CN117756670A - Synthesis method of rilpivirine intermediate - Google Patents

Abstract

The invention provides a method for synthesizing a rilpivirine intermediate: 4-bromo-2,6-dimethylaniline is used as a raw material, and cuprous cyanide is reacted in a DMF solvent to obtain 4-cyano-2,6-dimethylaniline, and then 4-cyano-2,6-dimethylaniline is reduced by DIBAL-H to obtain 4-amino-3,5-dimethylbenzaldehyde, and the aldehyde reacts with diethyl cyanomethyl phosphate under the catalysis of a base to obtain 3-(4-amino-3,5-dimethylphenyl) acrylonitrile (trans: cis=5:1), and the cis-trans mixture is crystallized and purified by hydrochloric acid isopropanol to obtain (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride. In the synthesis process, the raw materials used are cheap and easy to obtain, the synthesis process is simple, the reaction conditions are mild, and the process is suitable for the requirements of process amplification. Moreover, the route avoids the highly toxic acrylonitrile and the expensive palladium-carbon catalyst in the original synthesis route, and has good environmental value and economic value.

Description

A kind of synthesis method of rilpivirine intermediate

Technical field

The invention belongs to the field of organic synthesis and relates to a synthesis method of rilpivirine intermediate, specifically to a rilpivirine intermediate (E)-3-(4-amino-3,5-dimethylphenyl) ) Synthesis method of acrylonitrile hydrochloride.

Background technique

Rilpivirine, whose English name is Rilpivirine, is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by the American company Tibotec. It was launched in the United States in May 2011 and is used for the treatment of AIDS. It has the characteristics of easy synthesis, anti- It has strong viral activity, high oral bioavailability, and good safety. Its chemical name is: 4-[[4-[[4-[(E)-2-cyanoethylene]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile , the chemical structure is as follows:

According to existing and published literature reports, rilpivirine is mainly synthesized from two intermediates, namely Intermediate A: (E)-3-(4-amino-3,5-dimethylphenyl)propene Nitrile, and Intermediate B: 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile. The chemical structures of the two intermediates are as follows:

Among them, the common trading and storage methods of Intermediate A are in the form of hydrochloride, mainly using 4-iodo-2,6-dimethylaniline as the starting material and acrylonitrile in DMAC solvent, with palladium carbon (5% mol) is synthesized through catalysis, the reaction temperature is controlled at 130°C ~ 140°C, and the synthesis path is as follows:

In the synthesis process of this intermediate, expensive palladium catalysts and highly toxic acrylonitrile are used, which are harmful to operators and the environment. Post-processing is not easy to eliminate the harmfulness of the above raw materials, easily causing environmental pollution, and large-scale investment is very costly. , not suitable for industrial large-scale production.

For example, reference document CN105566162B discloses a synthesis method of rilpivirine intermediate. This synthesis method cannot avoid the use of palladium catalyst, and its synthesis route involves the reaction of 4-iodo-2,6-dimethylaniline and heck. The impurities produced in the product, once produced, are difficult to remove and affect later purification.

Therefore, there is an urgent need in this field for a safer, more efficient synthesis method of rilpivirine intermediates that does not use expensive catalysts.

Contents of the invention

In view of the above shortcomings, the present invention provides a synthesis method of rilpivirine intermediate, which has the advantages of cheap and easy-to-obtain raw materials and simple process, thereby solving the problems in the existing process of high toxicity of reagents, expensive catalysts, and easy generation of impurities that are difficult to remove. ; This invention has never been reported in the literature. It is a new preparation method of rilpivirine and provides a new synthetic idea for its similar compounds.

In view of the shortcomings of the prior art, the present invention provides a synthesis method of rilpivirine intermediate.

In order to achieve the above objects, the present invention adopts the following technical solutions:

A synthesis method of rilpivirine intermediate, the intermediate is (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile, the structural formula is as follows:

Wherein, the intermediate is synthesized through the following synthetic route:

Preferably, the following reaction steps are also included:

Step1: Under the protection of protective gas, add the raw materials 4-bromo-2,6-dimethylaniline and cuprous cyanide into the organic solvent. After the temperature is raised, the reaction starts. After the reaction of the raw materials is complete, the reaction system is cooled down. Lower to room temperature, add water to wash, extract the product, and concentrate to obtain 4-cyano-2,6-dimethylaniline;

Step2: Under protective gas protection, dissolve the 4-cyano-2,6-dimethylaniline obtained in Step 1 into the solvent, control the temperature and dropwise add the toluene solution of DIBAL-H; after tracking and detecting that the raw material reaction is complete, the reaction The liquid was quenched, then extracted and concentrated to obtain the product, 4-amino-3,5-dimethylbenzaldehyde;

Step3: Under protective gas protection, dissolve the 4-amino-3,5-dimethylbenzaldehyde and diethyl cyanomethylphosphate obtained in Step 2, control the temperature and add dropwise the tetrahydrofuran solution of sodium methoxide; after the raw material reaction is complete, The reaction solution was quenched, extracted, and concentrated to obtain 3-(4-amino-3,5-dimethylphenyl)acrylonitrile;

Step4: Dissolve the 3-(4-amino-3,5-dimethylphenyl)acrylonitrile obtained in Step3, raise the temperature to 60°C and add dropwise the hydrochloric acid isopropyl alcohol solution. After the dropwise addition is completed, keep the temperature until the reaction End; filter the reaction liquid and collect the filter cake to obtain the hydrochloride of product (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile.

Preferably, the organic solvent in Step 1 includes at least one of DMF or NMP, and the molar ratio of 4-bromo-2,6-dimethylaniline to cuprous cyanide is 1:2.0 to 1:2.5. The temperature is increased. to 140~150℃.

Preferably, in Step 1, ammonia is used as a detergent to wash away copper ions, and ethyl acetate is used as an extractant.

Preferably, the solvent in Step 2 is anhydrous tetrahydrofuran, the molar ratio of 4-cyano-2,6-dimethylaniline and DIBAL-H is 1:2.0~1:2.5, and the temperature is controlled to 0~10°C. .

Preferably, the quenching agent is dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1 to 4N, and the extracting agent is methyl tert-butyl ether.

Preferably, the solvent used for dissolution in Step 3 is anhydrous tetrahydrofuran, and the molar ratio of 4-amino-3,5-dimethylbenzaldehyde to diethyl cyanomethylphosphate is 1:1.1 to 1:1.5; 4 -The molar ratio of amino-3,5-dimethylbenzaldehyde to sodium methoxide is 1:3.0~1:4.0; the temperature is controlled to 0~5°C.

Preferably, the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1 to 4N, the extracting agent is ethyl acetate, and the obtained 3-(4-amino-3,5-dimethylphenyl)acrylonitrile is Structural formula ratio, trans: cis = 5:1.

Preferably, the solvent dissolved in Step 4 is absolute ethanol, and the molar ratio of the cis-trans isomer mixture of 3-(4-amino-3,5-dimethylphenyl)acrylonitrile to isopropanol hydrochloride is The ratio is 1:1.1~1:1.5, the insulation temperature is 60~65°C, and the end point mark of the end of the reaction is trans/(cis+trans)x100%=98%~100%.

Preferably, the protective gas in Steps 1 to 3 includes one of nitrogen or argon.

Beneficial effects of the present invention:

The present invention solves the problems of high toxicity of reagents and expensive catalysts in the existing process, and provides a new preparation method of rilpivirine intermediates, which has the advantages of cheap and easy-to-obtain raw materials and simple process; the synthesis route of the present invention It has never been reported in the literature. It is a brand-new preparation method of rilpivirine and provides a new synthetic idea for its similar compounds.

Description of the drawings

Figure 1 is a schematic diagram of HPLC of intermediate A;

Figure 2 is a schematic diagram of HNMR of intermediate A;

Figure 3 is a schematic diagram of the infrared spectrum of intermediate A.

Detailed ways

The present invention will be further described below through specific examples, but are not intended to limit the scope of the present invention.

Example 1:

Step1: 1L three-neck bottle, dry and clean, protected by nitrogen. Add 500ml DMF, 100g 4-bromo-2,6-dimethylaniline and 67.5g cuprous cyanide under mechanical stirring, raise the temperature to 145°C and react for about 10 hours. After checking that the reaction is complete, stop heating and lower to room temperature. Add 600g of 12% ammonia solution, add 500ml of ethyl acetate and extract twice. The combined ethyl acetate phases were washed twice with 200 ml of 5% ammonia water. Concentrate with a rotary evaporator to remove ethyl acetate to obtain 70.1g of product, with a yield of 96.5%. HNMR (solvent CDCl3; internal standard TMS): δ7.22 (s, 2H), δ2.18 (s, 6H).

