CN108997152A - Prepare the chloro- 2-(trifluoroacetyl group of 4-) the improvement technique of anilinechloride - Google Patents
Prepare the chloro- 2-(trifluoroacetyl group of 4-) the improvement technique of anilinechloride Download PDFInfo
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- CN108997152A CN108997152A CN201811014202.6A CN201811014202A CN108997152A CN 108997152 A CN108997152 A CN 108997152A CN 201811014202 A CN201811014202 A CN 201811014202A CN 108997152 A CN108997152 A CN 108997152A
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- Prior art keywords
- chloro
- trifluoroacetyl group
- anilinechloride
- isobutanol
- isobutyl ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
Abstract
The present invention provides a kind of improvement technique for preparing 4- chloro- 2- (trifluoroacetyl group) anilinechloride, it is related to compounds process for production thereof technical field, the present invention is using N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline as raw material, using isobutanol and pivalic acid isobutyl ester as solvent, then hydrochloric acid is added dropwise, temperature reaction is carried out again, last decrease temperature crystalline obtains product, the selection of isobutanol and pivalic acid isobutyl ester mixed solvent helps to improve product yield, and water and organic matter are layered in the filtrate systems generated, convenient for the recycling of solvent, advantageously reduce production cost, reduce later period environmental protection treatment pressure.
Description
Technical field
The invention belongs to compounds process for production thereof technical fields, and in particular to the preparation chloro- 2- of 4- (trifluoroacetyl group) aniline
The improvement technique of hydrochloride.
Background technique
Efavirenz is a kind of non-nucleoside reverse transcriptase inhibitor, is treatment AIDS most efficient method --- " chicken
One of most important drug in tail wine therapy " has the advantages that toxic side effect is small, therapeutic effect is good, wherein the chloro- 2- (trifluoro of 4-
Acetyl group) anilinechloride be produce efavirenz important intermediate.Patent intermediate 4- chloro- 2- (trifluoroacetyl group) aniline
In the technique of the synthetic method (application No. is 201010185417.1) of hydrochloride, finally with N- acyl group -4- chloro- 2- (trifluoro second
Acyl group) aniline be raw material, using acetic acid as solvent, react with hydrochloric acid remove acyl group hydrochloric acid salt.But acetic acid solvent in the technique
Dosage it is larger, and solubility of the product in acetic acid solvent system is higher, and it is relatively low not only to result in yield, also results in preparation
The increase of cost.In addition, filtrate obtained in reaction process is mixed acid solution, relative difficulty, processing difficulty and environmental protection are recycled
Pressure is also larger.
Therefore, it is badly in need of that a kind of product yield high, solvent easily recycles, synthesis cost is lower, more environmentally friendly preparation 4-
The improvement technique of chloro- 2- (trifluoroacetyl group) anilinechloride.
Summary of the invention
The purpose of the present invention is being directed to the deficiency of prior art, provides and a kind of prepare 4- chloro- 2- (trifluoroacetyl group) aniline
The improvement technique of hydrochloride, the technique have product yield high, solvent easily recycles, synthesis cost is lower, more environmentally friendly
Advantage.
The present invention provides the following technical solutions:
Prepare the improvement technique of 4- chloro- 2- (trifluoroacetyl group) anilinechloride, including following synthesis step:
A, isobutanol is added in the reactor and pivalic acid isobutyl ester makees mixed solvent, then add N- pivaloyl group-
4- chloro- 2- (trifluoroacetyl group) aniline, stirs 1.5-2h at room temperature, and hydrochloric acid is added dropwise at 20-35 DEG C, then heats up for control temperature
4-6h is reacted to 75-80 DEG C, cools to 0-5 DEG C again after reaction and stirs 1h；
B, reaction solution made from step a is filtered at room temperature, gained filter cake is washed with ethyl acetate, and is subtracted
Product 4- chloro- 2- (trifluoroacetyl group) anilinechloride is obtained after pressure drying；
C, by gained filtrate static layering in step b, be then demultiplex out organic layer, vacuum distillation recycling obtain isobutanol and
The mixed liquor of pivalic acid isobutyl ester.
Preferably, the molar ratio of isobutanol and N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline is in step a
1.5-3.0:1, because isobutanol is reacted with by-product pivalic acid, to peomote reaction to the generation chloro- 2- of 4- (trifluoro second
Acyl group) anilinechloride hydrate direction carry out.
Preferably, the molar ratio of pivalic acid isobutyl ester and isobutanol is 0-2.5:1 in step a.
Preferably, the molar ratio of hydrochloric acid and N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline is 2.5- in step a
3.5:1 peomotes the generation of 4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate.
Preferably, the vacuum distillation condition in step c is control pressure in -0.09MPa, carries out heat temperature raising to filtrate,
Boiling point is collected in the fraction of 50-70 DEG C of range, to obtain the mixed liquor containing isobutanol and pivalic acid isobutyl ester.
