DE1911539A1 - New benzylthio, benzylsulfinyl and benzylsulfonylbenzoic acids - Google Patents

Description

New benzylthio, benzylsulfinyl and benzylsulfonylbenzoe

acids.

The present invention relates to new benzylthio, benzylsulfinyl and benzylsulfonylbenzoic acids and their ver «*! Turn to lower the lipid level ini blood of mammals \ animals «ι

• ι

Atherosclerosis, a form of arterioeolerosis, is due to an internal thickening of the main blood vessels a local accumulation of lipids, mainly made up of Cholesterol and other ß-lipoproteins such as triglycerides ^ -, exist, · marked »It was also found that to the-i Patients suffering from this disease have abnormally high blood cholesterol «While the causes of the disease are not fully recognized, it is assumed that ß-

i Lipoproteins, especially cholesterol, play an important role ι

play, ι

In the advanced stages of the disease accumulate Cholesterol and other platelets containing ß-linnroteins in the aorta, coronary, cerebral, and peripheral frteries of the

lower extremities. If these particles get bigger, they increase the risk of fibrin deposition leading to thrombosis and occlusion can lead.

While no safe method for preventing the disease has yet been found, it has been recommended to ensure a low level of ß-lipoproteins through an appropriate diet. In addition to this diet, various therapies were

Il

tica such as estrogens, thyroxine analogs, and sitosterol supplements used to lower cholesterol.

It has now been found that various benzylthio, benzylsulfinyl and benzylsulfonyl benzoic acid "potent hypolipemic Represent agents because of their ability to lower the level of lipids in the blood of mammals. It can therefore the compounds are expected to be useful in treating the Atherosclerosis and other cardiovascular diseases that associated with increased blood lipid levels are useful.

The present invention relates to new compounds

of the following formulas:

CO ₂ H

in which R = CH-,

CF,

or -NO ₉ -X, 1 '

H, -CH ₃ , CH ₃ O-, -KO ₂ , Br, I,

F, Cl, -CF ₃ or CF ₃ SO ₂ -JR ^x = Cl, Br, F, -OGF ₃ , -OCH ₃ , CF ₃ SO ₃ -, (CH-OCH ₀ CHl) ₀ -NSO ₉ -, or (R ^? R ³ JNSO ₀ -,

where R and E ^{J represent} hydrogen, alkyl groups with up to 10 carbon atoms, aryl and arylalkyl groups with up to 10 carbon atoms, or together polymethylene or alkylpolymethylene groups with up to 15 carbon atoms, among which

? 3

Provided that B "and Tr do not mean hydrogen at the same time,

§09844 / 1779

R ^ = H, -CH ₃ , -CF ₃ , -NO ₂ , Cl, Br, F, -OCH ₃ , -OCF ₃ , CF ₃ SO ₂ -, (CHoOCH ₀ CH ₀ ) _o NS0 _o -, or ( R ² R ³ ) NS0 ₉ -,

J (L C. C η C C.

where R and R ^ have the above meaning ",

IT I

-0 - (. 0H ₂ ) X / N) -X

where X has the above meaning, η a number between 0

ft is 7 and 3 inclusive and R and R 'are hydrogen, lower alkyl groups of up to 6 carbon atoms, or one radical

6 7

mean, with the proviso that R and R 'are not both hydrogen if η = 0,

also R ₅ = -CHg-Q -'- naphthyl, -CHg-ß-naphthyl, -CH ₂ - ^ t-thienyl, or -CH ₂ -ß-thienyl

as well as the amides, lower alkyl esters and salts of the above compounds with bases.

The present invention also relates to a method for reducing the lipid content in the blood of mammals Oral or parenteral administration of a pharmaceutical preparation containing a compound of the following formulas:

'° 2 ^H

NS,

SO,

8098A4 / 1779

CO ₀ H

■ Χ,

CO ₂ H

CO ₉ H

and

wherein R ^, H ^ and X have the above meaning} instead of this Compounds can also be used their amides, lower alkyl esters and salts with pharmaceutically acceptable bases. i

The compounds of the invention can be prepared by various methods. The reproduced in Reaction Scheme I method, an appropriately substituted benzyl either is reacted with a halobenzonitrile or I halobenzoic acid in the presence of alkali, usually .Kalium- \ or sodium hydroxide. In some cases it is advisable to add a small amount of a copper catalyst. l

Reaction scheme I.

CN

¹ CH ₂ SH

1-

CO _? H

Hvdrol

ΟΟΘ8Α4 / 1779

J oxide. \

Oxide.

If

- oxide.

In the above scheme, Y means a cyano or carboxyl group!

to last

Best

while R and X have the above meaning. Instead of

can also be a radical R ⁵ SH, where R- * has the above meaning.

If a chlorobenzonitrile is used as the starting material, thus one usually makes the benzyl mercaptide by treating the benzyl mercaptan with an alkali metal alkoxide all in one lower alkanol, e.g. with sodium ethylate in ethanol. The alkali metal benzyl mercaptide is isolated and poured into anhydrous Dissolved dimethylformamide. The correspondingly substituted chlorobenzonitrile is then added to this solution (Scheme I). After that Reaction mixture was stirred to complete the reaction at room temperature, it is poured into water and the crude, substituted benzylthiobenzonitrile is mixed with a

QÖälU / 1779

Suitable solvent, generally ether, extracted. The solvent is then evaporated and the crude product is hydrolyzed by refluxing with an aqueous sodium hydroxide solution containing a little ethanol. After evaporation of the ethanol, the remaining oil is extracted with ether. When the ether evaporates, an oil is obtained which is suspended in water. The aqueous suspension is acidified and the substituted benzylthiobenzoic acid which separates out is isolated.

Instead of chlorobenzonitriles, as can be seen from Scheme I, substituted chlorobenzoic acids can also be used as starting materials. "In this case, the chlorobenzoic acid is heated for several hours with a benzyl mercaptan and a strong base, e.g. potassium or sodium hydroxide, and usually a small amount of copper powder. The reaction mixture is then cooled, filtered and diluted with mineral acid, then the substituted benzylthiobenzoic acid is isolated -t.

The benzylsulfinyl and benzylsulfonylbenzoic acids are formed by oxidation of the corresponding benzylthiobenzoic acids manufactured. If appropriate, the benzylsulfonylbenzoic acids can also be obtained from the benzylsulfinylbenzoic acids by means of further Win oxidation. These oxidations can be carried out with conventional oxidizing agents such as nitric acid, potassium pernanganate or chromium trioxide can be carried out; however, it is particularly recommended Hydrogen peroxide in glacial acetic acid or in formic acid »

Another synthesis of the compounds according to the invention is shown in reaction scheme II:

9Ö984A / 17 7 9

■ • Reaction scheme II

CO ₂ H

O ₂ H

SH +

jC JLsoch

CO ₂ H

¹ CH ₂ HaI

/oxide. ^ Oxide.

Oxide.

SO ₂ CH ₂ //

In the above scheme, Hai means chlorine, bromine or iodine, while R and X have the above meaning. Instead of the rest

can also be a remainder R% al, in which R ' ^{5 has} the above meaning.

According to Reaction scheme II is a substituted mercaptobenzoic acid with a substituted benzyl halide in an alkaline mixture of a lower alkanol and water implemented. In general, sodium carbonate is preferred as the alkali. After brief heating, most of the solvent is evaporated off and the residue is diluted with water. When acidifying with dilute mineral acid, the desired one separates substituted benzylthiobenzoic acid.

809844/1779

The corresponding Benzyisulfinyl- and Benaylsulfonylben *. Zoic acids can then be prepared as described above will*

There was also a new method of manufacture the Benzylsulfonylbenzoesäüien according to the invention developed ^ which is reproduced below i

Üeakt i pns sßhemä II ί

CO ₀ H

1 * ENT 2.

CCLH

-> R ~ j- -H-SO ₉ H

¹ W ¹

X- * R '

CHpHaI

° 2 ^GH 2

O-·

In the above scheme, FIaI means chlorine, bromine or iodine, while R and X have the above meaning. Instead of the rest

can ^ g

Bed au tv.nv owned »

"f ti ■" - ■■ c

a remainder of R-HaI, in which R- the above

§844 / 1779

In this process, the corresponding aromatic amino acid is diacetated in a mixture of tetrahydrofuran-water. Copper is suspended in the cold solution * and sulfur Field dioxide is introduced into the mixture with vigorous stirring. After standing for several hours, the organic layer separates which is concentrated to a small volume. Chloroform is then added to this concentrate. The mixture is discharged * cools and the sulfinobenzoic acid is filtered off. The connection is then in acetonitrile with a sufficient amount of the appropriate benzyl halide and a tertiary amine implemented, the sulfone-containing ester being obtained. Through its hydrolysis in acidic solution, the desired Benzylsulfonylbenzoic acid is formed.

Most of the compounds used to prepare the compounds according to the invention The starting materials used are from the literature known. The benzylic compounds used as starting materials and cinnamyl halides are expediently known per se Made from the appropriately substituted toluene * For example, benzyl and cinnamyl chloride can easily be reacted; of the appropriately substituted toluene or allylbenzene with chlorine, preferably under UV radiation, synthesized * The production is also by reacting the compounds mentioned with sulfuryl chloride in the presence of a peroxide possible.

The benzyl and Cinnamylbromide can be prepared similarly from the corresponding toluenes and Allylbenzolen by reaction with elemental bromine under illumination * Further, the production is possible by bromination with 0. N-bromosuccinimide in carbon tetrachloride in the presence of a small amount of peroxide. ■

The required arylalkyl halides can also be replaced by halo * Four people get a higher temperature here is required.

09844 / 177Θ

The mercaptans are expediently prepared from the corresponding halides, which are first treated with thiourea in heated absolute ethanol, whereupon with further heating aqueous Sodium hydroxide solution is added. The bulk of the ethanol is evaporated off under reduced pressure and the remaining aqueous solution is acidified, the mercaptan is extracted with ether and purified in a manner known per se.

The sulfamylhalobenzoic acids used in Reaction Scheme I are obtained by chlorosulfonation of a halobenzoic acid and then / treatment of the resulting product made with the corresponding amine.

The required reactive halogen (see Reaction * scheme I) can be converted into the phenyl ring by diazotizing the amino group of an appropriately substituted aminobenzoic acid and treating the resulting diazonium salts; be formed with an inorganic halide, for example the Ausgan ^cr Pmaterial is 3-iodo-5-trifluoromethyl-benzoic acid by diazotization of 3-amino-5-trifluoromethyl-benzoic acid and treating the resulting diazonium salt with potassium iodide prepared.

The mercaptobenzoic acids used according to Re ^o .ktionsschema II are also prepared from the corresponding aryldiazonium salts. These diazonium salts can either be reacted with sodium sulfide to form an aryl disulfide, which on reduction with zinc dust-acetic acid gives the desired mercaptobenzoic acid, or with potassium ethylxanthate, which then leads to a phenyldithiocartonate which, after decomposition in an alkaline solution, also gives the desired product .

