0.5~1:1.
7. preparation method according to claim 1, it is characterised in that: return time is 4~20 hours in step (a).
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| CN201910068340.0A CN109851543B (en) | 2019-01-24 | 2019-01-24 | Method for preparing S-pregabalin lactam |
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| CN201910068340.0A CN109851543B (en) | 2019-01-24 | 2019-01-24 | Method for preparing S-pregabalin lactam |
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| CN109851543B CN109851543B (en) | 2023-07-07 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1349982A (en) * | 2000-10-24 | 2002-05-22 | 大连化学工业股份有限公司 | Prepn of lactam |
| CN1427821A (en) * | 2000-05-03 | 2003-07-02 | 巴斯福股份公司 | Method for producing cyclic lactams |
| CN104829515A (en) * | 2015-06-02 | 2015-08-12 | 浙江华海药业股份有限公司 | Pregabalin impurity preparation method |
| CN107641093A (en) * | 2016-07-20 | 2018-01-30 | 江西科维协同创新药物有限公司 | The method that one kind prepares the pyrrolidones of 4 (S) isobutyl group 2 |
| CN107793414A (en) * | 2016-09-06 | 2018-03-13 | 上虞京新药业有限公司 | The synthetic method of (S, S) 2,8 diazabicyclo [4.3.0] nonane |
-
2019
- 2019-01-24 CN CN201910068340.0A patent/CN109851543B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1427821A (en) * | 2000-05-03 | 2003-07-02 | 巴斯福股份公司 | Method for producing cyclic lactams |
| CN1349982A (en) * | 2000-10-24 | 2002-05-22 | 大连化学工业股份有限公司 | Prepn of lactam |
| CN104829515A (en) * | 2015-06-02 | 2015-08-12 | 浙江华海药业股份有限公司 | Pregabalin impurity preparation method |
| CN107641093A (en) * | 2016-07-20 | 2018-01-30 | 江西科维协同创新药物有限公司 | The method that one kind prepares the pyrrolidones of 4 (S) isobutyl group 2 |
| CN107793414A (en) * | 2016-09-06 | 2018-03-13 | 上虞京新药业有限公司 | The synthetic method of (S, S) 2,8 diazabicyclo [4.3.0] nonane |
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