CN103467369B - The preparation method of nimodipine impurity I - Google Patents

The preparation method of nimodipine impurity I Download PDF

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Publication number
CN103467369B
CN103467369B CN201310464944.XA CN201310464944A CN103467369B CN 103467369 B CN103467369 B CN 103467369B CN 201310464944 A CN201310464944 A CN 201310464944A CN 103467369 B CN103467369 B CN 103467369B
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nimodipine
impurity
add
suction filtration
yellow oil
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CN103467369A (en
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张博
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Shandong Xinhua Pharmaceutical Co Ltd
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Shandong Xinhua Pharmaceutical Co Ltd
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Abstract

The invention discloses a kind of preparation method of nimodipine impurity I, belong to pharmaceutical technology sectors.Preparation method of the present invention, adopts nimodipine dehydrogenation oxidation method, comprises the following steps: be dissolved in by nimodipine in solvent, add oxygenant, back flow reaction, add activated carbon decolorizing, steams and desolventizes, obtain yellow oil nimodipine impurity I after suction filtration; Highly purified nimodipine impurity I is prepared by chemical synthesis process, pharmacology and the toxicological study of impurity I can be further used for, to nimodipine product impurity side effect research sampling support, simultaneously can as nimodipine related substance HPLC analysis impurity working standard.

Description

The preparation method of nimodipine impurity I
Technical field
The present invention relates to the preparation method of nimodipine impurity I.
Background technology
Nimodipine (Nimodipine), has another name called that sharp class enlightening is flat, nimodipine, chemistry sec.-propyl-2-methoxyethyl-1 by name, 4-dihydro-2,6-dimethyl-4(3-nitrophenyl)-3,5-pyridine dicarboxylates, it is s-generation Isosorbide-5-Nitrae-dihydropyridine calcium channel antagonist.For selectively acting is in cerebrovascular Ca2+ overloading vasodilator, can effectively control intracellular calcium content.Be mainly used in the functional disorders of brain that apoplexy migraine, cerebral vasospasm, vascular dementia, sudden deafness, multiple ischemic cerebrovascular disease, dysmnesia disease and a variety of causes cause clinically.
Nimodipine impurity I (European Pharmacopoeia is defined as impurity A) its structural formula of Chinese Pharmacopoeia 2010 editions definition is:
Chemistry 2,6-dimethyl-4-(3-nitrophenyl by name)-3,5-dinicotinic acid-2-methoxyimino acetic acid isopropyl esters, there is liver renal toxicity, Chinese Pharmacopoeia 2010 editions and European Pharmacopoeia 7.0 editions control overflow≤0.1% to this impurity.
The synthetic method of existing bibliographical information impurity I is: get nimodipine raw material anhydrous alcohol solution, removes solvent under reduced pressure, column chromatography for separation under ultraviolet after long-time irradiation, and it is impurity I that collection component obtains red oil, productive rate 54%.But we are through test conditions duplicate acknowledgment, the reaction of this ultraviolet degradation is carried out very slow, and irradiate 1 time-of-week, TLC analysing impurity I only transforms about 10%, cannot prepare pure impurity I.Therefore, ultraviolet degradation method speed of response is slow, and low conversion rate, is not suitable for the preparation of impurity I standard substance.
Summary of the invention
The object of this invention is to provide a kind of high purity of nimodipine impurity I, high conversion, fast preparation method.
The preparation method of nimodipine impurity I of the present invention, adopt nimodipine dehydrogenation oxidation method, step comprises: be dissolved in solvent by nimodipine raw material, add oxygenant, back flow reaction, add activated carbon decolorizing, steam after suction filtration and desolventize, obtain yellow oil nimodipine impurity I.
Described solvent is the one in benzene, toluene, hexanaphthene or isobutyl acetate, preferred toluene;
Described nimodipine and the weight ratio of solvent are 1: 10 ~ 20;
Described back flow reaction temperature is 60 ~ 130 DEG C, preferably 105 ~ 110 DEG C; Reflux time is 1 ~ 6 hour, preferably 2 ~ 3 hours;
Described oxygenant is the one in Manganse Dioxide, nitric acid or hydrogen peroxide, preferred Manganse Dioxide; The mol ratio of nimodipine and oxygenant is 1: 2 ~ 6, preferably 1: 4;
The weight ratio of nimodipine and gac is 1: 0.2 ~ 0.7, preferably 1: 0.5.
Compared with prior art, the present invention has following beneficial effect:
By selecting suitable dehydrogenation oxidation agent, make the unsaturated fused heterocycle dehydroaromatizationof of nimodipine generate fused heterocycle aromatic hydrocarbons, and can not affect other oxidizable group, for preparing, impurity I is more satisfactory;
This method yield can reach more than 95%, HPLC content can reach more than 98%;
Highly purified nimodipine impurity I is prepared by chemical synthesis process, pharmacology and the toxicological study of impurity I can be further used for, to nimodipine product impurity side effect research sampling support, simultaneously can as nimodipine related substance HPLC analysis impurity working standard.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
Add nimodipine (20.9g being equipped with in thermometer, reflux condensing tube and churned mechanically reaction flask, 0.05mol), Manganse Dioxide (17.4g, 0.2mol) and 300ml benzene, be warming up to backflow under stirring, 78 ~ 81 DEG C of back flow reaction 2h, add gac 10g again, insulation backflow 30min, suction filtration obtains light yellow filtered liquid, underpressure distillation steams benzene, obtain pale yellow oil 19.2g, yield 92%, content 98.2%.
Embodiment 2
Add nimodipine (20.9g being equipped with in thermometer, reflux condensing tube and churned mechanically reaction flask, 0.05mol), Manganse Dioxide (17.4g, 0.2mol) and 300ml toluene, be warming up to backflow under stirring, 105 ~ 110 DEG C of back flow reaction 2h, add gac 10g again, insulation backflow 30min, suction filtration obtains light yellow filtered liquid, underpressure distillation steams toluene, obtain pale yellow oil 20.2g, yield 97%, content 98.9%.
Embodiment 3
Add nimodipine (20.9g being equipped with in thermometer, reflux condensing tube and churned mechanically reaction flask, 0.05mol), nitric acid (12.6g, 0.2mol) and 350ml hexanaphthene, be warming up to backflow under stirring, 78 ~ 81 DEG C of back flow reaction 2h, add gac 10g again, insulation backflow 30min, suction filtration obtains light yellow filtered liquid, underpressure distillation steams hexanaphthene, obtain pale yellow oil 17.7g, yield 85%, content 90.5%.
Embodiment 4
Add nimodipine (20.9g being equipped with in thermometer, reflux condensing tube and churned mechanically reaction flask, 0.05mol), hydrogen peroxide (scale 6.8g, 0.2mol) and 350ml isobutyl acetate, be warming up to backflow under stirring, 115 ~ 118 DEG C of back flow reaction 3h, add gac 10g again, insulation backflow 30min, suction filtration obtains light yellow filtered liquid, underpressure distillation steams isobutyl acetate, obtain pale yellow oil 18.9g, yield 91%, content 89.2%.

