CN101851192A - Method for synthesizing nimodipine by cyclic compounds as solvents - Google Patents
Method for synthesizing nimodipine by cyclic compounds as solvents Download PDFInfo
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- CN101851192A CN101851192A CN 201010204738 CN201010204738A CN101851192A CN 101851192 A CN101851192 A CN 101851192A CN 201010204738 CN201010204738 CN 201010204738 CN 201010204738 A CN201010204738 A CN 201010204738A CN 101851192 A CN101851192 A CN 101851192A
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Abstract
The invention discloses a method for synthesizing nimodipine finished products by cyclic compounds as solvents. The method comprises the following steps: using the cyclic compounds as the solvents for carrying out cyclization on 2-(m-nitryl methylene) isopropyl acetoacetate and amino crotonate to generate target products; distilling out the cyclic compounds; and adding isopropanol for recrystallization and refining to obtain the nimodipine, wherein the mol ratio of the cyclic compound solvents to the 2-(m-nitryl methylene) isopropyl acetoacetate is 2.5 to 4.6/1. The invention adopts the cyclic compounds as the solvents for replacing isopropanol which is different to be recovered and reused, and high-quality nimodipine finished products are obtained. The synthesis method of the invention has simple and convenient operation in industry, the solvents can be repeatedly recovered and reused, in addition, the reaction period is shortened, the quality of the finished products is greatly improved through being compared with the original process, at the same time, the energy sources and the work hour cost are saved, the work production rate is improved, and the invention is more favorable for large-scale industrial production.
Description
Technical field
The invention belongs to the organic chemistry synthesis technical field, relate to the preparation method of medicine intermediate, a kind of method of utilizing the synthetic nimodipine of cyclic compounds as solvents of saying so more specifically.
Background technology
Nimodipine is the dihydropyridine type calcium antagonists by Bayer A.G's research and development, diseases such as cerebral ischemia, neural function deficiency, senile dementia, sudden deafness and cerebrovascular insufficiency due to the clinical posthemorrhagic cerebral vasospasm of subarachnoid space that is used for the treatment of a variety of causes also have curative effect preferably to migraine.
Under the normal circumstances, the contraction of unstriated muscle depends on Ca
2+Enter in the cell, cause the depolarize of transmembrane current.Nimodipine is by stoping Ca effectively
2+Enter in the cell, suppress smooth muscle contraction, reach the purpose of removing vasospasm.Nimodipine is by the effect to neuronal acceptor relevant with calcium channel and cerebrovascular acceptor; the function of neuroprotective unit; improve cerebral blood supply; increase the ischemic tolerance of brain; this effect that studies show that in addition can not cause steal phenomenon; clinical global impression scoring, individual function obstacle, behavior observation and psychology test confirm that all nimodipine also has good effect to other type symptom.Experimentation on animals proves that nimodipine is many by force far beyond the effect of other position arteries of whole body to arteriocerebral effect, and because it has the very high fat characteristics of having a liking for, easily sees through hemato encephalic barrier.When being used for the hemorrhage treatment of subarachnoid space, the concentration in the cerebrospinal fluid can reach 12.5ng/ml.Inference can be used for preventing the posthemorrhagic vasospasm of subarachnoid space clinically thus, yet it is still unclear to use the mechanism of action of this medicine at human body.Still have protection in addition and promote the effect that memory, promotion intelligence are recovered.So optionally act on cerebrovascular unstriated muscle, expansion of cerebral vascular, the cerebral blood flow increasing amount significantly reduces the ischemic brain injury that vasospasm causes.
Nimodipine (nimodipine), Chinese is called 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-methoxyl group ethyl ester isopropyl ester.Nimodipine is a light yellow crystalline powder, and odorless is tasteless, and is easily molten in acetone, chloroform, in ethanol, dissolve, and slightly soluble in ether, insoluble in water.
Its structural formula is:
Synthetic method about nimodipine, according to existing technology, synthetic method is summarized as follows: obtain 2-(m-nitro fork base) ISOPROPYL ACETOACETATE by m-nitrobenzaldehyde and ISOPROPYL ACETOACETATE condensation, make with 3-amino-Ba Dousuan (2-methoxyl group) ethyl ester heating closed loop.Existing technology selected solvent when carrying out this of cyclization reaction is a Virahol in step, because Virahol and water dissolve each other, the water that generates in the reaction process can't be told, and produces impurity thereby side reaction takes place, the result is the too high levels that generates single impurity C, and final product quality and yield all have than great fluctuation process.The structural formula of impurity C is as shown in the figure:
We screen reaction solvent, mixed solvent method and direct solidification method through a large amount of experiments for this reason, have determined to use ring compound as reaction solvent at last, and its advantage is that reaction divides water fast, and solvent is recovery set usefulness all, and yield height and cost are low.
