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A kind of preparation method of cilnidipine

A technology of cilnidipine and concentrated hydrochloric acid, which is applied in the field of preparation of cilnidipine, can solve the problems of not very good purity of finished cilnidipine, high single and total impurities, and achieve less single and total impurities and short synthesis time , Reasonable effect of process design

Inactive Publication Date: 2018-04-20
芮城县虹桥药用中间体有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] For the above two methods, only the basic process and very few product performance data are recorded in the literature reports, and the purity of the finished product cilnidipine is not very good, and the single and total impurities are high, so the process needs to be improved.

Method used

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  • A kind of preparation method of cilnidipine
  • A kind of preparation method of cilnidipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] To prepare cilnidipine follow the steps below:

[0035] 1. In a 250ml bottle, put in material a: methoxyethyl 2-(3-nitrophenylidene)acetoacetate (54g, 0.184mol) and material b: cinnamyl 3-amino-2-butenoate (40g, 0.184mol) and absolute ethanol (80g), warming up to reflux for 1 hour;

[0036] 2. Add 3.68 ml of concentrated hydrochloric acid (>35%) to the reaction system in step 1, continue to reflux for 1 hour, then cool and crystallize, and filter to obtain the crude product of cilnidipine;

[0037] Crude yield: 80.7g

[0038] Yield 88.98%,

[0039] M.P.: 106.1~106.7℃

[0040] Maximum simple impurity: 0.2%

[0041] A total of 10 small impurity peaks

[0042] Content: 99.25%

[0043] 3. According to the weight ratio of ethanol:crude product=3:1, use absolute ethanol to recrystallize the crude product cilnidipine obtained in step 2 to obtain the finished product cilnidipine.

[0044] Yield 91.3%,

[0045] M.P.: 107.2~108.1℃

[0046] Maximum Simplex: 0.1380%

[00...

Embodiment 2

[0051] To prepare cilnidipine follow the steps below:

[0052] 1. In a 2500ml bottle, put in material a: 2-(3-nitrophenylidene) methoxyethyl acetoacetate (432g, 1.47mol) and material b: cinnamyl 3-amino-2-butenoate (400g, 1.84mol) and n-butanol (800g), warming up and refluxing for 0.5 hours;

[0053] 2. Add 46 ml of concentrated hydrochloric acid (>35%) to the reaction system in step 1, continue to reflux for 0.5 hours, then cool and crystallize, and filter to obtain the crude product of cilnidipine;

[0054] Crude product yield: 618g

[0055] Yield 85.19%,

[0056] M.P.: 107.2~107.9℃

[0057] Maximum Simplex: 0.28%

[0058] A total of 12 small impurity peaks

[0059] Content: 98.56%

[0060] 3. According to the weight ratio of ethanol:crude product=3:1, use absolute ethanol to recrystallize the crude product cilnidipine obtained in step 2 to obtain the finished product cilnidipine.

[0061] Yield 89.8%,

[0062] M.P.: 107.1~108.0℃

[0063] Maximum Simplex: 0.1380%

[...

Embodiment 3

[0068] To prepare cilnidipine follow the steps below:

[0069] 1. In a 500ml bottle, put in material a: methoxyethyl 2-(3-nitrophenylidene)acetoacetate (65g, 0.221mol) and material b: cinnamyl 3-amino-2-butenoate (40g, 0.184mol) and tetrahydrofuran (90g), heated and refluxed for 2 hours;

[0070] 2. Add 2.76 ml of concentrated hydrochloric acid (>35%) to the reaction system in step 1, continue to reflux for 3 hours, then cool and crystallize, and filter to obtain the crude product of cilnidipine;

[0071] Received product: 77.8g

[0072] Yield 85.78%,

[0073] M.P.: 106.0~106.8℃

[0074] Maximum Simplex: 0.27%

[0075] A total of 11 small impurity peaks

[0076] Content: 99.21%

[0077] 3. According to the weight ratio of ethanol:crude product=3:1, use absolute ethanol to recrystallize the crude product cilnidipine obtained in step 2 to obtain the finished product cilnidipine.

[0078] Yield 87.5%,

[0079] M.P.: 107.4~108.2℃

[0080] Maximum Simplex: 0.1460%

[0081...

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Abstract

The invention provides a cilnidipine preparation method. The method includes the steps that 2-(3-nitrophenyl methylidene) methoxyethyl acetoacetate and 3-amino-2-butenoic acid cinnamyl ester serve as reaction raw materials and react under catalysis of concentrated hydrochloric acid to obtain cilnidipine. A common inorganic catalyst is adopted in the method for catalysis reaction so that reaction time can be effectively shortened; besides, quality of a crude product is high, the yield is high, and cilnidipine has metallic luster. The requirement for refining of reaction is low. Purity of the crude product is good, and the quality requirement can be basically met through one time of refining. The technology is reasonable in design, purity of the refined cilnidipine product is high, and the quantity of any impurity and total impurities is small.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of cilnidipine. Background technique [0002] Cilnidipine (cilnid ipine), the chemical name is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-2-methoxy Ethyl (E)-cinnamyl ester, which belongs to 1,4-dihydropyridine calcium antagonists, was developed by Japan Fuji Co., Ltd., and was first listed in Japan in December 1995. Cilnidipine is a third-generation dual-channel dihydropyridine calcium channel blocker. In addition to having the L channel blocking effect of most calcium channel blockers, it also acts on the N channel of peripheral nerves. It will not cause increased heart rate after blood pressure reduction and the boosting response of baroreceptors to acute cold stimulation, thus becoming a new type of calcium channel blocker with unique pharmacological effects. Cinidipine is a new calcium antagonist with both L-type and N-t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
CPCC07B2200/13C07D211/90
Inventor 董小林赵万祥张伟华
Owner 芮城县虹桥药用中间体有限公司