CN104447372A - Preparation method of gabapentin - Google Patents
Preparation method of gabapentin Download PDFInfo
- Publication number
- CN104447372A CN104447372A CN201410695892.1A CN201410695892A CN104447372A CN 104447372 A CN104447372 A CN 104447372A CN 201410695892 A CN201410695892 A CN 201410695892A CN 104447372 A CN104447372 A CN 104447372A
- Authority
- CN
- China
- Prior art keywords
- gabapentin
- acid
- preparation
- parts
- add
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of gabapentin. The preparation method comprises the following steps: (1) preparing 1,1-cyclohexyl oxalic acid anhydride; (2) preparing 3,3-cyclopentane glutaramic acid; (3) adding the 3,3-cyclopentane glutaramic acid to an alkaline solution, dripping sodium hypochlorite for performing a reaction, adding benzene, performing a dehydrating and condensation reaction after heating, separating an organic phase and an aqueous phase, adding hydrochloric acid to the organic phase to perform a hydrolyzing reaction so as to separate the organic phase, and concentrating the aqueous phase so as to obtain gabapentin hydrochloride; (4) adding the gabapentin hydrochloride into deionized water, regulating the PH value to be 4-6, stirring the gabapentin hydrochloride and the deionized water for dissolving, adding activated carbon for adsorbing impurities, filtering the impurities, then regulating the PH value to be 8, performing cooling so as to separate out gabapentin hydrate, adding the gabapentin hydrate to ethyl alcohol to be stirred and mixed, after cooling and separating out wet gabapentin, and performing filtering and drying so as to obtain the gabapentin. The gabapentin prepared by the preparation method disclosed by the invention is high in content and yield.
Description
Technical field
The present invention relates to antiepileptic drug technical field, particularly relate to a kind of preparation method of gabapentin.
Background technology
Gabapentin is a kind of antiepileptic drug of novelty, and it is the derivative of γ-aminobutyric acid (GABA), and its pharmacological action is different from existing antiepileptic drug, and research recently shows that the effect of gabapentin changes GABA metabolism to produce.Gabapentin all shows the effect of prevention epilepsy in various animal model, in addition, in animal spasm, analgesia and amyotrophic lateral sclerosis model, also shows effect.The novel binding site of gabapentin to cerebral tissue has high affinity, and it is by amino acid transfer body by some barriers in body, and compare with other anticonvulsive drug, gabapentin has less behavior and cardiovascular side effects.The novel binding site of gabapentin to cerebral tissue has high affinity, and it is by amino acid transfer body by some barriers in body, and compare with other anticonvulsive drugs, gabapentin has less behavior and cardiovascular side effects.Can not the epileptic of Satisfactory Control or the outbreak of not tolerant limitation for conventional antiepileptic drug, and limitation outbreak the additional treatment of the epileptic of generalization then.
Gabapentin content prepared by existing method is not high, yield is on the low side.
Summary of the invention
In view of this, the invention provides a kind of preparation method of gabapentin, the gabapentin content that this preparation method obtains is high, yield is high.
A preparation method for gabapentin, comprises the following steps:
(1) 1,1-cyclohexanediacetic acid and aceticanhydride are added in reactor, reflux, evaporated under reduced pressure, obtain 1,1-cyclohexanediacetic acid acid anhydride;
(2) ammoniacal liquor is added in ammoniation kettle, drip described 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction, add hcl acidifying, obtained 3,3-pentamethylene glutaramic acid;
(3) by described 3,3-pentamethylene glutaramic acid adds in basic solution, drip clorox to react, add benzene, dehydration condensation is carried out in heating, is separated organic phase and aqueous phase, in organic phase, add hydrochloric acid to be hydrolyzed reaction, isolate organic phase, concentrated aqueous phase, obtains Gabapentin hydrochloride;
(4) described Gabapentin hydrochloride is added in deionized water, regulate pH value to 4 ~ 6, stirring and dissolving, adds charcoal absorption impurity, filters, regulate pH value to 8 again, gabapentin hydrate is separated out in cooling, is added in ethanol by described gabapentin hydrate and is uniformly mixed, and gabapentin wet product is separated out in cooling again, drying, obtains gabapentin.
Preferably, step (1) detailed process is: by mass parts, by 1,1-cyclohexanediacetic acid 80 parts deionized water wash, put moisture eliminator dry 1 ~ 1.5h at 95 ~ 100 DEG C into, put into after cooling in reactor, add aceticanhydride 50 ~ 60 parts, be heated to 135 DEG C of backflow 1 ~ 2h, evaporated under reduced pressure, obtain 1,1-cyclohexanediacetic acid acid anhydride.