Step2: 1L three-necked bottle, dry and clean, protected by nitrogen. Add 250ml THF and 50g 4-cyano-2,6-dimethylaniline under mechanical stirring, cool to 0~5°C in an ice-salt bath, control the temperature at 0~10°C, and add dropwise 230ml of 1.5M DIBAL-H solution. The addition reaction takes about 1 hour. After checking that the reaction is complete, add the reaction liquid dropwise to 300 ml of 4N dilute hydrochloric acid. Add 300 ml of methyl tert-butyl ether and extract twice. Combine the methyl tert-butyl ether phases and wash once with water and once with saturated brine. Concentrate with a rotary evaporator to remove methyl tert-butyl ether to obtain 21.5g of product, with a yield of 83.7%. HNMR (solvent CDCl3; internal standard TMS): δ9.74(s,1H), δ7.5(s,2H), δ4.21(s,2H), δ2.24(s,6H).

Step3: 1L three-neck bottle, dry and clean, protected by nitrogen. Add 250ml THF, 50g 4-amino-3,5-dimethylbenzaldehyde, and 65.3g diethyl cyanomethylphosphate under mechanical stirring. Cool to 0~5°C in an ice-salt bath. Control the temperature at 0~10°C and add 72.4 dropwise. g sodium methoxide and 350ml THF solution. The addition reaction lasts for about 1 hour. After checking that the reaction is complete, control the temperature at 0 to 10°C and add 300 ml of 4N dilute hydrochloric acid dropwise to the reaction solution. Add 300 ml of ethyl acetate and extract twice. The combined ethyl acetate phases were washed once with saturated aqueous sodium bicarbonate solution and once with saturated brine. Concentrate with a rotary evaporator to remove ethyl acetate to obtain 53.5g of product, with a yield of 92.7%.

Step4: 2L three-necked bottle, dry and clean, protected by nitrogen. Add 750ml absolute ethanol and 100g 3-(4-amino-3,5-dimethylphenyl)acrylonitrile (trans:cis=5:1) under mechanical stirring, raise the temperature to 60~65℃, and control the temperature Add 93.4g of 25% hydrochloric acid isopropyl alcohol solution dropwise at 60 to 65°C. After adding and keeping the reaction for about 15 hours, detect trans: cis ≥ 98:2 and stop the reaction, and lower the reaction solution to 20-25°C. Filter to obtain crude product. Purification of the crude product: Add the crude product to a mixed solution of 750 ml of absolute ethanol and 100 ml of isopropanol, beat at 50-55°C for 2 hours, lower to room temperature, and filter to obtain 96.3 g, with a yield of 79.5%. HNMR (solvent DMSO; internal standard TMS): δ8.47(s,3.36H), δ7.43(d,1H), δ7.34(s,2H), δ6.34(d,1H), δ2.33 (s,6H).

Example 2:

Step1: 1L three-neck bottle, dry and clean, protected by nitrogen. Add 500ml of N-methylpyrrolidone (NMP), 100g of 4-bromo-2,6-dimethylaniline and 67.5g of cuprous cyanide under mechanical stirring, raise the temperature to 145°C and react for about 10 hours. After checking that the reaction is complete, stop heating. , to room temperature. Add 600g of 12% ammonia solution, add 500ml of ethyl acetate and extract twice. The combined ethyl acetate phases were washed twice with 200 ml of 5% ammonia water. Concentrate with a rotary evaporator to remove ethyl acetate to obtain 70.1g of product, with a yield of 96.5%. HNMR (solvent CDCl3; internal standard TMS): δ7.22 (s, 2H), δ2.18 (s, 6H).