Preferably, with isobutanol and pivalic acid isobutyl ester contain in vacuum distillation gained mixed liquor in chromatography detecting step c
Amount, in order to recycle isobutanol and pivalic acid isobutyl ester, and does not influence product yield during use, works as isobutyl
When pure and mild pivalic acid isobutyl ester content summation is greater than 90%, the ability recovery mixed liquor makees mixed solvent in step a.
Synthetic route of the invention are as follows:
The beneficial effects of the present invention are: the present invention is using isobutanol and pivalic acid isobutyl ester as solvent, by-product pivalic acid with
Isobutanol reaction generates pivalic acid isobutyl ester, advantageously reduces polar solvent ratio in system, and then reduce the chloro- 2- (trifluoro of 4-
Acetyl group) solubility of the anilinechloride in system to improve reaction yield reduces production cost.It generates simultaneously
Filtrate systems in water and organic matter be layered, be conducive to being recovered and reused by for later period solvent, further reduced and be produced into
This, decreases later period environmental protection treatment pressure, more environmentally friendly.
Specific embodiment
But the scope of the present invention is not limited thereto is further illustrated to the content of present invention below by embodiment:
Comparative example 1
In the reactor plus 80g (1.33mol) acetic acid makees solvent, then adds 61.5g (0.20mol) N- pivaloyl
Base -4- chloro- 2- (trifluoroacetyl group) aniline, is stirred at room temperature 1.5-2h, and 65g (0.66mol) is added dropwise in control temperature at 20-35 DEG C
Then 37% concentrated hydrochloric acid is warming up to 75-80 DEG C and reacts 4-6h, cool to 0-5 DEG C after reaction and stir 1h, then will be anti-
Liquid is answered to filter, gained filter cake is washed with ethyl acetate, and decompression drying obtains product 4- chloro- 2- (trifluoroacetyl group) anilinechloride
50.5g, yield 90.82%, content 99.4%.
Embodiment 1
In the reactor plus 80g (1.08mol) isobutanol makees solvent, then adds 61.5g (0.20mol) N- pivaloyl
Base -4- chloro- 2- (trifluoroacetyl group) aniline, is stirred at room temperature 1.5-2h, and 65g (0.66mol) is added dropwise in control temperature at 20-35 DEG C
Then 37% concentrated hydrochloric acid is warming up to 75-80 DEG C and reacts 4-6h, cool to 0-5 DEG C after reaction and stir 1h, then will be anti-
Liquid is answered to filter, gained filter cake is washed with ethyl acetate, and decompression drying obtains product 4- chloro- 2- (trifluoroacetyl group) anilinechloride
52.2g, yield 92.68%, content 99.5%, yield increase 1.86% relative to comparative example 1.
Gained filtrate static layering, upper organic layer vacuum distillation, control pressure is -0.09MPa, is heated to filtrate
Heating collects boiling point in the fraction of 50-70 DEG C of range, the mixed liquor of vacuum distillation recycling is detected with chromatography, wherein isobutanol contains
Amount 56.8%, pivalic acid isobutyl ester content 39.2%.
Embodiment 2
In the reactor plus the mixed solvent of 30g (0.40mol) isobutanol and 55g (0.35mol) pivalic acid isobutyl ester, so
61.5g (0.20mol) N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline is added afterwards, 1.5-2h, control temperature is stirred at room temperature
65g (0.66mol) 37% concentrated hydrochloric acid is added dropwise in degree at 20-35 DEG C, is then warming up to 75-80 DEG C and reacts 4-6h, reaction terminates
After cool to 0-5 DEG C and stir 1h, then reaction solution is filtered, gained filter cake is washed with ethyl acetate, and decompression drying is produced
Object 4- chloro- 2- (trifluoroacetyl group) anilinechloride 53.6g, yield 96.74%, content 99.4%, yield is relative to comparative example 1
Increase 5.92%.
Gained filtrate static layering, upper organic layer vacuum distillation, control pressure is -0.09MPa, is heated to filtrate
Heating collects boiling point in the fraction of 50-70 DEG C of range, the mixed liquor of vacuum distillation recycling is detected with chromatography, wherein isobutanol contains
Amount 15.8%, pivalic acid isobutyl ester content 81.3%.
Embodiment 3
In the reactor plus 30g (0.40mol) isobutanol and embodiment 2 are evaporated under reduced pressure obtained 55g recycling design (isobutyl
Alcohol content 15.8%, pivalic acid isobutyl ester content 81.3%), the chloro- 2- of 61.5g (0.20mol) N- pivaloyl group -4- is then added
(trifluoroacetyl group) aniline, is stirred at room temperature 1.5-2h, and the dense salt of 65g (0.66mol) 37% is added dropwise in control temperature at 20-35 DEG C
Then acid is warming up to 75-80 DEG C and reacts 4-6h, cool to 0-5 DEG C after reaction and stir 1h, then by reaction solution mistake
Filter, gained filter cake are washed with ethyl acetate, and decompression drying obtains 4- chloro- 2- (trifluoroacetyl group) anilinechloride 53.5g, yield
96.69%, content 99.5%, yield increases 5.87% relative to comparative example 1.
