CN104447512A - Preparation method of 3, 3-pentamethylene glutarimide - Google Patents
Preparation method of 3, 3-pentamethylene glutarimide Download PDFInfo
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- CN104447512A CN104447512A CN201410696130.3A CN201410696130A CN104447512A CN 104447512 A CN104447512 A CN 104447512A CN 201410696130 A CN201410696130 A CN 201410696130A CN 104447512 A CN104447512 A CN 104447512A
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- pentamethylene
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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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 3, 3-pentamethylene glutarimide. The preparation method comprises the following steps: (1) adding an ammonia solution into an ammoniation kettle, dripping 1,1-cyclohexane acetic anhydride for performing an ammoniation reaction, and adding a sulphuric acid for acidification so as to obtain a 3,3-cyclopentane glutaramic acid; (2) adding the 3,3-cyclopentane glutaramic acid, a toluene solvent and a glacial acetic acid to a reaction kettle, heating and stirring the 3,3-cyclopentane glutaramic acid, the toluene solvent and the glacial acetic acid, performing regurgitation, lowering the temperature, and performing sucking filtration so as to obtain a filter cake; (3) adding the filter cake to the ammonia solution, mashing and stirring the filter cake and the ammonia solution, performing sucking filtration, performing cleaning with deionized water, and performing baking so as to obtain the 3,3-pentamethylene glutarimide. The 3,3-pentamethylene glutarimide prepared by the preparation method disclosed by the invention is high in content and high in yield.
Description
Technical field
The present invention relates to the intermediate technical field of gabapentin, particularly relate to a kind of preparation method of 3,3-pentamethylene glutarimide.
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.
3,3-pentamethylene glutarimide is a kind of important intermediate of synthesis antiepileptic drug gabapentin, adopts 1 in the prior art, 1-cyclohexanediacetic acid, aceticanhydride, the reactions such as ammonium acetate, obtain product through refining, but obtained product content 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 3,3-pentamethylene glutarimide, 3, the 3-pentamethylene glutarimide content that this preparation method obtains are high, yield is high.
A kind of preparation method of 3,3-pentamethylene glutarimide, comprises the following steps:
(1) ammoniacal liquor is added in ammoniation kettle, drip 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction, add sulfuric acid acidation, obtained 3,3-pentamethylene glutaramic acid;
(2) in reactor, add described 3,3-pentamethylene glutaramic acids, toluene solvant and Glacial acetic acid, heated and stirred, backflow, cooling, suction filtration obtains filter cake;
(3) filter cake is joined making beating in ammoniacal liquor to stir, suction filtration, by washed with de-ionized water, dry, obtain 3,3-pentamethylene glutarimide.
Preferably, in step (1), ammonia concn is 8 ~ 12%, and the aminating reaction time is 2 ~ 3h.
Preferably, step (1) detailed process is: by mass parts, is that 8 ~ 12% ammoniacal liquor 50 ~ 80 parts adds in ammoniation kettle, by concentration at temperature is 18 ~ 20 DEG C, within 1 ~ 1.5 hour, drip 1,35 ~ 50 parts, 1-hexamethylene diethyl acid anhydrides carries out aminating reaction, adds activated carbon filtration, is the sulfuric acid acidation of 60% by concentration, centrifugal white crystals, drying, obtained 3,3-pentamethylene glutaramic acid.
Preferably, step (2) detailed process is: in reactor, add described 3,3-pentamethylene glutaramic acid, toluene solvant 30 ~ 50 parts and 0.5 ~ 2 part, Glacial acetic acid, be heated to 50 ~ 60 DEG C of stirrings, reflux 12 ~ 15h at 110 ~ 120 DEG C, stop heating and being cooled to 18 ~ 20 DEG C, suction filtration obtains filter cake.
Preferably, in step (3), bake out temperature is 60 ~ 80 DEG C, and drying time is 1 ~ 3h.
Preferably, the detailed process of step (3) is: filter cake being joined concentration is stirring 3 hours of pulling an oar in 15% ammoniacal liquor 40 ~ 80 parts, suction filtration, the filter cake washed with de-ionized water that suction filtration is obtained, dry at 60 ~ 70 DEG C, obtain 3,3-pentamethylene glutarimide.
