JP2894804B2 - 2-Amino-5-methylbenzophenones and their production - Google Patents

Description

The present invention relates to 2-amino-5-methyl which is useful as a starting compound such as a quinoline derivative having an excellent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory activity. The present invention relates to a benzophenone derivative and an industrially advantageous production method thereof.

(B) Prior art As the most common method for synthesizing 2-aminobenzophenones, 4-substituted aniline and benzoyl chloride are heated to 200 to 230 ° C in the presence of zinc chloride, and the resulting quinazoline compound is subjected to severe conditions. Hydrolysis under acidic conditions is known [LHSternbach et al., Journal of Organic Chemistr.
y, 26, 4488 (1961) and 27, 3781 (1962
Year)].

However, an industrially advantageous method for producing 2-amino-5-methylbenzophenones has not been established, and particularly, a halogen atom or a substituent is further provided at the ortho-position of the phenyl group substituting the amino group and the methyl group. A compound having an alkyl or alkoxy group and a halogen atom or an optionally substituted alkyl or alkoxy group on the other phenyl group has never been synthesized by any method.

(C) Problems to be Solved by the Invention In the above-mentioned known method, not only the reaction conditions are too severe, but also the usual means (except when the yield and crystallinity of the final target product are both good) except in special cases. It is difficult to purify and isolate the target compound by chromatography (except when using chromatography), and it cannot be said to be an excellent method as an industrial production method.

The present inventors have studied various industrially advantageous production methods of 2-amino-5-methylbenzophenones. As a result, the present inventors have found that a novel method which reacts under mild conditions and does not require complicated isolation procedures such as chromatography. The present invention was completed by developing a new method.

(D) Means for Solving the Problems The present invention provides 2-amino-5-methylbenzophenones, which are starting compounds for producing pharmacologically useful compounds, and an industrially advantageous production method thereof. Things.

That is, the present invention uses the formula Wherein each of R ¹ and R ⁴ represents a hydrogen atom, a halogen atom or an optionally substituted alkyl or alkoxy group, and a compound (I) [Wherein R ² represents a halogen atom or an alkyl or alkoxy group optionally substituted with fluorine or chlorine, and X represents a halogen atom] with the compound (II) represented by the following formula in the presence of tin tetrachloride Let the formula [Wherein R ¹ , R ² and R ⁴ are as defined above], to produce a compound (III) represented by the formula: Wherein R ² and R ⁴ are as defined above, or a method for producing the compound (IV) or a salt thereof.

Further, the present invention provides a compound (IV) comprising a novel and particularly useful compound of the formula [Wherein, R ² has the same meaning as described above, and R ³ represents a halogen atom or an alkyl or alkoxy group optionally substituted with fluorine or chlorine] or a salt thereof.

In the above formula, as the halogen atom represented by R ¹ , R ² , R ³ and R ⁴ , fluorine, chlorine, bromine or iodine is used, and substituted halogen atoms represented by R ¹ , R ² , R ³ and R ⁴ are used. As the alkyl in the optionally substituted alkyl group, for example, alkyl having 1 to 3 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl and the like are used, and are represented by R ¹ , R ² , R ³ and R ⁴ Examples of the alkoxy in the optionally substituted alkoxy group include alkoxy having 1 to 3 carbons,
Specifically, methoxy, ethoxy, propoxy, isopropoxy and the like are used. Examples of the substituent in the optionally substituted alkyl or alkoxy group represented by R ¹ , R ² , R ³ and R ⁴ include, for example, fluorine and chlorine,
These substituents may be substituted by 1 to 3 alkyl or alkoxy groups, and may be different when substituted by 2 or more. Further, the substituents represented by R ¹ and R ² may be substituted at any position of the benzene ring, and may be substituted with 1 to 4 identical or different substituents, particularly Substitution at the ortho position is preferred. The substituents represented by R ¹ and R ² may be the same or different from each other, and preferably, R ¹ and R ² are the same. Further, the substituent represented by R ³ or R ⁴ may be substituted at any position of the benzene ring, may be substituted with 1 to 2 identical or different substituents, and particularly meta or Substitution at the (and) para position is preferred.

In the above formula, chlorine or bromine is used as the halogen atom represented by X, and chlorine is particularly preferable.

As the salt of compound (IV) or (V), for example, hydrochloric acid,
A salt with an inorganic acid such as hydrobromic acid, sulfuric acid, phosphoric acid or the like, or acetic acid or an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid is used.

