JPS5822032B2 - β-oxysulfoxide derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R'' and R2 are alkyl groups, and R3 is an alkyl group, an acyl group, or an aroyl group).

) and a method for producing the same.

Examples of the alkyl groups for R1 and R2 include alkyl groups such as methyl, ethyl, propyl, and butyl groups.

In addition, the alkyl group of R3 includes methyl, ethyl, propyl group, etc., and the acyl group includes acetyl, propionyl,
Examples include butyroyl and phenylacetyl groups.

Examples of the aroyl group include benzoyl and 2,4-dinitrobenzoyl groups.

Specific compounds include 1-methoxy-1-(3-chloro-4-allyloxyphenyl)-2-methylnurfinyl-2-methylthioethane, 1-acetoxy-1-(
3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane, ■-benzoyloxy-1-(3-chloro-4-allyloxyphenyl-2-methylnurfinyl-2-methylthioethane, etc. There is.

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

Furthermore, the compound obtained in the present invention can be derived in good yield into 3-4-4-allyloxyphenylacetic acid, which is prized as an anti-inflammatory agent, by applying appropriate chemical means (see reference side below). It is an important pharmaceutical intermediate.

The manufacturing method of the present invention is based on the general formula (In the formula, R'' and R2 are alkyl groups.

), and this compound can be easily produced by the method developed by Nagisa et al. of the present invention.

That is, 3-chloro-4-allyloxybenzoic acid ester and the general formula RISCH2SOR2 (III) (wherein R1 and R2 are alkyl groups).

) with a nulphoxyto having a nulphite bond at the α-position in the presence of a base (wherein R1 and R2 are alkyl groups).

) to obtain the desired compound (
II) can be produced (see reference side below) 01 The method of the present invention alkylates, acylates, acylates or aroylates α-hydroxyaldehyde mercaptal S-oxides represented by the general formula (II). It is characterized by this.

Alkylation can be achieved by reacting with the respective corresponding alkylating agent.

The alkylating agent ξ used here is an alkyl halide such as methyl iodide or benzyl bromide, a dialkyl sulfate such as dimethyl sulfate, or an alkyl nulphonate such as methyl fluoronurulfonate or methyl trifluoromethane sulfonate. Entel, etc. can be mentioned.

In this reaction, the presence of a base is preferred, and examples of the base that can be used include strong bases such as sodium hydride, n-7'' chilllithium, and lithium diethylamide.

Acylation and aroylation can be achieved by reacting the corresponding acid halide or acid anhydride in the presence or absence of a base, and the desired compound (I) can be obtained in good yield.
can be obtained.

(In the formula, R1 and R2 represent an alkyl group, and R3 represents an alkyl group, an acyl group, or an aroyl group).

In carrying out the present invention, benzene, toluene, pyridine, diethyl ether tetrahydrofuran,
Aprotic organic solvents that do not participate in the reaction, such as chloroform, can be used.

The reaction proceeds smoothly at room temperature without using any special heating or cooling means, but heating may be performed if desired.

Furthermore, when a large amount is used, heat may be generated, so a cooling means may be used to control the temperature.

The compound obtained in the present invention is unknown in literature, and its structure was confirmed by infrared absorption spectrum, nuclear magnetic resonance spectrum, elemental analysis, etc.

Next, this reaction will be specifically explained in Examples and Reference Examples, but is not limited thereto.

Example 1 1-Hydroxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane 1001n? , pyridine 2.5-1 acetic anhydride 2.
57! After stirring the mixture at room temperature for 15 hours, excess pyridine and acetic anhydride were distilled off under reduced pressure.

The residue was dissolved in 20 ml of chloroform, washed with water, dried with sodium sulfate, and 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-methylnurfinyl-2-methylthioethane as an oil.
mfI (yield 90%) was obtained.

IR (neat): 1740CrfL-1NMR
(CDCl2): δ2.08 (3H, - double line).

2.20 (3H, - double line), 2.69 (3H, - double line)
, 4.24 (IH, doublet, J=8 Hz).

4.66 (2H, doublet, J=4.5 Hz).

6.05 (IH, double line, J=8Hz), 5.2
5-6.30 (3H, multiplet), 6.7-7.7
(3H1 multiplet) Elemental analysis (C15H1,04S2C1): Calculated value %):
C・49.64; H, 5,27; S, 17.67° Experimental value (to): C, 49,58; H, 5,31; S, 1
7.77゜Example 2 ■-Hydroxy-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane in a solution of 1.2y in chloroform at 10% hydroxide l-IJ 2.2 g of benzoyl chloride was added dropwise with stirring at room temperature, and after the dropwise addition was completed, the mixture was further stirred for 16 hours. The chloroform layer was separated, washed with water, dried over potassium carbonate, and the chloroform was distilled off.