Preferably, step (2) detailed process is: be that 15% ammoniacal liquor 80 ~ 100 parts adds in ammoniation kettle by concentration, at temperature is 18 ~ 20 DEG C, 2 ~ 3h drips described 1,1-hexamethylene diethyl acid anhydrides carries out aminating reaction, add concentration be 40% hydrochloric acid regulate pH value to 4 ~ 5 to carry out acidifying, centrifugal white crystals, deionized water wash, drying under reduced pressure 2 ~ 3h at 100 DEG C, cooling, obtained 3,3-pentamethylene glutaramic acid.
Preferably, step (3) detailed process is: by described 3, it is in 15% sodium hydroxide solution that 3-pentamethylene glutaramic acid adds concentration, dripping concentration is 20% clorox 50 ~ 80 parts, heating is reacted, add benzene 40 ~ 60 parts, be heated to 90 ~ 100 DEG C and carry out dehydration condensation 3 ~ 4h, Separation of Benzene layer and aqueous phase, in benzene layer, add the hydrochloric acid 60 ~ 80 parts that concentration is 30%, be hydrolyzed reaction 3 ~ 4h at 90 ~ 95 DEG C, isolates organic phase, concentrated aqueous phase, to dry, obtains Gabapentin hydrochloride.
Preferably, step (4) detailed process is: be added in deionized water by described Gabapentin hydrochloride, regulate pH value to 4 ~ 6, stirring and dissolving, add gac and diatomite decolouring also adsorbing contaminant, filter, regulate pH value to 8 again, be cooled to 0 ~ 5 DEG C and separate out gabapentin hydrate, added in ethanol 60 ~ 100 parts by described gabapentin hydrate, be heated to 30 ~ 40 DEG C and be uniformly mixed, gabapentin wet product is separated out in cooling again, put into moisture eliminator dry 1.5 ~ 2h at 85 ~ 95 DEG C, obtain gabapentin.
Beneficial effect of the present invention: a kind of preparation method of gabapentin comprises the following steps: 1,1-cyclohexanediacetic acid and aceticanhydride add in reactor by (1), reflux, evaporated under reduced pressure, obtains 1,1-cyclohexanediacetic acid acid anhydride; (2) ammoniacal liquor is added in ammoniation kettle, drip described 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction, add hcl acidifying, obtained 3,3-pentamethylene glutaramic acid; (3) by described 3,3-pentamethylene glutaramic acid adds in basic solution, drip clorox to react, add benzene, dehydration condensation is carried out in heating, is separated organic phase and aqueous phase, in organic phase, add hydrochloric acid to be hydrolyzed reaction, isolate organic phase, concentrated aqueous phase, obtains Gabapentin hydrochloride; (4) described Gabapentin hydrochloride is added in deionized water, regulate pH value to 4 ~ 6, stirring and dissolving, adds charcoal absorption impurity, filters, regulate pH value to 8 again, gabapentin hydrate is separated out in cooling, is added in ethanol by described gabapentin hydrate and is uniformly mixed, and gabapentin wet product is separated out in cooling again, drying, obtains gabapentin.The gabapentin content that preparation method of the present invention obtains is high, yield is high.
Embodiment
Further illustrate technical scheme of the present invention respectively below in conjunction with the embodiments.
Raw material involved in following examples is commercially available.
Embodiment 1: the preparation method of a kind of gabapentin of the present embodiment, comprises the following steps:
By mass parts, by 1,1-cyclohexanediacetic acid 80 parts deionized water wash, puts moisture eliminator dry 1h at 95 DEG C into, puts in reactor after cooling, add aceticanhydride 50 parts, and be heated to 135 DEG C of backflow 1h, evaporated under reduced pressure, obtains 1,1-cyclohexanediacetic acid acid anhydride;
Be that 15% ammoniacal liquor 80 parts adds in ammoniation kettle by concentration, at temperature is 18 DEG C, 2h drips described 1,1-hexamethylene diethyl acid anhydrides and carries out aminating reaction, add concentration be 40% hydrochloric acid regulate pH value to 4 carry out acidifying, centrifugal white crystals, deionized water wash, drying under reduced pressure 2h at 100 DEG C, cooling, obtained 3,3-pentamethylene glutaramic acid;
By described 3, it is in 15% sodium hydroxide solution that 3-pentamethylene glutaramic acid adds concentration, and dripping concentration is 20% clorox 50 parts, and heating is reacted, add benzene 40 parts, be heated to 90 DEG C and carry out dehydration condensation 3h, Separation of Benzene layer and aqueous phase, in benzene layer, add the hydrochloric acid 60 parts that concentration is 30%, be hydrolyzed reaction 3h at 90 DEG C, isolate organic phase, concentrated aqueous phase, to dry, obtains Gabapentin hydrochloride;
Described Gabapentin hydrochloride is added in deionized water, regulate pH value to 4, stirring and dissolving, add gac and diatomite decolouring also adsorbing contaminant, filter, regulate pH value to 8 again, be cooled to 0 DEG C and separate out gabapentin hydrate, described gabapentin hydrate is added in ethanol 60 parts, be heated to 30 DEG C be uniformly mixed, gabapentin wet product is separated out in cooling again, puts into moisture eliminator dry 1.5h at 85 DEG C, obtains gabapentin.
