JPH07107026B2 - 2-aminobenzyl alcohol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 2-aminobenzyl alcohol derivative, more specifically, a compound represented by the following general formula (I): (Wherein R ¹ represents hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, and R ² represents hydrogen or alkyl).

The 2-aminobenzyl alcohol derivative represented by the above general formula (I) can be widely used as a synthetic intermediate for medicines, agricultural chemicals and the like, and in particular, antiulcer action and gastrointestinal cells found by the present inventors. General formula (X) having a protective action (In the formula, Y ¹ and Y ² represent hydrogen, halogen, alkoxy, alkyl, trifluoromethyl, amino and the like, and R ¹ and R ²
Is the same as the above) and is an important synthetic intermediate of a 2- (2-substituted aminobenzylsulfinyl) benzimidazole derivative (West German publication P3531487, Japanese Patent Application No. 61-82268, etc.).

The inventors of the present invention have conducted earnest research on an industrial-scale synthesis method of the benzimidazole derivative represented by the general formula (X), and as a result, the 2-aminobenzyl alcohol derivative represented by the general formula (I) is used. It was found that the benzimidazole derivative represented by the general formula (X) can be obtained by a simple operation and a high yield by using the above synthetic method, and completed the present invention.

An object of the present invention is to provide a 2-aminobenzyl alcohol derivative represented by the above general formula (I).

Further, it is an object of the present invention to provide a method for producing a 2-aminobenzyl alcohol derivative represented by the above general formula (I).

The present invention has the following general formula (I) (Wherein R ¹ represents hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, and R ² represents hydrogen or alkyl).

The alkyl of R ¹ and R ² of the general formula (I), methyl, ethyl, lower alkyl of C ₁ -C ₅ a propyl, R ¹
Examples of the alkoxy of R ¹ include C _{1 to} C ₅ alkoxy such as methoxy, ethoxy, and propoxy, and as the halogen of R ¹ ,
Examples include chlorine and fluorine.

The 2-aminobenzyl alcohol derivative represented by the general formula (I) can be obtained by the method shown below. That is, (method A) general formula (II) (Wherein R ¹ represents hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, and R ³ represents hydrogen, alkyl or aralkyl), and the compound represented by the general formula (III) (Wherein R ¹ is the same as above), and then the compound is subjected to N-alkylation reaction to give a compound of the general formula (IV) (In the formula, R ⁴ represents alkyl and R ¹ is the same as described above) to obtain a 2-aminobenzyl alcohol derivative. Also, (method B) general formula (V) (Wherein R ¹ represents hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, R ² represents hydrogen or alkyl, and R ⁵ represents alkyl or aralkyl). Let the general formula (VI) (Wherein R ¹ , R ² and R ⁵ are the same as above), and then the compound is subjected to a reduction reaction to give the 2-aminobenzyl alcohol derivative represented by the above general formula (I). Obtainable.

R ³ of the general formula (II), R ^{4 of} the general formula (IV), and R ^{4 of} the general formula (V)
Examples of the alkyl represented by R ⁵ include C ₁ -C ₅ lower alkyl such as methyl, ethyl, propyl, and the like.
R ³ of I), the aralkyl represented by R ⁵ in the general formula (V), benzyl, benzhydryl, and the like.

The reaction reagent used in the reduction reaction shown in Method A and Method B may be any reaction reagent capable of reducing amide and ester or carboxylic acid to amine and alcohol, respectively.
For example, diborane, a metal hydride complex compound such as lithium aluminum hydride, or a combination of NaBH ₄ and a Lewis acid, and preferably lithium aluminum hydride or NaBH
A combination of ₄ and AlCl ₃ or ZnCl ₂ is used. Examples of the reaction solvent in the reduction reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, and the reaction temperature is -5 ° C to
It is carried out at the reflux temperature.

As the N-alkylation reaction of Method A, a known N-alkylation method, for example, a method using an alkyl halide, a dialkyl sulfuric acid, or the like, or a method of subjecting to a reduction reaction after N-acylation can be mentioned.

As the acylating agent in Method B, a reagent used in a known acylation reaction, for example, isobutyric acid, isobutyric anhydride, isobutyric acid chloride or the like is used.

The compound of the general formula (II), which is the raw material of Method A, can be obtained, for example, by the method represented by the following formula. (Bull.Soc.Chim.Fran
ce '60, 337) Other compounds can be obtained by the same method.

When R ² is an alkyl in the raw material of Method B, the compound of the general formula (VI
I) (Wherein R ¹ and R ⁵ are the same as above) can be obtained by using a known N-alkylation method.

By using the thus obtained 2-aminobenzyl alcohol derivative represented by the general formula (I), for example, the 2- (2-substituted aminobenzyl represented by the above general formula (X) is represented by the following synthetic steps. A sulfinyl) benzimidazole derivative can be obtained.

The other compound represented by the general formula (X) can also be obtained by the same method as described above.

As described above, 2 represented by the general formula (I) which is the compound of the present invention
-Through an aminobenzyl alcohol derivative,
General formula (X) having anti-ulcer and gastrointestinal cytoprotective action
The 2- (2-substituted aminobenzylsulfinyl) benzimidazole derivative represented by can be obtained by a simple operation and in high yield. Further, the 2-aminobenzyl alcohol derivative represented by the general formula (I) is not only a synthetic intermediate of the 2- (2-substituted aminobenzylsulfinyl) benzimidazole derivative represented by the general formula (X) but also other pharmaceuticals. It is also useful as a synthetic intermediate for agricultural chemicals.

Next, the present invention will be described in more detail with reference to Examples and Reference Examples.

Reference Example 1 2-isobutyrylaminobenzoic acid methyl ester A mixture of 58 g of methyl anthranilate, 41 g of isobutyric acid chloride, 53 g of potassium carbonate and 1.21 of benzene is heated under reflux for 1 hour. After cooling to 20 ° C, the reaction solution was washed with water, 1N-HCl and saturated brine in that order, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil.

Example 1 2-Isobutylaminobenzyl alcohol Lithium aluminum hydride 40.9 g dry ether 1.31
A solution of dry ether 0.41 of 2-isobutyrylaminobenzoic acid methyl ester obtained in Reference Example 1 was added dropwise to the suspension over 30 minutes under ice cooling. The mixture is heated at room temperature for 20 minutes and further refluxed for 1 hour and then cooled. Saturated sodium mirabilite water is added to the reaction solution while cooling with ice to decompose excess lithium aluminum hydride. The insoluble matter is filtered off, and the filtrate is dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain 64 g (93%) of the desired product as a pale yellow oily substance. ¹ HNMR (CDCl ₃ ) δ: 0.96 (d, 6H, J = 8Hz) 1.6−2.1 (m, 1H) 2.92 (d, 2H, J = 8Hz) 3.16 (br, 2H) 4.56 (s, 2H) 6.4− 7.3 (m, 4H) 3380,2950,2860,1600, 1580,1510,1460,1310,990,740 Example 2 2- (N-isobutyl-N-methylamino) benzyl alcohol 2-isobutylaminobenzyl alcohol 64 g, dimethylsulfate 90 g, calcium carbonate 79 g and A mixture of 320 ml of water is stirred for 2 hours at room temperature. Ether 0.51 is added to the reaction solution, and the insoluble matter is filtered off. The filtrate is washed with water, extracted with 10% hydrochloric acid (0.71), and washed with ether. Next, potassium carbonate is added to the aqueous layer to make it alkaline, and the oily substance that has precipitated is extracted with ether and washed with saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure to give the desired product as a yellow oily substance, 63.3. g (92%) was obtained. ¹ HNMR (CDCl ₃ ) δ: 0.96 (d, 6H, J = 7Hz) 1.6−2.1 (m, 1H) 2.64 (s, 3H) 2.70 (d, 2H, J = 8Hz) 4.78 (s, 2H) 5.40 ( s, 1H) 7.0-7.4 (m, 4H) 3370,2950,1590,1450, 1020,760 Reference Example 2 2- (N-isobutyl-N-methylamino) benzyl chloride hydrochloride 63.3 g of benzyl alcohol obtained in Example 2 was dissolved in dry benzene 11 and cooled with ice. 49 g of thionyl chloride below
The 0.21 solution is added dropwise over 20 minutes. 1 hour at room temperature, then
Stir for 20 minutes at 50-55 ° C. Excessive thionyl chloride and benzene were distilled off under reduced pressure at 50 ° C. or lower, and the precipitated crystals were filtered, washed with benzene and dried under reduced pressure to obtain 64.4 g (79%) of the title compound as white crystals. ¹ HNMR (CDCl ₃ ) δ: 1.00 (d, 6H, J = 8Hz) 1.7−2.2 (m, 1H) 3.32 (s, 3H) 2.48 (d, 2H, J = 8Hz) 5.32 (s, 2H) 7.3− 7.8 (m, 4H) Reference Example 3 2- [2- (N-isobutyl-N-methylamino) benzylthio] benzimidazole 39 g 2-mercaptobenzimidazole, ethanol 640
A mixture of ml, 2- (N-isobutyl-N-methylamino) benzyl chloride hydrochloride 64.4 g is stirred at room temperature for 20 minutes. The deposited precipitate is collected by filtration, and the obtained solid is added to a mixed solution of chloroform 11 and 100 g of potassium carbonate in a solution of water 11, and the mixture is well stirred and separated. After the chloroform layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 84.5 g of an oily substance. A small amount of ether was added to this to crystallize, and the precipitated crystals were separated by filtration,
74.8g (89%) as white powder after drying under reduced pressure
Got

