JPS6027668B2 - 1-(4-isopropylthiophenyl)propane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 1-(4-isopropylthiophenyl)propane conductor, more specifically, it has the following formula (0
) 1-(4-isopropylthiophenyl)-2 represented by
The following formula (1) is useful as a synthetic intermediate for mono-n-octylaminopropanol (wherein, X represents a group or group=0).

) 1-(4-isopropylthiophenyl)propane derivatives.

Amino alcohol of formula (0) and its non-toxic salts, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or oxalic acid, lactic acid, tartaric acid, acetic acid, citric acid,
Salts of organic acids such as maleic acid have important pharmaceutical properties.

Since the aminoalcohol of formula (0) obtained by treating the compound (1) of the present invention with n-octylamine and reducing the Schiff base produced has two adjacent asymmetric carbon atoms, It exists as two stereoisomers, the stereoisomer and the threoisomer, and each is racemic.

These racemic compounds are formed into diastereomers by conventional methods using optically active acids such as tartaric acid, diacetyltartaric acid, tartoranilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid, etc. The mixture can be separated by crystallization, distillation, or chromatography, and then the separated diastereomers can be separated by liberating the optically active base. As mentioned above, the amino alcohol (B) produced from the compound (1) of the present invention is separated into the erythro form, the threo form, and each optically active compound, and the amino alcohol (B) is separated into the erythro form, the threo form, and the respective optically active compounds, and the amino alcohol (B) is separated into the erythro form, the threo form, and the respective optically active compounds. Can be used as a mixture of more than one form.

This compound has mirror linkage action, peripheral *vasodilatory action, and antihypertensive action, and exhibits protective action against myocardial oxygen deficiency. As a result of clinical research, it has been found to be extremely effective for cerebral and peripheral vascular circulation disorders, such as intermittent geniculate syndrome and cerebrovascular anoxia, which is accompanied by arteriosclerosis. The present compound can be administered orally or parenterally to a patient together with a pharmaceutically used carrier. Furthermore, the compounds can be used alone or in combination with other compounds with similar or different activities. Formula (0)
For example, the amino alcohol represented by
It is manufactured by the method described in Japanese Patent No. 135935 according to the following steps.

However, in all of these methods, various types of by-products are observed in the amination step, and it takes a long time to purify the target product.

On the other hand, in the production method using the synthetic intermediate of the present invention as a starting material, the desired amino alcohol can be obtained in good yield, and almost no by-products are observed, so purification can be carried out easily and in a short time. . In the production method, the amino alcohol and its salt (0) is 1-(4-isopropylthiophenyl)-1,2-propanedione represented by (la), or is 1-(4-isopropylthiophenyl)-1,2-propanedione represented by (lb).
4-isopropylthiophenyl)-1-hydro.

Using xypropan-2-one as the starting material (1), (m)
React with n-octylamine represented by (la)
It is produced by forming a Schiff base represented by (Wb) from (Wa) and (lb), further reducing these Schiff bases, and optionally converting them into pharmaceutically acceptable salts. Hereinafter, the present invention will be specifically explained in accordance with the above reaction formula.

'11 Production of Schiff's base (Wa), (Nb) To produce Schiff's base (Na), (Wb), the starting materials diketone (la) and keto alcohol (lb) are mixed in an organic solvent or without solvent. , if necessary in the presence of a base or acid, with n-octylamine (m).

If desired, this Schiff base may be used in the next reaction without being used alone. Starting Material The starting material diketone (la) is a new compound in which 1-(4-isopropylthiophenyl)propanone is isonitrosated, for example with a nitrite ester, to give 1-(4-
It can be produced by generating isopropylthiophenyl)innitrosopropanone and hydrolyzing it with an acid.

The starting material ketoalcohol (lb) is also a new compound, 1-(4-isopyroprthiophenyl)ethynylcarbyl obtained by condensing p-isopropylthiobenzaldehyde with acetylene in the presence of a steel catalyst. (Method A), a Grignard reaction of p-isopropylthiomandelic acid amide with methylmagnesium iodine (Method B), or 1-(4- (C
method) can be manufactured.

Method A n-octylamine The amount of n-octylamine used is in a molar ratio of 0.8 to 100, preferably 1 to 10, based on the starting material of formula (1).

Solvent When using a solvent, for example, methanol, ethanol, plastic.

Alcohols such as panol, butanol, and ethylene glycol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as ethyl ether, dioxane, and tetrahydrofuran, ethyl acetate, and chloroform are used, and the amount used is determined by the formula (1 ), preferably 5 to 50 times (by weight) of the compound. When a base is used as a base catalyst, for example, amines such as triethylamine, pyridine, and dimethylaniline, inorganic bases such as caustic soda, caustic potash, potassium carbonate, and sodium carbonate, and alkoxides such as sodium methoxide and sodium ethoxide are used. , the amount used is formula (1)
0.1 to 5 moles, preferably 0.5 to 6 moles, are used for the compound.

