JPS6140664B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula () This invention relates to piperidinoalkanols represented by

The compound () of the present invention, namely 1-(4-benzyloxyphenyl)-2-(4-benzylpiperidino)propan-1-ol, has the formula () useful as a cardiovascular drug. 1-(4-hydroxyphenyl)-2-(4-
It is easily derived from benzylpiperidino)propan-1-ol. In particular, the erythro form of the compound (), under the generic name ifenprodil, has been used as an ameliorating drug for cerebral infarction, cerebral hemorrhage sequelae, and the like. It is therefore an object of the present invention to provide useful intermediates for obtaining such pharmaceutical compounds.

Conventionally, as a method for producing the above compound (), for example, 1-(4-substituted phenyl)-
2-(4-benzylpiperidino)propane-1-
On (Special Publication No. 47-15348) or 1-
A method of catalytic reduction of [1-(4-benzyloxyphenylcarbonyl)ethyl]-4-benzylpyridinium bromide (Japanese Unexamined Patent Publication No. 1981-4081) is known, but in both methods, It cannot be said to be suitable as an industrial manufacturing method because it requires heating, pressurization, or pressurization.

In view of the above technical situation, as a result of studying a more effective method for producing compound (), it was discovered that the target compound () can be obtained via the compound () of the present invention through the route shown in the following chemical formula, and the present invention completed. That is, the compound of the present invention is a ketone body () obtained by reducing with a metal hydride. The metal hydrides used in this reduction reaction include sodium borohydride, lithium aluminum hydride, sodium aluminum diethyl dihydride, sodium dihydrobis2-methoxyethoxyaluminate, trimethoxylithium aluminum hydride, and aluminum hydride. For example, sodium borohydride is preferred. As the solvent used in this reaction, those commonly used may be used depending on the type of metal hydride used. For example, when sodium borohydride is used, water, lower alcohols such as methanol, ethanol, propanol, and isopropanol, tetrahydrofuran, 1,2-dimethoxyethane, diglyme, dimethylformamide, etc. can be used, but lower alcohols are preferably used. It is alcohol. A mixture of the above solvents may also be used. The reaction temperature and reaction time vary depending on the type of reducing agent used, but the reaction temperature is -
The temperature is about 20 to 100°C, preferably about 0 to 70°C. A reaction time of 0.5 to 20 hours is sufficient. Post-treatment of the reaction can be carried out by means known per se (e.g. extraction, liquid conversion, dissolution, concentration, column chromatography, crystallization, recrystallization, etc.) or by means such as recrystallization after forming an appropriate salt. It can also be refined.

It should be noted that in the above reduction, it was thought that both threo and erythro substances would be produced as products, but in the present invention, surprisingly, the erythro substance, which has stronger pharmacological activity, is more active than the threo substance. Interesting results were obtained that were preferentially obtained. The generated threo and erythro forms can be easily separated by column chromatography, but industrially it is easier to separate them by forming salts such as hydrochloride and taking advantage of the difference in solubility in solvents. I can do it.

Furthermore, the compound () from the compound () of the present invention
Debenzylation to lead to is easily carried out by catalytic reduction or the like. (See Reference Examples) As described above, in the method for producing () using the compound () of the present invention as an intermediate, the target substance can be obtained in high yield with cheaper and simpler operations than in the conventional method. The invention provides a manufacturing method that improves on the drawbacks of conventional methods.

Next, the method for producing the compound of the present invention will be illustrated by way of Examples. In addition, the reference example is from compound () to ()
This shows an example of conversion to .

Example 1 1-(4-benzyloxyphenyl)-2-
To a solution of 5.0 g of hydrochloride of (4-benzylpiperidino)propan-1-one in 100 ml of methanol and 10 ml of water, 2.0 g of sodium borohydride is added little by little while stirring and cooling on ice. After addition, stir at room temperature for 1 hour. Methanol was distilled off, and the residue was made acidic with 10% hydrochloric acid, further made alkaline with saturated aqueous sodium bicarbonate solution, and extracted with 200 ml of benzene. The solvent was distilled off, and the residue was subjected to column chromatography using 60 g of silica gel to separate the threo and erythro forms from the chloroform fraction.

By recrystallizing the separated threo compound from ethanol, threo-2-(4-benzylpiperidino)-
1-(4-benzyloxyphenyl)propane-
1.1 g (yield 27.4%) of 1-ol was obtained.

IR ν ^KBr _nax cm ^-1 : 3280 (OH) NMR (CDCl ₃ ) δ: 0.70 (3H, doublet, J=7Hz, CH-CH ₃ ) 1.0-3.2 (12H, multiplet) 4.16 (1H, Doublet, J = 10Hz, C H - OH) 4.5-5.3 (1H, wide singlet, O H ) 5.00 (2H, singlet, C ₆ H ₅ C H ₂ O) 6.6-7.6 (14H, multiplet , aromatic ring proton) Elemental analysis C ₂₈ H ₃₃ NO ₂ Calculated value: C, 80.92; H, 8.00; N, 3.37 Experimental value: C, 80.77; H, 7.96; N, 3.41 Furthermore, the erythro form is recrystallized from ethanol. Sometimes as colorless scaly crystals with a melting point of 126-127°,
Erythro-2-(4-benzylpiperidino)-1
-(4-benzyloxyphenyl)propane-1
-Oil 2.1g (yield 52.2%) was obtained.

IR ν ^KBr _nax cm ^-1 : 3150 (OH) NMR (CDCl ₃ ) δ: 0.81 (3H, doublet, J=7Hz, CH-CH ₃ ) 1.1-3.2 (12H, multiplet) 3.67 (1H, Broad singlet, O H ) 4.74 (1H, doublet, J=5Hz, C H -OH) 4.99 (2H, singlet, C ₆ H ₅ C H ₂ O) 6.7-7.6 (14H, multiplet, aromatic Ring proton) Elemental analysis C ₂₈ H ₃₈ NO ₂ Calculated value: C, 80.92; H, 8.00; N, 3.37 Experimental value: C, 80.96; H, 8.10; N, 3.27 Example 2 Enil) -2-
Dissolve 5.0 g of hydrochloride of (4-benzylpiperidino)propan-1-one in a mixture of 100 ml of methanol and 1 ml of water, and while stirring and cooling with ice while keeping the temperature of the reaction solution below 25°C, add borohydride. sodium
2.0g was added little by little. After the addition, the resulting crystals were stirred at room temperature for 2 hours and recrystallized from ethanol to give erythro-1-(4-benzyloxyphenyl)-2 as colorless flaky crystals with a melting point of 126-127°.
4.2 g (91.0%) of -(4-benzylpiperidino)propan-1-ol was obtained. After concentrating the reaction mother liquor, water was added and extracted with benzene, and the extract was washed with water.
After drying with Glauber's salt, the benzene was distilled off. The residue was recrystallized from ethanol to obtain the same erythro form as above.
Obtained 220 mg (4.8%).

Furthermore, the solvent was distilled off from the recrystallization mother liquor, the residue was subjected to column chromatography using 20 g of silica gel, and the initial chloroform eluate was recrystallized from ethanol to give colorless prism crystals with a melting point of 153 to 154 °C. as threo-1-(4-benzyloxyphenyl)-2-(4-benzylpiperidino)
10 mg (0.2%) of propan-1-ol was obtained.

Then chloroform-methanol (9:1)
The eluate was recrystallized from ethanol to obtain 40 mg (0.8%) of the same erythro form as above; total yield of erythro form 4.46 g (96.6%).

The erythro body and threo body obtained here are
The structure was confirmed by matching the specimen obtained in Example 1 with various equipment data.

Reference example 1 Threo-2-(4-benzylpiperidino)-1
-(4-benzyloxyphenyl)propane-1
- A solution of 800 mg of all in 5.0 ml of ethanol is subjected to catalytic reduction under a catalyst of 30% palladium chloride and 300 mg of carbon in a hydrogen stream until the calculated amount of hydrogen is absorbed. Separate the catalyst and distill off the solvent. The residue was crystallized from ethanol and ether and then recrystallized to give threo-2-(4-benzylpiperidino)-1-(4-hydroxyphenyl)propane hydrochloride having a melting point of 214-215° (decomposition point). 570 mg (yield 81.8%) of 1-ol was obtained.
Dissolve the product in water, make it alkaline with ammonia, and extract with chloroform. The extract was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol to give threo-2-(4
-benzylpiperidino)-1-(4-hydroxyphenyl)propan-1-ol was obtained.

NMR (CDCl ₃ ) δ: 0.72 (3H, doublet, J = 7Hz, CH - CH ₃ ) 0.9 - 3.1 (12H, multiplet) 4.19 (1H, doublet, J = 10Hz, CH - OH ) 5.47 (2H, broad singlet, 2× OH ) 6.87, 7.17 (4H, pair of doublets, CH―C ₆ H ₄ -OH) 7.24 (5H, singlet, C ₆ H ₅ ) Elemental analysis C ₂₁ H ₂₇ NO ₂ Calculated value: C, 77.50; H, 8.36; N, 4.30 Experimental value: C, 77.33; H, 8.30; N, 4.39 Reference example 2 Erythro-2-(4-benzylpiperidino)-
1-(4-benzyloxyphenyl)propane-
A solution of 1.5 g of 1-ol in 100 ml of ethanol is subjected to catalytic reduction under a 30% palladium chloride-carbon catalyst of 500 mg in a hydrogen stream until the calculated amount of hydrogen is absorbed. After separating the catalyst and distilling off the solvent, recrystallization from ethanol and ether yields erythrohydrochloride-2-(4-
benzylpiperidino)-1-(4-hydroxyphenyl)propan-1-ol 1.19 g (yield 91.1
%). Erythro-2-(4-benzylpiperidino)-1-(4-hydroxyphenyl)propane-1 is obtained by recrystallizing the free base of this product from isopropanol as colorless needle crystals with a melting point of 113-114°. -Get the oar.

The structure of this product was confirmed by matching data from various instruments with a specimen obtained by a known method.

Claims (1)

[Claims] 1 Formula () Piperidinoalkanols represented by