JPS6048968A - Compound having skeleton of tetrahydropyridinopropanol and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound having skeleton of a tetrahydropyridinopropanol shown by the formula I (R is H, or benzyl). EXAMPLE:Erythro-1-( 4-benzyloxyphenyl )-2-( 4-benzyl-1,2,5,6-tetrahydropyridino )- 1-propanol. USE:An intermediate for preparing 1-( 4-hydroxyphenyl )-2-( 4-benzylpiperidino )-1- propanol shown by the formula II useful as a remedy for sequelae of cerebrovascular disease. PREPARATION:A compound shown by the formula III is reduced with a metal hydride to give a compound shown by the formula I easily in high yield. This compound shown by the formula I is reduced to give a compound shown by the formula II. The compound shown by the formula III is obtained by halogenating a compound shown by the formula IV to give a compound shown by the formula V, reacting this compound with a compound shown by the formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound having a tetrahydrobilisiplovanol skeleton and a method for producing the same. More specifically, the compound C represented by the general formula (■): (wherein R is hydrogen or benzyl) is hereinafter referred to as compound (■). The same applies to compounds of other formula numbers] and a method for producing compound (1) by reduction of a pyridinium compound.

1-(4-hydroxyphenyl)'-2-(4-benzylpiperidino)-1- obtained by reducing compound (I)
Propatool (hereinafter referred to as compound (II)) 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 (TI).

(11 Method described in Japanese Patent Publication No. 15348/1981 (2) Method described in Japanese Patent Application Laid-Open No. 50-4081 (3) Method described in Japanese Patent Application Publication No. 43266/1983 (Formula (4) The method described in JP-A No. 56-81560 (3) (5) The method described in JP-A-56-79677 (in the formula , 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.

Compound H) in the present invention, which is classified as
is a new intermediate that does not go through any of the conventional methods mentioned above. Furthermore, the method disclosed in JP-A-56-79677 (4) involves the 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 pressure, but it is clearly stated that heating and pressurization are essential for all other hydrogenation catalysts, including palladium on carbon. has been done. 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 (1
We conducted intensive research on a more efficient manufacturing method for 1). As a result, the compound (1) can be easily obtained by reducing the compound represented by the general formula (■) = (wherein R has the same meaning as above and X is a halogen) with a metal hydride. The present inventors have discovered an industrially advantageous method in which the remaining double bonds can be reduced under mild conditions of room temperature and pressure, and have completed the present invention.

That is, according to the present invention, compound H), which is a new compound, can be easily obtained in high yield by reducing the pyridinium salt (III) 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 final useful compound (U).

Next, the production of compound N) and compound (1) of the present invention will be shown in a process formula, and each step will be explained in detail.

(In the formula, R and X have the same meanings as above, and ■ to ■ represent step numbers.) In the halogenation of step (■), halogen and bromine are 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. The reaction temperature of 3 hours varies depending on the solvent used, but 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 or 4-hydroxy-α-bromopropiophenone with 4-benzylpyridine in step (2) is carried out using methanol, ethanol,
Performed using a solvent such as alcohol such as propatool,
The compound (IIF) then produced can be isolated by a known method or directly introduced into the next step (2), but it is particularly advantageous to use a compound (IIF) in which these raw materials are soluble and the product (IIF) is soluble. It is carried out in a solvent in which [I) is sparingly soluble or insoluble. As this solvent, for example, aliphatic ketones such as methyl ethyl ketone and methyl isobutyl ketone, or esters such as ethyl acetate, 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 to 90(7)°C, and the reaction time is 3 to 10 hours. Compound (11) 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.

Examples include potassium borohydride, lithium aluminum hydride, aluminum hydride, and aminoborane 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 (1) thus obtained can be prepared using 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.

(8) In the reduction reaction in step (1), known catalysts include palladium, nickel, cobalt, platinum, etc., but palladium on carbon is preferred because it is inexpensive and easy to handle. As the solvent, lower alcohols such as methanol and 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 (1) of the present invention from the reaction solution can be performed by applying known techniques such as concentration, extraction, column chromatography, crystallization, recrystallization, etc.

Compound (1), which is the target compound of the method of the present invention, and Compound (II), which is the final useful compound, each have isomers having an erythrose-threo relationship.
In the reduction of compound (1) from [), the erythro form, which has strong pharmacological activity, can conveniently be obtained in a larger amount than the threo form.

These produced erythro and threo forms can be separated by methods such as thin layer chromatography, column chromatography, and recrystallization.

The compound (U) 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, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, acetate, benzoate, maleate, fumarate.

Succinate, tartrate, citrate, oxalate.

glyoxylate, aspartate, methanesulfonate, ethanesulfonate, propanesulfonate, methanedisulfonate, α,β-ethanedisulfonate,
Examples include benzenesulfonate.

