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

Abstract

The present invention discloses a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, belonging to the field of organic chemical synthesis, and specifically relates to a method for synthesizing an intermediate of ibrutinib, comprising the following steps: (a) dissolving phenol and p-halobenzonitrile in organic solvent A, adding a base, and carrying out a substitution reaction to obtain intermediate I-a; (b) dissolving intermediate I-a in ethanol, dropwise adding acetyl chloride, and carrying out an addition reaction to obtain intermediate I-b; (c) dissolving intermediate I-b, malononitrile and a base in organic solvent B, and carrying out a condensation reaction to obtain intermediate I-c; (d) dissolving intermediate I-c and hydrazine hydrate in ethanol, and carrying out a cyclization reaction to obtain the target product I-d. This synthesis method involves reactions such as substitution, addition, condensation and cyclization, with mild reaction conditions, simple operation, low cost, safe and controllable, avoiding the use of highly toxic 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 particularly relates to a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, an intermediate of ibrutinib. Background Art

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

[0003] Patent documents (CN 101610676 A, CN 102887900 A, CN 102746305 A, CN 101805341 A) disclose the preparation method of ibrutinib (1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-2-propen-1-one):

[0004] 1H-pyrazolo[3,4-d]pyrimidin-4-amine is halogenated and then undergoes a metal-catalyzed cross-coupling reaction. For example, phenylboronic acid undergoes a palladium-mediated cross-coupling under alkaline conditions to form intermediate 2. Then, it is coupled with N-Boc-3-hydroxypiperidine through the Mitsunobu reaction (Mitsunobu reaction) to obtain intermediate 3. The acid is deprotected and acyl chloride coupling is performed to obtain compound 4. This synthesis process has high synthesis costs and high requirements for reaction conditions.

[0005] The preparation method of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (intermediate 2 in the above figure):

[0006] 4-Phenoxybenzoic acid was added to thionyl chloride, refluxed for 1 h, distilled and filtered to obtain a compound containing acyl chloride. Malononitrile was added, and diisopropylethylamine and toluene were added at -10 °C, maintaining below 0 °C for 1 h and overnight. After filtration and evaporation, 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethylene was obtained 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. In formamide, it was heated at 180 °C for 4 h to obtain 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine.

[0007] In the above synthesis method, a large amount of sulfur dioxide and hydrogen chloride gases are released when thionyl chloride (also known as sulfuryl chloride) synthesizes acyl chloride, which corrodes production equipment and poses safety hazards; when trimethylsilyldiazomethane undergoes methylation reaction, the reaction exotherm is intense and the reaction time is long, and the atom economy is low.

[0008] In the improvement methods of the above process, dimethyl sulfate or diethyl sulfate is mostly used to replace trimethylsilyldiazomethane, as seen in Patent Document 2 (CN 103626774 A) and Patent Document 3 (CN 106188062 A). Dialkyl sulfate compounds have the disadvantages of being carcinogenic and teratogenic.

[0009] Patent Document 4 (CN 107641123 A) adopts the following process when synthesizing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine:

[0010] This process uses a one-pot method to synthesize the target product. Among them, the reaction temperatures in each step vary greatly. For example, in the first step, the reaction solution is alkaline, and adding phosphorus oxychloride will cause intense heat release, followed by low-temperature control, and then the temperature is raised to 180 °C. There are difficulties in control and large resource consumption.

[0011] The process for synthesizing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine in Patent Document 5 (CN 108727230 A) is as follows:

[0012] The synthesis process for the corresponding product in Patent Document 6 (CN 111606907 A) is as follows:

[0013] The synthesis process for the corresponding product in Patent Document 7 (CN 106608877 A) is as follows:

[0014] In the above-mentioned patent documents 5-7, the starting materials all have high costs, some of the raw materials are highly toxic, with great potential safety hazards, and are not suitable for industrial production.

[0015] The above content is only used to assist in understanding the technical solution of the present invention and does not represent an admission that the above content is prior art. Summary of the Invention

[0016] The main object of the present invention is to provide a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, an intermediate of ibrutinib, to overcome the technical problems of high cost, great potential safety hazards, and complex operations mentioned in the above technical background, which cannot meet the requirements of industrial production.

[0017] 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:

[0018] (a) Dissolve phenol and p-halobenzonitrile in organic solvent A, add a base, and carry out a substitution reaction to obtain intermediate I-a;

[0019] (b) Dissolve intermediate I-a in ethanol, dropwise add acetyl chloride, and carry out an addition reaction to obtain intermediate I-b;

[0020] (c) Dissolve intermediate I-b, malononitrile, and a base in organic solvent B, and carry out a condensation reaction to obtain intermediate I-c;

[0021] (d) Dissolve intermediate I-c and hydrazine hydrate in ethanol, and carry out a cyclization reaction to obtain the target product I-d.