Claims (1)

1. the preparation method of a nimodipine impurity I, it is characterized in that: add nimodipine 20.9g, hydrogen peroxide 6.8g being equipped with in thermometer, reflux condensing tube and churned mechanically reaction flask, and 350ml isobutyl acetate, be warming up to backflow under stirring, 115 ~ 118 DEG C of back flow reaction 3h, add gac 10g again, insulation backflow 30min, suction filtration obtains light yellow filtered liquid, underpressure distillation steams isobutyl acetate, obtain pale yellow oil 18.9g, yield 91%, content 89.2%;
The structural formula of described nimodipine impurity I is as follows:
CN201310464944.XA 2013-09-30 2013-09-30 The preparation method of nimodipine impurity I Active CN103467369B (en)

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CN110511180A (en) * 2019-06-12 2019-11-29 北京鑫开元医药科技有限公司 A kind of Preparation method and use of pyridine derivate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998007698A1 (en) * 1996-08-23 1998-02-26 Lusochimica S.P.A. A process for the preparation of dihydropyridines
US20080125595A1 (en) * 2006-11-28 2008-05-29 Navinta Llc. Processes of manufacturing substituted-1,4-dihydropyridines, improved aqueous solutions thereof, and processes of manufacturing the solutions
CN102174012A (en) * 2011-03-11 2011-09-07 山东新华制药股份有限公司 Preparation method of nimodipine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998007698A1 (en) * 1996-08-23 1998-02-26 Lusochimica S.P.A. A process for the preparation of dihydropyridines
US20080125595A1 (en) * 2006-11-28 2008-05-29 Navinta Llc. Processes of manufacturing substituted-1,4-dihydropyridines, improved aqueous solutions thereof, and processes of manufacturing the solutions
CN102174012A (en) * 2011-03-11 2011-09-07 山东新华制药股份有限公司 Preparation method of nimodipine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Oxidation of 4-Aryl- and 4-Alkyl-Substituted 2,6-Dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihidropyridines by Human Liver Microsomes and Immunochemical Evidence for the Involvement of a Form of Cytochrome P-450;Ronald H. Bocker,等;《Journal of Medicinal Chemistry》;19861231;第29卷(第9期);第1596-1603页 *
尼莫地平欧洲药典杂质合成与生产过程杂质控制;张博;《山东大学硕士学位论文》;20130515;第23-24页第3.1.3.1节 *

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