KR810000463B1 - Preparing process for benzoec amides - Google Patents

Abstract

N-substituted benzoic amides (I; A,R = C1-5 alkyl; Z = H, sulfomoyl) having good antiemetic and psychotropic action, were prepd. step by step. (1) VII and HX(X= Br, I) were reacted to give VIII. (2) VIII was treated with SOCl2 to give II, if necessary, II was converted to free base or acid addition salt.(3) II or their salt were reacted with RNH2(R = lower alkyl) at 0≰C ˜room temp. to give IV.(4) I was obtained by heating IV.

Description

New preparation method of substituted benzoic acid amide

The present invention relates to a novel process for preparing substituted benzoic acid amide, and more particularly, to a novel process for preparing substituted benzoic acid amide represented by the following formula (I).

In the formula, A represents a lower alkyl group, R represents a lower alkyl group, and Z represents a hydrogen atom or sulfamoyl group.

In the formula (I), the "lower alkyl group" may be linear or branched, for example, 1 to 1, such as methyl, ethyl, n- or iso-furophyll, n-, iso-sec- or tert-butyl group. Included are those having five carbon atoms, in particular ethyl groups.

Substituted benzoic acid amide of formula (I) is a compound having excellent soil action and psychotropic action, and is useful as a medicine. Especially

The compound represented by "Sulpyrid" is commonly used as a hypothalamic antiulcer agent.

Conventionally, many methods for producing the compound of formula (I) have been proposed (see, for example, Japanese Patent Nos. 44-23494 and 49-47751, etc.). However, the conventionally proposed method is disadvantageous in that the synthesis is difficult and expensive 1-lower alkyl-2-aminomethylpyrroline has to be used as a raw material, or it requires a complicated and complicated process. It is still not enough.

The present invention provides a novel process for preparing a substituted benzoic acid amide of formula (I) which does not have such drawbacks. According to the method of the present invention, (a) an oxazoline derivative represented by formula (II) or an acid addition salt thereof (B) Preparation of substituted benzoic acid amide of formula (I) consisting of heating in the presence of a primary amine represented by formula (III), or (b) heating a compound represented by formula (IV) or an acid addition salt thereof. A method is provided.

Wherein A and Z have the foregoing meanings, X is the reactive acid residue and R has the foregoing meaning.

According to the method of the present invention, both the compound of formula (II) and the primary amine of formula (III) are heated to react.

In formula (II), X is a reactive acid residue which can be released as HX together with the hydrogen atom of the primary amine of formula (III), and as such reactive acid residue, for example, a halogen atom, in particular a canceled or oxo atom, is advantageous. .

When the compound of formula (II) is heated in the presence of the primary amine of formula (III), the primary amine binds to the compound of formula (II) with the release of HX and isomerizes at the same time. One compound of formula (I) is produced.

The reaction may be carried out in the absence of a solvent, but generally inert organic solvents, for example, alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and ethylene glycol: ethers such as ethyl ether and tetrahydrofuran: acetic acid Esters such as ethyl: organic tertiary amines such as triethylamine, pyridine: hydrocarbons such as benzene, toluene: amides such as dimethylformamide: halogenated hydrocarbons such as dichloromethane, chloroform: dimethyl sulfoxide, etc. It is desirable to.

There is no strict limitation on the heating temperature, but a heating temperature which is at least 60 ° C., suitably a heating temperature ranging from 80 ° C. to the reflux temperature of the reaction mixture is advantageously used.

There is no particular restriction on the ratio of the use of both the compound of formula (II) and the amine of formula (III), but both the compound of formula (II) and the amine of formula (III) are at least equimolar amounts, and suitably It is advantageous to use an excess of amine, usually in an excess of 2 to 5 times the molar amount. The amine of formula (III) may be used in excess, thereby dissolving the amine and serving as an acid binder at the same time.