The obtained oil was separated and purified by column chromatography (silica gel, chloroform) to give 1-hendiyloxy-1-(3-'70rho-4-allyloxyphenyl)-
2-methylsulfinyl-2-methylthioethane i,o
, y (yield 64%) was obtained as a colorless oil.

IR (neat): i72ocm-', 1
640cIIl-” and 1060cm-”.

Example 3 ■-Hydroxy-1-(3-chloro-4-allyloxyphenyl)-2-methylnurfinyl-2-methylthioethane 6007nfI was mixed with dimethylnulfoxide 5rnl
After stirring to dissolve and add 1 Biao of methyl iodide, 1.1 (containing 50%) of sodium hydride is added.

Furthermore, methyl iodide lyd was added and stirred at room temperature for 10 hours.
Chloroform 1007727! ! After washing with water, dry the sodium sulfate and concentrate under reduced pressure.

The residue was separated by column chromatography (silica gel, chloroform) to give 1-methoxy-
1-(3-chloro-4-allyloxyphenyl)-2-
Methylnurfinyl-2-methylthioethane 470q (
A yield of 75% was obtained.

IR (neat): 1060crfL-”.

NMR (CDCl2): δ2.08 (3H, - double line).

2.80 (3H, - double line), 3.45 (3H,
- double line) 3.65 (IHs double line, J = 4.5Hz
), 4.8.5 (double line on 2H, J = 4.5 Hz
) 5.28-6.50 (4H1 multiplet), 7.
28-8.1 ('3H, multiplet).

Reference Example 1 Methyl methyl thiomethyl sulfoxide 1.09.9 was dissolved in 10 ml of tetrahydrofuran, and under water cooling, sodium hydride (containing 50%) 9007M? Add and stir 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.

After adding 40 parts of chloroform, 5 parts of acetic acid, and 2 parts of water, the mixture is dried 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 ■-oxo 1-(
1.95.9 (yield: 70%) of 3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2=methylthioechune was obtained as a pale yellow eraser.

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

IR (neat): 1660cm-' and 1050
cm-'.

NMR (CDCl2): Component A: δ2.12 (3H, - heavy line) 2.87 (3H1
- heavy line).

Component B: δ2.22 (3H, - double line) 2.64 (3H1
- heavy line).

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

Elemental analysis (C13H1503CIS2): Total J[H:C
, 48, 96; H, 474; S, 20.11° experimental value (
To): C, 48, 87; H, 4, 58; S, 19
．． 93° Reference Example 2 ■-Oxo-1-(3-chloro-4-allyloxyphenyl)-2-methylsulfinyl-2-methylthioethane 1. Dissolve OI in 50-methanol, add 120111fI of sodium borohydride under water cooling, and dissolve at room temperature for 30 minutes.
After stirring for an hour, excess sodium borohydride was decomposed with 1 l of acetone, and the mixture was concentrated under reduced pressure.

The residue is extracted with 30% of chloroform and washed with 10% of water.

The chloroform layer was dried over Glauber's salt, evaporated under reduced pressure, and crystallized from carbon tetrachloride to give ■-Hydroxy-1-(3-chloro-4=allyloxyphenyl)-2-methylsulfide:
Nyl-2-methylthioethane was obtained as a mixture of three stereoisomers in the form of colorless crystals in an amount of 520 μm (yield: 51%).

This mixture was fractionated and crystallized from methanol to obtain colorless needle-like crystals (isomer a) with a melting point of 162-163°C and colorless needle-like Σ 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 μl of a colorless clear product (isomer c) and 70 μl of a mixture of four isomers.

Overall yield 840 sq. (83%). Isomer (a): IR (KBr): 3200cIrL-1 and 104
0(1m-'.

NMR (δ6-DMSO): δ1.93 (3H, doublet), 2.77 (3H, doublet), 3.78 (IF5 wide singlet), 4.63 (2H, doublet, .

J = 4.5Hz) 5.20-6.35 (4H
1 multiplet), 6.8-7.7 (3H% multiplet).

Isomer (b): IR(KBr): 3200crn-' and 103
5CrfL-1°NMR (δ6-DMSO): δ2.0
5 (3H, single line), 2.80 (,3H, - double line), 3.57 (double line on IH, J=5Hz), 4.70
(Double line on 2H, J − = 4.5 Hz), 5.0
0 (I H-double, J=5Hz), 5.25-6.
40 (3H1 multiplet) 6.8-7.8 (3H, multiplet).

Isomer (C): IR (neat): 3300CIfL-” and 1
010 cm-1.