In this method, first, compound (I) and compound (II) are reacted in the presence of tin tetrachloride to produce compound (III). This reaction is carried out usually at about 100 to 160 ° C, preferably at about 120 to 150 ° C, in the absence of a solvent.

The amount of the compound (II) to be used is about 1-2 with respect to the compound (I).
Equivalent, preferably about 1 to 1.5 equivalents. The amount of tin tetrachloride to be used is about 1-2 equivalents, preferably about 1-1.2 equivalents, relative to compound (II). The reaction time is generally 0.5 to 20 hours, preferably 1 to 8 hours. The compound (III) thus obtained can be easily isolated by known means, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, filtration and the like. Thus, it can be collected as a substance of higher purity.

Next, the compound (III) is hydrolyzed to produce the compound (IV) or a salt thereof. This hydrolysis reaction is preferably performed under acidic conditions, and for example, a mineral acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid is preferably used. This reaction may be carried out using these mineral acids as a solvent, or may be carried out, if necessary, by adding acetic acid, ethylene glycol or the like as appropriate to dissolve the compound (III). The reaction temperature is usually about 100-200
° C, preferably about 120-180 ° C. The amount of the mineral acid to be used is about 5-20 mol, preferably about 8-15 mol, per 1 mol of compound (III). Reaction time is usually 5 minutes to 10 hours,
Preferably, it is 10 minutes to 2 hours. When the compound (IV) thus obtained is a free form, it may be converted to a salt with an inorganic acid or an organic acid as described above according to a conventional method, or when the compound (IV) is obtained as a salt, a conventional method Can be converted to a free amino form according to the formula. Compound (IV) or a salt thereof produced in this reaction can be easily isolated as crystals by a simple operation (eg, extraction, concentration, recrystallization), and if necessary, recrystallization is repeated. Higher purity can be collected.

Compound (I) used as a raw material in the above method of the present invention
For example, Comptes Rendus de 1 ′ Acadmie des
It is synthesized by the method described in Sciences, Srie C, vol. 262, p. 369 (1966) or a method analogous thereto.

The compound (IV) or a salt thereof obtained according to the present invention can be prepared, for example, by a method shown in the following figure.
It is useful as a starting material compound.

[Wherein R ² and R ⁴ have the same meanings as above] Compound (X) is a potent inhibitor of acyl-CoA: cholesterol acyltransferase, which inhibits absorption of cholesterol from the intestinal tract and cholesterol ester in atherosclerotic lesions Has the effect of suppressing the accumulation of
Extremely effective as a preventive / therapeutic agent for hypercholesterolemia, atherosclerosis and various diseases caused by these in mammals (eg, ischemic heart disease such as myocardial infarction and cerebrovascular accident such as cerebral infarction and stroke). It is a useful compound (Japanese Patent Application No. 1-75925).

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 (1) Tin tetrachloride (60.5 ml) was added dropwise to 2-chlorobenzoyl chloride (63.0 g) at room temperature (15 to 20 ° C.) while stirring, and the mixture was further stirred for 10 minutes. N- (2-Chlorobenzoyl) -2,4-xylidine (77.7 g) was added thereto, and 13
Heated on 0-140 ° C. oil bath for 2.5 hours. About 80 reaction mixture
C. and cooled carefully with ethyl acetate (100 ml). Then, water (100 ml) was added dropwise under ice cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, a 2N aqueous solution of sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from ethanol (150 ml) to give 2'-chloro-2- (2-chlorobenzoylamino) -3,5-dimethylbenzophenone.
Yield 56.2 g (47.1%). The product was further recrystallized from ethanol to give colorless needles. mp 142-143 ° C. Elemental analysis C ₂₂ H ₁₇ Cl ₂ NO ₂ Calculated: C, 66.34; H, 4.30 ; N, 3.52 Found: C, 66.38; H, 4.31 ; N, 3.51 (2) 2'- chloro-2- A mixture of (2-chlorobenzoylamino) -3,5-dimethylbenzophenone (56 g) and 70% sulfuric acid (280 ml) was stirred for 30 minutes while heating to 160 ° C., then added to ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, a 2N aqueous solution of sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated. Hexane was added to the residue to give 2-amino-2'-chloro-3,5-dimethylbenzophenone. Yield 34.2g
(93.7%). Recrystallization from ethyl ether-hexane gave yellow crystals. mp 78-80 ° C Elemental analysis: C ₁₅ H ₁₄ ClNO Calculated: C, 69.36; H, 5.43; N, 5.39 Found: C, 69.47; H, 5.45; N, 5.55 The compounds of Examples 2 to 6 were obtained.

