JPS6046110B2 - Method for producing 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1-(4-isopropylthiophenyl)-2-
The present invention relates to a new method for producing n-octylaminopropanol, and more specifically, formula (I)] CH-S H4
H-℃H3CH3OHNH.

1-(4-isopropylthiophenyl)-2-aminopropanol or its salt represented by (I) and formula (■)
CH3 (CH.

)6CH. Formula (■) characterized by reacting with a compound represented by X (■) (in the formula, x represents a halogen atom or an acid ester residue)] ) CHaOHNH(CH2)7CH3 1-(4-isopropylthiophenyl)-
The present invention relates to a method for producing 2-n-octylaminopropa, nol, or a salt thereof.

The amino alcohol of formula (■) is disclosed in JP-A-49-13593.
This is a compound described in Publication No. 5, which has antispasmodic, peripheral vasodilatory, and antihypertensive effects, and exhibits a protective effect against anoxia in the myocardium.

In addition, as a result of clinical research, it has been found to be extremely effective for cerebral and peripheral vascular circulation disorders, such as intermittent erectile dysfunction and cerebrovascular anoxia, which is often accompanied by arteriosclerosis. Since the amino alcohol of the formula (■) has two adjacent asymmetric carbon atoms, it contains two stereoisomers, a tritro-isomer and a threo-isomer, and each isomer is a racemate.

Optically active amino alcohols of formula (■) can be obtained from these racemic mixtures by conventional methods. That is, a diastereomer is formed from the racemate using an optically active acid such as tartaric acid, diacetyltartaric acid, tartoranilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid, etc., and a mixture of this diastereomer is crystallized and distilled. Alternatively, the diastereomers are separated by chromatography, and then the optically active base is released from the separated diastereomers. As mentioned above, the amino alcohol of formula (■) produced by the method of the present invention is separated into the optically active compound of the engineered compound, the threo compound, and each optically active compound by a conventional method, and each can be used alone or in two or more forms. Available as a mixture.

Non-toxic salts of amino alcohols of this formula (■), such as inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.
Alternatively, salts of organic acids such as oxalic acid, lactic acid, tartaric acid, acetic acid, citric acid, maleic acid, etc., also have important pharmaceutical properties similar to the amino alcohols of formula (■).

The amino alcohol of formula (■) can be administered orally or parenterally to a patient together with a pharmaceutically used carrier.

Furthermore, the amino alcohol of formula (■) can be used alone or in combination with other compounds having similar or different activities.

The method for synthesizing the amino alcohol of formula (■) is as follows:
For example, JP-A-49-1359357 discloses a method represented by the following reaction formula.

However, in all of those methods, many types of by-products were observed in the amination step. However, it has the disadvantage that it takes a long time to purify the target product. The present inventors have discovered that 1-(4-isopropylthiophenyl)-2- represented by formula (■)
As a result of intensive research into the manufacturing method of n-octylaminopropanol, we have found that the target compound can be synthesized in good yield with almost no by-products observed, and that the target product can be easily purified in a short time. The present invention was completed by discovering a manufacturing method that enables this.

In the course of this research, the present inventors discovered a new compound (1) which is a starting material for the method of the present invention, and also discovered an advantageous method for its production, leading to the completion of the present invention. The method of the present invention, that is, the N-alkylation reaction using the compound of formula (1) or a salt thereof as a starting material will be described in detail. Compound (1
), hydrochloride, hydrobromide, sulfate, phosphate, oxalate, lactate, tartrate, acetate, citrate, maleate, etc. are used.

As the alkylating agent in the N-alkylation reaction, a halogen compound represented by the formula (■) and an acid ester are used.

Examples of the halogen compound include octyl chloride, octyl bromide, and octyl iodide.

These are used in a molar amount of 0.5 to 5 times (preferably 0.8 to 1.2 times) the amount of compound (1) or its salt.
This reaction may be carried out with or without a solvent. When using a solvent, suitable solvents include hydrocarbons such as benzene, toluene, naphthalene, tetralin, and decalin, alcohols such as methanol, ethanol, propanol, butanol, amino alcohol, ethylene glycol, and glycerin, and ketones such as acetone and methyl ethyl ketone. , halogenated hydrocarbons such as chloroform and chlorobenzene, esters such as ethyl acetate, and ethers such as dioxane and tetrahydrofuran.

