阅读说明：本技术 一种连续流特立氟胺制备工艺 (Continuous flow teriflunomide preparation process ) 是由 庞玉宁 卓子健 闫刚云 于 2021-09-23 设计创作，主要内容包括：本发明公开了一种连续流特立氟胺制备工艺,使用连续流反应器,以氰基乙酸为起始物料,通过氯代制备氰基乙酰氯,通过氰基乙酰氯与对三氟甲基苯胺合成特立氟胺中间体,中间体与乙酰氯合成特立氟胺。本发明具有安全性高、成本低、耗能低、生产收率高的优点。(The invention discloses a continuous flow teriflunomide preparation process, which uses a continuous flow reactor, takes cyanoacetic acid as a starting material, prepares cyanoacetyl chloride through chlorination, synthesizes teriflunomide intermediate through cyanoacetyl chloride and p-trifluoromethylaniline, and synthesizes teriflunomide through the intermediate and acetyl chloride. The invention has the advantages of high safety, low cost, low energy consumption and high production yield.)

1. A continuous flow teriflunomide preparation process is characterized by comprising the following steps:

A. preparation of Cyanoacetyl chloride T0

a 1: dissolving cyanoacetic acid SM2 in a solvent;

a 2: preparing a chlorinated reagent: if a solid chlorinated reagent is adopted, adding the solid chlorinated reagent into a solvent to prepare a mixed solution, and then adding the mixed solution into the solution obtained in the step a 1; if a liquid chlorinated reagent is adopted, direct sample injection can be carried out;

a 3: respectively conveying the solutions prepared in the steps a1 and a2 to a microchannel reactor through a metering pump, and reacting for 50s-140s at the temperature of 10-60 ℃ and under one atmospheric pressure to obtain cyano-acetyl chloride T0;

B. preparation of intermediate 2-cyano-N- [4- (trifluoromethyl) phenyl ] -acetamide T1

b 1: dissolving para-trifluoromethylaniline SM1 in a solvent, and then adding triethylamine, pyridine or inorganic base;

b 2: respectively conveying the cyanoacetyl chloride T0 prepared in the step A and the solution in the step b1 to a microchannel reactor through a metering pump, reacting for 50s-140s at the temperature of 10-60 ℃ and under one atmospheric pressure, receiving reaction liquid, and then quenching, filtering, pulping and drying to prepare an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1;

C. preparation of teriflunomide I

c 1: dissolving the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 in a solvent, adding an alkali reagent, and uniformly mixing;

c 2: and c, respectively conveying the mixed solution obtained in the step c1 and acetyl chloride into a microchannel reactor through a metering pump, reacting for 50-140s at the temperature of 10-60 ℃ and under one atmospheric pressure, receiving the reaction solution, and then quenching, filtering, pulping and drying to prepare teriflunomide I.

2. The continuous-flow teriflunomide production process of claim 1, wherein: the solvent in the step a1, the step b1 and the step c1 comprises dichloromethane and tetrahydrofuran.

3. The continuous-flow teriflunomide production process of claim 1, wherein: the ratio of cyanoacetic acid SM2 to solvent in step a1 was 1 g: 5ml to 30 ml.

4. The continuous-flow teriflunomide production process of claim 1, wherein: the ratio of the chlorinated reagent to the cyanoacetic acid SM2 in the step a2 is 1.1-1.5: 1, and the ratio of chlorinated reagent to solvent is 1 g: 5ml to 15 ml.

5. The continuous-flow teriflunomide production process of claim 1, wherein: the flow rate of the step a3, the step b2 and the step c2 when being conveyed into the microchannel reactor through the metering pump is in the range of 10g/min-60 g/min.

6. The continuous flow teriflunomide production process of claim 2, wherein: the ratio of the trifluoromethyl aniline SM1 to the solvent in the step b1 is 1 g: 5ml-15ml, wherein the molar ratio of the trifluoromethylaniline SM1 to triethylamine, pyridine or inorganic base is 1: 2-5.

7. The continuous flow teriflunomide production process of claim 2, wherein: the ratio of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 to solvent in step c1 was 1 g: 5ml to 20 ml; the alkali reagent is sodium hydride or sodium hydroxide, and the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 to the alkali reagent is 1: 2-5.

8. The continuous-flow teriflunomide production process of claim 1, wherein: the chlorinating reagent in the step a2 comprises thionyl chloride, phosphorus pentachloride and phosphorus trichloride.