Embodiment 2: the preparation method of a kind of gabapentin of the present embodiment, comprises the following steps:
By mass parts, by 1,1-cyclohexanediacetic acid 80 parts deionized water wash, puts moisture eliminator dry 1h at 100 DEG C into, put into after cooling in reactor, add aceticanhydride 55 parts, be heated to 135 DEG C of backflow 1.5h, evaporated under reduced pressure, obtains 1,1-cyclohexanediacetic acid acid anhydride;
Be that 15% ammoniacal liquor 90 parts adds in ammoniation kettle by concentration, at temperature is 18 DEG C, 2.5h drips described 1,1-hexamethylene diethyl acid anhydrides and carries out aminating reaction, add concentration be 40% hydrochloric acid regulate pH value to 4 carry out acidifying, centrifugal white crystals, deionized water wash, drying under reduced pressure 2.5h at 100 DEG C, cooling, obtained 3,3-pentamethylene glutaramic acid;
By described 3, it is in 15% sodium hydroxide solution that 3-pentamethylene glutaramic acid adds concentration, and dripping concentration is 20% clorox 60 parts, and heating is reacted, add benzene 50 parts, be heated to 100 DEG C and carry out dehydration condensation 3.5h, Separation of Benzene layer and aqueous phase, in benzene layer, add the hydrochloric acid 70 parts that concentration is 30%, be hydrolyzed reaction 3.5h at 95 DEG C, isolate organic phase, concentrated aqueous phase, to dry, obtains Gabapentin hydrochloride;
Described Gabapentin hydrochloride is added in deionized water, regulate pH value to 5, stirring and dissolving, add gac and diatomite decolouring also adsorbing contaminant, filter, regulate pH value to 8 again, be cooled to 1 DEG C and separate out gabapentin hydrate, described gabapentin hydrate is added in ethanol 80 parts, be heated to 30 ~ 40 DEG C be uniformly mixed, gabapentin wet product is separated out in cooling again, puts into moisture eliminator dry 1.5 ~ 2h at 85 ~ 95 DEG C, obtains gabapentin.
Embodiment 3: the preparation method of a kind of gabapentin of the present embodiment, comprises the following steps:
By mass parts, by 1,1-cyclohexanediacetic acid 80 parts deionized water wash, puts moisture eliminator dry 1.5h at 100 DEG C into, put into after cooling in reactor, add aceticanhydride 60 parts, be heated to 135 DEG C of backflow 2h, evaporated under reduced pressure, obtains 1,1-cyclohexanediacetic acid acid anhydride;
Be that 15% ammoniacal liquor 100 parts adds in ammoniation kettle by concentration, at temperature is 20 DEG C, 3h drips described 1,1-hexamethylene diethyl acid anhydrides and carries out aminating reaction, add concentration be 40% hydrochloric acid regulate pH value to 5 carry out acidifying, centrifugal white crystals, deionized water wash, drying under reduced pressure 3h at 100 DEG C, cooling, obtained 3,3-pentamethylene glutaramic acid;
By described 3, it is in 15% sodium hydroxide solution that 3-pentamethylene glutaramic acid adds concentration, and dripping concentration is 20% clorox 80 parts, and heating is reacted, add benzene 60 parts, be heated to 100 DEG C and carry out dehydration condensation 4h, Separation of Benzene layer and aqueous phase, in benzene layer, add the hydrochloric acid 80 parts that concentration is 30%, be hydrolyzed reaction 4h at 95 DEG C, isolate organic phase, concentrated aqueous phase, to dry, obtains Gabapentin hydrochloride;
Described Gabapentin hydrochloride is added in deionized water, regulate pH value to 6, stirring and dissolving, add gac and diatomite decolouring also adsorbing contaminant, filter, regulate pH value to 8 again, be cooled to 5 DEG C and separate out gabapentin hydrate, described gabapentin hydrate is added in ethanol 100 parts, be heated to 40 DEG C be uniformly mixed, gabapentin wet product is separated out in cooling again, puts into moisture eliminator dry 2h at 95 DEG C, obtains gabapentin.
