CN104016924A - One-pot method for synthetizing enzalutamide - Google Patents
One-pot method for synthetizing enzalutamide Download PDFInfo
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- CN104016924A CN104016924A CN201410264149.0A CN201410264149A CN104016924A CN 104016924 A CN104016924 A CN 104016924A CN 201410264149 A CN201410264149 A CN 201410264149A CN 104016924 A CN104016924 A CN 104016924A
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- add
- methylalanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
Abstract
The invention provides a one-pot method for synthetizing enzalutamide and belongs to the field of medicinal chemical synthesis. The method comprises the following steps: firstly, carrying out copper-catalyzed Buchwald reaction on N-methyl-4-bromo-2-fluoro-benzamide and 2-methyl alanine, adding halogenated hydrocarbon, reacting to generate ester, finally adding a key intermediate 4-isothiocyano-2-(trifluoromethyl) cyanophenyl and carrying out bucherer-Bergs reaction to generate the enzalutamide. The method is simple in operation and high in product yield and has the advantages that the intermediate products are not needed to be separated and directly reacted, so that the process flow cycle is shortened; the final product is easy to separate and purify.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, be specifically related to a kind of method of preparing the assorted Shandong of grace amine.
Background technology
The assorted Shandong of grace amine is a kind of new drug of male hormone inhibitor, it is the prostate cancer medicine by Astellas and the cooperative development of Medivation company, chemical name is 4-[3-[4-cyano group-3-(trifluoromethyl) phenyl]-5,5-dimethyl-4-oxo-2-thioketones-1-imidazolidyl] the fluoro-N-methyl-benzamide of-2-, its structural formula is as follows:
。
The amine Shi You University of California research the earliest of the assorted Shandong of compound grace is synthetic, referenced patent CN101460467B, and its synthetic route is as follows:
。
This synthetic method adopts prepares the fluoro-N-methyl-benzamide compound of 4-amino-2-with iron powder as catalyzer under acidic conditions, in this preparation process, can produce a large amount of waste water, and product yield and purity not high, be not suitable for mass industrialized production; In addition adopt hypertoxic chromium trioxide to make oxygenant, human body and environment are had to larger toxic action.Therefore, Medivation company improves its synthesis technique, refers to Patent Document CN103108549A, and concrete synthetic route is as follows:
。
The method obtains the assorted Shandong of target product grace amine through four-step reaction, and this synthetic route aftertreatment technology is complicated, complex operation.
Summary of the invention
It is simple that technical problem to be solved by this invention is to provide a kind of reaction process, easy handling, and environmental pollution is little, the assorted Shandong of the grace amine synthetic method that economic benefit is high.
For solving the problems of the technologies described above, the technical solution used in the present invention is the assorted Shandong of " one kettle way " synthetic grace amine, the method is utilized the fluoro-benzamide of the bromo-2-of N-methyl-4-to carry out Buchwald with 2-methylalanine to react, add subsequently halogenated alkane reaction to generate ester, finally add key intermediate 4-isothiocyano-2-(trifluoromethyl) cyanophenyl that Bucherer-Bergs reaction occurs and generate the assorted Shandong of grace amine, reaction equation is:
。
Concrete operation step is as follows:
The fluoro-benzamide of the bromo-2-of a certain amount of N-methyl-4-, 2-methylalanine, mineral alkali and copper (I) catalyzer are dissolved in to dimethyl sulfoxide (DMSO) (DMSO), under nitrogen protection, are heated to 120 ℃ of stirring reactions, by LC-MS method detection reaction process; Reaction solution is cooled to 30 ~ 40 ℃ subsequently, adds alkylating reagent, the reaction times is 30 ~ 60min, by LC-MS method detection reaction process; Then add a certain amount of 4-isothiocyano-2-(trifluoromethyl) cyanophenyl in batches, at 80 ℃, react and spend the night, by LC-MS method detection reaction process; Continue to add methyl alcohol, reaction solution is cooled to 20 ~ 30 ℃ stir 45min at 80 ℃ after, add Iso Butyl Acetate, water, Virahol layering, water layer extracts with Iso Butyl Acetate, merges organic phase, with anhydrous sodium sulfate drying, filter, concentrated, add Virahol, be heated to 80 ℃ and dissolve completely, be cooled to 0 ℃ and separate out solid, filter washed with isopropyl alcohol, the dry product that obtains.