In addition, the reaction may be carried out in the presence of an acid binder, and examples of the acid binder that can be used include triethylamine, pyridine, piperadine, dimethyl aniline, and the like, and these acid binders are usually formula (II). The compound may be used in an equivalent amount of at least 1 equivalent to 1.5 times.

The reaction time can be changed in a wide range depending on the heating temperature, the compound of the formula (II) used and the kind of the amine of the formula (III), and the like. .

Representative examples of the compound of formula (II) which can be used as starting materials in the method (a) are as follows.

2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole,

2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-oxopropyl) -4,5-dihydrooxazole,

2- (2'-methoxyphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole,

2- (2'-ethoxy-5-sulfurmoylphenyl) -5- (3'-oxodopropyl) -4,5-dihydrooxazole,

2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-chloropropyl) -4,5-dihydrooxazole,

2- (2'-methoxyphenyl) -5- (3'-oxodopropyl) -4,5-dihydrooxazole,

2- (2'-methoxyphenyl) -5- (3'-chloropropyl) -4,5-dihydrooxazole,

And acid addition salts of the compounds.

Such a compound of Formula (II) is a novel compound of the conventional literature, and can be produced by, for example, the following synthesis process.

Substituted benzoic acid represented by formula (V) or its reactive derivatives (e.g., acid halides, esters, mixed acid anhydrides, etc.) and amines represented by formula (VI) or its reactive derivatives (e.g., isocyanates, phosphorazo compounds, etc.) The amidation reaction with can be carried out according to various methods known per se (see Japanese Patent Application No. 51-22246).

For example, this amidation can be performed by direct condensation of the substituted benzoic acid represented by the formula (V) with the amine represented by the formula (VI). The reaction can also be carried out in the absence of solvents, generally in an inert organic solvent, for example hydrocarbons such as benzene, toluene and xylene: ethers such as tetradrofuran, dioxane, dimethoxyethane and diglyme: dimethylform Amides such as amide and dimethylacetamide: halogenated hydrocarbons such as dichloromethane and chloroform: dimethyl sulfoxide and the like. There are no particular restrictions on the reaction temperature and pressure, and the reaction temperature and pressure can be varied widely depending on the raw materials used. The reaction temperature is usually about 0 ° C to the reflux temperature of the reaction mixture, preferably room temperature to 200 ° C, and the pressure is normal pressure. It is advantageous. The reaction can be carried out in the presence of a condensation agent if necessary, and examples of the condensing agent that can be used include N-ethyl-N'-diethyl, such as Lewis acid, especially silicon tetrachloride, trichlorophenylsilane, and titanium tetrachloride. Aminopropyl carbodiimide, N, N'- dicyclohexyl carbodiimide, etc. Combination of a triaryl phosphine and a disulfide: Strong acidic ionic resins, such as invaarite IR-120, etc. are mentioned.

Further, the amidation is carried out between the reactive derivative as described above of the substituted benzoic acid represented by the above formula (V) (for example, lower alkyl carbonate anhydride, lower alkyl ester, etc.) and the free amine represented by the formula (VI). Alternatively, it may be carried out between the substituted benzoic acid of the glass represented by the electric formula (V) and the reactive derivative as described above of the amine represented by the electrical formula (VI). The present amidation can also be carried out without the use of a solvent if necessary, and it is usually advantageous to carry out in the above-mentioned inert organic solvent or high boiling alcohols (for example, ethylene glycol, glycerin, etc.). The reaction temperature and pressure are not critical, but usually as the reaction temperature, the reflux temperature of the reaction mixture is preferably in the range of 0 ° C to 180 ° C, preferably at 0 ° C to 180 ° C.

The compound of formula (VII) thus obtained can be converted to the compound of formula (VIII) by treating with hydrogen halide (HX ') to heat the tetrahydrofuran ring of the compound of formula (VII).