The reaction is carried out at a temperature of 20 to 200°C (preferably 50 to 150°C).
), and can be carried out for 1 to 10 hours (preferably 2 to 10 hours). In addition, when alkylating using chloride or bromide, the reaction can also be carried out by adding an equimolar amount of sodium iodide to the compound of formula (1). As the ester, sulfonic acid esters and esters of inorganic acids having an octyl group are used.

Sulfonic acid ester is CH3(CH2)6CH2-0
It is represented by S02-R'', where R'' represents a C1-10 alkyl group or a C,-10 aryl group.

Examples include octyl methanesulfonate, octyl ethanesulfonate, octyl butanesulfonate, octyl octanesulfonate, octyl benzenesulfonate, octyl p-toluenesulfonate, and the like.

As an ester of an inorganic acid, CH3(CH2)6CH2
Sulfuric ester represented by 10S02-0R'' (the meaning of R'' is the same as above).

) Examples include methyloctyl sulfate, ethyl octyl sulfate, butyloctyl sulfate, dioctyl sulfate, phenyl octyl sulfate, and p-tolyloctyl sulfate. Other examples include sulfite esters such as dioctyl sulfite, phosphate esters such as trioctyl orthophosphate, and nitric esters such as octyl nitrate.

Even when using the esters of the above-mentioned acids, the reaction can be carried out under the same conditions as when using the above-mentioned alkyl halides. In this case, the reaction is preferably carried out in the presence of a base such as caustic soda, caustic soda octacarbonate, potassium carbonate, pyridine, or triethylamine. In this reaction, sodium iodide is not added. The amino alcohol of formula (m) prepared by the method described above can be isolated by extraction, crystallization or, if necessary, chromatography of the reaction mixture or by forming a salt with a suitable acid. In the case of isolation as a salt, for example, the amino alcohol of formula (■) and a suitable acid may be reacted in equimolar amounts in a solvent such as alcohol, and then miscible with the initial solvent (alcohol, etc.); however, if the salt is insoluble, It is precipitated as a salt by adding an acid to an ethereal solution of the aminoalcohol (by adding some other solvent, such as diethyl ether), by adding the acid to an ethereal solution of the aminoalcohol, or by adding the aminoalcohol to an ethereal solution of the acid.

Suitable acids for forming salts include, for example, inorganic acids such as pentahydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or perchloric acid, formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, citric acid. acids, succinic acid, ascorbic acid, fumaric acid,
Examples include organic acids such as maleic acid, tartaric acid, phenylacetic acid, benzoic acid, anthranilic acid, O-salicylic acid, methanesulfonic acid, and ethanedisulfonic acid.

Next, the compound of formula (1), which is the starting material for the method of the present invention, can be produced by the method shown below.

(In the formula, Y represents a halogen atom.) The steps illustrated above will be explained in more detail.

1) Synthesis of azide compound (■) The azide compound is an α-haloketone of formula (■), for example, α-
It is obtained by mixing bromo-4-isopropylthiopropiophenone and a metal azide compound in a suitable solvent and reacting the mixture.

Examples of the metal azide compound include sodium azide, barium azide, iron azide, etc., and the amount thereof is 0.8 to 5 times (preferably 1.5 times) the number of moles of the haloketone.
0-2.皓) to use.

Examples of the solvent include chloroform, tetrahydrofuran, acetone, methyl ethyl ketone, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, hexamethyltriphosphoramide, methylpyrrolidone, etc., and the amount is 1 to 100 times (preferably 5 to 5 times) the weight of the haloketone.皓) to use.

The reaction temperature is -10 to 100°C (preferably 0 to 50°C)
), the reaction time is 1 to 48 hours (preferably 30 minutes to 2 hours).
@ between).

The azide compound obtained in this way can be extracted, crystallized,
In some cases, chromatography. It can be subjected to the next reaction after being isolated and purified using the same method, or simply by distilling off the solvent without purification.

From the azide compound (V) thus obtained, aminoalcohol (1) can be obtained directly by reduction or via aminoketone (■).

2) Synthesis of aminoketone (■) As a method for reducing only the azide group while leaving the carbonyl group of compound (V), for example, stannous chloride/hydrogen chloride,
There are 7 methods using zinc, acetic acid, hydrogen halide, etc.

When using stannous chloride/hydrogen chloride, stannous chloride in an amount of 1 to 5 (preferably 2 to 1 molar) based on the azide is mixed with acetic acid saturated with hydrogen chloride, and the reducing agent is preliminarily mixed with the acetic acid. Prepare in advance. In this case, the amount of acetic acid used is 2 to 20 (preferably 5 to 10) by weight based on tin chloride. An azide compound was added to this reducing agent, and the reaction time was 5.
minutes to 1 hour (preferably 1 gin to 1 hour), reaction temperature -2
The reduction reaction is carried out at 0 to 100°C (preferably 0 to 50°C). When using zinc and acetic acid, use 1 to 10 moles (preferably 10 to 5 moles) of zinc per mole of the azide compound, and use water, methanol, ethanol, acetic acid, etc. as a solvent, such as water, methanol, ethanol, acetic acid, etc. The reduction is carried out using ~20 ml (preferably 5 to 10 ml).

Reaction time is 5 minutes to 2 servings (preferably 1 to 10 hours),
The reaction temperature is -20 to 50°C (preferably 0 to 30°C)
It is. When using a hydrogen halide such as hydrogen bromide or hydrogen iodide, the hydrogen halide is used in an amount of 2 to 5 moles (preferably 3 to 1 mole) relative to the azide compound.

As a solvent, water, methanol, ethanol, acetic acid, etc. are used in an amount of 2 to 200 times (preferably 5 to 10 times) the weight of the azide compound.
皓) to use. This reduction is usually carried out by dissolving hydrogen halide in a solvent in advance and adding the azide compound thereto. Reaction time is 5 minutes to 4 hours (preferably 10 minutes to 24 hours)
time) and the reaction temperature is -10 to 1000C (preferably 0 to 30C). 3) Amino alcohol (1)
Synthetic amino alcohol (1) can be obtained by the method of reducing the aminoketone (■) and the method of reducing the azide compound (■), as shown in the process diagram described above.

The aminoketone (■) can be reduced by a conventional method.

A method using a reducing agent As the reducing agent, an alkali metal hydride such as sodium borohydride, lithium borohydride, potassium borohydride, lithium aluminum hydride, and lithium hydride is used.

These can be used individually or in combination with each other, or as a complex of sodium borohydride and a Lewis acid (aluminum chloride, boron fluoride, etc.). When using lithium aluminum hydride, the number of moles is 0.2 to 5 times (preferably 0.5 to 1 times) the aminoketone (■), and when using lithium hydride, the aminoketone (■) is used. The number of malls is 0.8 to 20 times (preferably 2 to 5 times)
use

Suitable solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, and dibutyl ether.

When using sodium borohydride, lithium borohydride, potassium borohydride, or a complex of sodium borohydride and Lewis compounds, the number of moles is 0.5 to 5 (preferably 0.75 to 5 times)
Use.

Suitable solvents include water, alcohols such as methanol, ethanol, propanol and butanol, and pyridine. The above reduction reaction is performed on the aminoketone (■) in a solvent with a weight of 2 to 50 cm (preferably 10 to 10 @) at a reaction temperature of -50 to 100°C (preferably 0 to 8 °C).
0℃), reaction time 5 minutes to North time (preferably 10 to 2 hours)
@ between).

B Catalytic Reduction Method Hydrogenation is carried out using a metal catalyst such as palladium, Raney-Etzkel, platinum oxide, or ruthenium as it is or in the presence of a catalyst supported on carbon, barium sulfate, or the like.

The amount of catalyst is from 0.01 to aminoketone (■) by weight.
1x (preferably 0.05 to 1x) is used.

