CN102675125A - Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof - Google Patents
Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof Download PDFInfo
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Abstract
The invention relates to a simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof. The 4-chloro-2-trifluoroacetylaniline can be used as a key midbody for synthesizing the anti-AIDS (Acquired Immune Deficiency Syndrome) drug efavirenz.
Description
Technical field:
The present invention relates to the compound method of the new simple and effective of 4-chloro-2-trifluoroacetyl aniline (formula I) and analogue thereof, wherein 4-chloro-2-trifluoroacetyl aniline can be used as the key intermediate of synthetic hiv reverse transcriptase inhibitor efavirenz (formula II).With 4-chloro-2-trifluoroacetyl aniline is example; This method mainly generates 3-hydroxyl-3-trifluoro methyl indole-2-ketone through the methyl esters or the efficient cyclization of ethyl ester of cheap aniline and trifluoropropyl ketone acid; Obtain 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone with N-chlorosuccinimide reaction preference chloro again, last under alkaline condition the high yield of oxidation open loop obtain 4-chloro-2-trifluoroacetyl aniline.
Background technology:
It is peculiar that reverse transcription is that retrovirus duplicates.Virus replication requires the reversed transcriptive enzyme of encoding viral to produce the DNA copy of virus sequence through the genomic reverse transcription of viral RNA.Because the inhibition to the reversed transcriptive enzyme of encoding viral can be interrupted virus replication, therefore, for the chemotherapy of retroviral infection, reversed transcriptive enzyme is a clinical relevant target spot.
Chemical compound lot is effectively in treatment HIV (HIV), and this virus can cause human immunity system carrying out property destruction and cause the retrovirus of AIDS morbidity.To suppressor factor based on nucleosides; Zidovodine and for example based on the suppressor factor of non-nucleosides; Suppressor factor through to hiv reverse transcriptase is the known valid treat-ment, has been found that at present the benzoxazine ketone is the useful hiv reverse transcriptase inhibitor based on non-nucleosides.In addition; HIV (HIV) is prone to sudden change; This can cause resistance, and the Efavirenz, DPC961 and the DPC083 that are researched and developed by E.I.Du Pont Company have highly active HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs), but because it is easy to produce resistance; The important medical of also considering simultaneously the RTI compounds is worth and social effect, is badly in need of economy and asymmetric synthesis technology efficiently that exploitation is used to prepare Efavirenz (formula II).
Formula (I)
Formula (II)
People (J.Org.Chem., 1998,63 such as Michael E.Pierce; 8536-8543) described the compound method of a kind of 4-chloro-2-trifluoroacetyl aniline (formula I), be shown in the following figure, it is to protect earlier through p-Chlorobenzoic acid amide; (20 ℃) take out behind the proton and the Trifluoroacetic Acid Ethyl Ester reaction with n-Butyl Lithium more at low temperatures, introduce trifluoroacetyl group, obtain 4-chloro-2-trifluoroacetyl aniline after removing the protection base under the strong acidic condition; Generally to experience four-step reaction, wherein use normal highly basic n-Butyl Lithium and strong acid, and require low temperature and anhydrous and oxygen-free reaction; Complex operation and high to the requirement of equipment is unfavorable for large-scale commercial prodn.
In addition, people (J.Med.Chem., 2000 such as Jeffrey W.Corbett; 43,2019-2030), people (Tetrahedron Letters such as Andrew S.Thompson; 1995,36,8937-8940); With people (Bioorganic Medicinal Chemistry letters, 1999,9 such as Mona Patel; 2805-2810) and European patent 582455A1 also all used similar methods and prepared 4-chloro-2-trifluoroacetyl aniline or its analogue, not only still have above-mentioned defective, and combined coefficient is often very low.