The add-on of the fluoro-benzamide of the bromo-2-of N-methyl-4-is 1.0 ~ 1.2 equivalents of 2-methylalanine, mineral alkali is salt of wormwood, its add-on is 2.0 equivalents of 2-methylalanine, copper (I) catalyzer is the sub-ketone of iodate, its add-on is 0.05 equivalent of 2-methylalanine, alkylating reagent is methyl iodide, iodoethane, iodopropane, butyl iodide, benzyl iodide or monobromethane, monobromethane, N-PROPYLE BROMIDE, n-butyl bromide, bromotoluene, and the add-on of alkylating agent is 1.0 equivalents of 2-methylalanine.
The present invention, by improving reaction process, adopts the assorted Shandong of " one kettle way " synthetic grace amine, and intermediate product need not separated direct reaction, has shortened the technical process cycle, and operating process is simple, and the finished product separation and purification is simple, and product yield is high.
Above-mentioned explanation is only the general introduction of technical solution of the present invention, in order to better understand technique means of the present invention, and can be implemented according to the content of specification sheets, describes in detail below with preferred embodiment of the present invention.The specific embodiment of the present invention is provided in detail by following examples.
Embodiment
Embodiment mono-
Step 1): the preparation of 4-isothiocyano-2-(trifluoromethyl) cyanophenyl
。
In 20L there-necked flask, add 5.94L water, 270mL thiophosgene, temperature is controlled at 20 ~ 30 ℃, under agitation condition, add 457g 4-amino-2-(trifluoromethyl) cyanobenzene in batches, after adding, continue stirring reaction 1h, complete by TLC method detection reaction, with dichloromethane extraction (1L * 3), merge organic phase, with anhydrous sodium sulfate drying, filter, concentrated, add sherwood oil making beating, logical liquid nitrogen crystallization, filters, dry, obtain product 500g, yield 89.3%.
1H?NMR?(400?MHz,?DMSO-d
6)?δ?7.95?(dd,?J?=?8.7?and?2.6?Hz,?1H),?8.16?(d,?J?=?2.6?Hz,?1H),?8.28?(d,?J?=?8.7?Hz,?1H)；LC-MS:?m/z=229.1?(C
9H
3F
3N
2S?+?H
+)。
Step 2): the preparation of the fluoro-benzamide of the bromo-2-of N-methyl-4-
。
At room temperature, the fluoro-4-bromo-benzoic acid of 200g 2-is dissolved in 1400mL ethyl acetate, then under nitrogen protection, in mixed solution, add successively 1g N, dinethylformamide and 150g thionyl chloride, treat raw material add after back flow reaction 4h, concentrate drying, obtain the bromo-2-fluorobenzoyl chloride of 4-crude product 230g, add 1000mL acetic acid ethyl dissolution, this solution is added drop-wise to slowly in the mixed solution (volume ratio is 1:1) of 800mL methylamine and ethyl acetate, temperature is controlled at 30 ~ 35 ℃, continue stirring reaction 15min, after complete by TLC detection reaction, add 400mL saturated common salt water stratification, water layer adds 500mL ethyl acetate, layering, merge organic phase, with anhydrous sodium sulfate drying, filter, concentrated, the dry white solid 195g that obtains, yield 92%.