[0022] Preferably,

[0023] The reaction temperature of the substitution reaction is 60°C to 150°C, and the reaction time of the substitution reaction is 2 h to 8 h;

[0024] The reaction temperature of the addition reaction is 0°C to 10°C, and the reaction time of the addition reaction is 17 h to 19 h;

[0025] The reaction temperature of the condensation reaction is 20°C to 25°C, and the reaction time of the condensation reaction is 2 h to 4 h;

[0026] The reaction temperature of the cyclization reaction is 80°C to 100°C, and the reaction time of the cyclization reaction is 5 h to 7 h.

[0027] Preferably,

[0028] The reaction temperature of the substitution reaction is 80°C, and the reaction time of the substitution reaction is 3 h;

[0029] The reaction temperature of the addition reaction is 0°C, and the reaction time of the addition reaction is 18 h;

[0030] The reaction temperature of the condensation reaction is 25 °C, and the reaction time of the condensation reaction is 3 h;

[0031] The reaction temperature of the cyclization reaction is 90 °C, and the reaction time of the cyclization reaction is 6 h.

[0032] Among them:

[0033] The p-halobenzonitrile is selected from one of p-fluorobenzonitrile, p-chlorobenzonitrile and p-bromobenzonitrile.

[0034] The base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine.

[0035] The organic solvent A is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide.

[0036] The organic solvent B is selected from one or more of methanol, ethanol, isopropanol, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide.

[0037] The synthesis method of 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole provided by the present invention has the following advantages:

[0038] 1. The process conditions are simple, the reaction by-products are few, and the post-treatment is simple.

[0039] 2. The raw materials and reagents required by this process method are inexpensive, the cost is low, and the economic benefit is good.

[0040] 3. This process avoids the use of dangerous reagents such as thionyl chloride, trimethylsilyldiazomethane, sulfuric acid diester, etc., is safer and more environmentally friendly, and meets the requirements of industrial production. Description of the Drawings

[0041] Figure 1 It is the 1H NMR spectrum of the target product I-d in the embodiment of the present invention.

[0042] The realization, functional characteristics and advantages of the object of the present invention will be further described in conjunction with the embodiments and with reference to the drawings. Detailed Embodiments

[0043] To make the objectives, technical solutions, and advantages of the embodiments of the present disclosure clearer, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present disclosure. Apparently, the described embodiments are only a part of the embodiments of the present disclosure, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the described embodiments of the present disclosure without creative efforts fall within the scope of protection of the present disclosure.

[0044] The present invention provides a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, comprising the following steps:

[0045] (a) Dissolve phenol and p-halobenzonitrile in organic solvent A, add a base, and carry out a substitution reaction to obtain intermediate I-a;

[0046] Wherein: the p-halobenzonitrile is selected from one of p-fluorobenzonitrile, p-chlorobenzonitrile, and p-bromobenzonitrile.

[0047] The base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and N,N-diisopropylethylamine.

[0048] The organic solvent A is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dimethyl sulfoxide.

[0049] 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.

[0050] (b) Dissolve intermediate I-a in ethanol, dropwise add acetyl chloride, and carry out an addition reaction to obtain intermediate I-b;

[0051] 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 17 h to 19 h, preferably 18 h.

[0052] (c) Dissolve intermediate I-b, malononitrile, and a base in organic solvent B, and carry out a condensation reaction to obtain intermediate I-c;

[0053] Wherein: the base is selected from one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and N,N-diisopropylethylamine.

[0054] 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.

[0055] The reaction temperature of the condensation reaction is 20°C to 25°C, preferably 25°C; the reaction time of the condensation reaction is 2 h to 4 h, preferably 3 h.

[0056] (d)Dissolve intermediate I-c and hydrazine hydrate in ethanol and carry out a cyclization reaction to obtain the target product I-d.

[0057] Among them: the reaction temperature of the cyclization reaction is 80°C to 100°C, preferably 90°C; the reaction time of the cyclization reaction is 5 h to 7 h, preferably 6 h.

[0058] Example 1

[0059] (a)Weigh 2.82 kg of phenol and 1.21 kg of p-fluorobenzonitrile separately and add them to a 30 L reaction kettle. Add 10 L of N,N-dimethylformamide and 3.18 kg of sodium carbonate, and carry out a substitution reaction. The reaction temperature is 80°C and the reaction time is 3 h. After the reaction is completed, cool to room temperature. Add the reaction solution to 50 L of ice water, a large amount of white solid precipitates, filter by suction, wash with water, and vacuum dry for 6 h to obtain 1.82 kg of intermediate I-a in the form of a white solid, with a yield of 93%.

[0060] (b)Add 1.82 kg of intermediate I-a obtained in step (a) to a 30 L reaction kettle, add 15 L of ethanol, and dropwise add 3.66 kg of acetyl chloride to carry out an addition reaction. The reaction temperature is 0°C. After dropping, raise the temperature to room temperature and continue the reaction for 18 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain 2.10 kg of intermediate I-b in the form of a beige solid.

[0061] (c)Add 2.10 kg of intermediate I-b obtained in step (b) and 0.92 kg of malononitrile to a 30 L reaction kettle, add 15 L of tetrahydrofuran, and add 2.96 kg of sodium carbonate to carry out a condensation reaction. The reaction temperature is 25°C and the reaction time is 3 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to 3 L, add it to 10 L of water, extract three times with dichloromethane (5 L × 3), combine the organic layers, wash, and rotary evaporate to obtain 2.08 kg of intermediate I-c in the form of a yellow solid. The overall yield of steps (b) and (c) is 85%.