When using an acid as an acid catalyst, for example, an organic acid such as para-toluenesulfonic acid, benzenesulfonic acid, or acetic acid, or an inorganic acid such as hydrochloric acid or sulfuric acid is used, and the amount used is based on the compound of formula (1). 0.1 to 5M sound in mole number, preferably 0.
5-5 borrowed.

Temperature, time reaction temperature is -30 to 200qC, preferably -10 to 1
50 qo, reaction time is 1 minute to 24 hours, preferably 3 pieces to 1 piece.

Since the Schiff base produced is unstable in air, it is preferable to use it as it is in the next step without isolation.

In that case, if the solvent used is the same as the solvent used in the next step, use the reaction solution as is, but if the solvent used to prepare the Schiff base is different from the solvent used in the next step, After removing the solvent, it is subjected to the next reaction. '
Reduction of 2' Schiff base The Schiff base (Wa) or (Wb) obtained in the previous step is then reduced in the presence of an organic solvent to obtain the desired 1-(4-isopropylthiophenyl)-2. 1n-Octylaminopropanol (b) is produced.

This reduction can be carried out in the usual manner. Alkali metal hydrides, such as sodium borohydride, lithium aluminum hydride, NaNH2 (OCH2CH
20CH3)2, (iso-Butyl)2A
When using IH, lithium hydride, diporan, etc.
The amount used is 0.1 to 1 mol, preferably 0.25 molar based on the compound of formula (1) used in the production of Schiff's base.
For example, in the case of sodium borohydride, alcohols such as methanol, ethanol, propyl, pyridine, etc., and solvents such as lithium aluminum hydride, (iso-Butyl)2AIH, etc. case, ethyl ether, tetrahydrofuran, dioxane,
A solvent such as ethers such as diglyme is used in an amount of 1 to 100 times, preferably 5 to 5 times, the weight of the compound of formula (1) used in the production of Schiff's base.

The reaction temperature is -30 to 200°C, preferably -10 to 10
0 o'clock ○, reaction time is 10 minutes to 24 hours, preferably 30 minutes
It takes 1 minute to 1 field time. In addition, sodium borohydroxide is
If necessary, it can be used with Lewis acids such as boron fluoride, aluminum chloride, cobalt chloride, zinc chloride, and the like. After the reaction is complete, the reaction mixture is poured into water and extracted with an organic solvent.

After concentrating the organic layer, the desired product is obtained by conventional purification methods such as recrystallization and column chromatography. It is also possible to form a salt with a suitable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, picric acid, etc. for post-purification. In addition, when carrying out catalytic reduction, the catalyst may be, for example, palladium supported on carbon, barium sulfate, etc.
Ruthenium, rhodium, Raney nickel, platinum oxide, etc. are added 0.01 to 5 times, preferably 0.05 to 2 times (by weight), relative to the compound of formula (1) used in the production of Schiff base.
The solvent used is alcohols such as methanol, ethanol, propanol, ethers such as dioxane, tetrahydrofuran, acetic acid, etc. 1 to 10 beeps, Preferably it is used 5 to 50 times (by weight).

The reaction temperature is -10 to 20,000, preferably -5 to 15
0°C, reaction time is 5 minutes to 2 hours, preferably 3 minutes to
1q hours, and hydrogenation is carried out under normal pressure or, if necessary, under increased pressure. After the reaction is complete, remove the catalyst and concentrate the reaction mixture.
After that, if necessary, the desired product can be obtained by using a suitable salt, recrystallization, column chromatography, or other conventional purification methods. A feature of the catalytic reduction method is that the compound of formula (1) can be reacted with n-octylamine (m) and simultaneously reduced to produce the desired amino alcohol (b).

In that case, the conditions such as catalyst, solvent and the amount used, reaction temperature, reaction time, etc. are the same as in the case where the Schiff base is once produced and then reduced. Example 11-(4-isopropylthiophenyl)-1,2-propanedione (la)
Preparation method: 1. Dissolve 2.08 parts of (4-isopropylthiophenyl)propanone in 20 parts of ethanol, then add 1.2 parts of butyl nitrite.

Sodium ethylate (made from 0.3 ml of sodium metal and 1 ml of ethanol) was added at room temperature, and the mixture was refluxed for 5 hours. The reaction solution was concentrated, 10% hydrochloric acid was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. When the solvent was removed, crystals were precipitated. When recrystallized from benzene-hexane, m. p. 80-80.5o0 crystals are 2.
Obtained in 19 days (yield 92.4%). IR (KBr, inhibitor-1): 3250 (〇H), 1660 (C2N) 2.19% of the thus obtained 1-(4-isopropylthiophenyl)innitrosopropanone was dissolved in 30% sulfuric acid. 20 and steam distilled.