Technical Field

The invention relates to the technical field of chemical synthesis, and particularly relates to a continuous flow teriflunomide preparation process.

Background

Teriflunomide (Teriflunomide), chemical name: (Z) -2-cyano-3-hydroxy-N- [4- (trifluoromethyl) phenyl ] -2-butenamide. Teriflunomide is an oral pyrimidine synthase inhibitor and immunomodulator developed by penoxepine-amphetamine france, and can reverse the inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme associated with de novo pyrimidine synthesis. DHODH is a flavin-dependent mitochondrial enzyme containing iron, a key enzyme in pyrimidine synthesis in nucleic acids, catalyzing the fourth step of the pyrimidine de novo biosynthetic pathway. DHODH is an important target of immune-related diseases, inhibits DHODH, can prevent synthesis of new pyrimidine, causes DNA synthesis disorder, inhibits proliferation of activated T lymphocyte, B lymphocyte and tumor cell, and plays an important role in immunosuppression and tumor resistance. The known mechanism of action includes the prevention of de novo pyrimidine synthesis in lymphocytes by inhibition of DHODH, and interference with tyrosine kinase activity, which is a promising market.

The patent EP2280938a2 discloses a synthesis method of teriflunomide: the method is characterized in that ethyl cyanoacetate reacts with acetic anhydride to obtain an intermediate under the action of potassium carbonate, and then the intermediate reacts with p-trifluoromethylaniline to obtain teriflunomide.

In the traditional preparation process of teriflunomide, a kettle-type reactor is mostly adopted, a plurality of dangerous chemical reagents such as acyl chloride, thionyl chloride, phosphorus pentachloride and the like can be used in the reaction process, and the reagents can generate a large amount of acid mist, so that the reagents are harmful to human bodies, have strong corrosivity to equipment, reduce the service life of the equipment and increase the environmental pollution.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a continuous flow teriflunomide preparation process, so as to solve the problem that acid mist is harmful to equipment in the synthetic preparation process of teriflunomide, and reduce the potential safety hazard in the production process.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows.

A continuous flow teriflunomide preparation process specifically comprises the following steps:

A. preparation of Cyanoacetyl chloride T0

a 1: dissolving cyanoacetic acid SM2 in a solvent;

a 2: preparing a chlorinated reagent: if a solid chlorinated reagent is adopted, adding the solid chlorinated reagent into a solvent to prepare a mixed solution, and then adding the mixed solution into the solution obtained in the step a 1; if a liquid chlorinated reagent is adopted, direct sample injection can be carried out;

a 3: respectively conveying the solutions prepared in the steps a1 and a2 to a microchannel reactor through a metering pump, and reacting for 50s-140s at the temperature of 10-60 ℃ and under one atmospheric pressure to obtain cyano-acetyl chloride T0;

B. preparation of intermediate 2-cyano-N- [4- (trifluoromethyl) phenyl ] -acetamide T1

b 1: dissolving para-trifluoromethylaniline SM1 in a solvent, and then adding triethylamine, pyridine or inorganic base;

b 2: respectively conveying the cyanoacetyl chloride T0 prepared in the step A and the solution in the step b1 to a microchannel reactor through a metering pump, reacting for 50s-140s at the temperature of 10-60 ℃ and under one atmospheric pressure, receiving reaction liquid, and then quenching, filtering, pulping and drying to prepare an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1;

C. preparation of teriflunomide I

c 1: dissolving the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 in a solvent, adding an alkali reagent, and uniformly mixing;

c 2: conveying the 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 and acetyl chloride to a microchannel reactor through a metering pump respectively, completing the reaction within 50s-140s at the temperature of 10-60 ℃ and under one atmospheric pressure, receiving the reaction liquid, and then quenching, filtering, pulping and drying to prepare teriflunomide I.

According to the further optimized technical scheme, the solvent comprises dichloromethane and tetrahydrofuran.

Further optimizing the technical scheme that the ratio of the cyanoacetic acid SM2 to the solvent in the step a1 is 1 g: 5ml to 30 ml.

Further optimizing the technical scheme, the ratio of the chlorinated reagent to the cyanoacetic acid SM2 in the step a2 is 1.1-1.5: 1, and the ratio of chlorinated reagent to solvent is 1 g: 5ml to 15 ml.

According to the further optimized technical scheme, the flow rate range of the step a3, the step b2 and the step c2 when the materials are conveyed into the microchannel reactor through a metering pump is 10g/min-60 g/min.

