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Preparation method of diaminomethyl cyclobutane oxalate

A technology of diaminomethyl cyclobutane and aminomethyl cyclobutane is applied in the field of preparation of diaminomethyl cyclobutane oxalate, and can solve the problem of affecting the lobaplatin synthesis reaction speed, product yield and purity, and reverse reaction. Formula-diaminomethylcyclobutane has problems such as unstable performance, limited product yield and purity, etc., to achieve the effects of easy storage and transportation, stable properties, and easy operation to control

Active Publication Date: 2013-12-04
海南长安国际制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, trans-diaminomethylcyclobutane has unstable performance, which directly affects the reaction speed, product yield and purity of lobaplatin synthesis in the later stage, resulting in incomplete reaction and limited product yield and purity.
And trans-diaminomethylcyclobutane is liquid, there are many inconveniences in storage and transportation
There is no bibliographical report about the synthesis technology and the process of diaminomethylcyclobutane oxalate at present

Method used

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  • Preparation method of diaminomethyl cyclobutane oxalate
  • Preparation method of diaminomethyl cyclobutane oxalate
  • Preparation method of diaminomethyl cyclobutane oxalate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Take 200ml of acrylonitrile, add 0.05g of Fecl3 and 0.044g of p-methoxyphenol at a temperature of 215°C and pressurize nitrogen to 17bar, and mix and react for 8 hours. After the reaction is complete, 20ml of dark red liquid is obtained. After distillation at 175°C, 12g of crude dicyanocyclobutane was obtained, with a cis-to-trans ratio of about 4:6, and then the crude product was rectified at 150°C to obtain 7.5g of trans-dicyanocyclobutane, with a melting point of 37.5°C;

[0030] (2), after feeding ammonia gas into the trans-dicyanocyclobutane, the temperature rises to 80°C, the hydrogen gas is pressurized to 20bar, catalyzed by active nickel, the reaction time is 20h, and 16ml of light yellow liquid is obtained, that is, trans Formula - diaminomethylcyclobutane;

[0031] 3. Stir 16ml of trans-diaminomethylcyclobutane and 3.5g of anhydrous oxalic acid at 70°C under normal pressure for 3.5h, combine to form 3.3g of crude diaminomethylcyclobutane oxalate, and then ...

Embodiment 2

[0033] 1. Take 100ml of acrylonitrile, add 0.03g of Fecl3 and 0.025g of p-methoxyphenol at a temperature of 200°C and pressurize nitrogen to 17bar, and mix and react for 6 hours. After the reaction is complete, 10ml of dark red liquid is obtained. After distillation, 6.3 g of crude dicyanocyclobutane was obtained, with a cis-to-trans ratio of about 4:6, and then the crude product was subjected to rectification at 140°C to obtain 4 g of trans-dicyanocyclobutane, with a melting point of 37.5°C;

[0034] 2. After passing 4 g of trans-dicyanocyclobutane through ammonia gas, the temperature rose to 85°C, the hydrogen was pressurized to 20 bar, catalyzed by active nickel, the reaction time was 15 hours, and 8.4 ml of light yellow liquid was obtained, namely trans- Diaminomethylcyclobutane;

[0035] 3. Stir 8.4ml of trans-diaminomethylcyclobutane and 2g of anhydrous oxalic acid at 65°C under normal pressure for 5h, combine to form 1.7g of crude diaminomethylcyclobutane oxalate, and t...

Embodiment 3

[0037] 1. Take 150ml of acrylonitrile, add 0.038g of Fecl3 and 0.033g of p-methoxyphenol at a temperature of 235°C and pressurize nitrogen to 17bar, and mix and react for 9 hours. After the reaction is complete, 15ml of dark red liquid is obtained. After distillation, 9.2 g of crude dicyanocyclobutane was obtained, with a cis-to-trans ratio of about 4:6. Then, the crude product was subjected to rectification at 160°C to obtain 6.2 g of trans-dicyanocyclobutane, with a melting point of 37.5°C;

[0038] 2. After passing 6.2 g of trans-dicyanocyclobutane through ammonia gas, the temperature rose to 70°C, the hydrogen gas was pressurized to 20 bar, catalyzed by active nickel, the reaction time was 25 hours, and 11.7 ml of light yellow liquid was obtained, that is, trans - Diaminomethylcyclobutane;

[0039] 3. Stir 11.7ml of trans-diaminomethylcyclobutane and 2.5g of anhydrous oxalic acid at 80°C under normal pressure for 3h, combine to form 2.5g of crude diaminomethylcyclobutane o...

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Abstract

The invention relates to a preparation method of diaminomethyl cyclobutane oxalate, which comprises the following steps: carrying out dimerization on acrylonitrile used as a raw material to generate a cis-dinitrile cyclobutane / trans-dinitrile cyclobutane mixture, carrying out distillation separation on the generated cis-dinitrile cyclobutane / trans-dinitrile cyclobutane mixture, and converting into trans-dinitrile cyclobutane by reduction; by using active nickel as a catalyst, introducing ammonia, and pressurizing with hydrogen to react, thereby obtaining trans-diaminomethyl cyclobutane; adding oxalic acid to obtain a crude diaminomethyl cyclobutane oxalate product; and finally, purifying with alcohol to obtain the finished diaminomethyl cyclobutane oxalate product. By using the method provided by the invention, the raw material is accessible, the operation is easy to control, the obtained product can be used as an intermediate to participate in the synthesis of Lobaplatin, and the obtained Lobaplatin has more stable properties and is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of diaminomethylcyclobutane oxalate. It belongs to the technical field of medicine and chemical industry. Background technique [0002] Diaminomethylcyclobutane oxalate can be used as an intermediate in the synthesis of platinum-based antineoplastic drug lobaplatin. Lobaplatin has strong anticancer activity, low toxicity, good solubility and stability in water. It is mainly used for the treatment of breast cancer, small cell lung cancer and chronic myelogenous leukemia. At present, most of its preparations are based on acrylonitrile or 1,2-dicyanocyclobutane as raw materials, and the intermediate products are all trans-diaminomethylcyclobutane. However, trans-diaminomethylcyclobutane has unstable performance, which directly affects the reaction speed, product yield and purity of lobaplatin synthesis in the later stage, resulting in incomplete reaction and limited product yield and purity. And trans-diami...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/36C07C209/48C07C55/07C07C51/41
Inventor 窦啟玲钟洪生周黎亚彭雯
Owner 海南长安国际制药有限公司
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