JPH07138236A - Production of synthetic intermediate for oxatomide - Google Patents

Abstract

PURPOSE:To provide a process for the industrially advantageous synthesis of 1-[3-[4(diphenylmethyl)-1isopropenyl-1,3-dihydro-2H-benzimidazol-2-one useful as a synthetic intermediate for oxatomide in high quality and yield. CONSTITUTION:This process for the production of 1-[3-[4-(diphenylmethyl)-1- piperazinyl]propyl]-3-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one is characterized by the reaction of 1-isopropenyl-l,3-dihydro-2H-benzimidazol-2-one with 1-diphenylmethyl-4-chloropropylpiperazine or its salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to oxatomide useful as an antiallergic agent: 1- [3
It relates to a method for producing a synthetic intermediate of-[4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazol-2-one.

[0002]

2. Description of the Related Art Oxatomide has been conventionally synthesized by various methods (Japanese Patent Publication No. 62-30990, Japanese Patent Publication No. 62-31707, Monatsch. Chem. 1985 , 639).
~ 644, Span. ES8604204, Span.
ES8604205, Span. ES8604206,
Span. ES8604207, Span. ES541
562, Ger. DD299587 and Ger. DD
299588). One of these synthetic routes is
[3- [4- (Diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one was treated with hydrogen chloride in ethanol to give oxatomide. There is a method of induction (Japanese Patent Publication No. 62-31707).

1- [3-, which is a synthetic intermediate of this route
[4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H
-Benzimidazol-2-one is conventionally 1-isopropenyl-3-chloropropyl-1,3-dihydro-2H.
-Synthesized by condensation of benzimidazol-2-one with 1-diphenylmethylpiperazine. However, this method cannot be said to be industrially advantageous because the raw material is expensive and the yield is not sufficiently high.

Therefore, the object of the present invention is to synthesize 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H which is a synthetic intermediate of oxatomide. -Benzimidazole-
It is an object of the present invention to provide a novel production method capable of industrially advantageously producing 2-one from an inexpensive raw material with high quality and high yield.

[0005]

SUMMARY OF THE INVENTION The present inventors have developed a synthetic intermediate of oxatomide, 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3. Various studies have been conducted on various methods for producing -dihydro-2H-benzimidazol-2-one. By using a reaction route which has not been tried before, that is, 1-isopropenylbenzimidazol-2-one and 1-isopropenylbenzimidazol-2-one
Surprisingly, the desired 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-by reacting with diphenylmethyl-4-chloropropylpiperazine or a salt thereof. 1,3-
It has been found that dihydro-2H-benzimidazol-2-one can be produced in high quality and in high yield. The present invention is
It was completed as a result of further research based on this knowledge.

That is, the gist of the present invention is (1) reacting 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one with 1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof. 1- [3- [4- (diphenylmethyl) -1-
Piperazinyl] propyl] -3-isopropenyl-1,
Method for producing 3-dihydro-2H-benzimidazol-2-one, (2) Reaction in an inert solvent in the presence of metal hydroxide or an aqueous solution thereof, (1) Production method (3) The production method according to (2), wherein the inert solvent is at least one selected from the group consisting of toluene, methanol, ethanol and isopropanol, (4) reacting a quaternary ammonium salt as a phase transfer catalyst. (5) The method according to any one of (1) to (3), (5) comprising N, N-dimethylformamide, dimethylsulfoxide and N, N-dimethylacetamide in the presence of a metal hydride. Reacting in one or more solvents selected from the group, and (6) reacting using metal iodide as a catalyst The method of manufacturing features to (5), wherein the bringing relates.

[0007]

[Chemical 1]

The present invention will be described in detail below.
1-isopropenyl-1,3 used in the present invention
-Dihydro-2H-benzimidazol-2-one is
HELVETICA CHIMICA ACTA, Volumen XL III, Fasciculus
V (1960) -No.163 P1298-1313 and J. Chem, Soc, Pe
It can be synthesized by the method described in rkin Trans.1, 1982, P261-270. 1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof used in the present invention can be synthesized by the method described in CHEMICAL ABSTRACTS 106: 1860u, 107: 7217g. As the salt, a hydrochloride, a sulfate, an acetate or the like is usually used.

As the condensation reaction, any method used for the condensation reaction between an alkyl chloride and a secondary amine can be used as long as it does not decompose a raw material compound or a product. Hereinafter, three typical modes will be described.