Step2: 1L three-necked bottle, dry and clean, protected by nitrogen. Add 250ml THF and 50g 4-cyano-2,6-dimethylaniline under mechanical stirring, cool to 0~5°C in an ice-salt bath, control the temperature at 0~10°C, and add dropwise 230ml of 1.5M DIBAL-H solution. The addition reaction takes about 1 hour. After checking that the reaction is complete, add the reaction liquid dropwise to 300 ml of 1N dilute hydrochloric acid. Add 300 ml of methyl tert-butyl ether and extract twice. Combine the methyl tert-butyl ether phases and wash once with water and once with saturated brine. Concentrate with a rotary evaporator to remove methyl tert-butyl ether to obtain 21.5g of product, with a yield of 83.7%. HNMR (solvent CDCl3; internal standard TMS): δ9.74(s,1H), δ7.5(s,2H), δ4.21(s,2H), δ2.24(s,6H).

Step3: 1L three-neck bottle, dry and clean, protected by nitrogen. Add 250ml THF, 50g 4-amino-3,5-dimethylbenzaldehyde, and 65.3g diethyl cyanomethylphosphate under mechanical stirring. Cool to 0~5°C in an ice-salt bath. Control the temperature at 0~10°C and add 72.4 dropwise. g sodium methoxide and 350ml THF solution. The addition reaction takes about 1 hour. After checking that the reaction is complete, control the temperature at 0 to 10°C and add 300 ml of 1N dilute hydrochloric acid dropwise to the reaction solution. Add 300 ml of ethyl acetate and extract twice. The combined ethyl acetate phases were washed once with saturated aqueous sodium bicarbonate solution and once with saturated brine. Concentrate with a rotary evaporator to remove ethyl acetate to obtain 53.5g of product, with a yield of 92.7%.

Step4: 2L three-necked bottle, dry and clean, protected by nitrogen. Add 750ml absolute ethanol and 100g 3-(4-amino-3,5-dimethylphenyl)acrylonitrile (trans:cis=5:1) under mechanical stirring, raise the temperature to 60~65℃, and control the temperature Add 93.4g of 25% hydrochloric acid isopropyl alcohol solution dropwise at 60 to 65°C. After adding and keeping the reaction for about 15 hours, detect trans: cis ≥ 98:2, and lower the reaction solution to 20-25°C. Filter to obtain crude product. Purification of the crude product: Add the crude product to a mixed solution of 750 ml of absolute ethanol and 100 ml of isopropanol, beat at 50-55°C for 2 hours, lower to room temperature, and filter to obtain 96.3 g, with a yield of 79.5%. HNMR (solvent DMSO; internal standard TMS): δ8.47(s,3.36H), δ7.43(d,1H), δ7.34(s,2H), δ6.34(d,1H), δ2.33 (s,6H).

Comparative example 1:

1L three-neck bottle, dry and clean, protected by nitrogen. Add 500ml of N-methylpyrrolidone (NMP), 100g of 4-bromo-2,6-dimethylaniline and 67.5g of cuprous cyanide under mechanical stirring, raise the temperature to 135°C and react for about 10 hours. After checking that the reaction is not complete, continue Heating; react for about 15 hours, and after detecting that the reaction is not complete, continue heating; react for about 25 hours, and after detecting that the reaction is not complete, observe that the color of the reaction system in the bottle is different, stop the reaction and lower it to room temperature; similarly, add 600g of 12% ammonia aqueous solution, add 500 ml ethyl acetate and extract twice. The combined ethyl acetate phases were washed twice with 200 ml of 5% ammonia water. Concentrate with a rotary evaporator to remove ethyl acetate to obtain 31.3g of product, with a yield of 43.1%. HNMR (solvent CDCl3; internal standard TMS): δ7.22 (s, 2H), δ2.18 (s, 6H).

Comparing Comparative Example 1 with Example 1/2, it can be seen that the feed ratio of reactants is within the set range, reagent replacement and reasonable changes in concentration will not significantly affect the yield and purity of the product, but in the initial feed Step 1 If the reaction temperature is lower than 140°C, the reaction time will be greatly extended, the final raw material conversion will be incomplete, and the yield will be low;

