CA1077524A - 1-alkyl (or aryl) sulfinyl-1-alkyl (or aryl) thio-2-(3'-chloro-4'-allyloxyphenyl) ethylene - Google Patents

Abstract

Abstract of the Disclosure Novel compounds of the formula:

(I) in which R1 and R2 each represents an alkyl or aryl group, are disclosed as well as a process for their preparation by reacting 3-chloro-4-allyloxy-benzaldehyde with a formaldehyde mercatal S-oxide of the formula:

R1SCH2SOR2 (III) in the presence of a base. The compounds (I) are useful as intermediates for preparing pharmaceuticals.

Description

This invention relates to l-alkyl(or phenyl)-sulfinyl-l-alkyl tor phenyl)thio-2-~3'-chloro-4'-allyloxyphenyl)ethylenes of the formula ,''`
~ Cl SRl . ~
CH2=CHCH2 ~ CH C ~ (I) wheTein Rl and R2 each represents alkyl of 1 to 3 carbon atoms or ~ ph0JIyl 9 - and to a process for preparation thereof.
The compounds of formula (I~ are novel compounds, and specific ` examples thereof include l-methylsulfinyl-l-methylthio-2-(3'-chloro-4'-,, allyloxyphenyl)ethylene, l-ethylsulfinyl-l-ethylthio-2-(3'-chloro-4'-; 10 allyloxyphenyl)ethylene, 1-propylsulfinyl-1-propylthio-2-~3'-chloro-4'- ~
allyloxyphenyl) ethylene, and l-phenylsulfinyl-l-phenylthio-2-~3'-chloro- ~;
4'-allyloxyphenyl)ethylene.
The compounds of the invention are useful as intermediates for preparing pharmaceuticals. The compounds of formula (I) can be easily converted to (3-chloro-4-allyloxyphanyl)acetic acid, i.e. alclofenac, which is known as a therapeutic agent, par~icularly as a superior anti-inflammatory agent. The alclofenac and a process for its preparation will ba described later in this specification.
One method for preparing the compounds of this invention comprises reacting 3-chloro-4-allyloxybenzaldehyde of the formula Cl CH2=CHCH20 ~ - CH0 (II) !

- 2 -,~

1~7S2~ ~

with a formaldehyde mercaptal S-oxide of the ormula RlSCH2SOR2 (III) wherein Rl and R2 each represents alkyl of l to 3 carbon atoms or phenyl, in the presence of a base. This reaction is a dehydrocondensation reaction schematically shown below.

:
` Cl \

`~ CH2=CHCH2 ~ CH0 ~ RlSCH2SOR2 ~ ~II} (III~
'"' > CH2-cilca2o ~ C ~ SR2 ~I) The 3-chloro-4-allyloxybenzaldehyde of formula ~II) used as a reactant in the above reaction is prepared, for example, by reacting

3-chloro-4-hydroxyben~aldehyde with an allyl halide, and is readily available commercially. The sulfoxide of for~ula (III) containing a sulfide bond at the a-position is described in United States Patent 3,742,066 (1973) granted to the present inventors, and can be easily produced commercially.
The above reaction for forming the compounds of this invention is carried out in the presence of a base.

'~'`' 1 ~

~75;~

Preferably~ relatively ~trong ba~es~ such as ~odium hydride, trimethylbenzylammonium hydroxide, sodium hydroxide, and pota~sium hydroxide, are used. Since the strong base is not consumed in the reaction but acts as a catalyst, its amount can be ~mall. For practical purposes, the amount is at least Q.01 equivalent, preferabl~ at least 0~05 eguivalent~ based on either one vf the reaction materials~
The reaction is promoted with increa~ing amount of the strong base.
The reaction proceeds smoothly at room tempera~
ture to 150C. Particularly suitable reaction temperatures are 50 to 110 C The reaction is carried out preferably in a solvent. Usable reaction solvents are common organic solvents such as dimethylformamide, tetrahydrofuran, di-oxane, methanol, ethanol, and benzene. The reaction time varies depending upon the reaction temperature and other reaction conditions, but usually periods of 1 to 30 hours are sufficientr After the reaction is over, the reaction mixture 20 iB treated by known methods (for example, neutralization, extraction, concentration, column chromatography, or dis-tillation) to isolate the intended product (I) in good yield.
The product has not been described in the literature, and its structure is determined by infrared absorption spectro-scopy, nuclear magnetic resonance spectroscopy, and ele-`! mental analysis-'.! The compounds of this ln~ention and pr0paration thereof will be described in Examples 1 to 6 belo~
Now, alclofenac, i.e., (3-chloro-4-allyloxyph~nyl) ....
;",~
~ 4 ~ ~

