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Method for preparing vorapaxar intermediate

An intermediate and equivalent technology, applied in the field of preparation of Vorapaxa intermediate VRPX-200, can solve the problems of unstable yield, high safety hazard, harsh reaction conditions, etc., and achieves low safety risk, stable yield, mild response

Inactive Publication Date: 2018-12-07
BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to provide a method for the industrial production of Vrapasar intermediate VRPX-200, so as to overcome technical difficulties such as harsh reaction conditions, high safety hazards, and unstable yield in the existing process

Method used

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  • Method for preparing vorapaxar intermediate
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  • Method for preparing vorapaxar intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Step-1: Preparation of intermediate VRPX-101

[0026] Compound VRPX-100 (1.5Kg, 442mmol) was dissolved in 9.0L anhydrous tetrahydrofuran, cooled to -5~0°C, and borane dimethyl sulfide (504g, 663mmol) was added dropwise to control the internal temperature at -5~0°C, React for 5-10 hours; TLC monitors that the reaction of compound VRPX-100 is complete, add 400 grams of methanol, quench the reaction, and distill it under vacuum to dryness, and add 3.0L of anhydrous tetrahydrofuran to the remaining concentrate, and distill it under vacuum To dryness, the residue was directly put into the next reaction.

[0027] Step-2: Preparation of intermediate VRPX-200

[0028] Dissolve the crude product of VRPX-101 from the previous step in 4.5L DMSO, at room temperature 20-25°C, add pyridine sulfur trioxide (915g, 575mmol) in batches, stir for about 2-3 hours, TLC shows that the substrate is complete, add 9.0L to purify Quench the reaction with water, add 4.5L ethyl acetate for extra...

Embodiment 2

[0030] Step-1: Preparation of intermediate VRPX-101

[0031] Dissolve compound VRPX-100 (15g, 4.4mmol) in 90mL of anhydrous tetrahydrofuran, lower the temperature at -5~0°C, add borane dimethyl sulfide (3.3g 4.4mmol) dropwise, react at -5~0°C for 15~ 20 hours; TLC showed that most of the reaction of compound VRPX-100 was complete, adding 4g of methanol, quenching the reaction, distilling under vacuum and reducing to dryness, and adding 30mL of anhydrous tetrahydrofuran to the remaining concentrate, distilling under vacuum and reducing to dryness, the remaining directly into the next reaction.

[0032] Step-2: Preparation of intermediate VRPX-200

[0033] Dissolve the crude product of VRPX-101 from the previous step in 45mL DMSO, at room temperature 20-25°C, add pyridine sulfur trioxide (7.1g) in batches, stir for about 2-3 hours, TLC shows that most of the substrates have reacted completely, add 90mL to purify Quench the reaction with water, add 45 mL of ethyl acetate for ex...

Embodiment 3

[0035] Step-1: Preparation of intermediate VRPX-101

[0036] Dissolve compound VRPX-100 (15g, 4.4mmol) in 90mL of anhydrous tetrahydrofuran, lower the temperature to -5~0°C, add borane dimethyl sulfide (10.0g 13.2mmol) dropwise, and react at -5~0°C for 3~ 6 hours; TLC showed that the compound VRPX-100 was completely consumed. Add 4g of methanol to quench the reaction. Distill in vacuum to dryness. For the remaining concentrate, add 30 mL of anhydrous tetrahydrofuran and distill in vacuum to dryness. The residue was directly into the next reaction.

[0037] Step-2: Preparation of intermediate VRPX-200

[0038] Dissolve the crude VRPX-101 from the previous step in 45mL DMSO, at room temperature 20-25°C, add sulfur trioxide pyridine (14.2g) in batches, stir for about 2-3 hours, TLC shows that the reaction of the substrate is complete, add 90mL purified water to quench Inhibit the reaction, add 45mL ethyl acetate for extraction, separate the layers, extract the aqueous phase twi...

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Abstract

The invention provides a method for preparing vorapaxar intermediate, which belongs to the technical field of chemical drug synthesis. The method comprises the following steps: step 1: in a tetrahydrofuran solvent, a compound VRPX-100 is selectively reduced by borane dimethyl sulfide to generate alcohol VRPX-101; and step 2: a alcohol intermediate obtained in the step 1 is oxidized by sulfur trioxide pyridine without separation to obtain VRPX-200. The method of the invention stably increases the total reaction yield from 20-60% to 70-80%; reduces the difficulty of production operation and safety risk, and is suitable for industrial production of kilogram scale.

Description

technical field [0001] The invention relates to the field of medicines, and relates to a preparation method of Vrapaxar intermediate VRPX-200. Background technique [0002] Vorapaxar sulfate is a protease-activated receptor-1 (PAR-1) antagonist indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). Vorapaxar sulfate has been shown to reduce the combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. Vorapasa Sulfate Tablets (trade name Zontivity) was developed by Merck, launched in Europe in February 2014, and approved by FDA in May 2014. [0003] The preparation method of Vrapasar intermediate VRPX-200 is disclosed in CN 101137647A. In this route, the compound VRPX-100 is converted into the acid chloride compound VRPX-102 under the action of oxalyl chloride / DMF, and then reduced by hydrogen gas under the catalysis of palladium carbon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/92
CPCC07D307/92
Inventor 姚云凡甄志彬王博张翔高世静刘昆陶新华
Owner BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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