Synthetic method of 3-amino-5-(4-phenoxy phenyl)-4-cyano-1H-pyrazole

Abstract

The invention discloses a synthesis method of 3-amino-5-(4-phenoxy phenyl)-4-cyano-1H-pyrazole, belongs to the field of organic chemical synthesis, and particularly relates to a synthesis method of an ibrutinib intermediate, which comprises the following steps: (a) dissolving phenol and p-halobenzonitrile in an organic solvent A, adding alkali, and carrying out substitution reaction to obtain an intermediate I-a; (b) dissolving the intermediate I-a in ethanol, dropwise adding acetyl chloride, and carrying out an addition reaction to obtain an intermediate I-b; (c) dissolving the intermediate I-b, malononitrile and alkali in an organic solvent B, and performing condensation reaction to obtain an intermediate I-c; and (d) dissolving the intermediate I-c and hydrazine hydrate in ethanol, and carrying out cyclization reaction to obtain a target product I-d. The synthesis method adopts substitution, addition, condensation, cyclization and other reactions, has the advantages of mild reaction conditions, simple operation, low cost, safety and controllability, avoids the use of high-toxicity and volatile reagents, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and in particular to a method for synthesizing an ibrutinib intermediate 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole. Background Art

[0002] Ibrutinib is the world's first approved Bruton's tyrosine kinase (BTK) inhibitor. It was approved by the US FDA in November 2013 and launched in China in August 2017. Ibrutinib is also suitable for chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), gastric cancer, etc. It is the variety with the most indications among all the BTK inhibitors currently on the market.

[0003] Patent documents (CN 101610676 A, CN 102887900 A, CN 102746305 A, CN 101805341A) disclose a method for preparing ibrutinib (1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-2-propene-1-one): 2006-12-28

[0004] 1H-pyrazolo[3,4-d]pyrimidine-4-amine is halogenated, and then subjected to a metal-catalyzed cross-coupling reaction, such as palladium-mediated cross-coupling of phenylboronic acid under alkaline conditions to form intermediate 2, and then coupled with N-Boc-3-hydroxypiperidine through the Mitsunobu reaction to obtain intermediate 3, acid deprotection, and acyl chloride coupling to obtain compound 4. This synthesis process has high synthesis costs and high requirements for reaction conditions.

[0005]

[0006]

[0007] Preparation method of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (intermediate 2 in the figure above):

[0008] 4-Phenoxybenzoic acid was added to thionyl chloride, refluxed for 1 hour, distilled and filtered to obtain a compound containing an acid chloride, and malononitrile was added. Diisopropylethylamine and toluene were added at -10°C, and the temperature was maintained below 0°C for 1 hour. Overnight, the mixture was filtered and evaporated to obtain 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethylene with a yield of 56.58%. Diisopropylethylamine and trimethylsilyldiazomethane were added to obtain 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethylene, which was treated with hydrazine hydrate to obtain 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole. The mixture was heated at 180°C for 4 hours in formamide to obtain 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.

[0009]

[0010] In the above-mentioned synthesis method, when thionyl chloride (also known as thionyl chloride) is synthesized into acyl chloride, a large amount of sulfur dioxide and hydrogen chloride gas will be released, which will corrode production equipment and pose a safety hazard; when trimethylsilyldiazomethane is subjected to methylation reaction, the reaction is highly exothermic and the reaction time is long, and the atom economy is low.

[0011] In the improved methods of the above process, dimethyl sulfate or diethyl sulfate is often used to replace trimethylsilyldiazomethane, see Patent Document 2 (CN 103626774 A) and Patent Document 3 (CN 106188062A). Dialkyl sulfate compounds have the disadvantages of being carcinogenic and teratogenic.

[0012] Patent document 4 (CN 107641123 A) adopts the following process when synthesizing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine:

[0013]

[0014] This process uses a one-pot method to synthesize the target product, in which the reaction temperature in each step varies greatly. For example, in the first step, the reaction liquid is alkaline, and the addition of phosphorus oxychloride will cause a violent release of heat, and then low-temperature control is performed, and the temperature is subsequently raised to 180°C, which is difficult to control and consumes a lot of resources.