Further optimizing the technical scheme that the ratio of the trifluoromethyl aniline SM1 to the solvent in the step b1 is 1 g: 5ml-15ml, wherein the molar ratio of the trifluoromethylaniline SM1 to triethylamine, pyridine or inorganic base is 1: 2-5.

In a further optimized technical scheme, the ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 in the step c1 to the solvent is 1 g: 5ml to 20 ml; the alkali reagent is sodium hydride or sodium hydroxide, and the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 to the alkali reagent is 1: 2-5.

In a further optimized technical scheme, the chlorinated reagent in the step a2 comprises thionyl chloride, phosphorus pentachloride and phosphorus trichloride.

Due to the adoption of the technical scheme, the technical progress of the invention is as follows.

The invention provides a continuous flow teriflunomide preparation process, which takes cyanoacetic acid as a starting material to synthesize a teriflunomide intermediate by preparing cyanoacetyl chloride and p-trifluoromethylaniline, and synthesizes the teriflunomide intermediate with acetyl chloride; the continuous flow reactor which can more effectively carry out chemical synthesis is used in the whole reaction process, so that the reaction is more sufficient, the reaction time is reduced to 50-140s from 3-12h, the process operation is stable, the damage influence of acid mist formation is solved, and the potential safety hazard is reduced. The invention has the advantages of high safety, low cost, low energy consumption and high production yield.

Drawings

FIG. 1 is a process flow equation of the present invention;

FIG. 2 is a NMR spectrum of the final product of example 1 in the present invention;

Detailed Description

The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.

A process for preparing teriflunomide by continuous flow includes such steps as preparing cyanoacetyl chloride by chloro method using cyanoacetic acid as initial raw material, synthesizing teriflunomide intermediate by cyanoacetyl chloride and p-trifluoromethyl aniline, and synthesizing teriflunomide by the intermediate and acetyl chloride, and features simple process, low cost and high output rate. The method specifically comprises the following steps:

A. preparation of Cyanoacetyl chloride T0

a 1: dissolving cyanoacetic acid SM2 in a solvent, wherein the solvent is dichloromethane or tetrahydrofuran, and the cyanoacetic acid SM2 is dissolved in 5ml-30ml of the solvent per 1 g;

a 2: preparing a chlorinated reagent: if a solid chlorinating reagent is used, the molar ratio of the solid chlorinating reagent to the SM2 is 1.1-1.5: 1, adding the solid chlorinated reagent into a solvent (dichloromethane or tetrahydrofuran) to prepare a mixed solution, and controlling the ratio of the chlorinated reagent to the solvent to be 1 g: 5ml to 15 ml; adding the mixture into the solution obtained in the step a 1; if a liquid chlorinating reagent is used, the preparation and cyanoacetic acid SM2 molar ratio is 1.1-1.5: 1, namely a liquid chlorinating reagent;

a 3: respectively conveying the solutions prepared in the steps a1 and a2 into a microchannel reactor at the flow rate of 10g/min-60g/min through a metering pump, and reacting at the temperature of 10-60 ℃ and one atmospheric pressure for 50-140s to obtain cyanoacetyl chloride T0;

B. preparation of intermediate 2-cyano-N- [4- (trifluoromethyl) phenyl ] -acetamide T1

b 1: dissolving para-trifluoromethylaniline SM1 in a solvent which is dichloromethane or tetrahydrofuran, and controlling the ratio of the para-trifluoromethylaniline SM1 to the solvent to be 1 g: 5ml to 15 ml; and adding triethylamine, pyridine or inorganic base, and controlling the molar ratio of the trifluoromethylaniline SM1 to the triethylamine, the pyridine or the inorganic base to be 1: 2-5;

b 2: respectively conveying the cyanoacetyl chloride T0 prepared in the step A and the solution in the step b1 to a microchannel reactor at the flow rate of 15g/min-40g/min through a metering pump, reacting at the temperature of 10-60 ℃ under one atmospheric pressure, pouring the reaction liquid into purified water after receiving the reaction liquid, stirring for 30min, and quenching; then filtering, and washing a filter cake by using purified water; pulping, and drying to obtain intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1;

C. preparation of teriflunomide I

c 1: dissolving the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 prepared in the step B in a solvent, wherein the solvent is dichloromethane or tetrahydrofuran, and controlling the weight-to-volume ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 to the solvent to be 1 g: 5ml to 20 ml; adding an alkali reagent which is sodium hydride or sodium hydroxide, controlling the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 to the alkali reagent to be 1:2-5, and uniformly mixing;

c 2: mixing a mixture of 1: 1.2-1.5 of 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 and acetyl chloride are respectively conveyed into a microchannel reactor through a metering pump at the flow rate of 20g/min-60 g/min; reacting at 10-60 ℃ under one atmospheric pressure for s, pouring the reaction liquid into purified water after receiving the reaction liquid, stirring for 30min, and quenching; then filtering, and washing a filter cake by using purified water; pulping, and drying to prepare teriflunomide I.

