JPS5829774B2 - Alpha - Chikanpropionsan Oyobi Sonoen no Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing propionic acid derivatives that exhibit pharmacological effects such as anti-inflammatory effects and are useful as pharmaceuticals.

More specifically, the present invention relates to the general formula (wherein R1 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, and R2 is a hydrogen atom, a halogen atom, or an alkyl group). The present invention relates to a method for obtaining the propionic acid derivatives and salts thereof very simply and in high yields.

According to the present invention, the general formula (wherein R1 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, R2 is a hydrogen atom, a halogen atom, or an alkyl group, R3 and R4 are the same or By heat-treating glycidic acid esters represented by different linear or branched alkyl groups having 1 to 6 carbon atoms in the presence of an acidic reagent, that is, under acidic conditions, The target compound and its salt can be obtained.

The acidic reagent used in the present invention is not particularly limited, but it is convenient to use an aqueous solution such as hydrochloric acid or sulfuric acid.
It is.

The reaction temperature and reaction time used vary considerably depending on other reaction conditions such as the type and concentration of the acid used, but the reaction is usually carried out in a range of 3 to 10 hours using the boiling point of the reaction mixture.

The compound represented by the general formula (2) used in the present invention is a new compound that has not been described in any literature, for example, the general formula (R1 in the formula
and R2 have the same meanings as above) and dihalogenoacetic acid esters.

The compound of general formula (II) thus obtained may be used after being purified, or may be used unpurified as it is.

The target compound of the present invention can be easily separated and obtained as a free acid from the reaction mixture by conventional methods such as organic solvent extraction.

If desired, they can also be obtained as corresponding salts by treatment with inorganic or organic bases.

The present invention will be explained in more detail with reference to Examples below.
The scope of the present invention is not limited thereto.

Reference example 1 Anhydrous methyl alcohol 1 in which 4.6 g of sodium was dissolved
17.6 g of inbutylacetophenone and 28.6 g of methyl dichloroacetate were cooled on ice and stirred in a 40-d container. ? and was added dropwise over a period of 30 minutes.

After dropping, the mixture was returned to room temperature and stirred for 20 hours.

Next, 70% of methyl alcohol was added under reduced pressure at a bath temperature of 40°C or less.
- was distilled off, and the remaining liquid was mixed with 100ml of ice water and 100ml of toluene.
Pour into the mixture of step 1 while stirring.

After stirring for 5 minutes, adjust the pH to 7.2 with 1N hydrochloric acid, shake well, and collect the separated toluene layer.

The aqueous layer is further extracted twice with toluene, combined with the previous fraction, washed with water, and dried over anhydrous sodium sulfate.

After evaporating toluene, 3-(4-inbutylphenyl)-2-
Methoxy-2゜3-epoxybutyric acid methyl ester18.
Get 1j9.

Boiling point 115-117 °C (0.3 miHg), yield 65
%.

The obtained ester is subjected to silica gel column chromatography, eluted with benzene, and the desired fraction is concentrated to dryness to form a white waxy solid.

Melting point 36-38°c.

The resulting ester is a mixture of cis and trans isomers.

Reference example 2 Anhydrous methyl alcohol 2 in which 9.2 g of sodium was dissolved
24 g of acetophenone and 57.2 g of methyl dichloroacetate were added dropwise to a 80 ml solution over 30 minutes while cooling on ice and stirring.

After completion of the dropwise addition, the mixture was returned to room temperature and stirred for 12 hours for reaction.

Next, 1 ml of methyl alcohol was added under reduced pressure at a bath temperature of 40°C or less.
40 ml was distilled off, and the remaining liquid was poured into a mixture of 200 ml of ice water and 200 TFLl of toluene while stirring.

After stirring for 5 minutes, the pH was adjusted to 7.0 with 1 ml of hydrochloric acid, and after shaking well, the separated toluene layer was collected.

The aqueous layer is further extracted twice with toluene, combined with the previous fraction, washed with water, and dried over anhydrous sodium sulfate.

After evaporating toluene, 3-phenyl-2-methoxy-2,3 is obtained by fractional distillation under high vacuum.
- Epoxybutyric acid methyl ester 32.1 is obtained.

Boiling point 104-108'C (1 mrttHg), yield 72%.

The obtained ester was subjected to silica gel column chromatography, eluted with benzene:hexane (2:1), and the desired fraction was concentrated to dryness to give a white waxy solid.

The ester obtained, melting point 53-54.5°C, is a mixture of cis and trans isomers.

