JPS6026780B2 - 1-(4-isopropylthiophenyl)-2-aminopropane derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel aminopropane derivative and a method for producing the same.

More specifically, general formula (1) (wherein, X represents group = 0 or a group).

), a salt thereof, and a method for producing the same, i.e., formula (0) (wherein, Y represents a halogen atom).

1. A method for producing a compound of formula (1), which comprises azating a Q-haloketone derivative represented by ) to derive a compound represented by formula (m), and further reducing this compound (m). It is something.

The compound of formula (1) of the present invention has the general formula (W) (wherein, X
has the same meaning as above.

) 1-(4-isopropylthiophenyl)-2 represented by formula (V) using Schiff base represented by as an intermediate
It is useful as a synthetic intermediate in the production of -n-octylaminopropanol.

1-(4-isopropylthiophenyl)-2-n-octylaminopropanol represented by formula (V) is disclosed in Japanese Patent Application Laid-open No. 4
It is a compound described in Publication No. 9-135935, and has a keyboard effect, a peripheral vasodilatory effect, and an antihypertensive effect, and also shows a protective effect against anoxia in the myocardium. In addition, as a result of clinical research, it has been found to be extremely effective in treating vascular anoxia and peripheral vascular circulation disorders, such as intermittent skeletal syndrome and vascular anoxia, which is accompanied by arteriosclerosis. Formula (V
) Since the amino alcohol has two adjacent asymmetric carbon atoms, there are two stereoisomers, erythro and threo, and each is racemic.

These racemates were prepared using conventional methods to obtain the optically active formula (
The amino alcohol of V) can be obtained. That is, a diastereomer is formed from the racemate using an optically active acid such as tartaric acid, diacetyltartaric acid, diacetyltartaric acid, tartoranilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid, etc., and a mixture of this diastereomer is crystallized. The diastereomers are separated by , distillation, or chromatography, and then an optically active base is liberated from the separated diastereomers. Formula (V
As mentioned above, the amino alcohol of (2) is separated into erythro-form, threo-form, and each optically active compound by a conventional method, and each can be used alone or as a mixture of two or more forms.

A non-toxic salt of the amino alcohol of formula (V), an inorganic acid such as phosphoric acid or sulfuric acid, or oxalic acid, lactic acid, tartaric acid,
Salts of organic acids such as acetic acid, citric acid, maleic acid, etc. also have the formula (V
) has important medicinal properties similar to amino alcohols.

The present compound can be administered orally or parenterally to a patient together with a pharmaceutically used carrier.

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

As a method for synthesizing the amino alcohol of formula (V),
For example, JP-A-49-1359357 discloses a method represented by the following reaction formula.

However, in all of these methods, many types of by-products were observed at the amination stage (according to additional tests by the present inventors, several spots were found by thin-layer chromatography), and the objective It has the disadvantage that it takes a long time to purify the product. The present inventors have discovered that 1-(4-isopropylthiophenyl)-21n-
As a result of intensive research on synthetic intermediates used in the production of octylaminopropanol, we succeeded in obtaining a new compound represented by formula (W), and by using this compound, almost no by-products were observed. The present inventors have completed the present invention by discovering that useful compound (V) can be synthesized in a good yield without any problems, and that its purification can be easily carried out in a short period of time.

- The compound of formula (1), which is a synthetic intermediate for the amino alcohol represented by formula (V), can be produced by the following steps.

(In the formula, Y represents a halogen atom such as C1, Br or 1.

) The steps illustrated above will now be described in more detail.

1 Synthesis of azide compound (m) The azide compound can be obtained by mixing a Q-haloketone of formula m), such as Q-from-4-isopropylthiopropiophenone, with 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 of the metal azide compound is 0.8 to 5 times (preferably 1.0 to 2
．． M-K) 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. Pion) is used.

The reaction temperature is -10 to 100 qo (preferably 0 to 500 qo)
0), reaction time is 10-4 chick hours (preferably 30-2
4 hours).