1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof, 1-isopropenyl-
1,3-dihydro-2H-benzimidazol-2-one and one or more metal hydroxides such as sodium hydroxide and potassium hydroxide selected from the group consisting of methanol, ethanol and isopropanol, or an inert solvent such as toluene. In addition to the above, when heated and stirred, the target product is produced in a high yield of 90% or more. Here, the amount of metal hydroxide is
It is usually 2 to 5 times mol, preferably 2.5 to 3.5 times mol, relative to 1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof, and the amount of the inert solvent used is
1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one is usually 4.5 to 45 times,
It is preferably 5.7 to 10 times. The reaction temperature is usually 2
The temperature is 0 ° C to the reflux temperature. The reaction time varies depending on the reaction temperature, but is usually about 1 to 10 hours, preferably 1 to 5 hours.

After completion of the reaction, when the reaction is carried out using methanol, ethanol, isopropanol or the like as a solvent, each reaction solvent is concentrated and toluene is added to dissolve it. When the reaction is performed with toluene as a solvent, the toluene layer is separated. Then, the toluene solution is washed with an aqueous sodium hydroxide solution and then with water. After dehydration with magnesium sulfate, toluene was distilled off, and 1- [3- [4
-(Diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H-
Benzimidazol-2-one is obtained.

1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one was added to N, N-dimethylformamide, dimethyl sulfoxide and N, N-dimethylformamide.
1 selected from the group consisting of N-dimethylacetamide
Dissolve in more than one kind, add metal hydride such as sodium hydride and potassium hydride, and stir for about 30 minutes. Then N, N
-The addition of 1-diphenylmethyl-4-chloropropylpiperazine dissolved in one or more selected from the group consisting of dimethylformamide, dimethylsulfoxide and N, N-dimethylacetamide, and the presence of a metal iodide such as potassium iodide Under or absent, usually 60-19
When the mixture is heated at 0 ° C., preferably 60 to 70 ° C. for 1 to 20 hours, preferably 5 to 15 hours with stirring, it is 9
The target product is produced in a high yield of 0% or more. Here, the amount of the metal hydride such as sodium hydride and potassium hydride used is 1 to 1.5 times mol with respect to 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one. When the reaction is performed in the presence of metal iodide, the amount used is also 0.1 to 0.3 times the molar amount.

1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof and 1-isopropenyl-
1,3-dihydro-2H-benzimidazol-2-one is added to a phase transfer catalyst such as sodium hydroxide in the presence of a quaternary ammonium salt such as triethylbenzylammonium chloride, tetraethylammonium chloride, or trioctylmethylammonium chloride. About 10% in a mixed solvent of an aqueous solution of the metal hydroxide of toluene and an inert solvent such as toluene, benzene, diethyl ether, methylene chloride or chloroform, or one or more selected from the group consisting of methanol, ethanol and isopropanol. ~ 30 hours, preferably 15 ~
The desired product can be obtained by heating under reflux for 20 hours. Here, the amount of the quaternary ammonium salt used is 1-
The amount is usually 0.05 to 0.5 times mol, preferably 0.05 to 0.1 times mol, of diphenylmethyl-4-chloropropylpiperazine or a salt thereof. The amount of the aqueous metal hydroxide solution used is also 2 to 5 times mol, preferably 2 to 5 times mol.
The molar ratio is 3 times and the mixing ratio of the metal hydroxide aqueous solution and the inert solvent is 1: 1 to 1:10, preferably 1: 3 to 1:
It is 4.

After completion of the reaction, the reaction solution is poured into water, toluene is added thereto and well stirred, and then the toluene layer is separated.
After dehydrating this toluene solution with anhydrous magnesium sulfate, toluene is distilled off to obtain an oily crude product containing paraffin. The obtained crude product was purified by column chromatography to obtain the desired product, 1- [3- [4- (diphenylmethyl) -1-piperazinyl] -propyl] -3-.
Isopropenyl-1,3-dihydro-2H-benzimidazol-2-one is obtained.

The oxatomide synthetic intermediate thus obtained can be easily converted to oxatomide as shown in Reference Examples.

[0016]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 1-Diphenylmethyl-4-chloropropylpiperazine hydrochloride (36.54 g, 0.10 M) and 1-isopropenyl-1,3-dihydro-2H-benzimidazole-
2-one (17.42 g, 0.10 M) and methanol (30 ml) and 8% aqueous sodium hydroxide solution (100
(ml) was added to toluene (300 ml), and the mixture was stirred with heating under reflux for 15 hours.

After completion of the reaction, the toluene layer was separated and a 2% aqueous sodium hydroxide solution (100 ml) was added, followed by water (100 m).
After washing with 1) and dehydration with magnesium sulfate (4.0 g), toluene was distilled off to give 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-.
43.72 g of isopropenyl-1,3-dihydro-2H-benzimidazol-2-one were obtained (yield 93.7).
%). NMR (60 MHz CDCl ₃ ) δ (ppm):
1.92 (m, 2H, CH ₂ ), 2.21 (s, 3H,
_{CH 3), 2.32 (m,} 2H, CH 2), 2.38
(S, 8H, 4CH ₂ ), 3.93 (t, J = 6.4H
_Z , 2H, CH ₂ ), 4.17 (s, 1H, CH),
5.25 (m, 2H, CH ₂ ), 7.21 (m, 14
H, Ar-H).

Example 2 1-Isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (17.42g, 0.10M)
And N, N-dimethylformamide (70 ml) and 60
% Sodium hydride (4.80 g, 0.12 M, containing paraffin) was added, and the mixture was stirred for 30 minutes. Next, potassium iodide (1.66 g, 0.01 M) and 1-diphenylmethyl-
4-chloropropylpiperazine (32.89 g, 0.1
0M) dissolved in N, N-dimethylformamide (20 ml) was added, and the mixture was stirred at 70 ° C. for 10 hours. After completion of the reaction, the reaction solution was poured into water (400 ml), toluene (300 ml) was added, and the mixture was shaken well and the toluene layer was separated. After dehydrating this toluene solution with anhydrous magnesium sulfate (4.0 g), toluene was distilled off to obtain 51.48 g of an oily crude product containing paraffin. Next, the obtained crude product was purified by silica gel column chromatography to give 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H-. 43.44 g of benzimidazol-2-one was obtained (yield 93.1%).

Example 3 1-Diphenylmethyl-4-chloropropylpiperazine hydrochloride (36.54g, 0.10M), 1-isopropenyl-1,3-dihydro-2H-benzimidazole-
2-one (17.42 g, 0.10 M) and sodium hydroxide (10.8 g, 0.27 M) were added to isopropanol (100 ml), and the mixture was stirred with heating under reflux for 3 hours. After the reaction was completed, the reaction solution was concentrated, and toluene was added to dissolve it. Next, 2% sodium hydroxide aqueous solution (100 m
l) and then washed with water (100 ml) and dehydrated with magnesium sulfate (4.0 g), and then toluene was distilled off to obtain 1
-[3- [4- (Diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one 43.96 g
Was obtained (yield 94.2%).

Example 4 1-Diphenylmethyl-4-chloropropylpiperazine hydrochloride (36.54 g, 0.10 M), 1-isopropenyl-1,3-dihydro-2H-benzimidazole-
2-one (17.42 g, 0.10 M) and triethylbenzylammonium chloride (1.14 g, 0.00
5M) and 8% aqueous sodium hydroxide solution (100 ml)
Was added to toluene (300 ml), and the mixture was stirred with heating under reflux for 20 hours. After the completion of the reaction, toluene was collected, and a 2% sodium hydroxide aqueous solution (100 ml) was added.
ml) and dehydrated with magnesium sulfate (4.0 g), then toluene was distilled off to give 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1. 20.16 g of 3,3-dihydro-2H-benzimidazol-2-one were obtained (yield 43.2).
%).

Reference Example 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H-benzimidazole-obtained in Examples 1-3 2-one (23.33g, 0.05M) was dissolved in methanol (150ml) and 35% hydrochloric acid (15.63) was added.
g, 0.15M) and the mixture was stirred at 60 ° C. for 1 hour. At this time, crystals precipitated as the reaction proceeded. After the reaction was completed, the reaction solution was cooled to 10 ° C or lower and the crystals were collected by filtration. Next, it was washed with cold methanol (50 ml) and 1- [3- [4-
(Diphenylmethyl) -1-piperazinyl] propyl]
-2-benzimidazol-2-one-2 hydrochloride 20.
84g was obtained (yield 83.5%).

[0023]

According to the production method of the present invention, 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one and 1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof are used. Thus, 1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one, which is a synthetic intermediate of oxatomide, was It can be industrially synthesized with high quality and high yield.

Claims (6)

[Claims] 1. A method of reacting 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one with 1-diphenylmethyl-4-chloropropylpiperazine or a salt thereof 1- [ 3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -3
-Method for producing isopropenyl-1,3-dihydro-2H-benzimidazol-2-one. 2. The production method according to claim 1, wherein the reaction is carried out in an inert solvent in the presence of metal hydroxide or an aqueous solution thereof. 3. The method according to claim 2, wherein the inert solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol and toluene. 4. A quaternary ammonium salt is reacted as a phase transfer catalyst, and the quaternary ammonium salt is reacted.
The manufacturing method according to any one of 1. 5. N, N-dimethylformamide, dimethylsulfoxide and N, N in the presence of a metal hydride.
The method according to claim 1, wherein the reaction is carried out in one or more solvents selected from the group consisting of dimethylacetamide. 6. The method according to claim 5, wherein metal iodide is used as a catalyst for the reaction.