JPS5811437B2 - 1-Sulfinyl-1-thio-2-(3-chloro-4-allyloxyphenyl)ethylene - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R1 and R2 are an alkyl group or an aryl group).

) 1-sulfinyl-1-thio-2~(3-
chloro-4-allyloxyphenyl)ethylene.

Specific compounds of the present invention include 1-methylsulfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene, 1-ethylsulfinyl-1
-ethylthio-2-(3-chloro-4-allyloxyphenyl)ethylene, 1-propylsulfinyl-1-propylthio-2-(3-chloro-4-allyloxyphenyl)ethylene, ■-phenylsulfinyl-1-phenylthio -2=(3-chloro-4-allyloxyphenyl)ethylene and the like.

All of the compounds of the present invention are substances unknown in the literature, and their anti-inflammatory effects were observed in anti-inflammatory assays using the carrageenan edema method using rats, making them useful as pharmaceuticals.

1. When the compound of the present invention is reacted in the presence of a mineral acid in water or alcohol, arylacetic acid and its derivatives represented by the general formula (IV), which are known to have an anti-inflammatory effect, can be obtained, which is an important pharmaceutical product. It is an intermediate for manufacturing.

The compound of the present invention has the general formula (wherein R1 and R2 are an alkyl group or an aryl group, and R3 is hydrogen, an alkyl group, an acyl group, an aroyl group, an alkylsulfonyl group, or an aryl group and a fonyl group.

) is produced by treating β-oxysulfoxide shown in the formula with a base.

The compound represented by the general formula (II) used as a raw material can be easily produced by the method developed by the present inventors.

That is, 3-chloro-4-allyloxybenzoic acid ester and the general formula RISCH2SOR2-(■) (wherein R1 and R2 are an alkyl group or an aryl group).

) with a sulfoxide having a sulfide bond at the α-position in the presence of a base.

) and then optionally alkylated, acylated, or sulfonylated to obtain the desired compound (II
) can be manufactured.

(See reference side below).

The method for obtaining the compound of the present invention requires that the compound of general formula (II) be treated with a base.

Bases include alkali gold carbonates such as sodium carbonate and potassium carbonate, alkali metal and alkaline earth metal hydroxides such as sulfur hydroxide, potassium hydroxide, and calcium hydroxide, sodium hydride, and potassium hydride. alkali metal hydrides such as sodium methoxide, alkali metal alkoxides such as sodium ethoxide,
A wide range of amine compounds such as ammonia, triethylamine, and pyridine, quaternary ammonium hydroxides such as trimethylbenzylammonium hydroxide (Triton B), and alkali metal salts of carboxylic acids such as sodium acetate can be used.

A catalytic amount of the base is sufficient for the raw material (II), but an excess amount may be used.

In carrying out the reaction, it is preferable to use a solvent, such as common organic solvents such as methanol, ethanol, ether, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide and dimethylsulfoxide.

When a liquid amine compound such as triethylamine or pyridine is used as a base, the base itself can be used as a solvent by using an excess amount.

The reaction proceeds smoothly at room temperature to 150°C.

Another method for producing the compound of the present invention represented by the general formula (■) is to use 3-chloro-4-allyloxybenzaldehyde and the general formula R15CH2SOR2(IIl) (
In the formula, R1 and R2 are an alkyl group or an aryl group.

) can be produced by reacting a sulfoxide having a sulfide bond at the α-position in the presence of a base.

The structures of the compounds unknown in the literature of the present invention were confirmed by infrared absorption spectra, nuclear magnetic resonance absorption spectra, and elemental analysis.

Next, the present invention will be specifically explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 Methylmethylthiomethylsulfoxide 3.7g and 40%
2.87 g of trimethylbenzylammonium hydroxide methanol solution and 5 g of 3-chloro-4-allyloxybenzaldehyde were added to 8 ml of tetrahydrofuran and heated under reflux for 6 hours.

After cooling, add 150 ml of chloroform, then 15 ml of dilute sulfuric acid.
Washed with.

The chloroform layer was dried over anhydrous potassium carbonate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, ether) to give 7.0 g (yield 91.5%) of 1
-Methylsulfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene was obtained.

IR (neat): 1060 cm-1 HMR (CD106O: δ2.28 (3H, - double line),
2.70 (3H, - doublet), 4.60 (2H, wide doublet).

J=4.5Hz), 5.1-6.4(3 H2 multiplet), 6.89 (1H.

Double line, J=8.5Hz), 7.44 (1H2-double line), 7.65 (I H5 quartet, J-2± and 8.5Hz), 8.06 (1H, double line, J=2Hz).

Elemental analysis (C13H1502S2C1): Calculated value (%)
:C,51,56;H,4,99;S.

21.17° Experimental values (%): C251,62; H54,93; S.

21.25゜Example 2 1.25g of methylthiomethylsulfoxide was dissolved in 10ml of dioxane, 1ml of 40% methanol solution of Triton B and 2.0g of 3-chloro-4-allyloxybenzaldehyde were added, and the mixture was stirred at 80°C for 10 hours. did.

After cooling, add 100ml of chloroform, then add 10ml of water.
Add fLl and 1 ml of concentrated hydrochloric acid and stir to sweeten.

The aqueous layer is extracted with 50 d of chloroform, the organic layers are combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was separated and purified by column chromatography (silica gel, ether) to obtain 2.6 g (yield: 87%) of l-methylsulfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene. Ta.

Motoichi confirmed the identity because it completely matched the infrared absorption spectrum of the specimen obtained in Example 1.

Example 3 2.25 g of methyl methylthiomethyl sulfoxide was dissolved in 10 ml of tetrahydrofuran, 1.0 g of sodium hydride (containing 50%) was added under water cooling, and the mixture was stirred for 1 hour.
At -30°C, 3.9 g of 3-chloro-4-allyloxybenzaldehyde was added.

After stirring at -30°C for 3 hours and at room temperature for 1 hour, 50 ml of chloroform was added and insoluble matter was filtered off.

The filtrate was concentrated under reduced pressure and then separated and purified by column chromatography (silica gel, ether) to obtain 3.2 g of 1-methylsulfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene (yield 54%). )Obtained.

Example 4 Ethyl ethylthiomethyl sulfoxide 930■, 40%
1 ml of trimethylbenzylammonium hydroxide methanol solution, 1193 g of 13 and 3-chloro-4-allyloxybenzaldehyde were added to 10 ml of tetrahydrofuran, and the mixture was heated under reflux for 16.5 hours.

After cooling, add 50 ml of methylene chloride, then add 1 ml of IN dilute sulfuric acid.
0rnl! After washing with water, it was dried with anhydrous potassium carbonate.

After concentration under reduced pressure, separation and purification by column chromatography (silica gel, methylene chloride) yielded 1.272 g of 1-ethylsulfinyl-1-ethylthio-2-(3-chloro-4-allyloxyphenyl)ethylene (yield 63%). was obtained as a pale yellow oil.

IR (neat): 1060 cm ” NMR (CDC12): δ1.21 (6H, triple line, J
= 7.5Hz), 2.52-3.17 (4H2 multiplet), 4.59 (2H2 wide doublet, J = 4.5Hz), 5.1-6.4 (3H.

multiplet), 6.88 (1H,,2 Heavy line, J=8.5Hz), 7,40 (1H2-double line), 7.67 (1H2 quartet, J=2Hz and 8.5Hz), 8.09(I H, J=2Hz).

Example 5 Ethyl ethylthiomethyl sulfoxide 930■ and 3
-Chloro-4-allyloxybenzaldehyde 1.19
1-Inpropylsulfinyl-1-
1.557 g (yield 72%) of isopropylthio-2-(3-chloro-4-allyloxyphenyl)ethylene was obtained as a pale yellow oil.

IR(neat): 1060cm'NMR(C
DC12): δ1.02 (3H, double line, J=7Hz)
, 1.22 (3H, double line.

J=7Hz), 1.25(3H, 2 Heavy line, J=7Hz), 1.41 (3 H2 doublet, J=7Hz), 3.0 -3.5 (2H, multiplet), 4.59 (2H2 wide doublet, J- 4,5Hz), 5.1-6.4 (3H.

multiplet), 6.87 ('1H, double line, J=8.5Hz), 7.38(I U5-heavy line), 7.77 (I H.

quartet, J=2Hz and 85 H'z), 8.15 (1H, double line, J=2Hz).

Example 6 Example except that 807 mg of phenylphenylthiomethyl sulfoxide and 710 m'i of 3-chloro-4-allyloxybenzaldehyde were used instead of ethyl ethylthiomethyl sulfoxide and 1.193 g of 3-chloro-4-allyloxybenzaldehyde. 650 m9 (yield: 44%) of 1-phenylsulfinyl-l-phenylthio-2-'(3'-chloro-4-allyloxyphenyl)ethylene was obtained as a pale yellow oil.

I'R. (neat):1 0 5 5'crn'
NMR (CDC13): δ 4.5.3 (2H, broad doublet J=4.5Hz), 5.1-6.4 (3H, multiplet), 6.78 (1H.

Double line, J=8.5Hz), 7.09 (5H, - double line), 7.0-7.8 (6H, multiplet), 7.94 (I H, - heavy line), 7.95 (1H.

double line, T-2Hz).

Example 7 450 mg of 1-acetoxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane was dissolved in 25t7111 of methanol, and 0.4 ml of triethylamine was added, followed by heating for 8 hours. Reflux.

After distilling off the solvent under reduced pressure, it was separated and purified by column chromatography (silica gel, chloroform) to obtain 340 mg of -methylsulfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene (yield 80%).
) was obtained.

Example 8 410~ of 1-acetoxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane was dissolved in 25 U of ethanol, and 220 mg of potassium acetate was added thereto, followed by heating under reflux for 18 hours. do.

After the solvent was distilled off under reduced pressure, 50 ml of chloroform was added and insoluble materials were filtered off.

After concentrating the filtrate under reduced pressure, it was separated and purified by column chromatography (silica gel, chloroform) to obtain -methylsulfinyl-1-methylthio-2-(3'-chloro-
4-allyloxyphenyl)ethylene 264 ■ (yield 7)
7%).

Example 9 ■-Hydroxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane (mixture of 4 stereoisomers) 2.0 g, pyridine 6rn13: mixture of acetic anhydride 8 rul 11 at room temperature
After stirring for an hour, excess pyridine and acetic anhydride are distilled off under reduced pressure.

The residue was dissolved in 200rrL of chloroform and 50I of water.
Wash with 71g.

After drying over magnesium sulfate, the solvent was distilled off to give crude 1-acetoxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane 2.
．． Obtain 1g.

This compound was subjected to the next reaction without purification.

Dissolved in methanol 80711, triethylamine 2.
, 2rnl, and then heated under reflux for 13 hours.

After distilling off the solvent under reduced pressure, it was separated and purified by column chromatography (silica gel, chloroform) to obtain 1 as an oil.
-methylsulfinyl-1-methylthio-, 2:, =(
3=lioo-4-allyloxyphenyl)ethylene 1
5 g (yield 86%) was obtained.

Example 10 1-Methoxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane 351 ~ was dissolved in tetrahydrofuran, and 55"9 of sodium hydride (containing 50%) was dissolved. The mixture was added and stirred at room temperature for 3 hours.

After adding 50 ml of methylene chloride and filtering off insoluble matter, the filtrate was concentrated under reduced pressure and separated by column chromatography (silica gel, chloroform) to give 1-methylsulfinyl-1-methylthio-2-C3-chloro-4-'7. '
J-oxyphenyl)ethylene 221~ (yield 70%)
I got it.

Example 11 1-Hydroxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane (crystalline mixture of three stereoisomers obtained in Reference Example 2) 1 9 t of potassium t-butoxide in 8'■
-Butanol solution (prepared from 075 g of metallic potassium and 25 rILl of t-butanol) IU was added and stirred at room temperature for 33 hours.

After adding methylene chloride 50I71A and filtering off insoluble matter, the filtrate was concentrated under reduced pressure.

