JPS5829949B2 - α-(p-isobutylphenyl)propionic acid thiol ester - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, R is a lower alkyl group.

)-(p-isobutylphenyl)propionic acid thiol ester.

The compound in which R is a methyl group in the general formula (I) has the following physical properties.

Boiling point: ■10-112℃/0.8 mmHg.

IR (neat): 1690crrL' (νc
=o).

NMR (CDCl2): δ0.89 d (6H, J=
6Hz), 1.51 d (3H, J=7Hz),
1.84m (LH), 2.213 (3H), 2.43
d (2H, J=7H2), 3.84q (IH1J=
7Hz), 7.14A2B2(1(4H1J=8Hz)
.

The compound of the present invention represented by the general formula (i) can be easily converted to α-(p-isobutylphenyl)propionic acid by hydrolysis (see reference side below).
.

This compound is called ibuprofen and is known to have anti-inflammatory, analgesic, and antipyretic effects.

Conventionally, many methods have been proposed for producing ibuprofen, and representative examples are as follows.

(1) The corresponding malonic ester is produced by reacting p-inbutylphenyl acetate with an alkyl carbonate in the presence of a base. Next, this malonic ester is methylated with methyl iodide, and then hydrolyzed and Subsequently, a method for obtaining the desired propionic acid by thermal decomposition (Japanese Patent Publication No. 4077491
).

(2) p-isobutylacetophenone is converted into the corresponding hydantoin by the action of potassium cyanide and ammonium carbonate, which is then hydrolyzed to form an α-amino acid, further alkylated to form a dialkylamine compound, and then reduced to an α-amino acid. (p-inbutylphenyl)
Method for reducing propionic acid (Special Publication No. 47-18105)
).

(3) The corresponding epoxycarboxylic acid ester was obtained by the Darzen reaction of p-isobutylacetophenone and monochloroacetic acid ester, which was hydrolyzed and decarboxylated to once form α-(p-isobutylphenyl)propionaldehyde. Method of oxidizing nicole and adding the desired propionic acid (Special Publication No. 47-24550)
.

However, these conventional methods are not sufficient for industrial production because methods (1) and (3) require a long number of steps, and method (2) uses toxic potassium cyanide.

Part 3 In order to solve the drawbacks of conventional methods, the present inventors have studied compounds that can be commercially advantageously converted into α-(p-isobutylphenyl)propionic acid, and have completed the present invention. be.

That is, the compound of the present invention can be produced according to the following formula 6. (1) → (III) In this step, p-isobutylacetophenone (II) is reacted with formaldehyde mercaptal S-oxide norithio salt. The lithio salt can be easily formed by reacting formaldehyde mercaptal S-oxide with an organic lithio compound such as methyllithium or butyllithium in an aprotic solvent such as tetrahydrofuran or toluene, preferably under cooling.

In the reaction of this step, the lithio compound (III) can be formed simply by adding p-isobutylacetophenone under the conditions for forming the lithio salt.

(m)→(IV) This step is carried out by reacting the lithio compound (m) with an acetylating agent such as acetic anhydride or acetyl chloride in the same solvent used in the previous step.

At this time, it is preferable to maintain the reaction temperature between 00°C and around room temperature.

(IV) → (V) This is carried out by treating the acetylated product (IV) formed in the above step with a base. Examples of the base include sodium hydride, potassium t-butoxide, and sodium hydroxide. I can do it.

It is preferable to use a solvent in the reaction, and for example, tetrahydrofuran, t-butanol, methanol, etc. can be used, although the reaction varies depending on the type of base used.

In this step, deaceticated ketene mercaptal S-oxide (V) is formed.

(V)→(I) This step requires that ketene mercaptal S-oxide (V) be subjected to acid hydrolysis treatment.

As the acid substance used for acid hydrolysis, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, and phosphoric acid can be used, but hydrogen halides such as hydrochloric acid and hydrobromic acid are preferred because the reaction proceeds smoothly. Acids are preferred.

Solvents are not necessary, but if desired, tetrahydrofuran, dioxane, 1,2-dimethoxyethane can be used.
Aprotic solvents such as benzene can be used.

The present invention will be explained in more detail below using Examples and Reference Examples.

Example 1 Formaldehyde dimethyl mercaptal S oxide]
,, dissolve 151P in 10 ml of tetrahydrofuran,
6 ml of a hexane solution of butyl lithium (25f/250 mA) was added dropwise at -20°C to -30°C under an argon atmosphere.

After lowering the temperature to -75°C, p-inbutylacetophenone 1. trrtl, and stirred for 20 minutes to form a lithio salt [R is a methyl group in general formula (III)]
I got it.

Add acetic anhydride to tetrahydrofuran solution (3,1
17P/25mA') was added dropwise.

After raising the reaction temperature to room temperature, the mixture was further stirred for 1.5 hours.

Add saturated sodium bicarbonate solution and extract with methylene chloride (50TrLl
x2 times), and then the organic layer was dried over anhydrous sodium sulfate.

After concentration under reduced pressure, the residue was subjected to column chromatography [
1-Methylsulfinyl-
A mixture of stereoisomers of 1-methylthio-2-acetoxy-2-(p-isobutylphenyl)furopane was obtained as a viscous oil at 3.075S'.

IR(neat): 2950.2920.1750.
124011040.1018.730crfL-1° This product was deaceticated by the following base treatment to lead to 1-methylsulfinyl-1-methylthio-2(p-inbutylphenyl)-1-propene.

1-methylsulfinyl-1 obtained as above
-Methylthio-2-acetoxy-2-(, p-butylphenyl)propane is dissolved in 10 TILl of t-butanol, and a solution of potassium t-butoxide in t-butanol (3.556 S' of metallic potassium and 150 TIL of t-butanol) is dissolved in 10 TILl of t-butanol.
(Prepared from 1rLl) 15.4TrLl was added and stirred at room temperature for 10 minutes.

After adding 20rnl of water, extraction with methylene chloride (50T
The organic layer was dried over anhydrous sodium sulfate.

After concentration under reduced pressure, the product was separated by column chromatography (silica gel, methylene chloride and ether) to obtain 1.912 f of 1-methylsulfinyl-1-methylthio-2-(p-inbutylphenyl)-1-7''ropene.

This product was a mixture of two types of geometric isomers, and NMR revealed that the abundance ratio was 3:1.

Simple distillation of this material (oil bath 180℃ 10.015 m 11 L)
Hg) and subjected to analysis.

IR(neat): 2950.2920.1040
．． 1018CTL' Calculated value as C15H220S2: C, 63,78; H, 7,85; 8 22.
70 Measured value: C163,41;I(,7,84;S,22.
51° Further recrystallization from ether-hexane allowed isolation of the main component.

Melting point near 8.2-78.5°C (colorless needles).

IR (KBr): 2950.2920.1040.
957.800crrL-1°NMR(CDCl3)2 δ0.89 d
(6H, J=6Hz), i, s 3m (I H),
2.46 s (6H), 2.46 d (2H, J=
71 (z), 2.52 s (3H), 6.96A2
Calculated value as B2q(4H), Cl5H2□O82: C, 63,78; H, 7,85; S, 22.7
0° measurement value: C, 63,78; H17,70; S, 22.5
6° Example 2 113 ml of 1-methylsulfinyl-1-methylthio-2(p-inbutylphenyl)-1-propene was dissolved in 1 ml of dioxane, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours.

After adding 50rrl of methylene chloride, the mixture was dried over magnesium sulfate and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, n-
(hexane-benzene) to prepare α-(p-inbutylphenylene)propionic acid methanethiol ester as a colorless liquid at 80 mI? Obtained.

Yield 85%. Boiling point: 110-112°C, 10.8 Hg.

IR(neat): 1690cm-1°NMR
(CDC13): δ0.89 d (6H, J=6Hz
), 1.51 d (3H, J=7Hz'), 1.
84m (LH), 2.21s (3H), 2.43d
(2H, J=7Hz), 3.84 q (IH1J
=7Hz), 7.14A2B2q (4H, J=8Hz
), Reference example α-(p-inbutylphenyl)propionic acid methanethiol ester 131■ 1,2-dimethoxyethane 2
ml, 1 ml of 2N KOH aqueous solution was added, and the mixture was stirred at room temperature for 15 hours.

Add 50ml of water and extract with methylene chloride (50Tnl x 2
After that, the aqueous layer was made acidic with 9N dilute sulfuric acid and extracted with methylene chloride (50 ml×3 times).

This methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce α-(p-inbutylphenyl).
112 m9 of propionic acid were obtained.

Yield: 98% 0 Purification was performed by recrystallization from n-hexane, but the pure product obtained was colorless crystals with a melting point of 75.5-76.5°C.

Claims (1)

[Claims] 1 General formula [wherein R is a lower alkyl group] ] α-(p-Inbutylphenyl)propionic acid thiol ester. 2. The compound according to claim 1, wherein R is a methyl group.