CN101417975A - Method for preparing gabapentin intermediate - Google Patents
Method for preparing gabapentin intermediate Download PDFInfo
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- CN101417975A CN101417975A CNA2008101363967A CN200810136396A CN101417975A CN 101417975 A CN101417975 A CN 101417975A CN A2008101363967 A CNA2008101363967 A CN A2008101363967A CN 200810136396 A CN200810136396 A CN 200810136396A CN 101417975 A CN101417975 A CN 101417975A
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- methanol
- reaction
- methyl cyanoacetate
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- gabapentin
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Abstract
The invention relates to a method for preparing a gabapentin intermediate. The intermediate is alpha, alpha'-dicyan-beta, beta'-pentylidene glutarimide, and is prepared by cyclohexanone and methyl cyanoacetate which react in the presence of methanol ammonium containing 0 to 30 percent of water and ammonium acetate. Methanol has stronger ability to dissolve ammonium, so the mass preparation of the methanol for the production is feasible; a reaction substance adopts the methyl cyanoacetate, the methanol is generated during the reaction, and the selection of the methanol as a solvent is favorable for the reclamation of a solvent system and can achieve the aim of reducing the cost; the method simultaneously has higher reaction yield and product purity, the mass yield of the method is more than 95 percent, and the product purity is more than 99.8 percent calculated based on a target intermediate.
Description
Technical field
The present invention relates to a kind of gabapentin intermediate, particularly α, α '-dicyano-β, the preparation method of β '-pentylidene glutarimide.
Background technology
α, α '-dicyano-β, β '-pentylidene glutarimide are one of important intermediate of synthetic gabapentin medicine.In the prior art, be dissolved in the presence of the alcoholic acid gaseous ammonia, pimelinketone and ethyl cyanacetate react under water-less environment, and this reaction is expressed as follows:
The Guareschi reaction efficiency is low, and finishing reaction needs 48 hours at least, and dissolve with ethanol ammonia is limited in one's ability, and the gaseous ammonia that is dissolved in the ethanol of preparation is unrealistic on a large scale.
Publication number is that the application for a patent for invention of CN1471507A discloses a kind of pimelinketone and ethyl cyanacetate prepares α in the presence of ammonium hydroxide, α '-dicyano-β, the method of β '-pentylidene glutarimide, this method can be finished in 24 hours substantially, this method also can be to carry out in the presence of alcoholic solvent such as methyl alcohol, alcoholic acid simultaneously, but the yield of this method is still not ideal enough about 85%.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of α in order to overcome the deficiencies in the prior art, α '-dicyano-β, the preparation method of β '-pentylidene glutarimide, this method yield height.
For solving above technical problem, the present invention takes following technical scheme:
A kind of gabapentin intermediates preparation, this intermediate are α, α '-dicyano-β, and β '-pentylidene glutarimide, it is obtained by pimelinketone and methyl cyanoacetate prepared in reaction in the presence of moisture 0～30% methanol ammonia and ammonium acetate.
The molar ratio of described methyl cyanoacetate, pimelinketone and ammonium acetate is preferably 2～2.5:1:0.04～0.07, is 2.1～2.2:1:0.05～0.06 the best with molar ratio.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1, the ability of dissolve with methanol ammonia is stronger, and it is practicable that the mass preparation methanol ammonia is used for producing;
2, reactive material adopts methyl cyanoacetate, in reaction process, has methyl alcohol to generate, and selecting methyl alcohol for use is that solvent helps applying mechanically repeatedly of solvent systems, thereby reaches the purpose that reduces cost;
3, the reaction times shorter, reaction process only needs 20～24 hours;
4, reaction yield is higher, calculates with the target intermediate, and its mass yield is more than 95%, and product purity is more than 99.8%.
Embodiment
Below the specific embodiment of the present invention is described, but be not limited to these embodiment.
Embodiment 1
In a 5000L reactor that reflux exchanger is housed, input contains 1700 kilograms of the methanol ammonia of the water of 9% ammonia and 20%, stirring is cooled to about 0 ℃, drop into 18 kilograms of ammonium acetates, the mixture of 936 kilograms and 430 kilograms pimelinketone of suction methyl cyanoacetate in header tank, slowly drip this mixture, added in about 8 hours, temperature is controlled at-5 ℃～5 ℃, drips to finish, be incubated 20～24 hours, insulation finishes, and the chuck refrigerated brine is pressed, and is warming up to 20～25 ℃, and adding sulfuric acid about 50% to pH2, temperature remains on 50～55 ℃ in the acidifying process.The colod-application slightly whizzer water dumping of reactant is got filter cake, wash this filter cake with less water, about 1400 kilograms of the filter cake of drying, moisture about 31%, give money as a gift 963 kilograms, calculated yield 95%, purity assay are 99.8%.
Embodiment 2
In a 5000L reactor that reflux exchanger is housed, input contains 1900 kilograms of the methanol ammonia of the water of 9% ammonia and 10%, stirring is cooled to about 0 ℃, drop into 20 kilograms of ammonium acetates, the mixture of 960 kilograms and 430 kilograms pimelinketone of suction methyl cyanoacetate in header tank, slowly drip this mixture, added in about 9 hours, temperature is controlled at about 5 ℃, drips to finish, be incubated 20～24 hours, insulation finishes, and the chuck refrigerated brine is pressed, and is warming up to 20～25 ℃, and adding sulfuric acid about 50% to pH2, temperature remains on 50～55 ℃ in the acidifying process.The colod-application slightly whizzer water dumping of reactant is got filter cake, wash this filter cake with less water, about 1432 kilograms of the filter cake of drying, moisture about 31%, give money as a gift 988 kilograms, calculated yield 97.5%, purity assay are 99.8%.
Claims (3)
1, a kind of gabapentin intermediates preparation, this intermediate is α, α '-dicyano-β, β '-pentylidene glutarimide is characterized in that: obtain described intermediate by pimelinketone and methyl cyanoacetate prepared in reaction in the presence of moisture 0～30% methanol ammonia and ammonium acetate.
2, a kind of gabapentin intermediates preparation according to claim 1, it is characterized in that: the molar ratio of described methyl cyanoacetate, pimelinketone and ammonium acetate is 2～2.5:1:0.04～0.07.
3, a kind of gabapentin intermediates preparation according to claim 2, it is characterized in that: the molar ratio of described methyl cyanoacetate, pimelinketone and ammonium acetate is 2.1～2.2:1:0.05～0.06.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101363967A CN101417975A (en) | 2008-12-01 | 2008-12-01 | Method for preparing gabapentin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101363967A CN101417975A (en) | 2008-12-01 | 2008-12-01 | Method for preparing gabapentin intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101417975A true CN101417975A (en) | 2009-04-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101363967A Pending CN101417975A (en) | 2008-12-01 | 2008-12-01 | Method for preparing gabapentin intermediate |
Country Status (1)
| Country | Link |
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| CN (1) | CN101417975A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369530A (en) * | 2018-11-15 | 2019-02-22 | 河北三川化工有限公司 | A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile |
-
2008
- 2008-12-01 CN CNA2008101363967A patent/CN101417975A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369530A (en) * | 2018-11-15 | 2019-02-22 | 河北三川化工有限公司 | A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile |
| CN109369530B (en) * | 2018-11-15 | 2022-03-04 | 河北三川化工有限公司 | Preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
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| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20090429 |