[0015] Patent document 5 (CN 108727230 A) discloses a process for synthesizing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine:

[0016]

[0017] The synthesis process of the corresponding product in Patent Document 6 (CN 111606907 A) is:

[0018]

[0019] The synthesis process of the corresponding product in Patent Document 7 (CN 106608877 A) is:

[0020]

[0021] In the above-mentioned patent documents 5-7, the starting raw materials are all of high cost, some of the raw materials are highly toxic, and have great safety hazards, and are not suitable for industrial production.

[0022] The above contents are only used to assist in understanding the technical solution of the present invention and do not constitute an admission that the above contents are prior art. Summary of the invention

[0023] The main purpose of the present invention is to provide a method for synthesizing an ibrutinib intermediate 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, which overcomes the technical problems mentioned in the above technical background, such as high cost, great safety hazards, complex operation, and inability to meet the needs of industrial production.

[0024] To achieve the above object, the present invention provides a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, comprising the following steps:

[0025] (a) dissolving phenol and p-halobenzonitrile in an organic solvent A, adding a base, and performing a substitution reaction to obtain an intermediate Ia;

[0026] (b) dissolving the intermediate Ia in ethanol, adding acetyl chloride dropwise, and performing an addition reaction to obtain the intermediate Ib;

[0027] (c) dissolving the intermediate Ib, malononitrile and a base in an organic solvent B to carry out a condensation reaction to obtain an intermediate Ic;

[0028] (d) The intermediate Ic and hydrazine hydrate are dissolved in ethanol and subjected to a cyclization reaction to obtain the target product Id.

[0029] Preferably,

[0030] The reaction temperature of the substitution reaction is 60°C to 150°C, and the reaction time of the substitution reaction is 2h to 8h;

[0031] The reaction temperature of the addition reaction is 0°C to 10°C, and the reaction time of the addition reaction is 17h to 19h;

[0032] The reaction temperature of the condensation reaction is 20°C to 25°C, and the reaction time of the condensation reaction is 2h to 4h;

[0033] The reaction temperature of the cyclization reaction is 80°C to 100°C, and the reaction time of the cyclization reaction is 5h to 7h.

[0034] Preferably,

[0035] The reaction temperature of the substitution reaction is 80°C, and the reaction time of the substitution reaction is 3h;

[0036] The reaction temperature of the addition reaction is 0°C, and the reaction time of the addition reaction is 18h;

[0037] The reaction temperature of the condensation reaction is 25°C, and the reaction time of the condensation reaction is 3h;

[0038] The reaction temperature of the cyclization reaction is 90°C, and the reaction time of the cyclization reaction is 6 h.

[0039] in:

[0040] The p-halobenzonitrile is selected from one of p-fluorobenzonitrile, p-chlorobenzonitrile and p-bromobenzonitrile.

[0041] The base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and N,N-diisopropylethylamine.

[0042] The organic solvent A is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran and dimethyl sulfoxide.

[0043] The organic solvent B is selected from one or more of methanol, ethanol, isopropanol, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dimethyl sulfoxide.

[0044] The synthesis method of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole provided by the present invention has the following advantages:

[0045] 1. The process conditions are simple, the reaction by-products are few, and the post-treatment is simple.

[0046] 2. The raw materials and reagents required for this process are cheap, the cost is low, and the economic benefits are good.

[0047] 3. This process avoids the use of dangerous reagents such as thionyl chloride, trimethylsilyldiazomethane, and sulfuric acid diesters. It is safer and more environmentally friendly and meets the needs of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 It is the hydrogen spectrum nuclear magnetic resonance image of the target product Id in the embodiment of the present invention.

[0049] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, rather than all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present disclosure.

[0051] The present invention provides a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, comprising the following steps:

[0052]

[0053] (a) dissolving phenol and p-halobenzonitrile in an organic solvent A, adding a base, and performing a substitution reaction to obtain an intermediate Ia;

[0054] Wherein: the p-halobenzonitrile is selected from one of p-fluorobenzonitrile, p-chlorobenzonitrile and p-bromobenzonitrile.

[0055] The base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and N,N-diisopropylethylamine.

[0056] The organic solvent A is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran and dimethyl sulfoxide.

[0057] The reaction temperature of the substitution reaction is 60° C. to 150° C., preferably 80° C.; the reaction time of the substitution reaction is 2 h to 8 h, preferably 3 h.

