JP3538889B2 - Method for producing alkylthioacetamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to international publication WO92 / 0.
N- (2,6-diisopropylphenyl) -2- useful as an ACAT inhibitor described in US Pat.
The present invention relates to a method for producing (alkylthio) acetamide.

[0002]

2. Description of the Related Art As a method for producing N- (2,6-diisopropylphenyl) -2- (alkylthio) acetamide, the present inventors have described in International Publication WO92 / 09572 and JP-A-6-40898. But
In any of the methods, since a mercaptan which is unstable in the air is used as a raw material, it is not a sufficient method for mass production in a simple and high yield.

[0003] Further, 2,6-diisopropylaniline, which is used as a starting material and is industrially inexpensive and supplied in large quantities, contains a large amount of impurities such as isomers. (2,6-diisopropylphenyl) -2-chloroacetamide, N- (2,6-diisopropylphenyl) -2- (acetylthio) acetamide and the final product N- (2,6-diisopropylphenyl) -2- ( A major problem is that impurities such as isomers are mixed in a large amount into the (alkylthio) acetamide, and it is difficult to remove impurities by a refining operation such as recrystallization which can be performed industrially at low cost and in a large amount. .

[0004]

SUMMARY OF THE INVENTION N- (2,6-diisopropylphenyl) -2- useful as an ACAT inhibitor
An object of the present invention is to produce (alkylthio) acetamide with high purity and industrially at a low cost, in a large amount, in a simple and high yield.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies for solving the above-mentioned problems, and as a result, using 2,6-diisopropylaniline, which is industrially inexpensive and supplied in large quantities, as a starting material, Is treated with an acid to form a salt, and then produced according to the method shown in the following reaction route.
The present inventors have found that (2,6-diisopropylphenyl) -2- (alkylthio) acetamide can be obtained easily and in high yield, and completed the present invention.

[Reaction pathway]

[0007]

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That is, the present invention provides

[0009]

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In the production of N- (2,6-diisopropylphenyl) -2- (alkylthio) acetamide represented by the formula: ## STR1 ## wherein R represents an alkyl group having 1 to 20 carbon atoms. , 6-Diisopropylaniline is treated with an acid to form a salt, purified by a recrystallization method, and then reacted with 2-chloroacetyl chloride in the presence of a base to give N-.
(2,6-diisopropylphenyl) -2-chloroacetamide, which is reacted with thioacetic acid or a salt thereof in the presence or absence of a base to give N-
(2,6-diisopropylphenyl) -2- (acetylthio) acetamide, which is represented by the formula RX in the presence of a base, wherein R is as defined above and X is a halogen atom. Characterized in that it reacts with an alkyl halide represented by the formula (I) in the presence or absence of a reaction accelerator.
This is a method for producing (2,6-diisopropylphenyl) -2- (alkylthio) acetamide.

Hereinafter, the present invention will be described in more detail.

The alkyl group having 1 to 20 carbon atoms of the present invention is a linear or branched alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group. , T-butyl, octyl, decyl, dodecyl, tetradecyl, pentadecyl, eicosanyl and the like.

The base includes, for example, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, organic bases such as triethylamine, diisopropylethylamine and pyridine, sodium methoxide, sodium ethoxide and potassium tert-butoxide. Etc., as well as sodium hydride, potassium hydride, sodium amide and the like.

Acids are, for example, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and hydroiodic acid.

The reaction in the present invention is carried out in an organic solvent, water or a mixture of an organic solvent and water. An organic solvent is
Organic acids such as acetic acid, alcohols such as methanol, ethanol, 2-propanol and t-butyl alcohol; ethers such as dioxane and tetrahydrofuran; N, N
-Dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, acetone, toluene and the like.

The salts of thioacetic acid include, for example, alkali metal salts such as potassium thioacetate and sodium thioacetate.

The reaction accelerator in the present invention is, for example, a phase transfer catalyst such as potassium iodide or tributylbenzylammonium halide.

[0018]

According to the present invention, even when 2,6-diisopropylaniline, which is industrially inexpensive and supplied in large quantities, is used as a starting material, it can be treated with an acid, converted into a salt, and then recrystallized. High purity N- (2,6) which can remove various isomers and is useful as an ACAT inhibitor.
-Diisopropylphenyl) -2- (alkylthio) acetamide compounds can be produced inexpensively, in large quantities, easily and with high yield, and industrial supply has become possible.

[0019]

The present invention will be described more specifically with reference to the following examples.