The cleavage reaction of the tetrahydrofuran ring of the compound of formula (VII) with hydrogen halide is usually obtained by dissolving the compound of formula (VII) in an aqueous solution of hydrogen halide (hydrogen halide) and warming it to room temperature or slightly (up to about 50 ° C). This can be done by keeping under state. It is preferable that the concentration of the aqueous solution of hydrogen halide is as high as possible. For example, in the case of hydrofluoric acid, the concentration of commercially available products is about 47%, so that the hydrogen sulfide is blown before or after dissolution of the compound of formula (VII) and saturated concentration ( About 66%). In addition, when using hydrofluoric acid, it is advantageous to use about 50% of concentration.

In general, hydrofluoric acid is more active than hydrofluoric acid, so when using hydrofluoric acid, the reaction temperature is preferably carried out at a relatively low temperature of 30 ° C. or lower, and slightly warm to 50 ° C. when using hydrochloric acid. It is advantageous to carry out the reaction under conditions.

The reaction varies depending on the temperature to be used, the type of hydrofluoric acid, and the like, but usually ends in 15 minutes to 48 hours.

Alternatively, the compound of formula (VII) is dissolved or dispersed in an inert organic solvent such as ethers such as ethyl ether and dimexane, ketones such as acetone and diethyl ketone, and organic acid esters such as methyl acetate and ethyl acetate. The above cleavage reaction can also be achieved by blowing a gas of hydrogen or hydrogen iodide therein, or by adding hydrogen or hydrocyanic acid.

Hydrogen embrittlement or hydrogen iodide may be used in an amount of at least equimolar amount, suitably in excess, such as 2 times or more, relative to the compound of formula (VII).

Treatment of the compound of formula (VIII) with thionyl chloride thus obtained (cyclization reaction) is, for example, in a solvent-free state to the compound of formula (VIII) or preferably inert organic solvent such as ethyl acetate, methyl acetate Esters such as: chloroform, carbon tetrachloride, halogenated hydrocarbons such as dichloromethane and dichloroethane: hydrocarbons such as benzene and toluene xylene: dissolved in ethers such as dimethyl ether, tetrahydrofuran and dioxane, about 0 to 50 It is carried out by adding thionyl chloride at a temperature between ° C, usually at room temperature.

The amount of thionyl chloride used is not exact and can vary widely depending on the type of the compound of formula (VIII), the reaction temperature, and the like, and is generally used in an excess of at least an equivalent weight, preferably 1.1 to 1.5 times the equivalent weight. .

The reaction generally ends in 15 minutes to 1 hour. Separation and purification of the compound of formula (II-a) from the reaction mixture after the reaction can be carried out by any means known per se, such as filtration extraction, recrystallization, chromatography, and the like.

In the above cyclization, the compound of formula (II-a) is usually obtained in the form of hydrochloride. Therefore, if the free base is desired, the hydrochloride obtained thereby can be easily converted into a free base by treating it with an alkali such as a weak inorganic base such as sodium bicarbonate or potassium bicarbonate, or an organic tertiary amine such as triethylamine or pyridine. The free base thus obtained can be converted into an acid addition salt by treating with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or paratoluenesulfonic acid.

The compound of formula (II) can be used in the form of a free base or in the form of its acid addition salt. As such acid addition salt, salt with inorganic acids, such as hydrochloric acid, a sulfuric acid, phosphoric acid, a perchloric acid, or organic acids, such as acetic acid, a fish acid, a propionic acid, a fumaric acid, a paratoluenesulfonic acid, is mentioned, for example.

According to the method (b) of the present invention, the compound of formula (IV) can be converted into the substituted benzoic acid amide of formula (I) as desired by heat isomerization.

This heat isomerization may be carried out in a solvent-free state, but it is usually advantageous to carry out in an inert organic solvent as described above with respect to the method (a). The temperature of isomerization can be at least 60 degreeC, suitably 80 degreeC-the range temperature of the reflux temperature of a reaction mixture.

This isomerization reaction proceeds extremely easily, and therefore it does not require the use of an isomerization catalyst in particular, but if necessary, a catalyst commonly used in a normal isomerization reaction may be used.

