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Preparation method of carfilzomib intermediate and carfilzomib

A carfilzomib and intermediate technology, which is applied in the field of carfilzomib intermediate and carfilzomib preparation, can solve problems such as unfavorable large-scale industrial production, poor controllability, complex and diverse solvents and the like

Inactive Publication Date: 2014-07-23
苏州科耐尔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods generally have some problems, such as low synthesis yield, product loss caused by extraction and separation of various intermediates, so more starting materials are consumed; moreover, there are many types of all-liquid phase synthesis reactions, and the reaction conditions and solvents used are complex and diverse, which are controllable. Poor performance, not conducive to large-scale industrial production

Method used

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  • Preparation method of carfilzomib intermediate and carfilzomib
  • Preparation method of carfilzomib intermediate and carfilzomib
  • Preparation method of carfilzomib intermediate and carfilzomib

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Experimental program
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Effect test

Embodiment 1

[0069] The preparation of embodiment 1Fmoc-Phe-resin

[0070] Take 10 g of Wang Resin (1.7 mmol / g) and place it in a polypeptide reactor, add 100 mL of DCM, blow and stir with nitrogen gas for 30 minutes, make the resin fully swell, and then drain the DCM. Weigh Fmoc-Phe-OH19.8g, HOBt8.3g, add DMF80mL and stir to dissolve, ice bath for 5 minutes, add DIC9.5mL, ice bath activation for 15 minutes. Filtrate, add the filtrate into the polypeptide reactor, and blow with nitrogen to stir the reaction. Take 0.75 g of DMAP and add 20 mL of DMF to dissolve it, drop it into the polypeptide reactor, drain the reaction solution after 2 hours of reaction, wash with DMF 3 times, 100 mL each time, 1 minute. Take 8.0mL of acetic anhydride, 6.8mL of pyridine, and 80mL of DMF into the polypeptide reactor, blow with nitrogen and stir for 6 hours. Drain the reaction liquid, wash with DMF 3 times, 100 mL each time, 1 minute. Wash with DCM 4 times, 100 mL each time, for 10 minutes. Remove the r...

Embodiment 2

[0071] The preparation of embodiment 2Fmoc-Phe-resin

[0072] Take 8g of CTC Resin (1.5mmol / g) and place it in a polypeptide reactor, add 80mL of DCM, blow and stir with nitrogen gas for 30 minutes, fully swell the resin, and drain the DCM. Weigh 13.9g of Fmoc-Phe-OH, add 80mL of DMF and stir to dissolve, add 18.9mL of DIEA, put it into the polypeptide reactor after 15 minutes of ice bathing, blow and stir with nitrogen for 2 hours, drain the reaction solution, wash with DMF 3 times, each time 80 mL, 1 minute. Add blocking reagent (anhydrous methanol / DIEA / DCM=1 / 2 / 17 (volume ratio)) to block twice, 80 mL each time, for 10 minutes. DCM was washed 4 times, 80 mL each time, for 10 minutes. Remove the resin and dry it. Obtained Fmoc-Phe-CTC Resin11.7g. The degree of substitution was 0.76 mmol / g.

Embodiment 3

[0073] The preparation of embodiment 3Fmoc-Phe-resin

[0074] Take 80g of CTC Resin (1.5mmol / g) and place it in a polypeptide reactor, add 800mL of DCM, blow and stir with nitrogen gas for 30 minutes, fully swell the resin, and drain the DCM. Weigh 139g of Fmoc-Phe-OH, add 800mL of DMF and stir to dissolve, add 189mL of DIEA, put it into the polypeptide reactor after 15 minutes of ice bathing, blow and stir with nitrogen gas for 2 hours, then drain the reaction solution, wash with DMF 3 times, 800mL each time, 1 minute . Add blocking reagent (anhydrous methanol / DIEA / DCM=1 / 2 / 17 (volume ratio)) to block twice, 800 mL each time, for 10 minutes. DCM was washed 4 times, 800 mL each time, for 10 minutes. Remove the resin and dry it. Fmoc-Phe-CTC Resin 108g was obtained. The degree of substitution was 0.75 mmol / g.

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Abstract

The invention relates to a preparation method of a carfilzomib intermediate and carfilzomib. The method comprises the following steps: (1) enabling a solid-phase resin carrier to couple with Fmoc-Phe-OH in the presence of an activator to obtain Fmoc-Phe-resin; (2) enabling Fmoc-Phe-resin to sequentially couple with Fmoc-Phe-OH, Fmoc-HoPhe-OH and 4-morpholine acetic acid through a solid-phase synthesis method to obtain tetrapeptide intermediate resin, wherein the coupling is performed in the presence of a coupling agent system, the coupling agent system comprises a condensing agent and a reaction solvent, and the resin firstly removes Fmoc protecting group before coupling; (3) performing pyrolysis on the tetrapeptide intermediate resin by a pyrolysis agent, and removing the resin to obtain the carfilzomib tetrapeptide intermediate. The method provided by the invention has the advantages of high yield, low pollution and simple and controllable reaction, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a carfilzomib intermediate and a preparation method of carfilzomib. Background technique [0002] The foreign name or generic name of Carfilzomib is Carfilzomib, which has the following structure: [0003] [0004] On July 20, 2012, the U.S. Food and Drug Administration (FDA) approved the listing of ONYXPHARMSINC’s product Carfilzomib (Carfilzomib) freeze-dried powder for injection. Carfilzomib can be used to treat patients who have received at least two drugs before (including Bortezomib and immunomodulators) in patients with multiple myeloma. Multiple myeloma is a malignant clonal disease of plasma cells. The incidence rate is increasing year by year, ranking second among hematological malignancies. With the improvement of treatment level, although the complete remission rate is high, the survival rate is still low. One of the main reasons is relapse. The approval of carfilzomib provides a treatment option for patients ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/117C07K5/06C07K1/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 王蔡典冯福权余军
Owner 苏州科耐尔医药科技有限公司
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