JPS6185375A - 2,3-dihydrobenzo(b)furan derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [X is NR5 or O; R1 is lower alkyl, aryl or aralkyl; R2 and R3 are H or lower alkyl, or R2 and R3 may together optionally with N having other O, S or substituent group (lower alkyl, aryl or aralkyl form a ring; R4 is H, halogen, lower alkyl or lower alkyloxy; R5 is H or acyl]. EXAMPLE:2-Dimethylamino-3-imino-2,3-dihydrobenzo[b]furancarboxylic acid methyl ester. USE:Drug having centralnervous action. Some of the compounds are useful as intermediates which can be converted easily to various derivatives having 3- imino-2,3-dihydrobenzo[b]furan structure and 3(2H)-benzofuranone derivative which have hitherto been difficult to be produced. PREPARATION:The compound of formula I (X is NH) can be prepared by treating the compound of formula II with a strong base.

Description

Detailed Description of the Invention The present invention is based on the following general formula (wherein, X means N-R5 or an oxygen atom, R1 means a lower alkyl group, aryl group or aralkyl group, and R2 and R3 are - If the number is different, it means a hydrogen atom or a lower alkyl group, or R2 and R3 are bonded to each other, or
3 may form a ring with another oxygen atom, sulfur atom, or a nitrogen atom substituted with a lower alkyl group, aryl group, or aralkyl group, and R4 is a hydrogen atom, 8 halogen atoms, a lower alkyl group, or It means a lower alkyloxy group, and R5 means a hydrogen atom or an acyl group. The present invention relates to a novel 2,3-dihydrobenzo(b) furan derivative represented by: and a novel method for producing the same.

The term "lower alkyl group" used in this specification means a straight or branched chain having 1 to 6 carbon atoms (e.g., methyl group, ethyl group, propyl group, inpropyl group, etc.), Aryl group means phenyl group or substituted phenyl group (e.g. tolyl group, p-methoxyphenyl group, p-nitrophenyl group, etc.), and aralkyl group means substituted or unsubstituted phenylalkyl group (
For example, benzyl group.

A strong base means a phenethyl group, etc.), a rosin atom, fluorine, chlorine, bromine, iodine, an acyl group, an acetyl group, a benzoyl group, etc.
Base agents capable of abstracting active hydrogen (e.g., sodium hydride, sodium methoxide).

(sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, etc.).

Still, it means a ring tohapyrrolidine, piperidine, hexamethyleneimine, etc. formed by combining R2 and R3 with each other, and R2 and R3 are another oxygen atom or sulfur atom.

Or, the ring formed with a nitrogen atom substituted with a lower alkyl group, aryl group, or aralkyl group is morpholine,
Thiomorpholine, 4-methylpiperazine.

It means 4-phenylpiperazine, 4-benzylpiperazine, etc.

3-Imino-2,3-dihydrobenzo(b)furan derivatives have not been disclosed hitherto. As a result of intensive research into the method for producing this compound, the present inventors found that a 3-imino-2,3-dihydrobenzo(b) furan derivative can be easily produced by reacting a 1゜2-benzisoxazole derivative with a strong base. The present invention was completed based on the discovery that the product is useful as a medicine.

According to the present invention, the desired general A 2,3-dihydrobenzo(b) furan derivative represented by the formula (wherein R+, R2, R3 and R4 are the same as above) can be easily obtained.

The reaction from compound (It) to compound (It) can be carried out in an inert solvent such as dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or in a lower alcohol such as anhydrous methanol or ethanol.
It is carried out by stirring the starting compound (II) at -20 to 50°C, preferably -10 to 10°C, for several minutes to several tens of hours, usually for 20 to 60 minutes, in the presence of 1 equivalent or more of a strong base. .

The compound of formula (1) in which R5 is an acyl group can be produced by acylating the compound of formula ([) obtained by the above method under neutral to basic conditions by a conventional method. can do.

In addition, the compound of formula [1] in which X is an oxygen atom is a compound of formula ([
) can be produced by acid hydrolysis of the compound. A dilute mineral acid or an organic acid is used as the acid, and suitable acids include organic acids such as oxalic acid and maleic acid.

The raw material compound (II) is based on the literature (H, Uno et al.
, Chem.

Pharm, Bull, Vol. 24, p. 632, 197
It can be manufactured by the method described in 2006) or a method similar thereto.

The compounds [1] of the present invention obtained as described above are all new compounds, and some have central effects,
Expected to be used as a medicine. Furthermore, the compound of the present invention represented by the formula ([) can be prepared using 3
-Imino-2,3-dihydrobenzo[b) has a furan structure, and is not only useful as a raw material for producing various derivatives thereof, but also can be easily converted into 3(2H)-benzofuranone derivatives, so its production It is also a valuable compound as an intermediate.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 2-dimethylamino-3-imino-2,3-dihydrobenzo(b) Furan-2-carboxylic acid methyl ester (1) α-dimethylamino-1,2-benzisoxazole-3-acetic acid methyl ester 2. Oy was dissolved in 10 me of anhydrous dimethylformamide, and 450 rng of sodium 60 thihydride was added while cooling with water. After stirring at room temperature for 30 minutes, the mixture was cooled with water and ether and 15% ammonium chloride aqueous solution were added. After adding more water, the ether layer was separated, washed with water, and dried over anhydrous sodium sulfate. The ether was distilled off and the residue was recrystallized from ether-〇-hexane to give 2-
Dimethylamino-3-imino-2゜3-dihydrobenzo(b)furan-2-carboxylic acid methyl ester 760F
Obtain 71g.

m, p, 119 121℃ MS m/z: 234 (M”) IRv: 3210.1740.1650cm (
2) Dissolve 18 otng of α-dimethylamino-1,2-benzisoxazole-3-acetic acid methyl ester in 1.5 met/C of anhydrous dimethylformamide, add 89 rnl of potassium monobutoxide, and stir at room temperature for 1 hour.

Following treatment in the same manner as in (1), 2-dimethylamino-3
-imino-2,3-dihydrobenzo(b)furan-2-
70 μ of carboxylic acid methyl ester are obtained. The city is (1)
It was consistent with the compound obtained in .

Example 2 2-Methylamino-3-imino-2,3-dihydrobenzoCb) Furan-2-carboxylic acid methyl ester α-methylamino-1,2-benzisoxazole-
800 ml of 3-acetic acid methyl ester was dissolved in 5 ml of anhydrous dimethylformamide, and while cooling with water, 612 ml of potassium-butoxide was added and stirred for 30 minutes. Example 1-(
1) to obtain 400 fng of 2-methylamino-3-imino-2,3-dihydrobenzo(b) furan-2-carboxylic acid methyl ester.

m, p, 135 137°C (recrystallized from ethanol-〇-hexane) MS m/z: 220 (M+) IRz, ; 3275, 3180, 1735, 1
650 Cm' Example 3 2-hexamethyleneimino-3-imino-2,3-dihydrobenzo(b) Furan-2-carboxylic acid methyl ester α-hexamethyleneimino-1,2-benzisoxazole-3 -Methyl acetate 42y is dissolved in anhydrous dimethylformamide 37me, and 60% sodium hydride 1y is added little by little while cooling with water. After stirring for 20 minutes while cooling with water, ether and water were added, and the mixture was neutralized with dihydrochloric acid. The ether layer is separated, washed with water, and then dried over anhydrous sodium sulfate. The ether was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 1.3y of 2-hexamethyleneimino-3-imino-2,3-dihydrobenzo(b) furan-2-carbo/acid methyl ester. get.

m, p, 93-95°C (recrystallized from ether-hexane) Example 4 3-imi/-2-(4-phenylpiperazin-1-yl)-2,3-dihydropene:/(b) Furan-2 -carboxylic acid methyl ester α-(4-yenylpiperazine-1-1)-1゜2
-benzisoxazole-3-acetic acid methyl ester 2
202 was dissolved in anhydrous dimethylformamide 15me,
Add 2751 ng of 60% sodium hydride while cooling with water. After stirring for 30 minutes under water cooling, chloroform and an aqueous solution of 15-ammonium chloride are added. After further adding water, the chloroform layer is separated, washed with water, and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was recrystallized from methanol to give 3-imino-2-(4-phenylpiperazin-1-yl L-2,3-dihydrobenzo(b)furan-
770 μ of 2-carboxylic acid methyl ester are obtained.

m, p, 178 180°C h4S m7'z: 351 (M+)Br IRν: 3225.1745. 1650 cyi-'
Example 5 3-Imino-2-morpholino-2,3-dihydrobenzo[b]furan-2-carboxylic acid methyl ester α-morpholino-1,2-benzisoxazole-3
-Dissolve 2.14y of methyl acetate in 15+ne of anhydrous dimethylformamide and hydrogenate to 60% under water cooling)
Add 341 cm of IJum and stir for 30 minutes. Hereinafter, the same treatment as in Example 1-(1) was carried out to obtain 3-imino-2-morpholino-2,3-dihydrobenzo [b) furan-2-
550 μm of carboxylic acid methyl ester are obtained.

m, p, 136 137 °C (recrystallized from diisopropyl ether) MS m/z: 276 (M +) TRl)
: 3225. 1740. The following compound was prepared in the same manner as 1650 Cm.

2-Diethylamino-3-imino-2,3-dihydrobenzo(b) Furan-2-carboxylic acid methyl ester (oil) MS ex/z: 262 (M+) 3-imino-2-(1-pyrrolidinyl)- 2,3-dihydrobenzo(b) furan-2-carboxylic acid methyl ester (oil) MS m/z: 260 (M”) 3-imino-2-(4-methylpiperazin-1-yl)
-2,3-dihydrobenzo(b)furan-2-carboxylic acid methyl ester (oil) MS m/z: 2
89(M”) Example 6 3-acetylimino-2-dimethylamino-2゜3-dihydrobenzo (b) Furan-2-carboxylic acid methyl ester 2-dimethylamino-3-imino-2,3-dihydrobenzo (b) Furan-2-carboxylic acid methyl ester 15
9fflf, pyridine 0.8ml', acetic anhydride 0.4m
The mixture of e. is stirred at room temperature for 5 hours. After the reaction solution was concentrated to dryness under reduced pressure, n-hexane was added. The obtained crude crystals were recrystallized from ether-〇-hexane to obtain 3-acetylimino-2-dimethylamino-2,3-dihydrobenzo[, b) furan-2-carboxylic acid methyl ester 13
Get 0fng.

m, p, 90-91°C MS m/z: 276 (M+) IRv; 1755.1700.1660cm'
Example 7 3-acetylimino-2-hexamethyleneimino-2,
3-dihydroben: / (b) Furan-2-carboxylic acid methyl ester 2-hexamethyleneimino-3-imino-2,3-dihydrobenzo (b) Furan-2-carboxylic acid methyl ester 148■, Pyri 9F A mixture of 2me and 1me acetic anhydride is left at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified using silica gel column chromatography.
120 ml of oily 3-acetylimino-2-hexamethyleneimino-2,3-dihydrobenzo(b)furan-2-carboxylic acid methyl ester is obtained.

MS m/z: 330 (M+) Example 8 3-acetylimino-2-(1-pyrrolidinyl)-2,
2.0 y of 3-dihydrobenzo[b]furan-2-carboxylic acid methyl ester α-(1-pyrrolidinyl)-1,2-benzisoxazole-3-acetic acid methyl ester was dissolved in 15 m+' of anhydrous dimethylformamide and cooled with water. Add 338 fflli of sodium 60 thihydride to the mixture and stir for 30 minutes. Ether and 15% ammonium chloride aqueous solution are added to the reaction solution. After adding more water, the ether layer was separated, washed with water, and dried over anhydrous sodium sulfate. The ether was distilled off, the residue was dissolved in 30 me of chloroform, 09y of 4-dimethylaminopyridine and 1 me of acetic anhydride were added thereto, and the mixture was stirred at room temperature for 1 hour. Chloroform was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 3-acetylimino-241-pyrrolidinyl)-2,
520 μm of 3-dihydrobenzo(b) furan-2-carboxylic acid methyl ester are obtained.

