Preparation method of benidipine hydrochloride

A technology of benidipine hydrochloride and concentrated sulfuric acid, applied in organic chemistry and other directions, can solve the problems of complicated operation, high operation risk, long reaction time, etc., and achieves mild reaction process conditions, simple operation and post-processing, and short reaction steps. Effect

Inactive Publication Date: 2021-04-20
济南朗科医药技术有限公司
View PDF7 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction time of this route is longer and the yield is lower. The synthesis of N-benzyl-3-piperidinyl acetoacetate needs to use raw materials with a danger of pol

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of benidipine hydrochloride
  • Preparation method of benidipine hydrochloride
  • Preparation method of benidipine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048]Embodiment 1: the preparation of intermediate 2-(3-nitrobenzylidene)-methyl acetoacetate (Ⅰ)

[0049] Add 34.8g (0.3mol) of methyl acetoacetate and 5.0ml of glacial acetic acid into the reaction flask, then slowly add 5.0ml of concentrated sulfuric acid at 0-10°C, stir for 15 minutes, then slowly add 30.2g (0.2mol) of 3-nitrobenzaldehyde, the temperature of the mixture was controlled at 20-30°C and the reaction was stirred for 1-2 hours, then 20ml of absolute ethanol was added, and stirred for 30 minutes, a large amount of solid crystals appeared, filtered, and the filter cake was used in 10ml of anhydrous After washing with water and ethanol, the solid was air-dried at 60-70° C. for 8 hours to obtain 43.0 g of a white solid, with a yield of 86.3%. HPLC purity (area normalization method): 98.855%. For HPLC results, see figure 1 .

Embodiment 2

[0050] Embodiment 2: the preparation of intermediate 2-(3-nitrobenzylidene)-methyl acetoacetate (Ⅰ)

[0051] Add 34.8g (0.3mol) of methyl acetoacetate and 5.0ml of glacial acetic acid into the reaction flask, then slowly add 5.0ml of piperidine at 0-10°C, stir for 15 minutes, then slowly add at 0-10°C 30.2g (0.2mol) of 3-nitrobenzaldehyde, the temperature of the mixture was controlled at 20-30°C and the reaction was stirred for 1-2 hours, then 20ml of absolute ethanol was added, and stirred for 30 minutes, a large amount of solid crystals appeared, filtered, and the filter cake was used in 10ml of anhydrous After washing with water and ethanol, the solid was air-dried at 60-70° C. for 8 hours to obtain 41.0 g of a white solid, with a yield of 82.2%. HPLC purity (area normalization method): 98.689%. For HPLC results, see figure 2 .

Embodiment 3

[0052] Example 3: Preparation of intermediate 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate (II)

[0053] Add 20.0 g (0.08 mol) of 2-(3-nitrobenzylidene)-methyl acetoacetate, 11.5 g (0.1 mol) of methyl β-aminocrotonate and 150 ml of absolute ethanol in the reaction flask, and control the temperature of the mixture Stir and react at 40-50°C for 2-4 hours. After the reaction is complete, place in an ice-water bath at 0-10°C to cool and crystallize. After stirring for 1 hour, off-white crystals precipitated, filtered, and the solid was air-dried at 50-60°C for 8 hours to obtain 24.2 g of a light yellow solid, with a yield of 87.3%. HPLC purity (area normalization method): 99.868%, HPLC see results image 3 .

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention belongs to the field of chemical synthesis of drugs, and particularly relates to a preparation method of a hypotensive drug benidipine hydrochloride. The method comprises the following steps: carrying out a Knoevenagel reaction, a Michael addition reaction, cyclization and hydrolysis on starting raw materials 3-nitrobenzaldehyde and methyl acetoacetate in the presence of a catalyst, reacting with thionyl chloride, directly reacting with 1-benzyl-3-hydroxypiperidine, and refining to obtain the benidipine hydrochloride. The benidipine hydrochloride obtained by adopting the preparation method of the benidipine hydrochloride is high in purity, column chromatography isolation is not needed, and the HPLC purity of the product is 99.5% or above. The yield of the obtained benidipine hydrochloride is relatively high and can reach 68% or above.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of medicines, and in particular relates to a preparation method of benidipine hydrochloride, an antihypertensive drug. Background technique [0002] Hypertension has become an important disease seriously affecting human health. Among them, severe complications such as stroke, myocardial infarction, heart failure, and renal insufficiency caused by high blood pressure have a high disability and mortality rate, which brings a heavy burden to the patient, the patient's family, and the society, and seriously consumes medical and social resources. . At present, the prevalence of hypertension in my country is increasing. According to statistics, the number of hypertensive patients in my country has reached 250 million, the prevalence of hypertension in adults is 25%-30%, and 3.5 million people die from cardiovascular and cerebrovascular diseases every year. More than half of these deaths were related t...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D211/90
Inventor 邵长凯胡来龙娄焕军
Owner 济南朗科医药技术有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap