JP2542274B2 - 3- [4- (1-imidazolylmethyl) phenyl] -2-propen-1-al and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] And a method for producing the same. The compound represented by the formula (I) can be reduced to lead to a corresponding alcohol derivative, which itself can be induced to a compound having a vasodilatory action and a platelet aggregation inhibitory action based on a calcium antagonistic action. It is possible (see JP-A-1-250375).

[Conventional technology]

Conventionally, as a method for producing 3- [4- (1-imidazolylmethyl) phenyl] -2-propen-1-ol, 4- (1-imidazolylmethyl) cinnamic acid ethyl ester, lithium aluminum hydride or the like was used. There is known a method of synthesizing by reduction using the method (Japanese Patent Laid-Open No. 61-
197578).

[Problems to be solved by the invention]

However, the conventional method has a drawback that a large amount of lithium aluminum hydride has to be used, and that the post-treatment operation requires careful attention in addition to the reaction operation itself.

[Means for solving problems]

The present inventors have studied to overcome the conventional drawbacks, and as a result, under mild conditions, without using dangerous reagents and the like, 3-
The present invention has been completed by finding a method for producing [4- (1-imidazolylmethyl) phenyl] -2-propen-1-al.

 The present invention can be represented by the following formula.

(In the formula, X is chlorine, bromine, iodine, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and Y is
_{^{H, X 1- · R 1 3}} P + - , a group represented by or R ^{₂ 2} P (O) - Yes group represented, R ³ is an aldehyde or a protected aldehyde. R ¹ is a lower alkyl group, dialkylamino group or a substituted or unsubstituted phenyl group, X ¹ is chlorine, bromine or iodine, and R ² is a lower alkoxy group. ) [Step 1] In this step, the compound represented by the formula (III) is produced by reacting the compound represented by the formula (II) with imidazole at 0 ° C to 100 ° C. is there.

The compound represented by the formula [II] can be easily obtained by obtaining a commercially available product or halogenating p-tolunitrile. The reaction is 0 ℃ to 100 ℃
However, it is preferably performed at room temperature in consideration of economical efficiency. Incidentally, in the reaction in the high temperature range of the above range, a large amount of imidazole as a raw material is used,
The reaction can be carried out without solvent.

Further, this step is preferably carried out in the presence of a base, and for example, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or the like can be used. It is also possible to substitute imidazole in an equimolar amount or more with respect to the above compound and substitute for the effect.

[Second Step] In this step, the compound represented by the formula [III] obtained in the first step is reduced in the presence of a catalyst such as Raney nickel to produce a compound represented by the formula [IV]. It is a thing.

The reaction is carried out at room temperature to 150 ° C, but is preferably carried out at 100 ° C to 140 ° C in consideration of easiness of reaction control.

It is desirable to carry out the reaction in a solvent, formic acid, acetic acid, hydrochloric acid-ethanol, water-acetic acid-
Pyridine or the like can be used.

[Third Step] In this step, the compound of the above formula [IV] obtained by the second step is reacted with the compound of the above formula [V] in the presence of a base. VI] (wherein R ³ represents the same group as described above, examples of the protective group for aldehyde include acyclic acetals such as dimethyl acetal, diethyl acetal, dimethyl mercaptar, diethyl mercaptal, and ethylene. Cyclic acetals such as acetals, propylene acetals, and ethylenedithioacetals, ethylimino groups, isopropylimino groups, cyclohexylimino groups, cyclopentylimino groups, and other imine derivatives can be mentioned), followed by acid treatment to give the above formula ( I] to produce the compound represented by the formula.

The reaction for obtaining the compound represented by the above formula [I] is desirably carried out in a solvent, and for example, methylene chloride, tetrahydrofuran, ether, methanol, ethanol and the like can be used. The compound represented by the above formula [VI] (R ³ represents the same group as described above), which is a reaction intermediate, can be isolated if necessary.

The reaction from the formula [IV] to the formula [VI] is −50 ° C.
It is carried out at a temperature of -50 ° C to 50 ° C, preferably -20 ° C to 0 ° C. In this step, it is desirable to carry out the reaction in the presence of a base, for example, alkoxides such as sodium methoxide, sodium ethoxide, potassium-t-butoxide, n-butyllithium, lithium diisopropylamide or , Sodium hydride and the like can be used.

Further, it is preferable to carry out the acid treatment from the above formula [VI] to [I] in an aqueous solution. Acids that can be used are mineral acids such as hydrochloric acid and sulfuric acid, or organic acids such as p-toluenesulfonic acid, and the acid concentration in the reaction system is 3
It is desirable to be below the regulation. The acid treatment can be carried out at 80 ° C. to 130 ° C., but it is preferably carried out under water reflux because the operation is simple.

[Fourth Step] In this step, the compound represented by the above formula [I] obtained in the third step is reduced by a method such as sodium borohydride, lithium borohydride, catalytic reduction or the like. ] It manufactures the compound represented by these.