The compound of formula (IV) used in the above method (b) is also a novel compound which is not disclosed in the prior art, and this compound is, for example, of the formula (II) used as starting material in the above method (a). At least equimolar amounts, preferably 2 to 5 times the molar amount of the electrical formula (III), in a solvent-free state or in an inert organic solvent described for the method (a), at a low temperature in the range of 0 ° C to room temperature. It can be manufactured easily by reacting with an amine. Representative examples of the compound of formula (IV) thus obtained are as follows.

2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-ethylaminopropyl) -4,5-dihydrooxazole, 2- (2'-methoxy-5'-sulfur Moylphenyl) -5- (2-methylaminopropyl) -4,5-dihydrooxazole, 2- (2'-methoxyphenyl) -5- (3'-ethylaminopropyl) -4,5-di Hydrooxazole, 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3-methylaminopropyl) -4,5-dihydrooxazole, 2- (2'-ethoxyphenyl) -5- (3'-ethylaminopropyl) -4,5-dihydrooxazole. The compound of formula (IV) can be used not only in the form of the free base but also in the form of acid addition salts. Examples of such acid addition salts are as described above with respect to the compound of formula (II).

Separation and purification of the compound of formula (I) obtained by the method (a) or (b) from the reaction mixture can be carried out by a method known per se, for example, by filtration, extraction, recrystallization chromatography, or the like. .

Illustrating the compound of formula (I) provided by the process of the invention is as follows.

N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxy-5-sulfurmoylbenzoic acid amide, N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-ethoxy -5-Sulfamoyl benzoic acid amide, N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxybenzoic acid amide, N- (1'-ethyl-2'-pyrrolidinylmethyl) -2 -Methoxy-5-sulfurmoylbenzoic acid amide, thus, according to the method of the present invention, it is difficult to synthesize a substituted benzoic acid of formula (I), which has excellent earth action, antiulcer action and psychotropic effect, and is useful as a medicine. It can be produced with high yield and high purity without requiring any expensive and expensive reaction raw materials and without any complicated manufacturing process.

Compounds of formula (I) provided by the present invention are in the form of free bases or in the form of acceptable acid addition salts (such as hydrochlorides, sulfates, phosphates, etc.), which are acceptable in the form of antacids, antipsychotics, antiulcers It can be used as an active ingredient of medicines such as drugs.

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

Example 1

(a-1)

23.1 g of 2-methoxy-5-sulfurmoyl benzoic acid is dissolved in 14.1 ml of triethylamine and 150 of dimethylformamide, and 9.7 ml of ethyl chloro formate is added dropwise under cooling. After stirring for 2 hours, 10.3 g of tetrahydrofurfurylamine is added dropwise under cooling. After stirring for 4 hours at room temperature, the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from acetone to obtain 26.2 g of N- (2'-tetrahydrofuranylmethyl) -2-methoxy-5-sulfurmoylbenzoate. Melting point 201-202 degreeC. 1.8 g of crystals are obtained again from the mother liquor.

IR (KBr tablet, cm ⁻¹ ); 3360, 3260, 3080, 1620.

NMR (DMSO, δ); 1.8 (4H, multiple line, 3.37 (2H, triplet, J = 6 Hz), 3.8 (3H, multiple line), 3.96 (3H, singlet, 7.25 (2H, broad singlet), 7.18 (1H, Doublet, J = 8.5 Hz, 7.88 (1H, quartet, J = 2.5 and 8.5 Hz), 8.23 (1H, doublet, J = 2.5 Hz), near 8.2 (1H, multiplet).

(a-2)

To a 50 ml solution of 3.13 g of diethylchlorophosphite toluene was added dropwise a mixture of 2.02 g of tetrahydrofurfurylamine and 2.02 g of triethylamine to 0 ° C. After stirring for 30 minutes, the insolubles were filtered off and 2.31 g of 2-methoxy-5-sulfurmoyl benzoic acid was added to the filtrate. The reaction solution is heated to reflux for 1.5 hours. Cool, filter the precipitated crystals and wash with water. Washing again with ether and drying gave 2.02 g of N- (2'-tetrahydrofuranylmethyl) -2-methoxy-5-sulfurmoylbenzoic acid amide. This is consistent with that obtained in (a-1) above.

(a-3)

2.59 g of 2-methoxy-5-sulfurmoyl benzoic acid ethyl esters are dissolved in 10 ml of ethylene glycol, when heated, and then 2.2 g of tetrahydrofurfurylamine is added, and the reaction solution is heated to 55 to 60 ° C. for 64 hours. The reaction solution is poured into water and the crystals are filtered off. After washing with ether and drying, 2.7 g of N- (2'-tetrahydrofuranyl methyl) -2-methoxy-5-sulfurmoylbenzoic acid amide is obtained. This is consistent with that obtained in (a-1) above.

(b-1)

5 g of N- (2'-tetrahydrofuranylmethyl) -2-methoxy-5-sulfurmoyl benzoic acid amide obtained in (a-1) to (a-3) above was dissolved in 20 ml of 47% hydrochloric acid, Saturate through. The reaction solution is warmed to 40 ° C. for 15 minutes, and then the hydrogenated hydrogen is distilled off as much as possible under reduced pressure. It is then poured into water, neutralized with sodium bicarbonate solution, and the crystals are filtered to yield 4.9 g of N- (2'-hydroxy-5'-bromobentyl) -2-methoxy-5-sulfurmoylbenzoate. Melting point 98-99 degreeC.

IR (KBr tablet cm- ¹ ); 3500, 3400, 3320, 3140, 1620.

NMR (DMSO, δ, around 1.7 (4H, multiplet), 3.54 (2H, triplet, J = 6Hz), 3.1 to 4.1 (3H, multiplet), 3.96 (3H, singlet), 7.29 (1H, doublet J = 8.5 Hz), 7.27 (2H, wide midline), 7.87 (1H, quadruple, J = 2.5 and 8.5 Hz), 8.23 (1H, double, J = 2.5 Hz), near 8.2 (1H, multiline ).

(b-2)

2.56 g of N- (2'-tetrahydrofuranylmethyl) -2-methoxy-5-sulfurmoylbenzoic acid amide obtained in (a-1) to (a-3) above was dissolved in 26 ml of 50% hydrofluoric acid and 25 Let stand overnight at ℃. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with sodium thiosulfate solution and then with water. The solvent was distilled off under reduced pressure to obtain 2.4 g of N- (2'-hydroxy-5'-oxobentyl) -2-methoxy-5-sulfurmoylbenzoic acid amide as crystals. Melting point 87-88 degreeC.

IR (KBr tablets, cm ⁻¹ ); Near 3500, 3390, 3300, 3100, 1620.

NMR (DMSO, δ); 1.8 (4H, multiple line) 3.29 (2H, triplet, J = 6Hz), 3.8 (3H, multiline), 3.96 (3H, singlet), 7.30 (1H, doublet, J = 8.5Hz), 7.26 (2H, broad singlet), 7.88 (1H, quartet, J = 2.5 and 8.5 Hz), 8.24 (1H, doublet, J = 2.5 Hz). 8.2 vicinity (1H, multiplet).

(c-1)

4.9 g of N- (2'-hydroxy-5'-bromopentyl) -2-methoxy-5-sulfurmoylbenzoic acid amide obtained in the above (b-1) was suspended in 49 ml of ethyl acetate, and thionyl chloride Add dropwise 2.2g. After stirring for 15 minutes at room temperature, 100 ml of ether was added to precipitate precipitated crystals. Quantity 4.6g, 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole hydrochloride by recrystallization from acetone-methanol mixed solvent Get Melting Point 177 ~ 178 ℃

IR (KBr tablets, cm ⁻¹ ); 1640.