The amides, lower alkyl esters and various pharma- ^; Zeutically permissible salts of the inventions described above. Compounds according to the present invention are also effective agents for reducing the level of lipid levels in the blood of mammals. Although the pharmacological effect of the molecule appears from the anion,

909844/1779

SAD

it is necessary to use a salt with a pharmaceutically acceptable cation. Usually, one works with cations such as ammonium, ⁿ atrium, potassium, calcium and magnesium ions. The salts of the compounds described above are prepared in a known manner, for example by adding the acid to an aqueous solution which contains an equivalent amount of a pharmaceutically acceptable base, ie a base which contains one of the above cations, and then concentrating the resulting solution Mixture. Hydroxides, carbonates and bicarbonates are suitable as bases. While salts with pharmaceutically unacceptable bases cannot be used in therapy, they can still be used to purify the above compounds and also to produce pharmaceutically acceptable salts.

For example, a crude acid can be purified by you can not use them in an aqueous solution of a pharmaceutical grade permissible base dissolves and the resulting solution is extracted with a suitable organic solvent to avoid the « remove acidic impurities. By acidifying the remaining Solution, the pure acid is deposited ^ & i © can be filtered. In the manner described above, this acid can then be converted into a pharmaceutically acceptable salt to be convicted »

The esters and amides can also be prepared by processes known per se. The esters are expediently formed by refluxing the acid in the corresponding alcohol, which contains a small amount of acid as a catalyst " In general, any lower alkyl ester can be used, but for practical reasons it follows that si * Esterj * from alcohols with one lying above butanol Molecular weight does not bring any advantages. The amides are conveniently prepared from the esters by converting the latter treated in alcohol in ammonia.

As already mentioned, the benzyl according to the invention are

thio-, benzylsulfinyl- and benzylsulf'onylbenzoic acids and their pharmaceutically acceptable salts, lower alkyl esters and amides are effective hypolipemic agents, ie they lower the lipoid level in the blood of mammals. This property has been proven in Hatten. Groups of four animals each (male Sprague-Dawley (Charles River) rats from 160 to 220 g) were fed a diet containing 0.25% of the compounds described above for two feeding periods of one night each. On the morning of the third day, the animals were anesthetized and bled from the abdominal aorta. - The total plasma cholesterol was then determined according to the method of JJ Cari * and IJ Drekter, Glin. Chem., 2_, 353 (1956). The plasma alcohol esterol content of the treated animals was significantly lower than that of the animals that had not received the test compounds.

The ability of the compounds according to the invention to lower the content of fiX triglycerides in the blood was demonstrated in an experiment with dogs. A dose of 50 to 100 mg / kg of the solid compound in gel capsules was administered to the dogs twice a day. The treatment was continued for two weeks and blood cholesterol and triglyceride levels were determined every other day. The colesterol content was determined by the method given above, while the triglyceride content was determined by the method of E, Ven Handel and D. B, Zilversmith, J. lab & Clin & Med, £ 0, 152 (1957).

When comparing the triglyceride content of the blood "of dogs, who received the test compounds with the triglyceride content in the blood of untreated animals it was found that the test compounds had caused a noticeable reduction.

In the case of oral administration in capsules, one uses as Excipients are preferably lactose or high molecular weight polyethylene glycols. In aqueous suspensions, the active ingredients are with

Emulsifiers and / or suspending agents combined. Diluents such as ethanol, propylene glycol, glycerin and various Mixtures of diluents can be used.

A typical dosage form for oral administration People has the following composition:

2-Benzylthio-5-trifluoromethyl-benzoic acid 255.00 mg.

Corn starch, dry 17.50 mg.

Lactose 163.50 mg,

Magnesium stearate 17.10 mg,

Sodium Lauryl Sulphate 1.90 mg,

455.00 mg.

The compounds according to the invention can be administered both parenterally and orally. For parenteral administration, solutions or suspensions in sesame or peanut oil or in aqueous propylene glycol are used. Sterile aqueous solutions of corresponding water-soluble salts are particularly suitable. These dosage forms are particularly suitable for intramuscular and subcutaneous injection. Aqueous solutions, including salt solutions in pure distilled water, are also allowed. intravenous injection provided that the pH is adjusted accordingly. Such solutions should, if necessary, be appropriately buffered and the liquid diluent must have been made isotonic with saline or glucose. Appropriate sterile aqueous media can easily be produced in the usual catfish. For example, distilled water is used as a diluent, Ψ

the Inalösung through a suitable bacterial filter such as a GIA tilter or a filter of diatomaceous earth or unslasiertem Pöi-iäellan · Preferred filters of this type are the Berkfeld- and CIfI ^ iiiberland-filter and the Seitz filter, wherein the fluid through a Jt Filter candle is conveyed through a sterile container with the aid of a suction pump lL. Of course, aseptic conditions must always be observed in the preparation of these injection liquids

The dose required to reduce the lipid content depends on the nature and extent of the symptoms. In general, small doses are administered first, which are gradually increased until the optimum value is reached. In the case of oral administration, larger amounts of the active ingredient must generally be used In order to achieve the same effect as the smaller amounts with parenteral administration, noticeable effects are generally achieved with about 100 to 500 mg of the active ingredient per kg of body weight, in the form of one or more Ddisis units. The average effective daily dose is ■ in humans with oral or par «» enteral administration between about O ₉ 30 and 3.0 g per day «

Manufacture of the raw materials

^ .General Method for Making the Benzyl and Cinnamyl

mercaptaii © from the corresponding halides,.,

₈ O 50 moles TUs entspFeehenden Bensyl- or Ginnamylhalogenids

about three pieces of itlianol are boiled for a long time .O ₈ 50 mol of thiourea in about 250 to ΗΌ0 ml of absolute itlianol under reflux. Then about 300 ml of a 1 Origan £% tPiiirafaydr oxy solution of the resulting. Solution suggested, unfi fiss G-eiaisch is refluxed for a further two hours.

The bulk of the ethanol is "removed at reduced pressure and the aqueous mixture is a" bgekühlt _p UNAE acidified with sulfuric acid with ether extracted The ether extracts and evaporated dried over anhydrous sodium sulfate, The remaining crude mercaptan is then purified in a conventional manner.

B. Preparation of sulfamylbenzoic acids

117 g (1.00 mol) of chlorosulfonic acid are added to 31 g (0.20 col) of o-chlorobenzoic acid. The mixture is heated for five hours at 95 ⁰ G and overnight at room temperature "" left is then gently poured into ^ 00 ml of ice water and which separates crude 2-Ghlor »5-chloFsulfonylbenzoesäure is filtered off and washed with water (F ₉ 3Λ "7-14 · 9 ° Ο) -»

§ ö § a ukf 17 7 §

The crude acid is dissolved in 4-00 ml of hot chloroform and dried first over sodium sulfate and then over magnesium sulfate. The solution is evaporated to dryness and the crude acid is then placed in 300 ml of liquid ammonia, which is in a 1 liter Erlenmeyer flask. The mixture is stirred until all of the ammonia has evaporated. The gummy residue is then dissolved in water and the mixture is acidified with 6N hydrochloric acid. The melting point of the filtered, crude 2-chloro-5-ßulfamylbenzoesäure is ⁰ to 212 C. After recrystallization from water, the melting point 217-219 ° Cj yield 19 g.

Using the appropriate amines, the following compounds are produced according to the above procedure * 2-chloro-5-tf-i-n-hexylsulfamy! Benzoic acid, 2-chloro-5-di-isopropylsulfamylbenzoic acid, 2-chloro-5-diethylsulfamylbenzoic acid, 2-chloro-5-dimethylsulfamylbenzoic acid, 2-chloro-5- <li-n-decylsulfamy! Benzoic acid, 2-chloro-5-di-n-dodecylsulfamy! Benzoic acid, 2-chloro-5-cLi-n-hexadecylsulfamy! Benzoic acid, 2-chloro-5-diphenylsulfπmy! Benzoic acid, 2-chloro-5-di-p-tolylsulfaniy! Benzoic acid, 2-chloro-5-c-libenzylsulfamylbenzoic acid, 2-chloro-5-di- (ß-p-tolylethyl) -sulfamylbenzoic acid, 2-chloro-5-di-C ^ -naphthyl) sulfamyl benzoic acid, 2-chloro-5-N-phenyl-N-ethylsulfamylbenzoic acid, 2-chloro-5-N-p-tolyl-N-n-hexadecylsulfamy! Benzoic acid, 2-chloro-5-N-benzyl-N-ethylsulfamy! Benzoic acid, 2-chloro-5-N-naphthyl-N-phenylsu.lfamy! Benzoic acid, 2-chloro-5-di- (p-isopropylbenzyl) sulfamylbenzoic acid, 2-chloro-5-N-ethylsulfamylbenzoic acid 2-chloro-5-N-phenylsulfamylbenzoic acid 2-chloro-5-N-p-tolylsulfamylbenzoic acid

80§§44 / 1778

Further, the following acids are obtained by the above method

COpH obtained:. ''

R ²

NSO ₉

² and. R ^ » · connection

-CHpCHp- 2-chlorine ~ 5-N, N-ethylene-

^{ά d} . sulfamylbenzoic acid

- (CHp) ₁ , - 2-chloro-5-N, N-tetramethyl-

^^ en-sulfainylbenzoic acid

- (CHp) ₁ - 2-chloro-5-N, N-pentamethyl-

^ * en-sulfamylbenzoic acid

Jo-CH (CpHj- 2-ρωοΓ-5-Ν, Ν- (ΐ ', 5 ¹ - - ^ diethylpentamethylene ^ ·

sulf ^ my! benzoic acid

2-chloro-5-N, N-decamet.hylen- * ~ ^{αν /} sulfamylbenzoic acid

- (CH J ₁₉ - 2-chloro-5-N, N-dodeca-

methylene sulfamy! benzoic acid

-CH (nC _q H ₇ ) -CHp-CH (nC ₃ H ₇ ) -CH ₂ CH (nC ₃ H ₇ ) -

2-chloro-5-N, N- (l ^f , 3 ^l i5 ^t tri-n-propyl ^ -pentamethylene} · sulfamylbenzoic acid

-CH (n-CoH ₇ ) - (CHp) ₇ -CH (n-CoH ₇ ) -2-chloro-5-N, N- (1 ', 8'-di- -''' - 'n-propylfr -nonamethyleny-

sulfamylbenzoic acid

-CHp-CH (CH ₃ ) - (CHp) p- 2-chloro-5-N, N- (2'-methylfr-

^J tetramethylene) ~ sulfamyl-

benzoic acid

-CH-CH (CpH.) - (CHp) o- 2-chloro-5-N, N- (2'-ethy1fr-

~ pentamethylene ^ sulfamyl-

benzoic acid.

Co Her ^ telliang of the activated haloerene benzoic acids

4.2 e- (0.0205 mol) 3-amino-trifluoromethylbenzoic acid are mixed with 35 ml of water and 29 ml of OH-sulfuric acid in e? N O ^ misoh. Then, the mixture is heated for a few minutes on the steam bath and then cooled to 3 ⁰ C "Then, a solution of 1.5 g (0 ^ 021? Mol) of sodium nitrite in 10 ml water

Ο04ί * 4 / Ι7ϊβ BADora _{Q (NAL}

- Ί8 -.

added over 10 minutes. The resulting mixture is stirred for one hour at a temperature below 5 ° C.

This mixture is then added to a solution of 9.3 g of potassium iodide in 10 ml of water containing 50 mg of copper metal. The resulting mixture is stirred at room temperature for one hour and then heated to the boil and kept at this temperature for 15 minutes with stirring. It is then filtered and the crude 3-iodo-5-trifluoromethylbenzoic acid is washed with water. The yield is 5.2 g. The crude acid is by sublimation at 135 ° C. / O _t cleaned mm O5, P. 180 g to 181 ⁰ C, yield 4.5.