Summary of the invention
The objective of the invention is to improve the stability of nimodipine final product quality, a kind of method that adopts the synthetic nimodipine of cyclic compounds as solvents is provided, and guarantees the higher yield of product in order to shorten the reaction times.For achieving the above object, the invention provides following technical scheme:
A kind of method that adopts the synthetic nimodipine of cyclic compounds as solvents, it is characterized in that in the ring compound solvent, amino crotonate and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE are carried out cyclization, then the ring compound solvent is steamed to the greatest extent, use the Virahol recrystallization again, obtain nimodipine; Wherein the mol ratio of ring compound solvent and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE is 2.5～4.6: 1, and the mol ratio of amino crotonate and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE is 1.08～1.2: 1.
Synthetic method of the present invention, the mol ratio of wherein preferred ring compound solvent and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE is 2.5～4.6: 1, in 8～15 hours reaction times, is preferably 14 hours.Temperature of reaction is 80～150 ℃.
Synthetic method of the present invention after wherein condensation reaction is finished, is used the Virahol recrystallization, the refining nimodipine elaboration that obtains.
Ring compound solvent of the present invention refers to: toluene, dioxane, 1, pyridine or hexanaphthene.
The inventor explores the synthetic method of having determined this step through test repeatedly, and synthetic method is optimized on the basis of reference and inspection information, has shortened the reaction times, has reduced cost, has simplified operating process,
Ring compound of the present invention refers to that atom is often referred to organic compound with the compound of circular permutation in the molecule, as benzene.Several atoms are arranged in the ring, and this ring just claims " several units ring ".The number of " many rings " finger ring surpasses 1.For example, toluene, ethylbenzene, dioxane, 1, pyrimidine, pyrazine, pyrans, pyridine or hexanaphthene.
Organic synthesis send out should in, the ring compound solvent is compared with other organic solvents, has solvent toxicity than low two ranks of benzene, and equipment is not had any infringement, recyclable repeatedly the use.Product is easily separated, after reaction is finished, as long as distillation can be used repeatedly, does not have the characteristics of exhaust gas emission.
Another characteristics of the present invention are that reaction times with former Virahol technology was by original 23 hours, shorten to 8～15 hours, be preferably 14 hours, then the ring compound solvent is steamed to the greatest extent, use the Virahol dissolving-recrystallization again, nimodipine can effectively be separated with the impurity of generation, obtain high-quality nimodipine after making with extra care.
The selected ring compound solvent of the present invention has been avoided having improved final product quality because of the dissolve each other generation of the impurity C that obtains of Virahol and water.Product reaches BP and USP version standard simultaneously except that reaching 2010 editions standards of pharmacopoeia of China, and stable yield.
Reaction process of the present invention is as follows:
The characteristics that the synthetic method of nimodipine intermediate disclosed by the invention is had compared with prior art are:
(1) synthetic method of the present invention has shortened the reaction times, on industrial production the operation easier, solvent can reclaim use repeatedly, environmental protection helps large-scale industrial production.
(2) synthetic method of the present invention has improved final product quality, and product reaches BP and USP version standard simultaneously except that reaching 2010 editions standards of pharmacopoeia of China, and stable yield.
(3) the present invention has reduced the generation of side reaction, and the content of single impurity C is reduced in below 0.1%.
Embodiment
For simple and purpose clearly, hereinafter appropriate omission the description of known technology, in order to avoid those unnecessary details influences are to the description of the technical program.The present invention is described further below in conjunction with example.Amino crotonate that is wherein adopted and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE all has commercially available.
Preparation embodiment 1
With 50g 2-(m-nitro fork base) ISOPROPYL ACETOACETATE (0.18mol), the amino crotonate (0.195mol, 1.08 times) of 31g, 38ml ring compound (dioxane 0.45mol, 2.5 times) drops in the reaction flask, 113～115 ℃ of temperature of reaction, refluxed 14 hours, solvent evaporated is steamed to 130 ℃ in decompression, then with 140ml Virahol dissolving 1 hour, behind the backflow recrystallization, obtain nimodipine elaboration light yellow crystalline powder 66g, yield 87.47%.The content 0.12% of single impurity C.
Preparation embodiment 2
With 50g 2-(m-nitro fork base) ISOPROPYL ACETOACETATE (0.18mol), amino crotonate (0.198mol, 1.1 times) 62ml ring compound (the toluene 0.58mol of 31.48g, 3.2 doubly), drop in the reaction flask 120 ℃ of temperature of reaction, refluxed 15 hours, decompression is steamed to 130 ℃, and solvent evaporated is then with 140ml Virahol dissolving 2 hours, behind the backflow recrystallization, obtain nimodipine elaboration light yellow crystalline powder 64g, yield 84.82%, the content 0.10% of single impurity C.
Preparation embodiment 3
With 50g 2-(m-nitro fork base) ISOPROPYL ACETOACETATE (0.18mol), the amino crotonate (0.198mol, 1.1 times) of 31.48g, 64ml ring compound (1 0.68mol, 3.8 times), drop in the reaction flask, 86 ℃ of temperature of reaction refluxed 10 hours, and decompression is steamed to 130 ℃, solvent evaporated, with behind the 140ml Virahol dissolving backflow recrystallization, obtain nimodipine elaboration light yellow crystalline powder 61g, yield 80.84% then.The content 0.14% of single impurity C.