The azide compound obtained in this way can be subjected to the next reaction after being purified by distillation or crystallization, in some cases by chromatography, or by simply distilling off the solvent without purification. .

From the azide compound thus obtained, directly by reduction,
Alternatively, aminoalcohol (1'') can be obtained via aminoketone (1').

2. A method for reducing only the azide group while leaving the carbonyl group of the aminoketone (1') synthesis compound (m+) is, for example, stannous chloride/hydrogen chloride,
There is a method using zinc, acetic acid, hydrogen halide, etc.

When using stannous chloride/hydrogen chloride, for azide,
A reducing agent is prepared in advance by mixing 1 to 50 times (preferably 2 to 10 times) molar amount of stannous chloride with acetic acid saturated with hydrogen chloride.

In this case, the amount of acetic acid used is between 2 and 20 pm (preferably between 5 and 10 pm) by weight relative to stannous chloride. A dide compound is added to this reducing agent, the reaction time is 5 minutes to 1 hour (preferably 10 to 1 hour), and the reaction temperature is -20 to 10 minutes.
The reduction reaction is carried out at 0q○ (preferably 0 to 50q○). When using zinc and acetic acid, the number of moles of zinc is 1 to 10 pm (preferably 10 to 5 pm) relative to the azide compound.
The reduction is carried out using, for example, water, methanol, ethanol, acetic acid, etc. as a solvent in an amount of 2 to 20 degrees (preferably 5 to 10 degrees) of the azide compound by weight.

Reaction time is 5 minutes to 24 hours (preferably 1 to 1 hour)
, the reaction temperature is -20 to 50qo (preferably 0 to 30qo)
○). When using hydrogen halides such as hydrogen bromide and hydrogen iodide, the hydrogen halides are
The number of moles used is 2 to 5 sounds (preferably 3 to 1 sounds).
As a solvent, water, methanol, etarail, acetic acid, etc. are used in an amount of 2 to 200 times (preferably 5 to 10 times) the weight of the azide compound.
Needle pain) used. This reduction is usually carried out by dissolving hydrogen halide in a solvent in advance and adding the hairzide compound thereto. The reaction time is 5 minutes to 48 hours (preferably 10 to 48 hours).
2 hours), and the reaction temperature is 10 to 10,000°C (preferably 0 to 30°C). 3 Ami/alcohol (1
Synthesis of Aminoalcohol (1'') Aminoalcohol (1'') can be obtained by the method of reducing aminoketone (1') and the method of reducing azide compound (m), as shown in the process diagram described above.

The aminoketone (1') 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 1.3 times) the aminoketone (1'). '), 0.8 to 20 times (preferably 2 to 5 times) in terms of moles
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 a Lewis acid, the amount is 0.5 to 50 times (preferably by mole) the aminoketone (1'). 0.75 to 5 times).

Suitable solvents include water, alcohols such as methanol, ethanol, propanol and butanol, and pyridine. The above reduction reaction is performed on the aminoketone (1') in a solvent with a weight of 2 to 50 M sonic sound (preferably 10 to ION sonic sound) at a reaction temperature of -50 to 100°C (preferably 0 to 80°C), Reaction time 5-4 hours (preferably 1 hour)
0 to 24 hours).

B Catalytic Reduction Method Hydrogenation is carried out using a metal catalyst such as palladium, Raney nickel, 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 0.01 by weight based on aminoketone (1')
~10 times (preferably 0.05 to 1 times) is used. Suitable catalysts include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran,
Examples include acetic acid, and it is used in an amount of 5 to 500 times (preferably 10 to 10 pm) the weight of aminoketone (1').
Reaction temperature is 0 to 150°C (preferably 20 to 80 pm)
, reaction time is 1 to 4 hours (preferably 2 to 2 hours)
It is. The reduction of the azide compound (m) can be carried out in the same manner as described above using lithium aluminum hydride or lithium hydride. The target 1-(4-isopropylthiophenyl)-2-octylaminopropanol of formula (V) using the new compound of formula (1) as a starting material can be obtained by the following reaction route. It can be produced via Schiff base (W) as follows.

