CN107501237B - Synthetic method of Apalutamide - Google Patents
Synthetic method of Apalutamide Download PDFInfo
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- CN107501237B CN107501237B CN201710755384.1A CN201710755384A CN107501237B CN 107501237 B CN107501237 B CN 107501237B CN 201710755384 A CN201710755384 A CN 201710755384A CN 107501237 B CN107501237 B CN 107501237B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a new synthesis method of Apalutamide, which comprises the steps of firstly, reacting 1-aminocyclobutanecarboxylic acid with 4-bromo-2-fluoro-N-methylbenzamide to obtain 4- (1-carboxy-cyclobutylamino) -2-fluoro-N-methyl-benzamide, and then reacting the benzamide with 5-amino-3-trifluoromethyl-2-cyanopyridine and thiophosgene to obtain the product, wherein sodium cyanide or potassium cyanide raw materials are not required in the whole production process, so that safety accidents caused by the toxic raw materials are avoided; meanwhile, the 1-aminocyclobutanecarboxylic acid has stable property, is easier to refine than a cyclobutanone process, and has less other impurities in a synthesized final product; the method can reduce the cost by more than 35 percent, thereby being beneficial to market promotion and benefiting the vast patients.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a novel synthesis method of Apalutamide.
Background
Prostate cancer is the most common malignancy of the male reproductive system, with the onset increasing with age, second only to lung cancer, and the second leading cause of cancer death in men. The traditional method for treating the prostatic cancer is to treat the prostatic cancer through operation or androgen antagonists such as Bicalutamide (Bicalutamide), abiraterone or enzalutamide and the like, but a patient can generate drug resistance after 2 to 4 years, and the enzalutamide is not applied for marketing in China, and the clinical experiment shows that the apalcuamide is an effective substitute drug. The original synthetic route of apalcuamide is shown in documents such as WO2008119015, US20110003839, US20100190991, US20130116258 and WO 2014190895 a1, and the specific synthetic route is shown in fig. 1, wherein a large amount of sodium cyanide or potassium cyanide is used in the production process of an intermediate TMSCN, so that the adverse effects such as poisoning and the like are caused to operators, and the generated wastewater has potential risk of polluting the environment. In addition, the initial raw material cyclobutanone used in the route is restricted by process safety, and the commercial production is difficult, so that the price of downstream products is high.
Disclosure of Invention
The invention aims to provide a novel synthesis method of Apalutamide, which aims to overcome the defects in the prior art. .
The technical scheme for solving the technical problems is as follows:
a novel synthesis method of Apalutamide comprises the following steps:
1) respectively adding 4-bromo-2-fluoro-N-methylbenzamide, 1-aminocyclobutanecarboxylic acid, an acid-binding agent, 2-acetyl cyclohexanone, water and DMF into a reaction kettle, stirring and dissolving, adding cuprous iodide under the protection of inert gas, heating to 120 ℃, reacting for 12-36 hours, cooling, adding water and adding ethyl acetate for extraction;
2) keeping the water phase, adjusting the pH value to be 3 by using hydrochloric acid, filtering the separated solid, and pulping by using water to obtain 4- (1-carboxyl-cyclobutylamino) -2-fluorine-N-methyl-benzamide for later use;
3) adding thiophosgene dropwise into 500ml of a dimethylacetamide solution of 4- (1-carboxyl-cyclobutylamino) -2-fluoro-N-methyl-benzamide and 5-amino-3-trifluoromethyl-2-cyanopyridine, heating to 65 ℃, and after 12 hours, adding 500ml of methanol, 500ml of water and 200ml of concentrated hydrochloric acid, and heating and refluxing for 2 hours;
4) adding ethyl acetate into the solution obtained in the step 3) for extraction, washing with brine, drying with anhydrous sodium sulfate, concentrating to obtain a brown yellow solid, and recrystallizing with ethyl acetate and petroleum ether to obtain the product Apalutamide.