Example 1:

A. preparation of Cyanoacetyl chloride T0

a 1: 30g of cyanoacetic acid SM2 were dissolved in 150ml of tetrahydrofuran;

a 2: adding 80.78g of phosphorus pentachloride into 500ml of tetrahydrofuran to prepare a mixed solution;

a 3: respectively conveying the solutions prepared in the steps a1 and a2 to a microchannel reactor through a metering pump, wherein the flow rate of the solution prepared in the step a1 is 20g/min, and the flow rate of the solution prepared in the step a2 is 64 g/min; reacting at 25 ℃ under one atmosphere for 100s to obtain cyanoacetyl chloride T0;

B. preparation of intermediate 2-cyano-N- [4- (trifluoromethyl) phenyl ] -acetamide T1

b 1: 38g of p-trifluoromethylaniline SM1 was dissolved in 380ml of tetrahydrofuran, and 76g of triethylamine was added;

b 2: respectively conveying the cyanoacetyl chloride T0 prepared in the step A and the solution in the step b1 to a microchannel reactor through a metering pump, wherein the flow rate of the solution in the step b1 is 28g/min, and the flow rate of the solution in the step b 0 is 53 g/min; reacting at 25 deg.C under one atmosphere, receiving the reaction solution, pouring the reaction solution into 5L purified water, stirring for 30min, and quenching; then, filtering is carried out, and 2L of purified water is used for washing a filter cake; then carrying out alcohol pulping, and finally drying to prepare 43g of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1;

C. preparation of teriflunomide I

c 1: dissolving 40g of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 prepared in the step B in 400ml of tetrahydrofuran, and then adding 20g of sodium hydroxide to mix uniformly;

c 2: respectively conveying the solution prepared in the step c1 to a microchannel reactor through a metering pump at the flow rate of 40g/min and acetyl chloride at the flow rate of 2g/min, reacting at the temperature of 35 ℃ under one atmospheric pressure, receiving the reaction liquid, pouring the reaction liquid into 2L of purified water, stirring for 30min, and quenching; then filtering is carried out, and the filter cake is washed by 500mL of purified water; then carrying out alcohol pulping, and finally drying to prepare teriflunomide I.

And (3) identifying the obtained white solid compound by using a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data corresponding to the graph 2 are as follows:¹h NMR (600MHz, DMS0-d6) δ 10.76(s, 1H), 7.77(d, J ═ 8.5Hz, 2H), 7.66(d, J ═ 8.6Hz, 2H), 2.26(s, 3H), was essentially identical to the reported hydrogen spectrum shifts for teriflunomide, indicating that the resulting product was teriflunomide.

Example 2:

A. preparation of Cyanoacetyl chloride T0

a 1: 30g of cyanoacetic acid SM2 were dissolved in 300ml of dichloromethane;

a 2: preparing a chlorinated reagent: adding 55g of thionyl chloride into 500ml of tetrahydrofuran to prepare a mixed solution;

a 3: respectively conveying the solutions prepared in the steps a1 and a2 to a microchannel reactor through a metering pump, wherein the flow rate of the solution prepared in the step a1 is 50g/min, and the flow rate of the solution prepared in the step a2 is 6.7 g/min; reacting at 30 ℃ under one atmosphere for 100s to obtain cyanoacetyl chloride T0;

B. preparation of intermediate 2-cyano-N- [4- (trifluoromethyl) phenyl ] -acetamide T1

b 1: 38g of p-trifluoromethylaniline SM1 was dissolved in 380ml of dichloromethane, and 95g of triethylamine was added;

b 2: respectively conveying the cyanoacetyl chloride T0 prepared in the step A and the solution in the step b1 to a microchannel reactor through a metering pump, wherein the flow rate of the solution in the step b1 is 25g/min, and the flow rate of the solution in the step b 0 is 70.5 g/min; reacting at 30 ℃ under one atmospheric pressure, receiving the reaction solution, pouring the reaction solution into 6L of purified water, stirring for 30min, and quenching; then, filtering is carried out, and 2L of purified water is used for washing a filter cake; then the alcohol is beaten, and finally the drying is carried out, thus preparing 37g of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1;

