Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride

A technology of heterocyclobutane and benzhydryl, applied in the direction of organic chemistry, can solve the problems of increased cost and environmental pollution, long total reaction time, poor repeatability, etc., achieves no amplification effect, and the method is simple and easy to operate , the effect of easy temperature control

Inactive Publication Date: 2015-02-18
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The preparation method of 1-benzhydryl-3-hydroxyazetidine hydrochloride reported in the above-mentioned patent literature has a long total reaction time, high energy consumption, and low yield, and long-term reflux is likely to cause a large amount of solvent loss , increase cost and environmental pollution; the repeatability is not strong, not suitable for stable large-scale production

Method used

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  • Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride
  • Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride
  • Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride

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Embodiment 1

[0035] 1) Preparation of reaction solution I: Take diphenylmethylamine (1500g, 8.19mol) and add it to a 5L four-neck flask, control the temperature at 20-25°C, add 1.5L methanol, and then add epichlorohydrin (984.52g, 10.64mol) , stir evenly, and the molar ratio of xylidine and epichlorohydrin is 1:1.3.

[0036] 2) Preparation of reaction solution II: React the reaction solution I at 27±2°C for 48 hours to prepare the reaction solution II, 99% of the benzhydrylamine is converted into the intermediate state B, and only a small amount of benzhydrylamine remains. No other impurities are formed. The reaction equation is:

[0037]

[0038] 3) Preparation of 1-benzhydryl-3-hydroxyazetidine hydrochloride: raise the temperature of the reactor to 230°C, set the pressure to 1.8MPa, and pump the reaction solution with a flow rate of 1-200ml / min Add II into the microreactor, and set the flow rate to 70ml / min. After 1.1 minutes, the reaction liquid flows out of the microreactor and is...

Embodiment 2

[0046] 1) Preparation of reaction solution Ⅰ: Add diphenylmethylamine (1500g, 8.19mol) into a 5L four-neck flask, control the temperature at 20-25°C, add 1.5L of ethanol, and then add epichlorohydrin (984.52g, 10.64mol) , stir evenly, and the molar ratio of xylidine and epichlorohydrin is 1:1.3.

[0047] 2) Preparation of reaction solution II: reaction solution I was reacted at 27±2° C. for 50 hours to prepare reaction solution II.

[0048] 3) Preparation of 1-benzhydryl-3-hydroxyazetidine hydrochloride: raise the temperature of the reactor to 230°C, set the pressure to 2MPa, and use a pump with a flow rate of 1-200ml / min to pump the reaction solution II Add in the microreactor, the flow rate is set to 60ml / min, after 1.2 minutes, the reaction solution flows out of the microreactor, is collected in the liquid storage tank, and continues to feed until all the materials are consumed.

[0049] Separation and purification: transfer the reaction solution to a rotary evaporator, ke...

Embodiment 3

[0055] 1) Preparation of reaction solution I: Take diphenylmethylamine (1000g, 5.46mol) and add it into a 5L four-neck flask, control the temperature in a water bath at 20-25°C, add 1.5L of n-butanol, and then add epichlorohydrin (656.35g, 7.09mol), stir evenly, and xylidine and epichlorohydrin are 1:1.3 according to the molar ratio.

[0056] 2) Preparation of reaction solution II: reaction solution I was reacted at 30° C. for 40 hours to prepare reaction solution II.

[0057] 3) Preparation of 1-benzhydryl-3-hydroxyazetidine hydrochloride: raise the temperature of the reactor to 230°C, set the pressure to 1.8MPa, and pump the reaction solution with a flow rate of 1-200ml / min Add II into the microreactor, and set the flow rate to 50ml / min. After 1.2 minutes, the reaction solution flows out of the microreactor and is collected in the liquid storage tank, and continues to feed until all the materials are consumed.

[0058] Separation and purification: transfer the reaction solu...

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Abstract

The invention provides a preparation method of an azelnidipine intermediate, namely 1-benzhydryl-3-hydroxylazetidine hydrochloride. The preparation method comprises the following steps: 1) preparation of a reaction solution I: mixing dimethylaniline and epoxy chloropropane in proportion and adding an organic solvent to prepare the reaction solution I; 2) preparation of a reaction solution II: letting the reaction solution I react at 0-60 DEG C to prepare the reaction solution II; and 3) preparation of 1-benzhydryl-3-hydroxylazetidine hydrochloride: adding the reaction solution II into a microreactor by the use of a pump with flwo velocity of 1-200ml/min, heating to 60-250 DEG C at pressure of 0-2 MPa, completely reacting, and carrying out separation purification to obtain white crystals, namely 1-benzhydryl-3-hydroxylazetidine hydrochloride.

Description

technical field [0001] The technical field of medicine of the present invention, in particular, relates to a preparation method of dihydropyridine calcium antagonist azendipine intermediate 1-benzhydryl-3-hydroxyazetidine hydrochloride. Background technique [0002] 1-Benzhydryl-3-hydroxyazetidine hydrochloride is a key intermediate in the synthesis of Azelnidipine, which belongs to the dihydropyridine (DHP) calcium channel blocker (CCB) and is used as a first-line Antihypertensive drugs are widely used due to the reliability of their antihypertensive effect. Azedipine was developed with the goal of "an ideal CCB antihypertensive drug with mild and long-lasting antihypertensive effect and less stimulation to the heart". The antihypertensive effect of the drug is very similar to the third-generation DHP CCB drug amlodipine, and the effect lasts for a long time and the effect is mild. However, Azedipine is different from amlodipine in terms of its effect on the heart and pha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04
CPCC07D205/04
Inventor 陈兴曾涛王灿辉徐骁廉郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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