Example 1 (1) 2,6-diisopropylaniline (4.0 kg)
To a mixture of and 2-propanol (20 L), 95% sulfuric acid (1 kg) was added dropwise. The reaction mixture was heated to 63 ° C. to form a uniform solution, and then gradually cooled with stirring, and the precipitated crystals were collected by filtration. The crystals were washed with 2 L of 2-propanol, and then heated and dissolved again in 20 L of 2-propanol to form a homogeneous solution. After cooling slowly with stirring, the precipitated crystals were collected by filtration, dried and dried to give 2,6-diisopropyl. 3.1 kg of aniline 1/2 sulfate (61% yield) was obtained. Its purity was measured by high performance liquid chromatography to find 99.5%
Met. (Melting point: 173 to 174.5 ° C.) (2) An aqueous sodium hydroxide solution (95% sodium hydroxide solution: 1) was added to a toluene (15 L) suspension of 2,6-diisopropylaniline 1/2 sulfate (3.1 kg). 733k
g, water (4.8 L), chloroacetyl chloride (1.37 L) was added dropwise at about 40 ° C. or less over about 90 minutes, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added aqueous hydrochloric acid (concentrated hydrochloric acid 0.7 L / water 8 L), and then the organic solvent layer and the aqueous layer were separated. The organic solvent layer was washed three times with warm water at 55 to 60 ° C. and distilled off under reduced pressure to obtain a crude product of N- (2,6-diisopropylphenyl) -2-chloroacetamide.

(3) N- (2,6-diisopropylphenyl) -2-chloroacetamide obtained above was dissolved in N, N-dimethylformamide (10 L), and potassium thioacetate (1.77 kg) was added thereto. (The temperature of the reaction mixture was raised from room temperature to about 45 ° C.), and the mixture was stirred for 1 hour.
Water (10 L) was added to the reaction mixture, and the precipitated crystals were collected by filtration, dried and dried with N- (2,6-diisopropylphenyl).
3.96 kg of -2- (acetylthio) acetamide was obtained. (Yield 98%) (4) N- (2,6-diisopropylphenyl) -2-
An aqueous sodium hydroxide solution (1.437 kg of 95% sodium hydroxide / 4 L of water) was added to a suspension of (acetylthio) acetamide (3.96 kg) in 2-propanol (18 L), and the mixture was stirred at room temperature for 20 minutes to form a uniform solution. Obtained. 1-Bromotetradecane (3.74 kg) was added to the reaction solution, and the mixture was heated under reflux for 1 hour, and then 2-propanol contained in the reaction mixture was distilled off under reduced pressure. N-Heptane (18 L) was added to the residue, washed three times with warm water (5 L) at about 60 ° C., allowed to cool under stirring, and the precipitated crystals were collected by filtration. The crystals and the filtrate were concentrated (approximately 7 L), allowed to cool with stirring, collected by filtration, and dissolved together in 2-propanol (17 L) by heating. Water (3 L) was added to this solution with stirring, the mixture was left to cool with stirring, and the precipitated crystals were collected by filtration to obtain 5.01 kg of N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide. Was. Water (5 L) was added to a solution in which the crystals were dissolved again by heating in 2-propanol (20 L), and the mixture was allowed to cool under stirring, and the precipitated crystals were collected by filtration, dried, and dried to give N- (2,6-diisopropylphenyl) -2-. Tetradecylthioacetamide 4.5
7 kg (75.8% yield) were obtained.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Toshiya Noguchi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Masami Goi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (56) References JP-A-6-40898 (JP, A) JP-A-2-157260 ( JP, A) WO 92/009572 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 319/14 C07C 323/52 C07C 209/84 C07C 211/43 C07C 231/02

Claims (1)

(57) [Claims] 1. A compound of the formula (In the formula, R represents an alkyl group having 1 to 20 carbon atoms.) In producing N- (2,6-diisopropylphenyl) -2- (alkylthio) acetamide represented by Diisopropylaniline is treated with an acid to form a salt, purified by a recrystallization method, and then reacted with 2-chloroacetyl chloride in the presence of a base to give N- (2,6).
-Diisopropylphenyl) -2-chloroacetamide, which is reacted with thioacetic acid or a salt thereof in the presence or absence of a base to give N- (2,6-diisopropylphenyl) -2- (acetylthio) acetamide; This is reacted with an alkyl halide represented by the formula RX (wherein R is as defined above and X represents a halogen atom) in the presence of a base in the presence or absence of a reaction accelerator. N-
A method for producing (2,6-diisopropylphenyl) -2- (alkylthio) acetamide.