Synthesis method of rilpivirine key intermediate

Abstract

The invention relates to a synthesis method of a rilpivirine key intermediate, and belongs to the technical field of pharmacy. The name of the intermediate is (E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile hydrochloride; the method comprises the following steps: 1, taking 2, 6-dimethylaniline as a starting material, and carrying out halogenation reaction and amino protection one-pot reaction to obtain an intermediate 1; step 2, carrying out Heck reaction and post-treatment on the intermediate 1 and acrylamide to prepare an intermediate 2; and step 3, carrying out dehydration reaction on the amide group of the intermediate 2 and carrying out one-time deprotection reaction on the amino group to finally obtain the required (E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile hydrochloride. According to the method, high temperature, high pressure, toxic and harmful gas and the like are avoided in each step of operation, the method is very suitable for industrial production, and the technical scheme is high in yield and has great commercial application value.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a key intermediate of rilpivirine, and belongs to the technical field of pharmaceuticals. Background Art

[0002] Rilpivirine is a new type of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTIs) developed by Tibotec, an American company. It was approved by the U.S. FDA in May 2011 and is marketed under the trade name It has the characteristics of strong antiviral activity, high oral bioavailability and good safety. In clinical applications, rilpivirine is used in combination with other antiretroviral drugs for the first treatment of adult patients infected with HIV-1 who have never received antiretroviral treatment. Currently, there are 5 NNRTI anti-HIV drugs on the market, namely nevirapine, efavirenz, delavirdine, etravirine, and rilpivirine. Compared with nevirapine, delavirdine, etravirine, etc., rilpivirine has the advantages of one tablet once a day, first-line medication, low drug resistance and high safety. It has the same efficacy as efavirenz and better safety, so rilpivirine is used as a new treatment for patients infected with HIV-1.

[0003] Rilpivirine, chemical name is 4-[[4-[[4-[(1E)-2-cyanoethylene]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, the structural formula is as follows:

[0004]

[0005] From the structural formula of rilpivirine, it can be seen that rilpivirine has three main structural fragments, namely 2-cyanoethylene]-2,6-dimethylphenyl, pyrimidine ring and cyanophenyl group:

[0006]

[0007] Among them, 2-cyanoethylene]-2,6-dimethylphenyl is a very important main fragment. There are several synthetic methods for preparing this fragment. At present, a domestic article introducing the synthetic route of rilpivirine has introduced various synthetic routes in detail (Rilpivirine Synthetic Route Diagram [J]. China Pharmaceutical Industry Journal, 2016, 47(03): 352-354). This patent mainly studies a new synthetic method for (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride (CAS: 661489-23-2):

[0008]

[0009] Sheng Han, Yali Sang, et al. reported (Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles. ACS Infectious Diseases 2020, 6(5), 787-801), in which 2,6-dimethylaniline was used as the starting material, and iodinated with iodine chloride to generate 4-iodo-2,6-dimethylaniline, which was then reacted with acrylonitrile to obtain (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile by HECK reaction:

[0010]

[0011] This route has only two steps of reaction and the synthesis principle is simple, but the synthesis reaction uses iodine chloride and acrylonitrile as reaction raw materials, both of which are highly toxic compounds, and are therefore not suitable for laboratory operations and workshop production.

[0012] CN102503903A (Janssen Pharmaceuticals Co., Ltd., 1,2,4-triazines for inhibiting HIV) reports another synthesis scheme, which uses 3,5-dimethyl-4-nitrobenzoic acid as the starting material, generates 3,5-dimethyl-4-nitrobenzyl alcohol through a reduction reaction, and then oxidizes to prepare 3,5-dimethyl-4-nitrobenzaldehyde, which is then condensed with diethyl cyanomethyl phosphate, and then subjected to nitro reduction to obtain the desired product:

[0013]

[0014] This synthetic route has five chemical reactions to obtain the product. The synthetic route is relatively long. In addition, the market for 3,5-dimethyl-4-nitrobenzoic acid is not mature at present and cannot be purchased in large quantities. The price is relatively expensive, so this route is not advisable.

[0015] CN101816658B (Janssen Pharmaceuticals Co., Ltd., pyrimidine derivatives for inhibiting HIV) reported that (E)-N'-(4-bromo-2,6-dimethylphenyl)-N,N-dimethylimidoformamide was used as the starting material, and the aldehyde group was condensed with diethyl cyanomethyl phosphate, and then the desired compound was obtained through aminolysis reaction:

[0016]

[0017] This synthetic route is made with only three chemical reactions, but considering that (E)-N'-(4-bromo-2,6-dimethylphenyl)-N,N-dimethylimidoformamide is not easy to purchase, it is not easy to commercialize. In addition, when adding formaldehyde in the first step, the reaction requires n-butyl lithium and the reaction must be below -70°C, so this synthetic route is even less suitable for commercial production.

[0018] CN100475815C (Janssen Pharmaceuticals Co., Ltd., adenine derivatives that inhibit HIV replication) reported the use of 4-bromo-2,6-dimethylaniline as a starting material, and acrylamide was reacted with palladium acetate to undergo a Heck reaction, and then a dehydration condensation reaction was performed to obtain the product:

[0019]

[0020] This synthetic route omits acrylonitrile as a raw material, avoids contact with highly toxic substances, and can be well implemented in industrial production. However, literature reports that the Heck reaction uses nearly 10% (compared with 4-bromo-2,6-dimethylaniline) of palladium acetate as a catalyst. The catalyst palladium acetate is very expensive, which leads to a significant increase in product production costs, which is not conducive to commercial production.

[0021] In the above literature, the Heck reaction is due to the fact that the amino group in 4-bromo-2,6-dimethylaniline is an electron-donating group, which leads to a decrease in the activity of the benzene ring. During the Heck reaction, the ability of the palladium metal to form a ligand with the benzene ring is weakened. Therefore, when performing the Heck reaction, if the raw material is to increase the conversion rate, the amount of the ligand, i.e., the amount of palladium acetate, needs to be increased. However, as a precious metal, palladium acetate has a high market price. If the amount of palladium acetate is increased, the production cost of the product is also increased. Therefore, the present invention has developed a method that can greatly reduce the amount of metal catalyst without affecting the yield and quality of the product so as to develop a lower cost and better quality intermediate (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride, and develop a lower cost and better quality medicine for the country and society.

[0022] In summary of the above synthesis methods, some routes use highly toxic compounds, some routes use expensive raw materials, and the production conditions are relatively harsh. Therefore, the above synthesis routes are not suitable for commercial production. Summary of the invention

[0023] The purpose of the present invention is to provide a method for synthesizing a key intermediate of rilpivirine, which is better adapted to industrial production.

[0024] In order to achieve the above object, the technical solution adopted by the present invention is:

[0025] A method for synthesizing a key intermediate of rilpivirine, the specific method is as follows:

[0026] The intermediate is called (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride, and its chemical formula is as follows:

[0027]

[0028] The reaction synthesis route is as follows:

[0029]

[0030] Step 1: Using 2,6-dimethylaniline as the starting material, intermediate 1 is obtained through a one-pot reaction of halogenation and amino protection;

[0031] Step 2: intermediate 1 is reacted with acrylamide through Heck reaction and post-treatment to prepare intermediate 2;

[0032] Step 3: The intermediate 2 is subjected to a dehydration reaction of the amide group and a one-time deprotection reaction of the amino group to finally obtain the desired (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride.

[0033] A further improvement of the technical solution of the present invention is as follows: the R1 group used can be a chlorine atom, a bromine atom or an iodine atom among halogens; the halogenating agent used can be elemental chlorine, elemental bromine or elemental iodine, or can be halogenating agents such as NCS, NBS or NIS; elemental bromine and NBS are preferred; the R2 group used can be protecting groups such as Boc, Cbz, Fmoc, and sulfonyl.

[0034] A further improvement of the technical solution of the present invention is that during the halogenation reaction, the molar ratio of 2,6-dimethylaniline to the halogenation reagent is 1.00:(0.80-3.00), preferably 1.00:(1.00-1.60), and most preferably 1.00:(1.10-1.50); ​​the reaction temperature is -80-100°C, preferably -20-60°C, and most preferably 0-30°C.

[0035] A further improvement of the technical solution of the present invention is that the solvent used in the preparation of intermediate 1 for the halogenation reaction of R1 and R2 groups can be dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, ethyl acetate, methanol, ethanol, acetic acid, etc. The preferred reaction solvents are acetonitrile, N,N-dimethylformamide, dichloromethane, and chloroform; the most preferred reaction solvents are dichloromethane and chloroform; the solvents used in the reaction are not limited to protic solvents or aprotic solvents or mixtures of different solvents.

[0036] A further improvement of the technical solution of the present invention is that when the intermediate 1 is subjected to the amino protection reaction, the protecting reagent is benzyl chloroformate (CbzCl), Boc anhydride, 9-fluorenylmethyl chloroformate (FomcCl), trifluoroacetyl chloride, trifluoroacetic anhydride, preferably Boc anhydride and benzyl chloroformate (CbzCl); the molar ratio of 2,6-dimethylaniline to the protecting reagent is 1:(0.90-3.00), preferably 1.00:(1.00-1.80), and most preferably 1.00:(1.05-1.20).

[0037] The acidifying agent used is a base such as triethylamine, diisopropylethylamine, DMAP, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably DMAP, diisopropylethylamine or triethylamine, most preferably triethylamine.

[0038] A further improvement of the technical solution of the present invention is that the metal catalyst used in the preparation of intermediate 2 is palladium carbon, palladium chloride, Pd(OAc)2, Pd2(dba)3 or Pd(dppf)Cl2; the percentage of the amount of catalyst to intermediate 1 is 0.01-5%, preferably the molar amount of the catalyst is 0.05-0.1% of the intermediate 1, and most preferably 0.08-0.12%;

[0039] The solvent used in the preparation of intermediate 2 is a protic solvent such as water, alcohols, acetonitrile, N,N-dimethylformamide; or an aprotic solvent; it can be a single solvent or a mixed solvent of two or more;

[0040] The Heck reaction in the preparation of intermediate 2 has a reaction temperature of 20°C to 140°C, preferably 80°C to 120°C;

[0041] When the intermediate 2 is prepared by Heck reaction, the base used can be an inorganic base or an organic base such as sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate, etc.

[0042] A further improvement of the technical solution of the present invention is that in step 3, when performing the two reactions of dehydration and amino deprotection, the reactions can be carried out in steps or in one pot.

[0043] A further improvement of the technical solution of the present invention is that in step 3, during the dehydration reaction and the amino deprotection reaction, the solvents used in these two steps can be organic solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and N,N-dimethylformamide, and are not limited to using only one solvent;

[0044] Step 3: In the dehydration reaction and the amino deprotection reaction, the dehydration reagents used in these two steps are phosphorus oxychloride, oxalyl chloride, thionyl chloride, trifluoroacetic anhydride and other reaction solvents; the reaction can be carried out with one reagent or with a mixture of two or more reagents;

[0045] In step 3, during the dehydration reaction and amino deprotection reaction, the acidifying agent used is a base such as triethylamine, diisopropylethylamine, potassium carbonate, and sodium carbonate, among which the preferred acidifying agents are triethylamine and diisopropylethylamine.

[0046] A further improvement of the technical solution of the present invention is that in step 3, during dehydration and deprotection, the molar ratio of the intermediate 2 to the reagent used is 1:(0.80-5.00), preferably 1.00:(1.00-2.00), and the optimal molar ratio is 1.00:(1.05-1.80);

[0047] The reaction temperature is -20°C to 120°C, preferably -10°C to 60°C, and most preferably 0°C to 20°C.

[0048] A further improvement of the technical solution of the present invention is that the post-reaction treatment includes extraction, crystallization, recrystallization, drying and refining.

[0049] Due to the adoption of the above technical solution, the technical effects achieved by the present invention are as follows:

[0050] Compared with the current (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride synthesis technology, the present invention achieves a yield of more than 90% through the first two chemical reactions (halogenation reaction, amine protection) in one pot, uses a small amount of 0.1% palladium chloride to perform Heck reaction to achieve the characteristics of less raw materials and high product yield, so that the intermediate yield reaches more than 95%, and the last two steps of chemical reactions (dehydration, deprotection) are completed in one pot, so that the product yield also reaches more than 90%. In addition, each step of the operation does not have high temperature, high pressure, toxic and harmful gases, etc., and is very suitable for industrial production. Therefore, the invention has great commercial application value.

[0051] The method of the present invention has the characteristics of sufficient source of raw and auxiliary materials, low cost, high safety of synthesis process, high yield, less pollution of three wastes, etc. It is suitable for large-scale commercial production and has high industrial production value. DETAILED DESCRIPTION

[0052] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further explained below in conjunction with specific implementation methods.

[0053] The technical solution of the present invention is a method for synthesizing a key intermediate of rilpivirine, which is used for preparing the key intermediate of rilpivirine.

[0054] The intermediate is called (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride, and its chemical formula is as follows:

[0055]

[0056] The reaction synthesis route is as follows:

[0057]

[0058] The reaction synthesis route is mainly divided into three steps.

[0059] Step 1 uses 2,6-dimethylaniline as a starting material, and undergoes a one-pot reaction of halogenation and amino protection to obtain intermediate 1.

[0060] Step 2: Intermediate 2 is prepared by reacting intermediate 1 with acrylamide through Heck reaction and post-treatment.

[0061] Step 3: The intermediate 2 is subjected to a dehydration reaction of the amide group and a one-time deprotection reaction of the amino group to finally obtain the desired (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride.

[0062] The R1 group used in the above reaction step 1 can be a chlorine atom, a bromine atom or an iodine atom among halogens; the halogenating agent used can be elemental chlorine, elemental bromine or elemental iodine, or can be halogenating agents such as NCS, NBS or NIS; preferably, elemental bromine and NBS; the R2 group used can be protecting groups such as Boc, Cbz, Fmoc, and sulfonyl.

[0063] In the halogenation reaction of step 1, the molar ratio of 2,6-dimethylaniline to the halogenation reagent is 1.00:

[0064] (0.80~3.00), preferably 1.00:(1.00~1.60), most preferably 1.00:(1.10~1.50); ​​the reaction temperature is -80~100℃, preferably -20~60℃, and most preferably 0~30℃.

[0065] When preparing intermediate 1 in step 1, the solvent used in the halogenation reaction of R1 and R2 groups can be dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, ethyl acetate, methanol, ethanol, acetic acid, etc. The preferred reaction solvents are acetonitrile, N,N-dimethylformamide, dichloromethane, and chloroform; the most preferred reaction solvents are dichloromethane and chloroform; the solvents used in the reaction are not limited to protic solvents or aprotic solvents or mixtures of different solvents.

[0066] In step 1, during the amino protection reaction of the intermediate 1, the protecting reagent is benzyl chloroformate (CbzCl), Boc anhydride, 9-fluorenylmethyl chloroformate (FomcCl), trifluoroacetyl chloride, trifluoroacetic anhydride, preferably Boc anhydride and benzyl chloroformate (CbzCl); the molar ratio of 2,6-dimethylaniline to the protecting reagent is 1: (0.90-3.00), preferably 1.00: (1.00-1.80), and most preferably 1.00: (1.05-1.20).

[0067] Step 1 The acylating agent used in the reaction of preparing intermediate 1 is a base such as triethylamine, diisopropylethylamine, DMAP, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably DMAP, diisopropylethylamine or triethylamine, and most preferably triethylamine.

[0068] In step 2, a metal catalyst is usually required for preparing intermediate 2. The metal catalyst used is palladium carbon, palladium chloride, Pd(OAc)2, Pd2(dba)3 or Pd(dppf)Cl2. The percentage of the catalyst to intermediate 1 is 0.01-5%, preferably the catalyst molar amount is 0.05-0.1% of intermediate 1, and most preferably 0.08-0.12%;

[0069] The solvent used in step 2 for preparing intermediate 2 is a protic solvent such as water, alcohol, acetonitrile, N,N-dimethylformamide, etc.; or it can be an aprotic solvent; it can be a single solvent, or a mixed solvent of two or more;

[0070] In step 2, the Heck reaction in the preparation of intermediate 2 has a reaction temperature of 20°C to 140°C, preferably 80°C to 120°C;

[0071] Step 2 In the Heck reaction for preparing intermediate 2, the base used can be an inorganic base or an organic base, such as sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate and the like.

[0072] Step 3 mainly includes two reactions: dehydration reaction and amino deprotection reaction. These two reactions can be carried out in steps or in one pot. The one pot reaction here means that two reactions are completed in one reaction vessel at one time.

[0073] Step 3: During the dehydration reaction and the amino deprotection reaction, the solvents used in these two steps can be organic solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, etc., and are not limited to using only one solvent;

[0074] Step 3: In the dehydration reaction and the amino deprotection reaction, the dehydration reagents used in these two steps are reaction solvents such as phosphorus oxychloride, oxalyl chloride, thionyl chloride, trifluoroacetic anhydride, etc.; one reagent can be used in the reaction, or two or more mixed reagents can be used;

[0075] In step 3, during the dehydration reaction and amino deprotection reaction, the acidifying agent used is a base such as triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, etc., among which the preferred acidifying agent is triethylamine and diisopropylethylamine.

[0076] In step 3, during the dehydration and deprotection reaction, the molar ratio of intermediate 2 to the reagent is 1:(0.80-5.00), preferably 1.00:(1.00-2.00), and the optimal molar ratio is 1.00:(1.05-1.80). The reaction temperature is -20°C to 120°C, preferably -10°C to 60°C, and most preferably 0°C to 20°C.

[0077] The reaction of the above-mentioned synthetic route is a major chemical reaction, and a series of treatments are required after the reaction, mainly including extraction, crystallization, recrystallization, drying, refining and other post-treatment steps.

[0078] The following are specific embodiments

[0079] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or the conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional raw materials, reagents, etc. that can be purchased commercially.

[0080] Example 1: Preparation of Intermediate 1 (tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate)

[0081] Weigh 20.00g (165.04mmol) of 2,6-dimethylaniline and add it to a three-necked reaction bottle, add 160ml of dichloromethane and 0.10g (0.5%) of azobisisobutyronitrile (AIBN), lower the temperature by 0-5°C, add 30.84g (173.30mmol) of NBS in batches under stirring, raise the temperature to 10-20°C and stir for 1-3 hours. After the reaction is completed under TLC monitoring, add 80ml of purified water to dichloromethane to quench, separate the aqueous layer, wash the dichloromethane with 80ml of 5% sodium bicarbonate aqueous solution once, and then wash it with 80ml of saturated brine once, separate the aqueous layer, dry the dichloromethane with sodium sulfate, and add 1% ethanol to dichloromethane. Add 25.05g (247.57mmol) of triethylamine, cool to 0-10℃, add 43.22g (198.05mmol) of Boc anhydride dropwise with stirring, heat to 20-30℃ and stir for 2 hours after the addition is completed. After the reaction is completed under TLC monitoring, add 75ml of purified water to the system, stir and extract, then wash once with 50ml of 5% acetic acid aqueous solution, wash once with 50ml of 3% sodium bicarbonate aqueous solution, wash once with 50ml of saturated brine, separate dichloromethane, dry with sodium sulfate, concentrate, and recrystallize with a mixed liquid of 30ml of ethyl acetate and 90ml of petroleum ether to obtain 45.87g (198.05mmol), with a yield of 92.58%.

[0082] MS (ESI, m / z): 300.0 [M+H] + , 1 HNMR(400MHz, CDCl3)δ:1.42(9H,s),2.19(6H,s),7.19(2H,s),6,32(bs,1H).

[0083] Example 2: Preparation of Intermediate 1 (tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate)

[0084] Weigh 30.00g (247.57mmol) of 2,6-dimethylaniline and add it to a three-necked reaction bottle, add 300ml of dichloromethane, add 27.56g (272.32mmol) of triethylamine, lower the temperature to -5 to 5°C, and slowly add 39.56g (247.57mmol) of bromine under rapid stirring and temperature control. After adding, control the temperature and stir for 1 hour. After the reaction is completed by TLC monitoring, add 80ml of purified water to dichloromethane to quench, separate the aqueous layer, wash dichloromethane with 50ml of 5% sodium thiosulfate aqueous solution once, and then wash it with 80ml of saturated brine once. After drying dichloromethane with sodium sulfate, filter out the sodium sulfate, and add 32.57g of (321.84mmol) triethylamine, lower the temperature to 0-10℃, add 59.43g (272.32mmol) Boc anhydride dropwise under stirring, raise the temperature to 20-30℃ and stir for 2 hours after the addition is completed, monitor the reaction by TLC, add 80ml purified water to the system, stir and extract, wash once with 60ml 5% acetic acid aqueous solution, wash once with 60ml 3% sodium bicarbonate aqueous solution, wash once with 50ml saturated brine, separate dichloromethane, dry with sodium sulfate and concentrate the dichloromethane, recrystallize the concentrate with 30ml ethyl acetate and 90ml petroleum ether mixed liquid to obtain 68.23g (227.29mmol), the yield is 91.81%.

[0085] Example 3: Scaled-up preparation of intermediate 1 (tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate)

[0086] Weigh 5.00kg (41.26mol) of 2,6-dimethylaniline and add it to a 100L laminated glass reactor, add 40L of dichloromethane, add 25g (0.5%) of azobisisobutyronitrile (AIBN), lower the temperature by 0-5°C, add 7.71kg (43.32mol) of NBS in batches under stirring, control the temperature and stir for 1 hour after adding, and after the reaction is completed by TLC monitoring, add 20L of purified water to dichloromethane to quench, separate the water layer, wash the dichloromethane with 20L of 5% sodium bicarbonate solution once, and then wash it with 20L of saturated brine once, separate the water layer, dry the dichloromethane with 1.0kg of sodium sulfate, and add Add 6.26 kg (61.89 mol) of triethylamine, cool to 0-10°C, add 10.81 kg (49.51 mol) of Boc anhydride dropwise with stirring, heat to 20-30°C and stir for 2 hours after the addition is completed. After the reaction is completed under TLC monitoring, add 20 L of purified water to the system, stir and extract, then wash once with 10 L of 5% acetic acid aqueous solution, wash once with 10 L of 3% sodium bicarbonate aqueous solution, wash once with 10 L of saturated brine, separate dichloromethane, dry with 1.00 kg of sodium sulfate, and concentrate. The concentrate is recrystallized with a mixed liquid of 7.5 L of ethyl acetate and 22.5 L of petroleum ether to obtain 11.50 kg with a yield of 92.85%.

[0087] Example 4: Preparation of Intermediate 2 ((4-tert-butoxycarbonylamino-2,6-dimethylphenyl)acrylamide)

[0088] Weigh 20.00g (4-bromo-2,6-dimethylphenyl) carbamic acid tert-butyl ester and add it to 200ml toluene, add 5.21g (1.10eq) acrylamide, 11.81mg (0.1% mol) palladium chloride and 87.37mg phosphorus ligand, 10.13g (1.20eq) potassium carbonate, replace with nitrogen 3 times after adding, heat (108-112°C) and reflux for 6-8 hours. After the reaction is completed, cool to 10-30°C, add 80ml water to the system, stir to dissolve the solid, extract by layers, wash the toluene layer with 80ml purified water and 80ml saturated brine, dry the toluene with sodium sulfate, filter after drying, concentrate the toluene, and recrystallize the concentrate with ethyl acetate and n-heptane to obtain 18.13g of product (yield 93.72%).

[0089] MS (ESI, m / z): 273.2 [M+H] + , 1 HNMR(400MHz, CDCl3)δ:1.40(9H,s),2.33(6H,s),5.83(1H,d),7.01(2H,s),6.48(1H,bs),7.43(1H,s).

[0090] Example 5: Preparation of Intermediate 2 ((4-tert-butoxycarbonylamino-2,6-dimethylphenyl)acrylamide)

[0091] Weigh 20.00g (4-bromo-2,6-dimethylphenyl) carbamic acid tert-butyl ester and add it to 100ml DMF, add 7.10g (1.50eq) acrylamide, 5.91mg (0.05% mol) palladium chloride and 43.69mg phosphorus ligand, 12.89g (1.40eq) potassium carbonate, replace with nitrogen 3 times after adding, and then heat (125-130°C) to react for 10-12 hours. After the reaction is completed, cool to 10-20°C, add 300ml purified water to the system under stirring, then cool to 0-5°C and stir for 2 hours to crystallize, filter out the product, and use ethanol / purified water to recrystallize the product and dry it to obtain 17.68g of intermediate 2 (yield: 91.39%).

[0092] Example 6: Preparation of Intermediate 2 ((4-tert-butoxycarbonylamino-2,6-dimethylphenyl)acrylamide)

[0093] Weigh 11.00kg (4-bromo-2,6-dimethylphenyl) tert-butyl carbamate and add it to 95kg toluene, add 3.91kg (1.50eq) acrylamide, 6.50g (0.05% mol) palladium chloride and 48.05g phosphorus ligand, 6.08kg (1.20eq) potassium carbonate, replace with nitrogen 3 times and heat (108-112°C) to react for 8 hours. After the reaction is completed, cool to 10-20°C, add 30kg purified water to the system under stirring, stir to dissolve the solid, extract by layers, wash the toluene layer with 30kg purified water and 30kg saturated brine, dry the toluene with sodium sulfate, filter after drying, concentrate the toluene, and recrystallize the concentrate with ethyl acetate and n-heptane to obtain 10.04kg (yield 94.35%).

[0094] Example 7: Preparation of the final product ((E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride)

[0095] Weigh 20.00 g (1.00 eq) of intermediate 2 ((4-tert-butoxycarbonylamino-2,6-dimethylphenyl) acrylamide) and add it to 100 ml of dichloromethane, add 13.94 g (2.00 eq) of triethylamine, cool to -5 to 5°C with stirring, add 15.91 g (1.10 eq) of trifluoroacetic anhydride dropwise with stirring, and after the addition is complete, control the temperature at 0 to 10°C and stir for 1 to 2 hours. After the reaction is completed by TLC detection, control the temperature and add 50 ml purified water, after the addition is completed, the layers are extracted, the water layer is separated, the dichloromethane layer is washed once with 50 ml of 5% sodium bicarbonate, once with 30 ml of saturated brine, dried with sodium sulfate, filtered, and concentrated dichloromethane. 75g of isopropanol hydrochloric acid (content: 5%) solution is added to the concentrate, the temperature is raised to 35-40°C, stirred for 3 hours, cooled to 5-15°C, stirred for 2 hours, the solid product is filtered out, and 12.87g of the product is obtained after vacuum drying (yield: 89.53%).

[0096] MS (ESI, m / z): 173.1 [M+H] + , 1 HNMR(400MHz,D2O)δ:2.35(6H,s),5.99(1H,d),7.14(2H,s),7.47(1H,s),9.08(1H,bs).

[0097] Example 8: Preparation of the final product ((E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride)

[0098] Weigh 15.00 g (1.00 eq) of intermediate 2 ((4-tert-butoxycarbonylamino-2,6-dimethylphenyl) acrylamide) and add it to 150 ml of toluene. Heat to 100-110° C. with stirring, control the temperature and stir for 4-6 hours. After TLC detection, the reaction is complete. Lower the temperature to 10-20° C. and stir for 2 hours. Filter out the solid, beat the filter cake with anhydrous ethanol at 50-60° C. for 1 hour, lower the temperature to 0-10° C., stir for 2 hours, filter and dry to obtain 9.30 g of the product (yield: 86.26%).

[0099] Example 9: Preparation of the final product ((E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride)

[0100] Weigh 10.00 kg of intermediate 2 ((4-tert-butoxycarbonylamino-2,6-dimethylphenyl) acrylamide) and add it to a 100 L glass reactor filled with 50 L of dichloromethane, add 7.00 kg of triethylamine, and lower the temperature in the reactor to -5 to 5 ° C while stirring. Add 8.00 kg of trifluoroacetic anhydride dropwise while stirring. The addition is completed in about 1 hour, and the temperature is controlled at 0 to 10 ° C and stirred for 2 hours. 25 kg of purified water is added dropwise while controlling the temperature. After the addition is completed, the layers are extracted and the water layer is separated. The dichloro layer is washed once with 25 kg of 5% sodium bicarbonate and once with 20 kg of saturated brine, dried with sodium sulfate, filtered, and the dichloromethane is concentrated. 37.7 kg of isopropyl hydrochloride (content: 5%) solution is added to the concentrate, the temperature is raised to 35 to 40 ° C, stirred for 3 hours, cooled to 5 to 15 ° C and stirred for 2 hours, the solid product is filtered out, and 6.59 kg of the product is obtained after vacuum drying (yield: 91.69%).

[0101] The yield of the product of the above embodiment can reach 90%, which is a very high yield in industrial production. Therefore, the preparation method of the key intermediate of rilpivirine (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride in the technical scheme can be suitable for industrial production, and the overall production cost is low.

[0102] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing a key intermediate of rilpivirine, characterized in that: The specific method is as follows: The intermediate is called (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride, and its chemical formula is as follows: The reaction synthesis route is as follows: Step 1: Using 2,6-dimethylaniline as the starting material, intermediate 1 is obtained through a one-pot reaction of halogenation and amino protection; Step 2: intermediate 1 is reacted with acrylamide through Heck reaction and post-treatment to prepare intermediate 2; Step 3: The intermediate 2 is subjected to a dehydration reaction of the amide group and a one-time deprotection reaction of the amino group to finally obtain the desired (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride.

2. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: The R1 group used can be a chlorine atom, a bromine atom or an iodine atom among halogens; the halogenating agent used can be elemental chlorine, elemental bromine or elemental iodine, or can be halogenating agents such as NCS, NBS or NIS; preferably, elemental bromine and NBS; the R2 group used can be protecting groups such as Boc, Cbz, Fmoc, and sulfonyl.

3. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: During the halogenation reaction, the molar ratio of 2,6-dimethylaniline to the halogenation reagent is 1.00:(0.80-3.00), preferably 1.00:(1.00-1.60), and most preferably 1.00:(1.10-1.50); ​​the reaction temperature is -80-100°C, preferably -20-60°C, and most preferably 0-30°C.

4. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: The solvent used in the halogenation reaction of R1 and R2 groups in the preparation of intermediate 1 can be dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, ethyl acetate, methanol, ethanol, acetic acid, etc. The preferred reaction solvents are acetonitrile, N,N-dimethylformamide, dichloromethane, and chloroform; the most preferred reaction solvents are dichloromethane and chloroform; the solvents used in the reaction are not limited to protic solvents or aprotic solvents or mixtures of different solvents.

5. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: When the intermediate 1 is synthesized by the amine protection reaction, the protecting reagent is benzyl chloroformate, Boc anhydride, 9-fluorenylmethyl chloroformate, trifluoroacetyl chloride, trifluoroacetic anhydride, preferably Boc anhydride and benzyl chloroformate; the molar ratio of 2,6-dimethylaniline to the protecting reagent is 1:(0.90-3.00), preferably 1.00:(1.00-1.80), and most preferably 1.00:(1.05-1.20). The acidifying agent used is a base such as triethylamine, diisopropylethylamine, DMAP, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably DMAP, diisopropylethylamine or triethylamine, most preferably triethylamine.

6. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: The metal catalyst used in the preparation of intermediate 2 is palladium carbon, palladium chloride, Pd(OAc)2, Pd2(dba)3 or Pd(dppf)Cl2; the percentage of the catalyst amount to intermediate 1 is 0.01-5%, preferably the catalyst molar amount is 0.05-0.1% of intermediate 1, and most preferably 0.08-0.12%; The solvent used in the preparation of intermediate 2 is a protic solvent such as water, alcohols, acetonitrile, N,N-dimethylformamide; or an aprotic solvent; it can be a single solvent or a mixed solvent of two or more; The Heck reaction in the preparation of intermediate 2 has a reaction temperature of 20°C to 140°C, preferably 80°C to 120°C; When the intermediate 2 is prepared by Heck reaction, the base used can be an inorganic base or an organic base such as sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate, etc.

7. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: In step 3, when performing the two reactions of dehydration and amino deprotection, the reaction can be carried out in steps or in one pot.

8. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: Step 3: During the dehydration reaction and the amino deprotection reaction, the solvents used in these two steps can be organic solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and N,N-dimethylformamide, and are not limited to using only one solvent; Step 3: In the dehydration reaction and the amino deprotection reaction, the dehydration reagents used in these two steps are phosphorus oxychloride, oxalyl chloride, thionyl chloride, trifluoroacetic anhydride and other reaction solvents; the reaction can be carried out with one reagent or with a mixture of two or more reagents; In step 3, during the dehydration reaction and amino deprotection reaction, the acidifying agent used is a base such as triethylamine, diisopropylethylamine, potassium carbonate, and sodium carbonate, among which the preferred acidifying agents are triethylamine and diisopropylethylamine.

9. The method for synthesizing a key intermediate of rilpivirine according to claim 1, characterized in that: In step 3, during dehydration and deprotection, the molar ratio of intermediate 2 to the reagent used is 1:(0.80-5.00), preferably 1.00:(1.00-2.00), and the optimal molar ratio is 1.00:(1.05-1.80); The reaction temperature is -20°C to 120°C, preferably -10°C to 60°C, and most preferably 0°C to 20°C.

10. A method for synthesizing a key intermediate of rilpivirine according to any one of claims 1 to 9, characterized in that: Post-reaction treatment includes extraction, crystallization, recrystallization, drying and purification.

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