NMR spectrum (CC14) internal standard TMS example
1 3-(4-isobutylphenyl)-2-methoxy-2,
5.6 g of 3-epoxybutyric acid methyl ester was added to 100 d of 4N hydrochloric acid, and the mixture was stirred and refluxed for 6 hours at a bath temperature of 110°C to 120°C.

After cooling, 40 rnl of ether is added for extraction.

The aqueous layer is further extracted twice with 20 rrtl of ether, combined with the previous fraction, and the ether is distilled off under reduced pressure.

Add 100TLl of 1N sodium hydroxide to the residue,
Once washed with 20 ml of hexane, the cooled sewage layer is acidified with concentrated hydrochloric acid.

The precipitated oil was extracted three times with 40ml of hexane, dried over anhydrous sodium sulfate, and the hennasan was distilled off.
Crystals of 2-(4-isobutyl)phenylpropionic acid precipitate.

Yield 3,111, yield 76%.

Example 2 When 3 g of 2-(4-isobutyl)phenylpropionic acid obtained in Example 1 was dissolved in 30 ml of 1N sodium hydroxide and left to cool, white needles of the sodium salt of 2-(4-isobutyl)phenylpropionic acid were obtained. crystals precipitate.

Yield 2.3g, yield 69% Melting point 100-102°C IR spectrum (KBr tablet) 1560c
IrL-” Carboxylate elemental analysis value (C15
H170, as Na) CHNa Actual value 68.48 7.73 10.26 Calculated value 6
8.42 7.46 10.09 Example 3 Add 4.4 g of 3-phenyl-2-methoxy-2,3-epoxybutyric acid methyl ester to 100 M of 5N hydrochloric acid and stir at a bath temperature of 110°C to 120°C for 5 hours. Reflux.

40ml of ether after cooling! Add and extract.

Add 20m1 of ether to the water layer! Extract twice with water, combine with the previous fraction, and dry with anhydrous magnesium sulfate.

The ether was distilled off under reduced pressure, and the residue was diluted with 1N sodium hydroxide at 50 mA! Dissolve in 20 TL of hexane
The cooled aqueous layer is then acidified with concentrated hydrochloric acid.

The precipitated oil is extracted three times with 40 mA' of ether and dried over anhydrous magnesium sulfate.

When the ether is distilled off under reduced pressure, 2-phenylpropionic acid is obtained as a slightly yellow oil.

Yield 2.1 g, yield 70% Boiling point 123-125°C (3 Hg) NMR spectrum (CDC13) Internal standard TMS Example 4 Cool on ice in 140 rnl of anhydrous methyl alcohol in which 1.4.1 sodium was dissolved and stir. while inbutylacetophenone 5.6g and methyl dichloroacetate 5.6g
and 8.95 g of methyl dichloroacetate were added dropwise over 30 minutes.

After dropping, the mixture was returned to room temperature and stirred for 20 hours.

After adding 20ml of water and stirring at room temperature for 20 minutes, methyl alcohol is distilled off under reduced pressure at a bath temperature of 40°C or less.

Add 100 yd of water to the residue and add 40171 yd of concentrated hydrochloric acid.
1 was added, and the mixture was stirred and refluxed for 5 hours at a bath temperature of 1100 to 120°C.

After cooling, sodium hydroxide was added to adjust the pH to 13, and the mixture was extracted twice with 20 TrL of benzene.

The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and 100 rfL of hexane was added.
Extract twice with l.

After washing the hexane layer with 100 ml of water, it is dried over anhydrous sodium sulfate.

When hexane is distilled off, 3.8 g of crude crystals of 2-(4-isobutyl)phenylpropionic acid are obtained.

Dissolve this in 20rnl of 01N sodium hydroxide,
When concentrated under reduced pressure, sodium salt of 2-(4-isobutyl)phenylpropionic acid is precipitated.

After washing this with acetone to remove colored substances, it was dissolved again in 50 mA of water, and the pH was adjusted to 2 with hydrochloric acid.

The precipitated oil was extracted twice with 50rrLl of hexane,
After washing the hexane layer with 50 mA of water, it is dried over anhydrous sodium sulfate.

When hexane is distilled off, white crystals of 2-(4-isobutyl)phenylpropionic acid are precipitated.

Yield: 3.0 g, yield: 46%.

Melting point 76-77°c.

Claims (1)

[Scope of Claims] General formula 1 (wherein R1 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, R2 is a hydrogen atom, a halogen atom, or an alkyl group, R3 and R4 are the same - or a different linear or branched alkyl group having 1 to 6 carbon atoms) is heat-treated under acidic conditions. A method for producing α-(4-substituted phenyl)propionic acid and its salts represented by (having the same meaning as above).