NMR (DMSO, δ); 2.0 (4H, multiple line), 3.63 (2H, triplet, J = 6 Hz), 3.84 (1H, quartet, J = 3 and 12 Hz), 4.10 (3H, singlet), 4.41 (1H, quartet, J = 10 and 12 Hz), 5.4 (1H, multiplet), 7.58 (1H, doublet, J = 8.5Hz), 7.5 (2H, multiplet), 7.55 (1H, doublet, J = 8.5Hz) 8.2 Near (2H, multiplet).

(c-2)

The acid acid obtained in the above (c-1) is dissolved in a rare oil and neutralized with an aqueous sodium bicarbonate solution. The precipitated crystals were filtered off and dried after washing with water to quantitatively obtain 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxysol. Obtained. Recrystallization from acetone gives a crystal having a melting point of 161 to 162 캜.

IR (KBr tablet, cm ⁻¹ ), 3280, 1645.

NMR (DMSO, δ); Near 1.8 (4H, multiwire), 3.60 (2H, triplet J = 6 Hz), 3.55 (1H, quartet, J = 2.5 and 14 Hz), 4.06 (1H, quartet, J = 9.5 and 14 Hz). 3.90 (3H, single line), 4.74 (1H, multiline), 7.26 (1H, double line), J = 8.5 Hz, 7.28 (2H, broad single line), 7.88 (1H, quartet, J = 2.5 and 8.5 Hz), 8.4 (1H, doublet, J = 2.5 Hz).

(c-3)

2.4 g of N- (2'-hydroxy-5'-oxodopentyl) -2-methoxy-5-sulfurmoylbenzoic acid amide obtained in the above (b-2) was reacted with thionyl chloride as in Example 1 , 2.5 g of 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-oxodopropyl) -4,5-dihydroxyxazole hydrochloride is obtained. Melting point 153-154 캜.

IR (KBr tablets, cm ⁻¹ ); 1650.

NMR (DMSO, δ); 2.02 (4H, multiplet) 3.72 (2H, triplet, J = 6Hz), 3.82 (1H, quadruple, J = 3.5 and 12Hz). 4.11 (3H, singlet), 4.29 (1H, quartet, J = 9.2 and 12 Hz), 5.45 (1H, multiplet), 7.5 vicinity (2H, multiplet), 7.57 (1H, doublet, J = 8.5Hz ), 8.2 (2H, multiplet).

2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-oxodopropyl) -4,5-hydrooxazole is obtained from this hydrochloride. Melting point 147-148 degreeC.

IR (KBr tablets, cm ⁻¹ ); 3280, 1645.

(d-1)

4.6 g of 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole hydrochloride obtained in the above section (c-1) was ethyl It is dissolved in 20 ml of amine and 20 ml of dimethylformamide, and after being left at room temperature overnight, excess ethylamine is distilled off under reduced pressure. After the residue was warmed to 100 ° C. for 2 hours, the solvent was distilled off under reduced pressure, water was added to the obtained residue, ammonia water was added, the solution was made slightly alkaline, and extracted with chloroform. When the solvent was distilled off after washing with water, 3.33 g of N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxy-5-sulfurmoyl benzoate was obtained as crystals. Melting point 179-180 degreeC.

(d-2)

2.1 g of 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole obtained in the above section (c-2) was added to ( In the same manner as in d-1), 1.4 g of N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxy-5-sulfurmoylbenzoate was obtained. Melting point 179-180 ° C.

(d-3)

1 g of 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-oxopropyl) -4,5-dihydrooxazole hydrochloride obtained in the above section (c-3) was added to (d In the same manner as in -1), 0.6 g of N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxy-5-sulfurmoylbenzoic acid amide is obtained. Melting point 179-180 degreeC.