Suitable solvents include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, acetic acid, etc., and are used in an amount of 5 to 50 (preferably 10 to 10) by weight per aminoketone (■). The reaction temperature is 0 to 150'C (preferably 20 to 80C),
The reaction time is between 1 and 1 hour (preferably between 2 and 2 hours). The reduction of the azide compound (V) can be carried out in the same manner as described above using lithium aluminum hydride or lithium hydride.

The present invention will be explained in more detail below using reference examples and examples.

Reference Example 1 Synthesis of 1-(4-isopropylthiophenyl)-2-aminopropanone 1-(4-isopropylthiophenyl)-2-prompropanone 2.52g (10mm01)
was dissolved in 10 Tnt of dimethyl sulfoxide, and while stirring, 0.98 g (15 rm01) of sodium azide was gradually added.

After continued stirring at room temperature for 2 hours, 50 mL of water was added,
Extracted three times with 20 ml of benzene. After drying the organic layer with magnesium sulfate, benzene was distilled off to obtain 2.0 g of a pale yellow semi-solid substance. This substance was subjected to infrared absorption spectrum and nuclear magnetic resonance spectroscopy without further purification, and was confirmed to be 1-(4-isopropylthiophenyl)-2-azidopropanone. Separately, 4.5 g of stannous chloride dihydrate (20rT
After heating 1 m01) and 4 mt of acetic anhydride at reflux temperature, 8 m1 of glacial acetic acid was added thereto, and the mixture was saturated with hydrogen chloride to prepare a reducing agent.

This reducing agent was cooled on ice, and 1.25 g of 1-(4-isopropyl, thiophenyl)-2-azidopropanone (5 mm 0
A solution consisting of 1) and 2 ml of glacial acetic acid was added with stirring.

1 After continuing to stir the powder, acetic acid was distilled off under reduced pressure, and 10%
20 ml of caustic soda was added and extracted with 50 ml of ether, hydrogen chloride was immediately passed through the mixture, and the precipitated crystals were filtered out.

Yield 0.72g (yield 55%), Mp. l8O~188
°C (decomposition). This compound was confirmed to be 1-(4-isopropylthiophenyl)-2-aminopropanone hydrochloride by infrared absorption spectrum and nuclear magnetic resonance spectrum. Reference Example 2 Synthesis of 1-(4-isopropylthiophenyl)-2-aminopo/manol
ml was dissolved in 10 mt of methanol, 200 m9 of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours.

After methanol was distilled off, 10 ml of water was added and extracted with chloroform. It was dried over magnesium sulfate and chloroform was distilled off to obtain crystals of 360Tn9. (yield 80%
), Mp. lOO~101°C. The product was confirmed to be 1-(4-isopropylthiophenyl)-2-aminopropanol by infrared absorption spectrum and nuclear magnetic resonance spectrum. Example 1 1.12g (MmOl) of the amino alcohol obtained in Reference Example 2 and 1.0g (5.5n1m0I) of octyl bromide were mixed in 50ml of ethanol.
The mixture was refluxed in 1 for 2 days.

After the reaction was completed, ethanol was distilled off and crystals were precipitated.
Wash with water and ether, dry and hydrobromide 1.3g
(Yield 69.5%) crystals were obtained. 0.5 g of this crystal was dissolved in a solution of 94 mg of caustic potash in 5 ml of methanol, 10 mt of water was added thereto, and the mixture was left in a cold place to precipitate crystals, which was further recrystallized from n-pentane. Mp. 6l~6
3℃. A mixing test using the product synthesized by the method described in JP-A-49-135935 as a standard and comparison of infrared absorption spectra revealed that this crystal was the desired 1-(4-isopropylthiophenyl)- It was confirmed that it was 2-n-octylaminopropanol (retroform). Example 2 1.12 g of amino alcohol obtained as in Reference Example 2
(5rnm01) and octyl p-toluenesulfonate 1
．． 42g (5n1m01) in 10ml of benzene
It was refluxed for 4 hours.

Claims (1)

[Claims] 1 1-(4-isopropylthiophenyl)-2 represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼
-Aminoprobanol or its salt and formula CH_3(C
H_2) _6CH_2X (wherein, (4-isopropylthiophenyl)-2
- A method for producing n-octylaminopropanol or a salt thereof.