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Synthesis method of amlodipine besylate degradant impurities

A kind of technology of amlodipine besylate and synthesis method, applied in the field of medicinal chemistry, can solve the problems such as compound synthesis methods that are not reported in the literature, and achieve the effects of improving quality standards, simple process, and easy availability of starting materials

Active Publication Date: 2018-01-12
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is no synthetic method of this compound reported in the literature

Method used

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  • Synthesis method of amlodipine besylate degradant impurities
  • Synthesis method of amlodipine besylate degradant impurities
  • Synthesis method of amlodipine besylate degradant impurities

Examples

Experimental program
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Embodiment 1

[0032] The preparation of embodiment 1 compound 1

[0033] Benzyl acetoacetate (25g), aqueous ammonia (75mL) and methanol (50mL) were added to 250mL, and stirred overnight at room temperature; TLC showed that the reaction was complete; after most of the methanol and aqueous ammonia were spinned out at room temperature, ethyl acetate (250mL) and water ( 100mL) was separated, the aqueous phase was extracted twice with ethyl acetate (100mL), the combined organic phase was washed with saturated brine, dried, and spin-dried to obtain compound 1 (light yellow oil, 25.0g), which could be used directly in Next reaction.

Embodiment 2

[0034] The preparation of embodiment 2 compound 2

[0035] SM2 (25.0g, 60% purity), o-chlorobenzaldehyde (6.6g) and isopropanol (100ml) were added in the reaction flask, piperidine (0.5mL) and acetic acid (0.75mL) were added respectively, and the temperature was raised to 40 degree, reacted overnight; TLC showed that the reaction was complete, and spin-dried after cooling down, then added ethyl acetate (400mL) to dissolve, washed with water (100mL) and saturated brine (100mL) respectively, and dried and spin-dried to obtain a yellow oil; After adding isopropanol (100mL) to the oil to dissolve, compound 1 (9.0g) was added, and the temperature was raised to 75°C to react overnight; TLC showed that after the reaction was complete, the temperature was lowered and spin-dried, and purified by column to obtain 10g of crude compound 2. The crude compound was added into 50 mL of methanol and stirred for 30 minutes, filtered and dried to obtain pure compound 2 (4.0 g, pale yellow solid)...

Embodiment 3

[0036] The preparation of embodiment 3 compound 3

[0037] Add compound 2 to a mixed solvent of THF (150mL) and methanol (50mL), add Pd / C (500mg) to replace hydrogen, and react overnight at 25°C; filter and spin dry to obtain a solid, and add ethyl acetate to the above solid After the ester (20 mL) and dichloromethane (20 mL) were dissolved, petroleum ether (150 mL) was added, followed by crystallization, filtration, and drying to obtain compound 3 (2.0 g, white solid).

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Abstract

The invention provides a preparation method of amlodipine besylate degradant impurities. The method comprises the following steps: a) preparation of a compound 1: generating corresponding imine, namely, the compound 1 by using an acetylacetic ester compound SM1 as a raw material and using lower alcohol as a solvent under the condition of an ammonia source; b) preparation of a compound 2: performing a Hantzsch reaction on a compound SM2, the compound 1 and o-chlorobenzaldehyde SM3 as raw materials, so as to obtain the compound 2; c) preparation of a compound 3: removing R-base protection from the compound 2, so as to obtain the compound 3; d) preparation of a compound TM: removing R' from the compound 3, so as to obtain the compound TM. The invention provides a synthesis method of the amlodipine besylate degradant impurities and provides the preparation method of a reference substance for the study on the quality of amlodipine besylate, so that the important guiding significance is provided for safe medication of the amlodipine besylate.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a kind of amlodipine besylate degradation impurity 6-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-5-(ethoxy Synthetic method of -2-methyl-1,4-dihydropyridine-3-carboxylic acid. Background technique [0002] Amlodipine besylate is a dihydropyridine calcium antagonist. The contraction of cardiac muscle and smooth muscle depends on extracellular calcium ions entering cells through specific ion channels. Amlodipine besylate is a peripheral arterial dilator that acts directly In vascular smooth muscle, reduce peripheral vascular resistance, thereby lowering blood pressure. In addition, amlodipine besylate has a significant effect on alleviating angina pectoris, coronary ischemia and spasm, so amlodipine besylate is currently the most widely used dihydropyridine calcium antagonist. [0003] Amlodipine besylate structural formula is shown in the following formula (I): [0004] [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
Inventor 张弛王庆辉牛明玉冯虹钧史登健
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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