1H?NMR?(400?MHz,?DMSO-d
6):?δ?2.83?(s,?3H),?7.33–7.48?(m,?2H),?7.78–7.84?(m,?1H),?8.46?(s,?1H)；LC-MS:?m/z=232.1?(C
8H
7BrFNO?+?H
+)。
Step 3): the preparation of the assorted Shandong of grace amine
。
The fluoro-benzamide of the bromo-2-of 278.4g N-methyl-4-, 103g 2-methylalanine, 276g salt of wormwood and 9.5g cuprous iodide are dissolved in to 2.3L dimethyl sulfoxide (DMSO) (DMSO), under nitrogen protection, be heated to 120 ℃ of stirring reaction 16h, reaction solution is cooled to 30 ~ 40 ℃ subsequently, add 218g benzyl iodide, after reaction 60min, add 342g 4-isothiocyano-2-(trifluoromethyl) cyanophenyl in batches, at 80 ℃, react and spend the night, by LC-MS method detection reaction process; Continue to add 100mL methyl alcohol, reaction solution is cooled to 20 ~ 30 ℃ stir 45min at 80 ℃ after, add 4L isopropyl acetate, 2L water, the layering of 1L Virahol, water layer extracts with Iso Butyl Acetate, merges organic phase, with anhydrous sodium sulfate drying, filter, concentrated, add 1L Virahol, being heated to 80 ℃ dissolves completely, be cooled to 0 ℃ and separate out solid, filter washed with isopropyl alcohol, the dry product 309g, yield 66.6% of obtaining.
Embodiment bis-
Step 1), step 2) with embodiment mono-.
Step 3): the preparation of the assorted Shandong of grace amine
。
The fluoro-benzamide of the bromo-2-of 232g N-methyl-4-, 103g 2-methylalanine, 276g salt of wormwood and 9.5g cuprous iodide are dissolved in to 2.3L dimethyl sulfoxide (DMSO) (DMSO), under nitrogen protection, be heated to 120 ℃ of stirring reaction 14h, reaction solution is cooled to 30 ~ 40 ℃ subsequently, add 142g methyl iodide, after reaction 40min, add 342g 4-isothiocyano-2-(trifluoromethyl) cyanophenyl in batches, at 80 ℃, react and spend the night, by LC-MS method detection reaction process; Continue to add 100mL methyl alcohol, reaction solution is cooled to 20 ~ 30 ℃ stir 45min at 80 ℃ after, add 4L isopropyl acetate, 2L water, the layering of 1L Virahol, water layer extracts with Iso Butyl Acetate, merges organic phase, with anhydrous sodium sulfate drying, filter, concentrated, add 1L Virahol, being heated to 80 ℃ dissolves completely, be cooled to 0 ℃ and separate out solid, filter washed with isopropyl alcohol, the dry product 262g, yield 56.5% of obtaining.
The experimental data of the assorted Shandong of grace amine:
1h-NMR (400 MHz, DMSO-d
6): δ 1.58 (s, 6H), 2.82 (s, 3H), 7.33 – 7.48 (m, 2H) 7.78 – 7.84 (m, 1H), 8.08 – 8.12 (m, 1H), 8.30 – 8.49 (m, 3H); LC-MS:m/z=465.1 (C
21h
16f
4n
4o
2s+H
+).
Claims (5)
1. one kind " one kettle way " synthesizes the method for the assorted Shandong of grace amine, it is characterized in that: the fluoro-benzamide of the bromo-2-of a certain amount of N-methyl-4-, 2-methylalanine, mineral alkali and copper (I) catalyzer are dissolved in to dimethyl sulfoxide (DMSO) (DMSO), under nitrogen protection, be heated to 120 ℃ of stirring reactions, by LC-MS method detection reaction process; Reaction solution is cooled to 30 ~ 40 ℃ subsequently, adds alkylating reagent, the reaction times is 30 ~ 60min; Then add a certain amount of 4-isothiocyano-2-(trifluoromethyl) cyanophenyl in batches, at 80 ℃, react and spend the night, treat that it reacts completely, continue to add methyl alcohol, stir 45min at 80 ℃ after, reaction solution is cooled to 20 ~ 30 ℃, adds Iso Butyl Acetate, water, Virahol layering, water layer extracts with Iso Butyl Acetate, merge organic phase, with anhydrous sodium sulfate drying, filter, concentrated, add Virahol, be heated to 80 ℃ and dissolve completely, be cooled to 0 ℃ and separate out solid, filter, washed with isopropyl alcohol, the dry product that obtains.
