CN103408447A - Process for synthesizing flutamide - Google Patents
Process for synthesizing flutamide Download PDFInfo
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- CN103408447A CN103408447A CN2013102696751A CN201310269675A CN103408447A CN 103408447 A CN103408447 A CN 103408447A CN 2013102696751 A CN2013102696751 A CN 2013102696751A CN 201310269675 A CN201310269675 A CN 201310269675A CN 103408447 A CN103408447 A CN 103408447A
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- flutamide
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- amido benzotrifluoride
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Abstract
The invention discloses a process for synthesizing flutamide. The process comprises the steps of taking 2-nitro-5-aminobenzotrifluoride as a raw material, selecting 1,2-dichloroethane as a solvent and N,N-dimethyl acetamide as an acid absorbent, dropwise adding isobutyryl chloride under the action of 4-dimethylamino pyridine while maintaining the temperature to be 5-10 DEG C, and reacting after the dropwise adding process is completed while maintaining the temperature to be 18-25 DEG C until 2-nitro-5-aminobenzotrifluoride reacts completely; adding water, heating to steam out 1,2-dichloroethane, carrying out elutriation, and filtering to obtain a flutamide crude product; and re-crystallizing by using ethanol, thereby obtaining a flutamide finished product. The process has the advantages of simplicity, few steps, easiness in operation, low cost and high product quality; the conversion ratio of the product is high and reaches over 96%; the activity of a catalyst is high, and side reactions are few; the reaction conditions are mild, and the reaction time is short; the purity of the product is high, and the impurities are few; the production cost is low, and the solvent 1,2-dichloroethane can be repeatedly used indiscriminately; and waste gases, waste water and waste residues are few, thus the environmental friendliness is facilitated.
Description
Technical field
The present invention relates to a kind of synthesis technique of flutamide, belong to the chemical synthesis process technical field.
Background technology
The synthetic route of flutamide is a lot, and more representational production method is usually with there being two kinds.(1) nitrated after first acidylate; (2) first nitrated rear acidylate.Compare and cut both ways: the advantage of route (1) is that production process is few; Shortcoming is that recrystallization more complicated, quality are not easy to control.The advantage of route (2) is that recrystallization is simple, good product quality; It is more complex that shortcoming is that production process is compared.
Summary of the invention
Purpose: in order to overcome the deficiencies in the prior art, the invention provides a kind of synthesis technique of flutamide.
Technical scheme: for solving the problems of the technologies described above, the technical solution used in the present invention is:
The synthesis technique of flutamide, is characterized in that,
2-nitro-5-the 5 amido benzotrifluoride of take is raw material, select 1, the 2-ethylene dichloride is made solvent, N, the N-N,N-DIMETHYLACETAMIDE is made acid-acceptor, in the lower temperature of DMAP (DMAP) effect, maintain 5～10 ℃ and drip isobutyryl chlorides, dropwise 18～25 ℃ of rear maintenance temperature and react and reacted completely to 2-nitro-5-5 amido benzotrifluoride in 0.5-1.5 hour; Add water and heat up and to steam 1,2-ethylene dichloride, elutriation, filter to obtain the flutamide crude product; With ethyl alcohol recrystallization, obtain the flutamide finished product.
The mol ratio of described isobutyryl chloride and 2-nitro-5-5 amido benzotrifluoride is 1.1-1.3:1.
Mol ratio as the described isobutyryl chloride of preferred version and 2-nitro-5-5 amido benzotrifluoride is 1.2:1.
The mol ratio of described DMAP and 2-nitro-5-5 amido benzotrifluoride is 0.11-0.13:1.