Beneficial effect of the present invention: a kind of preparation method of 3,3-pentamethylene glutarimide comprises the following steps: ammoniacal liquor adds in ammoniation kettle by (1), drips 1,1-hexamethylene diethyl acid anhydrides carries out aminating reaction, add sulfuric acid acidation, obtained 3,3-pentamethylene glutaramic acid; (2) in reactor, add described 3,3-pentamethylene glutaramic acids, toluene solvant and Glacial acetic acid, heated and stirred, backflow, cooling, suction filtration obtains filter cake; (3) filter cake is joined making beating in ammoniacal liquor to stir, suction filtration, by washed with de-ionized water, dry, obtain 3,3-pentamethylene glutarimide.3, the 3-pentamethylene glutarimide content that preparation method of the present invention obtains are 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 one 3, the 3-pentamethylene glutarimide of the present embodiment, comprises the following steps:
By mass parts, be that 10% ammoniacal liquor 50 parts adds in ammoniation kettle by concentration, at temperature is 18 DEG C, within 1 hour, drips 35 parts, 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction 2h, add activated carbon filtration, be the sulfuric acid acidation of 60% by concentration, centrifugal white crystals, dry, obtained 3,3-pentamethylene glutaramic acid;
Described 3 are added in reactor, 3-pentamethylene glutaramic acid, toluene solvant 30 parts and 0.5 part, Glacial acetic acid, be heated to 50 DEG C of stirrings, reflux 12h at 110 DEG C, stop heating and being cooled to 18 DEG C, suction filtration obtains filter cake, and filter cake being joined concentration is stirring 3 hours of pulling an oar in 15% ammoniacal liquor 40 parts, suction filtration, the filter cake washed with de-ionized water that suction filtration is obtained, at 60 DEG C, dry 1h, obtain 3,3-pentamethylene glutarimide.
Embodiment 2: the preparation method of one 3, the 3-pentamethylene glutarimide of the present embodiment, comprises the following steps:
By mass parts, be that 12% ammoniacal liquor 60 parts adds in ammoniation kettle by concentration, at temperature is 20 DEG C, within 1.5 hours, drips 40 parts, 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction 2.5h, add activated carbon filtration, be the sulfuric acid acidation of 60% by concentration, centrifugal white crystals, dry, obtained 3,3-pentamethylene glutaramic acid;
Described 3 are added in reactor, 3-pentamethylene glutaramic acid, toluene solvant 40 parts and 1 part, Glacial acetic acid, be heated to 55 DEG C of stirrings, reflux 13h at 120 DEG C, stop heating and being cooled to 18 DEG C, suction filtration obtains filter cake, and filter cake being joined concentration is stirring 3 hours of pulling an oar in 15% ammoniacal liquor 60 parts, suction filtration, the filter cake washed with de-ionized water that suction filtration is obtained, at 70 DEG C, dry 2h, obtain 3,3-pentamethylene glutarimide.
Embodiment 3: the preparation method of one 3, the 3-pentamethylene glutarimide of the present embodiment, comprises the following steps:
By mass parts, be that 12% ammoniacal liquor 80 parts adds in ammoniation kettle by concentration, at temperature is 20 DEG C, within 1.5 hours, drips 50 parts, 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction 3h, add activated carbon filtration, be the sulfuric acid acidation of 60% by concentration, centrifugal white crystals, dry, obtained 3,3-pentamethylene glutaramic acid;
Described 3 are added in reactor, 3-pentamethylene glutaramic acid, toluene solvant 50 parts and 2 parts, Glacial acetic acid, be heated to 60 DEG C of stirrings, reflux 15h at 120 DEG C, stop heating and being cooled to 20 DEG C, suction filtration obtains filter cake, and filter cake being joined concentration is stirring 3 hours of pulling an oar in 15% ammoniacal liquor 80 parts, suction filtration, the filter cake washed with de-ionized water that suction filtration is obtained, at 70 DEG C, dry 3h, obtain 3,3-pentamethylene glutarimide.
Embodiment 1 ~ 3 is obtained to 3,3-pentamethylene glutarimide and adopt 3,3-obtained pentamethylene glutarimides of background technology to carry out content and yield compares, result is as following table:
3, the 3-pentamethylene glutarimide 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 96%.
