JPS5824420B2 - Chikanzareta Propion Sanno Seihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to α-(4-monosubstituted This invention relates to a method for producing (phenyl)propionic acid and its salts.

The compounds according to the present invention have pharmacological effects such as anti-inflammatory effects and are useful as pharmaceuticals.

The present inventors have conducted intensive studies on methods for obtaining the above-mentioned phenylpropionic acid derivatives and salts thereof, and as a result, have invented a method for obtaining them extremely simply and in high yields.

According to the present invention, the compound represented by the general formula (I) is prepared by heat-treating an oxy-substituted glycidic acid represented by the general formula (n) [wherein R represents the above] or a salt thereof under acidic conditions. It can be obtained by

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.

In this case, an organic solvent that is miscible with water and does not interfere with the reaction may be used in order to improve the uniformity of the reaction system.

Examples of such substances include alkanols such as butanol, acetonitrile, dimethylformamide, ethylene glycol, and the like.

The reaction temperature and reaction time used vary considerably depending on other reaction conditions such as the type of acid used, its concentration, and the type of solvent.

The reaction is usually carried out for a period of 30 minutes to 10 hours depending on the boiling point of the reaction mixture.

The compound represented by the general formula (II) used in the present invention is a new substance, and for example, the method according to the invention of the present inventors,
That is, an acetophenone derivative represented by the general formula (In) [wherein R represents the above] is reacted with a dihalogenated acetate,
Then, the resulting alkoxy-substituted glycidic acid ester was treated with an alkali to form a compound of the general formula (IV) [wherein R represents the above-mentioned one, and Bi is a straight-chain or branched alkyl group having 1 to 6 carbon atoms] M represents an alkali or % alkaline earth metal] by acid treatment of a salt of an alkoxy-substituted glycidic acid.

The target product 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 an inorganic or organic base.

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

Reference Example 1 Anhydrous methanol 14 or
Inbutylacetophenone 17.
6P and methyl dichloroacetate 28-6P are added dropwise over 30 minutes.

After completion of the dropwise addition, the mixture was returned to room temperature and stirred for 20 hours.

After that, 70 TrL of methanol 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 toluene at 100rf.
Pour into the mixture of Ll under stirring.

After stirring for 5 minutes, the pH was adjusted to 7.2 with 1N hydrochloric acid,
After shaking well, separate the separated toluene layer.

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

After evaporation of toluene, 3-(4-isobutylphenyl)-2-methoxy-2,3-epoxybutyric acid methyl ester was obtained by fractional distillation under high vacuum.18. I
Get P.

b, p, 115-117 °C (0,3 miHg) yield 6
5% 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.

m, p, 36-38°C The ester obtained is a mixture of cis and trans isomers.

13.9 f of the ester thus obtained is added to a solution of 2.41 ml of sodium hydroxide in 50 ml of anhydrous methanol.

After stirring at room temperature for 3 hours, 0.2 rrLl of water was added under ice-cooling, and white crystals were precipitated when left to stand.

The sodium salt of 3-(4-isobutylphenyl)-2-methoxy-2,3-epoxybutyric acid 11.3
Get P.

Yield 79% m, p, 250℃ or higher 3-(4-isobutyl)phenyl-2-methoxy-2.
Add 2N hydrochloric acid to 9.21 sodium salt of 3-epoxybutyric acid to adjust the pH to 2.

After stirring at room temperature for 20 minutes, the mixture was extracted three times with 50 ml of ether.

After drying the ether layer over anhydrous magnesium sulfate, the ether is distilled off and the residue is dissolved in IN NaOH at room temperature.

After ether extraction, the aqueous layer was adjusted to pH again with concentrated hydrochloric acid.
2 and perform ether extraction as described above.

The ether layer is dried over anhydrous magnesium sulfate, the ether is distilled off, and the residue is dried under vacuum at room temperature to gradually crystallize.

Thus, 6.7 g of 3-(4-isobutyl)phenyl-2-oxy-2,3-epoxybutyric acid are obtained.

Yield 83.3% m, p.

54-56℃ Small Spectrum (CDC13) Internal Standard TMTrans) 1.50-2.17 (m, isobutyl〉CH-)2
-49 (d, isobutyl -CH2-J-6,5Hz) disappears by substitution) -7,12 (m, phenyl H) IR spectrum/L/ (KBr tablet)3
0H1740,1 derived from 400CIrL-1 alcohol
730,1700 cm Carbonyl elemental analysis value (C14Ht s 04 ) CH Actual value 67.32 7.38 Calculated value 67.18 7.25 Reference Example 2 Anhydrous methanol in which 9.21 sodium was dissolved 280 m
24 g of acetophenone and 57.2 g of methyl dichloroacetate were added dropwise to the solution under stirring under water cooling over 30 minutes.

After completion of the dropwise addition, the mixture was returned to room temperature and reacted with stirring for 12 hours.

After that, add 1401 rL of methanol under reduced pressure at a bath temperature of 40°C or less.
1 is distilled off, and the remaining liquid is mixed with ice water 2007711 and toluene 20
01rLl mixture under stirring.

