JPS6048966A - Preparation of 1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)-1- propanol - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a new drug suitable as a remedy for sequelae of cerebrovascular disease efficiently, by hydrogenating a specific novel compound in the presence of a resonable hydrogenating catalyst under mild conditions, optionally reacting the reaction product with an acid. CONSTITUTION:A 4-benzyl-1-[1-( 4-benzyloxyloxyphenylcarbonyl )ethyl]pyridinium halide shown by the formula I (X is halogen; Bel is benzyl) is reduced with a metal hydride such as NaBH4, etc. in a solvent at -40-70 deg.C for 30min-10hr to give novel 1-(4-benzyloxyphenyl)-2-(4-benzyl-1,2,5,6-tetrahydropyridino)-1-propanol shown by the formula II in high yield. This compound is hydrogenated in a solvent in the presence of hydrogenating catalyst such as 10wt% Pd/C, etc. at normal temperature under normal pressure, and, if necessary, the reaction product is reacted with an acid, to give the desired compound shown by the formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1-(4-hydroxyphenyl)-2-(4-
The present invention relates to a method for producing benzylpiperidino)-1-propatol (hereinafter referred to as compound (1)). More specifically, the present invention provides 1-(4-benzyloxyphenyl')-2-(
4-benzyl-1,2,5゜6-titrahydrobiridino)-1-propatur [hereinafter referred to as compound (II)]
This invention relates to a method for producing compound N) or an acid addition salt thereof, which comprises hydrogenating the compound N) in the presence of a hydrogenation catalyst, and then reacting it with an acid if necessary.

Compound (I) is a useful drug that is widely used as a therapeutic agent for the sequelae of cerebrovascular disorders.

Conventionally, the following methods are known as methods for producing compound (I).

(1) The method described in Japanese Patent Publication No. 47-15348 (2) The method described in Japanese Patent Application Publication No. 50-4081 (3) The method described in Japanese Patent Application Publication No. 56-43266 ( In the formula, XA represents a halogen atom) (4) The method described in JP-A-56-81560 (5) The method described in JP-A-56-79677 (3) (Formula (wherein, XA represents a halogen atom) These conventionally proposed methods involve i) reacting an α-haloketone with 4-benzylpiperidine, followed by catalytic reduction or reduction with a metal hydride;

ii) After reacting α-haloketone and 4-benzylpyridine, catalytic reduction is performed.

However, in the method of the present invention, the raw material compound (
n) is a novel method that does not belong to any category. The method disclosed in JP-A-56-79677 involves reduction of a piperidine derivative with a metal hydride, and the reduction of a pyridinium salt with a metal hydride in the present invention has never been seen before.

Conventional reduction of pyridinium salts generally requires conditions under high temperature and high pressure. For example, according to JP-A-56-135468, it is stated that only platinum oxide can be reduced at room temperature and (4) normal pressure, but other hydrogenation catalysts such as palladium on carbon can be reduced by heating or pressurization. is specified as essential. However, platinum oxide is very expensive and cannot be said to be industrially satisfactory.

In order to avoid these problems, the present inventors developed a compound (I
) and conducted intensive research on more efficient manufacturing methods.

As a result, by reducing 4-benzyl-1(1-,(4-benzyloxyphenylcarbonyl)ethyl)pyridinium halide [hereinafter referred to as compound (III)] with a metal hydride, the aforementioned compound (IT) was easily obtained. The present invention has been completed by discovering an industrially advantageous method in which the remaining double bonds can be reduced under mild conditions of room temperature and pressure. The compound (U) can be easily obtained in high yield by reducing a pyridinium salt with a metal hydride.

In addition, this compound can be hydrogenated under mild conditions using an inexpensive catalyst, and can be said to be an extremely useful compound for producing the target compound (1).

Next, the method of the present invention will be shown in a process formula, and each step will be explained in detail. For convenience, the manufacturing process of compound (III) is also shown.

(In the formula, B21 represents benzyl, and X represents halogen. Also, ■ to ■ represent step numbers.) In the halogenation of step (II), chlorine, bromine, and iodine are used as the halogen, but bromine is particularly preferred. The solvent used in the halogenation reaction may be ethers such as isopropyl ether, tetrahydrofuran, and dioxane, aromatics such as benzene, toluene, and xylene, or mixtures thereof, but preferably dioxane. Although the reaction temperature of 2 hours varies depending on the solvent used, a suitable reaction temperature is 0 to 60°C and a reaction time of 2 to 5 hours.

The condensation reaction of 4-benzyloxy-α-bromopropiophenone and 4-benzylpyridine in step (2) uses a solvent such as alcohol such as methanol, ethanol, propatool, etc. in which these raw materials and products are dissolved. The resulting compound (Tll) can then be isolated by a known method f, or it can be directly led to the next step (2), but it is particularly advantageous if these raw materials are soluble and The process is carried out in a solvent in which the product (Ill) is sparingly soluble or insoluble.