3.53 (1H, quartet, J = 7.5 and 15 Hz), 3.89 (3H, singlet), 4.04 (1H, quartet, J = 9.5 and 15 Hz), 4.7 (1H, multiplet), 7.26 (1H, doublet , J = 8.5 Hz). 7.90 (1H, quartet, J = 2.5 and 8.5 Hz), 8.05 (1H, doublet, J = 2.5 and 8.5 Hz), 8.05 (1H, doublet, J = 2.5 Hz).

MS (m / e); 341 (M ⁺ ).

0.1 g of 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-ethylaminopropyl) -4,5-dihydrooxazole is heated to reflux with 5 ml of isopropyl alcohol. After 2 hours, the solvent is distilled off to obtain 0.1 g of N- (1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxy-5-sulfurmoylbenzoic acid amide. Melting point 178-179 degreeC.

Example 2

0.2 g of 2- (2'-methoxy-5-sulfurmoylphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole obtained in (c-2) of Example 1 It is suspended in 4 ml of ethyl acetate. To this was added dropwise a mixture of 0.1 ml of triethylamine, 4 ml of ethylamine, and 2 ml of ethyl acetate. After overnight at room temperature, excess ethylamine and a part of the solvent were distilled off under reduced pressure, and the separated oil was taken out and washed with chloroform. Insoluble oils were purified by thin layer chromatography to obtain 2- (2'-methoxy-5'-sulfurmoylphenyl) -5- (3'-ethylaminopropyl) -4,5-dihydrooxazole as oil phase. Obtained as water

IR (oil phase, cm ⁻¹ ); Around 3200, 1640.

NMR (DMSO, δ); 1.57 (3H, triplet, J = 7Hz), 1.6 (4H, multiplet), 2.7 (4H, multiplet).

Example 3

3.04 g of 2-methoxybenzoic acid was reacted in the same manner as in the preparation of the raw material compound according to (a-1) of Example 1 to give N- (2'-tetrahydrofuranylmethyl) -2-methoxybenzoic acid amide 4.5 g is obtained as an oil.

IR (oil phase, cm ^-1 ), 3420, 1650.

NMR (CDCl ₃ , δ); Near 1.9 (4H, multiple line), Near 3.8 (3H, multiple line), 3.95 (3H, single line), 6.9-8.2 (4H, multiple line), Near 8.2 (1H, multiple line).

Subsequently, 0.2 g of N- (2'-tetrahydrofuranylmethyl) -2-methoxybenzoic acid amide was reacted in the same manner as in the production method of the raw material compound in Section (b-1) of Example 1, and the reaction liquid Is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and then dried with a forget-me-not. When the solvent is distilled off under reduced pressure, 0.25 g of N- (2'-hydroxy-5'-bromopentyl) -2-methoxybenzoic acid amide is obtained as an oily substance.

IR (oil phase, cm ^-1 ), 3380, 1620.

NMR (CDCl ₃ , δ); 1.8 (4H, multiplet), 3.44 (2H, triplet, J = 6Hz), 3.5 (2H, multiplet), 3.8 (1H, multiplet), 3.96 (3H, singlet), 6.9 to 8.2 (4H, multiplet), around 8.4 (1H, multiplet).

2.5 g of N- (2'-hydroxy-5'-bromopentyl) -2-methoxybenzoic acid amide thus obtained was the same as in the manufacturing method of the raw material compound of the example (c-1). To give 2.41 g of 2- (2'-methoxyphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole hydrochloride. Melting Point 148 ~ 150 ℃

IR (KBr tablets, cm ⁻¹ ); 1650.

NMR (DMSO, δ); 2.0 (H, multiple line), 3.7 (3H, multiple line), 4.06 (3H, single line), 4.30 (1H, quartet, J = 10 and 12 Hz), 5.45 (1H, multiple line), 7.0 to 8.1 (4H, multiplet).

From this hydrochloride, 2- (2'-methoxyphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole is obtained as an oil.

IR (oil phase, cm ⁻¹ ); 1650.