That is, (wherein, X is group=0 or group represents.

) The method of the invention illustrated above will now be described in more detail.

1. Production of Schiff's base Schiff's base can be easily produced by reacting Compound XI or a salt thereof with capryaldehyde in a suitable solvent.

As the salt of compound (1), hydrochloride, hydrobromide, sulfate, phosphate, oxalate, lactate, tartrate, acetate, citrate, maleate, etc. are used. Also,
If capryaldehyde is used in excess, the solvent can be omitted. Examples of the solvent used in this reaction include benzene toluene, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, and methanol.

In this case, capryaldehyde is 0.5 to 10 times (preferably 1 times) moles of compound XI) or its salt.
~2 times) to carry out the reaction. This reaction can use a small amount of acid or base as a catalyst.

Generally, acids include hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid, and bases include caustic soda, caustic potash, soda carbonate, potassium carbonate, sodium acetate, pyridine, triethylamine, etc. Can be mentioned. This reaction is carried out at a reaction temperature of -50 to 20,000 (
The reaction time is preferably 10 to 2 hours (preferably 30 to 6 hours).

After the reaction is completed, the obtained Schiff base can be subjected to the next reduction reaction without being particularly purified.

2. Reduction Reaction The synthesis of the compound of formula (V) by reduction of Schiff's base is carried out under the same conditions as the above-mentioned method for reducing aminoketone (1') to synthesize aminoalcohol (1'').

The desired amino alcohol of formula (V) produced 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, equivalent amounts of the amino alcohol of Shintsuji V) and a suitable acid may be mixed in a solvent such as alcohol, and then mixed with the first solvent (alcohol, etc.); however, if the salt is insoluble, It is precipitated as a salt 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 hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, or perchloric acid, or formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, citric acid, etc. Acid, succinic acid, ascorbic acid, fumaric acid, maleic acid, tartaric acid, phenylacetic acid, benzoic acid,
, anthranilic acid, salicylic acid, methanesulfonic acid, ethanedisulfonic acid, and other organic acids.

Next, the present invention will be explained in more detail with reference to Examples.

Example 11-(4-isopropylthiophenyl)-2
-Aminopropanone synthesis 1-2-frompropanone (1-4-isopropylthiophenyl) 2.52 hours (1 hour
1) was dissolved in 10 parts of dimethyl sulfoxide, and while stirring, 0.98 parts of sodium azide (1 mol) was gradually added.

After continuing to incubate for 2 hours at room temperature, add 50' of water,
Extracted three times with 20 g of benzene. After drying the organic layer with magnesium sulfate, benzene was removed to obtain a pale yellow semi-solid substance 2.0%. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this substance were directly measured without further purification, and it was confirmed that it was 1-(4-isopropylthiovenyl)-2-azidopropanone.
Separately, 4.5 hmol of stannous chloride dihydrate and 4 of acetic anhydride were heated at reflux temperature for 10 minutes, then 8' of glacial acetic acid was added, and hydrogen chloride was added to saturation. A reducing agent was prepared.

This reducing agent was cooled on ice, and 1.25 mol of 1-(4-isopropylthiophenyl)-2-azidopropanone (hmol
) and glacial acetic acid were added at intervals.

After continuing to stir for 1 minute, acetic acid was distilled off under reduced pressure.
20% caustic soda was added and extracted with 50% ether. Immediately hydrogen chloride was passed through and the precipitated crystals were collected in a furnace.

Yield 0.72 min (yield 55%) mp. 180-188q
o (decomposition). This compound was confirmed to be 1-(4-isopropylthiophenyl)-2-aminopropanone hydrochloride by infrared absorption spectrum and nuclear magnetic resonance spectrum. Example 2 Synthesis of 1-(4-isopropylthiophenyl)-2-aminopropanol 522 p (common hmol) of amiketone hydrochloride obtained in Example 1 above was dissolved in 10 parts of methanol, and 20 parts of sodium borohydride was dissolved.
I crawled and prayed for 2 hours at room temperature.