Example 2 (1) 2'-fluoro-2- (2-fluorobenzoylamino) -3,5-dimethylbenzophenone: yield 79.8%,
132-133 ° C (recrystallized from ethanol).

Elemental analysis C ₂₂ H ₁₇ F ₂ NO ₂ Calculated: C, 72.32; H, 4.69 ; N, 3.83 Found: C, 72.47; H, 4.70 ; N, 3.81 (2) 2- amino-2' Fluoro-3,5-dimethylbenzophenone: yield 83.8%, mp 85-86 ° C (recrystallized from hexane).

Elemental analysis value: C ₁₅ H ₁₄ FNO Calculated value: C, 74.06; H, 5.80; N, 5.76 Actual value: C, 74.09; H, 5.83; N, 5.60 Example 3 (1) 4′-Fluoro-2- (4-fluorobenzoylamino) -3,5-dimethylbenzophenone: yield 43.8%,
mp 162-164 ° C (recrystallized from ethanol).

Elemental analysis: as C ₂₂ H ₁₇ F ₂ NO ₂ Calculated: C, 72.32; H, 4.69; N, 3.83 Found: C, 72.37; H, 4.75; N, 3.77 (2) 2-amino-4'- Fluoro-3,5-dimethylbenzophenone: yield 96.3%, mp 47-48 ° C (recrystallized from hexane).

Elemental analysis value: C ₁₅ H ₁₄ FNO Calculated value: C, 74.06; H, 5.80; N, 5.76 Actual value: C, 74.17; H, 5.88; N, 5.65 Example 4 (1) 2′-chloro-2- (2-chlorobenzoylamino) -4,5-dimethylbenzophenone: yield 91.3%, mp13
5-136 ° C (recrystallized from ethanol).

Elemental analysis C ₂₂ H ₁₇ Cl ₂ NO ₂ Calculated: C, 66.34; H, 4.30 ; N, 3.52 Found: C, 66.39; H, 4.36 ; N, 3.44 (2) 2- amino-2' Chloro-4,5-dimethylbenzophenone: yield 92.3%, mp 119-120 ° C (recrystallized from ethanol).

Elemental analysis: C ₁₅ H ₁₄ ClNO Calculated: C, 69.36; H, 5.43; N, 5.39 Found: C, 69.41; H, 5.46; N, 5.37 Example 5 (1) 2′-Fluoro-2- (2-fluorobenzoylamino) -4,5-dimethylbenzophenone: yield 64.7%,
mp 205-206 ° C (recrystallized from ethanol-chloroform).

Elemental analysis: as C ₂₂ H ₁₇ F ₂ NO ₂ Calculated: C, 72.32; H, 4.69; N, 3.83 Found: C, 72.29; H, 4.72; N, 3.84 (2) 2-amino-2'- Fluoro-4,5-dimethylbenzophenone: yield 80.5%, mp 90-91 ° C (recrystallized from isopropyl ether-hexane).

Elemental analysis: as C ₁₅ H ₁₄ FNO Calculated: C, 74.06; H, 5.80; N, 5.76 Found: C, 73.87; H, 5.74; N, 5.62 Example 6 (1) 4-chloro-5,2 '-Dimethyl-2- (2-methylbenzoylamino) benzophenone: 52.9% yield, mp1
14-115 ° C (recrystallized from ethanol).

Elemental analysis: as C ₂₃ H ₂₀ ClNO ₂ Calculated: C, 73.11; H, 5.33; N, 3.71 Found: C, 73.34; H, 5.33; N, 3.67 (2) 2-amino-4-chloro-5 , 2'-Dimethylbenzophenone: yield 97.7%, mp 99-100 ° C (recrystallized from isopropyl ether-hexane).

Elemental analysis: as C ₁₅ H ₁₄ ClNO Calculated: C, 69.36; H, 5.43; N, 5.39 Found: C, 69.40; H, 5.49; N, 5.33 Example 7 N- (2-methylbenzoyl) -3 , 4-Xylidine (4
A mixture of 9.0 g), 2-methylbenzoyl chloride (45.7 g) and tin tetrachloride (36 ml) was heated on a 130 ° C. oil bath for 2 hours. The reaction mixture was cooled to 80 ° C and ethyl acetate (300m
l) was carefully added dropwise. Then, water (100 ml) was added under ice-cooling, and the ethyl acetate layer was separated, washed sequentially with water, a 2N-NaOH aqueous solution and water, and dried over sodium sulfate. By distilling off the solvent, 2- (2-methylbenzoylamino) -4,5,
2'-Trimethylbenzophenone was obtained as an oil.
Acetic acid (200 ml) and a 47% aqueous HBr solution (200 ml) were added to the oily substance, and the mixture was heated under reflux for 24 hours. After evaporating the solvent under reduced pressure, the mixture was made alkaline with a 25% aqueous ammonia solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized by adding ethanol-isopropyl ether to obtain 2-amino-4,5,2'-trimethylbenzophenone (21.5 g, 43.5%). Recrystallization from ethanol gave yellow prism crystals. mp92
-93 ° C.

Elemental analysis value: C ₁₆ H ₁₇ NO Calculated value: C, 80.30; H, 7.16; N, 5.85 Actual value: C, 80.36; H, 7.29; N, 5.86 Example 8 2-amino as in Example 7 -2'-bromo-5
-Methylbenzophenone was obtained. 51.7% yield, mp 72-74
C (recrystallized from isopropyl ether-hexane).

Elemental analysis value as C ₁₄ H ₁₂ BrNO Calculated value: C, 57.95; H, 4.17; N, 4.83 Actual value: C, 57.81; H, 4.06; N, 4.58 The starting compounds used in Examples 1 to 8 were as follows. It was synthesized by the method shown in Reference Example.

Reference Example 1 2,4-xylidine (48.4 g), potassium carbonate (55.2
g), isopropyl ether (200 ml) and water (300 ml)
Was added dropwise with stirring under ice-cooling. After stirring for 1 hour under ice-cooling, the precipitated crystals were collected by filtration.
(2-Chlorobenzoyl) -2,4-xylidine was obtained.
Yield 100.8 g (97.3%). Colorless needles were obtained by recrystallization from chloroform-methanol. Mp162～163 ° C. Elemental analysis C ₁₅ H ₁₄ ClNO Calculated: C, 69.36; H, 5.43 ; N, 5.39 Found: C, 69.21; H, 5.44 ; N, the following in the same manner as 5.34 Reference Example 1 The compound was prepared.

N- (2-fluorobenzoyl) -2,4-xylidine, mp
85-86 ° C.

N- (4-fluorobenzoyl) -2,4-xylidine, mp
158-159 ° C.

N- (2-chlorobenzoyl) -3,4-xylidine, mp12
7-128 ° C.

N- (2-fluorobenzoyl) -3,4-xylidine, mp
117-118 ° C.

3-Chloro-4-methyl-N- (2-methylbenzoyl) aniline, mp 138-139 ° C.

N- (2-methylbenzoyl) -3,4-xylidine, mp15
0-152 ° C.

N- (2-bromobenzoyl) -p-toluidine, mp146
~ 147 ° C.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 225 / 22,221 / 00 B01J 27/10 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] (1) Expression [Wherein R ² and R ³ each represent a halogen atom or an alkyl or alkoxy group optionally substituted with fluorine or chlorine] or a salt thereof. 2. The compound according to claim 1, wherein R ² is a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms. 3. The compound according to claim 1, wherein R ² is chlorine, methyl or methoxy. 4. The compound according to claim 1, wherein R ³ is a halogen atom or an alkyl group having 1 to 3 carbon atoms. 5. The method according to claim 1, wherein R ³ is a chlorine or methyl group.
A compound as described. (6) Wherein each of R ¹ and R ⁴ represents a hydrogen atom, a halogen atom, or an alkyl or alkoxy group optionally substituted by fluorine or chlorine; and a compound represented by the formula: Wherein R ² represents a halogen atom or an alkyl or alkoxy group which may be substituted with fluorine or chlorine, and X represents a halogen atom, in the presence of tin tetrachloride. formula Wherein R ¹ , R ² and R ⁴ are as defined above, and then hydrolyzing the compound. [Wherein R ² and R ⁴ are as defined above] or a salt thereof.