~75Z~ ::
': ' '' , acetic acid, and a proces~ for preparin~ alclof~nac from the compounds of formula (I) will be described~
The alclofenac and similar compounds, processes for th~ir preparation and the use of these compounds as anti-inflammatory, antipyretic, analg~sic and antispastic agents are described in Belgian Patents NosO 7O4~ 368 and 718,930. It ~as already been known that the alclofenac exhibits especially superior pharmacological actions.
Two typical known processes for preparing alclo- .
: ,. .
fenac are shown below.
Cl Cl (l) HO ~ C~I3I CH O ~ HCHO, HCl Methylation~ 3 Chloro~
methylation .':
Cl Cl `i~
, \ \
CH30 ~ CH Cl NaCN ~ 3 ~ CH2CN
.~ubstitution . :
,' ., Cl 480/o HBr _ _ HO ~ CH2COOH CH30H~ H2S04 ~ ~
Hydrolysis ~ W Esterification~ ; -.
Cl Cl C~I2=CHCH2Br >~ .
HO~ C~I2C02C~3 . ~ CH2=CHCH20 ~ CH2Co2cH3 -~ ~.ll~latlon Cl ,,.
~CH =CHCH 04/ ~ CH COOH :` -Hydrolysis2 2 ~ 2 ' ' : : ... ::.: , . :

"~
~L~7752~
:`
Cl Cl t2) H ~ CH2 CHCd2Br CH2=C}ICH20 Cl HCHO, HCl ~
Arsenic oxide CH2=CHCH20 4/ \ ~ CH2Cl NaCN ~-Chloro- ~ Substitution methylation Cl Cl CH2=CHCH20 ~ ~ 2 ~drolysls ~ -CH2c2H

The two conventional methods for alclofenac prepara-tion shown above involve a step of substitution with sodium cyanide and a step of chloromethylation with formaldehyde and hydrogen chloride. The sodium cyanide used has strong toxicity, and formaldehyde and hydrogen chloride used in the chloromethyl-ation step yield bis(chloromethyl) ether ~ClCH20CH2Cl), known to be a strongly carcinogenic substance, as a by-product. The conventional methods are not desirable commercially because they include such dangerous and detrimental steps.
In contrast, a process comprising hydrolyzing the compounds of formula ~I) in the presence of a mineral acid catalyst can afford alclofenac with good efficiency without `
involving any such danger or toxicity problems, and is very advantageous for commercial operation. This process is schematically shown as follows:

- ~a~7s2~ ' CH z = CHCH20 ~3 C H= C

Cl CH2=cHcH2o~cH2cooH .

When an alcohol is used instead of water in the above hydrolysis, alclofenac is obtained in the form of the corresponding ester. Hydrolysis of the ester affords alclofenac as free acid. The preparation of alclofenac from the compounds of formula (I) will be shown hereinbelow in Referential Examples 1 to 30 :: , Formaldehyde dimethyl mercaptal S-oxide ~3.7 g), 2.87 g of a l~o% methanol solution of trimethylbenzylammonium ~-hydroxide, and 5 g of 3-chloro-4~allyloxybenzaldehyde were added to 8 ml of tetrahydrofuran, and the mixture ~as heated under reflux for 6 hoursO After cooling, 150 ml of chloro-form was added. Th0 mixture wag washed with 15 ml of dilute sulfuric acid. The chloroform layer was dried with anhydrous potassium carbonate, and concentrated at reduced pressureO
The regidue ~ag purified by column chromatography on ~illca `~
gel ~eluted with ether~ to afford 7.0 g (91.5% yield) of `~
1-methylsulfinyl-1-methylthio-2-~3'-chloro-4'-allyloxy-phenyl)ethylene.
The regults of analyseg were as follows:
XR (neat): 1060 cm 1 -NMR (C~C13): ~2~28 ~3H, singlet), 2.70 (3H, singlet),

4.60 (2H! broad doublet, J=4.5 Hz), . ' , ' 1~75Z~

5.1-6.4 ~3H, multiplet), 6.89 (1}-l, doublet, J=8.5 Hz), 7.44 ~lH, singlet), 7.65 ~lH, quartet, J=2 Hz and 8.5 Hz), 8.06 ~lH, doublet, J=2 Hz).
Elemental analysis ~C13H1502S2Cl~:
Calculated (%): C, 51.56; H, 4.99; S, 21.17 Found ~%): C, 51.62; H, 4.93; S, 21.25 Example 2 Formaldehyde dimethyl mercaptal S-oxide ~1.25 g) was dissolved in 10 ml of dioxane, and 1 ml of a 40% methanol solution of trimethylbenzylammonium hydroxide and 2.0 g of 3-chloro-4-allyloxybenzaldehyde were added. The mixture was stirred at 80C. for 10 hours. After cooling, 100 ml o chloroform, 10 ml of water, and 1 ml of conc. hydrochloric acid ~ere added, and the resulting mixture was shaken. After the organic layer was separated, the aqueous layer was ex-tracted with 50 ml of chloroform. The organic layers were combined, dried uith anhydrous magnesium sulfate, and th0n concentrated at Teduced pressure. The residue was purified by column chromatography an silica gel ~eluted with ether) to aord 2.6 g ~87% yield~ of l-methylsulfinyl-l-methyl-thio-2-~3'-chloro-4'-allyloxyphenyl)ethylene.
The product was identified because its infrared absorption spectrum completely coincided with that of the standard product obtained in Example 1.
Bxample 3 , Formaldehyde dimethyl mercaptal S-oxide ~2.25 g) was dissolved in 10 ml of tetrahydrofuran. Under ice cooling, '~':
8 ~

