JPS5824561A - Preparation of piperidinoalkanol and its acid addition salt - Google Patents

Abstract

NEW MATERIAL:1-( 4-Hydroxyphenyl )-2-( 4-phenylhydroxymethyl-DELTA<3>-piperidino ) propane-1-ol shown by the formulaI. USE:An intermediate for piperidinoalkanol and its acid addition salt (improver for cerebral circulation metabolism). PROCESS:A quaternary ammonium salt shown by the formula II (X is halogen) is reduced with a metal hydrogen compound (e.g., sodium boron hydride, lithium aluminum hydride, etc.), to give a compound shown by the formulaI. This compound shown by the formulaIis hydrogenated in the presence of palladium on carbon, to give piperidinoalkanol shown by the formula III and its acid addition salt.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method for producing piperidinoalkanol and its acid f1 salt.

Piperidinoalkanol and its acid addition salts are useful as agents for improving cerebral circulation and metabolism.

Preparation of piperidinoalkanol and its acid addition salt (in the formula i
, R represents an aryl group, R represents a group that can be replaced by hydrogen or nitrogen, and X represents a halogen atom. )
We discovered a method of hydrogenating the quaternary ammonium salt represented by (referred to as diketone) is produced by metal hydrogenation (hereinafter referred to as aminoalcohol enol) and this aminoalcohol enol (1).
It has been discovered that a can be easily catalytically reduced at normal pressure to yield piperidinoalkanol CKHr in good yield, and the present invention has been completed.

The compound represented by the formula and the compound represented by the formula characterized by reducing the ammonium diketone (1) represented by the general formula with a metalated hydrogen compound are hydrogenated in the presence of a catalyst. This is a method for producing piperidinoalkanol and its acid addition salt.

The reaction formula for producing aminoalcohol enol (1) a from ammonium diketone (1) and the reaction for producing piperidinoalkanol CUJk from amino alcohol enol (1) a is as follows: ammonium diketone (1) from amino alcohol enol (1
) To produce a, ammonium diketone (1
) is reduced with a metallohydride compound.

The method for reducing with the metallohydrogen compound may be carried out in accordance with a known reduction method.

In order to produce piperidinoalkanol rl[)' from amino alcohol enol (1) a, amino alcohol enol (1) a is catalytically reduced, that is, ami/furcol enol (1) a is hydrogenated in the presence of a catalyst. do.

The catalytic reduction method itself may be carried out in accordance with a known catalytic reduction method.

Amino alcohol enol (1)a is easily catalytically reduced at normal pressure to give piperidinoalkanol CTiJ in good yield.

Amino alcohol enol (1) produced from ammonium diketone (1) in the first reaction to produce amino alcohol enol (1) a. The method for producing piperidinoalkanol and its acid addition salt can produce piperidinoalkanol and its acid addition salt with good yield in a short time and at normal pressure in both the first and second reaction steps. This is a particularly excellent manufacturing method.

In the first reaction, the ammonium diketone (1) is reacted with a hydrogen metal compound preferably in an amount of 2 to 10 times the molar amount of the dough, usually in the presence of a solvent.

Although the reaction temperature varies depending on the type of hydrogen metal compound used, it is usually selected to be about -20°C to 100°C, and in this case, a reaction time of about 0.5 to 10 hours is sufficient.

The reaction solvent varies depending on the type of metal hydrogen compound used, but for example, when using sodium borohydride, water, alcohol such as methanol or ethanol, ether such as isopropyl ether or tetrahydrofuran, methyl cellosolve, or methyl cellosolve are used. , diethylene glycol and other nityl alcohols are preferably used.

Examples of metal hydrogen compounds include sodium borohydride (NaBH4), lithium borohydride (Li
BW<1, hydrogenated fluminiram IJ') A (L
iAfflH4), aluminum borohydride (Al?
(B[(4)31), sodium trimethoxyborohydride (NaBH(QMe)3), lithium trimethoxyborohydride (LiBH(oMf3), etc.).

