CN106496051B - A kind of synthetic method of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4- - Google Patents
A kind of synthetic method of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4- Download PDFInfo
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- CN106496051B CN106496051B CN201610792250.2A CN201610792250A CN106496051B CN 106496051 B CN106496051 B CN 106496051B CN 201610792250 A CN201610792250 A CN 201610792250A CN 106496051 B CN106496051 B CN 106496051B
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- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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Abstract
The present invention relates to a kind of synthetic methods of efavirenz intermediate, more particularly to a kind of synthetic method of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4-, the synthetic method includes the following steps, acylating agent is added in aniline in organic solvent, and makes aniline that acylation reaction occur with 5~15 DEG C under alkaline condition and obtain compound A, compound A is reacted to obtain compound B under weak basic condition with chlorinating agent, above compound B reacts under the action of butyl lithium with Trifluoroacetic Acid Ethyl Ester, obtain compound C, by compound C and hydrochloric acid in 60~65 DEG C of back flow reactions, obtain the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4-.Reaction condition of the present invention is mild, energy consumption declines to a great extent, raw materials used readily available, low in cost, pollutes small；Operation of the present invention is simple, and total recovery is up to 77.2%, and for purity up to 99% or more, the quality of product is preferable, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic methods of efavirenz intermediate, and in particular to a kind of chloro- 2- trifluoroacetyl group of 4-
The synthetic method of anilinechloride hydrate.
Background technique
Efavirenz (Efavirenz), Chinese: 4 (S) -6- chloro- 4- (cyclopropyl acetylene) -4- (trifluoromethyl)-benzene
And -1,4- dihydro-oxazole -2- ketone；English language Chemical title: (4S) -6-Chloro-4- (cyclopropylethynyl) -1,4-
dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one；Molecular formula: C14H9ClF3NO2；Molecule
Amount: 315.68；CAS registration number: 154598-52-4.Efavirenz is to be used for a line AntiHIV1 RT activity by MSD Corp.'s research and development, production
Virus drugs belong to the non-nucleoside reverse transcriptase inhibitors of selectivity (NNRTIS) of human immunodeficiency virus -1's type (HIV-1), pass through
Noncompetitive combination simultaneously inhibits HIV-1 reverse transcriptase (RT) active, acts on template, primer or nucleoside triphosphate, has small portion concurrently
Divide emulative inhibiting effect, to prevent virus transcription and duplication.Suitable for other antiviral drugs combination therapies HIV-1
Adult, teenager and the children of infection.Because of its good effect, toxicity and Small side effects, the master of " cocktail therapy " is had become at present
Want one of medication.
The chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4- is the key intermediate of anti-AIDS drug efavirenz.
Document Tetrahedron, 1991,3207；J.Org.chem.63(23),1998,8536-8543；US5932726；
The preparation method of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4- is reported in US05925789, but positive fourth in the reaction
The dosage of base lithium is twice or more of parachloroanilinum mole；Although not used in the preparation method of CN 102675125B report
To n-BuLi, but trifluoropropyl ketone acid methyl esters or ethyl ester are used in its reaction, price is also higher than n-BuLi.
Summary of the invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide at low cost, the chloro- 2- tri- of the high 4- of product yield of one kind
The preparation method of acetyl fluoride base anilinechloride hydrate.
The object of the present invention is achieved like this:
A kind of synthetic method of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4-, which includes following step
Suddenly,
Acylating agent is added in a, aniline in organic solvent, and makes aniline occur to be acylated instead with 5~15 DEG C under alkaline condition
It should obtain compound A
B reacts compound A with chlorinating agent to obtain compound B under weak basic condition
C, above compound B react under the action of butyl lithium with Trifluoroacetic Acid Ethyl Ester, obtain compound C
D obtains the chloro- 2- trifluoroacetyl aniline hydrochloric acid salt water of 4- by compound C and hydrochloric acid in 60~65 DEG C of back flow reactions
Close object
Further, acylating agent used in the step a is chloroacetic chloride, propionyl chloride, valeric chloride or pivaloyl chloride；It is described
Alkali used in step a is sodium hydroxide, and the molar ratio of aniline and sodium hydroxide is 1:1~2；Have used in the step a
Solvent is benzene, toluene or methyl tertiary butyl ether(MTBE).
Preferably, acylating agent used in the step a is pivaloyl chloride, and the molar ratio of aniline and pivaloyl chloride is 1:1
~2.
Preferably, the molar ratio of the aniline and pivaloyl chloride is 1:1.08.
Further, organic solvent used in the step a is toluene.
Further, chlorinating agent used in the step b is hypochlorous acid, sodium hypochlorite, postassium hypochlorite or calcium hypochlorite.
Preferably, chlorinating agent used in the step b is calcium hypochlorite.
Further, compound B in the step c, n-BuLi, Trifluoroacetic Acid Ethyl Ester molar ratio be 1:1~1.2:1
~1.2.
Compound B in the preferably described step c, n-BuLi, Trifluoroacetic Acid Ethyl Ester molar ratio be 1:1.1:1.1.
Further, hydrochloric acid used in the step d, concentration are 30%~38%.
