A method of preparing apalutamide

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of apalutamide. The preparation method comprises the following steps: 4-amino-2-fluoro-N-methyl benzamide is reacted with 1-bromocyclobutane-1-methyl carboxylate under the catalysis of silver oxide, the obtained product is reacted with 5-isothiocyanate-3-(trifluoromethyl) pyridine-2-cyan to obtain apalutamide; the starting material is cheap and easy to obtain, and the existing technology avoids the Strecker reaction of N-methyl-2-fluoro-4-amino benzamide, sodium cyanide (or trimethyl silyl cyanide) and cyclobutanone, which needs to use a toxic cyanide reagent; meanwhile, the Ullmann reaction needs high temperature and equivalent copper, and the application solves the problems, and is simple to operate, has a higher yield, and is more suitable for industrial mass production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of apalutamide. BACKGROUND

[0002] Apalutamide is a second-generation non-steroidal androgen receptor (AR) antagonist, which is used for treating non-metastatic castration-resistant prostate cancer. In December 2017, a new drug marketing application was submitted to the US Food and Drug Administration (FDA), and in February 2018, it was approved for marketing. The English name is 4-[7-[6-cyano-5-(trifluoromethyl)-3-pyridinyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, the Chinese name is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, the CAS number is 956104-40-8, the molecular formula is C 21 H 15 F4N5O2S, the molecular weight is 477.44, and the structural formula is as follows:

[0003]

[0004] At present, the reported synthesis methods of apalutamide mainly include the following routes:

[0005] US2015 / 0191449A and CN104211683: N-methyl-2-fluoro-4-aminobenzamide is subjected to Strecker reaction with sodium cyanide (or trimethylsilyl cyanide) and cyclobutanone to obtain a cyclobutane cyanamide intermediate, then condensation cyclization is carried out with a thiocyanate intermediate under microwave conditions, and hydrolysis is carried out under hydrochloric acid-methanol conditions to obtain apalutamide. The synthesis route is as follows:

[0006]

[0007] Although the reaction route is short, the method needs microwave conditions, and the equipment requirement is high. In addition, a highly toxic substance, sodium cyanide (or trimethylsilyl cyanide), is used, which has extremely high toxicity when inhaled or contacted with the skin, and there is a safety hazard in industrial production.

[0008] Patent WO2016100645: 3-fluoro-4-iodoaniline and Strecker reaction of cyclobutanone, cyanide to obtain cyclobutane intermediate, and 2-cyano-3-trifluoromethyl-5-aminopyridine cyclization condensation under the action of thiocarbonyl compound, and then carbonyl insertion reaction under the catalysis of noble metal palladium to obtain carboxylic acid ester intermediate or after Grignard exchange with dry ice to obtain carboxylic acid (ester) intermediate, and finally amidation to obtain the final product apalutamide. This route not only uses toxic sodium cyanide, but also uses noble metal palladium catalyst, and the cost of large-scale production is high. The synthetic route is shown below,

[0009]

[0010] Chinese patent application CN107108507 and patent WO2016100652: APAL-007 and 1-Boc-amino cyclobutane-1-carboxylic acid as raw materials, amidation under the catalysis of N,N'-carbonyldiimidazole CDI / 1,8-diazabicyclo[5.4.0]undec-7-ene DBU, and then Boc is removed by chlorination to obtain 1-amino-N-(6-cyano-5-(trifluoromethyl)pyridin-3-) cyclobutane-1-carboxylic acid (APAL-022); compound 22 is coupled with 2-fluoro-4-chloro-N-methylbenzamide (APAL-023) to obtain APAL-024 under the catalysis of potassium acetate / copper powder; compound 24 is reacted with phenyl chlorothioformate under the catalysis of DMAP to obtain apalutamide. Although this route avoids the use of toxic cyanide and heavy metal catalysts, the CDI condensation method is still too high in cost for industrial production. In addition, this route has too many linear steps and the process operation is complicated, so the cost of industrial production is high. The synthetic route is shown below:

[0011]

