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Preparation method of trans-1, 2-diaminomethyl cyclobutane and hydrochloride thereof

A technology of diaminomethylcyclobutane and hydrochloride is applied in the field of preparation of lobaplatin intermediates, and can solve the problems of poor stability, poor operability and safety, affecting the quality and yield of lobaplatin products and the like, and achieves the The effect of excellent quality, avoidance of high-risk operations, and suitability for industrial production

Active Publication Date: 2021-12-21
SICHUAN HUIYU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, trans-1,2-diaminomethylcyclobutane is mostly synthesized from acrylonitrile or 1,2-dicyanocyclobutane, wherein, 1,2-dicyanocyclobutane is prepared from acrylonitrile The steps of preparing trans-1,2-diaminomethylcyclobutane by reduction of butane and 1,2-dicyanocyclobutane all need to use high temperature and high pressure, as in CN102093226A, 1,2-dicyanocyclobutane The reduction reaction of alkane needs to be carried out under a high pressure of 20 bar, which has poor operability and safety, and directly affects the product quality and yield of lobaplatin synthesis in the later stage
In addition, trans-1,2-diaminomethylcyclobutane has poor stability and is liquid, so there are many inconveniences in storage and transportation.

Method used

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  • Preparation method of trans-1, 2-diaminomethyl cyclobutane and hydrochloride thereof
  • Preparation method of trans-1, 2-diaminomethyl cyclobutane and hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] 1. Compound I (trans-N 1 ,N 2 -dibenzylcyclobutane-1,2-dicarboxamide) preparation

[0108]Add 30.0g trans-1,2-cyclobutanedioic acid (208mmol) and 174.1g HATU (458mmol) into a 2.0L reactor, add 450ml DMF, stir to dissolve and disperse, cool down to -10~10°C, stir rapidly, drop slowly Add DIPEA80.7g (624mmol), temperature control ≤ 25 ℃, nitrogen protection, dropwise, activation reaction 0 ~ 3h. After the activation is completed, after cooling down to -10-10°C, add 49.07g of benzylamine (458mmol), and control the temperature not to exceed 40°C. After dropping, when a large amount of white solids were precipitated, the stirring reaction was continued for 2 h. Turn off the stirring, pour the reaction liquid into 72L of purified water to quench, control the temperature not to exceed 30°C, complete the addition, stir, filter and drain, collect the filter cake and beat it with purified water, filter, drain, collect the filter cake, and place Dry in a blast drying oven at 4...

Embodiment 2

[0121] Carry out a series of experiments according to the same steps of Example 1, in the preparation process of compound II, change the addition amount of red aluminum under the situation that other conditions are constant, examine n (red aluminum) / n (compound I)=3.0,6.0 Experimental effect, and carry out follow-up experimental operation according to embodiment 1, the result is as shown in the following table:

[0122] Table 1 Experimental results of different red aluminum additions

[0123]

Embodiment 3

[0125] 1. Compound I (trans-N 1 ,N 2 -dibenzylcyclobutane-1,2-dicarboxamide) preparation

[0126] Add 600.04g trans-1,2-cyclobutanedioic acid (4.16mol) and 3482.10g HATU (9.16mol) to a 100L reactor, add 9000ml DMF, stir to dissolve and disperse, lower the temperature to -10~10℃, stir rapidly, slowly Add DIPEA1614.39g (12.49mol) dropwise, temperature control ≤ 25°C, nitrogen protection, after dropping, activate the reaction for 0-3h. After the activation is completed, the temperature is lowered to -10 to 10°C, and 981.48 g of benzylamine (9.16 mol) is added to control the temperature not to exceed 40°C. After dropping, when a large amount of white solids were precipitated, the stirring reaction was continued for 2 h. Turn off the stirring, pour the reaction liquid into 72L of purified water to quench, control the temperature not to exceed 30°C, complete the addition, stir, filter and drain, collect the filter cake and beat it with purified water, filter, drain, collect the f...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of trans-1, 2-diaminomethyl cyclobutane and hydrochloride thereof, which comprises a method for preparing trans-1, 2-diaminomethyl cyclobutane and hydrochloride thereof by taking trans-1, 2-cyclosuccinic acid as a raw material and reacting with benzylamine and a red aluminum solution. The method provided by the invention has the advantages of easily available raw materials, strong operability, high safety, avoidance of high-risk operation and reduction of experimental risks, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a lobaplatin intermediate. Background technique [0002] Lobaplatin: LBP, D-19466, its chemical name is: trans-1,2-diaminomethyl-cyclobutane-lactate platinum, the structural formula is as follows: [0003] [0004] Lobaplatin is a third-generation platinum-based antineoplastic drug developed by Zentaris AG, Germany. my country approved the import of lobaplatin in 1998, which was exclusively produced by Hainan Changan International Pharmaceutical Co., Ltd., and was first listed in China in 2003. Studies have shown that the anti-tumor effect of the drug is equivalent to or better than that of cisplatin and carboplatin, the toxicity is the same as that of carboplatin, and there is no cross-resistance with cisplatin. It is mainly used for the treatment of breast cancer, small cell lung cancer and chronic myeloid leukemia. [0005] Trans-1,2-diamin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/62C07C209/74C07C211/18C07C209/50C07C211/27C07C231/02C07C233/58
CPCC07C209/62C07C209/74C07C209/50C07C231/02C07C2601/04C07B2200/07C07C233/58C07C211/27C07C211/18Y02P20/55
Inventor 陈勇吴相牛坡胡和平孙健
Owner SICHUAN HUIYU PHARMA
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