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A kind of preparation method of carfilzomib

A technology of carfilzomib and compounds, which is applied in the field of preparation of carfilzomib, can solve the problems of long reaction time between PyBOP and HOBT, difficult removal of by-products, high temperature control requirements, etc., and achieve shortened preparation time, simple feeding and high reaction short time effect

Active Publication Date: 2017-01-18
河南海汇药物研究有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the published preparation method of carfilzomib, the condensing agents used for carfilzomib condensation are PyBOP and HOBT, but PyBOP and HOBT have long reaction time, complicated feeding, nitrogen protection and high temperature control requirements , the problem that by-products are difficult to remove

Method used

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  • A kind of preparation method of carfilzomib
  • A kind of preparation method of carfilzomib
  • A kind of preparation method of carfilzomib

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Compound A is prepared by the following steps: adding sodium hydroxide solution (wherein the content of sodium hydroxide is 0.38mol, The content of water is 200mL), then add 0.18mol of Boc anhydride, react at 25°C for 22h, then add acid under ice-water bath to pH 1, extract three times with ethyl acetate to obtain the organic phase, wash the organic phase twice with saturated saline , then dried to remove water, filtered to retain the filtrate, and the filtrate was spin-dried to obtain 40 g of a colorless viscous liquid, which became a paste after cooling, which was Compound A.

[0038] Compound B was prepared by the following steps: put 0.3mol of L-phenylalanine, 1.51mol of benzyl alcohol, 0.36mol of p-toluenesulfonic acid and 700mL of toluene into the reaction flask in sequence, raise the temperature to reflux, maintain reflux, and divide the water React until the reaction is complete (12 h), lower to 25°C, concentrate until solids are precipitated, add 400 mL ethyl a...

Embodiment 2

[0049] Compound A is prepared by the following steps: adding sodium hydroxide solution (wherein the content of sodium hydroxide is 0.30mol, The content of water is 200mL), then add 0.15mol of Boc anhydride, react at 20°C for 20h, then add acid in an ice-water bath until the pH is 2, extract with ethyl acetate three times to obtain the organic phase, wash the organic phase with saturated saline twice , and then dried to remove water, filtered to retain the filtrate, and the filtrate was spin-dried to obtain 35 g of a colorless viscous liquid, which became a paste after cooling, which was Compound A.

[0050] Compound B was prepared by the following steps: 0.3 mol of L-phenylalanine, 1.2 mol of benzyl alcohol, 0.3 mol of p-toluenesulfonic acid and 700 mL of toluene were sequentially put into the reaction flask, heated to reflux, kept reflux, and separated water React until the reaction is complete (10h), lower to 20°C, concentrate until solid precipitates, add 400 mL of ethyl ac...

Embodiment 3

[0061] Compound A is prepared by the following steps: adding sodium hydroxide solution (wherein the content of sodium hydroxide is 0.45mol, The content of water is 200mL), then add 0.225mol of Boc anhydride, react at 30°C for 24h, then add acid in ice-water bath until the pH is 0, extract three times with ethyl acetate to obtain the organic phase, and wash the organic phase twice with saturated saline , and then dried to remove water, filtered to retain the filtrate, and the filtrate was spin-dried to 39 g of a colorless viscous liquid, which became a paste after cooling, which was compound A.

[0062] Compound B was prepared by the following steps: put 0.3mol of L-phenylalanine, 1.8mol of benzyl alcohol, 0.45mol of p-toluenesulfonic acid and 700mL of toluene into the reaction flask in sequence, raise the temperature to reflux, keep reflux, and divide the water React until the reaction is complete (14h), lower to 30°C, concentrate until solid precipitates, add 400 mL of ethyl ...

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Abstract

The invention discloses a preparation method for carfilzomib. The method utilizes HATU as a condensing agent to perform condensation and comprises a plurality of steps. The method has the characteristics of short reaction time, simple feeding, no need for nitrogen protection, appropriate control the feeding temperature, no need for strict temperature control, and easier washing and removal of the by-product of HATU, greatly shortens the preparation time, and improves the work efficiency, thus being suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and in particular relates to a preparation method of carfilzomib. Background technique [0002] On July 20, 2012, the US Food and Drug Administration (FDA) approved carfilzomib (carfilzomib) for the treatment of multiple myeloma who have previously received at least 2 drugs (including bortezomib and immunomodulators). (MM) patients. Carfilzomib is administered intravenously and its safety and efficacy were evaluated in a study of 266 patients who had received at least 2 prior therapies (including bortezomib and thalidomide). Evaluate the complete or partial disappearance of tumors in patients after treatment (overall response rate). The results showed that the overall effective rate of patients was 23%, and the median remission time was 7.8 months. [0003] In the published preparation method of carfilzomib, the condensing agents used for carfilzomib condensation are PyBOP and HOB...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06
Inventor 叶乾堂叶福林范建华陈俊飞
Owner 河南海汇药物研究有限公司
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