CN102093289A - New preparation method of Blonanserin intermediate - Google Patents
New preparation method of Blonanserin intermediate Download PDFInfo
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- CN102093289A CN102093289A CN 201010529748 CN201010529748A CN102093289A CN 102093289 A CN102093289 A CN 102093289A CN 201010529748 CN201010529748 CN 201010529748 CN 201010529748 A CN201010529748 A CN 201010529748A CN 102093289 A CN102093289 A CN 102093289A
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Abstract
The invention discloses a new preparation method of a Blonanserin intermediate. In the method, 4-fluorobenzoylacetonitrile reacts with cyclooctanone to generate 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta pyridine-2(1H)-ketone at a high yield in the presence of a catalyst.
Description
Technical field
The present invention relates to the novel preparation method of blonanserin intermediate 4-(4-fluorophenyl)-5,6,7,8,9,10 ,-six hydrogen cyclooctane and pyridine-2 (1H)-ketone (I).
Background technology
The described blonanserin intermediate of this specification sheets is meant 4-(4-fluorophenyl)-5,6,7,8,9,10,-six hydrogen cyclooctane and pyridine-2 (1H)-ketone (I), this compound be a new generation anti-schizophrenia medicine blonanserin (Blonanserin) building-up process in key intermediate.
JP4099768A and EP0385237 have reported the synthetic method of formula I compound, this method is with 4-fluorobenzoyl acetonitrile (II) and cyclooctanone (III), and 120 ℃ of reactions, the bibliographical information yield is 60% in the presence of polyphosphoric acid, but prepare 4-(4-fluorophenyl)-5 by literature method through the inventor, 6,7,8,9,10 ,-six hydrogen cyclooctane and pyridine-2 (1H)-ketone (I), yield only are about 18%.And to use a large amount of polyphosphoric acid, produce a large amount of waste water, trivial operations.
CN 101747273A discloses the synthetic method of formula I, and reaction will be carried out in two steps, and will use a large amount of polyphosphoric acid, complicated operation.See following reaction formula:
Summary of the invention
Because the preparation method's yield shown in JP4099768A and the EP0385237 is lower, preparation method's step shown in the CN 101747273A is longer, and all to use a large amount of polyphosphoric acid, the synthetic method that be necessary to develop a kind of economic environmental protection, is fit to suitability for industrialized production, this patent is by a large amount of experiments, and we have developed the method for a kind of high yield, easy handling, oligosaprobic synthetic compound of formula i.Row reaction formula as follows:
According to the present invention, above-mentioned steps is the composition of the vitriol oil or other available strong acid and tosic acid at the catalyzer of using; The adding mode can add for mixing, adding reaction system that also can be in no particular order.
According to the present invention, catalyzer and 4-fluorobenzoyl acetonitrile (II) charge ratio are 0.1～5.Comparative optimization be 0.5～3.
According to the present invention, the charge ratio of the vitriol oil or other available strong acid and tosic acid is 0.01～2 in the catalyzer.Comparative optimization be 0.1～1.
According to the present invention, the catalyzer comparative optimization be the vitriol oil and tosic acid.
According to the present invention, temperature of reaction is 50～130 ℃, is preferably 70 ℃ of reflux temperatures to selected solvent.
According to the present invention, the reaction times is 1～15 hour.Be preferably 1～5 hour.
According to the present invention, reaction is not adopted solvent or is used organic solvent and is: a kind of in the benzene,toluene,xylene or the composition of several solvents wherein.The reaction preferred solvent is a toluene.
The present invention compared with prior art,
1, the present invention uses the common catalyzer that is easy to get of technical grade, avoids using the polyphosphoric acid more than 10 times of amounts, comparatively economic environmental protection.
2, reactions steps of the present invention is simple, and aftertreatment is simple, and yield is higher, can reach about 80%, relatively is fit to suitability for industrialized production.
Embodiment
Following examples only are to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1
Drop into toluene 100ml in the reaction flask, to fluorobenzoyl acetonitrile (II) 5g, cyclooctanone (III) 5g and tosic acid 5g, vitriol oil 5ml, heated and stirred refluxed 3 hours for about 110 ℃, in after control reacts completely, add water washing, extract layering, the organic layer decolouring concentrate crystal 6 .8g.Yield 82%, purity 98.4%, 236～238 ℃ of fusing points.
Embodiment 2
Drop into toluene 150ml, tosic acid 10g, heated and stirred in the reaction flask, continue to add to fluorobenzoyl acetonitrile 5g, cyclooctanone 5g and vitriol oil 5ml, refluxed 3 hours about 110 ℃, after middle control reacts completely, add water washing, extract layering, the organic layer decolouring concentrate crystal 7g.Yield 85%, purity 98.5%, 236～238 ℃ of fusing points.
Claims (8)
1. blonanserin intermediates preparation, its feature comprises following reactions steps: 4-fluorobenzoyl acetonitrile (II) and cyclooctanone (III) closed loop in the presence of catalyzer generates 4-(4-fluorophenyl)-5,6,7,8,9,10 ,-six hydrogen cyclooctane and pyridine-2 (1H)-ketone (I).
