Preparation method of apattamide intermediate

Abstract

The invention discloses a preparation method of an apattamide intermediate, and belongs to the technical field of medicine synthesis. The preparation method of the intermediate comprises the following steps: reacting a compound II under the conditions of a catalyst, an acid-binding agent and an organic solvent to prepare an intermediate compound I; according to the invention, the yield and purity of the product are improved, the use of high-toxicity and volatile thiophosgene is avoided, the yield and purity of the product are improved, and the method is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of an apalutamide intermediate. Background Art

[0002] Apalutamide is a novel androgen receptor (AR) inhibitor developed by Johnson & Johnson. It can competitively bind to AR to inhibit AR activation, prevent the AR complex from entering the nucleus to inhibit the nuclear transport of activated AR, and inhibit the binding of AR to DNA to block AR-mediated gene transcription. This drug was approved by the US Food and Drug Administration (FDA) for listing in the United States in February 2018, with indications for adult patients with metastatic endocrine therapy-sensitive prostate cancer (mHSPC) and adult patients with non-metastatic castration-resistant prostate cancer (NM-CRPC) at high risk of metastasis. Its trade name is Erleada, and it was launched in China in September 2019.

[0003] The chemical name of apalutamide is: 4-[7-[(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, and its structural formula is as follows:

[0004]

[0005] 5-Isothiocyanato-3-trifluoromethylcyanopyridine is a key intermediate in the preparation of apalutamide, and different preparation methods directly affect the quality of apalutamide.

[0006] The original research patent CN101454002B uses 5-amino-3-trifluoromethylcyanopyridine to react with thiophosgene, and through washing, drying, inspection and distillation operations, 5-isothiocyanato-3-trifluoromethylcyanopyridine is prepared. The process is as follows:

[0007]

[0008] The main drawback of this route is the use of highly toxic and volatile thiophosgene, which requires higher protection requirements in the workshop. Once leaked, the impact is greater. Therefore, it is not suitable for commercial production. At the same time, due to the two active sites of thiophosgene, there are more by-product polymers and the impurity spectrum is complex.

[0009] DR.reddy′s laboratories limite (WO2021 / 033098) uses 5-amino-3-trifluoromethylcyanopyridine to react with 1,1-thiocarbonyl DI-2(1H)-pyridine to prepare 5-isothiocyanato-3-trifluoromethylcyanopyridine. The reaction is as follows:

[0010]

[0011] However, 1,1-thiocarbonyl di-2(1H)-pyridine requires 3 equivalents to complete the reaction, with a large dosage, which brings a large amount of by-products, difficult post-treatment of the reaction, and is not suitable for commercial production.

[0012] In the process of preparing 5-isothiocyanato-3-(trifluoromethyl)pyridinecarbonitrile, the prior art mainly uses inexpensive thiophosgene. Given the extremely volatile nature of thiophosgene itself, it is very difficult to avoid volatilization and leakage during the production process, and the yield and purity of the prepared samples are relatively low. Therefore, it is of great significance to select a suitable reagent to prepare the apalutamide intermediate. Summary of the Invention

[0013] The purpose of the present invention is to provide a method for preparing an apalutamide intermediate, to solve the problems of using highly toxic and volatile thiophosgene, low yield and purity during the preparation of apalutamide, and at the same time reduce the environmental pollution caused during the production process.

[0014] During the research process, we surprisingly discovered a new method for preparing the apalutamide intermediate, with mild reaction conditions, no generation of irritating gases, reducing the damage to equipment and environmental pollution during the reaction, and being more suitable for commercial production.

[0015] To achieve the present invention, the present invention adopts the following technical solutions:

[0016] React compound II (5-amino-3-(trifluoromethyl)pyridinecarbonitrile) under the conditions of a catalyst, an acid-binding agent, and an organic solvent to prepare intermediate compound I (5-isothiocyanato-3-(trifluoromethyl)pyridinecarbonitrile);

[0017] The reaction route is as follows:

[0018]

[0019] Preferably, the catalyst is N,N-thiocarbonyl diimidazole (abbreviated as TCDI).

[0020] Preferably, the acid-binding agent is one or two of triethylamine or N,N-diisopropylethylamine; when there are two acid-binding agents, the molar ratio of triethylamine to N,N-diisopropylethylamine is 1:1.

[0021] Preferably, the organic solvent is dichloromethane.

[0022] Preferably, the molar ratio of compound II to N,N-thiocarbonyl diimidazole is 1:1.7 - 2.1.

[0023] Preferably, the molar ratio of compound II to the base is 1:1.3 - 2.0, preferably 1:1.5 - 1.7.

[0024] Preferably, the reaction temperature of compound II and N,N - thiocarbonyldiimidazole is 25 - 30 °C.

