JPS5829773B2 - Propion Sun Yudou Tainoseizouhouhou - Google Patents

Description

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

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

The present inventors have conducted extensive 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 easily and in high yields.

According to the present invention, the compound represented by the general formula (I) has the general formula (II) [wherein R represents the above-mentioned one, and R' has 1 to 1 carbon atoms]
6 represents a straight-chain or branched alkyl group, M represents an alkali or 1/2 alkaline earth metal]. 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.

Although the reaction temperature and reaction time used vary considerably depending on other reaction conditions such as the type and concentration of the acid used, the reaction is usually carried out within a range of 30 minutes to 10 hours using the boiling point of the reaction mixture.

The compound represented by general nI) used in the present invention is a new substance, and for example, it can be represented by the method according to the invention of the present inventors, that is, the general formula (III) [wherein R represents the above] Reacting an acetophenone derivative with dihalogenated acetate esters,
It can then be obtained by treating the obtained alkoxy-substituted glycidic acid ester with an alkali.

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 from Example I below.
The scope of the present invention is not limited thereto.

Reference Example 1 140ml of anhydrous methanol in which 4.6g of sodium was dissolved
1 in butylacetophenone 17.6 while stirring with water cooling.
g and methyl dichloroacetate 28.6. ? was added dropwise over a period of 30 minutes.

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

After that, add 70ml of methanol 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.
into the mixture under stirring.

After stirring for 5 minutes, the pH was adjusted to 7.2 with 1N 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 sulfuric acid.

After evaporation of toluene, 3-(4-inbutylphenyl 1-2-methoxy-2,3-epoxybutyric acid methyl ester 18.1
get g.

b, p115-117°G (0.3mJ!Hg) Yield 65% The obtained ester was subjected to silica gel column chromatography, eluted with benzene, and the desired fraction was concentrated to dryness to form a white waxy solid. Become.

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

Ester thus obtained 13. 'l is added to a solution of 2.4 g of sodium hydroxide in 50 m7 of anhydrous methanol.

After stirring at room temperature for 3 hours, 0.2 ml of water was added while cooling with water, and upon standing, white crystals precipitated.

This was removed, washed with a small amount of ether, and dried under vacuum to obtain sodium salt of 3-(4-inbutylphenyl)-2-methoxy-2,3-epoxybutyric acid 11. :
get l.

Yield: 79 m, p, 250°C or higher NMR spectrum (D20) Internal standard DSS: 1.50~
220 (m, >CH- of isobutyl) 2.45 (
d, -CH2- of isobutyl, J=65Hz)3.
38,3.45 (S, -0CH3cis, trans)
7.23 (m, phenyl H, J = 8 Hz) IR spectrum: carboxyl) 1630 cm-" Elemental analysis value (C45H1C45H1) CHNa Actual value 62.83 6.71 8.13 Calculated value 62
．． 93 6.64 8.04 Reference Example 2 Anhydrous methanol 280T in which 9.2 g of sodium was dissolved
24 g of acetophenone and 57.2 g of methyl dichloroacetate were added dropwise to Ll over 30 minutes while stirring with water cooling.

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

After that, 140 mJ of methanol was distilled off under reduced pressure at a bath temperature of 40°C or less, and the remaining liquid was mixed with 2001 rL of ice water and 200 m of toluene.
Add to mixture A' under stirring.

After stirring for 5 minutes, the pH was adjusted to 7.0 with 1N 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 was obtained by fractional distillation under high vacuum.32. (Get l.

b, p, 104-108'C (1 mwHg) 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.

m, 9. 53-54.5°C The ester obtained is a mixture of cis and trans isomers.

22.2 g of the ester thus obtained are added to a solution of 4.8 g of sodium hydroxide in 80 ml of anhydrous methanol.

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

The sodium salt of 3-phenyl-2-methoxy-2,3-epoxybutyric acid 19.8.9 is obtained by washing this separately with a small amount of ether and vacuum drying.

Yield 86%m, 9. 250°C or higher NMR spectrum (D, 0) Internal standard DSSIR spectrum; carboxylate 1620 cm, -' elemental analysis value (C11H110, Na) Example 1 = 3-(4-inbutylphenyl)-2-methoxy-2
・Add 5.7 g of sodium salt of 3-epoxybutyric acid to 100 ml of 4N hydrochloric acid, and boil at a bath temperature of 110°C to 120°C.
Stir and reflux for an hour.

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

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

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

The precipitated oil was extracted three times with 40 yd of hexane, dried over anhydrous sodium sulfate, and the hexane was distilled off.
-(4-isobutyl)phenylpropionic acid crystals are precipitated.

Yield 3.6g Yield 88φm. p, 74.5-77°C (recrystallized from hexane) NMR spectrum (CCJ'4) Internal standard TMS Example 2 3 g of 2-(4-isobutyl)phenylpropionic acid obtained in Example 1 was 1N hydroxylated. Sodium 307711
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 2.3g Yield 69% m, p, 100-102°
C IR spectrum (KBr tablet) 1560
cIrL-” Carboxylate elemental analysis value (C
tsH1702Na ) CHNa Demonstration II (Direct 68.48 7.73 10.
26 Calculated value 68.42 7.46 10.09 Example 3 4.6 g of sodium salt of 3-phenyl-2-methoxy-2,3-epoxybutyric acid was added to 100 M of 4N hydrochloric acid, and the bath temperature was 110°C to 120°C. Stir and reflux for 5 hours.

After cooling, ether 401rLl was added for extraction.

The aqueous layer is further extracted twice with ether 207711, 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 yellowish brown oil.

Yield: 2.5g Yield: 83 cups, p, 124-126°C (
4πmHg) 7.23 (S, phenyl H) 9.86 (b, s, OHD of carboxylic acid t
Disappears due to O substitution) IR spectrum (KBr tablet) 1735
CrIL-1 carbonic acid elemental analysis value C9H1,0°CH Actual value 71.83 Excellent 6.75 Calculated value 72.00φ 6.67φ

Claims (1)

[Scope of Claims] 1 General formula [wherein R represents a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms, R') a straight chain or branched chain having 1 to 6 oxygen atoms] represents an alkyl group, M is an alkali or l
/2 represents an alkaline earth metal] α( A method for producing 4-substituted phenyl)propionic acid and its salt.