JPS5824434B2 - Method for producing piperidino-propanol derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides piperidino- A novel method for producing propanol derivatives and acid addition salts thereof is provided.

The compound represented by the above general formula (I) is a substance useful as a medicine, particularly as a medicine effective in treating heart disease.

The present invention provides a new industrial method for producing the compound represented by the above general formula (I).

By the method of the present invention, a substituted pyridine having the general formula: (wherein R represents an alkyl group, an arylalkyl group or an aryl group) and a substituted pyridine having the general formula: (wherein, X represents a rogen atom) p -benzyloxy-α-halogropiofenone to produce an ammonium salt having the formula, where R has the above definition and X represents a halogen ion; By hydrogenating in the presence of a hydrogenation catalyst, the piperidinoglopanol derivative represented by the general formula (I) can be efficiently obtained.

The compound represented by the general formula is a substituted pyridine represented by the general formula (wherein R has the above definition) and the general formula (wherein X represents an atom atom, particularly a bromine atom). It can be obtained by reacting p-benzyloxy-α-halopropiophenone, which exists in
Generally, the reaction is carried out in a diluent in which the compound represented by the formula (I[) and the compound represented by the formula (I) are soluble, and the product of the general formula (2) is sparingly soluble or insoluble.

As this diluent, for example, an aliphatic saturated ketone having 3 to 5 carbon atoms such as acetone or methyl ethyl ketone can be used.

Alternatively, it is also possible to use diluents consisting of low-boiling aliphatic saturated alcohols, such as methanol, ethanol or isopropanol.

Products having the general formula can be isolated from the reaction mixture by conventional methods in organic chemistry.

Therefore, if the above-mentioned product formed precipitates in the reaction mixture, it can be isolated from the reaction mixture by concentrating the reaction mixture in advance and then filtering it, if necessary.

The ammonium salt represented by the formula (2) is then hydrogenated in the presence of a hydrogenation catalyst to form a 1-(
4-hydroxy-phenyl)-2-piperidino-1-propatol derivative.

As this hydrogenation catalyst, a catalyst based on a noble metal of Group 1 of the Periodic Table of the Elements (defined in the Journal of the French Society of Chemistry, January 1966 issue) is preferably used.

The treatment conditions for this hydrogenation are preferably as follows.

The amount of catalyst is 1 to 10% by weight based on the compound of formula (5),
More preferably, it is 2 to 5%, and the hydrogenation temperature is 20°
-100°C, preferably 40°-60°C.

Generally speaking, lower temperatures have a better effect on the purity of the final product.

Hydrogen pressure is 5-100 kg/crrt, but 10
A pressure of ~50 kg/crA is generally sufficient.

It is generally preferred that the above reaction is carried out in a solvent for the compound of formula (g), such as water or a low boiling aliphatic saturated alcohol such as methanol, ethanol or isopropanol.

Methanol and ethanol are particularly suitable, since the final products are soluble in these solvents, and the catalyst can be easily removed from the reaction mixture by filtration at the end of the reaction operation.

This hydrogenation is carried out on the spot where the compound of general formula (5) is produced, that is, in the reaction mixture produced by the reaction of the compound of formula ([[) and the compound of formula (e)]. It can also be carried out directly, without prior isolation of the product of formula (2).

The products obtained by this hydrogenation can be prepared by conventional methods in organic chemistry, such as precipitation by cooling followed by filtration (if necessary, concentration of the reaction mixture under reduced pressure is also preferred). ) can be isolated.

The hydrohalide of the product having the formula (I) obtained in this way can be converted into the corresponding base, but this conversion method may be a method known per se, and the addition salt can be converted into the corresponding organic base. Any method that can be used may be used.

For example, the hydrohalides described above can be treated with at least a stoichiometric amount of an alkali base such as ammonia in a solvent such as water or an aliphatic saturated alcohol such as methanol or ethanol.

The base thus obtained can then be converted into an addition salt with an inorganic acid, such as a hydrohalic acid, especially hydrobromic acid, or an organic acid, such as tartaric acid, by reaction with an acid in a suitable solvent.

The solvent used in this case is, for example, alcohol, ketone, ether or chlorinated solvent.

The salt produced will precipitate, and if necessary, the solution will be concentrated and then distributed.

Next, the present invention will be described with reference to Examples.

Example 1 (a) 4-methyl-pyridine (20'fI), p-benzyloxy-α-promopropiophenone (68,6
A mixture of f) and methyl ethyl ketone (200 ml) is heated under reflux and stirring for 4 hours.

The resulting solvent is slowly cooled to about 0°C.

The resulting precipitate was collected door to door, and methyl ethyl ketone (50 TLl
) and then dried under reduced pressure at 50°C.

Thus, l-41-(4-benzyloxyphenyl-
carbonyl)-ethylcou 4-methyl-pyridinium
Promide (79,]J) is obtained.

(b) 1-(1-(4-benzyloxyphenyl-
carbonyl)-ethylrho-4-methylhyricinium
A hydrogenation catalyst (2,S?) consisting of bromide (20f), anhydrous methanol (20QmA) and palladium (palladium content, 10%) deposited on activated carbon was
Place in rfLl autoclave.

