JPS62126170A - Production of 4-(4-pyridyl)cyclohexanone - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful for an intermediate for mecicines, by subjecting a 2-alkoxy-, 2-acetyloxy- or 2-allylsiloxybutadiene and 4- vinylpyridine to the Diels-Alder reaction and treating the cyclization product with an acid. CONSTITUTION:A compound expressed by formula I (R is methyl, ethyl, n-butyl, trimethylsilyl, tert-butyldimethylsilyl or acetyl) and a compound expressed by formula V are subjected to the Diels-Alder reaction in or without a solvent, e.g. benzene, chloroform or methylene chloride, etc., as necessary, in the presence of a Lewis acid or/and a polymerization inhibitor, e.g. phenyl-alpha-naphthylamine, hydroquinone, etc., at 0-250 deg.C, preferably 150-200 deg.C to afford a compound expressed by formula VI, which is then hydrolyzed with an acid, e.g. hydrochloric acid, acetic acid or trifluoroacetic acid, etc., to give the aimed compound expressed by formula II particularly useful as an intermediate for a cardiotonic agent (compound expressed by formula III).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 4-(4-pyridyl)cyclohexanone, and 4-(4-pyridyl)cyclohexanone is useful as a pharmaceutical intermediate. That is, isoquinoline derivatives possessing cardiotonic activity can be derived, for example, through the following reaction route, in which case 4-cyano-1-methyl-7-(4-
pyridyl)-5,6,7,8-tetrahydro-3(2H
)-As an intermediate for the production of isoquinoline (Ill) (1)
Cl1r) (LV)
As a method for producing cyclohexanone having a substituent at the 4-position, for example, in the production of 4-phenylcyclohexanone, 4
- There is a method to obtain 4-phenylcyclohexanol by selective hydrogenation of phenylphenol, and then to obtain 4-phenylcyclohexanone by oxidation.
There is no known method for producing (pyridyl)cyclohexanone.

While ■ is about to change to ``°'', the currently considered method for producing 4-(4-pyridyl)cyclohexanone is a combination of selective hydrogenation of 4-(4-pyridyl)phenol and oxidation reaction. Selectivity could not be achieved and a separate synthesis method was required.

+j In order to make ``1'', the inventor of the present invention continued to study the method for producing 4-(4-pyridyl)cyclohexanone, and as a result, discovered a method for obtaining 4-(4-pyridyl)cyclohexanone from 4-vinylpyridine and butadiene. We have arrived at the present invention.

In detail, the present invention relates to 2-alkoxy, 2 -7
The present invention relates to a method for producing 4-pyridylcyclohexanone by subjecting cetyloxy or 2-alkylsilyloxybutadiene to 4-vinylpyridine in a Diels-^1der reaction and then treating the cyclized product with an acid.

To describe the method of the present invention in more detail, the production method of the present invention is carried out by the reaction route shown below (R in the above reaction route means the same substituent as above.) 2-alkoxy or 2-alkylsilyloxy A cyclized product (Vl) is obtained by subjecting butadiene (r) and 4-vinylpyridine (V) to a D 1els-Alder reaction in a solvent such as benzene, chloroform, methylene chloride or in the absence of a solvent. At this time, a Lewis acid may be used in combination for the purpose of promoting the reaction. The reaction is carried out at 0 to 250°C, preferably at 150 to 200°C.

Further, in order to prevent polymerization, a polymerization inhibitor such as phenyl-α-naphthylamine or hydroquinone may be used.

4-(4-pyridyl)cyclohexanone (It) is obtained by hydrolyzing the cyclized product (Vl) using an acid such as hydrochloric acid, acetic acid, or trifluoroacetic acid.

Furthermore, according to the present invention, 4-(4-pyridyl)cyclohexanone, which is an intermediate for producing isoquinolinone derivatives, which is useful as a pharmaceutical intermediate, and particularly useful as a cardiotonic agent, can be produced.

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

Example 1 4-(4-pyridyl)cyclohexanone 34 g of 2-trimethylsilyloxybutadiene, 4-vinyl, and 21 lysine
Dissolve g in 50+ml of dry benzene to obtain phenyl-α-
Naphthylamine 1001 was added and heated at 200° C. for 24 hours in an autoclave under a nitrogen atmosphere.