Embodiment 1 ~ 3 is obtained gabapentin and existing gabapentin carries out content and yield compares, result is as following table:
The gabapentin content prepared of the present invention and yield are than existing methodical height as can be seen from the table, and content reaches more than 99.5%, and yield reaches more than 88%.
Preparation method's step of the present invention is simple, easy to operate, and obtained gabapentin yield is high, purity is high.
It should be noted that and understand, when not departing from the spirit and scope of accompanying claim the present invention for required protection, various amendment and improvement can be made to the present invention of foregoing detailed description.Therefore, the scope of claimed technical scheme is not by the restriction of given any specific exemplary teachings.
Applicant states, the present invention illustrates detailed process equipment and process flow process of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed process equipment and process flow process, namely do not mean that the present invention must rely on above-mentioned detailed process equipment and process flow process and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (7)
1. a preparation method for gabapentin, is characterized in that, comprises the following steps:
(1) 1,1-cyclohexanediacetic acid and aceticanhydride are added in reactor, reflux, evaporated under reduced pressure, obtain 1,1-cyclohexanediacetic acid acid anhydride;
(2) ammoniacal liquor is added in ammoniation kettle, drip described 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction, add hcl acidifying, obtained 3,3-pentamethylene glutaramic acid;
(3) by described 3,3-pentamethylene glutaramic acid adds in basic solution, drip clorox to react, add benzene, dehydration condensation is carried out in heating, is separated organic phase and aqueous phase, in organic phase, add hydrochloric acid to be hydrolyzed reaction, isolate organic phase, concentrated aqueous phase, obtains Gabapentin hydrochloride;
(4) described Gabapentin hydrochloride is added in deionized water, regulate pH value to 4 ~ 6, stirring and dissolving, adds charcoal absorption impurity, filters, regulate pH value to 8 again, gabapentin hydrate is separated out in cooling, is added in ethanol by described gabapentin hydrate and is uniformly mixed, and gabapentin wet product is separated out in cooling again, drying, obtains gabapentin.
2. preparation method according to claim 1, is characterized in that, step (1) drying temperature is 95 ~ 100 DEG C, and time of drying is 1 ~ 1.5h.
3. preparation method according to claim 1, it is characterized in that, step (1) detailed process is: by mass parts, by 1,1-cyclohexanediacetic acid 80 parts deionized water wash, put moisture eliminator drying into, put in reactor after cooling, add aceticanhydride 50 ~ 60 parts, be heated to 135 DEG C of backflow 1 ~ 2h, evaporated under reduced pressure, obtains 1,1-cyclohexanediacetic acid acid anhydride.
4. preparation method according to claim 1, is characterized in that, step (2) detailed process is: be that 15% ammoniacal liquor 80 ~ 100 parts adds in ammoniation kettle by concentration, at temperature is 18 ~ 20 DEG C, 2 ~ 3h drips described 1,1-hexamethylene diethyl acid anhydrides and carries out aminating reaction, add concentration be 40% hydrochloric acid regulate pH value to 4 ~ 5 carry out acidifying, centrifugal white crystals, deionized water wash, drying under reduced pressure 2 ~ 3h at 100 DEG C, cooling, obtained 3,3-pentamethylene glutaramic acid.
5. preparation method according to claim 1, it is characterized in that, step (3) detailed process is: by described 3, it is in 15% sodium hydroxide solution that 3-pentamethylene glutaramic acid adds concentration, dripping concentration is 20% clorox 50 ~ 80 parts, heating is reacted, add benzene 40 ~ 60 parts, be heated to 90 ~ 100 DEG C and carry out dehydration condensation 3 ~ 4h, Separation of Benzene layer and aqueous phase, the hydrochloric acid 60 ~ 80 parts that concentration is 30% is added in benzene layer, be hydrolyzed reaction 3 ~ 4h at 90 ~ 95 DEG C, isolate organic phase, concentrated aqueous phase is to dry, obtain Gabapentin hydrochloride.
6. preparation method according to claim 1, is characterized in that, in step (4), drying temperature is 85 ~ 95 DEG C, and time of drying is 1.5 ~ 2h.