After distilling off the methanol, 10 parts of water was added and extracted with chloroform. It was dried over magnesium sulfate, and the chloroform was distilled off to obtain crystals of 360-9. (yield 80%
) mp. 100-101℃. It was confirmed by infrared absorption spectrum and nuclear magnetic resonance spectrum that it was 1-(4-isopropylthiophenyl)-2-aminopropanol. Reference example a 1-(4-isopropylthiophenyl)-2-aminopropanone hydrochloride 2.60 molar (1 hmol) was dissolved in methanol 50 methanol, caprylic aldehyde 1.40 molar
(11 mmol), triethylamine 2.20 mmol (2
2 hmol) was added, and rope azusa was continued for 3 hours at room temperature.

After the reaction was completed, methanol was distilled off, and the residue was washed several times with small amounts of hexane to obtain 3.1 volumes of a pale yellow oily substance. The main component of this oily substance is gas chromatography, and 95%
In addition to the above, it can be inferred that the oily substance is a Schiff base from the fact that upon hydrolysis, caprylic aldehyde is produced as observed by gas chromatography, and from the infrared absorption spectrum of the oily substance. b. 1.69 ml of the above oily substance was dissolved in 30 ml of methanol, 20 ml of sodium borohydride was added and reduced for 1 hour at room temperature.

After distilling off methanol, add 30 pieces of water, extract with benzene, wash with 5% caustic soda, dry the benzene layer with magnesium sulfate, remove the benzene,
1.59 pieces of crude crystals (yield 93%) were obtained. Thin layer chromatography showed that the crude crystals were mostly the target amino alcohol of formula (V), and were a mixture of erythro and threo forms. The crystals were dissolved again in 20% of ether, concentrated hydrochloric acid was added, and the precipitated hydrochloride crystals were collected in a furnace and recrystallized from methanol-water.

Yield 1.07 mP. (yield 57%). 231.5-23
Chi 0. In addition, no decrease in melting point was observed even when mixed with the starting product synthesized by the method described in Tokukan Sho 49-135935, so the hydrochloride of the target amino alcohol (erythro form) of formula (V) It was confirmed that The obtained hydrochloride was dissolved in a solution of 94 parts of caustic potash and 5 parts of methanol, 10 parts of water was added thereto, and the mixture was allowed to stand in a cold place to precipitate crystals, followed by recrystallization with n-bentane.

The obtained crystals have mp. 61-6y0 was confirmed to be the desired amino alcohol of formula (V) by a blending test and a comparison of infrared absorption spectra. Reference Example 2 After synthesizing a Schiff base using exactly the same machine as Example $,
Immediately, sodium borohydride paper 0x9 was added to carry out reduction.

After the same post-treatment as described in Example, coarse crystals 3.
10 days (yield: 9200), and 2.11 times (yield: 56%) of erythro form hydrochloride were obtained. It was confirmed by a water melt test and an infrared absorption spectrum that it was the desired amino alcohol of formula (V). Reference example 3 1-(4-isopropylthiophenyl)-2-2-aminopropanol 2.25 mmol (1 hmol) was mixed with 5 methanol
0 and caprylic aldehyde 1.4 m (11 m
mol), triethylamine 1.1 mol (11 mmol)
was added and stirred at room temperature for 3 hours, then 350 parts of sodium borohydride was added, and the stirring continued for an additional 2 hours.

Claims (1)

[Claims] 1. Compounds represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X represents a group = 0 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼), and salt. 2 By azidizing the α-haloketone derivative represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y represents a halogen atom), the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. The formula is characterized by obtaining the α-azidoketone derivative shown and reducing it ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X is a group = 0 or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ) 1-(4-isopropylthiophenyl)-
Method for producing 2-aminopropane derivative.