JPH0316338B2 - - 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.

The methanesulfonate salt of 3,4-di(p-tolyloxy)-α-(tert-butylaminomethyl)benzyl alcohol is known to be a useful substance as a drug, particularly as a sympathomimetic agent.

Conventionally, methods for producing this compound include 3,4-
A method is known in which the two hydroxyl groups of dihydroxyphenyl tertiary butylaminomethyl ketone are tolylated and then the ditolylated compound is catalytically reduced in ethanol or reduced with sodium borohydride in methanol. It is being
(Japanese Patent Publication No. 53-14544) However, such ester compounds are susceptible to solvolysis in solvents such as ethanol or methanol, and therefore, under these reducing conditions, it is difficult to avoid the formation of by-products. The existence of drawbacks has made it difficult to implement these known methods industrially.

The present inventors separately conducted various studies on the synthesis of oxirane derivatives and developed an excellent synthesis method. By utilizing this method of synthesizing oxirane derivatives, we have succeeded in providing an excellent industrial method for the production of oxirane derivatives. That is, the present invention provides 3,4-di(p -Tolyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol is provided.

The method of the invention is of great value from an industrial point of view. The present invention will be explained in more detail below.

The following formula serves as a starting material or intermediate product for each step in the method of the present invention:
The compounds represented by are all new substances created by the present inventors, and these substances are
It is a useful intermediate material for the production of 3,4-di(p-toluyloxy)-α-(tert-butylaminomethyl)benzyl alcohol.

(In the formula, R means a substituted or unsubstituted α-alkoxyalkyl group, 2-oxacycloalkyl group, or trialkylsilyl group.) (R in the formula has the same meaning as above.) (In the formula, R has the same meaning as above.) 3,4-(dibenzyloxy)styrene oxide represented by the above formula is obtained by reacting 3,4-(dibenzyloxy)benzaldehyde with trimethylsulfonium methylsulfate. Manufactured by In this case, it is preferable to prepare a mixed solution of trimethylsulfonium methylsulfate and sodium methoxide in advance, and then add 3,4-(dibenzyloxy)benzaldehyde to this. As the solvent, dioxane, tetrahydrofuran or acetonitrile is used, the reaction temperature is preferably in the range of -20°C to 20°C, and the reaction time is usually sufficient in the range of 30 minutes to 5 hours.

3,4-(dibenzyloxy) represented by the formula
-α-(tertiary butylaminomethyl)benzyl alcohol can be easily produced by reacting a compound of the formula with tertiary butylamine.

In this reaction, a solvent such as ethanol, acetonitrile, benzene or dimethylformamide can be used, and the reaction can also be carried out without a solvent. Further, the reaction temperature is usually in the range of 50°C to 150°C, and the reaction time is usually about 1 to 4 days.

3,4-(dibenzyloxy) represented by the formula
-α-Aminomethylbenzyl alcohol derivatives are compounds represented by the formula (a) acid, e.g.
A vinyl ale compound such as 2,3-dihydropyran, ethyl vinyl ether or isopropenyl methyl ether is reacted in the presence of p-toluenesulfonic acid, methanesulfonic acid, phosphorus oxychloride, boron trifluoride, etc. or (b) a base, e.g. It can be easily produced by reacting with trimethylchlorosilane or tertiary-butyldimethylchlorosilane in the presence of pyridine, imidazole, triethylamine, or the like.

In these reactions, toluene, dichloromethaneacetonitrile, dimethylformamide, tetrahydrofuran, or the like can be used as a solvent. Further, the reaction temperature is usually in the range of 0°C to 50°C, and the reaction time is usually about 1 hour to 24 hours.

3,4-dihydroxy- represented by the general formula
The 2-aminomethylbenzyl alcohol derivative is
It is produced by catalytic hydrogenation of the compound using palladium on charcoal as a catalyst. This reaction is usually carried out at 0°C using ethanol, methanol or tetrahydrofuran as a solvent.
The reaction is carried out at a temperature ranging from room temperature to room temperature, and a reaction time of 1 hour to 6 hours is usually sufficient.

The 3,4-di(p-tolyloxy)-α-aminomethylbenyl alcohol derivative represented by the general formula It is produced by reacting with p-toluyl. In this case, an inert solvent such as benzene, toluene, dichloromethane, acetonitrile, pyridine or dimethylformamide is used as the solvent, and the reaction is usually carried out at a temperature range of 0°C to 30°C, and the reaction time is usually A period of 30 minutes to 4 hours is sufficient.

By removing the protecting group R of the compound thus obtained, the final target 3,
4-di(p-tolyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol is produced. Removal of this protective group is carried out by a conventional method, but when treating with an acid, the acid may be hydrochloric acid,
Examples include sulfuric acid, acetic acid, p-toluenesulfonic acid, and zinc bromide. Examples of solvents used include acetone, tetrahydrofuran, acetic acid, and dichloromethane. These solvents can also be used as a mixture with water if desired. This reaction usually takes place at room temperature for 1 to 10 hours.