After cooling, a portion was purified by distillation under reduced pressure to obtain 4-(4-pyridyl)-1-)dimethylsilyloxy-2-cyclohexene.

bp 135-137℃ 10.3 Dragon HgrR (Nea
t)' MIIX 295012920.1660.
1590.1250.1190S1180.900.8
80.84ONl'1R (CC14) δpp+m:
0.19 (s, 911), 1.7-2.4 (n+, 61
1), 2.7 (a+, IH), 4.82 (m, 11
1), 7.06 (m, 211), 8.40 (a, 2H) The above crude product was diluted with 50 ml of chloroform, and after cooling with water, 30 ml of trifluoroacetic acid and 20 ml of water were added.
The mixture was stirred for a minute.

Subsequently, the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with chloroform, dried, concentrated, and purified using a silica gel column to obtain 11.9 g of 4-(4-pyridyl)cyclohexanone.

mp: 35 to 37°C IR""ateffl-': 3010.2920.
2860.1700.1600.140O NMR (CDCh) δppm: 1.7 ~ 2.
6 (m, 8H), 2.8 ~ 3.2 (m, 1tl)
, 7.15 (a+, 2H), 8.51 (m, 2
H), mutual 2- 1.55N-n-butyllithium hexane solution 52ml
diisopropylamine cooled to -50°C 12.3
Add to 40 ml of dry tetrahydrofuran solution of +++1, return to -20°C, stir for 20 minutes, add 13.9ml of hexamethylphosphoramide cooled to -50°C, add dropwise 5.6ml of methyl vinyl ketone, and stir for 30 minutes. Afterwards, a solution of 12 g of t-butyldimethylchlorosilane in dry tetrahydrofuran was added dropwise over 30 minutes.

Return the mixture to room temperature and stir for 3.5 hours, then add 200 ml of hexane.
ml was added and washed with water and saturated saline. The hexane solution was concentrated and then distilled under reduced pressure to obtain 5.5 g of 2-(dobutyldimethylsilyloxy)butadiene.

bp: 68-70℃/40℃/HgNMR (CDC
l2) δppm: 0.2 (s, 6H), 1.0 (s,
9H), 4.3 (s, 2H), 5.04 (d, J=6H
z, LH), 5.48 (d, J.

8Hz, IH), 6.16(dd, J=6.8)1z
, LH) 2-2.4-(4-pyridyl)cyclohexanone 2-(t-butyldimethylsilyloxy)butadiene 1
．． 1 g and 2 g of 4-vinylpyridine in 7 ml of dry toluene
5 mg of phenyl-α-naphthylamine was added to the 'fii liquid, and the mixture was heated at 180° C. for 15 hours in an autoclave under a nitrogen atmosphere.

After cooling, 50X acetic acid aqueous solution 611 was added and heated at 100° C. for 4 hours. After adding 10 ml of water and adjusting the pH to 8 with a 2N aqueous sodium hydroxide solution, the mixture was extracted with ethyl acetate, dried, concentrated, and purified using a silica gel column to obtain 0.2 g of 4-(4-pyridyl)cyclohexanone.

IR and NMR values were consistent with the compound of Example 1.

Example 3 To a solution of 0.9 g of 2-acetoxyptadi'ene and 1.7 ml of 4-vinylpyridine in 31 Ill of dry toluene was added 1 g of phenyl-α-naphthylamine 2I, and the mixture was heated at 180°C in an autoclave under a nitrogen atmosphere for 10 hours. . After cooling, 50x acetic acid aqueous solution 20a+1 was added and heated under reflux for 4 hours.

After cooling again, it was diluted to pi 8 with 2N aqueous sodium hydroxide solution, extracted with ethyl acetate, dried, and dried. l11i! , 0.1 g of 4-(4-pyridyl)cyclohexanone was obtained by purification using a silica gel column.

IR and NMR values were consistent with the compound of Example 1.

Claims (1)

[Claims] General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R is a methyl group, ethyl group, n-butyl group, trimethylsilyl group, t-butyldimethylsilyl group 4-( 4-
A method for producing (pyridyl) cyclohexanone.