JPH0316339B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 3,4-di(p-toluyloxy)
The present invention relates to a novel method for producing -α-(tertiary butylaminomethyl)benzyl alcohol.

3,4-di(p-tolyloxy)-α-(tert-butylaminomethyl)benzyl alcohol is a compound with useful pharmaceutical uses, and its methanesulfonate salt has been used as a drug, especially as a sympathomimetic agent. It is used.

Conventionally, methods for producing this compound include 3,4-
Methods are known in which dihydroxyphenyl tertiary butylaminoketone is ditolylated and then catalytically reduced in ethanol or reduced with sodium borohydride in methanol (see Japanese Patent Publication No. 14544/1986).

However, in addition to the problem that such a method requires complicated steps to obtain the starting materials, such ditolylated ester compounds are subject to solvolysis in solvents such as ethanol or methanol. However, there are difficulties in carrying out the process industrially, such as the production of by-products being unavoidable under the above-mentioned reducing conditions.

As a result of intensive research to solve these problems, the inventors found that the formula 3,4-di(p-toluyloxy) represented by
We succeeded in establishing a method for obtaining 3,4-di(p-tolyloxy)-α-(tert-butylaminomethyl)benzyl alcohol in just three steps using -benzaldehyde as a starting material.

In the method of the present invention, the intermediates leading to the target substance represented by the formula are all produced through steps that can be performed easily and under mild reaction conditions using easily and inexpensively available raw materials or reagents. Since it can be manufactured using
- By adopting a tertiary butylation method,
It has now become possible to obtain a compound represented by the formula extremely simply. That is, the present invention provides 3,4-
As a method for producing di(p-tolyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol,
It provides a method of great value from an industrial point of view. The present invention will be explained in more detail below.

The compound represented by the formula can be produced by the steps shown in the diagram below.

In addition, in each method of the present invention, each compound represented by the formula, and as a starting material or intermediate in the above steps is a new substance created by the present inventors and has not been published in any literature. The substance is 3,4-di(p-toluyloxy)-α
- (Tertiary butylaminomethyl) is a useful intermediate material in the production of benzyl alcohol.

First, the above-mentioned first step is carried out by reacting 3,4-di(p-tolyloxy)benzaldehyde () with nitromethane in the presence of a tertiary amine such as triethylamine. The compound of the formula can be obtained in high yield. In this reaction, examples of solvents include acetonitrile,
Dimethylformamide or pyridine is used, but the reaction can also be carried out without a solvent. The reaction temperature is preferably in the range of room temperature to 80°C, and the reaction time is usually sufficient in the range of 3 to 24 hours.

The compound of the formula of the starting material used in the above step is:
It can be obtained very easily and in high yields by esterification of readily available protocatechyaldehyde with p-tolyl chloride in the presence of a tertiary amine such as triethylamine or pyridine. . Any inert solvent can be used for this reaction, but suitable solvents include benzene, toluene, dichloromethane, acetonitrile, dimethylformamide, pyridine, and triethylamine, and the reaction temperature ranges from -30°C to 50°C. is preferred. Further, a reaction time of 30 minutes to 4 hours is usually sufficient.

The second step is carried out by reducing the α-nitromethylbenzyl alcohol derivative of the formula thus obtained. This results in
An α-aminomethylbenzyl alcohol derivative represented by the formula is obtained. The reduction method used in this reaction is catalytic hydrogenation in the presence of a noble metal catalyst such as Raney nickel, or a reduction reaction using a transition metal such as iron powder or zinc powder.

In the case of the Raney Nickel reduction method, a suitable solvent such as dioxane, tetrahydrofuran, or acetic acid is used in which
The reaction is carried out at temperatures between 0.degree. C. and 60.degree. C. and atmospheric pressure until the stoichiometric amount of hydrogen has been absorbed. The reaction time is
Usually 5 to 10 hours is sufficient. In addition, in the case of the reduction method using bad lead powder, it is advantageous to carry out the reduction using a suitable solvent such as aqueous dioxane or aqueous tetrahydrofuran at 20 to 65°C and adding ammonium chloride. be. Further, a reaction time of up to 6 hours is usually sufficient.