Gained filtrate static layering, upper organic layer vacuum distillation, control pressure is -0.09MPa, is heated to filtrate
Heating collects boiling point in the fraction of 50-70 DEG C of range, the mixed liquor of vacuum distillation recycling is detected with chromatography, wherein isobutanol contains
Amount 17.2%, pivalic acid isobutyl ester content 76.4%
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, although referring to aforementioned reality
Applying example, invention is explained in detail, for those skilled in the art, still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features.It is all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (6)
1. preparing the improvement technique of 4- chloro- 2- (trifluoroacetyl group) anilinechloride, which is characterized in that walked including following synthesis
It is rapid:
A, isobutanol is added in the reactor and pivalic acid isobutyl ester makees mixed solvent, it is chloro- then to add N- pivaloyl group -4-
2- (trifluoroacetyl group) aniline, stirs 1.5-2h at room temperature, and control temperature is added dropwise hydrochloric acid at 20-35 DEG C, then heats to 75-
4-6h is reacted at 80 DEG C, cools to 0-5 DEG C again after reaction and stirs 1h；
B, reaction solution made from step a is filtered at room temperature, gained filter cake is washed with ethyl acetate, and depressurizes baking
Product 4- chloro- 2- (trifluoroacetyl group) anilinechloride is obtained after dry；
C, by gained filtrate static layering in step b, organic layer is then demultiplex out, vacuum distillation recycling obtains isobutanol and spy penta
The mixed liquor of sour isobutyl ester.
2. the improvement technique according to claim 1 for preparing 4- chloro- 2- (trifluoroacetyl group) anilinechloride, feature exist
In the molar ratio of isobutanol and N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline is 1.5-3.0:1 in step a.
3. the improvement technique according to claim 1 for preparing 4- chloro- 2- (trifluoroacetyl group) anilinechloride, feature exist
In the molar ratio of pivalic acid isobutyl ester and isobutanol is 0-2.5:1 in step a.
4. the improvement technique according to claim 1 for preparing 4- chloro- 2- (trifluoroacetyl group) anilinechloride, feature exist
In the molar ratio of hydrochloric acid and N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline is 2.5-3.5:1 in step a.
5. the improvement technique according to claim 1 for preparing 4- chloro- 2- (trifluoroacetyl group) anilinechloride, feature exist
In the vacuum distillation condition in step c is control pressure in -0.09MPa, carries out heat temperature raising to filtrate, collects boiling point in 50-
The fraction of 70 DEG C of ranges.
6. the improvement technique according to claim 1 for preparing 4- chloro- 2- (trifluoroacetyl group) anilinechloride, feature exist
In, in chromatography detecting step c in vacuum distillation gained mixed liquor isobutanol and pivalic acid isobutyl ester content, when isobutanol and
When pivalic acid isobutyl ester content summation is greater than 90%, the recovery mixed liquor makees mixed solvent in step a.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811014202.6A CN108997152A (en) | 2018-08-31 | 2018-08-31 | Prepare the chloro- 2-(trifluoroacetyl group of 4-) the improvement technique of anilinechloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811014202.6A CN108997152A (en) | 2018-08-31 | 2018-08-31 | Prepare the chloro- 2-(trifluoroacetyl group of 4-) the improvement technique of anilinechloride |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998045278A1 (en) * | 1997-04-07 | 1998-10-15 | Du Pont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones via new intermediates |
| CN101844990A (en) * | 2010-05-27 | 2010-09-29 | 浙江沙星医药化工有限公司 | Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate |
| CN105801442A (en) * | 2015-10-16 | 2016-07-27 | 浙江沙星医药化工有限公司 | Preparation method of 4-chloro-2-(trifluoroacetyl) aniline hydrochloride hydrate |
-
2018
- 2018-08-31 CN CN201811014202.6A patent/CN108997152A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998045278A1 (en) * | 1997-04-07 | 1998-10-15 | Du Pont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones via new intermediates |
| CN101844990A (en) * | 2010-05-27 | 2010-09-29 | 浙江沙星医药化工有限公司 | Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate |
| CN105801442A (en) * | 2015-10-16 | 2016-07-27 | 浙江沙星医药化工有限公司 | Preparation method of 4-chloro-2-(trifluoroacetyl) aniline hydrochloride hydrate |
Non-Patent Citations (1)
| Title |
|---|
| 胡争朋 等: "依非韦伦关键中间体的合成", 《中国医药工业杂志》 * |
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Application publication date: 20181214 |