[0012] Chinese patent application CN109988077 provides a new preparation method of apalutamide, which uses 2-fluoro-4-bromo-N-methylbenzamide and 1-amino cyclobutyl carboxylic acid hydrochloride as starting materials, and prepares 1-((3-fluoro-4-(methylcarbamoyl) phenyl) amino) cyclobutane-1-carboxylic acid through substitution reaction; then esterification is carried out to obtain 1-((3-fluoro-4-(methylcarbamoyl) phenyl) amino) cyclobutane-1-carboxylic acid ester; and finally, ring closure reaction is completed with 2-cyano-3-trifluoromethyl-5-isothiocyanopyridine to obtain apalutamide. This route also avoids the use of toxic cyanide and heavy metal catalysts, but when preparing compound I, it needs to be reacted at a relatively high temperature (110°C) for a long time (10-11 hours), and needs to be protected by inert gas (argon); when preparing compound II, iodomethane or acetyl chloride is needed, which has safety hazards in industrial production. The synthetic route is shown below:

[0013]

[0014] Chinese patent application CN108383749 takes N-methyl-2-fluoro-4-halogen-benzamide compound 1 and cyclobutane oxalic acid hydrochloride 2 as starting materials, condenses to obtain intermediate compound 3 through Ullmann reaction, esterifies to obtain intermediate compound 4, then cyclizes to obtain compound 5 by reacting with thiocyanate salt, and finally, compound 5 is coupled with compound 6 to obtain apalutamide. This route also avoids the use of toxic cyanide and heavy metal catalysts, and the two Ullmann reactions (preparation of compound 3 and apalutamide 7) need to be carried out at a high temperature for a long time and need to be protected by inert gas (nitrogen); in addition, the use of thionyl chloride and potassium thiocyanate has a great safety hazard in industrial production. The synthetic route is shown as follows:

[0015]

[0016] Therefore, in view of the defects in the prior art, there is an urgent need for an apalutamide synthesis method which is simple in process, suitable for industrial production, high in yield and low in cost, so as to meet the market demand. SUMMARY

[0017] In view of the above deficiencies, the present application aims to provide a synthetic route and method suitable for industrial production of apalutamide. In this route, the use of toxic cyanide and heavy metal catalysts is successfully avoided, the process cost is reduced, the operation is simple, the reaction conditions are mild, the safety is high, the pollution is small, and the product with high yield can be obtained, which is more suitable for industrial scale-up.

[0018] The present application is specifically implemented by the following technical solutions:

[0019]

[0020] Compound II, i.e. 4-amino-2-fluoro-N-methylbenzamide, is reacted with 1-bromocyclobutane-1-carboxylic acid methyl ester under the catalysis of silver oxide to obtain compound IV; compound IV is reacted with compound V to obtain apalutamide.

[0021] Preferably, the following parts will describe the above steps in detail:

[0022] Preparation of compound IV

[0023] At room temperature, compound II and compound III are added to organic solvent A, purified water and silver oxide are added, and temperature control stirring is carried out until the reaction is completed to obtain compound IV.

[0024] Preferably, the organic solvent A is selected from one or a combination of acetonitrile, tetrahydrofuran and 1,4-dioxane, and acetonitrile is particularly preferred.

[0025] Preferably, the molar ratio of compound II, compound III and silver oxide is 1:1.0-2.0:1.0-2.0, wherein 1:1.2:1.05 is particularly preferred.

[0026] Preferably, the reaction temperature is 40-70℃, wherein 60℃ is particularly preferred.

[0027] In a preferred embodiment, the reaction needs to be post-treated, and the specific steps are as follows: cooling the reaction solution, filtering the reaction solution through diatomite and collecting the filtrate. The filtrate is recovered under reduced pressure to remove the organic solvent, the residue is added into ethyl acetate, washed with water, concentrated under reduced pressure to remove the solvent, and then the product compound IV is obtained by beating in ethyl acetate / petroleum ether.