[0062] (d) Add 2.08 kg of intermediate I-c obtained in step (c) to a 30 L reaction kettle, add 10 L of ethanol, slowly add 1.79 kg of hydrazine hydrate, carry out a cyclization reaction, heat under reflux (90 °C), with a reaction time of 6 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to 2 L, add it to 10 L of water, extract with dichloromethane three times (5 L × 3), combine the organic layers, wash, and rotary evaporate to obtain 1.92 kg of the target product I-d as a dark red solid, with a liquid phase purity of 100% and a total yield of the four-step reaction of 70%.

[0063] As Figure 1 shown, wherein: nuclear magnetic resonance hydrogen spectrum 1 H NMR(400 MHz, DMSO- d 6) (ppm): δ 12.14(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).

[0064] Example 2

[0065] The difference between this example and Example 1 lies in:

[0066] In (a), 1.21 kg of p-bromobenzonitrile, 4.15 kg of potassium carbonate as the base, and 10 L of N-methylpyrrolidone as the organic solvent, with a reaction temperature of 60 °C and a reaction time of 8 h; 1.78 kg of intermediate I-a was obtained, with a yield of 91%.

[0067] In (b), 3.60 kg of acetyl chloride, with a reaction temperature of 10 °C and a reaction time of 19 h; 2.09 kg of intermediate I-b was obtained.

[0068] In (c), 0.9 kg of malononitrile, 10 L of N,N-dimethylformamide as the organic solvent, with a reaction temperature of 20 °C and a reaction time of 2 h; 1.71 kg of intermediate I-c was obtained, and the total yield of steps (b) and (c) was 72%.

[0069] In (d), 1.47 kg of hydrazine hydrate, with a reaction temperature of 80 °C and a reaction time of 5 h; 1.68 kg of the target product I-d was obtained.

[0070] The remaining conditions remain unchanged.

[0071] The liquid phase purity of the target product I-d is 98.5%, and the total yield of the four-step reaction is 61%.

[0072] Example 3

[0073] In (a), 1.38 kg of 4-chlorobenzonitrile, 5.21 kg of sodium hydroxide as the base, 10 L of tetrahydrofuran as the organic solvent, reaction temperature of 150 °C, and reaction time of 2 h; 1.65 kg of intermediate I-a was obtained with a yield of 84%.

[0074] In (b), 3.32 kg of acetyl chloride, reaction temperature of 0 °C, and reaction time of 17 h; 1.71 kg of intermediate I-b was obtained.

[0075] In (c), 0.84 kg of malononitrile, 2.57 kg of triethylamine as the base, 10 L of ethanol as the organic solvent, reaction temperature of 22 °C, and reaction time of 4 h; 1.83 kg of intermediate I-c was obtained, and the overall yield of the two steps of (b) and (c) was 83%.

[0076] In (d), 1.58 kg of hydrazine hydrate, reaction temperature of 100 °C, and reaction time of 7 h; 1.78 kg of the target product I-d was obtained.

[0077] The remaining conditions remain unchanged.

[0078] The liquid-phase purity of the target product I-d was 98.1%, and the total yield of the four-step reaction was 64%.

[0079] Using phenol and p-halobenzonitrile as raw materials, 4-phenoxybenzonitrile (intermediate I-a) was obtained after a substitution reaction, and then ethyl 4-phenoxybenziminocarboxylate hydrochloride (intermediate I-b) was obtained by an addition reaction with ethanol. Then, it was condensed with malononitrile and cyclized with hydrazine hydrate to obtain the final product: 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole (target product I-d). The present invention avoids the use of highly toxic and volatile methylation reagents in the existing process, has a novel synthesis route, mild reaction conditions, simple production operation, low cost, and 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, It includes the following steps: ； (a) Dissolve phenol and p-halobenzonitrile in organic solvent A, add a base, and carry out a substitution reaction to obtain intermediate I-a; (b) Dissolve intermediate I-a in ethanol, dropwise add acetyl chloride, and carry out an addition reaction to obtain intermediate I-b; (c) Dissolve intermediate I-b, malononitrile and a base in organic solvent B, and carry out a condensation reaction to obtain intermediate I-c; (d) Dissolve intermediate I-c and hydrazine hydrate in ethanol, and carry out a cyclization reaction to obtain the target product I-d.

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

3. The method according to claim 1, wherein the reaction temperature of the substitution reaction is 80°C, and the reaction time of the substitution reaction is 3 h; the reaction temperature of the addition reaction is 0°C, and the reaction time of the addition reaction is 18 h; the reaction temperature of the condensation reaction is 25°C, and the reaction time of the condensation reaction is 3 h; 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 1-3, 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, N,N-diisopropylethylamine.

5. The method according to claim 4, wherein The organic solvent A is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, 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, dimethyl sulfoxide.

Images