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Synthetic method of efavirenz intermediate namely 1-(2-amino-5-chlorphenyl)-2, 2, 2-trifluoroethanone

A technology of efavirenz and trifluoroethyl ketone, which is applied in the field of synthesis of pharmaceutical and chemical intermediates, can solve the problems of isopropylmagnesium bromide being expensive, not meeting the requirements of green chemistry, and difficult reaction conditions, so as to reduce the generation of three wastes Quantity, short steps, and the effect of shortening the reaction steps

Pending Publication Date: 2021-11-30
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This route has three steps in total. The price of isopropylmagnesium bromide and equivalent butyllithium used in the Grignard exchange reaction is relatively expensive, and the corresponding harsh reaction conditions are difficult to industrialize. Compliant with Green Chemistry Requirements

Method used

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  • Synthetic method of efavirenz intermediate namely 1-(2-amino-5-chlorphenyl)-2, 2, 2-trifluoroethanone
  • Synthetic method of efavirenz intermediate namely 1-(2-amino-5-chlorphenyl)-2, 2, 2-trifluoroethanone
  • Synthetic method of efavirenz intermediate namely 1-(2-amino-5-chlorphenyl)-2, 2, 2-trifluoroethanone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of 1-(2-nitrophenyl)-2,2,2-trifluoroethanone (IV)

[0040] Take a 500mL four-necked bottle equipped with a condenser, a mechanical stirrer, a dropping funnel, and a thermometer, add 7.6g (320mmol) of magnesium chips, 1.79g of initiator bromobenzene (11mmol), and 52mL of tetrahydrofuran. Bromobenzene (40.8g, 260mmol diluted with 180mL tetrahydrofuran) was added dropwise under reflux state, and the dropwise addition time was 1-2h, and the reflux reaction was continued for 4h after dropping to obtain phenylmagnesium bromide Grignard reagent. The preparation method of the invented phenylmagnesium chloride Grignard reagent is the same as that of the above phenylmagnesium bromide Grignard reagent; after the reaction system is cooled to -20°C, o-iodonitrobenzene (200mmol, 49.8g) is dissolved in 40mL of tetrahydrofuran solution and added dropwise During the dropwise addition, the temperature should not exceed -10°C. After the dropwise reaction was complet...

Embodiment 2

[0043] Example 2: Preparation of 1-(2-aminophenyl)-2,2,2-trifluoroethanone (V)

[0044] Take 500mL autoclave, add 1-(2-nitrophenyl)-2,2,2-trifluoroethanone (100mmol, 21.9g), 95% ethanol (140mL), Raney Ni catalyst (1.3g) successively , feed hydrogen, pressure to 0.6-0.7MPa, heat up to 50-60°C and keep stirring, wait until the reaction is complete, filter and recover the catalyst, concentrate the organic phase under reduced pressure to recover ethanol to dryness, and recrystallize the residue with n-octanol (60mL) Compound (V) was obtained as a dark yellow solid (17.4 g, yield 92%) with a melting point of 51-52°C.

[0045] Spectrum characterization of compound (Ⅳ):

[0046] 1 H NMR (400MHz, CDCl 3 )δ=7.75(d, J=8.4Hz, 1H), 7.38(t, J=7.8Hz, 1H), 6.71(dd, J=13.8, 8.2Hz, 2H), 6.41(s, 2H). 13 C NMR (100MHz, CDCl 3 )δ=180.8(q, J C-F =30Hz), 153.1, 136.6, 131.3, 117.4, 117.0 (q, J C-F =289Hz), 116.3, 111.0, 77.3, 77.0, 76.7.

Embodiment 3

[0047] Example 3: Preparation of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (I)

[0048] Take a 500mL two-necked round bottom reaction flask, add 1-(2-aminophenyl)-2,2,2-trifluoroethanone (100mmol, 19.2g), N-chlorosuccinimide (15.8g, 120mmol ), chloroform 150mL, catalyst dimethyl sulfoxide (0.71g, 10mmol), stirring at room temperature, until the reaction was complete, concentrated under reduced pressure to recover the solvent, and the residue was recrystallized from n-hexane (80mL) to obtain compound (I) ( 19.3 g, yield 86%), the product is a bright yellow solid with a melting point of 90-91°C and a purity of 98.5% as measured by HPLC (the mobile phase is acetonitrile:water=70:30, V / V).

[0049] Spectrum characterization of compound (I):

[0050] 1 H NMR (400MHz, DMSO-d 6 )δ=7.86(s,2H),7.45(d,J=2.8Hz,2H),6.98(d,J=8.4Hz,1H). 19 F NMR (376MHz, DMSO-d 6 )δ=-68.90,-83.12. 13 C NMR (100MHz, DMSO-d 6 )δ=178.2(q, J C-F =30Hz), 153.7, 137.2, 128.6, 120.7, 118.6, 117.2 ...

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Abstract

The invention discloses a synthesis method of an efavirenz intermediate, namely 1-(2-amino-5-chlorphenyl)-2, 2, 2-trifluoroethanone. The method comprises the following steps: taking o-halogen nitrobenzene as an initial raw material, firstly reacting with a trifluoroacetyl compound to obtain an intermediate compound, then performing catalytic reduction on the intermediate compound by Raney nickel under the action of hydrogen to obtain a reduced compound, and finally, reacting the reduced compound with N-chlorosuccinimide under the catalytic action of a catalyst (dimethyl sulfoxide) to prepare the target product 1-(2-amino-5-chlorphenyl)-2, 2, 2-trifluoroethanone. The method has the characteristics of short steps, simple process, simplicity and convenience in operation, mild aniline chlorination reaction conditions, high total yield and the like, so that the method has relatively high implementation value and social and economic benefits.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical and chemical intermediates, in particular to a preparation of the key intermediate 1-(2-amino-5-chlor The method of phenyl)-2,2,2-trifluoroethanone (I). Background technique [0002] Efavirenz was originally a non-nucleoside reverse transcriptase inhibitor developed by Merck in the United States, and it was first launched in the United States in February 1992. It is clinically used as one of the important drugs for AIDS treatment and has a half-life. Long-term, good tolerance, high selectivity, good therapeutic effect, small adverse reactions and other characteristics. At present, it has become the first-line drug for the treatment of AIDS in my country, and the prospect is bright. Therefore, the study on the synthesis method of its key intermediate 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (I) not only has theoretical research value, but also has certain economic be...

Claims

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Application Information

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IPC IPC(8): C07C221/00C07C225/22C07C201/12C07C205/45
CPCC07C221/00C07C201/12C07C205/45C07C225/22
Inventor 陈志卫唐伟袁其亮陈寅镐王超
Owner ZHEJIANG UNIV OF TECH
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