[0028] Preparation of compound I

[0029] Compound IV and compound V are added into a mixture of dimethyl sulfoxide and isopropyl acetate, the reaction is stirred at elevated temperature, and compound I is obtained by post-treatment of the reaction.

[0030] Preferably, the molar ratio of compound IV and compound V is 1:1.2.

[0031] Preferably, the reaction temperature is 75℃.

[0032] In a preferred embodiment, the reaction needs to be post-treated, and the specific steps are as follows: cooling the reaction solution, adding ethyl acetate and purified water into the reaction solution, stirring to separate the liquid, drying and concentrating the organic phase to obtain a brown solid. The solid is added into isopropyl alcohol, heated to reflux, cooled to room temperature and stirred, a large amount of solid is precipitated, suction filtration and drying to obtain the target compound.

[0033] Compared with the prior art, the present application has the following technical effects:

[0034] 1. The synthesis method of the present application has fewer reaction steps, mild reaction conditions, simple post-treatment and easy operation, avoids the use of toxic reagents such as sodium cyanide, reduces waste discharge, is environmentally friendly, and is suitable for industrial production.

[0035] 2. The present application uses 4-amino-2-fluoro-N-methyl benzamide and 1-bromocyclobutane-1-carboxylic acid methyl ester as starting materials, which are cheap and easy to obtain, and avoids the use of sodium cyanide (or trimethylsilyl cyanide) and cyclobutanone in the Strecker reaction in the prior art, which requires the use of toxic cyanide reagents. Meanwhile, the present application also solves the problem of high temperature and equivalent copper required in the Ullmann reaction. DETAILED DESCRIPTION

[0036] The application is further illustrated by the following examples. It should be understood that the examples of the application are only used to illustrate the application, but not to limit the application, so the simple improvement of the application under the premise of the method of the application is within the scope of the application.

[0037] The structure of the compound obtained by the application was confirmed:

[0038] Structure characterization of compound IV

[0039]

[0040] ESI-MS (m / z): 281.16 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.63 (m, 1H), 7,44 (t, J = 8.8 Hz, 1H), 7.23 (s, 1H), 6.18 (m, 1H), 5.96 (m, 1H), 3.65 (s, 3H), 2.77 (d, J = 4.4 Hz, 3H), 2.63 (m, 2H), 2.18 (m, 2H), 1.99 (m, 2H).

[0041] Structure characterization of compound I

[0042]

[0043] ESI-MS (m / z): 478.13 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 9.10 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.34 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.75 (m, 1H), 3.09 (d, J = 4.6 Hz, 3H), 2.73 (m, 2H), 2.57 (m, 2H), 2.27 (m, 1H), 1.71 (m, 1H).

[0044] Preparation of compound IV

[0045] Example 1

[0046] Compound II (16.8 g, 0.1 mol), compound III (23.0 g, 0.12 mol) were taken in acetonitrile (200 mL), stirred and purified water (10 mL) and silver oxide (24.3 g, 0.105 mol) were added, the reaction was stirred at 60 °C, after completion of the reaction, the reaction mixture was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 mL, V EA / V PE = 2:1) to get off-white solid compound VI in 97.5% yield with 99.92% HPLC purity.

[0047] Example 2

[0048] Compound II (16.8 g, 0.1 mol), compound III (19.3 g, 0.1 mol) were taken in tetrahydrofuran (200 mL), stirred and purified water (10 mL) and silver oxide (24.3 g, 0.105 mol) were added, the reaction was stirred at 40 °C, after completion of the reaction, the reaction mixture was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 mL, V EA / V PE = 2:1) to get off-white solid compound VI in 94.6% yield with 99.61% HPLC purity.

[0049] Example 3

[0050] Compound II (16.8 g, 0.1 mol), compound III (38.6 g, 0.2 mol) were taken in 1,4-dioxane (200 mL), stirred and purified water (10 mL) and silver oxide (24.3 g, 0.105 mol) were added, the reaction was stirred at 70 °C, after completion of the reaction, the reaction mixture was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 mL, V EA / V PE = 2:1) to get off-white solid compound VI in 95.1% yield with 99.54% HPLC purity.