Preparation embodiment 4
With 100g 2-(m-nitro fork base) ISOPROPYL ACETOACETATE (0.36mol), the amino crotonate (0.43mol, 1.2 times) of 68g, 165ml ring compound (hexanaphthene 1.5mol, 4.2 doubly), drop in the reaction flask 80 ℃ of temperature of reaction, refluxed 14 hours, decompression is steamed to 90 ℃, and solvent evaporated is then with behind the 280ml Virahol dissolving backflow recrystallization, obtain nimodipine elaboration light yellow crystalline powder 132g, yield 87.47%.The content 0.09% of single impurity C.
Preparation embodiment 5
With 50g 2-(m-nitro fork base) ISOPROPYL ACETOACETATE (0.18mol), the amino crotonate (0.2mol, 1.2 times) of 34g, 67ml ring compound (pyridine 0.83mol, 4.6 doubly), drop in the reaction flask 116 ℃ of temperature of reaction, refluxed 12 hours, decompression is steamed to 130 ℃, and solvent evaporated is then with behind the 140ml Virahol dissolving backflow recrystallization, obtain nimodipine elaboration light yellow crystalline powder 63g, yield 83.49%.The content 0.14% of single impurity C.
Nimodipine nuclear magnetic data: 1HNMR (CDCl
3) δ: 1.09 (d, J=6.2Hz, 3H), 1.26 (d, J=6.2Hz, 3H), 2.36 (s, 6H), 3.54 (m, 2H), 4.17 (m, 2H), 4.93 (m, 1H), 5.09 (s, 1H), 5.70 (s, 1H), 7.39 (dd, J=7.9and 7.8Hz, 1H), 7.67 (dd, J=7.7and 1.1Hz, 1H), 8.01 (m, 1H), 8.13 (m, 1H).
MS data: Mass spectrum m/z 418.9 (M+H)
+.
The structure warp of nimodipine
1H-NMR, MS spectrogram are confirmed consistent with bibliographical information.
Reference:
[1] Chen Xin, Gao Yaping, Huang Wenlong, etc. synthetic [J] of calcium antagonist nimodipine. Chinese Journal of Pharmaceuticals, 1989,20 (2): 52-53.
[2] Bao Chun and, Chen Ziming, Du Yuming. the improvement of nimodipine synthesis technique [J]. Chinese Journal of Pharmaceuticals, 1996,27 (7): 295-296.
[3]Meyer?H，Wehinger?E，Bossert?F，et?al.Nimodipine：synthesis?and?Metabolic?pathway[J].Arzneim-Forsch，1983，33(1)：106-112.
[4] Wu Sumin, Song Ming, Hua Feng, Hua Weiyi. the synthesis technique of nimodipine improves [J]. China Medicine University's journal, 1998,29 (3): 232-233
[5]Bocker?RH?et?al：J?Med?Chem?1986.29：1696。
Claims (4)
1. method that adopts the synthetic nimodipine of cyclic compounds as solvents, it is characterized in that in the ring compound solvent, amino crotonate and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE are carried out cyclization, then the ring compound solvent is steamed to the greatest extent, use the Virahol recrystallization again, obtain nimodipine; Wherein the mol ratio of ring compound solvent and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE is 2.5～4.6: 1, and the mol ratio of amino crotonate and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE is 1.08～1.2: 1.
2. the described synthetic method of claim 1, wherein the mol ratio of ring compound solvent and 2-(m-nitro fork base) ISOPROPYL ACETOACETATE is 2.5～4.6: 1, in 8～15 hours reaction times, temperature of reaction is 80～150 ℃.
3. the described synthetic method of claim 1 after wherein condensation reaction is finished, is used the Virahol recrystallization, the refining nimodipine elaboration that obtains.
4. each described synthetic method of claim 1-3, wherein the ring compound solvent refers to: toluene, dioxane, 1, pyridine or hexanaphthene.
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| CN 201010204738 CN101851192A (en) | 2010-06-22 | 2010-06-22 | Method for synthesizing nimodipine by cyclic compounds as solvents |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102174012A (en) * | 2011-03-11 | 2011-09-07 | 山东新华制药股份有限公司 | Preparation method of nimodipine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4672068A (en) * | 1984-05-04 | 1987-06-09 | Fujirebio Kabushiki Kaisha | Antihypertensive 1,4-dihydropyridines having a conjugated ester |
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2010
- 2010-06-22 CN CN 201010204738 patent/CN101851192A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4672068A (en) * | 1984-05-04 | 1987-06-09 | Fujirebio Kabushiki Kaisha | Antihypertensive 1,4-dihydropyridines having a conjugated ester |
Non-Patent Citations (1)
| Title |
|---|
| 《中国药科大学学报》 19981231 吴苏敏等 尼莫地平的合成工艺改进 232-233 1-4 第29卷, 第3期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102174012A (en) * | 2011-03-11 | 2011-09-07 | 山东新华制药股份有限公司 | Preparation method of nimodipine |
| CN102174012B (en) * | 2011-03-11 | 2013-03-20 | 山东新华制药股份有限公司 | Preparation method of nimodipine |
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Open date: 20101006 |