After stirring for 5 minutes, adjust the pH to 7.0 with normal hydrochloric acid.
After shaking well, separate the toluene layer.

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

After evaporation of toluene, 3-phenyl-2-methoxy-2,3-epoxybutyric acid methyl ester 32.01 is obtained by fractional distillation under high vacuum.

b, p, 104-108°C (1 mmHg) Yield 72% The obtained ester was subjected to silica gel column chromatography, eluted with benzene:hexane 2:1, and both desired fractions were concentrated to dryness to give a white waxy substance. Becomes a solid.

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

The ester thus obtained 22.9? is added to a solution of 4.81 ml of sodium hydroxide in 80 ml of anhydrous methanol.

After stirring at room temperature for 2 hours, 0.2 ml of water was added while cooling with water, and upon standing, white crystals precipitated.

This is taken from house to house, washed with a small amount of ether, and vacuum dried to obtain 19.8 g of sodium salt of 3-phenyl-2-methoxy-2,3-epoxybutyric acid.

Yield: 86% m, p, 250°C or higher 10 g of sodium salt of 3-phenyl-2-methoxy-2,3-epoxybutyric acid is dissolved in 1001 rLl of water, and 50 ml of 2N hydrochloric acid is added while cooling and stirring.

Although the liquid becomes cloudy, stir it for 10 minutes.

Afterwards, the mixture is extracted three times with ether 501711, and the ether layer is washed with water and dried over anhydrous magnesium sulfate.

The ether is distilled off under reduced pressure and the residue is dried under vacuum at room temperature and gradually crystallizes.

7.51 of 3-phenyl-2-oxy-2.3-epoxybutyric acid is thus obtained.

Yield 88.6% m, p, 94-96.5°C (recrystallized from chloroform-hexane) NMR spectrum (CDC13) internal standard disappeared by substitution with TMS) 7.30 (ml, phenyl H) IR spectrum (KBr tablet )3400
OH1750.1735 from crlL-1 alcohol
．． 1710cm Carbonyl elemental analysis value (C1oHto04) CH Actual value 61.93 5.25 Calculated value 61.86 5.19 Example 1 3-(4-isobutyl)phenyl-2-oxy-2.3
- Add 5.0 ml of epoxybutyric acid to 100 ml of 4N hydrochloric acid, and stir and reflux at a bath temperature of 110°C to 120°C for 5 hours.

After cooling, 40 TrLl of ether was added for extraction.

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

Add 1N sodium hydroxide 1007711 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 40 ml of hexane, dried over anhydrous sodium sulfate, and the hexane was distilled off.
-(4-isobutyl)phenylpropionic acid crystals are precipitated.

Yield 3.91 Yield 95% m, p, 75-77°C (recrystallized from hexane) NMR spectrum (CCI4) Internal standard TMS 1.33
〜2.12(m,〉-1 of isobutyl)2.40(d,
-CH2-J-7Hz of isobutyl) 7.03 (m, phenyl H) 12.03 (b, S, disappears with OHD20 substitution of carboxylic acid) ■R spectrum # (KB r tablet) 17
30CIrL-1 carboxylic acid elemental analysis value (C13Hts 02 ) H Actual value 75,52 8.95 Calculated value 75.73 8.74 Example 2 2-(4-isobutyl)phenylpropionic acid 3 obtained in Example 1 301fLl of 1N sodium hydroxide
When the solution is dissolved in water and left to cool, white needle-like crystals of sodium salt of 2-(4-isobutyl)phenylpropionic acid are precipitated.

Yield 2.11 Yield 63% m, p, 99.5-1
02℃ IR spectrum/L/ (KB rtablet)
1560CrrL-1 carboxylate elemental analysis value (C13H, 702Na) CHNa Actual value 68,60 7.76 10.23 Calculated value 68.42 7.46 10.09 Example
3 3-phenyl-2-oxy-2,3-epoxy butyric acid 3
．． 9 was added to 100rrLl of 3N hydrochloric acid, and the bath temperature was 11
Stir and reflux at 0°C to 120°C for 6 hours.

After cooling, ether 407711 is added and extracted.

The aqueous layer is further extracted twice with 2 oml of ether, combined with the previous fractions, 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 2.8g Yield 93% b, p, 123-125℃
(3 Hg) Todoroki Spectrum (CDC13) Internal standard TMS7.23 (S, phenyl H) '175 (p, S6, disappeared by OHD20 substitution of carboxylic acid) IR spectrum (KBr tablet) 1735
CIrL ” Carboxylic acid elemental analysis value C9H,.

0□CH Actual value 71.68% 6.63% Calculated value 72.00% 6.67%

Claims (1)

[Scope of Claims] 1. Oxy-substituted glycidic acid or its salt represented by the general formula [wherein R represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms] is heated under acidic conditions. Under heat treatment.
A process for producing α-(4-monosubstituted phenyl)propionic acid and its salts represented by the general formula [wherein R represents the preceding formula], characterized by: