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Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof

A technique for the synthesis of trifluoroacetylaniline and its synthesis method, which is applied in the field of key intermediates for the synthesis of the HIV reverse transcriptase inhibitor efavirenz, and can solve the problems of unfavorable large-scale industrial production, high requirements for equipment, and low synthesis efficiency. Achieve the effects of simple operation, low yield and mild reaction conditions

Active Publication Date: 2015-02-18
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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Problems solved by technology

[0010] In addition, Jeffrey W. Corbett et al. (J.Med.Chem., 2000, 43, 2019-2030), Andrew S. Thompson et al. (Tetrahedron Letters, 1995, 36, 8937-8940), and Mona Patel et al. ( Bioorganic Medicinal Chemistry letters, 1999,9,2805-2810) and European patent 582455A1 also all apply similar method to prepare 4-chloro-2-trifluoroacetylaniline or its analogue, not only still there is above-mentioned defective, and Synthetic efficiency is often very low
[0011] In summary, the above methods of synthesizing 4-chloro-2-trifluoroacetylaniline (formula I) or its analogues all use a large amount of dangerous reagents, such as strong base n-butyllithium or tert-butyllithium and strong acid , and requires low temperature and anhydrous and oxygen-free reaction, cumbersome operation and high requirements for equipment, which is not conducive to large-scale industrial production. Therefore, it is urgent to seek new 4-chloro-2-trifluoroacetyl that can adapt to large-scale industrial production The synthetic technique of base aniline, such synthetic technique can not only avoid or improve above-mentioned restrictive condition, but also can efficiently provide required 4-chloro-2-trifluoroacetylaniline

Method used

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  • Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof
  • Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof
  • Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0063] Example 1 Preparation of 3-hydroxy-3-trifluoromethylindol-2-one:

[0064] Aniline (1.4g, 15mmol) was dissolved in benzene (20mL), and methyl trifluoropyruvate (23.4g, 150mmol) was added dropwise. After the dropwise addition, the temperature was raised to about 130°C in an oil bath. After the reaction was carried out for 18 hours, the oil bath was removed, and it was naturally cooled to room temperature. A large amount of white solids were seen to precipitate out. The white solids were filtered off, then washed with petroleum ether, and dried to obtain the product (2.6 g, yield 78%), which did not require further purification The next reaction can be carried out.

[0065] 1 HNMR (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).

[0066] HRMS. Calculated value C 9 h 6 f 3 NO 2 : 217.0351. Measured value: 217.0353.

Embodiment 25

[0067] Example 2 Preparation of 5-chloro-3-hydroxy-3-trifluoromethylindol-2-one:

[0068] 3-Hydroxy-3-trifluoromethylindol-2-one (3.3g, 15.2mmol) and NCS (2.5g, 18.7mmol) were dissolved in DMF (50mL), and zirconium tetrachloride (180mg, 5% eq) As a catalyst, the temperature of the oil bath was raised to 50° C., and the reaction was completed after 48 hours. After the reaction was complete, ethyl acetate was added for extraction, washed with saturated sodium bicarbonate, washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product could be recrystallized from toluene / ethanol (20:1) to obtain the product (3.7 g, yield 98%).

[0069] 1 H 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);

[0070] 19 F NMR (acetone-d6) δ79.99;

[0071] MS (GC) m / z 251 (M + ).

Embodiment 34

[0072] Example 3 Preparation of 4-chloro-2-trifluoroacetylaniline:

[0073] At room temperature, 5-chloro-3-hydroxy-3-trifluoromethylindol-2-one (251mg, 1mmol) was dissolved in acetonitrile (10mL), water (3mL) was added, and KOH (280mg, 5mmol ), after fully dissolved, add K at one time 3 [Fe(CN) 6 ] (990mg, 3mmol), after the reaction of the raw materials was complete, ethyl acetate was added for extraction, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the product (211.9mg, yield 95%).

[0074] 1 H 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);

[0075] MS (ESI) m / z 222 (M-H);

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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: [0001] The present invention relates to a new simple and efficient synthetic method of 4-chloro-2-trifluoroacetylaniline (formula I) and analogues thereof, wherein 4-chloro-2-trifluoroacetylaniline can be used as synthetic HIV reverse transcriptase The key intermediate of the inhibitor efavirenz (formula II). Taking 4-chloro-2-trifluoroacetylaniline as an example, this method mainly generates 3-hydroxy-3-trifluoromethylindole- 2-ketone, and then selectively chlorinated with N-chlorosuccinimide to obtain 5-chloro-3-hydroxy-3-trifluoromethylindol-2-one, and finally oxidized under alkaline conditions 4-Chloro-2-trifluoroacetylaniline was obtained in high yield. Background technique: [0002] Reverse transcription is unique to retroviral replication. Viral replication requires the reverse transcription of the viral RNA genome by a virally encoded reverse transcriptase to produce a DNA copy of the viral sequence. Since inhibition of virally encoded reverse tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/52C07C211/45C07C209/62C07D265/18
Inventor 姜标张琛董佳家曹星欣陈华
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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