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Method for preparing amlodipine besylate intermediate by using micro-reaction device

A technology of amlodipine besylate and micro-reaction device, which is applied in the direction of organic chemistry, can solve the problems of poor appearance, low conversion rate, and many side reactions of ring-closing products, and achieve good product quality, small reaction volume, The effect of short reaction times

Active Publication Date: 2021-06-25
FUJIAN HAIXI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] U.S. Patent (WO20020068831) adopts the Michael reaction route, adopts phthalimide as the amino protecting group, and uses acetamide as the amination reagent to carry out the ring closure reaction. Because the conversion rate is not high, the appearance of the ring closure product obtained is relatively poor. and low yield
[0021] In summary, in the existing synthetic route of the amlodipine besylate intermediate, the ring closure step is a key step, and there are still problems such as low yield and many side reactions, so new ideas need to be adopted to improve this step. Improve the yield, reduce side reactions, simplify the post-treatment process, and achieve the purpose of further reducing production costs

Method used

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  • Method for preparing amlodipine besylate intermediate by using micro-reaction device
  • Method for preparing amlodipine besylate intermediate by using micro-reaction device
  • Method for preparing amlodipine besylate intermediate by using micro-reaction device

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Preparation of β-dicarbonyl compounds: Dissolve 2-chloroethanol (1.61g, 20mmol) and potassium phthalimide (4.06g, 22.0mmol) in N,N-dimethylformamide (20ml) , stirred at 50-60°C, after TLC detected that the reaction was complete, added water (40ml) and ethyl acetate (40ml) to the reaction solution, stirred, separated the liquid, discarded the water phase, and used saturated brine (30ml x2 ) was washed twice, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the crude product of the β-dicarbonyl compound intermediate, which was directly used in the next step. Dissolve the above crude product in N,N-dimethylformamide (20ml), add potassium tert-butoxide (2.46g, 22.0mmol) and stir at 20-25°C for about 15min, add ethyl 4-bromoacetoacetate (4.18 g, 20.0mmol), stirred at 20-25°C, after the reaction was detected by TLC, added water (40ml) and ethyl acetate (40ml) to the reaction solution, stirred, separated, discarded the aqueous p...

Embodiment 2

[0056] Refer to Example 1 for the preparation process of β-dicarbonyl compound.

[0057] The above β-dicarbonyl compound (3.19g, 10.0mmol), piperidine (43mg, 0.5mmol) and acetic acid (30mg, 0.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred evenly to obtain a homogeneous solution a. Dissolve o-chlorobenzaldehyde (1.40g, 10.0mmol) in ethanol (6.6ml) and stir evenly to obtain a homogeneous solution C. The homogeneous solution A and the homogeneous solution C are pumped into the Y-shaped mixer at a flow rate of 0.250mL / min respectively, and after mixing, they are passed into the first microreactor with a coil inner diameter of 1mm. The volume of the reactor is 15mL. The temperature was controlled at 90° C., and the reaction residence time was 20 minutes.

[0058] At the same time, methyl 3-aminocrotonate (1.15 g, 10.0 mmol) was dissolved in ethanol (6.6 ml), and stirred evenly to obtain a homogeneous solution B. The homogeneous solution B is pumped into the T-type ...

Embodiment 3

[0060] Refer to Example 1 for the preparation process of β-dicarbonyl compound.

[0061] The above-mentioned β-dicarbonyl compound (3.19g, 10.0mmol), piperidine (213mg, 2.5mmol) and acetic acid (150mg, 2.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred evenly to obtain a homogeneous solution a. Dissolve o-chlorobenzaldehyde (1.40g, 10.0mmol) in ethanol (6.6ml) and stir evenly to obtain a homogeneous solution C. The homogeneous solution A and the homogeneous solution C are pumped into the Y-shaped mixer at a flow rate of 0.250mL / min respectively, and after mixing, they are passed into the first microreactor with a coil inner diameter of 1mm. The volume of the reactor is 15mL. The temperature was controlled at 90° C., and the reaction residence time was 20 minutes.

[0062] At the same time, methyl 3-aminocrotonate (1.15 g, 10.0 mmol) was dissolved in ethanol (6.6 ml), and stirred evenly to obtain a homogeneous solution B. The homogeneous solution B is pumped into...

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Abstract

The invention provides a method for producing an amlodipine besylate intermediate by using a micro-reaction device. According to the method, o-chlorobenzaldehyde is used as a raw material, the amlodipine besylate intermediate is rapidly and safely prepared by using the micro-reaction device, and the method has the advantages of high reaction conversion rate, simple post-treatment, small reaction volume, short reaction time, low energy consumption and the like, and has relatively high commercial value.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a production process for preparing the intermediate of the antihypertensive drug amlodipine besylate by using a micro-reaction device. [0002] technical background [0003] Amlodipine Besylate, the chemical name is 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4- Dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate is a dihydropyridine calcium antagonist developed by Pfizer, mainly used for the treatment of hypertension and angina pectoris. Its structure is represented by the following formula: [0004] [0005] Amlodipine besylate can selectively inhibit myocardial and vascular smooth muscle extracellular calcium ions from entering cells through the calcium ion channel of the cell membrane, relax vascular smooth muscle, and achieve antihypertensive effect. Its mechanism of relieving angina pectoris is to reduce the peripheral r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90C07D401/12C07D209/48
CPCC07D211/90C07D401/12C07D209/48
Inventor 连昕龚轩王如勇
Owner FUJIAN HAIXI PHARMA
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