α expressed by the formula obtained above
-aminomethylbenzyl alcohol derivative N-
By tertiary butylation, 3,4-di(p-tolyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol represented by the general formula can be obtained. N used in this reaction
- Advantageous methods for tertiary butylation include tertiary butyl bromide under basic conditions or isobutene under acidic conditions.

In the case of the method using tertiary butyl bromide, in pyridine or triethylamine, or in a mixed solvent of dimethylformamide and tetrahydrofuran in the presence of sodium bicarbonate, under basic conditions at a temperature of 20°C to 60°C. It will be held in A reaction time of 24 hours or less is usually sufficient. In addition, in the case of a method using isobutene, the temperature is -20°C to -20°C in a suitable solvent such as ether, dichloromethane, dimethylformamide, tetrahydrofuran, or a mixed solvent thereof.
It is carried out at a temperature of 7 DEG C. in the presence of an acid such as p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, boron trifluoride or phosphoric acid. A reaction time of 1 to 5 hours is usually sufficient.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Production of 3,4-di(p-toluyloxy)-α-nitromethylbenzyl alcohol 3.74 g (0.01 mol) of 3,4-di(p-toluyloxy)benzaldehyde was mixed with 6.10 g of nitromethane.
(0.1 mol) and add triethylamine to this.
Add 1.01 g (0.01 mol) and stir at 60°C for 3 hours. Then, nitromethane was distilled off under reduced pressure.
Recrystallization of the residue in ethanol yields the title compound.
3.67 g (yield 84.3%) was obtained as pale yellow crystals.

Melting point 121-122℃ Elemental analysis value C ₂₄ H ₂₁ NO ₇ Calculated value (%) C: 66.20, H: 4.86, N: 3.22 Actual value (%) C: 66.18, H: 4.91, N: 3.08 Mass 70eV m/ e: 435 (M ⁺ ), 417, 375, 239,
136, 119, 91 NMR δ _CDCl3 : 2.33 (s, 6H) : 3.85 (brs, 1H, D ₂ O disappearance) : 4.53 (d, 2H, J = 6Hz) : 5.40 (t, 1H, J = 6Hz) : 7.06-7.97 (m, 11H, arom) IR _cn ^-1 : ν _OH 3480 : ν _C=0 1745 : ν _NO ² 1550 Note that 3,4-di(p-tolyloxy)benzaldehyde used as a starting material here was manufactured as follows.

Protocatechyaldehyde 1.38g (0.01mol)
was suspended in 10 ml of acetonitrile, 3.04 g (0.03 mol) of triethylamine was added, and while stirring at room temperature,
After 3.08 g (0.02 mol) of p-toluyl chloride was added dropwise over 15 minutes, the mixture was stirred for an additional 2 hours. Add to this solution 20 ml of benzene and 20 ml of 10% hydrochloric acid.
ml, separate the benzene layer, wash the benzene layer three times with 20 ml of water, dry with anhydrous sodium sulfate, and then evaporate the solvent. In this way, 3.59 g (yield 96.1%) of 3,4-di(p-tolyloxy)benzaldehyde was obtained as pale yellow crystals.

Melting point 109-111℃ IR _cn ^-1 : ν _C=0 1730, 1690 Mass 70eV m/e: 374 (M ⁺ ), 136, 119, 91 Example 2 3,4-di(p-toluyloxy)-α -Manufacture of aminomethylbenzyl alcohol a 3,4-di(p-tolyloxy)-α-nitromethylbenzyl alcohol 1.45g (0.0033
mol) was dissolved in 15 ml of dioxane and 5 ml of water, 3.27 g of zinc powder was added, and while stirring at room temperature, 5.35 mol of ammonium chloride was added over 20 minutes, followed by stirring for 1 hour. Next, filter out the insoluble matter, add 20 ml of water and 20 ml of dichloromethane, and separate the dichloromethane layer. The aqueous layer was extracted with 20 ml of dichloromethane, both dichloromethane layers were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the crude title compound.
1.30 g (yield 97.3%) was obtained. By treating this product with oxalic acid, a white crystalline oxalate salt was obtained.

Decomposition point 225.5℃ Elemental analysis value C ₂₅ H ₂₆ NO ₉ Calculated value (%) C: 63.03 H: 5.09 N: 2.83 Actual value (%) C: 92.98 H: 5.21 N: 2.77 IR _cn ^-1 :ν _C=0 1730, 1600 b 435 mg (0.001 mol) of 3,4-di(p-tolyloxy)-α-nitromethylbenzyl alcohol is dissolved in 5 ml of dioxane, 44 mg of Raney nickel is added, and the mixture is treated in a hydrogen atmosphere at room temperature for 7 hours. After passing through a Raney nickel filter, the solvent was distilled off to obtain 407 mg of the crude title compound. When this product is treated with oxalic acid, oxalate is obtained (decomposition point: 225°C). Various analytical data of this product are consistent with those obtained in a) above.

Example 3 Production of 3,4-di(p-toluyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol a 3,4-di(p-toluyloxy)-α-aminomethylbenzyl alcohol 405 mg (0.001 mol) in 4 ml of pyridine, add 1.37 g (0.01 mol) of tertiary butyl bromide, and stir at room temperature for 24 hours. Next, 30 ml of water and 20 ml of benzene were added to this, the benzene layer was separated, this benzene layer was washed three times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off, leaving a yellow oil.
350 mg was obtained. After this product was purified by silica gel column chloratography, treated with methanesulfonic acid and recrystallized from acetone, 175 mg (yield 31.4
%) obtained.

Elemental analysis value C ₂₉ H ₃₅ NO ₈ S Calculated value (%) C: 62.46 H: 6.33 N: 2.51 Actual value (%) C: 62.39 H: 6.41 N: 2.47 NMRδ _CDCl3 : 1.39 (s, 9H): 2.34 ( s, 6H) : 2.80 (s, 3H) : 3.15 (m, 2H) : 5.35 (m, 1H) : 7.05 to 7.99 (m, 11H) IR _cn ^-1 : ν _C=0 1730 : ν _OH 3340 Mass 70eV m/e: 461 (M ⁺ ), 443, 326, 241,
149,136,91,86,57 b Dissolve 405 mg (0.001 mol) of 3,4-di(p-tolyloxy)-α-aminomethylbenzyl alcohol in 5 ml of dimethylformamide, -
156 mg of p-toluenesulfonic acid under stirring at 20°C.
(0.001 mol), then a solution of 560 mg of isobutene absorbed in 10 ml of ether was added, and the mixture was stirred for 5 hours. Add 5% caustic soda aqueous solution to this solution and separate the ether layer. This ether layer was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 471 mg of a brown oil. After this product was purified by silica gel column chromatography, it was treated with methanesulfonic acid and crystallized using acetone, resulting in a melting point of 177-179℃.
132 mg (yield 23.7%) of the title compound having the following formula was obtained as its methanesulfonate salt. Various analytical data of this product were all consistent with those obtained in a above.

Claims (1)

[Claims] 1 formula 3,4-di(p-toluyloxy) represented by
-A formula characterized by N-tertiary butylation of α-aminomethylbenzyl alcohol 3,4-di(p-toluyloxy) represented by
-Production method of α-(tertiary butylaminomethyl)benzyl alcohol. 2 formulas The formula obtained by reducing the α-nitromethylbenzyl alcohol derivative represented by 3,4-di(p-toluyloxy) represented by
-A formula characterized by N-tertiary butylation of α-aminomethylbenzyl alcohol 3,4-di(p-toluyloxy) represented by
-Production method of α-(tertiary butylaminomethyl)benzyl alcohol. 3 formulas 3,4-di(p-toluyloxy) represented by
- obtained by reacting benzaldehyde and nitromethane, the formula The formula obtained by reducing the α-nitromethylbenzyl alcohol derivative represented by 3,4-di(p-toluyloxy) represented by
-A formula characterized by N-tertiary butylation of α-aminomethylbenzyl alcohol 3,4-di(p-toluyloxy) represented by
-A method for producing an α-(tertiary butylaminomethyl)benzyl alcohol derivative.