In sum; The method of more than synthetic 4-chloro-2-trifluoroacetyl aniline (formula I) or its analogue has all been used the reagent of a large amount of danger, like highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, and requires low temperature and anhydrous and oxygen-free reaction; Complex operation and high to the requirement of equipment; Be unfavorable for large-scale commercial prodn, therefore, be badly in need of seeking the synthesis technique of the new 4-chloro-2-trifluoroacetyl aniline that can adapt to large-scale industrialized production; Above-mentioned restricted condition can not only avoided or improve to such synthesis technique, and required 4-chloro-2-trifluoroacetyl aniline can also be provided efficiently.
For this reason; The invention provides a kind of new synthetic 4-chloro-2-trifluoroacetyl aniline (formula I) and the technology of analogue thereof, wherein 4-chloro-2-trifluoroacetyl aniline can be used as the key intermediate of the RTI efavirenz of synthetic human immunodeficiency virus (HIV).This method mild condition, easy and simple to handle, reaction yield is high and avoided the dangerous reagent of a large amount of uses, like highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, helps large-scale commercial prodn.
There is not one piece to describe this method of the present invention in the above citing document in order to synthetic key intermediate 4-chloro-2-trifluoroacetyl aniline as the hiv reverse transcriptase inhibitor efavirenz.
Summary of the invention
The invention provides the method for the new simple and effective of a kind of synthetic 4-chloro-2-trifluoroacetyl aniline (formula I) and analogue (formula III) thereof, wherein 4-chloro-2-trifluoroacetyl aniline can be used as the key intermediate of synthetic hiv reverse transcriptase inhibitor efavirenz (formula II).With 4-chloro-2-trifluoroacetyl aniline is example; This method mainly generates 3-hydroxyl-3-trifluoro methyl indole-2-ketone through the methyl esters or the efficient cyclization of ethyl ester of cheap aniline and trifluoropropyl ketone acid; Obtain 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone with N-chlorosuccinimide reaction preference chloro again; Last under alkaline condition the high yield of oxidation open loop obtain 4-chloro-2-trifluoroacetyl aniline; Reaction conditions is gentle, easy and simple to handle, yield is high and avoided the dangerous reagent of a large amount of uses, like highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, helps large-scale commercial prodn.
Formula (III)
Y is hydrogen, F, Cl or Br in the formula;
When Y was Cl, formula (III) compound was exactly a 4-chloro-2-trifluoroacetyl aniline (formula I);
The compound method of 4-chloro-2-trifluoroacetyl aniline provided by the invention (formula I) and analogue thereof specifically describes as follows:
With aniline is raw material (formula IV), and refluxing in organic solvent with trifluoropropyl ketone acid methyl esters or ethyl ester (formula V) obtains 3-hydroxyl-3-trifluoro methyl indole-2-ketone (formula VI);
The compound of formula (IV), formula V and formula (VI) has following structural formula:
Formula (IV),
Formula V,
R wherein
1Be methyl or ethyl;
Formula (VI),
Y in the formula
1Be hydrogen, F, Cl or Br;
Work as Y
1During for hydrogen, the compound of formula VI is 3-hydroxyl-3-trifluoro methyl indole-2-ketone of following formula VII:
Formula (VII).
The preferred reaction conditions of this step is:
The methyl esters of aniline described in the above-mentioned steps and trifluoropropyl ketone acid or the mol ratio of ethyl ester are 1: (1-10); Being recommended as the methyl esters of aniline and trifluoropropyl ketone acid or the mol ratio of ethyl ester is 1: (1-5);
The temperature of reacting described in the above-mentioned steps is between 100-200 ℃; Be recommended as between 100-150 ℃;
The time of reacting described in the above-mentioned steps is 10-20 hour;
Preferred organic is benzene, toluene, chlorobenzene, 1 in the above-mentioned steps, 2-dichlorobenzene, 1,4-dioxane; Further be preferably toluene, chlorobenzene or 1, the 2-dichlorobenzene.