[0051] Example 4

[0052] Compound II (16.8 g, 0.1 mol), compound III (23.0 g, 0.12 mol) were taken in acetonitrile (200 mL), stirred and purified water (10 mL) and silver oxide (23.2 g, 0.1 mol) were added, the reaction was stirred at 50 °C, after completion of the reaction, the reaction mixture was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 ml, V EA / V PE = 2:1) to get off-white solid compound VI in 93.5% yield with 99.71% HPLC purity.

[0053] Example 5

[0054] Compound II (16.8 g, 0.1 mol), compound III (23.0 g, 0.12 mol) were taken in 1,4-dioxane (200 mL), stirred and purified water (10 mL) and silver oxide (46.4 g, 0.2 mol) were added, the reaction was stirred at 70 °C, after completion of the reaction, the reaction mixture was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 ml, V EA / V PE = 2:1) to get off-white solid compound VI in 94.9% yield with 99.55% HPLC purity.

[0055] Example 6

[0056] Compound II (16.8 g, 0.1 mol), compound III (23.0 g, 0.12 mol) were taken in acetonitrile (200 mL), stirred and purified water (10 mL) and silver oxide (20.9 g, 0.9 mol) were added, the reaction was stirred at 35 °C, after completion of the reaction, the reaction mixture was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 ml, V EA / V PE = 2:1) to get off-white solid compound VI in 88.6% yield with 98.65% HPLC purity.

[0057] Example 7

[0058] Compound II (16.8 g, 0.1 mol), compound III (42.46 g, 0.22 mol) were taken in acetonitrile (200 mL), stirred and purified water (10 mL) and silver oxide (51.0 g, 0.22 mol) were added, the reaction was warmed to 35 °C and stirred, after completion of the reaction, the reaction mass was cooled, filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure to recover the organic solvent, the residue was taken in ethyl acetate (500 mL), washed with water, concentrated under reduced pressure to remove the solvent and the residue was slurried with EA / PE (500 mL, V EA / V PE = 2:1) to obtain compound VI as a white solid in 89.8% yield with 98.43% HPLC purity.

[0059] Preparation of compound I

[0060] Example 8

[0061] Compound IV (14.0 g, 50 mmol), compound V (13.8 g, 60 mmol) were taken in a mixture of DMSO (20 mL) and isopropyl acetate (40 mL), the reaction was warmed to 75 °C and stirred for 6 h. The reaction mass was cooled, ethyl acetate (160 mL) and purified water (100 mL) were added to the reaction mass, stirred and the organic phase was separated, dried and concentrated to obtain a brown solid. The solid was taken in isopropyl alcohol (100 mL), heated to reflux for 10 min, cooled to room temperature and stirred, a large amount of solid separated out, filtered under suction and dried to obtain the product as a white solid in 98.8% yield with 99.98% HPLC purity.

Claims

1. A process for the preparation of apalutamide, characterized in that, The preparation method comprises the following steps: 1) at room temperature, compound II, compound III are added into an organic solvent A, purified water and silver oxide are added, temperature control stirring is conducted until the reaction is completed, and compound IV is obtained; 2) compound IV and compound V are added into a mixture of dimethyl sulfoxide and isopropyl acetate, temperature control stirring reaction is conducted, and after treatment, compound I is obtained; The synthetic route is as follows:

2. The production method according to claim 1, characterized by, In step 1), the organic solvent A is selected from one or a combination of acetonitrile, tetrahydrofuran and 1,4-dioxane.

3. The preparation method according to claim 1, characterized in that, In step 1), the feeding molar ratio of compound II, compound III and silver oxide is 1:1.0-2.0:1.0-2.

0.

4. The method of claim 1, wherein, In step 1), the reaction temperature is 40-70 DEG C.

5. The preparation method according to claim 1, characterized in that, In step 2), the feeding molar ratio of compound IV and compound V is 1:1.

2.

6. The method of claim 1, wherein, In step 2), the reaction temperature is 75 DEG C.

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