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

Example 1゜(1) Step ■ 24 g of 4-benzyloxyprobiophenone was added to 65 ml of dioxane, and 16.4 g of bromine was added 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-like crystals of 4-benzyl-1-(1-(4-benzyloxyphenylcarbonyl)ethyl)pyridinium bromide were obtained by recrystallizing with isopropanol of 29.
3 g (83.3% yield) are obtained.

Melting point: 130.0-134.5°C TRl-'c+i-': 1670 (C=O) elemental analysis CrzsHtbNOz Br calculated value: C68
,90,N5.37. N2.87 actual value: C6B,
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 added to sodium borohydride while stirring under water cooling.

Add 4.7 g of lium little by little. 20-30℃ after addition
The mixture was stirred for 4 hours, and then the methanol was distilled off. 250 ml of water was added to the residue, extracted with 500 ml of chloro(11)form, the solvent was distilled off, and the residue was recrystallized from 100 ml of isolobanol to obtain erythro-1-(4-benzyloxyphenyl). )
13.9 g of colorless structured crystals of -2-(4-benzyl-1,2,5,6-titrahydrobiridino)-1-propatur
(yield 84.7%).

Melting point: 103-104.5°C IR eruption; cm-': 3400 (OH)N M
R (CD C7!s) δ: 0.84 (3H, doublet, J=Elllz, CI+-12) 1.2~
3.4 (9H, multiplet) 3.70 (IH, wide singlet, 0■) 4.82 (IH
, double line, J=5112. CL-Oll) 5.02
(2H, - double line, C6Hs C!iz O)5.35
(11-I, broad singlet, CHt C and =C:)6.
7-7.5 (14H, multiplet, aromatic proton) elemental analysis Cz @H3+ N Oz Calculated value: C$ 1.20. N7.54. N3.3
8 Actual measurement value: C81.31, N7.62. N3.36
Example 2゜(1) Steps (1) and (2) 60 g of 4-hydroxypropiophenone is added to 100 ml of dioxane, and 72 g of bromine (12) is added dropwise thereto over about 1 hour while cooling on ice. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to remove HBr from the system, followed by 67.7 g of 4-benzylpyridine and 600 g of methyl ethyl ketone. ml and heated under reflux for 5 hours. As the reaction progresses, products gradually precipitate. After cooling with water, the platelet was filtered, washed with methyl ethyl ketone, and then reconsolidated with a mixed solvent of acetone and methanol to produce 4-benzyl-
132.2 g (yield: 84.5%) of needle-like crystals of 1-(1-(4-hydroxyphenylcarbonyl)ethyl)pyridinium bromide are obtained.

Melting point: 153.5-155.5°C I Rp msy cm-” 1670 (C=O) elemental analysis Cz + Hz o N Oz B rcalculated value: C63,33,N5.06.N3.52 actual value: c6
3. t6. N5.10. N3.45 (2) Step ■ 20 g of 4-benzyl-1-(1-(4-human xyphenylcarbonyl)ethyl)pyridinium bromide
Dissolve in 00ml of methanol and add 5g of sodium borohydride little by little while cooling with water. After addition, 20-30℃
After stirring for 3 hours, methanol was distilled off. Add 2,001 ml of water to the residue and extract with 250+lll of chloroform. Distill off the chloroporum and collect 100ml of the residue.
Colorless needle-shaped crystals of erythro 1-(4-hydroxyphenyl)-2-(4-benzyl-1,2,5,6-titrahydroviridino)-1-propatur were obtained by recrystallizing with isopropatol. 13.8 g (81.4% yield) are obtained.

Melting point: 81.0-83.0°C IR9 == cm-': 3.400 (OH)NM
R: (CDC/!3) δ: 0.84 (3H, double line, J=811z, CHCH3
) 1.2 to 3.4 (9H, multiplet) 4.82 (2H, wide singlet, -0HX2) 4.83
(IH, double line, J=511z, CH-OH)5.
35 (IH, wide singlet, -c tan=Cte) 6.5-7
．． 5 (9H, multiplet, aromatic proton) elemental analysis Cz
+ Hzs N Oz Calculated value: C7B, 04. N7.80. N4.33
Actual value +C77,71,N7.98. N4.28 Reference example 1. (Step ■) Erythro 1-(4-benzyloxyphenyl)-2-(4-benzyl-1,2,
5,6-titrahydroviridino)-1-propatur L
Dissolve og in 200ml of methanol and add 10% palladium! ! Hydrogen was passed under 2σan Kayu-1W at -90 to 30°C for 7 hours. After filtering off the catalyst, methanol is distilled off. Erythro 1-(4-hydroxyphenyl)-2-(
6.5 g (yield: 82.6%) of colorless needle crystals of 4-benzylpyridino)-1-propatol are obtained.