NMR (CDCl ₃ , δ); 2.0 (4H, multiplet), 3.49 (2H, triplet, J = 6Hz) 3.7-4.1 (1H, multiplet), 4.31 (1H, quartet, J = 9.5 and 14Hz), 4.80 (1H, multiplet ), 3.98 (3H, singlet), 6.8 to 7.9 (4H, multiplet).

2.0 g of 2- (2'-methoxyphenyl) -5- (3'-bromopropyl) -4,5-dihydrooxazole was treated in the same manner as in the case of (d-1) of Example 1 to obtain N 1.43 g of-(1'-ethyl-2-pyrrolidinylmethyl) -2-methoxybenzoic acid amide is obtained as an oil.

IR (oil phase, cm ⁻¹ ); 3400, 1650.

NMR (CDCl ₃ , δ); 1.13 (3H, triplet, J = 7Hz), 1.8 (4H, multiple), 3.5 (7H, multiple), 3.94 (3H, singlet), 6.8-8.3 (4H, multiple), 8.4 (1H, multiplet).

Example 4

0.47 g of N- (2'-tetrahydrofuranylmethyl) -2-methoxybenzoic acid amide was treated in the same manner as in the manufacturing method of (b-1) of Example 1 to obtain N- (2'-hydroxy-5 0.59 g of '-oxodopentyl) -2-methoxybenzoic acid amide is obtained as an oily substance.

IR (oil phase, cm ⁻¹ ); 3400, 1640.

NMR (CDCl ₃ , δ); 1.8 (4H, multiple line), 3.20 (2H, triplet, J = 6 Hz), 3.54 (2H, quartet, J = 3 and 5.5 Hz), 3.8 (1H, multiple line), 6.9-8.2 (4H) , Multiplet), 8.34 (1H, multiplet).

Subsequently, 0.56 g of N- (2'-hydroxy-5'-oxodopentyl) -2-methoxybenzoic acid amide was treated in the same manner as in the case of (c-1) of Example 1 to give 2- (2'-meth 0.51 g of oxyphenyl) -5- (3'-oxopropyl) -4,5-dihydrooxazole hydrochloride is obtained. Melting Point 142 ~ 144 ℃

IR (KBr tablets, cm ⁻¹ ); 1650.

2- (2'-methoxyphenyl) -5- (3'-oxopropyl) -4,5-dihydrooxazole is obtained from this hydrochloride.

IR (oil phase, cm ^-1 ) 1650.

NMR (CDCl ³ , δ); Near 1.9 (4H, multiple), 3.63 (2H, triplet, J = 6 Hz), Near 3.7 (1H, multiple), 3.92 (3H, singlet), 4.19 (1H, quartet, J = 9 and 14 Hz ), 4.6 (1H, multiplet), 6.8-7.8 (4H, multiplet).

2.0 g of 2- (2'-methoxyphenyl) -5- (3'-oxodopropyl) -4,5-dihydrooxazole was treated in the same manner as in (d-1) of Example 1 to obtain N- ( 12.6 g of 1'-ethyl-2'-pyrrolidinylmethyl) -2-methoxybenzoic acid amide can be obtained.

Claims (1)

As described above, the compound of formula (VII) is reacted with hydrogen halide HX in which X is bromine or iodine atom to obtain a compound of formula (VIII), and the compound of formula (VIII) is converted to thionyl chloride. After treatment, if necessary, the hydrochloride obtained is converted into a free base or an acid addition salt thereof and the resulting oxazoline derivative of formula (II) or acid addition salt thereof is reacted with a primary amine of formula (III) under heating. Or reacting with a primary amine of general formula (III) at 0 ° C. to room temperature to obtain a compound of general formula (IV), and then heating the method of preparing substituted benzoic acid amide of general formula (I) .

Wherein A is a lower alkyl group, Z is a hydrogen atom or sulfamoyl group, X is a bromine or iodine atom, and R is a lower alkyl group.