Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof

A technology of trifluoroacetate and compound, which is applied in the field of chemistry and pharmacy, and can solve the problems of expensive raw materials, many raw materials, and expensive prices

Inactive Publication Date: 2017-03-22
ZHEJIANG TIANYU PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] There are some methods reported in the literature on the synthesis of 2,2,2-trifluoro-(3'-chlorophenyl)ethanone: 1. Grignard reaction between m-chlorobromobenzene or m-chloroiodobenzene and metal magnesium to form a Grignard intermediate , and then react with trifluoroacetylpiperidine, trifluoroacetic acid, trifluoroacetic anhydride, trifluoroacetonitrile, trifluoroacetyl diethylamine to obtain 2,2,2-trifluoro-(3'-chlorophenyl)ethanone (Journal of Medicinal Chemistry, 1966, vol.9, p.176-178; Canadian Journal of Chemistry, 1980, vol.58, p.2497–2503; Journal of Organic Chemistry USSR (English Translation), 1982, vol.18, p.317–324; Zhurnal Organicheskoi Khimii, 1982, vol.18, #2p.365–373; Bulletin of the Chemical Society of Japan, 1990, vol.63, #4 p.1129–1137; Journal of the American Chemical Society, 1980, vol.102, #12p.4167–4172; Bioorganic and Medicinal Chemistry, 2004, vol.12, #5p.979-993), these methods have low yields and expensive raw materials, and can only be used for small-scale reactions in laboratories. in mass production
2. Use m-chlorobenzaldehyde as a raw material to generate 2,2,2-trifluoro-(3'-chlorophenyl)ethanol, and then oxidize to obtain 2,2,2-trifluoro-(3'-chlorophenyl)ethane Ketones (Tetrahedron Letters, 2013, vol.54, #33p.4483–4486; Journal of Fluorine Chemistry, 2012, vol.137, p.99–104), the raw materials of this method are very expensive, and the industrial production of oxidants is not safe
This synthetic method has many raw materials, is expensive, and has a long route, so it is not suitable for industrial production

Method used

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  • Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof
  • Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof
  • Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof

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[0101] In a preferred embodiment of the present invention, the preparation method of 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and its free base comprises steps:

[0102] In the first step, adopt the method provided by the present invention to obtain 2,2,2-trifluoro-(3'-chlorophenyl)ethanone; for example, m-chlorobromobenzene (3-chlorobromobenzene), m-chloroiodine Benzene (3-chloroiodobenzene) or m-dichlorobenzene is dissolved in tetrahydrofuran, methyl tert-butyl tert-butyl ether, petroleum ether and other ether solvents, or dissolved in benzene, toluene, pentane, hexane, heptane and other solvents , or dissolved in a mixed solvent of these solvents, and obtain an intermediate by halogen-metal exchange with butyllithium or isopropylmagnesium chloride lithium chloride at low temperature, and then react with trifluoroacetate or trifluoroacetate metal salt , adding acid (including hydrochloric acid, sulfuric acid, phosphoric acid); preferably hydrochloric acid) a...

Embodiment 1

[0112] Preparation of 2,2,2-trifluoro-(3'-chlorophenyl)ethanone

[0113] Accurately weigh m-chlorobromobenzene (3-chlorobromobenzene) (19.15 g, 0.1 mol) and dissolve it in 100 ml of tetrahydrofuran, cool the solution in an ethanol dry ice bath to minus 78 to minus 50°C, and add butyllithium dropwise solution (0.12mol), after the dropwise addition was completed, it was kept at minus 78 to minus 50°C for 1 hour, and then ethyl trifluoroacetate (18.4 g, 0.13mol) was added dropwise at this temperature, and the cold bath was removed after the dropwise addition was completed. Naturally raised to room temperature, then hydrochloric acid (30ml, 0.3mol) was added dropwise, stirred and separated, and the organic layer was desolvated under reduced pressure to obtain crude product 2,2,2-trifluoro-(3'-chlorophenyl)ethanone 20.7 gram, distilled to obtain 20.3 grams of colorless transparent liquid, content 95%, yield 97.3%

[0114] GC-MS: 208.6. H-NMR: 7.655-7.687(t, 1H); 7.854-7.875(m, 1H...

Embodiment 2

[0116] Preparation of 2,2,2-trifluoro-(3'-chlorophenyl)ethanone

[0117] Accurately weigh m-chloroiodobenzene (3-chloroiodobenzene) (23.85 grams, 0.1mol) and dissolve it in 120 ml of methyl tert-butyl ether, and cool the solution in an ethanol dry ice bath to minus 20 to minus 10°C. Add dropwise isopropylmagnesium chloride solution (0.13mol), after the dropwise addition is completed, keep warm between minus 20 and minus 10°C for 1 hour, then add ethyl trifluoroacetate (18.4 grams, 0.13mol) dropwise at this temperature, dropwise After completion, remove the cold bath and stir to rise to normal temperature naturally, then add hydrochloric acid (30ml, 0.3mol) dropwise, stir and separate layers, and the organic layer is decompressed to remove the solvent to obtain 2,2,2-trifluoro-(3'-chlorobenzene Base) 20.5 grams of ethyl ketone crude product, distill to obtain 18.3 grams of colorless transparent liquid, content 95.9.7%, yield 88%

[0118] GC-MS: 208.6. H-NMR: 7.655-7.687(t, 1H...

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Abstract

The invention discloses a method for preparing a 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof. The method comprises the steps: (1) subjecting an intermediate, which is obtained through subjecting a compound with a structure represented by a formula IV shown in the description to a reaction, to a reaction with trifluoroacetate or a compound with a structure represented by a formula V or a formula VI shown in the description, and then, carrying out acid treatment, so as to obtain a compound with a structure represented by a formula I shown in the description; (2) subjecting the compound with the structure represented by the formula I to a nitration reaction under the catalysis of an acid, so as to obtain a compound with a structure represented by a formula II shown in the description; and (3) subjecting the compound with the structure represented by the formula II to nitro-to-amino reduction, thereby obtaining a compound with a structure represented by a formula III shown in the description.

Description

technical field [0001] The invention relates to the fields of chemistry and pharmacy, in particular to a preparation process of 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and its free base. Background technique [0002] 4-Chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and its free base are important intermediates of the antiviral drug efavirenz. Now there are some processes and preparation methods. The most important process method is p-chloroaniline and Pivaloyl chloride reaction, the obtained intermediate reacts with butyllithium and then reacts with ethyl trifluoroacetate, and then removes pivaloyl under acidic conditions to form a salt to obtain 4-chloro-2-(trifluoroacetyl) Aniline hydrochloride hydrate, or add alkali to obtain its free base. [0003] There are some methods reported in the literature on the synthesis of 2,2,2-trifluoro-(3'-chlorophenyl)ethanone: 1. Grignard reaction between m-chlorobromobenzene or m-chloroiodobenzene and metal ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/46C07C49/80C07F3/02C07C201/08C07C205/45C07C221/00C07C225/22
CPCC07C45/46C07C201/08C07C221/00C07F3/02C07C49/80C07C205/45C07C225/22
Inventor 屠勇军陈克喜
Owner ZHEJIANG TIANYU PHARMA
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