Anal. Ber. for C ₈ Hj ₊ P ₃ IO ₂ : C; 30.40; H; 1.28. Found: Cs 3O.74j, H: 1.14.

The following compounds are also produced using the above process manufactured:

3-Niro-5-iodbenzoese.ure 3-trifluoromethoxy-5-joabenzoes ^ ure 3-trifluoromethylsulfonyl-5-iodo-benzoic acid 3-Dimethylsulfamyl-5-iodobenzoic acid, 3-di-n-butylsulfamyl-5-iodobenzoic acid 3-Di-n-hexylsulfamyl-5-iodo-benzene acid

3-di-isopropylsulfamyl-5-, iodo-benzoic acid 3-diethylfulamyl-5-iodo-benzoic acid

3-di-n-decylsulfamyl-5-iodo-benzoic acid ^ -Di-n-dodecylsulfamyl - ^ - iodo-benzoic acid 3-Bi-n-hexadecylsulfamyl-5-, iodo-benzoic acid 3-diphenylsulfamyl-5-iodo-benzoic acid 3-Di-p-tolylsulfamyl-5-iodo-benzoic acid 3-Dibenzylsulfamyl-5-iodo-benzoic acid -

3-di- (ß-p-tolylethyl) sulfamyl-5-iodobenzoic acid 3-di- (oi-naphthyl) -sulfamyl-5-iodo-benzoic acid 3-K * phenyl-N-ethylsulfamyl-5-iodo-benzoic acid 3 », N-, p-toly; l-N-n-hexadecyl-sulfaniyl-5-iodo-benzoic acid ß-N-Benzyl-N-ethylsulfamyl ^ -iodo-benzoic acid

3-N-Naphthy1-N-phenylsulfamyl-5-iodo-benzoic acid, 3-di- (p-isopropyrbenzyl) -sulfamyl-5-, iodo-benzoic acid 3-N, N-ethylene sulfomyl-5-iodo-benzoic acid 3-N , N-Tetramethylene sulfamyl-5-'30a-benzoic acid 3-N _f N-pentamethylene sulfam3rl-5-iodo-benzoic acid 3-N, N- ( ^{1.5 t} -diethylpentamethylene) f? Ulfamyl-5-iodo-benzoic acid '

3-N, N-decamethylene sulfamyl-5-iodo-benzoic acid 3-N _f N-doaecamethylene sulfainyl-5-iodo-benzoic acid

3-N, H- (I, 3, 5 ^l -Tri-n-propyl) -pent8methylene sulfamyl-5-

3-N, N- (.1 ·, 8 · -Di-n-propyl) -nonamethylene sulf n my 1-5-Iodo-benzoic acid

3-N _> N- (2 ^l -methyl) -tetramethylene-sulfamyl-5-iodo-l) enzoic acid 3-N, N- (2 -ethyl) -pentamethylene sulfamyl-5- iodo-benzoic acid 3-N-ethylsulfamyl-5 -iodo-benzoic acid 3-N-phenylsulfamyl-5-iodo-benzoic acid 3-Np-tolylsulfamyl-5-iodo-benzoic acid

D. Preparation of mercaptobenzoic acids

1. Mercado-benzoic acid from aryl disulfides

To 95 ml of boiling water are 86 he (0.355 mol) Na _? S. 9H ₂ O and 11.2 g of sulfur powder to-rpfreben. When the solution is complete, 13 μl of sodium hydroxide (0.33 Hol) in 33 ml of water are added, and the repeating solution is ^{cooled to 0} ° C. and set aside.

In a mixture of 165 ml of water and 66 ml of concentrated hydrochloric acid four 50 g (0.331 I ⁴ O) of 5-He thy! Anthranilic acid are added. The mixture is cooled to about 0 ° C., and then a solution of 23 c (0.331 kol) of nitrium nitrite in 93 ml of water is introduced under vigorous stirring over the course of about 10 minutes below the surface of the mixture. It is ensured that the temperature de. *? Mixtures below 5 ° C remains, and for this purpose about 200 ρ crushed ice are added in the course of the addition of the sodium nitrite solution.

The resulting solution then becomes the above

Prepare 0 solution in the course of 20 minutes at 0 C for 30 minutes.

fiöÖÖU / 1779

During the Zuagbe ice to keep the temperature of the mixture 'at about O ⁰ G is added sufficient.

The resulting solution is then allowed to come to room temperature and stir for 2 hours. Then up to the congo red endpoint acidified with about 50 ml of concentrated hydrochloric acid. The crude 2,2'-dicarboxy-di-4-tolyl-disulfide that separates out is collected and washed with water. The sulfur impurities it contains are removed by dissolve in e-infl-r solution of 20 g sodium carbonate in 660 ml water, the mixture is heated and the remaining sulfur is filtered off triert. The filtrate is acidified with concentrated hydrochloric acid and the precipitate is dried, giving 66 g of 2,2'-dicarboxy-di-4-tolyl disulfide receives.

This compound is then added to a mixture of ^ 5 g zinc * dust in 500 ml glacial acetic acid. The mixture is refluxed for about k hours, the mixture is cooled and the crude acid is filtered off. This crude product is dissolved in hot, aqueous sodium hydroxide solution and the resulting solution is filtered depositing 5 ~ Kethyl-2-mercaptobenzoic acid is collected, washed with water and dried in vacuo at k-5 ° C dried "The yield is 23 g, P. 16'3-16 ^ ^O C.

The following acids are also prepared from the corresponding starting materials by the above process s 2-chloro-2-mercaptobenzoic acid,
2-bromo-2-mercaptobenzoic acid,
5-fluoro-2-mereaptobenzoic acid,
5-trifluoromethyl-2-mercaptobenzoic acid, 5-methoxy-2-mercaptobenzoic acid,

5-trifluoromethylsulfonyl-2-mercaptobenzoic acid, 5-nitro-2-mercaptobenzoic acid, 5-trifluoromethoxy-2-mercaptobenzoic acid, ^ -Di-n-hexylsulfamyl ^ -mercaptobenzoic acid, 5-di-n-hexaecylsulfamyl-2-mercaptobenzoic acid,

5-Diphenylsulfamyl-2-mercaptobenzoic acid, 5-Dibenzylsulfamyl-2-mercaptot> en2oesäure, 5-N-phenyl-N-2-äthylsulfamyl.-mercaptobenzoic acid, 5-N-benzyl-N-äthylsulfamyl-2-mercaptot) enzoesäure _l 5 -N, N ^T etramethylensulfamyl-2-mercaptobenzoösäure,

5-N, N-pentamethylene sulfamyl-2-mer-captobenzoic acid,

5-N, N- (2 · -Methyl) -te tramethylene sulfamyl-2-mereaptot) enzoic acid

5-N, N- (2'-ethyl) -pen tame thy lensulf amyl-.2-.mercapto'benzoic acid,

^ -Chlor-2-mercapto'benzoic acid, ^ -Brora ^ -meroaptobenzoesaure ^ -Pluoro-2-mercaptobenzoic acid, 4-trifluoromethyl-2-mercaptobenzoic acid, 4-methoxy-2-mercaptobenzoic acid il'-trifluoromethyl-nitro-benzoic acid 4-mercaptobenzoic acid 2-mercaptotienoic _{acid f} ^ -trifluoromethoxy-2-meroaptobenzoic acid, 4-di-n-hexylsulfamyl-2-mercaptobenzoic acid, ^ -di-n-hexadecylsulfamyl ^ -mercaptobenzoic acid, k- diphenylsulfamyl-2-mercaptlenz-sulfamyl-2-meroobaptyl-benzoic acid , ■ ^ -N-Phenyl-N-äthylsulfarayl-H-mercaptobenzoic acid, ^ _N-Benzyl-N- ^ thylsulfarayl-2-meroaptobenzo, esic acid, 4-NjN-tetramethylene sulfamyl ^ -mercaptobenzoic acid, 4-N, N-peiitamethylene sulf amyl 2-meroaptabenzoic acid,

4-N, N- (2'-methyl) -tetramethylene sulfamyl-2-mercaptobenzoic acid, ,

^ -N, N- (2-ethyl) -pen tame thy lensulf ainyl-2-inercaptobenzoe-. acid,

5-chloro-3-mercaptobenzoic _{acid f} 5-brine-3-mercaptobenzoic acid, 5-fluoro-3-mercaptobenzoic acid, 5-trifluoromethyl-3-πlercaρtobenzoic acid, 5-methoxy ~ 3-mercaptobenzoic acid, 5-N-ethylsulfamyl-3-benzoic acid, 3-benzoic acid 5-N-phenylsulfamyl-3-mercaptobenzoic acid, 5-Np-tolylsulfamyl-3-inercaptobenzoic acid,

19TT539

5-trifluoromethylsulfonyl-3-roercaptobenzoic acid, 5-nitro ~ 3-mercaptobenzoic acid, 5-tifluoromethoxy-3-mercaptobenzoic acid, 5-di-n-hexylsulfamyl-3-mercaptobenzoic acid _{f 5-di-n-hexadecylsulfamyl-3-enzoic acid} 5-diphenylsulfamyl-3-mercaptobenzoic acid,

5-DitιenzyXsulfarayl-3-mercaptobenzoic acid, _

5-N-PhenyX-N-äthylsulfaInyi-3-InercaptobenzoesäuΓe, 5_N-Benzyl-N-ethylsulfamyl-3-mercaptobenzoic _{acid, 5-iN i} N-Tetramethylene sulfamyl-3-niercaptobenzoic acid, 5-N-mero-pentamethylene-benzoic acid, 5-N-mero-pentamethylene

5-N | N- (2'-methyl) -tetramethylene sulfamyl-3-mercaptobenzoe acid,

5-N, N- (2 '-ethyl) -pen tame thylenesulfamyl-.3-mer cap to ^ enzoic acid,

3-chloro-4-mercaptobenzoic acid,

3-fluoro-4 »raercaptobenzoic acid, 3-trifluprmethyl-i (- mercaptobenzoic acid, 3-methoxy - ^ - mercaptobenzoic acid, 3-trifluoromethylsulfonyl-4-mercaptobenzoic acid, 3-nitro-4-mercaptobenzoic _{acid f} S-trifluoromethapoxy - ,. 3-Di-n-hexylsulfamyl-fr-mercaptobenzoic acid, 3-di-n-hexaάeoylsulfamyl-i ^ -mβrcaptobenzoic acid, 3 * biphenylsulfamyl - ^ - mercapfcobenzoic acid, 3-dibenzylsulfarayl - ^ - phenyl-3-naptobenzoic acid -äthylsulfamyl-4-meΓcaptobenzoic acid, 3-N-Ö! enz | rl-.N-ethylsulfainyl - ^ - mercaptobenzoic acid, 3-N "H" ^f ^ e tramethylene sulfamyl - ^ - mercaptobenzoic acid 3-N | N-pentamethylene-sulfamyl-4 -Inercaptobenzoic acid,

3-N _f N- (2 ^l -methyl) «tetraraethylene sulfamyl-4-mercapt6benzpic acid,

3-N, N- (2'-ethyl) pentamethylene sulfamyl - ^ - mercaptobenzoic acid

2. Mercaptobenzoic acids from the Aryläthyldithiocarbonaten.

To a mixture of 48 ml of 1N hydrochloric acid and 70 ml of methanol 4.1 g (0.02 mol) of 2-amino-4-trifluoromethylbenzoic acid are obtained