- ~77~

, 1~0 g of sodium hydride ~50% content) ~YaS added, and the mixture was stirred for 1 hour. Thenp 3r9 g of 3-chloro-4-allyloxybenzaldehyde was added at -30 C~ The mix-ture ~as stirred for 3 hours at -30C. and then for 1 hour at room temperature. Then, 50 ml of chloroform wa~ added, and the insoluble matter was separated by filtration. The filtrate ~ras concentrated at reduced pressure, and purified by column chromatography on silica gel (elu~ed with ether) to afford 3~2 g (54% yield) of l-methylsulfinyl-l-methyl-! 10 thio-2-(3'-chloro-4'-allylo~yphenyl)ethylene.
Example 4 Formaldehyde diethyl mercaptal S-oxide (930 mg~, 1 ml of a 40/~ methanol solution of trimethylbenzylammonium hydroxide, and 10193 g of 3-chloro-4-allyloxyben~aldehyde were added to 10 ml of tetrahydrofura7l~ and the mixture heated under reflux for 16,5 hoursO After cooling, 50 ml of methylene chloride was added. The mixture was washed with 10 ml of lN dilute sulfuric acid, and dried with anhydrous potassium carbonateO The dried solution was concentrated at reduced pressure, and purified by column chromatography on silica gel (eluted with methylene chloride) to afford 1.272 g (63b yield) of l-ethylsulfinyl-l-ethylthio-2-(3'-chloro-4'-allyloxyphenyl)ethylene as a pale yellow oily substanceO
The results of analyses were as follows:
IR (neat): lQ60 cm 1 NMR (CDC13): ~1021 (6H, triplet, J=7.5 Hz), 2052-3~17 (4~I, multiplet), 4059 _ g _ ' ~775;Z
'~
~2H, broad doublet, J=4.5 Hz), 5.1-6.4 ~3H, multiplet), 6.88 ~lH, doublet, J=8.5 Hz), 7.40 ~lH, singlet), 7.67 ~lH, quartet, J=2 Hz and J=8.5 Hz), 8.09 (lH, J=2 Hz).
Example 5 Example 4 was repeated except that 1.088 g of ormaldehyde diisopropyl mercaptal S-oxide and 1.188 g of 3-chloro-4-allyloxybenzaldehyde were used instead of 930 mg of formaldehyde diethyl mercaptal S-oxide and 1.193 g of 3-chloro-4-allyloxybenzaldehyde. As a result, 1.557 g (72% yield) of 1-isopropylsulfinyl-1-isopropylthio-2-~3'-chloro-4'-allyloxyphenyl)ethylene was obtained as a pale yellow oily substance.
The results of analyses were as follows:
IR ~neat): 1060 cm NMR ~CDC13): ~ 1.02 (3H, doublet, J=7 Hz), 1.22 ` (3H, doublet, J=7 Hz), 1.25 (3H, doublet, J=7 Hz), 1.41 ~3H, doublet, J=7 Hz), 3.0-3.5 ~2H, multiplet), 4.59 ~2H, broad doublet, J=4.5 Hz), , .
5.1-6.4 ~3H, multiplet), 6.87 ~lH, doublet, J=8.5 Hz), 7.38 ~lH, singlet), ~ 7.77 ~lH, quartet, J=2 H7 and 8.5 ; Hz), 8.15 llH, doublet, J=2 Hz).
Example 6 ~ Example 4 was repeated except that 807 mg of form-aldehyde diphenyl mercaptal S-oxide and 710 mg of 3-chloro-:, ~, . ~ - 10 -: '~
' .
, ,. . ., .. ., ~- .. . : ,, ~C~775Z4 4-allyloxybenzaldehyde were used instead of 930 mg of formaldehyde diethyl mercaptal S-oxide and 1.193 g of 3-chloro-4~allyloxybenzaldehyde. As a result, 605 mg ~4~% yield) of 1-phenylsulfinyl-1-phenylthio-2-(3'-chloro-4'-allyloxyphenyl)ethylene was obtained as a pale yellow oily substance.
The results of analyses were as follows:
IR tneat): 1055 cm NMR (CDC13): ~ 4.53 (2H, broad doublet, J=4.5 Hz), lQ 5.1-6.4 (3H, multiplet), 6.78 ~lH, doublet, J=8.5 Hz), 7.09 (5H, singlet), 7.0-7.8 ~6H, multiplet), ` , 7.94 ~lH, singlet~, 7.95 ~lH, doublet, J=2 Hz).
Referential Example 1 l-Methylsulfinyl-l-methylthio-2-~3~-chloro-4'-allyloxyphenyl)ethylene ~2.6 g) was dissolved in 20 ml of 1,2-dimethoxyethane, and 8 ml of conc. hydrochloric acid was added in small portions. The mixture was stirred at room temperature for 25 hours. Chloroform ~150 ml) and 30 ml o water were added, and then, after separating the `
organic layerJ the aqueous layer was extracted with 50 ml of chloroform. The organic layers were combined, and dried with anhydrous magnesium sulfate. The chloroform was eva-poTated, and lQ0 ml of ether was added to the residue. The mixture was extracted twice with 6Q ml of a saturated aqueous solution of sodium bicarbonate each time. The aqueous layer was acidified with hydrochloric acid, and extracted three times with lOO ml of chloroform each time.

775;Z~
~"
The extracts were com~ined, and dried with anhydrous magnesium sulfate, and the solvent evaporated. Crystallization and recrystallization from cyclohexane afforded 1.68 g (86.8%
yield) of (3-chloro-4-allyloxyphenyl)acetic acid as colorless needles having a melting point of 91 - 92 C.
IR tKBr): 1690 cm 1 `~
MMR ~CDC13): ~ 3.52 ~2H, singlet), 4.58 ~2H, ' doublet, J=4.5 Hz), 5.18-6.32 ~3H, multiplet)~ 6.72-7.52 ~3H, multiplet), 11~56 ~lH, singlet). ~
Elemental analysis ~CllHllO3Cl): '"
Calculated ~%): C, 60.98; H, 5.11 ~ound ~%~: C, 61.05; H, 5.06 Referential Example 2 One gram of l-methy'lsulfinyl-l-methylthio-2-~3'- ~
chloro-4'-allyloxyphenyl)ethylene was dissolved in 40 ml --o anhydrous ethanol, and under ice cooling, saturated with ' hydrogen chloride. The solution was then stirred at room temperature for 16 hours, and then the ethanol was evaporated. '~
Chloroform ~50 ml) and 10 ml of water were added, and the mixture shaken. The chloroform layer was separated, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled at reduced pres-sure to afford 700 mg ~83% yield) of ethyl 3-chloro-4- ~1 allyloxyphenylacetate as a colorless oil having a boiling '~ ' point of 139 C. ~0.7 mmHg).
The results of analyses were as follows:
IR ~liquid): 1730 and 1640 cm NMR (CDC13}~ 20 ~3H, triplet, J-7.5 Hz), .,~, , :
~` :

` 1~775Z~L

3.43 ~2H, singlet), 4.08 (2H, quartet, J=7.5 Hz), 4.51 (2H, doublet, J=4.5 Hz), 5.06~6.24 (3H, multiplet), 6.70-7.46 (3H, multiplet).
Elemental analysis (C13H15O5Cl):
Calculated ~%): C, 61.29; H, 5.93 Found (%): C, 61.33; H, 5.87 ;-Referential Example 3 --. .
One gram of l-methylsulfinyl-l-methylthio-2-~3'-chloro-4'-allyloxyphenyl)ethylene was dissolved in 20 ml of anhydrous ethanol, and 1 g of ethanol saturated with -~
hydrogen chloride was added. The mixture was heated under reflux for 20 hours. After cooling, 1 g of sodium hydroxide was added, and the mixture heated for 5 hours on a boiling water bath. After cooling, 50 ml of water was added, and the mixture washed with ethyl ether~ The aqueous layer was acidified with 20% hydrochloric acid. The crystals pre-cipitatsd were collected by suction filtration. Recrystal-lization from cyclohexane afforded 574 mg t77% yield) of 3-chloro-4-allyloxyphenylacetic acid having a melting point of 91 to 92C.

.

,.
, ~

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a l-alkyl(or phenyl)sulfinyl-l-alkyl (or phenyl)thio-2-(3'-chloro-4'-allyloxyphenyl)ethylene of the general formula (I) wherein R1 and R2 each represents alkyl of 1 to 3 carbon atoms or phenyl, which comprises reacting 3-chloro-4-allyloxybenzaldehyde with a formaldehyde mercaptal S-oxide of the formula RlSCH2SOR2 (III) wherein R1 and R2 are as defined above, in the presence of a base.

2. A l-alkyl(or phenyl)sulfinyl-l-alkyl (or phenyl)thio-2-(3'-chloro-4'-allyloxyphenyl)ethylene of the general formula (I) wherein R1 and R2 each represents alkyl of 1 to 3 carbon atoms or phenyl, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

3. A process for preparing l-methylsulfinyl-l-methylthio-2-(3'-chloro-4'-allyloxyphenyl)ethylene, which comprises reacting 3-chloro-4-allyloxybenzaldehyde with formaldehyde dimethyl mercaptal S-oxide in the presence of trimethylbenzylammonium hydroxide.

4. 1-Methylsulfinyl-1-methylthio-2-(3'-chloro-4'-allyloxyphenyl) ethylene, whenever prepared by the process claimed in claim 3, or by an obvious chemical equivalent thereof.

5. A process for preparing l-ethylsulfinyl-l-ethylthio-2-(3'-chloro-4'-allyloxyphenyl]ethylene, which comprises reacting 3-chloro-4-allyloxybenzaldehyde with formaldehyde diethyl mercaptal S-oxide in the presence of trimethylbenzylammonium hydroxide.

6. 1-Ethylsulfinyl-1-ethylthio-2-(3'-chloro-4'-allyloxyphenyl) ethylene, whenever prepared by the process claimed in claim 5, or by an obvious chemical equivalent thereof.

7. A process for preparing l-isopropylsulfinyl-1-isopropylthio-2-(3'-chloro-4'-allyloxyphenyl)ethylene, which comprises reacting 3-chloro-4-allyloxybenzaldehyde with formaldehyde diisopropyl mercaptal S-oxide in the presence of trimethylbenzylammonium hydroxide.

8. 1-Isopropylsulfinyl-1-isopropylthio-2-(3'-chloro-4'-allyloxy-phenyl)ethylene, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.

9. A process for preparing l-phenylsulfinyl-1-phenylthio-2-(3'-chloro-4'-allyloxyphenyl)ethylene, which comprises reacting 3-chloro-4-allyloxybenzaldehyde with formaldehyde diphenyl mercaptal S-oxide in the presence of trimethylbenzylammonium hydroxide.

10. l-Phenylsulfinyl-1-phenylthio-2-(3'-chloro-4'-allyloxyphenyl) ethylene, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.