Preparation process of hypotensive drug optically pure cilnidipine
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A preparation process and technology of cilnidipine are applied in the field of chiral drug synthesis to achieve the effect of simple process steps and suitability for industrial production
Inactive Publication Date: 2018-04-06
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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[0005] Due to the unique and interesting biological effects of chiral drugs, the drug molecule of cilnidipine contains a chiral center, but the single chiral compound of cilnidipine has not been extensively studied
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Embodiment 1
[0028] In a round bottom flask, add cyanoethyl acetoacetate 1.7g (11mmol), m-nitrobenzaldehyde 1.51g (10mmol) and 3-amino-2-butenoic acid methoxyethyl ester 1.91g (12mmol), (S)-BINAP 0.31g (0.5mmol), ferric bromide 1.18g (4mmol) and 30ml of isopropanol, heated to 50°C for 6 hours of contact reaction, after the reaction was completed, concentrated under reduced pressure, and recrystallized from n-hexane Dry to give (R)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-3-(2-cyanoethyl ester )-5-(2-methoxyethyl ester) 2.8g, yield 65.2%, ee value 99.49%.
Embodiment 2
[0030] In a round bottom flask, add cyanoethyl acetoacetate 1.86g (12mmol), m-nitrobenzaldehyde 1.51g (10mmol) and 3-amino-2-butenoic acid methoxyethyl ester 1.91g (12mmol), (S)-BINAP 0.62g (1mmol), ferric chloride ferric chloride 0.32g (2mmol) and 30ml of isopropanol, heated to 60 ° C contact reaction for 6 hours, after the reaction was completed, concentrated under reduced pressure, and dried by n-hexane recrystallization Obtain (R)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-3-(2-cyanoethyl ester) -5-(2-methoxyethyl ester) 2.75g, yield 64.1%, ee value 99.37%.
Embodiment 3
[0032] In a round bottom flask, add cyanoethyl acetoacetate 1.7g (11mmol), m-nitrobenzaldehyde 1.51g (10mmol) and 3-amino-2-butenoic acid methoxyethyl ester 1.75g (11mmol) , (S)-BINAP 0.93g (1.5mmol), ferric compound ferric bromide 0.89g (3mmol) and 30ml of isopropanol, heated up to 40 ℃ contact reaction for 8 hours, the reaction was completed, concentrated under reduced pressure, and weighed in n-hexane Crystallization was dried to obtain (R)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-3-(2-cyanoethyl Ester)-5-(2-methoxyethyl ester) 2.8g, yield 65.3%, ee value 99.47%.
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Abstract
The invention discloses a preparation process of a hypotensive drug optically pure cilnidipine. The preparation process comprises the following steps: 1) in the presence of (S)-BINAP and a ferric ironcompound, adding ethyl cyano acetoacetate, m-nitrobenzaldehyde and 3-amino-2-methoxyethyl butenoate into isopropanol to react to obtain (R)-1,4-dihydro-2,6-dimethul-4-(3-nitryl phenyl)-3,5-dipicolinic acid-3-(2-cyano ethyl ester)-5-(2-methoxyl ethyl ester); 2) stirring the product in a tetrahydrofuran aqueous solution of alkali to react to obtain (R)-1,4-dihydro-2,6-dimethyl-4-(3-nitryl phenyl)-3,5-dipicolinic acid-5-(2-methoxyl ethyl ester); and 3) carrying out an esterification reaction with cinnamyl alcohol to obtain the optically pure (R)-cilnidipine. The three-step yield of the (R)-cilnidipine reaches up to 41%, ee% reaches up to 99.5%, and the preparation process is simple and suitable for industrial production.
Description
technical field [0001] The invention belongs to the field of chiral drug synthesis, and in particular relates to a preparation method of (R)-cilnidipine. Background technique [0002] Hypertension is the most common new cerebrovascular disease in the world. In recent years, surveys on the situation of hypertension in my country have shown that there are more than 100 million hypertensive patients in my country, and 3.5 million new hypertensive patients are added every year. Hypertension not only has a high prevalence rate, but also often causes heart, brain, and kidney complications. It is the main risk factor for stroke and coronary heart disease, and has become the primary factor causing human death. [0003] Cilnidipine was listed as an antihypertensive drug in 1996. It is a long-acting 1,4-dihydropyridine calcium channel antagonist (the specific chemical structure is as follows). The drug was developed by Fujirebio in Japan in the form of racemate medicine. Cilnidipin...
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