Work as Y
1During for hydrogen, the compound of formula VI is 3-hydroxyl-3-trifluoro methyl indole-2-ketone of formula VII.Under 0-120 ℃, in organic solvent, the 3-of formula VII hydroxyl-3-trifluoro methyl indole-2-ketone and halide reagent reaction add zirconium tetrachloride catalysis, obtain formula (VIII) compound;
Formula (VIII)
Y wherein
2Be Cl or Br;
Halide reagent is NCS (N-chlorosuccinimide) or NBS (N-bromo-succinimide) in the above-mentioned steps;
The preferred reaction conditions of this step is:
The molar ratio of above-mentioned steps Chinese style (VI) compound and NCS or NBS is 1: (1-3);
The mol ratio of formula VI compound and zirconium tetrachloride is 1: (0.02-0.2);
The temperature of reacting described in the above-mentioned steps between 0-120 ℃, preferred 40-80 ℃;
The time of reacting described in the above-mentioned steps is 24-72 hour;
Used organic solvent is preferably THF, methyltetrahydrofuran, 1 in this step; 4-dioxane, t-butyl methyl ether, diethylene glycol dimethyl ether, acetonitrile, ETHYLE ACETATE, n-butyl acetate, N; Dinethylformamide or DMAC N,N; Further be preferably THF, 1,4-dioxane, N, dinethylformamide, t-butyl methyl ether or acetonitrile.
In the mixed solvent of organic solvent and water, formula (VI) or formula (VIII) compound are under alkaline condition, and the adding oxidizer oxygen melts ring and obtains formula (III) compound;
The preferred reaction conditions of this step is:
Used alkali is LiOH, NaOH or KOH in the above-mentioned steps; Be recommended as KOH;
Used oxygenant is K in the above-mentioned steps
3[Fe (CN)
6], peroxy tert-butyl alcohol or H
2O
2Be recommended as K
3[Fe (CN)
6];
Used organic solvent is preferably THF, methyltetrahydrofuran, 1 in the above-mentioned steps; 4-dioxane, t-butyl methyl ether, diethylene glycol dimethyl ether, acetonitrile, ETHYLE ACETATE, n-butyl acetate, N; Dinethylformamide or DMAC N,N; Further be preferably THF, 1,4-dioxane, N, dinethylformamide, t-butyl methyl ether or acetonitrile;
The volume ratio of organic solvent and water is (1-5) in the above-mentioned steps: 1;
The molar ratio of above-mentioned steps Chinese style (VI) or formula (VIII) compound and alkali and oxygenant is 1: (1-10): (1-6); Be recommended as 1: (1-5): (1-3);
The temperature of reacting described in the above-mentioned steps is between 0-100 ℃;
The time of reacting described in the above-mentioned steps is 0.5-24 hour.
Method of the present invention also can represent that route is synthetic with following typical reaction formula:
Y can be Y in the formula
1Or Y
2Wherein Y, Y
1, Y
2Or R
1Definition as previously mentioned.
The invention provides the method for the new simple and effective of a kind of synthetic 4-chloro-2-trifluoroacetyl aniline (formula I) and analogue (formula III) thereof, wherein 4-chloro-2-trifluoroacetyl aniline can be used as the key intermediate of synthetic hiv reverse transcriptase inhibitor efavirenz (formula II).This method mainly generates 3-hydroxyl-3-trifluoro methyl indole-2-ketone through the methyl esters or the efficient cyclization of ethyl ester of cheap aniline and trifluoropropyl ketone acid; Obtain 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone with N-chlorosuccinimide reaction preference chloro again; Last under alkaline condition the high yield of oxidation open loop obtain 4-chloro-2-trifluoroacetyl aniline; Reaction conditions is gentle, easy and simple to handle, yield is high and avoided the dangerous reagent of a large amount of uses; Like highly basic n-Butyl Lithium or tert-butyl lithium and strong acid, help large-scale commercial prodn.
Embodiment
Following examples help to understand this patent but are not limited thereto scope.
The preparation of embodiment 1
3-hydroxyl-3-trifluoro methyl indole-2-ketone:
(1.4g 15mmol) is dissolved in the benzene (20mL) aniline, and (23.4g 150mmol), after dropwising, is warming up to about 130 ℃ of oil bath to drip trifluoropropyl ketone acid methyl esters.After reaction is carried out 18 hours, remove oil bath, naturally cool to room temperature, visible a large amount of white solids are separated out, and leach white solid, petroleum ether then, drying, product (2.6g, yield 78%), need not be further purified and can carry out next step reaction.
1HNMR(Acetone-d
6，400MHz)δ6.51(s，1H)，7.03(d，J＝5.7Hz，1H)，7.13(t，J＝11.4Hz，5.7Hz，1H)，7.42(t，J＝11.4Hz，5.7Hz，1H)，7.52(d，J＝5.7Hz，1H)，9.76(s，1H).
HRMS. calculated value C
9H
6F
3NO
2: 217.0351. measured value: 217.0353.
The preparation of embodiment 2
5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone:
(3.3g, 15.2mmol) (2.5g 18.7mmol) is dissolved among the DMF (50mL) 3-hydroxyl-3-trifluoro methyl indole-2-ketone, and (180mg, 5%eq) as catalyzer, oil bath is warming up to 50 ℃, reacts after 48 hours and finishes to add zirconium tetrachloride with NCS.Question response fully after, add ethyl acetate extraction, saturated sodium bicarbonate washing, water successively again, saturated common salt washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, bullion can be used toluene/ethanol (20: 1) recrystallization, obtains product (3.7g, yield 98%).
1H?NMR(500MHz，acetone-d
6)δ6.77(s，1H)，7.08(d，1H，J＝8.0Hz)，7.47(dd，1H，J＝1.5Hz，J＝8.5Hz)，9.96(s，1H)；
19F?NMR(acetone-d6)δ79.99；
MS(GC)m/z?251(M
+).
The preparation of embodiment 3
4-chloro-2-trifluoroacetyl aniline:
Under the room temperature, get 5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone (251mg 1mmol) is dissolved in the acetonitrile (10mL), adds entry (3mL), add again KOH (280mg, 5mmol), after the dissolving fully, disposable adding K
3[Fe (CN)
6] (990mg 3mmol), treats that raw material reaction is complete, adds ethyl acetate extraction, the organic phase water, and the saturated common salt washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, obtains product (211.9mg, yield 95%).
1H?NMR(300MHz，CDCl
3)δ6.46(brs，2H)，6.70(d，1H，J＝9.0Hz)，7.32(dd，1H，J＝2.1Hz，9.0Hz)，7.71(d，1H，J＝2.1Hz)；
MS(ESI)m/z?222(M-H)；
The preparation of embodiment 4
5-bromo-3-hydroxyl-3-trifluoro methyl indole-2-ketone:
(4.5g, 20.7mmol) (2.5g 18.7mmol) is dissolved in 1 to 3-hydroxyl-3-trifluoro methyl indole-2-ketone, in the 2-ethylene dichloride (60mL), adds zirconium tetrachloride (180mg) as catalyzer, and the operation with reference to embodiment 2 obtains product then, yield 96% with NBS.
1H?NMR(500MHz，acetone-d
6)δ6.75(s，1H)，7.02(d，1H，J＝8.5Hz)，7.59-7.62(m，2H)，9.95(s，1H)；
MS(GC)m/z?295(M
+).
The preparation of embodiment 5
4-bromo-2-trifluoroacetyl aniline:
(295mg 1mmol) is dissolved in 1, in the 4-dioxane (15mL) to get 5-bromo-3-hydroxyl-3-trifluoro methyl indole-2-ketone; Add entry (3mL), add again KOH (560mg, 10mmol); After the dissolving fully, disposable adding peroxy tert-butyl alcohol (540.7mg, 6mmol; 70%), the operation with reference to embodiment 3 obtains product then, yield 93%.