7. preparation method according to claim 1, it is characterized in that, step (4) detailed process is: be added in deionized water by described Gabapentin hydrochloride, regulate pH value to 4 ~ 6, stirring and dissolving, add gac and diatomite decolouring also adsorbing contaminant, filter, regulate pH value to 8 again, be cooled to 0 ~ 5 DEG C and separate out gabapentin hydrate, described gabapentin hydrate is added in ethanol 60 ~ 100 parts, be heated to 30 ~ 40 DEG C be uniformly mixed, gabapentin wet product is separated out in cooling again, puts into moisture eliminator dry, obtains gabapentin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410695892.1A CN104447372A (en) | 2014-11-26 | 2014-11-26 | Preparation method of gabapentin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410695892.1A CN104447372A (en) | 2014-11-26 | 2014-11-26 | Preparation method of gabapentin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104447372A true CN104447372A (en) | 2015-03-25 |
Family
ID=52894207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410695892.1A Pending CN104447372A (en) | 2014-11-26 | 2014-11-26 | Preparation method of gabapentin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447372A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232295A (en) * | 2018-10-24 | 2019-01-18 | 河北三川化工有限公司 | A kind of method for crystallising of 1,1- cyclohexanediacetic acid monoamides |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1896050A (en) * | 2006-06-12 | 2007-01-17 | 浙江手心医药化学品有限公司 | Production of gabapendin |
| US20080103334A1 (en) * | 2006-10-26 | 2008-05-01 | Ipca Laboratories Ltd | Process For Synthesis Of Gabapentin |
| CN101417960A (en) * | 2008-12-01 | 2009-04-29 | 太仓市运通化工厂 | Method for preparing 1,1-cyclohexanediacetic acid mono amide |
| CN102093237A (en) * | 2011-01-04 | 2011-06-15 | 大连理工大学 | Synthesis method of gabapentin hydrochloride |
-
2014
- 2014-11-26 CN CN201410695892.1A patent/CN104447372A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1896050A (en) * | 2006-06-12 | 2007-01-17 | 浙江手心医药化学品有限公司 | Production of gabapendin |
| US20080103334A1 (en) * | 2006-10-26 | 2008-05-01 | Ipca Laboratories Ltd | Process For Synthesis Of Gabapentin |
| CN101417960A (en) * | 2008-12-01 | 2009-04-29 | 太仓市运通化工厂 | Method for preparing 1,1-cyclohexanediacetic acid mono amide |
| CN102093237A (en) * | 2011-01-04 | 2011-06-15 | 大连理工大学 | Synthesis method of gabapentin hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232295A (en) * | 2018-10-24 | 2019-01-18 | 河北三川化工有限公司 | A kind of method for crystallising of 1,1- cyclohexanediacetic acid monoamides |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103880625B (en) | Method for preparing D, L-mandelic acid and derivative of D, L-mandelic acid | |
| CN104356016B (en) | A method of with recycling preparation 3- isobutylglutaric acid monoamides | |
| WO2014166273A1 (en) | Β−hydroxy−β−methylbutyric acid purification method | |
| CN106045879A (en) | Preparation method for cyanoacetic acid | |
| CN103554179A (en) | Method for producing N-(phosphonomethyl)iminodiacetic acid and recycling mother solution by hydrogen chloride desalinization | |
| CN102320960A (en) | Preparation method of 6-fluoro salicylic acid | |
| CN103420881A (en) | Novel method for preparing medicinal despun hydroxyl methionine calcium | |
| CN104262210B (en) | A kind of method extracting paratoluenesulfonic acid sodium salt from Tiamulin synthetic wastewater | |
| CN104496833A (en) | Gabapentin synthesis technology | |
| CN104447372A (en) | Preparation method of gabapentin | |
| CN103265443A (en) | Industrial production method of high-purity iminodiacetic acid | |
| CN104478802A (en) | Process for synthesizing 3,3-pentamethylene glutarimide | |
| CN107311892A (en) | A kind of preparation method of smart sulfanilamide (SN) | |
| CN103012509B (en) | Method of separating and purifying sucrose-6-acetate mother liquor by salt fractionation | |
| CN103274954A (en) | Production process of Gly | |
| EP1558564A2 (en) | A process for synthesis of 1-(aminomethyl)cyclohexane acetic acid hydrochloride | |
| CN103951596A (en) | Preparation method of medicinal D, L-alpha-hydroxymethionine calcium | |
| CN104447512A (en) | Preparation method of 3, 3-pentamethylene glutarimide | |
| CN104447303A (en) | Preparation technology of carboxybenzaldehyde | |
| CN110713440A (en) | Preparation method of vigabatrin | |
| CN103554178B (en) | The production of pmida98 and mother liquor phosphorus trichloride desalination recycled method | |
| CN103755577B (en) | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor | |
| CN103421043A (en) | Hydrosis process improvement method for synthesizing glyphosate by alkyl ester process | |
| CN104402796A (en) | Preparation method for 3,3-amylidene butyrolactam | |
| CN105418489A (en) | Synthesis method of bupivacaine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150325 |