The beneficial effects of the present invention are:
Reaction condition of the present invention is mild, energy consumption declines to a great extent, raw materials used readily available, low in cost, pollutes small；This hair
Bright easy to operate, total recovery is up to 77.2%, and for purity up to 99% or more, the quality of product is preferable, is suitable for industrialized production.
Specific embodiment
The content of present invention is further illustrated below by embodiment, but provided embodiment should not be construed as to this hair
Bright protection scope is construed as limiting.
Embodiment 1
The synthesis of pivaloyl aniline
Aniline 18.6g is added in the reactor, toluene 150mL is cooled to 0~5 DEG C, the sodium hydroxide of 30g30% is added
Solution controls temperature at 5~15 DEG C, 27.8g pivaloyl chloride is then added dropwise, and about 15min is added dropwise, stirs at 5~15 DEG C
60min, sample detection are layered after reaction, and organic layer is washed twice, and organic phase is cooled to 0~5 DEG C, keeps the temperature 120min, are taken out
Filter, the appropriate water washing of filter cake are drained, and pivaloyl aniline 34.4g, yield 97.2%, content 99.1% are obtained after vacuum drying.
The synthesis of N- chloro pivaloyl aniline
Manufactured pivaloyl aniline 35.4g, sodium bicarbonate 50.4g, ether 1000mL and water 400mL are put into reactor
In, being sufficiently stirred makes organic phase and water phase is clarified solution, then cools to 0 DEG C, be slowly added to the calcium hypochlorite 63g now matched and
Water 800mL water white suspension reacts 3.5 hours, sample detection, and after completion of the reaction, layering, water layer extracts two with appropriate ether
It is secondary, merge organic phase, molecular sieve is dry, and ether is concentrated under reduced pressure at 0~5 DEG C, obtains product 37.3g, yield 88.2%, content
98.3%.
The synthesis of N- chloro 2- trifluoroacetyl group pivaloyl aniline
In the reactor, under nitrogen protection, N- chloro pivaloyl aniline 21.2g, methyl tertiary butyl ether(MTBE) 258mL is added,
Tetramethylethylenediamine 11.6g, stirring cool to -20 DEG C, and the hexane solution 6.6g of n-BuLi is added dropwise, and temperature control is lower than 5 DEG C, are added dropwise
It finishes, is stirred 2 hours at 0~5 DEG C, then cool to -15 DEG C again, rapidly join Trifluoroacetic Acid Ethyl Ester 15.6g, stir 30 points
Clock, TLC monitoring, end of reaction, control temperature are lower than -10 DEG C, water 50mL are added dropwise, and then use 1mol/L hydrochloric acid tune pH=2.5 again
~3.5, it is layered after being sufficiently stirred, organic layer is washed with water twice, and solvent is concentrated under reduced pressure, obtains N- chloro 2- trifluoroacetyl group pivaloyl
Aniline grease 29.3g, content 98.5%, yield 96.0%.
The synthesis of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4-
N- chloro 2- trifluoroacetyl group pivaloyl aniline 30.8g is added in the reactor, the salt of 52g35% is then added
Acid is sufficiently stirred, and is warming up to 60~65 DEG C of back flow reactions, and TLC monitoring after completion of the reaction, adds acetic acid 210g, the reaction was continued
4 hours, end of reaction cooled to 0 DEG C and stirs 2 hours, filters, and for filter cake with ethanol washing 2 times, solid vacuum at 50 DEG C is dry
It is dry, obtain the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate 26.1g of 4-, content 99.2%, yield 93.8%.
Embodiment 2
The synthesis of antifebrin
Aniline 18.6g is added in the reactor, toluene 150mL is cooled to 0~5 DEG C, adds the hydroxide of 30g30%
Sodium solution controls temperature at 5~15 DEG C, 17g chloroacetic chloride is then added dropwise, and about 15min is added dropwise, stirs at 5~15 DEG C
60min, sample detection are layered after reaction, and organic layer is washed twice, and organic phase is cooled to 0~5 DEG C, keeps the temperature 120min, are taken out
Filter, the appropriate water washing of filter cake are drained, and antifebrin 26.2g, yield 96.8%, content 99.2% are obtained after vacuum drying.
The synthesis of acetochloroanilide
In manufactured antifebrin 27g, sodium bicarbonate 50.4g, ether 1000mL and water 400mL investment reactor, fill
Point stirring makes organic phase and water phase is clarified solution, then cools to 0 DEG C, is slowly added to the calcium hypochlorite 63g now matched and water
800mL water white suspension reacts 3.5 hours, sample detection, and after completion of the reaction, layering is extracted twice with appropriate ether, closes
And organic phase, molecular sieve is dry, and ether is concentrated under reduced pressure at 0~5 DEG C, obtains product 30.5g, yield 90%, content 98.5%.