Wherein the volume of the reaction kettle in the step 1) is 200L, and the volume of the 4-bromo-2-fluoro-N-methylbenzamide is 12.0kg and 51.7 moles; 6.3kg of 1-aminocyclobutanecarboxylic acid, 61.7 mole; the acid-binding agent is 16.5kg of potassium carbonate with 155 mole; 0.12kg of 2-acetyl cyclohexanone, 1.05mole and 1.2L of water; DMF was 70L; cooling and adding water to 120L;
wherein the equivalent concentration of the hydrochloric acid in the step 2) is 1N;
wherein, the thiophosgene in the step 3) is 32g, 0.26 mole; 4- (1-carboxy-cyclobutylamino) -2-fluoro-N-methyl-benzamide 80g, 0.26 mole; 50g of 5-amino-3-trifluoromethyl-2-cyanopyridine, 0.26 mole;
wherein, the solvent ratio used in the crystallization in the step 4) is 1: 3-1: 5;
the method provided by the invention has the advantages that: in the whole production process, sodium cyanide or potassium cyanide raw materials are not needed, so that safety accidents caused by the toxic raw materials are avoided; meanwhile, the 1-aminocyclobutanecarboxylic acid has stable property, is easier to refine than a cyclobutanone process, and has less other impurities in a synthesized final product; the method can reduce the cost by more than 35 percent, thereby being beneficial to market promotion and benefiting the vast patients.
Drawings
FIG. 1 is a synthetic roadmap for a prior art Apalutamide;
FIG. 2 is a diagram of the synthetic route shown for the novel synthesis of Apalutamide;
Detailed Description
The present invention will be described in detail with reference to the following embodiments.
A novel synthesis method of Apalutamide comprises the following steps:
1) respectively adding 4-bromo-2-fluoro-N-methylbenzamide, 1-aminocyclobutanecarboxylic acid, an acid-binding agent, 2-acetyl cyclohexanone, water and DMF into a reaction kettle, stirring and dissolving, adding cuprous iodide under the protection of inert gas, heating to 120 ℃, reacting for 12-36 hours, cooling, adding water and adding ethyl acetate for extraction;
2) keeping the water phase, adjusting the pH value to be 3 by using hydrochloric acid, filtering the separated solid, and pulping by using water to obtain 4- (1-carboxyl-cyclobutylamino) -2-fluorine-N-methyl-benzamide for later use;
3) adding thiophosgene dropwise into 500ml of a dimethylacetamide solution of 4- (1-carboxyl-cyclobutylamino) -2-fluoro-N-methyl-benzamide and 5-amino-3-trifluoromethyl-2-cyanopyridine, heating to 65 ℃, and after 12 hours, adding 500ml of methanol, 500ml of water and 200ml of concentrated hydrochloric acid, and heating and refluxing for 2 hours;
4) adding ethyl acetate into the solution obtained in the step 3) for extraction, washing with brine, drying with anhydrous sodium sulfate, concentrating to obtain a brown yellow solid, and recrystallizing with ethyl acetate and petroleum ether to obtain the product Apalutamide.
