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Preparation method of 3, 5-dichlorobenzaldehyde and carboxamide triazole intermediate

A technology of dichlorobenzyl alcohol and carboxyamine triazole is applied in the field of pharmaceutical synthesis, can solve the problems of complicated separation and purification steps, low safety, many residues, etc., and can meet the requirements of pharmaceutical production quality, industrialized large-scale production, and production safety. The effect of high performance and overcoming the difficulty of temperature control

Active Publication Date: 2021-02-09
GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The above synthesis route has the following defects: 1) The reaction conditions are very harsh during the synthesis process, such as difficult temperature control, low safety, and explosion hazard; 2) The yield is low, only about 75%; 3) Separation and purification The steps are cumbersome and there are many residues

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  • Preparation method of 3, 5-dichlorobenzaldehyde and carboxamide triazole intermediate
  • Preparation method of 3, 5-dichlorobenzaldehyde and carboxamide triazole intermediate

Examples

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preparation example Construction

[0033] The invention provides a kind of preparation method of 3,5-dichlorobenzyl alcohol, comprising the steps of:

[0034] Mix 3,5-dichlorobenzoyl chloride, potassium borohydride and zinc chloride in a solvent, heat to reflux for reduction reaction; concentrate after the reduction reaction to prepare crude product;

[0035] Add hydrochloric acid aqueous solution and toluene to the crude product for extraction or add toluene for extraction, collect the toluene phase, wash with alkaline aqueous solution and water until neutral, and then concentrate to dryness, and the obtained solid is reconstituted with n-hexane or n-heptane crystallization.

[0036] The preparation method of the above-mentioned 3,5-dichlorobenzyl alcohol uses 3,5-dichlorobenzoyl chloride as a raw material, and carries out 3,5-dichlorobenzoyl chloride by using potassium borohydride and zinc chloride compatibility as a reducing system. Reduction, avoiding the use of LiAlH in traditional industrial production ...

Embodiment 1

[0057] The present embodiment is a kind of preparation method of carboxyamine triazole intermediate, and the steps are as follows:

[0058] (1) Add 20 kg of zinc chloride, 300 kg of THF, and 20 kg of potassium borohydride into the reaction pot, heat to 45°C and reflux for 2 hours, and add 55 kg of 3,5-dichlorobenzoyl chloride dropwise while maintaining the reflux state, Then rinse the feeding tube with a small amount of THF, heat to reflux at 45°C and keep for 3 hours. Then evaporate THF to dryness, cool to below 60°C, add 10 kg of water dropwise, then add water to 150 kg, add 3 kg of hydrochloric acid, 180 kg of toluene at the same time, separate layers and wash the toluene solution once, and use sodium carbonate aqueous solution (2 kg of sodium carbonate Add 150 kg of water to dissolve it) wash the toluene solution once, and wash with water until neutral. Evaporate toluene to dryness under reduced pressure at 100°C, add 50 kg of n-hexane after slight cooling, discharge and ...

Embodiment 2

[0067] This example is a preparation method of a carboxyamine triazole intermediate, the steps are the same as in Example 1, the difference is that in step (1) n-heptane is used instead of n-hexane, and in step (3) methyl tert-butyl ether is used Substitute for isopropyl ether.

[0068] Specific steps are as follows:

[0069] (1) Add 20 kg of zinc chloride, 300 kg of THF, and 20 kg of potassium borohydride into the reaction pot, heat to 45°C and reflux for 2 hours, and add 55 kg of 3,5-dichlorobenzoyl chloride dropwise while maintaining the reflux state, Then rinse the feeding tube with a small amount of THF, heat to reflux at 45°C and keep for 3 hours. Then evaporate THF to dryness, cool to below 60°C, add 10 kg of water dropwise, then add water to 150 kg, add 3 kg of hydrochloric acid, 180 kg of toluene at the same time, separate layers and wash the toluene solution once, and use sodium carbonate aqueous solution (2 kg of sodium carbonate Add 150 kg of water to dissolve), ...

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Abstract

The invention relates to a preparation method of 3, 5-dichlorobenzene methanol and a carboxylamine triazole intermediate. The preparation method of the 3, 5-dichlorobenzene methanol comprises the following steps: mixing the 3, 5-dichlorobenzene methanol with potassium borohydride and zinc chloride in a solvent, heating to reflux, and carrying out reduction reaction; after the reduction reaction isfinished, concentrating to prepare a crude product; and adding a hydrochloric acid aqueous solution and toluene into the crude product for extraction or adding toluene for extraction, collecting a toluene phase, washing the toluene phase with an alkaline aqueous solution and water to be neutral, then concentrating the toluene phase to be dry, and recrystallizing the obtained solid with n-hexane.According to the synthetic method of 3, 5-dichlorobenzene methanol, the raw materials are easy to obtain, the reaction conditions are mild and easy to control, the product is easy to purify, and the yield of the product is high.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of 3,5-dichlorobenzyl alcohol and carboxyamine triazole intermediates. Background technique [0002] Inhibition of angiogenesis in cancerous tissue is an effective approach in the treatment of solid tumors. Carboxyamidotriazole (CAI) is one of the most representative anti-angiogenic drugs. It specifically inhibits calcium ion-mediated signal transduction pathways, thereby inhibiting angiogenesis in cancerous tissues and reducing the invasion of cancer cells. Force and motility, affect the proliferation and metastasis of cancer cells. [0003] At present, the synthesis method of carboxytriazole mainly refers to "Wu Xiaofeng, Fang Gang et al., Synthesis of New Anticancer Drug L-651582 [J], China Journal of Pharmaceutical Industry, 2006, 37(3): 147-149", in the synthesis process It involves an important intermediate - 3,5-dichlorobenzyl alcohol, which i...

Claims

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Application Information

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IPC IPC(8): C07C29/147C07C33/46C07C45/64C07C49/83
CPCC07C29/147C07C45/64C07F7/188C07F7/1892C07C33/46C07C49/83Y02P20/55
Inventor 叶菜英李宗森池研生
Owner GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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