Examples of this solvent include aliphatic ketones such as methyl ethyl ketone and methyl isobutyl ketone, ethyl acetate,
Esters such as n-propyl acetate and n-butyl acetate are used, and these may be used alone or in combination. In this case, the reaction temperature is 40-90℃, and the reaction time is 3-90℃.
10 hours is appropriate. Compound (III) can thus be easily isolated from the reaction mixture by filtration after the completion of the reaction.

The reduction reaction in step (1) is carried out using a metal hydride in a solvent. Examples of metal hydrides include sodium borohydride and lithium borohydride.

In addition to potassium borohydride, lithium aluminum hydride, and aluminum hydride, examples include a(7) minoborane such as dimethylaminoborohydride.

As the solvent, commonly used solvents may be used depending on the type of metal hydride used.

For example, when sodium borohydride is used, water, lower alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and 1,2-dimethoxyethane can be used. The reaction temperature is preferably 0 to 70°C, and the reaction is completed in 30 minutes to 10 hours.

Compound (II) thus obtained can be prepared by known methods such as concentration, extraction, and column chromatography.

Although it can be isolated and purified by crystallization, recrystallization, etc., the reaction mixture can be used as it is in the next step.

Examples of the catalyst in the reduction reaction in step (1) include palladium, nickel, cobalt, and platinum, but palladium on carbon is preferred because it is inexpensive and easy to handle. Also, methanol is used as a solvent.

Lower alcohols such as ethanol and mixtures of these lower alcohols and water are used. The reaction is sufficient at room temperature and under normal pressure. Isolation and purification of the target compound (■) of the present invention from the reaction solution can be carried out by applying known techniques such as concentration, extraction, column chromatography, crystallization, recrystallization, etc. (8).

The compound (rl) obtained in step (1) of the present invention is a novel compound unknown in the literature. In addition, the intermediate compound (11>) and the target compound (H) in the method of the present invention each have isomers having an erythrose-threo relationship; In reduction, erythro forms with strong pharmacological activity are conveniently obtained in larger quantities than threo forms.These produced erythro forms,
The threo form can be separated by methods such as thin layer chromatography, column chromatography, and recrystallization.

The target compound (I) thus obtained can be converted into its acid addition salt by reacting with a desired acid in a suitable solvent. Such acid addition salts include hydrochloride and hydrobromide.

Hydroiodide, nitrate, sulfate, phosphate.

Acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, ethanesulfonate, propanesulfonate Salt, methanedisulfonate, alpha.

Examples include β-ethane disulfonate and benzenesulfonate.

The present invention will be explained in more detail with reference to Examples below.

Example 1゜ (Step 11 ■) Add 24 g of 4-benzyloxyprobiophenone to 65 ml of dioxane, and add 16.4 g of bromine while stirring under water cooling.
g is added dropwise over about 1 hour.

After the dropwise addition was completed, the mixture was stirred for an additional 30 minutes, and 20 ml of methanol and 30 ml of water were sequentially added. The precipitate was filtered, and the crystals were washed with water and recrystallized with 90 ml of methanol to obtain 26.0 g of colorless needle-like crystals (yield: 81.6
%) of 4-benzyloxy-α-bromopropiophenone. The melting point of the crystal is 75.0 to 78.0°C.

(2) Step ■ 4-benzyloxy-α-bromopropiophenone 23
g and 12.2 g of 4-benzylpyridine were dissolved in 180 ml of ethyl acetate, and heated under reflux for 3 hours over an aqueous solution. As the reaction progresses, products gradually precipitate. After cooling, the precipitate was filtered, washed with 40 ml of ethyl acetate, and then washed with 160 ml of
Needle crystals of 4-benzyl-1-(1-(4-benzyloxyphenylcarbonyl)ethyl)pyridinium bromide were obtained by recrystallizing with isopropanol of 29.
3 g (yield 83.3%) are obtained.

Melting point: 130. O~134.5℃ IR')4Q cm-': 1670 (C=0
) Elemental analysis CzaHzaNOz Br Calculated value: C68,90, N5.37. N2.87 actual value: C68,72, N5.36. N2.76 (3) Step ■ 20 g of 4-benzyl-1-(1-(4-benzyloxyphenylcarbonyl)ethyl)pyridinium bromide
was dissolved in 250 ml of methanol, and 4.7 g of sodium borohydride was added little by little while stirring under water cooling.

After the addition, the mixture was stirred at 20-30°C for 4 hours, and then methanol was distilled off. Erythro 1-(4-benzyloxyphenyl)-2 was obtained by adding 250 ml of water to the residue, extracting with 500 ml of chloroform, distilling off the solvent, and recrystallizing the residue from 100 ml of isobrobanol. Colorless needle crystals of -(4-benzyl-1,2,5,6-titrahydrobiridino)-1-propatol 13.
9 g (yield 84.7%) are obtained.