Preparation method's step of the present invention is simple, easy to operate, and 3,3-obtained pentamethylene glutarimide yields are 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 (8)
1. the preparation method of a pentamethylene glutarimide, is characterized in that, comprises the following steps:
(1) ammoniacal liquor is added in ammoniation kettle, drip 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction, add sulfuric acid acidation, obtained 3,3-pentamethylene glutaramic acid;
(2) in reactor, add described 3,3-pentamethylene glutaramic acids, toluene solvant and Glacial acetic acid, heated and stirred, backflow, cooling, suction filtration obtains filter cake;
(3) filter cake is joined making beating in ammoniacal liquor to stir, suction filtration, by washed with de-ionized water, dry, obtain 3,3-pentamethylene glutarimide.
2. preparation method according to claim 1, is characterized in that, step (1) ammonia concn is 8 ~ 12%.
3. preparation method according to claim 1, is characterized in that, step (1) the aminating reaction time is 2 ~ 3h.
4. preparation method according to claim 1, is characterized in that, step (1) detailed process is: by mass parts, ammoniacal liquor 50 ~ 80 parts is added in ammoniation kettle, at temperature is 18 ~ 20 DEG C, within 1 ~ 1.5 hour, drips 35 ~ 50 parts, 1,1-hexamethylene diethyl acid anhydrides and carry out aminating reaction, add activated carbon filtration, be the sulfuric acid acidation of 60% by concentration, centrifugal white crystals, dry, obtained 3,3-pentamethylene glutaramic acid.
5. preparation method according to claim 1, is characterized in that, in step (2), reflux temperature is 110 ~ 120 DEG C, and return time is 12 ~ 15h.
6. preparation method according to claim 1, it is characterized in that, step (2) detailed process is: in reactor, add described 3,3-pentamethylene glutaramic acid, toluene solvant 30 ~ 50 parts and 0.5 ~ 2 part, Glacial acetic acid, be heated to 50 ~ 60 DEG C of stirrings, at backflow 12 ~ 14h, stop heating and being cooled to 18 ~ 20 DEG C, suction filtration obtains filter cake.
7. preparation method according to claim 1, is characterized in that, in step (3), bake out temperature is 60 ~ 80 DEG C, and drying time is 1 ~ 3h.
8. preparation method according to claim 1, it is characterized in that, the detailed process of step (3) is: described filter cake being joined concentration is stirring 3 hours of pulling an oar in 15% ammoniacal liquor 40 ~ 80 parts, suction filtration, the filter cake washed with de-ionized water that suction filtration is obtained, dry at 60 ~ 70 DEG C, obtain 3,3-pentamethylene glutarimide.
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| CN201410696130.3A CN104447512A (en) | 2014-11-26 | 2014-11-26 | Preparation method of 3, 3-pentamethylene glutarimide |
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| CN201410696130.3A CN104447512A (en) | 2014-11-26 | 2014-11-26 | Preparation method of 3, 3-pentamethylene glutarimide |
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Cited By (2)
| 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 |
| CN112574100A (en) * | 2020-12-30 | 2021-03-30 | 南京德尔诺医药科技有限公司 | Preparation method of glutarimide derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1603295A (en) * | 2004-07-30 | 2005-04-06 | 常州天汁化工有限公司 | Process for preparing substituted glutaric anhydride |
| WO2012093411A2 (en) * | 2011-01-07 | 2012-07-12 | Dr Braja Sundar Pradhan | Process for the preparation of r-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid and the intermediates |
| CN103450080A (en) * | 2012-05-31 | 2013-12-18 | 盐城拜克化学工业有限公司 | Preparation method of 3,3-pentamethylene glutarimide |
-
2014
- 2014-11-26 CN CN201410696130.3A patent/CN104447512A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1603295A (en) * | 2004-07-30 | 2005-04-06 | 常州天汁化工有限公司 | Process for preparing substituted glutaric anhydride |
| WO2012093411A2 (en) * | 2011-01-07 | 2012-07-12 | Dr Braja Sundar Pradhan | Process for the preparation of r-(-)-3- (carbamoylmethyl)-5-methylhexanoic acid and the intermediates |
| CN103450080A (en) * | 2012-05-31 | 2013-12-18 | 盐城拜克化学工业有限公司 | Preparation method of 3,3-pentamethylene glutarimide |
Cited By (2)
| 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 |
| CN112574100A (en) * | 2020-12-30 | 2021-03-30 | 南京德尔诺医药科技有限公司 | Preparation method of glutarimide derivative |
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