001 * 44/177 $

admitted. The resulting equipment is cooled to about 3 ° C., then 1.4 g (0.02 mol) of sodium nitrite, dissolved in 15 ml of water, are added over the course of about 5 minutes. The temperature of the mixture is kept below 5 ° C. during the addition. The resulting mixture is stirred for a further 10 minutes at about 4 to 5 ^° C. and then in the course of 5 minutes to a solution of 3.7 g (0.023 mol) of lialiumethylxanthate and 1.3 g of potassium hydroxide (O ₉ 02 mol) in 50 ml Water that had previously been warmed to around 40 ° C is added * During the addition,. the temperature of the reaction mixture between 35 and 4O ⁰ C. When the addition is complete, the resulting mixture is stirred at 40 G for half an hour. Then, the methanol is evaporated at 40 ⁰ C and the zurückblelebende solution is acidified with concentrated hydrochloric acid and extracted with ether · The Äth @ rextrakt is separated, washed with water and evaporated to dryness. The residue is triturated with 20 ml of η-hexane and then filtered _? 1.4 g of 2-carboxy-5-trifluoromethylphenyl-ethyl carbonate are obtained

To a solution of 5 g of sodium hydroxide in 20 ml of water, 3.4 g of 2-carboxy-5-trifluorometh; flpli © nFX ethyl dithiocarbonate are added. The mixture is refluxed under a nitrogen atmosphere for 4 1/2 hours and filtered. The piltrate is acidified with concentrated hydrochloric acid, and the 2-mercapto-4-trifluoromethylbenzoic acid which separates out of the solution is isolated and washed first with water and then with n-hexane. After drying in a drying oven of a product of melting point 157-162 ⁰ C. to obtain 2.4 g of

The mercaptobenzoic acids listed in Section D 1 can also be produced using this process *

example 1

12.4 g (0.10 mol) of eenzyl mercaptan are added to 100 ml of ethanol admitted. While passing nitrogen through the solution, 100 ml of a 1 molar sodium ethylate solution are added. in ethanol ' to. The solvent is then evaporated and the crude, solid Na.triummercap.tid is mixed with 100 ml of anhydrous dimethylformamide

Ö44 / .17TÖ

■ - 24 -

offset. The resulting solution is then 21 g (0.10 mol) ^ -Chlor-3-cyanobenzotrifluoride added · The reaction mixture is stirred under nitrogen at room temperature for half an hour and then poured into about 800 ml of ice water. After 5 minutes Stirring this mixture is extracted four times with 200 ml of ether each time.

The extracts are combined, dried over anhydrous sodium sulfate and evaporated to give, after drying under high vacuum, a pale yellow oil which crystallizes to a pesticide on standing. In this way, 27.4 g (9h%) of 2-benzylthio-5-trifluoromethyl-benzonitrile are obtained,

In about 15 ml of ethanol 17.5 g (0.06 mol) of the above raw compound is added, then 200 ml of 20% sodium «! · hydroxide solution added. ·

This reaction mixture is refluxed for about 27 hours. After removing most of the ethanol under reduced pressure, the oil present in the aqueous phase is extracted with 3 portions of 200 ml of ether each. The ether extracts are combined and evaporated, the remaining oil is suspended in about 500 ml of water. This suspension is acidified with 6N hydrochloric acid and the white solid which separates out is filtered off. This gives 15.7 g (Bk%) of 2 'benzylthio-5-trifluoromethyl-benzoic acid of melting point I69 "17 ^ ^O C. After recrystallization from benzene the melting point is 180-181 ⁰ C.

Neutralization equivalent 315 Theoretical value: 312

Anal. Ber. for ^ 5H ₁₁ F ₃ O ₂ Si Cs 57.68j H: 3.55 Found: C: 5Ί M \ H: 3.6k

Using the appropriate starting materials, the following compounds are produced according to the above processί

s CO ₂ H 3'-trifluorom * 165-166 "C; ^ X Elemental analysis H Found H ^ SCH ₉
Ί I thyl 2 ' Ber. C. - ■ V C. 2.91 - 2.91 , - 4.01 52.24 4.22 51.95 3.83 59.12 3.90 F. ⁰ C 58.89 3.83 56.53 3.80 X 192-195 5 ■ 56.13 2.91 56.10 3.01 3'-methyl 183-184, 5 56.13 51.75 4'-chlorine 177-178, 5 51.95 3.27 3.18 4'-methyl 174-175, 50.34 4'-methoxy 207-209 ' 5 50.53 2'-methoxy 160-161, 3'-chlorine

2- i0cU-naphthylmethylenthio) -5-trifluoromethybenzoic acid,

F. 229_231 "C.

Anal. Ber. for Gef .:

C: 63.33, 'H: 3.63 C: 63.20} H: 3.67

CF

3—!

1"

Elemental analysis

H ⁰ R * χ F .. ⁰ G Ber. H Found H η H CH ₃ H 140-142 C. 4.01 C. 4.07 0 H H H 161-162 58.89 Wed 58th, 61st 4.06 Ι H C ₉ H ₆ F. Ι34-Ι39 58.89 4.44 39.25 4.50 Ο H H H 138-140 59.99 4.44 60, 05 4.85 2 59.99 60, 02

Furthermore, the following compounds were made according to the above ver * drive manufactured:

2- (3'-trifluoromethylbenzylthio) benzoic acid

2-benzylthio-benzoic acid,

3-benzylthio-benzoic acid,

3- (4'-chlorobenzylthio) benzoic acid,

2- (4 "-Bromobenzylthio) -5-trifluoromethylbenzoic acid 2- (2'-Pluorbenzylthio) -5-trifluoromethylbenzoic acid 2- (4'-Ni trobenzylthio) -5-trifluorme thybenzoic acid

2- (4 ¹ -trifluoromethylsulfonylbenzylthio) -5-trifluoromethylbenzoic acid

2- (3'-iodobenzylthio) -5-trifluoromethylbenzoic acid 2- (β-Naphthylmethylene thio) -5-trifluoromethylbenxes & are 2- ((& -Thienylmethylene thio) -5-trifluorme thy! Benzoic acid 2- (ß-Thienylmethylene thio) -5-trifluorme thylbeiizoic acid

HO 3-Cl

CH ₃ CH ₃ O

O 4-Br

4'-TolyI O 4'-CH ₃ OC ₆ H ₄ O 3'-CF ₃ C ₆ H ₄ O

H 1

riTT a

^> Πλ J.

CH ₃ 1

C ₆ H ₅ 2

4-CH _q O 2-CH ₃ O 4-CH ₃ 3-1 4-F 3-CF ₃ ^S0 2 4-NQ ₂ 3-CF ₃ SO ₂ 3-F ' H

2 H

R ⁶ R ⁷ η -Χ

HH 3 H

n «C ₅ H _u CH ₃ 3 4-CF ₃ SO ₂

C ₆ H ₅ C ₆ H ₅ 3 2-CH ₃

H 'C ₆ H ₅ . 3 3-CP ₃

4 ^β -ClC ₅ H ^ 4'-ToIyI 3. 3-NO ₂

Example 2

To 250 ml of dimethylformamide 10.1 g (0.05 mol) of 2-chloro-5-nitro-benzoic acid, 7 (3 g (0.05 mol) of m-methylbenzyl mercaptan, 150 ms copper powder and 6.6 g potassium hydroxide added »

The resulting, brown-yellow suspension is heated ^{to 125 ° C. in an oil bath for about 16 hours.} The reaction mixture is then cooled and filtered. The piltrate is poured into about 500 ml of cold 6N hydrochloric acid, and the yellow precipitate which forms is filtered off and washed with water. A yield of 10 ₀ 3 g (66%) _{0 is obtained.} This material is recrystallized from ethanol, whereby 3 g 7 g (36 $) of 2- (3'-methylbenzylthio) -5-nitro-benzoic acid with a melting point of 238-240 ° / C receives.

Anal. Ber. for C ₁₅ H ₁₃ NQ ^ Si, C: 59 * 2? Hi 4.27J N: 4.58 Gef.j Cj 59.68j H; 4.49f Nj k _t 5 &

From the appropriately substituted benzyl mereaptanes and benzoic acids, the following compounds are easily made J

2-Benzylthio-5-nitrobenzoic acid, 2- (3'-KethZ ^ OXybenZylthio) -5-nitrobenzoic acid, 2- (4 "- bromobenzylthio)""5-nitrobenzoic acid, 2- (4'-chlorobenzylthio) -5-nitrobenzoic acid , 2- (3'-fluorobenzylthio) -5-nitrobenzoic acid, 2- (3 ^l -iodobenzylthio) -5-nitrobenzoic acid, 2- (4'-nitrobenzylthio) -5-nitrobenzoic acid,

2- (4'-trifluoromethylsulfonylbpnzylthio) -5-nitrobenzoic acid, 2- (3'-trifluoromethylbenzylthio) -5-nitrobenzoic acid,

2- (oC-N3phthylmethylenthio) -5-nitrobenzoic acid,

906644/177 0

ILL NO.

NO. NO,

2- (ß-Naphthylmethylene thio) ~ 5-nitrobenzoic acid, 2 - (# - thienylmethylene thio) -5-nitrobenzoic acid, 2- (ß-thienylmethylene thio) -5 ~ nitrobenzoic acid, 2-benzylthio-5-trifluoromethoxybenzoic acid, 2- (3 '- Methylbenzylthio) -5 - »** i» e-trifluoromethoxybenzoic acid, 2- (4'-trifluoromethylbenzylthio) -5-trifluoromethoxybenzoic acid, 2- (3'-nitrobenzylthio) -5-trifluoromethoxybenzoic acid, 2- (2'-fluorobenzylthio) - 5-trifluoromethoxybenzoic acid, 2- (3'-methoxybenzylthio) -5-trifluoromethoxybenzoic acid, 2- (4 ^l -chlorobenzylthio) -5-trifluoromethoxybenzoic acid, 2- (4'-bromobenzylthio) -5-trifluoromethoxybenzoic acid, 2- (4 ^l- iodobenzyl ) -5-trifluoromethoxybenzoic acid,

2- (3'-trifluoromethylsulfonylbenzylthio) -5-trifluoromethoxybenzoic acid,

2-benzylthio-5-trifluoromethylsulfony! Benzoic acid,

2- (3-methylbenzylthlo) -5-trifluoromethylsulfonylbenzoic acid,

2- (4'-trifluoromethylbenzylthio) -5-trifluoromethylsulfonylbenzoic acid,

2- (5 -Ni trobenzylthio> -5-trifluoromethylsulfony Ibenzoic acid _a 2- (2'-fluorobenzylthio) -5-trifluoromethylsulfony! Benzoic acid,

2- (3'-Methoxybenzylthio) -5-trifluoromethylsulfonylbenzoic acid,

2- (k • -chlorobenzylthio) -5-trifluoromethylsulfonylbenzoic acid, 2- (4'-bromobenzylthio) -5-trifluoromethylsulfonylbenzoic acid, 2- (4 * -iodobenzylthio) -5-trifluoromethylsulfonylbenzoic acid,

2- (3'-trifluoromethylsulfonylbenzylthio) -5-trifluoromethylsulf ony! benzoic acid