The autoclave is purged with nitrogen and then the hydrogen pressure is brought to 25 kg/c4.

Stir the autoclave and increase the hydrogen pressure (25'/c
trl) at 50-55°C for 24 hours.

After purging the autoclave with nitrogen, the catalyst was removed from the reaction mixture by filtration and then heated with methanol (
60QrfLl).

Combine the p-solutions and concentrate to dryness under reduced pressure.

The resulting residue is taken up in water ('4orILl).

The crystals are washed individually with water and then dried under reduced pressure at 50°C.

Thus, 1-(4-hydroxy-phenyl)-2-(
4-Methyl-piperidino)-1-propatur hydropromide (1of) is obtained as a white powder.

Example 2 (a) 4-ethyl-pyridine (24,:l), p-benzyloxy-α-promopropiophenone (72,5
? ) and methyl ethyl ketone (250 wLl) is heated under reflux and stirring for 4 hours.

The reaction mixture is concentrated under reduced pressure to a volume of 80 rnl.

Upon cooling, a precipitate forms, and the mixture is kept at 0° C. for 2 hours and then separated.

The precipitate is washed with hexane and dried under reduced pressure at 50°C to obtain 1-(1-(4-benzyloxyphenyl-carbonyl)-ethylrho-4-ethyl-pyridinium bromide (74,29).

(b) 1-(1-(4-benzyloxyphenyl-
carbonyl)-ethyl]-4-ethylhyridinium
bromid (20?), anhydrous methanol (200 ml) and palladium (palladium content, 5%) deposited on activated carbon and with a specific surface area of 1000 rn”/
'if hydrogenation catalyst (47) is placed in a 500ml autoclave.

The inside of the autoclave is purged with nitrogen, and then the hydrogen pressure is set to 25 kg/c4.

The autoclave was stirred and hydrogen pressure (25 kg/c
rri) at 50-55°C for 70 hours.

After purging the autoclave with nitrogen, the catalyst is removed from the reaction mixture by filtration and washed twice with hot methanol (total volume, 80 rILl).

Combine the P solution and until the final volume is 35ml.
Concentrate under reduced pressure below 45°C.

After precipitation, the residue is cooled at 0°C for 1 hour, and the precipitate is separated and dried under reduced pressure at 50°C.

Thus, 1-(4-hydroxy-phenyl)-2-(
4-ethyl-piperidine)-propatur hydropromide (10, El) is obtained as a white powder.

Example 3 (a) 4-benzyl-pyridine (60,7P), p-penzyloxy-α-promopropiophenone (114
, 6f) and acetone (250 rILl) is heated under reflux and stirring for 2 hours.

After cooling to 20°C, the resulting precipitate is separated. The resulting product is placed in acetone (100 rnl), refluxed for 1 hour, then taken apart and dried under reduced pressure at 50°C.

Thus, 1-(1-(4-benzyloxyphenyl-
Carbonyl)-ethylcy4-benzyl-pyridinium bromide (x6x'7) is obtained.

(b) 1-(1-(4-benzyloxyphenyl-
carbonyl)-ethylcy4-benzyl-pyridinium bromide (20f), anhydrous methanol (200rIL
1) and a hydrogenation catalyst (2,5P) consisting of palladium (palladium content, 10%) deposited on activated carbon are placed in a 500 rILl autoclave.

The inside of the autoclave was purged with nitrogen, and then the hydrogen pressure was set to 25 kg/ca.

The autoclave was stirred and hydrogen pressure (25 kg/c
Keep under a) at 50-55°C for 23 hours.

After purging the inside of the autoclave with nitrogen, the catalyst was removed from the reaction mixture by filtration, and then hot methanol (600
7711).

Combine the f liquids and concentrate under reduced pressure until a tan residue is obtained.

This residue was dissolved in absolute ethanol (50 ml) and
Keep at 0℃ for 1 hour.

After cooling, the crystals are separated from P and dried under reduced pressure at 50°C.

Thus, 1-(4-hydroxy-phenyl)-2-(
4-Benzyl-piperidino)-1-7' lovanol hydropromide (12f) is obtained.

Thin layer chromatography (support, diatomaceous earth:solvent, chloroform-diethylamine, volume ratio 95-5) shows the presence of a single product (Rf#0.
35).

Example 4 (a) 4-benzyl-pyridine (42,5P), p-benzyloxy-α-promopropiophenone (79,
A mixture of 7s') and anhydrous methanol (240 rnl) is heated under reflux and stirring for 8 hours.

The solution obtained is used directly for the preparation of 1-(4-hydroxy-phenyl)-2-(4-benzyl-piperidino)-1-propatol.

(b) The above droplets, anhydrous methanol (840 r/'
Ll) and a hydrogenation catalyst (6 g) consisting of palladium (palladium content, 10%) deposited on activated carbon.
Place in autoclave 1.

The inside of the autoclave is purged with nitrogen, and then the hydrogen pressure is set to 25 kg/crA.

The autoclave was stirred and hydrogen pressure (25 kg/c
Keep at 50-55 °C under rA) for 24 hours.