Wherein the volume of the reaction kettle in the step 1) is 200L, and the volume of the 4-bromo-2-fluoro-N-methylbenzamide is 12.0kg and 51.7 moles; 6.3kg of 1-aminocyclobutanecarboxylic acid, 61.7 mole; the acid-binding agent is 16.5kg of potassium carbonate with 155 mole; 0.12kg of 2-acetyl cyclohexanone, 1.05mole and 1.2L of water; DMF was 70L; cooling and adding water to 120L;
wherein the equivalent concentration of the hydrochloric acid in the step 2) is 1N;
wherein, the thiophosgene in the step 3) is 32g, 0.26 mole; 4- (1-carboxy-cyclobutylamino) -2-fluoro-N-methyl-benzamide 80g, 0.26 mole; 50g of 5-amino-3-trifluoromethyl-2-cyanopyridine, 0.26 mole;
wherein, the solvent ratio used in the crystallization in the step 4) is 1: 3-1: 5;
referring to FIG. 2, 1-aminocyclobutanecarboxylic acid, after reaction with 4-bromo-2-fluoro-N-methylbenzamide, was reacted with 5-amino-3-trifluoromethyl-2-cyanopyridine, and after ring closure with thiophosgene, gave the final product, Apalutamide. The specific process is as follows:
the first step is as follows: synthesis of 4- (1-carboxy-cyclobutylamino) -2-fluoro-N-methyl-benzamide (intermediate 2): a200-liter reaction kettle is charged with 4-bromo-2-fluoro-N-methylbenzamide (12.0kg, 51.7mole), 1-aminocyclobutanecarboxylic acid (6.3kg, 61.7mole), potassium carbonate (16.5kg, 155mole), 2-acetylcyclohexanone (0.12kg, 1.05mole), water (1.2 liter), dissolved in 70 liters of DMF, added with CuI (0.2kg, 1.05mole) under stirring and nitrogen protection, heated to 110 ℃ and reacted for 24 hours. After the reaction, 120L of water was added thereto, and the mixture was cooled and extracted with ethyl acetate.
The aqueous phase was retained, the PH was adjusted to 3 with 1N hydrochloric acid, and the precipitated solid was filtered. Pulping with water to obtain 11.8 kg of pure product, 86% of product. HPLC: 99.2% MS: 266.32M + H.NMR in DMSO.
The second step is that: synthesis of 4- [7- (6-cyano-5-trifluoromethyl-3-pyridyl) -8-oxo-6-thioxo-5, 7-diazaspiro [3, 4] -5-octyl-2-fluoro-N-methyl-benzoyl (Compound 4): thiophosgene (32g, 0.26mole) was added dropwise to a solution of intermediate 2(80g, 0.26mole) and 5-amino-3-trifluoromethyl-2-cyanopyridine (50g, 0.26mole) in 500ml of dimethylacetamide, heated to 65 degrees overnight, 500ml of methanol, 500ml of water and 200ml of concentrated hydrochloric acid were added and heated under reflux for 2 h. Extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated. A tan solid was obtained. Recrystallization from ethyl acetate/petroleum ether gave 55.6g of product in 43.8% yield.
H-NMR (CD3OD，400MHz)：9.18(1H，d，J＝2.0Hz)，8.66(1H，d，J-2.0Hz)，7.95(1H， m)，7.42(2H，m)，2.99(3H，s)，2.73(2H，m)，2.60(2H，m)，2.16(1H，m)，1.67(1H， m).MS 478.1(M+H)。
The method provided by the invention has the advantages that:
1. the defect that sodium cyanide or potassium cyanide is used as a raw material and needs to react under the condition of acetic acid in the reaction is successfully avoided, and the problem that hydrogen cyanide is easy to cause safety accidents in production is avoided;
2. the 1-aminocyclobutanecarboxylic acid has stable property, is easier to refine than a cyclobutanone process, and has less other impurities in a synthesized final product.
3. Other raw materials used by the route are conventional products in the market, and the cost of the original route can be reduced by more than 35% by using the route, so that the route is favorable for market promotion and benefits of patients.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (5)
1. A synthetic method of Apalutamide is characterized by comprising the following steps: the method comprises the following steps:
1) respectively adding 4-bromo-2-fluoro-N-methylbenzamide, 1-aminocyclobutanecarboxylic acid, an acid-binding agent, 2-acetyl cyclohexanone, water and DMF into a reaction kettle, stirring and dissolving, adding cuprous iodide under the protection of inert gas, heating to 120 ℃, reacting for 12-36 hours, cooling, adding water and adding ethyl acetate for extraction;
2) keeping the water phase, adjusting the pH value to be 3 by using hydrochloric acid, filtering the separated solid, and pulping by using water to obtain 4- (1-carboxyl-cyclobutylamino) -2-fluorine-N-methyl-benzamide for later use;
3) adding thiophosgene dropwise into 500ml of a dimethylacetamide solution of 4- (1-carboxyl-cyclobutylamino) -2-fluoro-N-methyl-benzamide and 5-amino-3-trifluoromethyl-2-cyanopyridine, heating to 65 ℃, and after 12 hours, adding 500ml of methanol, 500ml of water and 200ml of concentrated hydrochloric acid, and heating and refluxing for 2 hours;
4) adding ethyl acetate into the solution obtained in the step 3) for extraction, washing with brine, drying with anhydrous sodium sulfate, concentrating to obtain a brown yellow solid, and recrystallizing with ethyl acetate and petroleum ether to obtain the product Apalutamide.