Melting point: 103-104.5℃ ■R9 approved cIll-': 3400 (OH)N M
R(CD Cj! s) δ: (11) 0.84 (3H, doublet, J=8Hz, CI CH
i) 1.2-3.4 (9H, multiplet) 3.70 (IH, wide singlet, O and) 4.82 (LH
, double line, J=5Hz, CH-OH)5.02(2
H, - doublet, C, N5 C and, 0) 5.35 (LH, broad singlet, CH! cu=c=>6.7~7.5(1
4H, multiplet, aromatic proton) elemental analysis Cml H
a+ N O□ Calculated value: C81, 20, N7゜54. N3.38 Actual value: C81,31, N7.62. N3.36 (4) Step ■ Erythro 1-(4-benzyloxyphenyl)-2-
(4-benzyl-1,2,5,6-titrahydrobiridino)-1-propatool 10g in methanol 200ml
2 g of 10% palladium on carbon was added, and under normal pressure,
Pass hydrogen for 7 hours at 20-30°C. After filtering off the catalyst, methanol is distilled off. Erythro 1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)-1 was obtained by recrystallizing the residue with 50 ml of isopropanol.
- 6.5 g of colorless needle crystals of propatool (yield 82.6%)
).

Melting point = 117.0-120.0°C NMR: (CDCIls) δ: (12) 0.90 (3H, doublet, J = 8Hz, CHCH3
) 1.2 to 3.4 (12H, multiplet) 4.62 (IH, doublet, J=5Hz, CH-OH)
4.80. 9.18 (2H, wide singlet, -01
×2) 6.6 to 7.5 (9H, multiplet, aromatic proton) The above data agree well with the data of the standard product obtained by a known method.

Example 2 Erythro 1-( produced in Example 1 (4)
660 g of 4-hydroxyphenyl)-2-(4-benzylpiperidino)-1-propatool was added to 301 g of methanol.
Add and dissolve 1.4 g of tartaric acid in the solution. This is cooled, and the precipitated crystals are filtered off, washed with methanol, and dried to obtain 6.7 g (yield: 90.7%) of the tartrate of the above compound as white crystals. The melting point of the crystals obtained is 145.
The temperature is 5 to 147.0°C.

Patent Applicant (102) Kyowa Hakko Kogyo Co., Ltd. Procedural Amendment 1, Description of the Case 1982 Patent Application No. 157519 2, Name of the Invention 1-(4-Hydroxyphenyl)-2-(4-benzylphenyl) Perijino)-1-Proper tool manufacturing method 3, relationship with the amended case Patent applicant postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name
(1,02) Kyowa Hakko Kogyo Co., Ltd. (Tl1L:
03-201-7211 Extension 2751) 5. Contents of correction (1) ``56-(2
) In the bottom two lines of page 4, correct the word ``for example'' to ``for example.''

(3) On page 5, line 2, correct "Carbon first" to "Carbon first."

(4) On page 5, line 13, "double bond" is corrected to "double bond and benzyl group."

(5) The process formula in lines 2 and 3 of page 6 should be corrected as follows.

(6) “The reaction temperature is preferably 0 to 70°C” on page 8, line 8.
[The reaction temperature is -40 to 70°C, preferably -30 to 2
It is corrected to "0℃".

(7) On page 8, lines 15-16, ``For example, the catalyst'' is corrected to ``For example, a known catalyst.''

(Correct "r 130.0-134.5°C" on page 8111, line 2 to "r 153.5-155.5°C."

(rJ = 8HzJ on page 9112, line 1 is set to rJ = 7.
Correct to 2HzJ.

0012 page 2 line "1.2~3.4" is changed to "1.6~3.
Corrected to 4.

(11) rJ = 5HzJ on page 12, line 4, as rJ = 3
．． Correct to 6HzJ.

(12) rDMs rcDc1* J in the bottom line of page 12
.

-d6”.

(13) rJ = 8HzJ on page 13, line 1, rJ = 7
．． Ql (corrected to zJ.

(14) rJ = 5HzJ on page 13, line 3, as rJ = 4
．． Correct to 0HzJ.

(15) Page 13, 4 lines, Hetes i.e. r4.80...-
0Hx2)" is deleted.

Claims (1)

[Claims] (111-(4-benzyloxyphenyl)-2-(4
-benzyl-1,2,5,6-titrahydroviridino)
-1-(4-hydroxyphenyl)-2-( characterized by hydrogenating 1-propatool [hereinafter referred to as compound (n)] in the presence of a hydrogenation catalyst, and then reacting with an acid if necessary. A method for producing 4-benzylpiperidino)-1-propatol or an acid addition salt thereof. (2) Compound (II) is 4-benzyl-1-C1-(4
-benzyloxyphenylcarbonyl)ethyl]pyridinium halide with a metal hydride.