Preparation and separation purification methods of drug intermediate

A product and compound technology, applied in the direction of organic chemistry, can solve the problems of three wastes discharge energy, long process cycle, waste, etc., and achieve the effect of saving energy and cost, saving process time, and reducing the discharge of three wastes

Inactive Publication Date: 2016-04-06
上海欣生源药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis process of intermediate compound I still has the problems

Method used

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  • Preparation and separation purification methods of drug intermediate
  • Preparation and separation purification methods of drug intermediate
  • Preparation and separation purification methods of drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of compound I:

[0032] Add 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine (compound II) (0.5 g, 1.8 mmol) and DMF (10 mL) into a 50 mL four-necked flask, and stir to dissolve. Slowly add phenyl chloroformate (0.28mL, 2.2mmol) dropwise at 0-10°C, continue to react at room temperature for 1-3h after the dropwise addition, after the reaction is monitored by HPLC, add 2-[(1S,2S )-1-ethyl-2-benzyloxypropyl]hydrazine carboxaldehyde (compound III) (0.6g, 2.5mmol) and triethylamine (0.36mL, 2.5mmol), heated to 90-100°C for 15-24h , HPLC monitoring after the end of the reaction, stop heating, the reaction solution down to room temperature.

[0033] Isolation of Compound I:

[0034] At room temperature, the reaction solution was slowly poured into water (100mL), a large amount of solids precipitated, continued to stir for 1h, filtered, the filter cake was washed with water (10mL*3), the solid was dissolved in THF (10mL) after draining, and activated carbon was...

Embodiment 2

[0038] Preparation of compound I:

[0039] Add 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine (compound II) (5.0 g, 18 mmol) and DMF (100 mL) into a 250 mL four-necked flask, and stir to dissolve. Slowly add phenyl chloroformate (2.4mL, 18.9mmol) dropwise at 10-20°C, and continue to react at room temperature for 2-5h after the dropwise addition is completed. After the reaction is monitored by HPLC, add 2-[(1S, 2S )-1-ethyl-2-benzyloxypropyl]hydrazine carboxaldehyde (compound III) (5.1g, 21.6mmol) and triethylamine (3.1mL, 21.6mmol), heated to 100 ~ 110 ℃ reflux reaction for 12 ~ After 15 hours, after the reaction was monitored by HPLC, the heating was stopped, and the reaction solution was cooled to room temperature.

[0040] Isolation of Compound I:

[0041] At room temperature, the reaction solution was transferred to an Erlenmeyer flask, and saturated sodium chloride solution (200mL) and dichloromethane (200mL) were added, stirred vigorously for 30min and left to separat...

Embodiment 3

[0045] Preparation of compound I:

[0046] Add 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine (compound II) (5.0 g, 18 mmol) and DMSO (100 mL) into a 250 mL four-necked flask, and stir to dissolve. 25~30℃, slowly add phenyl chloroformate (3.5mL, 27mmol) dropwise, continue to react at room temperature for 6~8h after the dropwise addition, after the reaction is monitored by HPLC, add 2-[(1S,2S) -1-Ethyl-2-benzyloxypropyl]hydrazinecarbaldehyde (compound III) (6.8g, 28.8mmol) and triethylamine (4.1mL, 28.8mmol), heated to 110-120°C for 5-8h , HPLC monitoring after the end of the reaction, stop heating, the reaction solution down to room temperature.

[0047] Isolation of Compound I:

[0048] At room temperature, the reaction solution was transferred to an Erlenmeyer flask, and saturated sodium chloride solution (200mL) and ethyl acetate (200mL) were added, stirred vigorously for 30min and left to separate the liquids, and the aqueous phase was extracted with ethyl acetate (200m...

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Abstract

The invention provides a preparation method of 1-((2S,3S)-2-(benzyloxy) amyl-3-)-4-(4-(4-(4-hydroxyphenyl) piperazine-1-yl)-1H-1,2,4-triazole-5-(4H) ketone. The preparation method comprises: adding substituted or unsubstituted phenyl chloroformate into a reaction solution of a compound II for reaction for 12 hours at a temperature of -10 to 30 DEG C; and then adding a compound III and an alkali into the reaction system, and heating to 80 to 120 DEG C to continuously carry out reflux reaction for 5-24 hours. In comparison with the prior art, according to the preparation method provided by the invention, the process time is greatly saved, the total yield is improved by 10-15%, the discharge of three wastes is reduced, the energy source and cost are saved, and certain contributions can be generated for reduction of the synthetic cost of an important drug intermediate.

Description

technical field [0001] The invention relates to an important pharmaceutical intermediate compound 1-((2S,3S)-2-(benzyloxy)pentyl-3-)-4-(4-(4-(4-hydroxyphenyl)piperazine The preparation method of -1-yl)-1H-1,2,4-triazol-5(4H)ketone technical field. Background technique [0002] The chemical name of Posaconazole is 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4 -Triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentane -3-yl]-1,2,4-triazol-3-one, which is mainly used for the prevention and treatment of invasive fungal infections, drug-resistant or invasive fungal infections that are ineffective by other drugs, and its compound structure is as follows: [0003] [0004] Posaconazole, also known as "Noxafil", was developed by Schering-Plough (now owned by Merck), and its oral suspension was launched in the United States in 2006. It entered the Chinese market with the approval of SFDA in 2013. It is a new type of triazole antifung...

Claims

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Application Information

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IPC IPC(8): C07D249/12
Inventor 吕志良李超朱骏杰呼达古拉
Owner 上海欣生源药业有限公司
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