2. The method of synthesizing apalcutamine according to claim 1, wherein: the volume of the reaction kettle in the step 1) is 200L, and the volume of the 4-bromo-2-fluoro-N-methylbenzamide is 12.0kg and 51.7 moles; 6.3kg of 1-aminocyclobutanecarboxylic acid, 61.7 mole; the acid-binding agent is 16.5kg of potassium carbonate with 155 mole; 0.12kg of 2-acetyl cyclohexanone, 1.05mole and 1.2L of water; DMF was 70L; the water was added for cooling to 120L.
3. The method of synthesizing apalcutamine according to claim 1, wherein: the equivalent concentration of hydrochloric acid in the step 2) is 1N.
4. The method for synthesizing apalcuamide according to claim 2, wherein: the thiophosgene in the step 3) is 32g, 0.26 mole; 4- (1-carboxy-cyclobutylamino) -2-fluoro-N-methyl-benzamide 80g, 0.26 mole; 50g, 0.26mole of 5-amino-3-trifluoromethyl-2-cyanopyridine.
5. The method for synthesizing apalcuamide according to claim 2, wherein: and 4) using a solvent for crystallization in the step 4) in a ratio of ethyl acetate to petroleum ether of 1: 3-1: 5.
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| TW201831461A (en) * | 2017-01-18 | 2018-09-01 | 台灣神隆股份有限公司 | Process for preparing apalutamide |
| CN108047200A (en) * | 2017-12-05 | 2018-05-18 | 上海丰瑞医药科技有限公司 | A kind of Preparation Method And Their Intermediate of diaryl thiohydantoin class compound |
| CN109988077A (en) * | 2017-12-29 | 2019-07-09 | 上海法默生物科技有限公司 | A kind of synthetic method and intermediate of A Palu amine |
| CN108383749B (en) * | 2018-01-30 | 2021-03-09 | 杭州科巢生物科技有限公司 | Synthetic method of apaluamide and intermediate thereof |
| US10513504B2 (en) | 2018-03-08 | 2019-12-24 | Apotex Inc. | Processes for the preparation of apalutamide and intermediates thereof |
| CN108311155B (en) * | 2018-05-14 | 2020-11-06 | 上海奥萝拉医药科技有限公司 | Method for catalytically preparing apalumide intermediate serving as medicine for treating prostate cancer |
| IT201800005874A1 (en) * | 2018-05-30 | 2019-11-30 | PROCESS FOR THE PREPARATION OF APALUTAMIDE | |
| CN110511206A (en) * | 2019-06-17 | 2019-11-29 | 扬子江药业集团江苏海慈生物药业有限公司 | Aryl -2- thiohydantoin class compound intermediate, preparation method and application |
| CN113402466B (en) * | 2021-06-18 | 2022-08-16 | 南京方生和医药科技有限公司 | Apaglucone intermediate and method for preparing apalone |
| CN113292535B (en) * | 2021-06-18 | 2022-07-01 | 南京方生和医药科技有限公司 | Method for preparing apaluamide intermediate and apaluamide |
| CN115536634A (en) * | 2022-10-17 | 2022-12-30 | 上海博悦生物科技有限公司 | Synthetic method of apatamide |
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