The oil was extracted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crystals. Yield: 1.01 m (yield 50%) Melting point: 143-14 0 m (KBr, Ka-1): 172 F 1670 (CO) M
S: 222 (M 10) 179 (M-43) 137 (M-42) Example 2 Process for producing 1-(4-isopropylthiophenyl)-1-hydroxypropan-2-one (ratio) 1-(4 -isopropylthiophenyl)-2-dibenzylamino-propanone (786 ml) was dissolved in 2 parts of acetic acid and 5 parts of water;
The mixture was heated at 100°C for q hours.

10 parts of water was added, extracted with ether, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution, diluted hydrochloric acid, and then water, dried over anhydrous magnesium sulfate, and the solvent was concentrated. The oily substance of Qiansa was developed and separated using chloroform using silica gel column chromatography. Colorless oil 9 of 290 (yield 6
5%). TCL(CHC13:CH3COOC2
Day 5 = 2:1): Rf = 0.58m (rock salt plate, arc-1)
: 1722 (C:○), 1595 (aromatic) MS: 224 (M+), 181 (M-43), 178 (M-4
5), 139 (M-85), 137 (M-87) Reference example 1 1-(4-isopropylthiophenyl)-2-Production method of n-octylaminopropanol 1-(4-isopropylthiophenyl)- 1.2-propanedione 2.22 evening (
(low mol) was dissolved in 50 mol of methanol, 1.42 mol of n-octylamine (11 mol) and 1.11 mol of triethylamine (11 mol) were added, and the mixture was allowed to stand at room temperature for 1 hour.

The mixture was cooled on ice, and sodium borohydride was added to the mixture, and the mixture was kept at room temperature for 4 hours, concentrated, and 50% of water was added, and 5% caustic soda was added to give a concentration of 11. Extracted with benzene. The organic layer was washed with water, dried and concentrated to give 2.99 g of an oil.
Yield 89%. According to thin layer chromatography, the obtained substance was the target compound 1-1 (4-isopropylthiophenyl) synthesized by the method described in Tokkanwa No. 49-135935.
It corresponded to a mixture of erythro and threo isomers of 2-n-octylaminopropanol, and contained almost no other impurities.

The oily substance was dissolved in 50 parts of ether, and 5 parts of concentrated hydrochloric acid was added thereto while cold. The precipitated crystals were collected in a furnace, washed with water and ether, and recrystallized from methanol-water.

m. P. White crystals (hydrochloride) 231-233.5℃
．． I got 20 evenings. Yield 59%. This hydrochloride was made into a free base with methanol-caustic acid-water, and the precipitated crystals were collected in a furnace to obtain m.p. p. 1.92 pieces of white crystals of 61-6yo were obtained.

Yield 57%. This product was confirmed by the mixed melting test in 49-13
It was the same substance as the erythro form of 1-(4-isopropylthiophenyl)-21-n-octylaminopropanol obtained by the method described in No. 5935. Reference Example 2 Method for producing 1-(4-isopropylthiophenyl)-121n-octylaminopropanol 1-(4-isopropylthiophenyl)-1-hydroxypropane-2-one 900 (4 units mol) Dissolved in 20 parts of methanol, 570 parts of n-octylamine (4.4 mmol)
444 mmol of triethylamine (4.4 mmol) was added to the mixture, and the mixture was incubated at room temperature for one morning.

The reaction solution was ice-cooled, 150 ml of sodium borohydride was added, and after heating at room temperature for 4 hours, methanol was distilled off, and then water was added to 2 ml of water.
0 skin was added, and 5% caustic soda was further added to make pHil, and the mixture was extracted with benzene. The organic layer was washed with water, dried, and concentrated to obtain 1.21 g of an oily substance. Yield 90%. When analyzed by thin layer chromatography in the same manner as in Example 3, this product was found to be the target product 1-(4-isopropylthiophenyl)-2
-n-octylaminopropanol - corresponded to a mixture of erythro and threo forms, and contained almost no other impurities. Dissolve the oily substance in 20 parts of ether,
Concentrated hydrochloric acid 2 was added to the mixture while it was cold, and the precipitated crystals were collected in a furnace, washed with water and ether, and then recrystallized with tanol-water.

m. p. Hydrochloride 838-9 of 231-234 was obtained as white crystals. Yield spot %. This hydrochloride was made into a free base with methanol and caustic water, and the precipitated crystals were collected in a furnace and m.p. p. 9 of 760 white crystals with a temperature of 61-63°C were obtained.

Claims (1)

[Claims] 1 formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X is a group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Or represents group=0. ).