1HNMR(CDCl
3，300MHz)δ6.49(brs，2H)，6.64(d，J＝9.0Hz，1H)，7.42(d，J＝9.0Hz，1H)，7.82(s，1H).
19FNMR(CDCl
3，300MHz)δ70.13
The preparation of embodiment 6
2-trifluoroacetyl aniline:
(217mg 1mmol) is dissolved in the THF (12mL), adds entry (6mL) to get 3-hydroxyl-3-trifluoro methyl indole-2-ketone; Add again KOH (224mg, 10mmol), after the dissolving fully; Disposable adding hydrogen peroxide (204mg, 6mmol, 30%); Operation with reference to embodiment 3 obtains product then, yield 90%.
1H?NMR(300MHz，CDCl
3)δ6.24(brs，2H)，6.67(d，1H，J＝1.2Hz)，6.73(dd，1H，J＝1.8Hz，3.9Hz)，7.38(dd，1H，J＝1.2Hz，J
1/
43.9Hz)，6.67(d，1H，J＝1.8Hz)；MS(ESI)：188(M-H)；
The preparation of embodiment 7
4-fluoro-2-trifluoroacetyl aniline:
Under the room temperature, get 5-fluoro-3-hydroxyl-3-trifluoro methyl indole-2-ketone (235mg 1mmol) is dissolved in N, in the dinethylformamide (10mL), adds entry (3mL), add again NaOH (400mg, 10mmol), after the dissolving fully, disposable adding K
3[Fe (CN)
6] (990mg 3mmol), treats that raw material reaction is complete, adds ethyl acetate extraction, the organic phase water, and the saturated common salt washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, obtains product (196.7mg, yield 95%).
1H?NMR(300MHz，CDCl
3)δ
1H?NMR(300MHz，CDCl
3)δ7.43(d，J＝9.6Hz，1H)，7.19(m，1H)，6.71(dd，J＝9.2，4.5Hz，1H)，6.36(s，2H).
The preparation of embodiment 8
5-chloro-3-hydroxyl-3-trifluoro methyl indole-2-ketone:
(3.8g, 30mmol) (51.3g 300mmol), after dropwising, is warming up to about 150 ℃ of oil bath to middle dropping trifluoroacetone acetoacetic ester to p-Chlorobenzoic acid amide.After reaction is carried out 15 hours, remove oil bath, naturally cool to room temperature, visible a large amount of white solids are separated out, and leach white solid, petroleum ether then, drying, product (4.9g, yield 75%), need not be further purified and can carry out next step reaction.
The preparation of embodiment 9
3-hydroxyl-3-trifluoro methyl indole-2-ketone:
(2.1g 23mmol) is dissolved in 1 to aniline, and in the 2-dichlorobenzene (25mL), (19.6g 115mmol), after dropwising, is warming up to about 200 ℃ of oil bath to drip the trifluoroacetone acetoacetic ester.After reaction is carried out 10 hours, remove oil bath, naturally cool to room temperature, visible a large amount of white solids are separated out, and leach white solid, petroleum ether then, drying, product (4.0g, yield 82%), need not be further purified and can carry out next step reaction.
1HNMR(Acetone-d
6，400MHz)δ6.51(s，1H)，7.03(d，J＝5.7Hz，1H)，7.13(t，J＝11.4Hz，5.7Hz，1H)，7.42(t，J＝11.4Hz，5.7Hz，1H)，7.52(d，J＝5.7Hz，1H)，9.76(s，1H).
HRMS. calculated value C
9H
6F
3NO
2: 217.0351. measured value: 217.0353.