After purging the autoclave with nitrogen, the catalyst was removed from the reaction mixture by filtration, and then heated with methanol (100
ml).

Combine the lachrymal fluid and add methanol until a precipitate forms.
Distill under reduced pressure at 35-40° C. through a plate column.

Then, after adding water (410 rILl) to the residue, the methanol is removed again as above, without exceeding 30-35° C. at the top of the column.

After removing the methanol, the residue was soaked with water (200 rfLl
) is added.

Thus, ■-(4-hydroxy-phenyl)-2-(
A suspension of 4-benzyl-piperidino)-1-propatur hydropromide is obtained.

Dichloroethane (1600ml) and concentrated ammonia (d=
0.92 ) (35 ml) is added to the cono suspension and the mixture is heated to 70° C. for 1 hour.

The organic phase is decanted while hot and then washed four times with water at 70° C. (total volume 1600 rI'Ll).

A precipitate appears on cooling to about 20°C, and after cooling the mixture to 0°C for 1 hour, the resulting precipitate is separated.

After washing with hexane (300 ml) and drying under reduced pressure at 50°C, 1-(4-hydroxy-phenyl)-2-(4-
benzyl-piperidino)-1-propertool (71ti
? ) is obtained as a white powder.

Thin layer chromatography (support, diatomaceous earth; solvent, chloroform-diethylamine, volume ratio 95-5) was performed by ultraviolet light examination. , indicating the presence of a single product (Rf#
0.35).

Example 5 ■-(4-Hydroxy-phenyl)-2-(4-penzyl-piperidino)-1-propatool (31') (obtained as described in Example 4) at 50 to 55 °
Dissolve C in anhydrous methanol (90 ml).

A solution of tartaric acid (6,94?) in anhydrous methanol (39 ml) is added to the above solution under stirring at 50-55°C and the reaction mixture is kept at 50-55°C for 15 minutes.

It is then cooled to about 20°C and then kept at 0°C for 2 hours.

After washing the precipitate with methanol (30 ml),
Dry under reduced pressure at 0°C.

Thus, 1-(4-hydroxy-phenyl)-2-(
4-Benzyl-piperidino)-1-propatol tartrate (32,6f) Obtained as a white powder.

Thin layer chromatography (support, diatomaceous earth; solvent, chloroform-diethylamine, volume ratio 95-5) shows the presence of a single product (Rf#0.
35).

Example 6 (a) 4-phenyl-pyridine (2Of), p-benzyloxy-α-promopropiophenone (41,2f)
) and methyl ethyl ketone (200 ml) is heated under reflux and stirring for 4 hours.

The resulting solution is cooled to about 20°C and then kept at 0°C for 1 hour.

The resulting precipitate was taken from house to house and poured into cold methyl ethyl ketone (50ml
) and then dried under reduced pressure at 50°C.

Thus, 1-[1-(4-benzyloxyphenyl-
Carbonyl)-ethylter-4-phenylhyridinium bromide (57?) is obtained.

(b) 1-(1-(4-benzyloxyphenyl-
carbonyl)-ethylter-4-phenylhyridinium bromide (14,71?), methanol (200 rI
Ll) and palladium (palladium content, 5%) deposited on activated carbon and with a specific surface area of 1000 m
”/P hydrogenation catalyst (42) is placed in a 500 ml autoclave.

The autoclave was purged with nitrogen and the hydrogen pressure was increased to 2
Set it to 5kg/crA.

The autoclave was stirred and hydrogen pressure (25 kg/c
m) at 50-55 °C for 24 hours.

After purging the autoclave with nitrogen, the catalyst is removed from the reaction mixture by filtration and then washed twice with hot methanol (total volume 80 rrLl).

The f liquids are combined and the methanol is distilled off under reduced pressure without exceeding 45° C. until the volume is 50 ml.

After cooling to about 20°C and then keeping at 0°C for 3 hours, the resulting precipitate is separated, washed with hexane (60ml) and then dried under reduced pressure at 50°C.

Thus, 1-(4-hydroxy-phenyl)-2-(
4-phenyl-piperidino)-1-7'' lovanol hydropromide (9,3S') is obtained as a white powder.

Claims (1)

[Claims] 1. Hydrogenating an ammonium salt having the general formula (wherein R represents an alkyl group, an arylalkyl group, or an aryl group, and Xe represents a halogen ion) in the presence of a hydrogenation catalyst. A method for producing a piperidinoglopanol derivative represented by the general formula (wherein R has the above definition) and an acid addition salt thereof, characterized by: 2 Substituted pyridine having the general formula (in the formula, R represents an alkyl group, arylalkyl group or aryl group) and p-benzyloxy-α-halopropylene having the general formula (in the formula, X represents a halogen atom) An ammonium salt having the general formula: where R has the above definition and X represents a halogen ion is prepared by reacting with piophenone, which is then reacted in the presence of a hydrogenation catalyst A method for producing a piperidinoglopanol derivative represented by the formula (wherein R has the above definition) and an acid addition salt thereof, which is characterized by hydrogenation.