In carrying out the reaction, water or alcohols such as methanol, ethanol and 2-propanol, or diglyme, dimethylformamide, dimethylsulfoxide and the like can be used as a solvent. The reaction is
It can be carried out at -30 ° C to 80 ° C, but -10 ° C to 5 ° C is preferable for efficient performance.

Reference Example 1 Synthesis of α-bromo-p-tolunitrile 300 ml of dry benzene was added to 19.482 g (166 mmol) of p-tolunitrile, 32.572 g (183 mmol) of N-bromosuccinimide and 2.01 g (8.3 mmol) of benzoyl peroxide to obtain 1
After heating under reflux for a period of time, the insoluble matter was filtered off at room temperature. After washing with water and drying over anhydrous sodium sulfate, benzene was distilled off under reduced pressure to obtain crude α-bromo-p-tolunitrile. Recrystallize from isopropyl ether to give 19.577g of the title compound.
(Yield 60%) was obtained.

Melting point 115-117 ° NMR (CD Cl ₃ ) δppm: 4.48 (2H, s), 7.50 (2H, d, J = 8H
z), 7.65 (2H, d, J = 8Hz) Example 1 Synthesis of 4- (1-imidazolylmethyl) benznitrile 50.488 g (79 mmol) of α-bromo-p-tolunitrile
It was dissolved in 0 ml of acetonitrile. 26.89 g of imidazole
(395 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Acetonitrile was distilled off under reduced pressure, and the residue was dissolved in chloroform. After washing with water and drying over anhydrous sodium sulfate, chloroform was distilled off to obtain 13.180 g of crude 4- (1-imidazolylmethyl) benznitrile (yield 91.1%).

Recrystallize from toluene to give 11.203 g (77% yield) of the title compound.
%) Was obtained.

Melting point 100.9-102.4 ° C NMR (CD Cl ₃ ) δppm: 5.23 (2H, s), 6.91 (1H, s), 7.16
(1H, s), 7.23 (2H, d, J = 7.5Hz), 7.66 (2H, d, J = 7.5H
z), 7.67 (1H, s) IR (cm ⁻¹ , KBr) ν _CN = 2236, ν _{C = C} = 1514 Example 2 Synthesis of 4- (1-imidazolylmethyl) benzaldehyde 1.83 g (10m mo of p-imidazolylmethylbenznitrile
A mixture of l), Raney nickel 1.83 g and 75% formic acid 27.4 ml was heated to reflux at 130 ° C. for 1 hour. After cooling, the catalyst is filtered off,
It was neutralized with saturated aqueous sodium hydrogen carbonate solution. It was extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure to obtain 1.7 g (91.4%) of crude p-imidazolylmethylbenzaldehyde. Purification by vacuum distillation (bp.150 ° / 0.2 mm) gave 1.33 g (yield 71.6%) of the title compound.

NMR (CD Cl ₃ ) δppm: 5.22 (2H, s), 6.92 (1H, s), 7.14
(1H, s), 7.28 (2H, d, J = 8Hz), 7.59 (1H, s), 7.87 (2
H, d, J = 8 Hz), 10.01 (1 H, s) IR (cm ⁻¹ , film) ν _C═O 2840,2760,1696, ν _C═C 1508 Example 3 4- (1-imidazolylmethyl) benzaldehyde Synthesis of 4- (1-imidazolylmethyl) benznitrile 21.6
94 g (118.4 mmol) were suspended in 100 ml dry toluene. −
Cool to 40 ° C, and add 160 ml (240 mmol) of a 1.5 M solution of lithium diisobutylaluminum hydride in toluene.
After dropping over a period of time, the mixture was stirred for 20 hours. The mixture was acidified with 1N-hydrochloric acid and washed with toluene. The aqueous layer was neutralized with saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform.
After washing with water, it was dried over anhydrous sodium sulfate and chloroform was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.987 g (45.3%) of the title compound.

Example 4 3- [4- (1-Imidazolylmethyl)] phenyl-2
-Synthesis of propen-1-al 8.32 g of sodium methoxide in an inert gas (Ar)
(0.154mol) suspended in 83ml of dry dichloromethane,
36.84 g (0.141 mol) of diethyl-2- (cyclohexylimino) ethylphosphonate was dried with dichloromethane.
The solution dissolved in 370 ml was added dropwise, and after completion of the addition, the mixture was further stirred for 1 hour. 23.85 g (0.128 mol) of p-imidazolylmethylbenzaldehyde was added to this solution in dry dichloromethane.
A solution dissolved in 0 ml was added dropwise. After further stirring for 2 hours, 550 ml of 1N-hydrochloric acid was added and stirred for 10 minutes. The aqueous layer was separated and washed twice with 250 ml of dichloromethane. The aqueous layer was heated under reflux for 1 hr, neutralized with sodium hydrogen carbonate under ice cooling, and the precipitated crystals were collected by filtration to give the title compound [I] as white crystals (24.18 g, yield 89%).