The synthesis of N- chloro 2- trifluoroacetyl group antifebrin
In the reactor, under nitrogen protection, acetochloroanilide 17g, methyl tertiary butyl ether(MTBE) 258mL, tetramethyl is added
Base ethylenediamine 11.6g, stirring cool to -20 DEG C, and the hexane solution 6.6g of n-BuLi is added dropwise, and temperature control is lower than 5 DEG C, drips
Finish, stirred 2 hours at 0~5 DEG C, then cool to -15 DEG C again, rapidly join Trifluoroacetic Acid Ethyl Ester 15.6g, stirs 30 points
Clock, TLC monitoring, end of reaction, control temperature are lower than -10 DEG C, water 50mL are added dropwise, and then use 1mol/L hydrochloric acid tune pH=2.5 again
~3.5, it is layered after being sufficiently stirred, organic layer is washed with water twice, and solvent is concentrated under reduced pressure, obtains N- chloro 2- trifluoroacetyl group acetophenone
Amine grease 25.2g, content 98.8%, yield 94.8%.
The synthesis of the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4-
N- chloro 2- trifluoroacetyl group antifebrin 26.6g is added in the reactor, the hydrochloric acid of 52g35% is then added,
It is sufficiently stirred, is warming up to 65~70 DEG C of back flow reactions, TLC monitoring after completion of the reaction, adds acetic acid 210g, and it is 4 small that the reaction was continued
When, end of reaction cools to 0 DEG C and stirs 2 hours, filters, with ethanol washing 2 times, solid is dried in vacuo filter cake at 50 DEG C, is obtained
The chloro- 2- trifluoroacetyl aniline hydrochloride hydrate 25.8g of 4-, content 99.3%, yield 92.8%.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this theory
The equivalent structure or the transformation of equivalent process that bright book content is done, are applied directly or indirectly in other correlative technology fields,
It similarly include in scope of patent protection of the invention.
Claims (9)
1. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4-, it is characterised in that: the synthetic method packet
Include following steps,
Acylating agent is added in a, aniline in organic solvent, and makes aniline that acylation reaction occur with 5~15 DEG C under alkaline condition and obtain
To compound A
B reacts compound A with chlorinating agent to obtain compound B under weak basic condition
C, above compound B react under the action of butyl lithium with Trifluoroacetic Acid Ethyl Ester, obtain compound C
D obtains the chloro- 2- trifluoroacetyl aniline hydrochloride hydrate of 4- by compound C and hydrochloric acid in 60~65 DEG C of back flow reactions
Acylating agent used in the step a is chloroacetic chloride, propionyl chloride, valeric chloride or pivaloyl chloride, used in the step a
Alkali is sodium hydroxide；
Chlorinating agent used in the step b be hypochlorous acid, hypochlorous acid receive, postassium hypochlorite or calcium hypochlorite.
2. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 1, special
Sign is: the molar ratio of aniline and sodium hydroxide is 1:1~2；Organic solvent used in the step a is benzene, toluene or first
Base tertbutyl ether.
3. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 1 or 2,
It is characterized by: acylating agent used in the step a is pivaloyl chloride, the molar ratio of aniline and pivaloyl chloride is 1:1~2.
4. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 3, special
Sign is: the molar ratio of the aniline and pivaloyl chloride is 1:1.08.
5. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 2, special
Sign is: organic solvent used in the step a is toluene.
6. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 1, special
Sign is: chlorinating agent used in the step b is calcium hypochlorite.
7. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 1, special
Sign is: compound B in the step c, n-BuLi, Trifluoroacetic Acid Ethyl Ester molar ratio be 1:1~1.3:1~1.3.
8. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 7, special
Sign is: compound B in the step c, n-BuLi, Trifluoroacetic Acid Ethyl Ester molar ratio be 1:1.1:1.1.
9. a kind of synthetic method of the chloro- 2-trifluoroacetyl aniline hydrochloride hydrate of 4- according to claim 1, special
Sign is: hydrochloric acid used in the step d, and concentration is 30%~38%.
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| CN109400495A (en) * | 2018-12-22 | 2019-03-01 | 山东国邦药业股份有限公司 | A kind of preparation method of acetochloroanilide |
| CN110204450B (en) * | 2019-05-24 | 2022-05-03 | 浙江江北药业有限公司 | Synthesis method of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate |
| CN112358413A (en) * | 2020-11-09 | 2021-02-12 | 扬州联博药业有限公司 | Preparation method of N-chloroacetanilide |
| CN113717064B (en) * | 2021-09-30 | 2024-02-23 | 浙江工业大学 | Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone |
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| 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 |
| CN105001101A (en) * | 2015-05-28 | 2015-10-28 | 乐平市瑞盛制药有限公司 | Synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride |
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| US9073817B2 (en) * | 2008-01-31 | 2015-07-07 | Laurus Labs Private Limited | Efficient process to induce enantioselectivity in procarbonyl compounds |
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| 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 |
| CN105001101A (en) * | 2015-05-28 | 2015-10-28 | 乐平市瑞盛制药有限公司 | Synthetic method of 4-chlorine-2-trifluoroacetyl aniline aquo-complex hydrochloride |
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| Practical Asymmetric Synthesis of Efavirenz (DMP 266), an HIV-1 Reverse Transcriptase Inhibitor;Cheng-yi Chen et al.;《J.Org.Chem.》;19981021;8536-8543 |
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