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A kind of preparation method of crude drug olbitasvir

A technology for obitasvir and bulk drug, which is applied in the field of preparation of bulk drug obitasvir, can solve the problems of high cost, complicated process and the like, and achieves the effects of high yield and easy separation and purification of products

Active Publication Date: 2021-08-31
安徽拜善晟制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] One of the purposes of the present invention is to overcome the defects in the prior art and provide a method for preparing the bulk drug olbitasvir to solve the problems of high cost and complicated process in the prior art

Method used

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  • A kind of preparation method of crude drug olbitasvir
  • A kind of preparation method of crude drug olbitasvir
  • A kind of preparation method of crude drug olbitasvir

Examples

Experimental program
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Effect test

Embodiment 1

[0043] With A4 as raw material, according to the valine peptide coupling reaction conditions mentioned in CN102333772 A, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride as valine peptide coupling reagent , dichloromethane is used as solvent, and the concrete technological process is:

[0044] Add 50L of dichloromethane, 25L of nitrogen methylmorpholine, 10kg of MOC-L-valine, 11kg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride into a 11kg In the reactor of A4, stir for 3 hours, keep warm at 15-25° C., monitor by TLC, and TLC shows that the reaction is complete.

[0045] Post-processing: start stirring, add ethanol into the reaction kettle, put in the crude product and activated carbon, heat up to 50-60°C, stir for 30 minutes, dissolve, filter, and the filtrate enters the crystallization kettle, cools down to 20-25°C, and crystallizes for 4 hours. Centrifuge, dry under reduced pressure at 40-45° C. for 4-6 hours, and weigh to obtain 11 kg of white solid...

Embodiment 2

[0048] The difference between embodiment 2 and embodiment 1 is that nitrogen methylmorpholine is added in the reaction system, and the volume ratio of dichloromethane to nitrogen methylmorpholine is 1:1.

Embodiment 3

[0050] Example 3 Using A3 as a raw material, obitasvir was prepared through a two-step reaction of amino deprotection and valine peptide coupling.

[0051] The process is as follows: in a dry 500L reactor, add 45kg of ethanol, 15kg of raw material intermediates, 20L of hydrochloric acid ethanol solution, control the temperature at 10-15°C, and stir for 1 hour to obtain 10.5kg of A4 intermediates with a yield of 93 %.

[0052] In the above process, the solvent for the amino group deprotection reaction is ethanol, which can be replaced by other reaction solvents or combinations of solvents in the summary of the invention.

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Abstract

The invention discloses a preparation method of a bulk drug olbitasvir, which comprises bis Nitro reduction reaction S1, diamino proline peptide coupling reaction S2, pyrrolidine amino deprotection reaction S3, and pyrrolidine amino valine peptide coupling reaction S4. 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is used as the valine peptide coupling reagent in the preparation method of the raw material drug obitavir, which is disclosed in the prior art Compared with peptide coupling reagents such as EDAC / HOBT, PyBOP, HATU, and T3P, the final product synthesis step has a higher yield, and the separation and purification of the product is easier.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a crude drug olbitasvir. Background technique [0002] Ombitasvir, also known as ombitasvir, is one of the main components of ABT triple anti-hepatitis C drugs, which has the following structure: [0003] [0004] CN102333772 A, CN103172620 A, CN103819459 A disclose a series of synthetic methods of antiviral compounds, which include intermediate 1-(4-(tert-butylphenyl)-2,5-bis(4-nitrophenyl) ) Reduction of dinitro group in pyrrolidine, proline peptide coupling reaction of diamino group, deprotection of pyrrolidine amino group and valine peptide coupling of pyrrolidine amino group. [0005] Among them, regarding the proline-peptide coupling reaction of the diamino group and the valine-peptide coupling treatment of the pyrrolidine amino group in the last step, the following content is disclosed in the patent document: The compounds of the present ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/072C07K1/10A61K9/20A61K38/05A61P1/16A61P31/14
CPCA61K9/2004A61K38/05C07K5/06104
Inventor 吴章栓常松王喆明魏勇慕龙治范征
Owner 安徽拜善晟制药有限公司
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