The method of the present invention uses inexpensive and easily available starting materials, and each step is carried out by simple operations under mild and easily set reaction conditions.
Target 3,4-di(p-toluyloxy)-
This method has excellent advantages as an industrial production method, such as being able to produce α-(tertiary butylaminomethyl)benzyl alcohol in high yield and with high purity.

Examples of the present invention are listed below, or the present invention includes:
The present invention is not limited to these examples.

Example 1 Production of 3,4-(dibenzyloxy)styrene oxide 7.57 g (0.06 mol) of dimethyl sulfate was dissolved in 20 ml of acetonitrile, and while stirring under ice cooling,
Add 4.10 g (0.066 mol) of dimethyl sulfide and let stand at room temperature overnight to prepare an acetonitrile solution of trimethylsulfonium methyl sulfate. The solution was then cooled to 0° C. and 3.57 g (0.066 mol) of sodium methoxide was added to it under stirring, followed by 12.74 g (0.04 mol) of 3,4-(dibenzyloxy)benzaldehyde in 20 ml of acetonitrile. Add the dissolved solution dropwise over a period of 30 minutes. After stirring for 1 hour while cooling, the solvent was distilled off under reduced pressure, and 40 ml of water and 50 ml of benzene were added to the resulting residue.
Add and dissolve, and separate the organic layer. Extract this aqueous layer twice with 20 ml of benzene, combine the extract with the organic layer, and combine it with 0 ml of water and 40 ml of saturated saline.
and then dried using anhydrous sodium sulfate. It was then filtered and the filtrate was concentrated to obtain 13.06 g (yield 98.2%) of the title compound.

NMR δ _CDCl3 : 2.72 (d, d, 1H) 3.06 (d, d, 1H) 3.84 (t・like, 1H) 5.23 (s, 4H) 6.90 (m, 3H) 7.43 (m, 10H) MS 50eV m/ e: 332 (M ⁺ ), 298, 241 Example 2 Production of 3,4-(dibenzyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol (a) 3,4-(dibenzyloxy)styrene 11.20 g (0.0337 mol) of oxide is dissolved in 24.65 g (0.337 mol) of tertiary butylamine and stirred at 65° C. for 3 days in a sealed tube. Excess tertiary butylamine in the reaction product was distilled off under normal pressure, and the resulting residue was recrystallized from 20 ml of acetonitrile to obtain 11.06 g (yield: 80.9%) of the title compound.

Melting point 94.0~95.0℃ NMR δ _CDCl3 : 1.04 (s, 9H) 2.62 (m, 4H, 2H disappears in D ₂ O) 4.50 (d, d, 1H) 5.10 (s, 2H) 5.13 (s, 2H) 6.85~ 7.5 (m, 13H) MS 70eV m/e405 (M ⁺ ), 387, 319, 314,
138,91,86 Elemental analysis value C ₂₆ H ₃₁ NO ₃ Calculated value (%) C: 77.01, H: 7.71, N: 3.45 Actual value (%) C: 77.14, H: 7.66, N: 3.23 (b) 3 , 9.97 g (0.03 mol) of 4-(dibenzyloxy)styrene oxide and 10.97 g (0.15 mol) of tertiary butylamine in 30 ml of ethanol.
and stir in a sealed tube at 60℃ for 24 hours. Next, the solvent was distilled off, and the resulting acid distillate was recrystallized using 20 ml of acetonitrile, giving a melting point of 93.5.
7.40 g of the title compound showing ~94.9°C (yield 60.8
%)was gotten. Various analytical data of this product were consistent with those obtained in (a) above.

Example 3 Production of N-tertiary butyl-β-(3,4-dibenzyloxyphenyl)-β-(2-tetrahydropyranyloxy)ethylamine 3,4-(dibenzyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol 2.03g
Dissolve (0.005 mol) in 5 ml of toluene and add p
- Add 1.03 g (0.006 mol) of toluenesulfonic acid. This solution was then stirred at 0°C for 2,
A solution of 505 mg of 3-dihydropyran dissolved in 5 ml of toluene was added dropwise over 15 minutes, and the mixture was stirred for an additional 2 hours. Next, add 10% ammonia water to this
ml, separate the organic layer, wash twice with 10 ml of water and once with 10 ml of saturated saline, and dry over anhydrous sodium sulfate. Next, this was filtered, the solvent was distilled off, and the resulting residue was purified by alumina column chromatography to obtain 2.14 g (yield: 87.5%) of the title compound as a colorless oil.