[0058] (b) dissolving the intermediate Ia in ethanol, adding acetyl chloride dropwise, and performing an addition reaction to obtain the intermediate Ib;

[0059] Wherein: the reaction temperature of the addition reaction is 0°C to 10°C, preferably, 0°C; the reaction time of the addition reaction is 17h to 19h, preferably, 18h.

[0060] (c) dissolving the intermediate Ib, malononitrile and a base in an organic solvent B to carry out a condensation reaction to obtain an intermediate Ic;

[0061] Wherein: the base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and N,N-diisopropylethylamine.

[0062] The organic solvent B is selected from one or more of methanol, ethanol, isopropanol, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dimethyl sulfoxide.

[0063] The reaction temperature of the condensation reaction is 20°C to 25°C, preferably 25°C; the reaction time of the condensation reaction is 2h to 4h, preferably 3h.

[0064] (d) The intermediate Ic and hydrazine hydrate are dissolved in ethanol and subjected to a cyclization reaction to obtain the target product Id.

[0065] Wherein: the reaction temperature of the cyclization reaction is 80°C to 100°C, preferably 90°C; the reaction time of the cyclization reaction is 5h to 7h, preferably 6h.

[0066] Example 1

[0067] (a) 2.82 kg of phenol and 1.21 kg of p-fluorobenzonitrile were weighed separately and added to a 30 L reactor, 10 L of N,N-dimethylformamide and 3.18 kg of sodium carbonate were added to carry out substitution reaction at 80° C. for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and added to 50 L of ice water to precipitate a large amount of white solid. The solid was filtered, washed with water and dried in vacuo for 6 h to obtain 1.82 kg of intermediate Ia in the form of a white solid with a yield of 93%.

[0068] (b) 1.82 kg of the intermediate Ia obtained in step (a) was added to a 30 L reactor, 15 L of ethanol was added, and 3.66 kg of acetyl chloride was added dropwise to carry out addition reaction. The reaction temperature was 0 ° C. After the addition was completed, the temperature was raised to room temperature and the reaction was continued for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 2.10 kg of the intermediate Ib as a beige solid.

[0069] (c) 2.10 kg of intermediate Ib obtained in step (b) and 0.92 kg of malononitrile were added to a 30 L reactor, 15 L of tetrahydrofuran was added, 2.96 kg of sodium carbonate was added, and a condensation reaction was carried out at a reaction temperature of 25 ° C. The reaction time was 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to 3 L and added to 10 L of water. The mixture was extracted three times with dichloromethane (5 L × 3). The organic layers were combined, washed, and spin-dried to obtain 2.08 kg of intermediate Ic as a yellow solid. The yield of (b) and (c) was 85%.

[0070] (d) 2.08 kg of the intermediate Ic obtained in step (c) was added to a 30 L reactor, 10 L of ethanol was added, 1.79 kg of hydrazine hydrate was slowly added, and a cyclization reaction was carried out. The mixture was heated (90 ° C.) and refluxed for 6 h. After the reaction was completed, the reaction solution was concentrated to 2 L under reduced pressure and added to 10 L of water. The mixture was extracted with dichloromethane three times (5 L × 3). The organic layers were combined, washed, and dried to obtain 1.92 kg of the target product Id as a dark red solid. The liquid phase purity was 100%, and the total yield of the four-step reaction was 70%.

[0071] like Figure 1 As shown, where: H NMR spectrum 1 H NMR (400 MHz, DMSO-d 6 )(ppm): δ12.14(brs,1H),7.80(d,J=8.4Hz,2H),7.42(dd,J=7.8Hz,7.8Hz,2H) ,7.18(dd,J=7.4Hz,7.4Hz,1H),7.08(dd,J=7.8Hz,7.8Hz,4H),6.42(brs,2H).

[0072] Example 2

[0073] The difference between this embodiment and embodiment 1 is that:

[0074] (a) 1.21 kg of p-bromobenzonitrile, 4.15 kg of potassium carbonate as the base, 10 L of N-methylpyrrolidone as the organic solvent, reaction temperature 60° C., reaction time 8 h; 1.78 kg of intermediate Ia was obtained, with a yield of 91%.

[0075] (b) The amount of acetyl chloride was 3.60 kg, the reaction temperature was 10°C, and the reaction time was 19 h; 2.09 kg of intermediate Ib was obtained.

[0076] In (c), the amount of malononitrile is 0.9 kg, the organic solvent is 10 L of N,N-dimethylformamide, the reaction temperature is 20° C., and the reaction time is 2 h; 1.71 kg of intermediate Ic is obtained, and the yield of (b) and (c) is 72%.

[0077] (d) contains 1.47 kg of hydrazine hydrate, the reaction temperature is 80° C., and the reaction time is 5 h; 1.68 kg of the target product Id is obtained.

[0078] The rest of the conditions remain unchanged.

[0079] The liquid phase purity of the target product Id was 98.5%, and the total yield of the four-step reaction was 61%.

[0080] Example 3

[0081] (a) 1.38 kg of p-chlorobenzonitrile, 5.21 kg of sodium hydroxide as the base, 10 L of tetrahydrofuran as the organic solvent, the reaction temperature is 150° C., and the reaction time is 2 h; 1.65 kg of intermediate Ia is obtained with a yield of 84%.

[0082] (b) The amount of acetyl chloride was 3.32 kg, the reaction temperature was 0°C, and the reaction time was 17 h; 1.71 kg of intermediate Ib was obtained.

[0083] In (c), the amount of malononitrile is 0.84 kg, the base is 2.57 kg of triethylamine, the organic solvent is 10 L of ethanol, the reaction temperature is 22° C., and the reaction time is 4 h; 1.83 kg of intermediate Ic is obtained, and the yield of (b) and (c) is 83%.

[0084] (d) contains 1.58 kg of hydrazine hydrate, the reaction temperature is 100° C., and the reaction time is 7 h; 1.78 kg of the target product Id is obtained.

[0085] The rest of the conditions remain unchanged.

[0086] The liquid phase purity of the target product Id is 98.1%, and the total yield of the four-step reaction is 64%.

[0087] Phenol and p-halobenzonitrile are used as raw materials, 4-phenoxybenzonitrile (intermediate Ia) is obtained after substitution reaction, and then 4-phenoxybenzimidic acid ethyl ester hydrochloride (intermediate Ib) is obtained by addition reaction with ethanol, and then condensed with malononitrile and ring-closed with hydrazine hydrate to obtain the final product: 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole (target product Id). The invention avoids the highly toxic and volatile methylating agents used in the existing process, has a novel synthesis route, mild reaction conditions, simple production operation, low cost, high safety, and is suitable for large-scale industrial production.

Claims

1. A method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, characterized in that: The following steps are involved: (a) dissolving phenol and p-halobenzonitrile in an organic solvent A, adding a base, and performing a substitution reaction to obtain an intermediate Ia; (b) dissolving the intermediate Ia in ethanol, adding acetyl chloride dropwise, and performing an addition reaction to obtain the intermediate Ib; (c) dissolving the intermediate Ib, malononitrile and a base in an organic solvent B to carry out a condensation reaction to obtain an intermediate Ic; (d) The intermediate Ic and hydrazine hydrate are dissolved in ethanol and subjected to a cyclization reaction to obtain the target product Id.

2. The method according to claim 1, characterized in that The reaction temperature of the substitution reaction is 60°C to 150°C, and the reaction time of the substitution reaction is 2h to 8h; The reaction temperature of the addition reaction is 0°C to 10°C, and the reaction time of the addition reaction is 17h to 19h; The reaction temperature of the condensation reaction is 20°C to 25°C, and the reaction time of the condensation reaction is 2h to 4h; The reaction temperature of the cyclization reaction is 80°C to 100°C, and the reaction time of the cyclization reaction is 5h to 7h.

3. The method according to claim 1, characterized in that The reaction temperature of the substitution reaction is 80°C, and the reaction time of the substitution reaction is 3h; The reaction temperature of the addition reaction is 0°C, and the reaction time of the addition reaction is 18h; The reaction temperature of the condensation reaction is 25°C, and the reaction time of the condensation reaction is 3h; The reaction temperature of the cyclization reaction is 90°C, and the reaction time of the cyclization reaction is 6 h.

4. The method according to any one of claims 1 to 3, characterized in that: The p-halobenzonitrile is selected from one of p-fluorobenzonitrile, p-chlorobenzonitrile and p-bromobenzonitrile; the base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and N,N-diisopropylethylamine.

5. The method according to claim 4, characterized in that The organic solvent A is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dimethyl sulfoxide; the organic solvent B is selected from one or more of methanol, ethanol, isopropanol, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dimethyl sulfoxide.

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