m, p, 100-102°C (recrystallized from ether-hexane) Example 9 3-acetylimino-2-diethylamino-2゜3-dihydrobenzoCb) Furan-2-carboxylic acid methyl ester α-diethylamino-1, 1.6y of 2-benzisoxazole-3-acetic acid methyl ester was dissolved in 10me of anhydrous dimethylformamide, 244 ml of sodium 60 thihydride was added under water cooling, and the mixture was stirred for 30 minutes.

Ether and an aqueous solution of ammonium chloride are added to the reaction solution. After adding more water, the ether layer was separated, washed with water, and dried over anhydrous sodium sulfate. The ether was distilled off, the residue was dissolved in 2me of pyridine, 1me of acetic anhydride was added, and the mixture was left at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain oily 3-acetylimino-2-diethylamino-2,3-dihydrobenzo(b) furan-2-carboxylic acid methyl ester 2804. obtain.

MSm/z: 304 (M+) Example 10 3-acetylimino-2-(4-methylpiperazine-1
-yl)-2,3-dihydrobenzo(b)furan-2-
Carboxylic acid methyl ester α-(4-methylpiperazin-1-yl)-1゜2-benzisoxazole-3-acetic acid methyl ester 1.4
1y was dissolved in 10 ffle of anhydrous dimethylformamide, 19 of 60% sodium hydride was added while cooling with water, and the mixture was stirred for 30 minutes. The following treatment was carried out in the same manner as in Example 9 to obtain 270 μl of oily 3-acetylimino-2-(4-methylpiperazine-11l)-2,3-)hydrobenzo[b]furan-2-carboxylic acid methyl ester. get.

MS m/z: 331. (M+) Example 11 2-morpholino-3(2H)-benzofuranone-1-I
J Rubonic acid methyl ester 3-imino-2-morpholino-2,3-dihydrobenzo(b)furan-2-carboxylic acid methyl ester 63rn
Dissolve g in methanol 9me and add 43f cyanoic acid to this.
ng and 0.2 me of water were added and left overnight at room temperature.

After distilling off the methanol and adding an aqueous solution of potassium carbonate to the residue, the mixture is extracted with dichloromethane. Wash the extract with water and dry. The solvent was distilled off and the residue was recrystallized from ether-hexane to obtain 52fng of 2-morpholino-3(2H)-benzofuranone-2-carboxylic acid methyl ester.

m, p, 141-142℃ The following compounds were produced in the same manner.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X means N-R_5 or an oxygen atom, R_
1 means a lower alkyl group, aryl group or aralkyl group, R_2 and R_3 are the same or different and mean a hydrogen atom or a lower alkyl group, or R_2
and R_3 may be bonded to each other, or R_2 and R_3 may form a ring together with another oxygen atom, sulfur atom, or nitrogen atom substituted with a lower alkyl group, aryl group, or aralkyl group, and R_4 is hydrogen R_5 means a hydrogen atom or an acyl group. ) A 2,3-dihydrobenzo[b]furan derivative represented by: (2) General formulas ▲ Numerical formulas, chemical formulas, tables, etc. or R_2 and R_3 combined with each other, or R_
2 and R_3 may form a ring together with another oxygen atom, sulfur atom, or nitrogen atom substituted with a lower alkyl group, aryl group, or aralkyl group, and R_4 is a hydrogen atom, a halogen atom, a lower alkyl group, or Means a lower alkyloxy group. ) The following general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (where R_1, R_2, R_3 and R_4 are the same as above), which is characterized by the action of a strong base on the 1,2-benzisoxazole derivative represented by ) A method for producing a 2,3-dihydrobenzo[b]furan derivative represented by: