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Continuous flow teriflunomide preparation process

A technology for teriflunomide and preparation process, which is applied in the field of continuous flow teriflunomide preparation technology, can solve problems such as hazards, and achieve the effects of solving the impact of ring damage, stable process operation, and reducing potential safety hazards.

Inactive Publication Date: 2021-11-19
河北凯威恒诚制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved in the present invention is to provide a continuous flow teriflunomide preparation process to solve the problem of acid mist causing harm to equipment during the synthesis and preparation of teriflunomide, and to reduce potential safety hazards in the production process

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] A. Preparation of cyanoacetyl chloride T0

[0043] A1: dissolved 30 g of cyanoacetic acid SM2 in 150 ml of tetrahydrofuran;

[0044] A2: 80.78 g of phosphorus addition in 500 ml of tetrahydrofuran is formulated in a mixed solution;

[0045]a3: the solution from step a1 and step a2 prepared was passed via a metering pump to the microchannel reactor, the flow rate of the solution wherein step a1 prepared was 20g / min, the flow rate of the solution of step a2 prepared was 64g / min; 25 ℃, a reaction under atmospheric pressure 100s, cyano chloride to give T0;

[0046] B. Preparation intermediate-2-cyano-N- [4- (trifluoromethyl) phenyl] -ecetamide T1

[0047] b1: The SM1 38g trifluoromethylaniline was dissolved in 380ml of tetrahydrofuran, was added 76g triethylamine;

[0048] b2: The cyanoacetyl chloride prepared in step b1 T0 and step A was separately conveyed via a metering pump into a microchannel reactor, wherein step b1 solution flow rate is 28g / min, T0 flow rate of 53g...

Embodiment 2

[0054] A. Preparation of cyanoacetyl chloride T0

[0055] a1: 30g of acetic acid was dissolved in 300ml cyano SM2 dichloromethane;

[0056] A2: Preparation chloro reagents: 55g thionyl chloride was added to 500ml of tetrahydrofuran was prepared a mixed solution;

[0057] a3: The solution prepared in step a1 and step a2 are passed via a metering pump into a microchannel reactor, wherein the flow rate of the solution prepared in step a1 of 50g / min, the flow rate of the solution prepared in step a2 of 6.7g / min; 30 ℃, at one atmosphere pressure, the reaction 100s, cyano chloride to give T0;

[0058] B. Preparation intermediate-2-cyano-N- [4- (trifluoromethyl) phenyl] -ecetamide T1

[0059] b1: The SM1 38g trifluoromethylaniline was dissolved in 380ml of dichloromethane, 95g of triethylamine was added;

[0060] b2: The cyanoacetyl chloride prepared in step b1 T0 and step A was separately conveyed via a metering pump into a microchannel reactor, wherein step b1 solution flow rate is...

Embodiment 3

[0066] A. Preparation of cyanoacetyl chloride T0

[0067] a1: 30g of acetic acid was dissolved in 600ml cyano SM2 dichloromethane;

[0068] a2: preparing chlorinated reagents: 68g of phosphorus trichloride was added 680ml of methylene chloride, stirring and blending;

[0069] a3: The solution prepared in step a1 and step a2 are passed via a metering pump into a microchannel reactor, wherein the flow rate of the solution prepared in step a1 of 60g / min, the flow rate of the solution prepared in step a2 is 70.5g / min; 30 ℃, at one atmosphere pressure, the reaction was completed, acetyl chloride to give a cyano T0;

[0070] B. Preparation intermediate-2-cyano-N- [4- (trifluoromethyl) phenyl] -ecetamide T1

[0071] b1: The SM1 38g trifluoromethylaniline was dissolved in 570ml of methylene chloride, 190g of triethylamine were added;

[0072] b2: The cyanoacetyl chloride prepared in step b1 T0 and step A was separately conveyed via a metering pump into a microchannel reactor, wherein ...

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Abstract

The invention discloses a continuous flow teriflunomide preparation process which comprises the following steps: using a continuous flow reactor, taking cyanoacetic acid as a starting material, preparing cyanoacetyl chloride through chlorination, synthesizing a teriflunomide intermediate through the cyanoacetyl chloride and p-trifluoromethylaniline, and synthesizing teriflunomide through the intermediate and acetyl chloride. The method has the advantages of high safety, low cost, low energy consumption and high production yield.

Description

Technical field [0001] The present invention relates to the field of chemical synthesis, and more particularly to a process of continuous fluorine amine. Background technique [0002] Teriflunomide, Chemical Name: (Z) -2-cyano-3-hydroxy-N- [4- (trifluoromethyl) phenyl] -2-butenamide. Tripfluorine is an oral pyrimidine synthase inhibitor and an immunomodulator developed by French Sanopi Avante, which can reverse the inhibitory dihydrochloric acid dehydrogenase (DHODH) - related to the primary synthesis A key enzyme. DHODH is a mitochondrase containing iron-free plain-dependent mitochromese, a critical enzyme in nucleic acid, catalyzed pyrimidine from the fourth step in the head biosynthesis pathway. DHODH is an important target of immune-related diseases, inhibiting DHODH, preventing neonatizine synthesis, causing DNA synthesis disorder, inhibiting activated T lymphocytes, B lymphocytes, and tumor cell proliferation, thereby plays importance in immunosuppression and anti-tumor eff...

Claims

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Application Information

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IPC IPC(8): C07C253/30C07C255/23
CPCC07C253/30C07C255/23C07C255/19
Inventor 庞玉宁卓子健闫刚云
Owner 河北凯威恒诚制药有限公司
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