2. according to the preparation method shown in the claim 1, it is characterized in that catalyzer is the composition of the vitriol oil or other available strong acid and tosic acid; The adding mode can add for mixing, adding reaction system that also can be in no particular order.
3. according to the preparation method shown in the claim 1, it is characterized in that catalyzer and 4-fluorobenzoyl acetonitrile (II) quality charge ratio are 0.1～5.Comparative optimization be 0.5～3.
4. according to the preparation method shown in the claim 2, it is characterized in that the quality charge ratio of the vitriol oil or other available strong acid and tosic acid is 0.01～2 in the catalyzer.Comparative optimization be 0.1～1.
5. according to the preparation method shown in the claim 2, it is characterized in that, the catalyzer comparative optimization be the vitriol oil and tosic acid.
6. according to the preparation method shown in the claim 1, it is characterized in that temperature of reaction is 50～130 ℃, be preferably 70 ℃ of reflux temperatures to selected solvent.
7. according to the preparation method shown in the claim 1, it is characterized in that the reaction times is 1～15 hour.Be preferably 1～5 hour.
8. according to the preparation method shown in the claim 7, it is characterized in that reaction is not adopted solvent or used organic solvent and is: a kind of in the benzene,toluene,xylene or the composition of several solvents wherein.The reaction preferred solvent is a toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 201010529748 CN102093289B (en) | 2010-10-29 | 2010-10-29 | New preparation method of Blonanserin intermediate |
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| CN 201010529748 CN102093289B (en) | 2010-10-29 | 2010-10-29 | New preparation method of Blonanserin intermediate |
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| CN102093289A true CN102093289A (en) | 2011-06-15 |
| CN102093289B CN102093289B (en) | 2012-12-19 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102297911A (en) * | 2011-08-10 | 2011-12-28 | 江苏万全特创医药生物技术有限公司 | High efficiency liquid chromatography method for separating blonanserin intermediate III from other intermediates |
| CN102297910A (en) * | 2011-08-10 | 2011-12-28 | 江苏万全特创医药生物技术有限公司 | Separation method of blonanserin intermediate IV and other intermediates by high performance liquid chromatography |
| WO2016076573A3 (en) * | 2014-11-11 | 2016-09-15 | 연성정밀화학(주) | Method for preparing blonanserin and intermediate therefor |
| CN106045909A (en) * | 2016-06-08 | 2016-10-26 | 南京远淑医药科技有限公司 | Synthetic method for Blonanserin |
| JP2018043989A (en) * | 2016-09-14 | 2018-03-22 | ルンドベック ファーマシューティカルズ イタリー ソシエタ ペル アチオニ | Method of producing blonanserin |
| CN113527205A (en) * | 2021-08-20 | 2021-10-22 | 湖南省湘中制药有限公司 | Preparation method of blonanserin intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0385237A2 (en) * | 1989-03-03 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
| CN101747273A (en) * | 2008-12-02 | 2010-06-23 | 浙江华海药业股份有限公司 | Preparing method of blonanserin intermediate |
-
2010
- 2010-10-29 CN CN 201010529748 patent/CN102093289B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0385237A2 (en) * | 1989-03-03 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
| CN101747273A (en) * | 2008-12-02 | 2010-06-23 | 浙江华海药业股份有限公司 | Preparing method of blonanserin intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 《科教文汇（中旬刊）》 20071231 王晓洁等 抗精神分裂症药布南色林的合成 第219页 1,6-8 , 第12期 2 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102297911A (en) * | 2011-08-10 | 2011-12-28 | 江苏万全特创医药生物技术有限公司 | High efficiency liquid chromatography method for separating blonanserin intermediate III from other intermediates |
| CN102297910A (en) * | 2011-08-10 | 2011-12-28 | 江苏万全特创医药生物技术有限公司 | Separation method of blonanserin intermediate IV and other intermediates by high performance liquid chromatography |
| CN102297911B (en) * | 2011-08-10 | 2012-12-12 | 江苏万全特创医药生物技术有限公司 | High efficiency liquid chromatography method for separating blonanserin intermediate III from other intermediates |
| CN102297910B (en) * | 2011-08-10 | 2012-12-12 | 江苏万全特创医药生物技术有限公司 | Separation method of blonanserin intermediate IV and other intermediates by high performance liquid chromatography |
| WO2016076573A3 (en) * | 2014-11-11 | 2016-09-15 | 연성정밀화학(주) | Method for preparing blonanserin and intermediate therefor |
| CN106045909A (en) * | 2016-06-08 | 2016-10-26 | 南京远淑医药科技有限公司 | Synthetic method for Blonanserin |
| JP2018043989A (en) * | 2016-09-14 | 2018-03-22 | ルンドベック ファーマシューティカルズ イタリー ソシエタ ペル アチオニ | Method of producing blonanserin |
| CN113527205A (en) * | 2021-08-20 | 2021-10-22 | 湖南省湘中制药有限公司 | Preparation method of blonanserin intermediate |
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| CN102093289B (en) | 2012-12-19 |
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