2 3

CH

-TpIyI

O
O
O

3-Cl 2-CH ₃ O

00084Α / Ί77 & -

Si
NO ₂

NO
NO
NO

NO ₂ NO ₂ NO ₂ CP ₃ O CP ₃ O CP ₃ O CP ₃ O CP ₃ O CP ₃ O CF ₃ O CF ₃ O CP ₃ O CF ₃ O CF ₃ O CF ₃ O CF ₃ SO ₂ CF ₃ SO ₂ CF ₃ SO ₂ CP ₃ SO ₂ CP ₃ SO ₂ CP ₃ SO ₂ CF ₃ SO ₂ CF ₃ SO ₂ CF ₃ SO ₂ CF ₃ SO ₉ CP ₃ SO ₂ CF ₃ SO ₉

₃ η- C ₄ H ₉

4'-BrC ₅ H ₄ 2 "-CH ₃ OC ₅ H ₄ HH 2 * '-

2'-CH ₃ OC ₆ H ₄

CH ₃

^C 6 ^H 5 HC ₆ H ₁₃

4'-ToIyI

4'-BrC ₆ H ₄

2'-CH ₃ OC ₆ H ₄

4'-ClC ₆ H ₄

3'-CP ₃ C ₅ H ₄

4'-ClC ₅ H ₄

C ₂ H ₅

4'-PC ₆ H ₄

4'-ToIyI

^C 6 ^H 5
4'-CP ₃ C ₆ H ₄

CH ₃

^C 6 ^H 5
H

4'-ToIyI

4'-ClC ₆ H ₄ C ₂ H ₅

4'-FC ₆ H ₄ 4'-ToIyI H

65
V-CF ₃ C ₅ H ₄

CH ₃

^C 6 ^H 5
H

4'-TolyI 3'-CF ₃ C ₅ H ₄

4'-PC ₆ H ₄ 4'-ToIyI H

HS
4'-CF ₃ C ₅ H ₄

3-1

3-P

4-CH ₃ 3-Br

2-CP ₃ 3-NO ₂ 3-Cl 4-CH ₃ O 3-CF ₃ SO ₂ 2-CH ₃ O 3-1

3-P

4-CH

2-CP ₃ 3-NO ₂ 3-Cl 4-CH ₃ O 3-CF ₃ SO ₂ 2-CH ₃ O

3-P

4-CH ₃ 3-Br

2-CF

3-N0

Example 3

To 4.48 g (0.02 mol) of 2-chloro-5-trifluoromethylbenzoic acid in 10 ml of dimethylformamide, 05 g (0.02 mol) of sodium _{fifthylate are added with itiokstoff i f.} Then four

1.05 pounds (0.02 moles) of sodium methylate and 3.0 g (0.02 moles) of cinnamyl mercaptan added in 10 ml of dimethylformamide.

The reaction mixture is then heated to 85 ° C. for 1 1/2 hours, cooled to tree temperature and poured into 100 ml of water. The resulting mixture is then added dropwise to a solution of 5 ml of concentrated hydrochloric acid in 200 ml of water.

The 2- (cinnamylthio) -5-trifluoromethylbenzoic acid which separates out is filtered off and dissolved in ether. The ethereal solution is dried over anhydrous sodium sulfate, treated with charcoal and concentrated. Then n-hexane is added to the solution and the 2- (cinnamylthxo) -5-trifluoromethylbenzoic acid which separates out is filtered off. A yield of 1.3 g is obtained. Melting point 190 to 191.5 C. From the mother liquor another crystals (900 mg, P. 190 to 191.5 ⁰ O).

Recrystallization from ether-n-hexane to obtain a product with P. "190-191, .5 ⁰ C

Anal, Ber.j for C ₁₇ H ₁₃ F ₃ O ₂ Sr C: 60.3 ^ -j H: 3.87 Oef · ':. C; 60.3? L H: 4.02

From the corresponding starting materials are after the above process the compounds summarized in the table above are established!

H
S. Ö - CH-OH-

L - ii_ £ _ χ

CF n-G ^ H GK It PW

CF ₃ SO ₂ C ₅ H ₅ C ₆ H ₅ 4-Cl

H CH ₃ ' ^C 2 ^H 5 - " ³ ' ^F

NOg p-Tolyl p-Tolyl 3-0H «O

CH ₃ ..- ■. H . η ' 2-f

, 6

F.
Supreme Court,

3'-CFC ₆ H ₄

^I 13 ⁾ 2 ^NSG 2

C ₆ H ₅

(η =

(C ₆ H ₅ I ₂ NSO ₂
(CH ₃ ) (C ₆ H ₅ ) NSO ₂ H
CH ₂ ) ^ - NSO ₂ C ₂ H ₅

₂ Η JfHSO ₂
C ₆ H ₅ NHSO ₂
P-CH ₃ C ₅ H ₄ NHSO ₂

C ₅ H ₅ C ₂ H ₅

^C 6 ^H 5

2'-GF ₃ SO ₂ G ₆ H ₄ CHo

CH, CH ^

3-Br

3-GF ₃

3-F 3-CH ₃ O

3-CF ₃ SO ₂ 3-CF ₃ H 3-CH ₃ O

Example 4

2.1 g (0.04 mol) of sodium methylate and a solution of 2.6 g (0.02 mol ) O ^ -Mercaptomethylthiophene added. The reaction mixture is heated for 3 hours with an oil bath at 90 ^° C., cooled and poured into 200 ml of water. The resulting mixture is then acidified with concentrated hydrochloric acid and the solid which separates out is isolated.The crude, dry 2- (G * - Thlenylmethylenthio) -5-trifluoromethylbenzoic acid obtained in this way is dissolved in ether, the lobum is treated with charcoal, filtered and concentrated. Then n-Hexnn is freeceben, and the acid which crystallizes out of the solution is isolated. Yield 1.9 p, melting point 150-151 ° C _e

In the case of UrrkriFte.il isler ^ n au? Ether-n-Hexf> n one obtains 1.2 g Acid before melting point 152-153 ° C,

. Under Ver '-' ^j f ^ n-iun the corresponding Ausganrsmaterialien be folpcr.dfj compounds n ^ ch obi £ © -EMC rfahren prepared:

2- (beta-T} iienylmethy3enthio) -5-trifluojtimethyl _{benzoeFäure-l} - ^ 2- (0i-Thier.ylmethylenthio) -5-cMorbenzoBSBure, 2- (Cf-Thienvlmethylenthi ο) -f-ni trobenape.F; _s äure _;

2- (? Qt Thi ^ nylmethylentr ο) -5-1 "rlf 1 uopjjietf OJC, y-ben _.oeFäurp,: SÖÖÖÜ4 / 1779

? _ (jC-Thienylmethylenthio) -5-trifluoromethylsulfonylbenzoe-

acid,

2- (α-Thienylmethylenethi ο) -5-dimethylsulfamyl-benzoic acid, 2- (ß-Thienylmethylene thio) -5-chlorobenzoic acid 2- (ß-thienylmethylene thio) -5-nitrobenzoic acid, 2- (ß-thienylmethylene thio) -5-trifluoromethoxy-benzoic acid,

2- (ß-Thienylmethylene thio) -5-trifluoromethylsulfonylbenzoic acid,

2- (ß-Thienylmethylene thio) -5-dimethylsulfamyl-benzoic acid, 2- (β-Thienylmethylene thio) -5-N-methylsulfamyl-benzoic acid

Example 5 I.

fe 'Vi "H · ■■' ': - · ■:

ψ In a three-necked round bottom flask with a capacity of 1 liter,

which was equipped with a magnetic stirrer and reflux condenser, 500 ml of Ν, Ν-dimethylformamide were added. Then 30.8 g (0.10 mol) of 2-bromo-5-d-imethylsulfamylbenzoic acid and then 13 »2 g (0.107 Hol) of benzyl mercaptan, then 0.3? p; (0.005 g-atoms) metallic lob and 13> 1 g (0.20 mol) potassium hydroxide added. The reaction mixture is heated to 1 ° C and stirred at this temperature overnight. It was then cooled to room temperature and the dimethylformamide cube was removed in a drum evaporator at reduced pressure. The oil that remains is poured into 500 ml of water, and then sufficient to dissolve the white precipitate _; Amount of a 5% sodium hydroxide solution added. The resulting

"An alkaline solution is then ir.it three times with diethyl ether extracted and acidified with 6N hydrochloric acid. The crude 2-benzylthio-5-dimethylsulfamyl-benzoic acid is filtered and washed with water. ..After repeated recrystallization from acetonitrile the melting point of the product is 223-225 ° C.

Using the appropriate starting materials the compounds summarized in the following table are obtained according to the above process:

(R ^? R ³ ) 1CS ©

'X

Elementary analysis e Ber. Found

R ² = X lP F., ⁰ C GH Cl CH ₃ 3-methyl 216-218 55.87 5.24 55.86 5.20 CH ₃ OCO ₂ CH ₂ H 142-144 54 65 5.73 -54 .86 5.79 CH ₃ CH ₂ CH ₂ CH ₂ H 142-144 60.66 6.71 60.34 6.67

In addition, the following compounds are produced from the corresponding starting materials:

2-benzylthio-5-dimethylsulfamy! Benzoic acid, 2- (3'-Chlorbency1thio) -5-dimethylsulfamylbenzoic acid, 2- (4'-fluorobenzylthio) -5-dimethylsulfamylbenzoic acid, 2- (3'-Rrombenzy1thio) -5-dimethylsulfamylbenzoic acid, 2- (4 * -iodobenzylthio) -5-dimethylsulfamy! Benzoic acid, 2- (4'-nitrobenzylthio) -5-dimethylsulfamylbenzoic acid, 2- (3'-Hethylbenzylthio) -5-dimethylsulfamylbenzoic acid,

2- (4'-Trifluoromethylbenzylthio) -5-dimethylsulfamylbenzoic acid,

2- (4'-trifluoromethylsulfonylbenzylthio) -5-dimethylsulfamylbenzoic acid,

2-benzylthio-5-di - ^n-hexylf: ulfamylbenzoesäure.! -2- (3 ^l -Chlorbenzylthio) -5-ö.in-hexylsulf e my benzoic acid, .- (4 '-Fluorbfinzylthio) -5-di-n-he: ^xylsulf::!) .My benzoic acid, 2- (3 ^l -Bromobenzylthio) -5- ⁱ 'di-n-hexylsulf? Imy! Benzoic acid, 2- (4' -JödbenzylthlöJ-S-tii-n-hexylnulfamy! Benzoic acid, 2- (4 -nitrobenzylthio) -5- di-n-hexylsulfamy! benzoic acid, 2- (3 '- ^ Hethy] benzylthio) -5-di-n-heyylsulfamy! benzoic acid,

? - (4 · -Trifluoromethylbonzylthio) ^ 5-di-n-hexylsulfamylbenzoic acid,

2- (4'-Trifluoroniothylsulfinylbenzylthio) -5-di-n »hexyl

2-Pi = nzylthio-5-di-n- ~ butylsulfamylbenzoic acid, 2 "(3 '-chlorobenzylthio) -5 ^to ai-il-butylsulfamylbenzoic acid, 2- (4'-fluorobenzylthio) -5-di-n -butylsulfamy! benzoic acid, 2- (3 *> - bromobenzylthio) -5-di-n-bntyli =! Ulfomy! benzoic acid, 2- (4 ¹ ^ JoCi benzyl thio) -5-f1i-n-butyleulfamyD benzoic acid, 2- (4 ¹ ^ Wi troben ^ .ylthio) -5-dl-n-butylsulfp.my! Benzoic acid, 2 ^ (3 '-i'i ^ thylbenzyl thio) -5 «c ¹ -i ⁱ * n« -butyl! ^: 5U.lfamylben2oic acid _#

benzoes whore

2_ (4 '-trifluoromethylsulfonylthio) -5-di-n-butylsulfnmylbenzoic acid,

2-Benzylthio-5-di (ß-methoxyethyl) sulfamylbenzoic acid,

2- (3'-chlorobenzylthio) -5-di (ß-methoxynfchyl) -sulfamylbenzoic acid,

2 - (/ 4- ^l -fluorobenzylthio) -5-di (ß-methoxyethyl) -sulf8mylbenzoic acid,

2- (3 «-Bromobenzylthio) -5-cLi (ß-methoxy? .Thyl) -sulfamylbenzoic acid,

2- (4 ^| .-Jo (ibenzylthio) -5-cLi (ß-raethoxväthyl) -sulfamylbenzoic acid,

2- (4-nitrobenzylthio) -5-di (ß-methoxyethyl) -s \ ilf amylbenzoic acid,

2- (3 '-Methylbenzylthio) -if-di (ß-raethoxyethyl) -sulf ρmylbenzoic acid,

2- (4-trifluoromethylbenzylthio) - ^ - di (ß-metboxyätliyl) sulfamy! Benzoic acid,

2 - (^ '- Trifluoromethylsulfonylbenzylthio) -5-di (β-thiiethoxyethyl). sulfamy! benzoic acid,

2- (3-chlorobenzylthio) -5-N-n-hexylsulfamylbenzoic acid, 2-benzylthio-5-di-n-dodecylsulfamy! Benzoic acid,

2- (3 ^l -chlorobenzylthio) -5-di-n-hexy ^f adi ⁱ cylsulfaniylbenzoic acid,

2- (3'-nitrobenzylthio) -5-dJphenylsulfamylbenzoic acid,

2- (/ + '-Tr if luorme thylbensy lthio) - 5-N-p-tolyl-N-ethylsulfamine benzoic acid,

2- (3 ^l -Bromb3nzylthio) -5-N-naphthyl-N-phenylsulfaniylbenzoic acid,

2- (i4- ^t »pluorbenzylthio) -5-dibenzylsulfaray! Benzoic acid,

2- (3'-methylbenzylthio) -5-di- (p-i! 3opropylbenzyl) -sulfamylbenzoic acid,

2- (31-Trifluoromethoxybenzylthio) -5-N, N-ethylene-sulfamylbenzoic acid »

2 "(^" "Jodbenzylthio) -5-N, N-tetramethylene sulfarrylbenzoeäu

2- (3'-trifluoromethylsulfonylbenzylthio) -5-N, N-pentamethylene sulfamylbenzoic acid,

2 ~ (3 -chlorobenzylthio) -5-N, N- (1, M iäthylpentamethylenpulfamy! Benzoic acid,

2 ~ (k * -nitrobenzylthio) -5-N, N-decamethylene sulfamy! Benzoic acid,

2 "(i |. ^| -Bromobenzylthio) -5-N, N-dodecamethylene sulfamylbenzoe-. acid,

2 _A (3 »-Trifluormethylbenzylthio) -5-N, N-il ^l, 3 ^l _i 5" n-propyl) -pentamethylensulfamy! Benzoic $

2- (2'-Methoxybenzylthio) -5-N, N- (1 ·, 8'edi-nr ^ öpyl methylensulfamy! Benzoic acid _t

2- (2 ^l -chlorobenzylthio) -5-N _s N- (2 «-methyl) ~ tetramethylene sulfarny! Benzoic acid,

2- (2 -ethylbenzylthio) -5-N, N- (2 -ethyl) -pentamethylene sulfamylbenzoic acid,

2- (Ä ~ Naphthylmethylenthio) -5-dimethylsulfamylbenzoic acid, 2- (OU-Naphthylme thy lenthio) -5-d "l-n-hexylsulf a my! Benzoic acid, 2 ~ (cUNaphthylmethylene thio) -5-di-n-butylsulfamylbenzoic acid,

2- (ß-Nnphthylmethylenthio) -5- (ii (ß-niethoxyethyl) -sulfamylbenzoic acid,

2- (ß-Naphthylmethylene thio) -5-di-n-öodeoylRulf ^ my! Benzoic acid,

2- (β-Naphthylmethylene thio) -_ 5-di-n-hexadeeylsulf.Tmyl ~ benzoic acid,

2- (c (-ThienylmethjQenthio) -5-diphenylsulfamylbenzoic acid _f

2- (C.-Thienylmeth3 ^r lenthio) -5-Np-tolyl-N-ethylsulfamylbenzoic acid,

2- (cC-Thieny! Methyl enth io) -5 ~ dibenzylsulfnmy! Benzoic acid,

2- (ß-Thienylmethylene thio) -5-di- (p-isopropylbenzyl) -fmlfamyl »- benzoic acids,

2- (ß-thienylmethylene thio) »5-N, K-pentrmethylene-riilfamylbenoic acid,

2- (ß-Thienylmethylene thio) -5-H _s H- (2'-methyl) tetramethylene-8 ulf ηmy! Benzoic acid ,

2- (ß-Thienylmefchylenethio) -5-N-phenylsulf ^ mylbenzoic acid, 2- (ß-Thienylmethylenthiο) -5-N-p-tolylsulfnmylbenzoic acid,

¹ ■ * ·:;>'η

R ² H ³ R ⁶ R ⁷ η 5 ^

CH ^ GH ^ CH ₃ GH ₃ O 3 -C1

ⁿ " ^C l6 ^H 33 ⁿ " ^G l6 ^H 33 ^η "' ^σ 6 ^Η ΐ-' ^ϊ . ^Η * P-GH ₃ O

CH ₃ 0C _? H _c 0H ₇ OC ₀ He V-CF ₃ C ₆ H ₄ 3'-CF ₇ C, 1 3-1

Γ \ ·

^C 2 ^H 5

2'-CH ₃ OC ₆ H ₄ 4'-ToIyI 2

R ² and R ³ =

-CHpCHp-

H
H

H'-

^OC 6 ^H 4

3
3
3

-CH ₂ -CH (C ₂ H ₅ ) - (CHg) ₃ - nC ₆ H ₁₃ C ₅ H ₅

"Ε ²

^ r NSO

CO ₀ H _Ό (

c ti

-. S.

C CH = CH

V ¹

2 3

4-Br

3-CF,

4-NO ^

4-Cl

ⁿ " ^C 12 ^H 25 CH ₃ HC ₆ H ₁₃ CH ₃ 4-CH ₃ ⁿ "° l6 ^H 33 C ₅ H ₅ C ₆ H ₅ C ₅ H ₅ Cl ^C 2 ^H 5 CH ₃ CH ₃ C ₂ H ₅ Br C ₆ H ₅ CH ₂ C ₆ H ₅ CH ₂ 4'-ToIyI 4'-ClC ₆ H ₄ F. 4'-NO ₂ C ₆ H ₄ 3'-FC ₅ H ₄ I. CH _? " CH ₃ 3'-CH ₃ OC ₅ H ₄ . 4'-BrC ₅ H ₄ CH ₃ O R ² and R ³ -CH ₂ CH ₀ - 3'-CP ^ SO ₂ C ₆ H ₄ 4 · -PC ₆ H ₄ CP ₃ - (CH ₂ ) ₄ - 4'-TC ₅ H ₄ 3'-CF ₃ C ₆ H ₄ CF ₃ SO ₂ - ^ ^ · π_ / 1 "™ o-tolyl H NO ₉ -CH ₀ -CH (Co H ₅ ) - (CH ₂ ) ₃ H H H Example 6

To 100 ml of Ν, Ν-diraethylformamide 200 ner copper powder, 7.9 g (0.12 KoI) potassium hydroxide, 7.5 e- (0.06 hol) benzyl mercaptan and 1? g (0.06 mol) of 3-iodo-5-trifluoromethyl-benzoic acid were added. The smell is left under nitrogen for 18 hours

heated to 14O ⁰ C. The dimethylformamide is then evaporated off under reduced pressure and the residue is treated with 200 ml of water. The mixture is filtered and the piltrate is acidified with concentrated hydrochloric acid. The 3-benzylthio-5-trifluoromethylbenzoic acid which separates out is filtered off and recrystallized from a mixture of chloroform and hexane. A yield of 16.5 g, mp 127-130 ⁰ C. After sublimation at 200 ° C. / 0.02 mm and recrystallization from ether-hexane, the melting point of 135 to 136.5 C.

Anal. Ber. for C ₁₅ H ₁₁ O ₂ P ₃ S: C, 57.68; H: 3.55 FOUND: C: 58.04} H: 3.60.

The following compounds were also made according to the above procedure manufactured:

3- (2'-methylbenzylthio) -5-trifluoromethybenzoic acid,

3- (3 · -trifluoromethylbenzylthio) -5-trifluoromethyl- j benzoic acid,

3- (4'-chlorobenzylthio) -5-trifluoromethy! Benzoic acid, 3- (3 ^! -Nitrobenzylthio) -5-trifluoromethy! Benzoic acid,

3-benzylthio-5-nitrobenzozoic acid, 3- (2'-methylbenzylthio) -5-nitrobenzoic acid,

3- (3 ^l -trifluoromethylbenzylthio) -5-nitr4benzoic acid

3- (4'-bromobenzylthio) -5-nitrobenzoic acid, 3- (2'-methoxybenzylthio) -5-nitrobenzoic acid, 3-benzylthio-5-trifluoromethoxybenzoic acid,

3- (2'-methylbenzylthio) -5-trifluoromethoxybenzoic acid,

3- (4'-TrIfluoromethylsulfonylbenzylthio) -5-trifluoromethoxybenzoic acid,

3- (2'-fluorobenzylthio) -5-trifluoromethoxybenzoic acid, 3- (3'-iodobenzylthio) -5-trifluoromethoxybenzoic ^{acid, 2- (3 l} -chlorobenzyltbio) -5-Nn-hexylsulfamylbenzoic acid, 3-benzylthio-5-trifluoromethylsul £ ny! Benzoic acid,

3- (3'-chlorobenzylthio) -5-trifluoromethylsulfonyl benzoic acid,

3- (2'-fluorobenzylthio) -5-trifluoromethylsulfonyl benzoic acid, 3- (4'-Nitrobenzylthio) -5-trifluoromethylsulfonylbenzoic acid,

3- (3'-Trifluoromethylbenzylthio) -5-trifluoromethylsulfonylb on ¹ Oe acid

3-Bpnzylthio-5-dimethylsulffimylben: -> oesäure,,

3- (3 "-Bromobenzylthio) -5-diniethylsulfamy! Benzoic acid,

3- (ty -Trifluoromethyltenzylthio) -5-dimethylsulfamylbenzoic acid,

3_ (ty -Kethylbenzylthio) -5-dimethylsulfamy! Benzoic acid, 3- (3'-Nitroben3ylthio) -5-dimethylsulfamylbenzoic acid, 3-eenzylthio-5-di-ri-l-butylsulfamylt> enzoic acid, 3- (3 "-BromobenzylthioJf-5-di-n-butylsulfamine! Benzoic acid,