The residue was separated by column chromatography (silica gel, methylene chloride) to obtain 1-methylsulfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene 102111II (yield 55%). .

Reference Example 1 1.09 g of methyl methylthiomethyl sulfoxide is dissolved in 10 d of tetrahydrofuran, and 900 ml of sodium hydride (containing 50%) is added under water cooling, followed by stirring for 30 minutes.

At room temperature, 2.0 g of methyl 3-chloro-4-allyloxybenzoate was added, and the mixture was further stirred for 19 hours.

Chloroform 40I7111 Acetic acid 5rrLj and Water 2
After adding rfLl, dry with Glauber's salt and potassium carbonate.

After concentrating the solvent under reduced pressure, it was separated by column chromatography (silica gel, chloroform) to give 1-oxo-1-(
1.9 sg (yield 70%) of 3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane was obtained as a pale yellow oil.

NMR revealed that this product was a 3:4 mixture of two stereoisomers.

IR(neat): 1660cm' and 1050cr
IL-1050crIL-1N: Component A, : δ2.12 (3H, - double line), 2.87 (3
H2-double line).

Component B: δ2.22 (3H, - double line), 2o64 (3H
2-double line).

Common to components A and B: δ4.65 (2H, double line, J=4.
5Hz), 5.18-6.30 (3H.

multiplet), 5.55 (IH, - multiplet), 6.85-8.0 (3H, multiplet).

Elemental analysis (C13H1503CIS2): Calculated value (%l
: C,48,96;f(,4,74;S.

20.11° Experimental values (%): C, 48,87; H, 4,58; S.

19.93° Reference Example 2 1-oxo-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane 1. (1 mL of methanol is dissolved, 120 ~ of sodium borohydride is added under water cooling, and after stirring at room temperature for 3 hours, excess sodium borohydride is decomposed with 1 rnL of acetone and concentrated under reduced pressure.

The residue was extracted by adding 30rrLj of chloroform, and 1 liter of water was added.
Wash with 0ml.

The chloroform layer was dried over Glauber's salt, evaporated under reduced pressure, and crystallized from carbon tetrachloride to give 1-hydroxy-1-(3-chloro-
4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane was obtained as colorless crystals as a mixture of three stereoisomers (yield: 51%).

This mixture was fractionally recrystallized from methanol to obtain colorless needle crystals (isomer a) with a melting point of 162-163°C and colorless needle crystals (isomer b) with a melting point of 103-105°C.

The carbon tetrachloride crystallization mother liquor was concentrated under reduced pressure and then separated by column chromatography (silica gel, chloroform) to obtain 250 kg of a colorless oil (isomer c) and 70 ~ of a mixture of four isomers.

Overall yield 840 mg (83%). Isomer (a): IR (KBr): 3200 cm and 1040 cm
1104Oδ6-D104O: δ1-93 (3H, - doublet), 2-77 (3H, - doublet'), 3.78 (IH2 wide singlet'), 4.63 (2H2 doublet, J=4 .5Hz), 5,. 20-6.35 (4H, multiplet), 6.8-7
°7 (3H, multiplet).

Isomer (b): IR (KBr): 3200crIL” and 10351
035CIrL-1N, DMSO'): δ2.05(3
H, - double line), 2.80 (3H, - double line), 3.57 (IH5 double line, J = 5Hz), 4.70 (2H, double line, J = 4.5Hz), 5 .00 (IH, doublet, J=5Hz), 5.25-6.40 (3H2 multiplet), 6.8-7.8 (3H1 multiplet).

Isomer (C): IR (neat): 3300CIrL-1 and 101Q
cilNM101QcilN: δ1.96 (3H, - doublet), 2.70 (3H1 - doublet), 3.76 (IH2 doublet, J = 8Hz), 4.52 (2H, doublet, J = 4 .5Hz), 4.82 (IH, doublet; J=8Hz), 5.10-6.30 (3H2 multiplet), 6.7-7.5 (3H2 multiplet).

Elemental analysis of a crystalline mixture of three stereoisomers (C13'H1□03S2C1): Calculated value (a): C, 4866; H, 5,34; S.

19.98.

Experimental values (a): C, 48,74; H, 5,33; S.

20.15° Reference Example 3 -Hydroxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane (isomer (c) obtained in Reference Example 2) 100"9
A mixture of 2.5 U of pyridine and 2.5 U of acetic anhydride is stirred at room temperature for 15 hours, and then excess pyridine and acetic anhydride are distilled off under reduced pressure.

The residue was dissolved in 20 mL of chloroform and dissolved in 5I71J of water.
After washing with sodium chloride and drying with sodium sulfate, the solvent was distilled off.

It was further separated and purified by column chromatography (silica gel, chloroform) to obtain ■-acetoxy 1-(3-
100% of chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane as an oil.
”? (yield 90%) was obtained.

IR (neat): 1740 cm-' NMR (CDC13): δ2.08 (3H, - double line),
2.20 (3H,-double line), 2.69 (3H2-double line), 4.24 (IH.

double line, J=8Hz), 4.66 (double line on 2H, J=4.5Hz), 6.05 (IH2 doublet, J=8Hz), 5.25-6.30 (3H, multiplet), 6.7-7.
7 (3H, multiplet).

Elemental analysis (CI5H190482CI): Calculated values (H: C, 49,64; H, 5,27; S.

17.67° Experimental values (a): C, 49,58; H, 5,31; S.

17.77゜Reference Example 4 1-Methylsulfinyl-1-mer-f-ruthio 2-(
After dissolving 2.6 g of 3-lior-4-'7'lJ-ruoxy)phenylethylene in 20 rui of 1,2-dimethoxyethane, 8 mA of concentrated hydrochloric acid was added little by little and stirred at room temperature for 25 hours.

After adding chloroform 150FLn and water 30ml, the aqueous layer is further extracted with chloroform 50I711.

The organic layers were combined, dried over anhydrous magnesium sulfate, chloroform was distilled off, and 100ml of ether was added to the residue.
Extract with saturated aqueous sodium bicarbonate solution (60 rILl
(twice).

The aqueous layer is made acidic with hydrochloric acid and then extracted with chloroform (
3 times at 100rnl).

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off.
Crystallized from cyclohexane, recrystallized with melting point 91-92
1.689 of 3-chloro-4-allyloxyphenylacetic acid (yield: 86.8%) was obtained as colorless needle-like crystals.

IR (KBr): 1690cIrL-1HMR (CD
C12): δ3.52 (2H, - double line), 4.58 (2
H, doublet, J=4.5 Hz), 5.18-6.32 (3H, multiplet), 6.72-7.52 (3H.

multiplet), 11.56 (IH, - multiplet line).

Elemental analysis (CIIHI□03C1): Calculated values (@: C, 60,98; H, 5, 11.

Experimental values (%l: C, 61,05; H, 5,06.

Antiinflammatory action of the compound of the present invention by carrageenan edema method (Experimental method) The compound of the present invention obtained in Example 1 was suspended in 03% sodium carboxymethyl cellulose (CMC-Ha),
It was orally administered to D-strain male and female rats (group of 5 rats, weight 110-140 g).

One hour after administration, 0.1 rIlil of a 1% carrageenan solution was subcutaneously administered to the right hind paw of each rat, and a constant volume was measured every hour thereafter. The value,
ED indicates the edema intensity of the study drug administration group), and the inhibition rate (
aA was calculated.

In addition, the control group received 0.3% CMC instead of the test drug.
-=Na alone was orally administered.

Furthermore, phenylbutadine (PB) was used as a control drug.

<Results> Table 1 shows the inhibition rates (values 3 hours after administration of the test drug) of the compound of the present invention and the control drug at each dose of 12.5.25°50 and 100''9/Kt.

As shown in Table 1, the compounds of the present invention exhibited anti-edema activity superior to PB.

Claims (1)

[Claims] 1 1-sulfinyl-1-thio-2- represented by the general formula (wherein R1 and R2 are an alkyl group or an aryl group)
(3-chloro-4-allyloxyphenyl)ethylene. 2. The compound according to claim 1, wherein R1 and R2 are a lower alkyl group having 1 to 4 carbon atoms or a phenyl group.