Melting point: 117. O~120.0°C NMR: (CDCNs) δ: 0.90 (3H, doublet, J=811z, CH-C
) 1.2 to 3.4 (12H, multiplet) 4.62 (IH, doublet, J = 5 Hz, CH-
OH) 4.80.9.18 (2H, broad 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.

Reference example 2. (Step ■) Erythro 1-(4-hydroxyphenyl)-2-(4-benzyl-1°2, 5.
6-titrahydroviridino)-1-propatool Log
was dissolved in 200 ml of methanol, 2 g of 10% palladium on carbon was added, and hydrogen was passed through the solution at 20 to 30° C. for 6 hours under normal pressure. After filtering off the catalyst, methanol is distilled off. 5 residues
7.6 g of colorless needle crystals of erythro 1-(15) (4-hydroxyphenyl)-2-(4-benzylpiperidino)-1-propatol were obtained by recrystallization with 0 ml of isopropatol (yield 75.6%).

This product has good agreement with standard specimens obtained by known methods and various instrumental analysis data.

Reference Example 3゜Erythro produced in Example 1 (3)] -(
6.0 g of 4-hydroxyphenyl)-2-(4-benzylpiperidino)-1-propatool was added to 30 m of methanol.
Add and dissolve 1.4 g of tartaric acid in 1. After cooling, the precipitated crystals were filtered, washed with methanol, and dried. 6.7 g of the tartrate of the above compound was obtained as white crystals (
Yield: 90.7%). 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. (16) Procedural Amendment Document 1982 to month ≠ day 1 Indication of the case 1982 Patent Application No. 157521 2 Name of the invention Tetrahydropyridinopropanol skeleton Compound and its manufacturing method 3, relationship with the case of the person making the amendment Patent applicant postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name
(102) Kyowa Hakko Kogyo Co., Ltd. (Location: 03-2
01-7211 Extension 2751 ) 5. Contents of correction (1) Correct r56-79677J on page 4, line 3 and bottom line to r56-79667J.

(2) In page 5, line 6, ``for example'' should be corrected to ``for example''.

(3) On page 5, line 9, "Carbon is the beginning" is corrected to "Carbon is the beginning."

(4) In the bottom three lines of page 5, "double bonds should be kept at room temperature" should be corrected to "if there are double bonds and benzyl groups, they should be kept at room temperature at the same time."

(5) Correct lines 1 and 2 of the process formula on page 6 as follows.

(6) "The reaction temperature is preferably 0 to 70°C" on the bottom line of page 8 should be changed to "The reaction temperature is -40 to 70°C, preferably 130 to 70°C."
The temperature is 20℃.''

(η page 11 line 12 r 130. D ~ 134.5℃
” is corrected to “r], 53.5-155.5°C”.

(8) rJ = 8HzJ on page 12, line 11, rJ = 7
．． Correct to 2HzJ.

(9) Change “1.2 to 3.4” on page 12, line 12 to “1.6 to
Corrected to ``34''.

r J = 5 on page 0112, line 14. OHz j to r
Correct to J = 3.6HzJ.

(II> Correct “C unigu” on page 12, line 16 to “C uni Cte”.

(+2) r on page 13, line 12 153.5-155.5℃
” is corrected to “r197.0-214.5℃”.

(13) + rJ = 8HzJ on page 10, rJ =
Correct to 7.2Hz J.

(+4) Change “1.2 to 3.4” on page 14, line 11 to “1.6”
~3,4”.

(15)+4 pages, all 12 lines, i.e. r4.82...
0"×2)" is deleted.

(16) On page 14, line 13, “J=5HzJ r J =
Correct to 3.4HzJ.

(17) +5 On page 4 and 5, "pennorpyridino" is corrected to "benzylpiperidino".

(+8) Page 15, line 8 (DrCDCl, J to rI) MSO
-dI! ” is corrected.

<19) rJ = 8HzJ on page 15, line 9 as “J = 7.
Correct to 0 Hz J.

(20) l”J=5HzJ in line II on page 15 as rJ=
Correct to 4.0HzJ.

(21)+5 pages, all 12 lines, i.e. r 4.80...
・Delete 0"×2)".

(3) 536-

Claims (1)

[Claims] (11) A compound represented by the general formula (wherein R is hydrogen or benzyl). (2) A compound represented by the general formula (wherein R is hydrogen or benzyl and X is a halogen) ) A method for producing a compound represented by the general formula (wherein R has the same meaning as above), which comprises reducing the compound represented by the formula with a metal hydride.