2. the method for the assorted Shandong of " one kettle way " according to claim 1 synthetic grace amine, is characterized in that: the add-on of the fluoro-benzamide of the bromo-2-of N-methyl-4-is 1.0 ~ 1.2 equivalents of 2-methylalanine.
3. the method for the assorted Shandong of " one kettle way " according to claim 1 synthetic grace amine, is characterized in that: mineral alkali is salt of wormwood, and its add-on is 2.0 equivalents of 2-methylalanine.
4. the method for the assorted Shandong of " one kettle way " according to claim 1 synthetic grace amine, is characterized in that: copper (I) catalyzer is the sub-ketone of iodate, and its add-on is 0.05 equivalent of 2-methylalanine.
5. " one kettle way " according to claim 1 synthesizes the method for the assorted Shandong of grace amine, it is characterized in that: alkylating reagent is methyl iodide, iodoethane, iodopropane, butyl iodide, benzyl iodide or monobromethane, monobromethane, N-PROPYLE BROMIDE, n-butyl bromide, bromotoluene, the add-on of alkylating agent is 1.0 equivalents of 2-methylalanine.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356068A (en) * | 2014-10-30 | 2015-02-18 | 杭州新博思生物医药有限公司 | Novel Xtandi crystal form and preparation method thereof |
| CN104710367A (en) * | 2015-03-27 | 2015-06-17 | 中国药科大学 | Method for synthesizing enzalutamide |
| CN107954936A (en) * | 2016-10-17 | 2018-04-24 | 成都海创药业有限公司 | A kind of method for preparing deuterated Imidazole diketone compound |
| CN109651256A (en) * | 2018-11-20 | 2019-04-19 | 上海健康医学院 | A kind of preparation method of the miscellaneous Shandong amine of the grace of formula (VIII) |
| CN113698310A (en) * | 2021-08-20 | 2021-11-26 | 江西金丰药业有限公司 | Preparation method of enzalutamide diester intermediate |
| CN115197084A (en) * | 2022-07-11 | 2022-10-18 | 中国船舶重工集团公司第七一八研究所 | Preparation method of enzalutamide key intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101222922A (en) * | 2005-05-13 | 2008-07-16 | 加利福尼亚大学董事会 | Diarylhydantoin compounds |
| CN103108549A (en) * | 2010-02-24 | 2013-05-15 | 梅迪维新前列腺医疗股份有限公司 | Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds |
-
2014
- 2014-06-16 CN CN201410264149.0A patent/CN104016924B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101222922A (en) * | 2005-05-13 | 2008-07-16 | 加利福尼亚大学董事会 | Diarylhydantoin compounds |
| CN103108549A (en) * | 2010-02-24 | 2013-05-15 | 梅迪维新前列腺医疗股份有限公司 | Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds |
Non-Patent Citations (1)
| Title |
|---|
| 刘子建.: "恩杂鲁胺", 《中国药物化学杂志》, vol. 23, no. 1, 28 February 2013 (2013-02-28), pages 79 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356068A (en) * | 2014-10-30 | 2015-02-18 | 杭州新博思生物医药有限公司 | Novel Xtandi crystal form and preparation method thereof |
| CN104710367A (en) * | 2015-03-27 | 2015-06-17 | 中国药科大学 | Method for synthesizing enzalutamide |
| CN107954936A (en) * | 2016-10-17 | 2018-04-24 | 成都海创药业有限公司 | A kind of method for preparing deuterated Imidazole diketone compound |
| CN107954936B (en) * | 2016-10-17 | 2021-03-19 | 海创药业股份有限公司 | Method for preparing deuterated imidazoldione compound |
| CN109651256A (en) * | 2018-11-20 | 2019-04-19 | 上海健康医学院 | A kind of preparation method of the miscellaneous Shandong amine of the grace of formula (VIII) |
| CN113698310A (en) * | 2021-08-20 | 2021-11-26 | 江西金丰药业有限公司 | Preparation method of enzalutamide diester intermediate |
| CN115197084A (en) * | 2022-07-11 | 2022-10-18 | 中国船舶重工集团公司第七一八研究所 | Preparation method of enzalutamide key intermediate |
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