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Preparation process of amlodipine intermediate

A technology for amlodipine and intermediates, which is applied in the field of preparation of amlodipine intermediates, can solve the problems of not obtaining target products and unsatisfactory results, and achieve the effects of reducing conditions and improving production safety

Active Publication Date: 2018-04-20
CHANGZHOU RUIMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] But we tried repeatedly, and the results were not satisfactory.
Some conditions didn't even get the target product

Method used

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  • Preparation process of amlodipine intermediate
  • Preparation process of amlodipine intermediate
  • Preparation process of amlodipine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of compound 2

[0044] 350ml of DMF, 49.5g of ethyl 4-chloroacetoacetate and 67.9g of sodium p-toluenesulfonate were added to the flask, and the temperature was raised to 105°C for 5.5h. About 2 / 3 of the solvent was distilled off under reduced pressure to obtain a solid-liquid mixture. Cool to room temperature, add 500ml of water and stir for 1h. Suction filtration and washing with water gave light brown solid. It was directly used in the second reaction without purification. Yield: 88.5%.

Embodiment 2

[0045] Embodiment 2: the preparation of compound 2

[0046] 350ml of DMF, 49.5g of ethyl 4-chloroacetoacetate and 67.9g of sodium p-toluenesulfonate were added to the flask, and the temperature was raised to 105°C for 5.5h. After cooling to room temperature, the reactant was poured into 1000ml of water, stirred for 1 hour, filtered with suction and washed with water to obtain a light brown solid. It was directly used in the second reaction without purification. Yield: 86.1%.

Embodiment 3

[0048] In the comparative experiment of the preparation of compound 2, the effect of replacing sodium p-toluenesulfonate with p-toluenesulfonic acid and triethylamine on the reaction was investigated.

[0049] Add 350ml of DMF, 49.5g of ethyl 4-chloroacetoacetate and 60.2g of p-toluenesulfonic acid into the flask, and cool to 5-10°C. Slowly add 35.4 g of triethylamine dropwise, keep warm for 1 h after the addition, and then raise the temperature to 105° C. for 5.5 h. About 2 / 3 of the solvent was distilled off under reduced pressure to obtain a solid-liquid mixture. Cool to room temperature, add 500ml of water and stir for 1h. There was oil sticking to the bottle wall, poured off the water layer, added 40ml of ethyl acetate and stirred overnight. Suction filtration and washing with water gave light brown solid. Yield: 26.7%.

[0050] It can be seen from the yield that the yield of compound 2 prepared by adding p-toluenesulfonic acid and triethylamine to ethyl 4-chloroacetoa...

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Abstract

The invention relates to a method for preparing an amlodipine intermediate safely and efficiently (the formula is as shown in the description). The method particularly comprises the following steps: step 1, heating 4-chloroacetoacetic acid ethyl ester and para-toluenesulfonic acid sodium salt which serve as raw materials in a reaction solvent and performing reaction to obtain a compound 2; and step 2, adding an alkaline compound serving as a catalyst into the compound 2 and N-hydroxyethylphthalimide, adding a phase transfer catalyst simultaneously and heating to obtain a compound 1. The intermediate compound 2 adopts 4-chloroacetoacetic acid ethyl ester protected by para-toluenesulfonic acid, and p-toluenesulfonate is adopted, so the condition of an etherification step is greatly reduced,dangerous or expensive reagents are avoided and the production safety is greatly improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation process of an amlodipine intermediate. Background technique [0002] Amlodipine is a calcium antagonist and can be used to treat various types of hypertension (alone or in combination with other drugs) and angina, especially spontaneous angina (alone or in combination with other drugs). This product has a certain protective effect on the kidneys. [0003] Amlodipine is characterized by a slow rate of binding and dissociation with receptors, so the drug effect occurs later and lasts longer. The selective effect on vascular smooth muscle is greater than that of nifedipine. In patients with myocardial ischemia, this product can increase cardiac output and coronary flow, increase myocardial oxygen supply and reduce oxygen consumption, and improve exercise capacity. In addition, this product may activate LDL receptors, reduce fat accumulation on the arterial wall an...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48Y02P20/584
Inventor 史卫明周禾王小亮
Owner CHANGZHOU RUIMING PHARMA
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