NMR δ _CDCl3 : 1.02 (s, 9H) 1.56 (m, 7H) 2.75 (d, d, 2H) 3.27-4.02 (m, 2H) 4.27 (m, 1H) 4.65 (d, d, 1H) 5.09 (s, 4H) 6.75-7.40 (m, 13H) MS 50 eV m/e: 489 (M ⁺ ), 404, 388, 319,
313,91,86,85 Example 4 Production of N-tert-butyl-β-(3,4-dibenzyloxyphenyl)-β-(2-tert-butyldimethylsilyloxy)ethylamine 3,4-( 2.77 g of dibenzyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol
(0.0068 mol) and imidazole 2.33 g (0.033
mol) in 20 ml of dichloromethane and stirred at room temperature to add 2.26 g of tert-butyldimethylchlorosilane.
(0.015 mol) is added. After stirring for 5 hours, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography.
2.933 g of the title compound as a colorless oil (yield 83.0%)
was gotten.

NMR δ _CDCl3 : 0.22 (s, 6H) 1.09 (s, 9H) 1.26 (s, 9H) 1.80 (brs, 1H) 2.77 (d, d, 2H) 4.70 (d, d, 1H) 5.21 (s, 4H) 6.8-7.45 (m, 13H) MS 70 eV m/e: 519 (M ⁺ ), 504, 462, 433,
343, 181, 91, 86 IRcm-1 NaCl: ν _NH 3300 ν _O-Si 1090 Example 5 N-tertiary butyl-β-(3,4-dihydroxyphenyl)-β-(2-tetrahydropyranyloxy ) Production of ethylamine N-tertiary butyl-β-(3,4-dibenzyloxy)-β-(2-tetrahydropyranyloxy)
2.14 g (0.0044 mol) of ethylamine is dissolved in 20 ml of absolute ethanol, 0.1 g of 10% palladium on charcoal is added thereto, and the mixture is stirred at room temperature under a hydrogen atmosphere for 3 hours. Thereafter, the solid matter was filtered off and the solvent was distilled off, yielding 1.36 g of the title compound (yield:
100.0%) was obtained.

NMR δ _CD3CN : 1.12 (s, 9H) 1.53 (m, 6H) 2.84 (d, d, 2H) 3.2-3.9 (m, 2H) 4.36 (m, 1H) 4.54 (d, d, 1H) 5.40 (brs, 3H D ₂ O disappearance) 6.75 (m, 3H) Example 6 Production of N-tertiary butyl-β-(3,4-dihydroxyphenyl)-β-(tert-butyldimethylsilyloxy)ethylamine N-tertiary Dissolve 1.04 g (0.002 mol) of butyl-β-(3,4-dibenzyloxyphenyl)-β-(tert-butyldimethylsilyloxy)ethylamine in 10 ml of ethanol, and dissolve 10% palladium on charcoal.
Dissolve 50 mg and stir at room temperature under hydrogen atmosphere for 5 hours. Next, insoluble matter is filtered out and the filtrate is concentrated.
0.681 g of light brown oil was obtained. This product was recrystallized from 2 ml of acetonitrile to obtain 642 mg of the title compound in the form of colorless crystals. (Yield 94.7%) Decomposition point 134.3-134.8℃ NMR δ _CD3OD : 0.20 (s, 6H) 1.03 (s, 9H) 1.25 (s, 9H) 2.82 (d, d, 2H) 4.73 (d, d, 1H) 6.84 (m, 3H) Example 7 Production of N-tertiary butyl-β-[3,4-di(p-tolyloxy)phenyl]-β-(2-tetrahydropyranyloxy)ethylamine N-tertiary butyl 1.236 g (0.004 mol) of -β-(3,4-dihydroxyphenyl)-β-(2-tetrahydropyranyloxy)ethylamine was dissolved in 5 ml of pyridine and added to this with stirring at 0°C.
- 1.36 g (0.0088 mol) of toluyl was added dropwise over 15 minutes and the mixture was stirred for 3 hours. Next, add 20 ml of benzene and 20 ml of aqueous ammonia to this,
The organic layer is separated, washed twice with 20 ml of water and once with 10 ml of saturated brine, and then dried over anhydrous sodium sulfate. This was then filtered and the filtrate was concentrated to obtain 2.08 g (yield 95.4%) of the title compound.

NMR δ _CDCl3 : 1.13 (s, 9H) 1.66 (m, 6H) 2.37 (s, 6H) 2.86 (d, d, 2H) 3.4~4.1 (m, 2H) 4.51 (m, 1H) 4.90 (d, d, 1H) 7.08-7.97 (m, 11H) MS 50 eV m/e: 545 (M ⁺ ), 459, 426, 119,
91.86 IRcm-1 NaCl: ν _C=0 1735 ν _NH 3440 Example 8 N-tertiary butyl-β-[3,4-di(p-tolyloxy)phenyl]-β-(tertiary butyldimethylsilyloxy) Production of ethylamine 3.39 g (0.01 mol) of N-tert-butyl-β-(3,4-dihydroxyphenyl)-β-(tert-butyldimethylsilyloxy)ethylamine and 3.03 g (0.06 mol) of triethylamine are dissolved in 30 ml of dichloromethane. Dissolve p-chloride into this under stirring at room temperature.
Toluyl 3.09g (0.02mol) dichloromethane 10
ml solution was added dropwise over a period of 20 minutes. After stirring as it is for 2 hours, wash with 20 ml of water 3 times,
Dry with anhydrous sodium sulfate. This was then filtered and the filtrate was concentrated to obtain 5.76 g (yield 100.0%) of the title compound.

NMR δ _CDCl3 : 0.17 (s, 6H) 0.98 (s, 9H) 1.14 (s, 9H) 1.90 (brs, 1H) D ₂ O disappearance 2.37 (s, 6H) 2.80 (d, d, 2H) 4.87 (d, d, 1H) 7.10-8.04 (m, 11H) MS 50 eV m/e: 575 (M ⁺ ), 560, 519, 489,
371, 313, 119, 91, 86, 57 IRcm-1 NaCl: ν _C=0 1738 ν _NH 3440 Example 9 3,4-di(p-tolyloxy)-α-(tertiary butylaminomethyl)benzyl alcohol (a) N-class butyl-β-[3,
4-di(p-tolyloxy)phenyl]-β
-(2-tetrahydropyranyloxy)ethylamine (2.08 g 0.0038 mol) with 10 ml of acetone and 10
% hydrochloric acid (5 ml) and stirred at room temperature for 3 hours. Add to this solution 20 ml of benzene and 10
Add 20 ml of % potassium carbonate aqueous solution and separate the organic layer. The organic layer is washed twice with 20 ml of water and once with saturated brine, and then dried over anhydrous sodium sulfate. This was then filtered and the filtrate was concentrated to obtain 1.72 g (yield 98.2%) of the title compound.

NMR δ _CDCl3 : 1.09 (s, 9H) 2.31 (s, 6H) 2.75 (d, d, 2H) 3.62 (brs, 2H, _D2O disappearance) 4.68 (d, d, 1H) 7.05-7.98 (m, 11H) ) MS 50 eV m/e: 461 (M ⁺ ), 443, 361, 326,
191, 136, 119, 91, 86 IRcm−1 NaCl: ν _C=0 1735 Elemental analysis value C ₂₈ H ₃₁ NO ₅ Calculated value (%) C: 72.86, H: 6.77, N: 3.03 Actual value (%) C :72.98, H:6.93, N:2.88 (b) N-tertiary butyl-β- obtained in Example 8
[3,4-di(p-tolyloxy)phenyl]-β-(tertiary butyldimethylsilyloxy)
2.88g (0.005mol) of ethylamine in 6ml of acetic acid
Dissolve in a mixed solvent of 2 ml of water and 2 ml of tetrahydrofuran, and stir at room temperature for 8 hours. This solution is concentrated under reduced pressure, the residue is dissolved in 15 ml of benzene and 20 ml of 10% potassium carbonate aqueous solution, and the benzene layer is separated. Next, this was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 2.05 g (yield: 88.9%) of the title compound. Various analytical data of this substance were consistent with that obtained in (a) above.

Claims (1)

[Claims] 1 formula 3,4-(dibenzyloxy)-α- represented by
After protecting the hydroxyl group of the aminomethylbenzyl alcohol derivative with a protecting group, catalytic hydrogenation was performed to obtain the general formula (In the formula, R is a protecting group for a hydroxyl group.) A 3,4-dihydroxy-α-aminomethylbenzyl alcohol derivative represented by 3,4-(ditolyloxy)-α- (wherein R has the above definition)
Formula characterized by removing protecting group R of aminomethylbenzyl alcohol derivative 3,4-di(p-toluyloxy) represented by
-α-(tertiary butylaminomethyl)benzyl alcohol production method 2 3,4-(dibenzyloxy)benzaldehyde is reacted with trimethylsulfonium methylsulfate and sodium methoxide, and the resulting formula is
The formula obtained by reacting 3,4-(dibenzyloxy)styrene oxide represented by and tertiary butylamine 3,4-(dibenzyloxy)-α- represented by
After protecting the hydroxyl group of the aminomethylbenzyl alcohol derivative with a protecting group, catalytic hydrogenation was performed to obtain the general formula (In the formula, R is a protecting group for a hydroxyl group.) A 3,4-dihydroxy-α-aminomethylbenzyl alcohol derivative represented by (wherein R has the above definition) 3,4-(ditolyloxy)-α-
Formula characterized by removing protecting group R of aminomethylbenzyl alcohol derivative 3,4-di(p-toluyloxy) represented by
-Production method of α-(tertiary butylaminomethyl)benzyl alcohol.