The synthesis technique of described flutamide, is characterized in that, specifically comprises the following steps:
A), in the reaction flask that stirrer, thermometer, dropping funnel and reflux dewatering device are housed, add 1,2-ethylene dichloride and N, the N-N,N-DIMETHYLACETAMIDE, under stirring, add 2-nitro-5-5 amido benzotrifluoride and DMAP, under the ice-water bath condition, control 5～10 ℃ of temperature and slowly drip isobutyryl chloride, it is muddy that yellow solution becomes gradually, dropwise, remove ice-water bath, temperature maintains 18～25 ℃ of stirring reaction for some time, and sampling TLC monitoring reaction, react completely and finish reaction to 2-nitro-5-5 amido benzotrifluoride;
B), change oil bath, in reaction flask, add suitable quantity of water, stir to heat up, control 105～120 ℃ of oil bath temperatures, reflux 1,2-ethylene dichloride purified, in bottle, separate out gradually a large amount of flaxen flutamide xln, stop heating up; The question response liquid temp is down to below 70 ℃ and is added suitable quantity of water again, stirs and is cooled to room temperature, discharging;
C), suction filtration, wash 60 ℃ of dryings 6 hours 2～3 times; Obtaining faint yellow particulate solid is the flutamide crude product, and theoretical yield is greater than 96%, mp:109～113 ℃, and purity is greater than 99%;
D), in the reaction flask that stirrer, thermometer and reflux are housed, add anhydrous alcohol for medical use, under stirring, add the flutamide crude product, heated and stirred refluxed 15 minutes, filtered while hot; The liquid that slips is placed in beaker and is stirred, and slowly adds distilled water in beaker, and faint yellow needle crystal is separated out, and standingly separates out fully to crystallization; Suction filtration, 60 ℃ of dryings obtained the flutamide product in 6 hours; Mp:111～113 ℃; Purity: be greater than 99.8%.
Beneficial effect: the synthesis technique of flutamide provided by the invention, (1) product yield is high, reaches more than 96%; (2) catalyst activity is high, side reaction is little; (3) reaction conditions gentleness, the reaction times is short; (4) product purity is high, impurity is few; (5) production cost is low, solvent 1, and the 2-ethylene dichloride can be applied mechanically repeatedly; (6) three wastes are few, environmental.With the flutamide crude product theoretical yield that the method is produced, can reach (being quantitative reaction basically) more than 96%; Purity is greater than 98%; After recrystallization, yield 92%, and purity is greater than 99.8%.
(1) the consumption mol ratio of isobutyryl chloride and 2-nitro-5-5 amido benzotrifluoride is proper with 1:1.2;
(2) N,N-dimethylacetamide is made acid-acceptor, and controlling the consumption reason is that consideration can produce a large amount of waste water;
(3) first heating recovery 1 in the reaction, 2-ethylene dichloride solvent, both reduced with the direct ice elutriation method and can produce a large amount of sewage (approximately more than 3 times); The quality of favourable raising crystallization simultaneously.
Embodiment
Below in conjunction with embodiment, the present invention is further described.
1, operational path: at first through type (1) nitration reaction makes 2-nitro-5-5 amido benzotrifluoride, 2-nitro-5-the 5 amido benzotrifluoride of take again is raw material, select 1, the 2-ethylene dichloride is made solvent, N, the N-N,N-DIMETHYLACETAMIDE is made acid-acceptor, in the lower temperature of DMAP (DMAP) effect, maintain 5～10 ℃ and drip isobutyryl chlorides, dropwise 18～25 ℃ of rear maintenance temperature and react and reacted completely to 2-nitro-5-5 amido benzotrifluoride in 0.5-1.5 hour, see formula (2); Add water and heat up and to steam 1,2-ethylene dichloride, elutriation, filter to obtain the flutamide crude product; With ethyl alcohol recrystallization, obtain the flutamide finished product.
Formula (1)
Mamino-trifluoromethyl benzene acetylate itrated compound 2-nitro-5-5 amido benzotrifluoride
Formula (2)
2-nitro-5-5 amido benzotrifluoride isobutyryl chloride flutamide
2, specifications of raw materials:
Embodiment 1:
A kind of synthesis technique of flutamide comprises the following steps:
A), stirrer is being housed, thermometer, in the 250mml reaction flask of dropping funnel and reflux dewatering device, add 1, 2-ethylene dichloride 40mml, and N, N-N,N-DIMETHYLACETAMIDE 10mml, under stirring, add 2-nitro-5-5 amido benzotrifluoride 20g and DMAP 1.46g, under the ice-water bath condition, control 5～10 ℃ of temperature and slowly drip isobutyryl chloride 12.2g, it is muddy that yellow solution becomes gradually, dropwise, remove ice-water bath, temperature maintains 18～25 ℃ of stirring reaction for some time, sampling TLC monitoring reaction, to 2-nitro-5-5 amido benzotrifluoride, react completely and finish reaction,
B), change oil bath, in reaction flask, add water 60mml, stir to heat up, control 105～120 ℃ of oil bath temperatures, reflux 1,2-ethylene dichloride purified, in bottle, separate out gradually a large amount of flaxen flutamide xln, stop heating up; The question response liquid temp is down to below 70 ℃ and is added water 60mml again, stirs and is cooled to room temperature, discharging;
C), suction filtration, wash 60 ℃ of dryings 6 hours 2～3 times; Obtain faint yellow particulate solid 25.78g, theoretical yield is greater than 96.2%, is quantitative reaction basically; Weight yield is 128.9%; Mp:109～113 ℃, purity is greater than 99%;
D), in the 250mml reaction flask of stirrer, thermometer and reflux is housed, add anhydrous alcohol for medical use 100mml, under stirring, add flutamide crude product 40g, heated and stirred refluxed 15 minutes, filtered while hot; The liquid that slips is placed in beaker and is stirred, and slowly adds distilled water 52.6mml in beaker, and faint yellow needle crystal is separated out, and separates out fully to crystallization in standing 30 minutes; Suction filtration, 60 ℃ of dryings obtained the flutamide product in 6 hours; Weigh: 36.72g; Mp:111～113 ℃; Purity: 99.84%.
In the present invention, the consumption mol ratio of (1) isobutyryl chloride and 2-nitro-5-5 amido benzotrifluoride is proper with 1:1.2; (2) N,N-dimethylacetamide is made acid-acceptor, and controlling the consumption reason is that consideration can produce a large amount of waste water; (3) first heating recovery 1 in the reaction, 2-ethylene dichloride solvent, both reduced with the direct ice elutriation method and can produce a large amount of sewage (approximately more than 3 times); The quality of favourable raising crystallization simultaneously.
The above is only the preferred embodiment of the present invention; be noted that for those skilled in the art; under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (5)
1. the synthesis technique of flutamide, is characterized in that,
2-nitro-5-the 5 amido benzotrifluoride of take is raw material, select 1, the 2-ethylene dichloride is made solvent, N, the N-N,N-DIMETHYLACETAMIDE is made acid-acceptor, temperature maintains 5～10 ℃ and drips isobutyryl chlorides under the DMAP effect, dropwises 18～25 ℃ of reactions of rear maintenance temperature 0.5-1.5 hour to 2-nitro-5-5 amido benzotrifluoride and reacts completely; Add water and heat up and to steam 1,2-ethylene dichloride, elutriation, filter to obtain the flutamide crude product; With ethyl alcohol recrystallization, obtain the flutamide finished product.
2. the synthesis technique of flutamide according to claim 1, it is characterized in that: the mol ratio of described isobutyryl chloride and 2-nitro-5-5 amido benzotrifluoride is 1.1-1.3:1.
3. the synthesis technique of flutamide according to claim 1, it is characterized in that: the mol ratio of described isobutyryl chloride and 2-nitro-5-5 amido benzotrifluoride is 1.2:1.
4. the synthesis technique of flutamide according to claim 1, it is characterized in that: the mol ratio of described DMAP and 2-nitro-5-5 amido benzotrifluoride is 0.11-0.13:1.
5. the synthesis technique of flutamide according to claim 1, is characterized in that, specifically comprises the following steps:
A), in the reaction flask that stirrer, thermometer, dropping funnel and reflux dewatering device are housed, add 1,2-ethylene dichloride and N, the N-N,N-DIMETHYLACETAMIDE, under stirring, add 2-nitro-5-5 amido benzotrifluoride and DMAP, under the ice-water bath condition, control 5～10 ℃ of temperature and slowly drip isobutyryl chloride, it is muddy that yellow solution becomes gradually, dropwise, remove ice-water bath, temperature maintains 18～25 ℃ of stirring reaction for some time, and sampling TLC monitoring reaction, react completely and finish reaction to 2-nitro-5-5 amido benzotrifluoride;
B), change oil bath, in reaction flask, add suitable quantity of water, stir to heat up, control 105～120 ℃ of oil bath temperatures, reflux 1,2-ethylene dichloride purified, in bottle, separate out gradually a large amount of flaxen flutamide xln, stop heating up; The question response liquid temp is down to below 70 ℃ and is added suitable quantity of water again, stirs and is cooled to room temperature, discharging;
C), suction filtration, wash 60 ℃ of dryings 6 hours 2～3 times; Obtaining faint yellow particulate solid is the flutamide crude product, and theoretical yield is greater than 96%, mp:109～113 ℃, and purity is greater than 99%;
D), in the reaction flask that stirrer, thermometer and reflux are housed, add anhydrous alcohol for medical use, under stirring, add the flutamide crude product, heated and stirred refluxed 15 minutes, filtered while hot; The liquid that slips is placed in beaker and is stirred, and slowly adds distilled water in beaker, and faint yellow needle crystal is separated out, and standingly separates out fully to crystallization; Suction filtration, 60 ℃ of dryings obtained the flutamide product in 6 hours; Mp:111～113 ℃; Purity: be greater than 99.8 %.
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| CN201310269675.1A CN103408447B (en) | 2013-07-01 | 2013-07-01 | Process for synthesizing flutamide |
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| CN201310269675.1A CN103408447B (en) | 2013-07-01 | 2013-07-01 | Process for synthesizing flutamide |
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| CN103408447B CN103408447B (en) | 2015-05-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115093041A (en) * | 2022-02-22 | 2022-09-23 | 邓国文 | Recycling treatment method for industrial wastewater generated by producing 5-amino-2-nitrobenzotrifluoride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1360001A (en) * | 1971-06-16 | 1974-07-17 | Scherico Ltd | Pharmaceutical compositions comprising substituted anilides |
| US4144270A (en) * | 1973-04-19 | 1979-03-13 | Schering Corporation | Substituted anilides as anti-androgens |
| CN102093229A (en) * | 2010-12-28 | 2011-06-15 | 天津市筠凯化工科技有限公司 | Preparation method of 4-nitro-3-trifluoromethylaniline |
| CN102746178A (en) * | 2011-04-20 | 2012-10-24 | 江苏天士力帝益药业有限公司 | New preparation method of flutamide |
-
2013
- 2013-07-01 CN CN201310269675.1A patent/CN103408447B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1360001A (en) * | 1971-06-16 | 1974-07-17 | Scherico Ltd | Pharmaceutical compositions comprising substituted anilides |
| US4144270A (en) * | 1973-04-19 | 1979-03-13 | Schering Corporation | Substituted anilides as anti-androgens |
| CN102093229A (en) * | 2010-12-28 | 2011-06-15 | 天津市筠凯化工科技有限公司 | Preparation method of 4-nitro-3-trifluoromethylaniline |
| CN102746178A (en) * | 2011-04-20 | 2012-10-24 | 江苏天士力帝益药业有限公司 | New preparation method of flutamide |
Non-Patent Citations (1)
| Title |
|---|
| 黄东，王昉: "氟他胺生产工艺改进", 《中国医药科学》, vol. 3, no. 6, 31 March 2013 (2013-03-31) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115093041A (en) * | 2022-02-22 | 2022-09-23 | 邓国文 | Recycling treatment method for industrial wastewater generated by producing 5-amino-2-nitrobenzotrifluoride |
| CN115093041B (en) * | 2022-02-22 | 2024-02-13 | 杨自林 | Recycling treatment method of industrial wastewater generated in production of 5-amino-2-nitrobenzotrifluoride |
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