3- (ty -Tr if luornethylbenzylthio) -5-di-n-butylsilf ^ myibenzoic acid,

3_ (ty »-Methylbenzylthio) -5-di-n-butylsu! Faraylbenzoic acid, 3- (3 '-Nitraobenzylthio) -5-d.i-n-butylsulffmyljenzeo acid, 3- (ÖLNaphthylraethylenthj ο) -5-trifluoromethylbe ^ zoesaure, 3_ (ol-Naphthylmethylenthio) -5-nitrobenzoic acid, 3- (cCNaphthylmethylenthio) -5-trifluoromethoxybenzoic acid,

3_ (<< ^ Naphthylmethylenthio) -5-trifluoromethylsulfonyl « benzoic acid,

3- (ß-Naphthylmethylenthio) -5-dimethylsulf? My! Benzoic acid, * 3- (oLThienylmethylenthio) -5-di-n-butylsulf ara.ylbenzoesMure, 3- (ß-Thienylmethylthio) -5-dipherylsulfi) my! benzoic acid 3- (3 ^l -bromobenzylthio) -5-diphenylsulfamylbenzoic acid, 3-eenzylthio-5-dibenzylsulfamylbenzoic acid,

3- (ty '-trifluoromethylbenzylthio) -5-N-phenyl-N - ?. t] "ylßulf amylbenzoic acid,

3- (3 '-Methylbenz? /! ^! ©) -5-N, N-tetramethylene sulfamz'l' _! Benzoic acid,

3- (ty '-Nitrobenzylthio) -5-N, K- (2 »-ä thy 1) pen tame thylenesulfamylbenzoic acid,

3- (ty ^| -Pluorobenzylthio) -5-ä.in-hexadecylsulfara.ylbenzoic acid, 3- (3'-ChlopbenzylthioJ - ^ - NyÄ-butylsulfnmy! Benzoic acid, 3- (2 ^l -Pluorobenzylthio) -5-N-phenylsulfρmy! benzoic acid,

90ÖÖ4A / 1779

CF ₃ O

CF ₃ O

CF ₃ SO ₂

CF ₃ SO ₂

CF ₃ SO ₂

(CHo) ₉ NSOp

JC. ti

^ CH ^ -NSOg
(C ₆ H ₅ ) (C ₂ H ₅ ) NSO ₂

₅ ) ₂ NS0 ₂

C ₂ H ₅ NHSO ₂

P-CH ₃ C ₆ H ₄ NHSO ₂

^C 6 ^H 5

4'-tolyl

3'-BrC ₆ H ₄

C ₂ H ₅ CH ₃

H H

3'-CF ₃ C ₆ H ₄ H

CH ₃ nu

HC ₂ H ₅ ^C 6 ^H 5

1 2

4'-ToIyI 1 2'-CH,

. ^0C ₆ V ^C 2 ^H 5
H

HH 3 O 2 2 3

3'-ClC ₆ H ₄ 2 "-CH ₃ C ₆ H _41. H
CH-,

3'-CF ₃ SO ₂ C ₆ H ₄ H ^C 6 ^H ₅
H

C ₂ H ₅

3-Cl

3-Br

4-1

2-OCH ₃

2-F

3-CF ₃

4-CH ₃

3-CF ₃ SO ₂

4-NO ₂

2-Π1

3-NO ₂

4-CF ₃

4-Br

3-CH ₃

4-F

4-CF ₃ SO ₂ H 3-Cl

H 1

ΟΙ, R '

CH = CH

R '

R '

3'-FC ₆ H ₄

3-Cl

4-Br

CF ₃ O

₃
CF ₃ SO ₂

4'-tolyl 3'-CF ₃ C ₆ 4 • -IC ₆ H ₄

₂
J ₂ NSO ₂

11-C ₃ Hr ₇ NHSO ₂

C ₆ H ₅ NHSO ₂

C ₆ H ₅ CH ₂ NHSO ₂

11-C ₃ Hr,

^C 6 ^H ₅
C ₂ H ₅

C / Kc 2-P 4'-C ₆ H ₄ 4-1 4'-tolyl 3-CF ₃ 3'-BrC ₆ H ₄ 2-OCH ₃ 4'-CH ₃ OC ₆ H ₄ 3-CH ₃ H 3-NO ₂ 3'-ToIyI 4-CF ₃ SO ₂ H H C ₂ H ₅ 3-CP ₃ nC ₄ H _g 4-Cl H H CH ₃ 3-Cl OH.. 3-CF,

Example 7 '

To a solution of 4.15 g (0.030 mol) of potassium carbonate in 50 ml of Warper are successively added 100 ml of ethanol, 5 »05 g (0.03%) of 5-methyl-2-merc £; pto-benzoic acid and 3.8 g (0.030 mol) of benzyl chloride added. As soon as the evolution of carbon dioxide subsides (ca _# 10 minutes), the mixture on a steam bath for one hour l «ng refluxed. Then, it is cooled and the bulk of the solvent at reduced pressure The cloudy, white liquid residue is diluted with water to a volume of about 600 ml. This mixture is then filtered, cooled and acidified with 6N hydrochloric acid After filtering and drying in a high vacuum, 6.9 % (89 ^) 2-benzylthio-5-methylbenzoic acid with a melting point of 169-171 ° C., sintering at 167 ° C., is obtained

In the same way, the following compounds are obtained: 2- (3'-nitrobenzylthio) -5-methylbenzoic acid

F .. ° C.

164-167 ° at. 162

2- (3'-Trifluoromethylbenzylthio) -5-methylbenzoene acid

9098AA / 1779

153-155

p., ° c

2- (4 ^l -chlorobenzylthio) -5-methyrbenzoic acid 188-191

2-Benzylthio-4-trifluoromethylbenzoic acid 157-158.5

2- (OL-methylbenzylthi ο) -5-chlorobenzoic acid 153-154

2- (Qk.thienylmethylene thio) -5-chlorobenzoic acid 154-156

2 - (* ß-Thienylmethylene thio) -5-chlorobenzoic acid 165-1 ^ 7

2- (cinnamylthio) -5-chlorobenzoic acid 179-180.5

The corresponding starting materials are also used the following connections made according to the above procedure:

2-benzylthiobenzoic acid

2- (3'-fluorobenzylthio) -5-methylbenzoic acid

2- (4-trifluoromethylbenzylthio) -5-methy! Benzoic acid,

2- (3'-methylbenzylthio) -5-chlorobenzoic acid, 2- (2 ^l -methoxybenzylthio) -5-chlorobenzoic acid,

2- (4'-trifluoromethylsulfonylbenzylthio) -5-methy! Benzoic acid,

2- (4 ^l -Chlorbenzylthio) -5-brombenzoe, ^c äure, 2- (3'-Brnmbenzylthio) -5-bromobenzoic acid, 2- (2 ^l -Fluorbenzylthio) -5-fluorobenzoic acid, 2_ (24.i_r4ethoxybenzylthio)! - 5-fluorobenzoic acid,

2- (3-trifluoromethylbenzylthio) -5-trifluoromethylbenzoic acid,

2- (4'-Nitrohenzylthio) -5-trifluoromethylbenzoic acid, 2- (3 ^l -iodbene ⁱ ? .Ylthio) -5-niethoxybenzoic acid

2- (T-trifluoromethylbenzylthi-o) -5-trifluoromethylsulfonyl-

2- (3 ^l -Nitroben ^ ylti-iio) -5-nitrobenzoic acid

2- (3'-trifluoromethylsulfonylbenzylthio) -5-trifluoromethoxy benzoes.H.ure,

? .- (4 '-Methylbensylthio) -5-di-n-hexylsulfomy! Benzoic acid,

2- (3 '-Pluorobenzylthio) -4-meth.; / - benzoic acid,

2- (4-trifluoromethylbenzylthio) -4-methy! Benzoic acid,

2- (3 '-I'Ht ^ vlbenÄylthio) -4-chlorobenzoic acid, 2- (2 ^I -I'feb ^l 'nxyben?; Ylthio) -4-chlorobenzosF5 acid _i

2- (^ '-Tri fluoromethylsulfonylbenzylthio) -4-methylben'2oe-

2- ( ¹ I- '-Ghlorbeiizylthio) -4-bronbenzoic acid, 2- (3' -P.ro "-.!" D η r / 1 bhio) -4-bronibenzoic acid,

909S44 / 1779

2- (2'-fluorobenzylthio) -4-fluorobenzoic acid,
2- (4'-methoxybenzylthio) -4-fluorobenzoic acid,
2- (3'-trifluoromethylbenzylthio) -4-trifluoromethylbenzoic acid, 2- (4'-nitrobenzylthio) -4-trifluoromethylbenzoic acid,
2- (3 ^l -iodobenzylthio) -4-methoxybenzoic acid = i _i

2- (3'-trifluoromethylbenzylthio) -4-trifluoromethylsulfonylbenzoic acid,

2- (3 · -nitroben ^ ylthio) -4-nitrobenzoic acid,

2- (3'-trifluoromethylsulfonylbenzylthio) - ^ - trifluoromethoyybenzoic acid,

2- (4 ^l -methylbenzylthio) -4-di-n-hexylsulfainylbenzoic acid, 3- (3 * -methylbenzylthio) -benzoic acid, 3- ( l \ "-chlorobenzylthio) -benzoic acid, 3- (3 * -fluorobenzylthio ) -5-methy! Benzoic acid, 3- (i + 1 -trifluoromethylbenzylthio) -5-methy! Benzoic acid, 3_ (3'-methylbenzylthio) -5-chlorobenzoic acid, 3- (2'-methoxybenzylthio) -5-chlorobenzoic acid ,

3_ (^ »_Tr if luorme thy lsulfonylbenzylthio) -5-nie thy! Benzoic acid,

3_ (4'-chlorobenzylthio) -5-bromobenzoic acid, 3- (3'-bromobenzylthio) -5-bromobenzoic acid, 3- (2'-fluorobenzylthioJ-f-fluorobenzoic acid, 3 -. (4> _Methoxybenzylthio) -5-fluorobenzoic acid,

3- (3-Trifluorraethylbenzylthio) -5-trifluoromethylbenzoic acid,

3_ (41-Nitrobenzylthio) -5-tr if luorirethylbenzofisäure, 3 ^ 3'-Jo <ibenzylthio) -5-methoxybenzoic acid _f

3 »(3'-trifluoromethylbenzylthio) -5-trifluoromethylsulfonylbenzoic acid, :

3- (3'-Nitrobenzylthio) -5-nitrobene?; Oesäure, "■ - ■:

3- (3 '-Trif luormetb ^ lpulf onylbenzylt-hi o) -5-trif luormetnoicy- -

3- (4'-ethylbenzylthio) -5-di-n-hexylsulfemy! Benzoic acid, 4- (3 '-fluorberizylthio) -3-me + ^- ethylben?: Oesäur * e, 4 -. (4 ^l -Trifluoromet ^v iylbenzylt " nio) -3-niethy! benzoic acid, 4- (3'-i-'ethylbenzyltnio) -3-chlorobono ioesäuro, 4- (2 ^l -Hst ^v ioxybenzylthio.) ^ 3-chlorobeiiz, acid, - ..... ..