IR (cm ^-1 , KBr) ν _{C = O} 1670, ν _{C = C} 978,1508 NMR (CD Cl ₃ ) δppm: 5.17 (2H, s), 6.71 (1H, dd, J = 15)
Hz, 7Hz), 6.92 (1H, s), 7.12 (1H, s), 7.21 (2H, d, J = 9
Hz), 7.47 (1H, d, J = 15Hz), 7.56 (2H, d, J = 9Hz), 7.57
(1H, s), 9.71 (1H, d, J = 7Hz) Mass spectrum C ₁₃ H ₁₂ N ₂ O Theoretical value 212.09501 Actual value 212.09741 Example 5 3- [4- (1-imidazolylmethyl) phenyl] -2
-Synthesis of propen-1-ol 3- [4- (1-imidazolylmethyl) phenyl] -2
24.18 g of -propyl-1-al was suspended in 242 ml of methanol, and 2.42 g (0.064mo) of sodium borohydride was cooled with ice.
A solution obtained by dissolving l) in 24 ml of methanol was added dropwise. After stirring for 30 minutes, 200 ml of 1N hydrochloric acid was added, and methanol was distilled off under reduced pressure. Neutralize with 10% sodium hydroxide under ice cooling, collect the precipitated crystals by filtration, wash with water and dry under reduced pressure to give the title crude product.
23.7 g (crude yield 86%) was obtained. Short stroke distillation equipment (Bath temperature 2
Purification at 00 ° C., 0.2 mmHg) gave 20.87 g of the title compound (yield from [IV]: 76.1%). Melting point 97.3-100.9 ° C IR (cm ^-1 , KBr) ν _{C = C} 980,1518 NMR (CD Cl ₃ ) δppm: 2.21 (1H, s), 4.33 (2H, d, J = 6H
z,), 5.09 (2H, s), 6.37 (1H, dt, J = 15Hz, 6Hz), 6.61
(1H, d, J = 15Hz), 6.89 (1H, s), 7.08 (1H, s), 7.09 (2
H, d, J = 9Hz), 7.36 (2H, d, J = 9Hz), 7.53 (1H, s), 7.08
(1H, s), 7.09 (2H, d, J = 9Hz,), 7.36 (2H, d, J = 9H
z,), 7.53 (1H, s) mass spectrometry C ₁₃ H ₁₄ N ₂ O theoretical value 214.11067 actual value 214.11187 [Effect of the invention] Can be derived into a useful compound having both. Further, the present invention is a method which is convenient for industrial mass production because the reaction operation for obtaining the compound of the present invention is simple.

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Claims (5)

(57) [Claims] 1. Structural formula 3- [4- (1-imidazolylmethyl) phenyl] -2-propen-1-al represented by 2. Structural formula A structural formula comprising reacting a compound represented by the formula with a compound represented by the general formula Y-CH ₂ -R ³ and further treating with acid. A method for producing 3- [4- (1-imidazolylmethyl) phenyl] -2-propen-1-al represented by the formula (Y in the formula:
^{Is, H, X 1- · R 1} 3 P + - , a group represented by or R ^{₂ 2} P (O) -, a group represented by, R ³ is an aldehyde, a non-cyclic acetal group,
Aldehyde group protected by a cyclic acetal group or an imino group, R ¹ is a lower alkyl group, a dialkylamino group or a substituted or unsubstituted phenyl group, X ¹ is chlorine, bromine or iodine, and R ² is a lower alkoxy. It is a base. ). 3. The structural formula A compound by reducing the compound represented by The resulting, then by reacting a compound represented by the general formula Y-CH ₂ -R ^3, the structural formula which comprises treating further acid A method for producing 3- [4- (1-imidazolylmethyl) phenyl] -2-propen-1-al represented by the formula (Y in the formula:
^{Is, H, X 1- · R 1} 3 P + - , a group represented by or R ^{₂ 2} P (O) -, a group represented by, R ³ is an aldehyde, a non-cyclic acetal group,
Aldehyde group protected by a cyclic acetal group or an imino group, R ¹ is a lower alkyl group, a dialkylamino group or a substituted or unsubstituted phenyl group, X ¹ is chlorine, bromine or iodine, and R ² is a lower alkoxy. It is a base. ). 4. A general formula By reacting the compound represented by The 4- (1-imidazolylmethyl) benznitrile represented by A 4- (1-imidazolylmethyl) benzaldehyde represented by the following formula is obtained, which is then reacted with a compound represented by the general formula Y-CH ₂ -R ³ and further treated with an acid. The method for producing 3- [4- (1-imidazolylmethyl) phenyl] -2-propen-1-al represented by the formula:
Is chlorine, bromine, iodine, methanesulfonyloxy group or p-toluenesulfonyloxy group, Y is H, X ¹ -.R
A group represented by ¹ ₃ P ⁺ -or a group represented by R ² ₂ P (O)-, R ³
Is an aldehyde, an acyclic acetal group, an aldehyde group protected by a cyclic acetal group or an imino group, R ¹ is a lower alkyl group, a dialkylamino group or a substituted or unsubstituted phenyl group, X ¹ is chlorine, bromine or It is iodine and R ² is a lower alkoxy group. ). 5. The structural formula Structural formula consisting of reducing the compound represented by A method for producing 3- [4-(-1-imidazolylmethyl) phenyl] -2-propen-1-ol represented by: