JPS6239154B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel 1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)-1-propanol (hereinafter referred to as ifenprodil) and its addition salt, which are useful as therapeutic agents for the sequelae of cerebrovascular disorders. related to manufacturing methods. All of the conventionally known methods for producing ifenprodil involve the use of α-bromo-4'-benzyloxypropiophenone (Japanese Patent Publication No. 15348/1983, Japanese Patent Application Laid-Open No. 1983-1989) (See Publication No. 4081). That is, in these conventional methods,
Using 4'-hydroxypropiophenone as a starting material, this is benzylated to give 4'-benzyloxypropiophenone, which is then brominated to give α-bromo-4'-benzyloxypropiophenone. I had to go through the process of obtaining it. Then, the 4'-benzyloxy group on the phenyl nucleus generated by the above-mentioned benzylation prior to this bromination is debenzylated in a later step, and in the end, the final target product, ifenprodil, is again 4'-benzyloxy. -The reason for performing benzylation before bromination is that the above bromination can be directly
This is because, when performed on hydroxypropiophenone, bromine substitution on the phenyl nucleus is likely to occur, making it difficult to achieve the desired bromine substitution at the α-position. However, as mentioned above, the 4'-benzyloxy group of the 4'-benzyloxypropiophenone will eventually become a 4-hydroxy group again in the final target product, ifenprodil. If it were possible to omit the benzylation of ifenprodil, it would bring significant advantages in terms of efficiency in the production of ifenprodil. The present inventors have conducted research on a method for producing ifenprodil with a good yield while omitting the benzylation step, and have first developed a new method that provides excellent industrial advantages. Although it was developed (see Japanese Patent Application No. 54-158112 and Japanese Unexamined Patent Publication No. 56-81560),
Furthermore, in the manufacturing process of this ifenprodil, the formula, After intensive research into the reduction reaction process of the ketone compound represented by It has been found that ifenprodil can be produced with good yield. The present invention has been made based on this knowledge. In the conventional methods mentioned above, when performing the above reduction reaction, palladium-carbon is used as a hydrogenation catalyst, and the reaction is always carried out under pressure (25 to 50 kg/kg).
cm ² ) (50 to 100° C.), but in these conventional methods, unless the conditions of heating under pressure are lacking, the desired reduction reaction will not proceed. The present inventors attempted the above reduction reaction using various reduction catalysts such as Raney nickel, Raney cobalt, rhodium-carbon, and copper chromium oxide in addition to palladium-carbon, but when using these catalysts, It was discovered that the reduction reaction did not proceed smoothly in the absence of pressurization and heating conditions. Therefore, it is understood that the finding that the desired reduction reaction can proceed smoothly by using a platinum oxide catalyst without applying pressure or heating is surprising and completely unexpected. It will be. It goes without saying that the fact that the above reduction reaction can proceed without applying pressure or heating brings significant advantages in terms of equipment, work safety, and operational efficiency in industrial implementation. Nor. The present invention therefore provides a new and highly advantageous industrial process for producing ifenprodil. The present invention will be explained in detail below. In the method of the present invention, the starting material 4'-hydroxypropiophenone is first brominated using one or more solvents selected from the group consisting of methanol, ethanol, and ethers. Examples of ethers include lower aliphatic ethers such as ethyl ether and n-butyl ether, and cyclic ethers such as tetrahydrofuran and dioxane. In the method of the present invention, the solvent used in the bromination reaction is one or more solvents selected from the group consisting of methanol, ethanol, and ethers, and the solvent used in the subsequent condensation reaction and reduction reaction is The solvent used in the reaction is methanol or ethanol, so when using an ether or a solvent containing ethers in the bromination reaction, the amount used is the same as that in methanol or ethanol, which is the solvent in the subsequent condensation reaction and reduction reaction. Preferably, the amount is within a range that does not inhibit the progress of the reaction even if it is present. Bromination is
It is carried out using a brominating agent used in ordinary bromination reactions. When this bromination reaction is carried out, α-bromo-4'-hydroxypropiophenone is produced in the reaction mixture, and an equimolar amount of hydrogen bromide is generated, but in the method of the present invention, the above reaction By passing an inert gas such as air or nitrogen gas through the mixture, the hydrogen bromide produced as a by-product is discharged from the reaction system. The present inventors discovered that by passing an inert gas such as air or nitrogen into the reaction mixture after the completion of the bromination reaction, the by-product hydrogen bromide was discharged from the reaction system, resulting in the following: It was found that the condensation reaction proceeded well. This inert gas can be vented by introducing a gas in a pressurized cylinder into the reaction system, or by reducing the pressure in the reaction system by a conventional means such as an aspirator. It may also be done by. The ventilation rate, time, etc. are not specified, but preferably,
It is best to carry out the process for about 10 to 60 minutes at a flow rate of 100 to 400 ml/min. The temperature may be room temperature, but the reaction may be carried out under heating at 50 to 60°C. Further, gas discharged outside the reaction system can be easily captured using a water trap or the like. In the method of the present invention, after this inert gas ventilation, 4-benzylpyridine and methanol or ethanol are added to the above reaction mixture, and the mixture is heated to reflux. At this time, a condensation reaction between α-bromo-4'-hydroxypropiophenone produced by the bromination reaction and 4-benzylpyridine proceeds. The amount of 4-benzylpyridine added is preferably 1 to 1.2 moles per mole of 4'-hydroxypropiophenone. The method of the present invention has the characteristic advantage that the bromination reaction, condensation reaction, and reduction reaction can be carried out successively in the same reaction vessel, but the amount of solvent used in the bromination reaction is more Since a small amount is preferable, after carrying out the bromination reaction with a small amount of solvent, the solvent is additionally added when carrying out the next condensation reaction (and reduction reaction). The amount of methanol or ethanol added in the condensation reaction depends on the 4'-
500ml for 1 mole of hydroxypropiophenone
~3000ml is the preferred amount. This results in a solvent system of sufficient boiling point to provide the heating temperature necessary for the condensation reaction to proceed under reflux. In addition, this solvent system has the formula that will be generated by this condensation reaction. This is sufficient to satisfy the condition that the ketone compound is present in a dissolved state in the reaction solution during the subsequent catalytic reduction. The condensation reaction between α-bromo-4'-hydroxypropiophenone produced by the bromination reaction and 4-benzylpyridine proceeds smoothly, and 4-benzyl-1-[1-( 4-Hydroxyphenylcarbonyl)ethyl]pyridinium bromide is produced. The reaction time for the above condensation reaction is suitably 4 to 5 hours, and the temperature is suitably 60 to 90°C. The reaction mixture thus obtained is then subjected to a reduction reaction. At this time, methanol or ethanol may be newly added as appropriate. The reduction reaction is preferably carried out for 7 to 12 hours without applying pressure or heating, with the addition of platinum oxide as a hydrogenation catalyst. Through this reduction reaction, 4-benzyl-1-[1-(4-hydroxyphenylcarbonyl)ethyl]pyridinium bromide present in the reaction mixture of the above condensation reaction is reduced to form ifenprodil hydrobromide. is produced in good yield. After removing solids such as the catalyst from the reaction mixture of this reduction reaction and concentrating it under reduced pressure if necessary, water or an organic solvent can be added thereto to crystallize it, or it can be cooled as it is. Ifenprodil hydrobromide can be obtained by forming a precipitate. Ifenprodil hydrobromide thus obtained can be prepared in a conventional manner, for example by reacting with a stoichiometric amount of an alkali such as sodium hydroxide or an excess amount of ammonia in an organic solvent such as methanol or ethanol. Ifenprodil can be converted to free ifenprodil. In addition, in actual production, ifenprodil hydrobromide is not isolated, but after the reduction reaction is complete, solids such as the catalyst are removed, aqueous ammonia is added to the liquid, and the solution is concentrated under reduced pressure. It is convenient to obtain ifenprodil as a residue. It is also possible to recover ifenprodil from the liquid obtained in crystallization and recrystallization by column chromatography. Ifenprodil thus obtained can be converted into its addition salt by reacting with a desired acid in a suitable solvent. The present invention will be explained below based on examples. Example 1 6.0 g of 4'-hydroxypropiophenone is added to 4 ml of dioxane, and 6.8 g of bromine is added dropwise at room temperature while stirring. After stirring for a further 10 minutes, nitrogen was passed through the reaction solution at a flow rate of 200 ml/min for 1 hour at 60°C.
Next, 7.5 g of 4-benzylpyridine, methanol
Add 100ml and heat under reflux for 5 hours. Next, after stopping the heating, 0.3 g of platinum oxide was added to the reaction mixture, then hydrogen was introduced into the reaction mixture, and the mixture was stirred at about 1 atm for 9 hours. After the reaction is complete, solids such as the catalyst are removed and concentrated to dryness under reduced pressure. The residue was washed with 15 ml of ether and then recrystallized with ethanol, yielding 11.5 g (71.0 g) of ifenprodil hydrobromide as white crystals.
%) is obtained. Melting point: 188-191°C Thin layer chromatography: Rf 0.35 (Diatomaceous earth was used as a support, and chloroform-diethylamine (95:5) was used as a developing solvent.
A single spot was confirmed by irradiation with ultraviolet light and a color development test using Dragendorff's reagent. ) Nuclear magnetic resonance absorption spectrum (DMSO- _d6 : ppm)
1.01 (3H, d, J = 6.5Hz,

【formula】 ) 5.22 (1H, broad d,

[Formula] )6.55-7.06 (9H, m, aromatic ring proton) Elemental analysis C ₂₁ H ₂₇ NO ₂・HBr Theoretical value C, 62.07; H, 6.94; N, 3.45 Experimental value C, 61.86; H, 7.13; N , 3.34 Example 2 6.0 g of 4'-hydroxypropiophenone is added to 4 ml of dioxane, and 6.8 g of bromine is added dropwise at room temperature while stirring. After stirring for an additional 10 minutes, nitrogen was passed through the reaction solution at a flow rate of 400 ml/min for 10 minutes at 60°C, and then 8.1 g of 4-benzylpyridine, methanol
Add 100ml and heat under reflux for 5 hours. Next, after stopping the heating, 0.3 g of platinum oxide was added to the reaction mixture, hydrogen was introduced, and 8
Stir for an hour. After the reaction is complete, remove solids such as the catalyst, add 30 ml of 10% aqueous ammonia to the solution, and concentrate to dryness under reduced pressure. Dissolve the residue in 100ml of methanol and add silica gel (trade name: Wakogel C-
200) Add 100g and dry under reduced pressure. This was layered on a column (4 cm in diameter) packed with 150 g of silica gel (trade name: Wako Gel C-200), eluted with a mixed solution of 2 chloroform and 500 ml of ethyl acetate, and the eluate was discarded. It was then eluted with 1.5 ml of ethyl acetate, the eluate was concentrated to dryness under reduced pressure, and the residue was crystallized from isopropanol.
Ifenprodil 12.5g (81.2g) as white crystals
%) is obtained. Melting point: 109-111°C Thin layer chromatography: Rf 0.35 (Diatomaceous earth was used as a support, and chloroform-diethylamine (95:5) was used as a developing solvent.
A single spot was confirmed by irradiation with ultraviolet light and a color development test using Dragendorff's reagent. ) Nuclear magnetic resonance absorption spectrum (DMSO- _d6 :
ppm): 0.86 (3H, d, J = 6.0Hz

【formula】 )4.39 (1H, d, J=6.0Hz

[Formula] ), 6.47-7.00 (9H, m, aromatic ring proton) Elemental analysis C ₂₁ H ₂₇ NO ₂・C ₃ H ₈ O Theoretical value C, 74.76; H, 9.15; N, 3.63 Experimental value C, 74.69; H, 9.19; N, 3.70 Example 3 6.0 g of 4'-hydroxypropiophenone is added to 4 ml of dioxane, and 6.8 g of bromine is added dropwise at room temperature while stirring. After stirring for an additional 5 minutes, nitrogen was passed through the reaction solution at a flow rate of 400 ml/min for 1 hour at room temperature, and then 6.8 g of 4-benzylpyridine, methanol
Add 50 ml and heat under reflux for 4 hours. Next, after stopping the heating, 0.2 g of platinum oxide and 50 ml of methanol were added to the reaction mixture, then hydrogen was introduced into the reaction mixture, and the mixture was stirred under about 1 atm for 9 hours. After the reaction is completed, the catalyst is removed and the mixture is concentrated to dryness under reduced pressure. The residue was washed with 15 ml of ether and then recrystallized with ethanol to obtain 10.0 g (61.7%) of ifenprodil hydrobromide as white crystals. The physical properties of this crystal matched those obtained in Example 1. Example 4 6.0 g of 4'-hydroxypropiophenone is added to 4 ml of dioxane, and 6.8 g of bromine is added dropwise at room temperature while stirring. After stirring for an additional 5 minutes, air was passed through the reaction solution at a flow rate of 200 ml/min for 1 hour at room temperature, and then 7.5 g of 4-benzylpyridine, methanol
Add 50 ml and heat under reflux for 4 hours. After stopping heating, add 0.5 g of platinum oxide and methanol to the reaction mixture.
Add 50 ml, then add hydrogen and press at 7 atm at about 1 atm.
Stir for an hour. After the reaction is complete, remove the catalyst, add 30 ml of 10% aqueous ammonia, and concentrate to dryness under reduced pressure. The residue was crystallized from a mixed solution of 15 ml of ether and 15 ml of petroleum ether under ice cooling, and then recrystallized from isopropanol to obtain 10.2 g (66.2%) of ifenprodil as white crystals. The physical properties of this crystal matched those obtained in Example 2. Example 5 6.0 g of 4'-hydroxypropiophenone is added to 4 ml of dioxane, and 6.8 g of bromine is added dropwise at room temperature while stirring. After stirring for a further 5 minutes, air was passed through the reaction solution at a flow rate of 100 ml/min for 1 hour at 60°C.
Next, 8.1 g of 4-benzylpyridine and 100 ml of ethanol were added, and the mixture was heated under reflux for 5 hours. After stopping the heating, 0.3 g of platinum oxide and 200 ml of ethanol were added to the reaction mixture, then hydrogen was introduced into the reaction mixture, and the mixture was stirred at about 1 atm for 12 hours. After the reaction is completed, the catalyst is removed and the mixture is concentrated to dryness under reduced pressure. The residue was washed with 15 ml of ether and then recrystallized with ethanol to obtain 10.7 g (66.0%) of ifenprodil hydrobromide as white crystals. The physical properties of this crystal matched those obtained in Example 1. Example 6 Add 6.0 g of 4'-hydroxypropiophenone to 15 ml of n-butyl ether and add bromine while stirring.
Add 6.6 g dropwise at room temperature. After stirring for an additional 10 minutes, nitrogen was passed through the reaction solution at a flow rate of 200 ml/min for 1 hour at room temperature, 7.5 g of 4-benzylpyridine and 100 ml of methanol were added, and the mixture was heated under reflux for 5 hours. After stopping the heating, the same treatment as in Example 2 is carried out. 11.3 g (73.4%) of ifenprodil are obtained as white crystals. The physical properties of this crystal matched those obtained in Example 2. Example 7 6.0 g of 4'-hydroxypropiophenone is added to 15 ml of ether, and 6.6 g of bromine is added dropwise at room temperature while stirring. After dropping the bromine, the same treatment as in Example 6 is carried out. Ifenprodil 12.0 as white crystals
g (77.9%) is obtained. The physical property values of this crystal matched those obtained in Example 2. Example 8 Add 6.0 g of 4'-hydroxypropiophenone to 5 ml of tetrahydrofuran and add bromine while stirring.
Add 6.8g dropwise at room temperature. After dropping the bromine, the same treatment as in Example 2 is carried out. 11.5 g (74.7%) of ifenprodil are obtained as white crystals. The physical property values of this crystal matched those obtained in Example 2. Example 9 6.0 g of 4'-hydroxypropiophenone is added to 10 ml of methanol, and 6.4 g of bromine is added dropwise at room temperature while stirring. After dropping the bromine, the same treatment as in Example 2 is carried out. Ifenprodil 9.0 as white crystals
g (58.4%) is obtained. The physical property values of this crystal matched those obtained in Example 2. Example 10 6.0 g of 4'-hydroxypropiophenone is added to 7 ml of ethanol, and 6.6 g of bromine is added dropwise at room temperature while stirring. After dropping the bromine, the same treatment as in Example 2 is carried out. Ifenprodil as white crystals
8.8g (57.1%) is obtained. The physical property values of this crystal matched those obtained in Example 2. Example 11 A mixed solution of 5 ml of dioxane and 1 ml of methanol
Add 6.0g of 4'-hydroxypropiophenone,
6.6 g of bromine is added dropwise at room temperature while stirring.
After dropping the bromine, the same treatment as in Example 2 is carried out. 10.1 g (65.6%) of ifenprodil is obtained as white crystals. The physical property values of this crystal matched those obtained in Example 2. Example 12 4.8 g of ifenprodil hydrobromide was dissolved in 25 ml of methanol, and 3% ammonia water was added to this.
After adding 100 ml and stirring, the mixture was concentrated under reduced pressure until the total volume was about 30 ml. The residue was crystallized from 15 ml of isopropanol to yield 4.3 g (94.5%) of ifenprodil as white crystals. The physical properties of this crystal matched those obtained in Example 1. Example 13 Add 5.0 g of ifenprodil to a solution of 1.0 g of tartaric acid dissolved in 15 ml of methanol and stir until dissolved. Cool this, collect the crystals that precipitate,
After washing with methanol and drying, ifenprodil tartrate 5.0g (92.8%) appears as white crystals.
was gotten. Melting point: 140-148°C Thin layer chromatography: Rf 0.35 (Diatomaceous earth was used as a support, and chloroform-diethylamine (95:5) was used as a developing solvent.
A single spot was confirmed by irradiation with ultraviolet light and a color development test using Dragendorff's reagent. ) Nuclear magnetic resonance absorption spectrum (DMSO- _d6 :
ppm): 0.95 (6H, d, J = 7.0Hz,

【formula】 ), 3.98 (2H, S,

【formula】 ), 4.96 (2H, broad-d,

[Formula] ), 6.55-7.04 (18H, m, 2 x aromatic ring proton), elemental analysis (C ₂₁ H ₂₁ NO ₂ ) ₂ C ₄ H ₆ O ₆・12/7H ₂ O theoretical value C66.42,; H, 7.69; N, 3.37 Experimental value C, 66.55; H, 7.80; N, 3.48

Claims (1)

[Claims] 1 brominating 4'-hydroxypropiophenone using one or more selected from the group consisting of methanol, ethanol, and ethers as a solvent, and then bubbling an inert gas into the reaction mixture to produce the above-mentioned Hydrogen bromide produced during the bromination of A catalytic reduction reaction is carried out by introducing hydrogen without applying pressure or heating to produce 1-(4-hydroxyphenyl)-2.
-(4-benzylpiperidino)-1-propanol hydrobromide 1
A method for producing -(4-hydroxyphenyl)-2-(4-benzylpiperidino)-1-propanol and its addition salt.