After the reaction, the reaction mixture is separated according to a conventional method known per se to obtain free aminoalcohol enol (])a.

The amino alcohol enol (1) a obtained in % is hydrogenated in the presence of a catalyst.

As a catalyst for the hydrogenation reaction, the following catalysts are usually used, such as palladium-attached activated carbon, Raney nickel, platinum black, and the like.

The hydrogenation reaction can be carried out under any selected conditions, such as under atmospheric pressure or under increased pressure.

Next, a case will be described in which palladium-attached activated carbon is used as a catalyst as a typical case, but the process can be carried out in the same manner when using other catalysts.

The solvents used in the reaction can be those used in ordinary hydrogenation reactions, such as water, methanol, ethanol, vinegar, dioxane, tetrahydrofuran, chlorohexane, ethyl acetate, etc., and these can be used alone or in combination. It's okay.

The palladium-coated activated carbon used as a catalyst is 5 to 10% palladium-coated activated carbon prepared by a conventional method, and the amino alcohol enol (11f') is used in an amount of A usually 1 to 50%, preferably 5 to 30% (z).

The reaction temperature is usually 0°C to 100°C, preferably 20°C to 60°C.

The hydrogen pressure Fia is normal atmospheric pressure. In this case, the reaction time depends on the reaction temperature, but at a reaction temperature of 20° C. to 60° C., about 0.5 to 10 hours is usually sufficient.

Piperidinoalkanol LD obtained in this way)
is a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, or an inorganic w1. Or acetic acid.

They can be obtained as acid addition salts by treatment with organic acids such as succinic acid, lactic acid, and tartaric acid.

In addition, ammonium diketone (1) is 4-benzo,
Lubilisin! :1-(4-hydroxyphenyl)-2
- It can be easily obtained by reacting with herropropane.

For example, 4-benzoylpyridine and 1-(4-hydroxyphenyl)-2-bromopropa7+7) anti[.

proceeds under conventional condensation conditions known per se in the presence of a solvent. Examples of solvents include ketones such as acetone, methyl ethyl ketone, and methyl inophyl ketone, alcohols such as methanol, ethanol, and propatool, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogens such as chloroform, dichloroethane, and trichloroethane. Hydrocarbons, cyclic ethers such as tetrahydrofuran and dioxane, and others are used, and these may be used alone or in combination.

Although the reaction temperature and reaction time vary depending on the solvent used, one reaction temperature is usually selected from 0°C to 150°C. Preferably 5
The reaction is carried out at 0°C to 100°C, and in this case, one reaction time of 10 minutes to 10 hours is sufficient. The ammonium diketone fil produced by the reaction can be isolated from the reaction mixture by a conventional method known per se.

In addition, 1-(4-hydroxyphenyl)-2-bromopropan-1-one is p-hydroxyglopiofenone y
It can be easily obtained by a method known per se by reacting with bromine.

Examples are shown below.

Example 1 +11 Br (Ila viridinium Clff id n) Br8.2.4 P(0
, 20 mol) was suspended in 500 ml of methanol, and sodium borohydride (NaBH4) 44 was suspended at room temperature.
．． 77 (1°20 mol) was added, and the mixture was stirred and reacted at the same temperature for 2 hours.

After the reaction, methanol is distilled off, the residue is dissolved in water, the pH is made slightly alkaline with IN hydrochloric acid, and the precipitated white crystals are collected and dried.

This was subjected to column chromatography to obtain the erythro form of +11&, ie, erythro 1-(4-hydroxyphenyl)-2-(4-phenylhydroxymethyl-Δ3~piperidino)furopan-1-ol 5o, sy (yield 74 .9% n and 6.9 y (yield 10.9%).
2).

Eri, 10 bodies mp155.7℃ (decomposition.Solvent methanol.)Eng.
1aXcrn: 3280 (Q H) Elemental analysis
C(≠) HC嗟) N'(S) Calculated value 74
．． 31 7,42 4.13 Experimental value? 4.11
7.45 4.27 Threo IR:, "$ ': 3280 (OH)w120
- and methanol 180 lll1 dissolved in a mixed solution of
catalytic reduction using normal pressure.