_{NMR (CDCl 3) δ: 0.98} (d, 6H, J = 7Hz) 1.8-2.2 (m, 1H) 2.68 (d, 2H, J = 8Hz) 2.80 (s, 3H) 4.48 (s, 2H) 6.9-7.8 (M, 8H) Reference Example 4 2- [2- (N-isobutyl-N-methylamino) benzylsulfinyl] benzimidazole 2- [2- (N-isobutyl-N-methylamino) benzylthio] benzimidazole 76.1 g Chloroform 1.1
Dissolve in 1 and chill with ice. To this, 50.2 g (purity 80%) of m-chloroperbenzoic acid was gradually added at 5 ° C or lower. 5 more
After stirring for 30 minutes at a temperature below ℃, add saturated aqueous sodium hydrogen carbonate to the reaction mixture and separate. The chloroform layer is further washed with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous sodium thiosulfate solution and saturated brine in that order, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. Add 100 ml of acetonitrile to the precipitated crystals and collect by filtration. It was washed with acetonitrile to obtain 70.5 g (88%) of the title compound. This product was recrystallized from methylene chloride-acetonitrile to obtain 59.7 g of the pure product of the title compound.

NMR (CDCl ₃ ) δ: 0.92 (d, 6H, J = 7Hz) 1.5−2.0 (m, 1H) 2.62 (d, 2H, J = 8Hz) 2.64 (s, 3H) 4.52 (d, 2H, J = 14Hz ) 4.90 (d, 2H, J = 14Hz) 6.8−7.9 (m, 8H) mp 126 to 126.5 ℃

Claims (3)

[Claims] 1. A general formula (In the formula, R ¹ represents hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, and R ² represents hydrogen or alkyl.) A 2-aminobenzyl alcohol derivative. 2. General formula (Wherein R ¹ represents hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, and R ³ represents hydrogen, alkyl or aralkyl), and the compound represented by the general formula (Wherein R ¹ is the same as above), and then the compound is subjected to an N-alkylation reaction. (Wherein R ⁴ represents alkyl and R ¹ is the same as above). 3. General formula (Wherein R ¹ represents hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, R ² represents hydrogen or alkyl, and R ⁵ represents alkyl or aralkyl) and acts an acylating agent on the compound represented by the formula Let the general formula (Wherein R ¹ , R ² and R ⁵ are the same as defined above), and then the compound is subjected to a reduction reaction. (In the formula, R ¹ and R ² are the same as defined above.) A method for producing a 2-aminobenzyl alcohol derivative.