The synthesis method of the present invention circumvents the shortcomings of the existing process, which relies on the highly toxic reagent acrylonitrile, does not use expensive palladium catalysts, and importantly, does not generate impurities that are difficult to purify, making rilpivirine The preparation method of the intermediate has the advantages of cheap and easy-to-obtain raw materials and simple process; it is a brand-new synthesis method with objective yield and considerable purity.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still describe the foregoing embodiments. Modify the technical solution, or make equivalent replacements for some of its technical features. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A synthetic method of rilpivirine intermediate, characterized in that the intermediate is (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile, and the structural formula is as follows: Wherein, the intermediate is synthesized through the following synthetic route: 2. a kind of synthetic method of rilpivirine intermediate according to claim 1, is characterized in that, also comprises the following reaction step: Step1: Under the protection of protective gas, add the raw materials 4-bromo-2,6-dimethylaniline and cuprous cyanide into the organic solvent. After the temperature is raised, the reaction starts. After the reaction of the raw materials is complete, the reaction system is cooled down. Lower to room temperature, add water to wash, extract the product, and concentrate to obtain 4-cyano-2,6-dimethylaniline; Step2: Under protective gas protection, dissolve the 4-cyano-2,6-dimethylaniline obtained in Step 1 into the solvent, control the temperature and dropwise add the toluene solution of DIBAL-H; after tracking and detecting that the raw material reaction is complete, the reaction The liquid was quenched, then extracted and concentrated to obtain the product, 4-amino-3,5-dimethylbenzaldehyde; Step3: Under protective gas protection, dissolve the 4-amino-3,5-dimethylbenzaldehyde and diethyl cyanomethylphosphate obtained in Step 2, control the temperature and add dropwise the tetrahydrofuran solution of sodium methoxide; after the raw material reaction is complete, The reaction solution was quenched, extracted, and concentrated to obtain 3-(4-amino-3,5-dimethylphenyl)acrylonitrile; Step4: Dissolve the 3-(4-amino-3,5-dimethylphenyl)acrylonitrile obtained in Step3, raise the temperature to 60°C and add dropwise the hydrochloric acid isopropyl alcohol solution. After the dropwise addition is completed, keep the temperature until the reaction End; filter the reaction liquid and collect the filter cake to obtain the hydrochloride of product (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile. 3. a kind of synthetic method of rilpivirine intermediate according to claim 2, is characterized in that, the organic solvent in described Step1 comprises N, N-dimethylformamide or N-methylpyrrolidone. At least one, the molar ratio of 4-bromo-2,6-dimethylaniline and cuprous cyanide is 1:2.0~1:2.5, and the temperature is raised to 140~150°C. 4. The synthesis method of rilpivirine intermediate according to claim 3, characterized in that, in the Step 1, ammonia is used as a washing agent to wash away copper ions, and ethyl acetate is used as an extraction agent. 5. the synthetic method of a kind of rilpivirine intermediate according to claim 2, is characterized in that, the solvent in described Step2 is anhydrous tetrahydrofuran, 4-cyano-2,6-dimethylaniline and The molar ratio of DIBAL-H is 1:2.0~1:2.5, and the temperature is controlled to 0~10℃. 6. The synthesis method of a rilpivirine intermediate according to claim 5, characterized in that the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1 to 4N, and the extraction agent is methyl tert-butyl base ether. 7. a kind of synthetic method of rilpivirine intermediate according to claim 2, is characterized in that, the solvent used for dissolving in described Step3 is anhydrous tetrahydrofuran, 4-amino-3,5-dimethylbenzene The molar ratio of formaldehyde to diethyl cyanomethylphosphate is 1:1.1~1:1.5; the molar ratio of 4-amino-3,5-dimethylbenzaldehyde to sodium methoxide is 1:3.0~1:4.0; control Warm to 0~5℃. 8. The synthesis method of a rilpivirine intermediate according to claim 7, characterized in that the quenching agent is a dilute hydrochloric acid solution, the concentration of the dilute hydrochloric acid is 1 to 4N, and the extraction agent is ethyl acetate, The obtained 3-(4-amino-3,5-dimethylphenyl)acrylonitrile has a structural formula ratio of trans:cis=5:1. 9. The synthesis method of a rilpivirine intermediate according to claim 2, characterized in that the solvent dissolved in the Step 4 is absolute ethanol, and the 3-(4-amino-3,5- The molar ratio of dimethylphenyl) acrylonitrile cis-trans isomer mixture to isopropanol hydrochloride is 1:1.1~1:1.5, the insulation is 60~65°C, and the end point mark at the end of the reaction is trans/(cis +trans)x100%=98%～100%. 10. The synthesis method of rilpivirine intermediate according to claim 2, characterized in that the protective gas in Steps 1 to 3 includes one of nitrogen or argon.