NMR (CDCl2): δ1.96 (3H, - double line)
.

2.70 (3H%-heavy line), 3.76 (heavy line on IH, J
= 8Hz), 4.52 (2H, double line, J = 4.5Hz
), 4.82 (IH, double line, J=s H2), 5.
10-6.30 (3H multiplet).

6, 7-7.5 (3H, multiplet).

Elemental analysis of crystalline mixture of three stereoisomers (C13H1□03S2C1): Calculated value (to): C, 48,66; H, 5,34; S
, 19.98.

Experimental value %)', C, 48,74; H, 5,33; S
, 20.15.

Reference Example 3 450 ml of -acetoxy 1-(3-chloro-4-allyloxyphenyl)-2-methylnurfinyl-2-methylthioethane was dissolved in 25 ml of methanol, and 0.4-triethylamine was added. Heat to reflux for 8 hours.

After distilling off the solvent under reduced pressure, it was separated and purified by column chromatography (silica gel, chloroform) to obtain ■-methylnurfinyl-1-methylthio-2-(3-chloro-4-allyloxyphenyl)ethylene 3407n+! (yield 8
0%) was obtained.

IR(neat): 1060CIrL-”.

NMR (CC14): δ2.30 (3H, - double line).

2.62 (3H, - double line), 4.62 (2H double line, J = 4.5Hz), 5.20-6.35 (3H
.

multiplet), 7.42 (IH, -multiplet), 6.89-8.
06 (3H, multiplet).

Elemental analysis (C13H150□52C1): Calculated value %):
C, 51,56; H, 4,99; S, 21.17° Experimental value (to): C, 51,62; H, 4,93; S, 21
．． 25° Reference Example 4 ■-Methylnurfinyl-1-methylthio-2-(3-
2.6 g of chloro-4-allyloxyphenyl)ethylene
After dissolving in 1,2-dimethoxyethane 20-, concentrated hydrochloric acid 87727! ! was added little by little and stirred at room temperature for 25 hours.

After adding 150rnl of chloroform and 30ml of water,
The aqueous layer is further extracted with 50 ml of chloroform.

The organic layers were combined, dried over anhydrous magnesium sulfate, and then chloroform was distilled off. Ether 100- was added to the residue, and extracted with a saturated aqueous solution of sodium bicarbonate (twice at 60 yd).

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

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off.
Crystallized from cyclohexane, recrystallized with melting point 91-92
3-chloro-4-allyloxyphenylacetic acid as colorless needles at 1,68,! i+ (yield 86.8%) was obtained.

IR (KBr): 1690cm-”.

NMR (CDCl2): δ3.52 (2H, - double line).

4.58 (2H, doublet, J=4.5Hz).

5.18-6.32 (3H, multiplet), 6.72-7
．． 52 (3H1 multiplet), 11.56 (IH% multiplet).

Elemental analysis (C1, Hl, 03C1): Calculated value %): C, 60,98; H, 5, 11 Experimental value (
): C,61,05; H,5,06 Experimental method for anti-inflammatory action of the present compound by carrageenan edema method> The present compound obtained in Example 1 was added to 0.3% carboxymethyl cellulone sodium (CMC). - suspended in Na);
SD male and female rats, 5 rats per group, body weight 110-14o, y
) was administered orally.

One hour after administration, 1% carrageenan solution 0.1- was subcutaneously administered to the right hind paw of each rat, and then a constant volume was measured every hour. ED indicates the edema intensity of the test drug administered group), and the inhibition rate (%) was calculated. In addition, the control group received 0.3% CMC instead of the test drug.
-Na alone was orally administered.

Furthermore, phenylbucusone (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 ml/KP.

, Table 1 Inhibition rate (% Dose (772≠p) 12.5 25 50 1
00 administration group control drug (PB) 11.7 16.7 32.9 3
7.5) Compound of the present invention 21.0 29.2 39.
4 49.5 (Example 1) As shown in Table 1, the compound of the present invention exhibited anti-edema activity superior to PB.

Claims (1)

[Scope of Claims] 1. A β-oxynulphoxide derivative represented by the general formula (wherein R1 and R2 are an alkyl group, and R3 is an alkyl group, an acyl group, or an aroyl group). 2. The compound according to claim 1, wherein R'' and R2 are methyl groups, and R'' is a methyl group, an acetyl group, or a benzoyl group. 3. A compound of the general formula (wherein R1 and R2 are alkyl groups) characterized by alkylating, acylating or aroylating α-hydroxyaldehyde mercaptal S-oxide represented by the general formula (wherein R1 and R2 are alkyl groups). (wherein, R1 and R2 are alkyl groups, and R3 is an alkyl group, an acyl group, or an aroyl group).