Claims (7)
1. the compound method of 4-chloro-2-trifluoroacetyl aniline and analogue thereof, the general structure of described 4-chloro-2-trifluoroacetyl aniline and analogue thereof is as follows:
Formula (III),
Y is hydrogen, F, Cl or Br in the formula;
It is characterized in that through following step (c), step (a) and (c), four kinds of steps of step (b)-(c) or step (a)-(c) obtain:
(a) aniline with formula IV is raw material, with the trifluoropropyl ketone acid methyl esters of formula V or ethyl ester in organic solvent or without organic solvent, obtained 3-hydroxyl-3-trifluoro methyl indole-2-ketone of formula VI in backflow 10-20 hour; The methyl esters of aniline and trifluoropropyl ketone acid or the mol ratio of ethyl ester are 1: (1-10);
Wherein said Y
1Be hydrogen, F, Cl or Br, R
1Be methyl or ethyl;
(b) work as Y
1During for hydrogen, the compound of formula VI is 3-hydroxyl-3-trifluoro methyl indole-2-ketone of formula VII; Under 0-120 ℃; In organic solvent, the 3-of formula VII hydroxyl-3-trifluoro methyl indole-2-ketone and halide reagent reaction add zirconium tetrachloride catalysis; Reaction obtained the compound of formula VIII in 24-72 hour, and said halide reagent is N-chlorosuccinimide or N-bromo-succinimide; The mol ratio of described formula VI compound and halide reagent is 1: (1-3); The mol ratio of described formula VI compound and zirconium tetrachloride is 1: (0.02-0.2);
Y wherein
2Be Cl or Br;
(c) in the mixed solvent of organic solvent and water and under 0-100 ℃, formula VI or formula VIII compound add the oxygenant oxidative cleavage and obtained the formula III compound in 0.5-24 hour under alkaline condition;
The mol ratio of described formula VI or formula VII compound and alkali and oxygenant is 1: (1-10): (1-6)
Wherein said alkali is LiOH, NaOH or KOH;
Described oxygenant is K
3[Fe (CN)
6], peroxy tert-butyl alcohol or H
2O
2
2. the method for claim 1 is characterized in that described Y and Y
2Be Cl, Y
1Be H, said halide reagent is the N-chlorosuccinimide, and the formula III compound is a 4-chloro-2-trifluoroacetyl aniline, and structure is:
3. the method for claim 1 is characterized in that organic solvent is benzene, toluene, chlorobenzene, 1 in the said step (a), 2-dichlorobenzene or 1,4-dioxane; Said step (b) and organic solvent (c) are THF, methyltetrahydrofuran, 1; 4-dioxane, t-butyl methyl ether, diethylene glycol dimethyl ether, acetonitrile, ETHYLE ACETATE, n-butyl acetate, N; Dinethylformamide or DMAC N,N.
4. method as claimed in claim 3 is characterized in that organic solvent is toluene, chlorobenzene or 1 in the said step (a), the 2-dichlorobenzene; Said step (b) and organic solvent (c) are THF, 1,4-dioxane, N, dinethylformamide, t-butyl methyl ether or acetonitrile.
5. the method for claim 1 is characterized in that the methyl esters of aniline described in the step (a) and trifluoropropyl ketone acid or the mol ratio of ethyl ester are 1: (1-5); The ratio of the formula VI of said step (c) or formula VII compound and alkali and oxygenant is 1: (1-5): (1-3).
6. the method for claim 1 is characterized in that the organic solvent of said step (c) and the volume ratio of water are (1-5): 1.
7. the method for claim 1 is characterized in that the alkali described in the step (c) is KOH; Described oxygenant is K
3[Fe (CN)
6].
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Cited By (4)
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| CN105777610A (en) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate |
| CN106946731A (en) * | 2017-03-14 | 2017-07-14 | 丽水学院 | A kind of synthetic method of trifluoroacetyl aniline derivative |
| CN108997150A (en) * | 2018-08-31 | 2018-12-14 | 江苏沙星化工有限公司 | A kind of preparation method of efavirenz intermediate |
| WO2024133619A1 (en) | 2022-12-23 | 2024-06-27 | Boehringer Ingelheim International Gmbh | New process for the manufacture of mdm2-p53 antagonists |
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