After the theoretical amount of hydrogen has been absorbed, the catalyst is removed, the acetic acid is neutralized with sodium bicarbonate, and the solvent is distilled off.

Extract with benzene to obtain 17.1 fl of 20 bodies of [u], 1-(4-hydroxyphenyl)-2-(4-benzylpiperidino)gulo-7pan-1-ol. Yield: 52.5. Those recrystallized from methanol have a mp of 114.0 to 114.7°C.

The structure of the favorite was confirmed by matching the standard specimen obtained by a known method with various equipment data.

Example 3 [■] Noerythro form Cherythro 1-(4-hydroxyphenyl)-27(4-benzylpiperidino)propan-1-ol 34.851- was heated and dissolved in 200 d of 50φ water-containing methanol, and then tartaric acid 8 .01 was added and cooled, the precipitated crystals were collected by fS and dried to form white powder crystals [n
), i.e. erythro 1-(4
-Hydroxyphenyl)-2-(4-benzylpiperidino)propan-1-ol tartrate 40.77 (yield 95.0) is obtained. mp148℃ (Tani Sakai).

In addition, pyridinium bromide (II) used in Example 1
Br can be easily obtained, for example, as follows.

That is, 22.9 parts of 1-(4-hydroxyphenyl)-z-bromopropan-1-one, 183 parts of 4-benzoylpyridine and 30 parts of dioxane were mixed and aged at 90 DEG C. for 2 hours with stirring. Add 100 parts of acetone to the reaction solution and collect the precipitated crystals.

1-(1-(4-Hydroxyphenylcarbonyl)ethyl)'4-pensoylpyridinium bromide or pyridinium bromide++)B is dried to form a slightly brown powder.
41.0 parts of r (yield 99.5%) are obtained.

Pyridinium bromide (11Br decomposition point 251.1-252.2℃ IR&)"cm": 1660 (Co), 305
0 (OH7ma! NMR (DMSO-d6) δ: 2.03 (3H
,d, :1=7)1z,CH-'C4),3.47'(
1'H,'S,OH).

6.97-9.53 (13H, m, aromatic ring proton) Elemental analysis Cxi Hll Non Br Calculated value: C61,18; H4,40; N3.40 Actual value: C61,05; H4,43; N3.29 patent applicant
Wako Pure Chemical Industries, Ltd. August 1980 Director General of the Japan Patent Office Mr. I Case Description 2 Title of Invention Method for producing piperidinoalkanol and its acid addition salt 3
Person making the amendment Relationship to the case Patent applicant postal code 541 Contact η rule □3-zyo-sst+5, Subject of amendment.

Application and specification.

6. Contents of amendment (1) Amend the application as shown in the attached sheet.

That is, "Patent application pursuant to the provisions of Article 38, Part I of the Patent Act" and [Number of inventions stated in the scope of claims: 3]
I hope to join fK.

(2) Amend the description as shown in the attached sheet.

Engraving of the detailed statement (no changes to the contents).

Amendment to the above procedures August 25, 1980 Director-General of the Patent Office 1, Indication of the case August 5, 1982] Patent application filed 2 Name of the invention Process for producing piperidinoalkanol and its acid addition salt 3
Relationship with the case of the person making the amendment Patent applicant postal code 541 Contact information 03-270-11571 5 Column for detailed explanation of the invention to be amended.

6 Contents of amendment (1) “Weakly alkaline” stated on page 11, line 7 of the specification?
Corrected as "slightly alkaline."

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Claims (1)

[Claims] A compound represented by the following. (In the formula, X represents a halogen atom.)
A method for producing a compound represented by reducing a class ammonium salt with a metal hydrogen compound. A method for producing piperidinoalkanol and its acid addition salt, which comprises hydrogenating a compound represented by n in the presence of a catalyst.