[0025] Compared with the prior art, the present invention has the following beneficial technical effects:

[0026] (1) The use of highly toxic and volatile thiophosgene is avoided, reducing the damage to equipment and environmental pollution. At the same time, during the post - treatment process, no gases such as hydrochloric acid gas and hydrogen sulfide are introduced, further reducing the risk of environmental pollution.

[0027] (2) Compared with the prior art, the product yield and purity of the technical solution of the present invention are both greatly improved, improving the quality and safety of the drug. Specific embodiments:

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the specific embodiments of the present invention will be described in detail below for better understanding of the present invention. All experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples can be obtained through commercial channels unless otherwise specified.

[0029] Example 1: Preparation of Compound I

[0030] Add 5.3 L of dichloromethane to a 50 - L reaction kettle. While stirring, add 1454.6 g (7.78 mol) of 5 - amino - 3 - trifluoromethylcyanopyridine and 2.63 kg (14.78 mol) of N,N - thiocarbonyldiimidazole. Rinse the tank wall with 200 mL of dichloromethane and displace with nitrogen three times. Start to dropwise add 1.18 kg of triethylamine (11.68 mol). After addition, raise the temperature to 25 - 30 °C and start timing the reaction.

[0031] Take a sample for detection after 10 h. When the reaction is complete, add 7.3 L of dichloromethane to the reaction kettle. Cool the reaction solution to 0 - 10 °C, and start to dropwise add 2 mol / L dilute hydrochloric acid. Control the temperature at 0 - 10 °C during the addition process. Add 14.5 L of dilute hydrochloric acid, let it stand, and separate the layers. The organic phase is extracted and separated with 7.3 L of saturated sodium chloride aqueous solution. Add 1.5 kg of anhydrous magnesium sulfate to the organic phase, stir and dry, filter, and distill the organic phase under reduced pressure at 25 - 30 °C to obtain 1754.74 g of compound I (5 - isothiocyanate - 3 - trifluoromethylcyanopyridine), with a yield of 98.5% and a purity of 99.817%.

[0032] The following are the result characterization data of compound I prepared in this example:

[0033] 1 1H NMR (600 MHz, DMSO-d6): δ 8.659 - 8.662 ppm (d, 1H), 9.105 - 9.109 ppm (d, 1H).

[0034] 13 13C NMR (150 MHz, DMSO-d6): δ 114.755 ppm, 119.088 - 124.452 ppm, 126.678 ppm, 129.782 - 130.454 ppm, 132.704 ppm, 132.704 - 133.123 ppm, 140.782 ppm, 152.186 ppm.

[0035] ESI-MS: [M + H] + Theoretical value: 230.0, Measured value: 230.0.

[0036] Example 2: Preparation of Compound I

[0037] Add 5.3 L of dichloromethane to a 50 L reaction kettle. While stirring, add 1454.6 g (7.78 mol) of 5-amino-3-trifluoromethylcyanopyridine and 2.35 kg (13.2 mol) of N,N-thiocarbonyl diimidazole. Rinse the kettle wall with 200 mL of dichloromethane and displace with nitrogen three times. Start to dropwise add 1.35 kg of triethylamine (13.4 mol). After addition, raise the temperature to 25 - 30 °C and start timing the reaction.

[0038] Take a sample for detection after 10 h. When the reaction is complete, add 7.3 L of dichloromethane to the reaction kettle. Cool the reaction solution to 0 - 10 °C, and start to dropwise add 2 mol / L dilute hydrochloric acid. Control the temperature at 0 - 10 °C during the addition. Add 14.5 L of dilute hydrochloric acid, let it stand, and separate the layers. Extract and separate the organic phase with 7.3 L of saturated sodium chloride aqueous solution. Add 1.5 kg of anhydrous magnesium sulfate to the organic phase, stir for drying, filter, and distill the organic phase under reduced pressure at 25 - 30 °C to obtain 1758.40 g of Compound I (5-isothiocyanato-3-trifluoromethylcyanopyridine), with a yield of 98.7% and a purity of 99.866%.

[0039] Example 3: Preparation of Compound I

[0040] Add 5.3 L of dichloromethane to a 50 L reaction kettle. While stirring, add 1454.6 g (7.78 mol) of 5-amino-3-trifluoromethylcyanopyridine and 2.91 kg (16.338 mol) of N,N-thiocarbonyl diimidazole. Rinse the kettle wall with 200 mL of dichloromethane and displace with nitrogen three times. Start to dropwise add 1.57 kg of triethylamine (15.56 mol). After addition, raise the temperature to 25 - 30 °C and start timing the reaction.

[0041] Sampling and detection were carried out at 10 h. After the reaction was completed, 7.3 L of dichloromethane was added to the reaction kettle. The reaction solution was cooled to 0 - 10 °C, and 2 mol / L dilute hydrochloric acid was started to be added dropwise. During the addition process, the temperature was controlled at 0 - 10 °C. 14.5 L of dilute hydrochloric acid was added. It was left to stand and separated by liquid. The organic phase was added with 7.3 L of saturated sodium chloride aqueous solution for extraction and separation. 1.5 kg of anhydrous magnesium sulfate was added to the organic phase, stirred and dried, filtered, and the organic phase was distilled under reduced pressure at 25 - 30 °C to obtain 1747.71 g of compound I (5-isothiocyanate-3-trifluoromethylcyanopyridine), with a yield of 98.1% and a purity of 99.728%.

[0042] Example 4: Preparation of Compound I

[0043] 5.3 L of dichloromethane was added to a 50 L reaction kettle. While stirring, 1454.6 g (7.78 mol) of 5-amino-3-trifluoromethylcyanopyridine and 2.63 kg (14.78 mol) of N,N-thiocarbonyl diimidazole were added. The tank wall was rinsed with 200 mL of dichloromethane, and nitrogen replacement was carried out three times. 1.30 kg of N,N-diisopropylethylamine (10.08 mol) was started to be added dropwise. After the addition was completed, the temperature was raised to 25 - 30 °C and the reaction was timed.

[0044] Sampling and detection were carried out at 10 h. After the reaction was completed, 7.3 L of dichloromethane was added to the reaction kettle. The reaction solution was cooled to 0 - 10 °C, and 2 mol / L dilute hydrochloric acid was started to be added dropwise. During the addition process, the temperature was controlled at 0 - 10 °C. 14.5 L of dilute hydrochloric acid was added. It was left to stand and separated by liquid. The organic phase was added with 7.3 L of saturated sodium chloride aqueous solution for extraction and separation. 1.5 kg of anhydrous magnesium sulfate was added to the organic phase, stirred and dried, filtered, and the organic phase was distilled under reduced pressure at 25 - 30 °C to obtain 1753.05 g of compound I (5-isothiocyanate-3-trifluoromethylcyanopyridine), with a yield of 98.4% and a purity of 99.792%.

[0045] Example 5: Preparation of Compound I

[0046] 5.3 L of dichloromethane was added to a 50 L reaction kettle. While stirring, 1454.6 g (7.78 mol) of 5-amino-3-trifluoromethylcyanopyridine and 2.63 kg (14.78 mol) of N,N-thiocarbonyl diimidazole were added. The tank wall was rinsed with 200 mL of dichloromethane, and nitrogen replacement was carried out three times. 589.84 g of triethylamine and 753.36 g of N,N-diisopropylethylamine were started to be added dropwise. After the addition was completed, the temperature was raised to 25 - 30 °C and the reaction was timed.

[0047] Sampling and detection were carried out at 10 h. After the reaction was completed, 7.3 L of dichloromethane was added to the reaction kettle. The reaction solution was cooled to 0 - 10 °C, and 2 mol / L dilute hydrochloric acid was started to be added dropwise. During the addition process, the temperature was controlled at 0 - 10 °C. 14.5 L of dilute hydrochloric acid was added, and then it was left to stand and separated by liquid. 7.3 L of saturated sodium chloride aqueous solution was added to the organic phase for extraction and liquid separation. 1.5 kg of anhydrous magnesium sulfate was added to the organic phase, stirred and dried, filtered, and the organic phase was distilled under reduced pressure at 25 - 30 °C to obtain 1760.20 g of compound I (5-isothiocyanate-3-trifluoromethylcyanopyridine), with a yield of 98.8% and a purity of 99.860%.

[0048] The above-described embodiments are some embodiments of the present invention, rather than all embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope claimed by the present invention, but merely represents the selected embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

Claims

1. A preparation method of an apalutamide intermediate, characterized in that, the method comprises the following steps: Reacting compound II under the conditions of a catalyst, an acid-binding agent, and an organic solvent to prepare intermediate compound I; The reaction route is as follows: 。 2. The method according to claim 1, characterized in that, the catalyst is N,N-thiocarbonyl diimidazole.

3. The method according to claim 1, characterized in that, the acid-binding agent is one or both of triethylamine or N,N-diisopropylethylamine.

4. The method according to claim 1, characterized in that, the organic solvent is dichloromethane.

5. The method according to claim 1, characterized in that, the molar ratio of compound II to the catalyst is 1:1.7 - 2.

1.

6. The method according to claim 1, characterized in that, the molar ratio of compound II to the base is 1:1.3 - 2.

0.

7. The method according to claim 1, characterized in that, the reaction temperature of compound II and N,N-thiocarbonyl diimidazole is 25 - 30 °C.

8. The method according to claim 3, characterized in that, when there are two acid-binding agents, the molar ratio of triethylamine to N,N-diisopropylethylamine is 1:

1.

9. The method according to claim 6, characterized in that, the molar ratio of compound II to the base is 1:1.5 - 1.7.

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