C. preparation of teriflunomide I

c 1: dissolving 35g of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 prepared in the step B in 350ml of tetrahydrofuran, and then adding 18g of sodium hydroxide and uniformly mixing;

c 2: b1, respectively conveying the solution in the step b1 to a microchannel reactor through a metering pump at the flow rate of 30g/min and acetyl chloride at the flow rate of 1.4g/min, reacting at the temperature of 35 ℃ under one atmospheric pressure, pouring the reaction liquid into 1.8L of purified water after receiving the reaction liquid, stirring for 30min, and quenching; then filtering is carried out, and the filter cake is washed by 500mL of purified water; then carrying out alcohol pulping, and finally drying to prepare teriflunomide I.

And (3) identifying the obtained white solid compound by using a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data corresponding to the graph 2 are as follows:¹h NMR (600MHz, DMS0-d6) δ 10.76(s, 1H), 7.77(d, J ═ 8.5Hz, 2H), 7.66(d, J ═ 8.6Hz, 2H), 2.26(s, 3H), was essentially identical to the reported hydrogen spectrum shifts for teriflunomide, indicating that the resulting product was teriflunomide.

Example 3:

A. preparation of Cyanoacetyl chloride T0

a 1: 30g of cyanoacetic acid SM2 were dissolved in 600ml of dichloromethane;

a 2: preparing a chlorinated reagent: adding 680ml dichloromethane into 68g phosphorus trichloride, and stirring and uniformly mixing;

a 3: respectively conveying the solutions prepared in the steps a1 and a2 to a microchannel reactor through a metering pump, wherein the flow rate of the solution prepared in the step a1 is 60g/min, and the flow rate of the solution prepared in the step a2 is 70.5 g/min; completing the reaction at 30 ℃ under one atmosphere to obtain cyanoacetyl chloride T0;

B. preparation of intermediate 2-cyano-N- [4- (trifluoromethyl) phenyl ] -acetamide T1

b 1: 38g of p-trifluoromethylaniline SM1 was dissolved in 570ml of dichloromethane, and 190g of triethylamine was added;

b 2: respectively conveying the cyanoacetyl chloride T0 prepared in the step A and the solution in the step b1 to a microchannel reactor through a metering pump, wherein the flow rate of the solution in the step b1 is 25g/min, and the flow rate of the solution in the step b 0 is 30 g/min; reacting at 30 ℃ under one atmospheric pressure, receiving the reaction solution, pouring the reaction solution into 5L of purified water, stirring for 30min, and quenching; then, filtering is carried out, and 2L of purified water is used for washing a filter cake; then the alcohol is beaten, and finally the drying is carried out, thus preparing 47g of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1;

C. preparation of teriflunomide I

c 1: dissolving 45g of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide T1 prepared in the step B in 550ml of tetrahydrofuran, and then adding 18g of sodium hydroxide and uniformly mixing;

c 2: b1, respectively conveying the solution in the step b1 to a microchannel reactor through a metering pump at a flow rate of 60g/min and acetyl chloride at a flow rate of 4.5g/min, reacting at the temperature of 35 ℃ under one atmospheric pressure, receiving the reaction liquid, pouring the reaction liquid into 2L of purified water, stirring for 30min, and quenching; then filtering is carried out, and the filter cake is washed by 500mL of purified water; then carrying out alcohol pulping, and finally drying to prepare teriflunomide I.

And (3) identifying the obtained white solid compound by using a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data corresponding to the graph 2 are as follows:¹h NMR (600MHz, DMS0-d6) δ 10.76(s, 1H), 7.77(d, J ═ 8.5Hz, 2H), 7.66(d, J ═ 8.6Hz, 2H), 2.26(s, 3H), was essentially identical to the reported hydrogen spectrum shifts for teriflunomide, indicating that the resulting product was teriflunomide.

From the above embodiments, compared with the tank-type preparation of teriflunomide, the continuous flow preparation adopted by the invention can more effectively carry out chemical synthesis, so that the reaction is more sufficient, the reaction time is reduced to 50-140s from 3-12h, the acid mist concentration is reduced by the continuous flow reaction, the safety protection of human bodies and the service life of equipment are greatly improved, the total yield of teriflunomide prepared by the process of the invention is up to more than 65%, the purity is more than 99.5%, the average purity is between 99.80% and 99.99%, and the cost is greatly reduced.