4- (4'-trifluoromethylsulfonylben ^ ylthi η) -3- ^. 4- (4 ^L -chlorobenzylthio) -3-brorabenzoe. ^c '.äure, 4- (3 ^l -Broinbenzylthio) -3-brombenzoe ^=? acid,''4-(2' -Fluorbenzylthio) -3-f luo

900844/1779

itu (lti-kethoxybenzylthlo) -3-f luorobenzoic acid,

4- (3 * -TrIfluoromethylbenzylthio) -3-trifluoromethylbenzoic acid,

4. (If ¹ -Ni trobenzylthio) -3-tr if luorme thy! Benzoic acid, ί | - (3 ^l -iodobenzylthio) -3-methoxybenzoic acid,

k- (3-trifluoromethylbenzylthio) -3-trifluoromethylsulfony1-benzoic acid,

4- (3'-Nitrobenzylthio) -3-nitrobenzoic acid _f

If- (3 «-trifluoromethylsulfonylbenzylthio) -3-trifluoromethoxybenzoic acid,

li .- (if «-Hethylbenzylthio) ~ 3-di-n-hexylsulfamylbenzoic acid,

2- (oC-Haphthylmethylene thio) -5-methy! Benzoic acid,

2- (ß-Naphthylmethylenthio) -5-trifluoromethylbenzoic acid,

2- (A ^ Haphthylmethylenthlo) - ^ - nitrobenzoic acid, 3- (it-thienylmethylenthio) -5-methylbenzoic acid, Ij, _ (C6i-thienylmethylenthio) -3-chlorobenzoic acid _i 2- (ß-thienylmethylenthio) -4 -bromobenzoic acid,

Z- (3'-bromobenzylthio) -5-di-n-hexadecylsulfamylbenzoic acid,

2-Benzylthio-5-diphenylBulfamylbenzoic acid,

2- (lf -Trif luorme thy lbenzylthio) -5-dibenzylsulfamylbenzoic acid,

2-i ^ ^l -Hethylbenzylthio) -5-methylsulfamy! Benzoic acid,

2- (2 ^l -Methoxybenzylthio) -5-N-phenyl-N-ethylsulfamy! Benzoic acid, 2- (3 ^l -chlorobenzylthio) -5-N, Nt) entamethylene sulfa my! Benzoic acid, 2-C2 ^I -fluorobenzylthio) ' ! -5-N, N-äodecy / amethylensulf π my benzoic acid, 2- (l | ^'l -Jodbenzylthio) -5-N-methyl-N-äthylsulfam3 ^r i Lben: oesäure,

2- (3 • -Trifluoromeths'lsulfonylbenzylthio) -5-H-benzy 1-N-phenylsulfainy! Benzoic acid ,

2- (lj ^| -Nitrobenzylthio) -5-di-phenaphthylsulfamylbenzoic acid, 2- (3-bromobenzylthio) -4-di-n-hexadecylsulfarty-benzoic acid, 2-benzylthio- ^ - diphpnylsulfamylbenzoic acid., 2- (lf ^l -Trifluoromethylbenzylthio) - ^ - dibenzylsulfamy! Benzoic acid, 2- (lf ^l -ethylbenzylthio) - ^ - methylsulfamylbenzoic ^{acid, 2- (2 l} -ethoxybenzylthio) -if-N-phenyl-K-ethy lsulfamine! Benzoic acid, 2- (3 ^l -chlorobenzylthio) -4-N, K-pentamethylene sulfamy! benzoic acid, 2- (2 ^l -Fluorobpnz; 'lthio) -'4'-N, N-do (iecarnethylenesulfamy! benzoic acid, 2- {l | - ^l - Jodb? Nryithio) -4-K-methyl-N-ethylsulfamine, benzoic acid,

2- (3 ■ «-Trif luorme thylsulfony lbenzylthio) - ^ -N-benzy 1-N-rheny 1-sulfamy! Benzoic acid,

2- (b ^| -i: itroben ^ ylthio) - ⁱⁱ -di-tt-naphthylsulfamine, benzoic acid, 2- (3 ^l -chlorobeiizylthio) -it-K- ^T i-propy

90Θ6Α4 / 1779

2 - (# 4'-FluorobenzylthioJ - ^ - N-benzylsulfamy! Benzoic acid, 2- (2'-methoxybenzylthio) - ^ - N-phenyl-sulfamylbenzoic acid, 3 (3'-erombenzylthio) -5-cLi-n-hexadeoylsulfamyl benzoic acid, 3-Benzyltbio-5-diphenylsulfamylbenzoic acid, 3 "(Zf '-trifluoromethylbenzylthio) -5- <iibenzylsulfamylbenzoic acid, 3- (ty" -Methylbenzylthio) -5-methylsulfamylbenzoic acid, 3- (2'-metfroxybenzylthio) -5- N-phenyl-N-ethylsulfamy! Benzoic acid, 3— (3 «-chlorobenzylthi ο) -5-N, N-pentamethylene sulfamy! Benzoic acid, 3_ (2 ¹ -fluorobenzylthio) -5-N, N-dodeoHmethylene sulfamy! Benzoic acid, 3- (^ '- Jodbenzylthio) -5-N-methyl-N-ethylsulfamy! Benzoic acid,

3- (3'-TrifluoromethylsulfonylbenzylthioJ - ^ - K-benzyl-N-phenylsulfamylbenzoic acid,

3- (i | «-. Nitrobenzylthio) -5- <ii-il * -naphthylsulfani3 '" lbenzoic acid, 4- (3-bromobenzylthi ο) -3-di-n-hexadeeylsulfamylbenzoic acid, 4-benzylthio-3-diphenylsulfamylbenzoic acid, k- {k ^l -TrifliJormethylben5 ^{> r} ylthio) -3-dibenzylsulfamy! benzoic acid, Li (W -ethylbenzylthi ο) -3-mefchylsulfamy! benzoic acid, 4- (2 ^l -I ^> lethoxybenzylthio) -3-N-rhenyl- N-Etnylsulf any! Benzoic acid, ^ - (3 ^l -C? Ilorbenzylthio) -3-N, l \ T-pontrmethylene sulfamy! Benzoic acid, Zi - (2'-Pluorbenzylthi o) -3-N, N-dodecamethylene sulfamy! Benzoic acid , ^ - (4'-Jodbenzylthio 5-3-N-TO ^ tIIy] -N-Hf hylsulfamy! Benzoic acid,

k- (3 ^t -Trifluormethylsulfonylbenzylthio) -3-N-benzyl-N-phenylsulfamy! benzoic acid

^ - (k ^l -nitroberzylthio) ~ 3-3i- ^ft -napht.hylsulf & my! benzoic acid

CO _? H

Position of the arylalkylthio-

5-er
5-F
ii-Cl

2 2 2 2 2

n-C ^ H,

CH,

chI

3 '-

0 H 1 3'-He 2 3 »-C η 1 4'-CF- 3 it «-I 2 2'-17

909844/1779

Position of

ι. Arylalkylthio- / ₇ ET group BT ET η X.

-NO ₂ 3 3'-ClC ₆ H ₄ J'-CH ₃ OC ₆ H ₄ 1 ί '-OH ₃ U

3/1 t C ^ Ό O ^ O TJ / 1 I C ^ TJ C ^ TJ O Ol ¹ M Λ

3 3'-NO ₀ C ^ H ,, C .Ή c 3 4'-GH _Q

2 6 4 -η p

3 G ^ H ₅ C ₆ H ^ 0 3'-Eq

4- (UC ₁ ^ H ₃₃ J ₂ NSO ₅ , 3 HH 2 4'-GF ₃

** 3 CaH. H 3 3'-Cl

GOpH,

I ² R ⁶

H ^ -IC 4P-S-C-CH = CH -TK ⁷ X

S— C— CH = CH "Ύ-fl .)

3, ^Χ W ¹ ^

_Η 7 VV

position

Cinnamylthio- ₆ "■

group H R ^

H H

5-CF ₃ 2 C ₆ H ₅ C ₆ H ₅ V

4-NO ₂ 2 CH ₃ CH ₃ 4'-I

5-Cl 3 4'-BrC ₆ H ₄ 3'-PC ₆ H ₄ 4'-Br

^ ~ 2 ^NS0 2 ^{3 Η} 4'-CP ₃ C ₆ H ₄ 3'-Cl

η * \ i, rip ^ ₁ -I - .. »Up j nO ^ H! ο nC ^ Ho 3'-NOr

3 C ₂ H ₅ Η "2 'CH,

3 CH ₃ H 2 "-p"

Example 8

Oie "Be ^^ ylsulfinylbenzoic acids are prepared by adding a colloid of the corresponding benzylthi ^ enzoic acid with a hol Wnnrv- <rntof- ^p O3rox.yd (as a 30 ^ solution) in glacial acetic acid or ant-HP. In general, the temperature is around 10O ⁰ C (steam bath) until all the substance peroxide has been used up (the amount of hydrogen peroxide is made with starch-iodide paper

90Θ & 4Α / 1779

Then the Res.ktionsgenisch is diluted with water and the benzylsulfiny! benzoic acid vnrd. isolated and from a suitable solvent crystallizes.

Using this procedure, the following compounds were obtained from the corresponding benzylthiobenzoic acids produced:

Eleirentaranalyse Ber. . Oef.

Compound F., ⁰ C C HC H

3-benzylsulfinylbenzoe-

acid 178.5-180 64.61 4.65 64.88 4.74

3-benzylsulfinyl-5-tri-

fluoromethylbenzoic acid 157-158 5 ^, 87 3.38 5 ^k , 94 -3.38

2- (4-chlorobenzylsulfi-

nyl) -5-chlorobenzoic acid 198 51.08 3.06 51.40 3.22

2- Benzylsulfiny1- 5- trifluoromethyltenzoe-

acid 193-194

2-Benzyl8ulfinyl-5-dimethylsulfamyltenzoic acid 173-174 52.30 4.66

2-Bena! Yl »ulfynyl-5-di (fl-

methoxyethyl) -eulf »myl-

benzoic acid 127-130 52.73 5.53

2-Beneyliulfiny1-5-di-n butyleulfaaylbenzo -

acid 171-174 58.51 6.47

2-benzylsulfinyl

Benzoic acid 161-162 64.59 4.65

2- (flUlaphthyIn · thyTer-

Eulfinyl) -5-tPlfluor-

methylbenzoic acid 178-179 60.31 3.47

Using the above procedure, the following substituted benzylsulfinylbenzoic acids produced:

3-benzylsulfiny! Benzoic acid

4-benzylsulfinylbenzoic acid,

2-Benzy lsulfynyl-5-thybenzoic acid, 2 ~ (3 ^l -fluorobenzylsulfinyl) -5-methylbenzoic acid,

909Ö44 / 1779

52.33 > 68 52.73 5, 57 58.21 6, 45 64.6? 79 60.22 3, 55

2- (i |. ¹ -chlorobenzyl8ulfinyl) -5-niethy! Benzoic acid, 2 - (3 "-liethylbenzylsulfynyl) -5-methylbenzoic acid,

3- (3-trifluoromethylbenzylsulfinyl) -5-methylbenzoic acid,

3- (4 ^l -NitrobenzylBulfinyl 5-5-methy! Benzoic acid, 3- (2 • -Hethoxybenzylsulfinyl) -5-methy! Benzoic acid,

2- (K- methylbenzylsulfinyl) -5-trifluoromethylbenzoic acid, 2- (3'-methoxybenzylsulfinyl) -5-trifluoromethybenzoic acid, 2- (M-bromobenzylsulfinyl) -5-trifluoromethylbenzoic acid,

2- (3 «-trifluoromethylsulfonylbenzylsulfinyl) -5-trifluoromethylbenzoic acid,

3-Benzysulfinyl-5-nitrGt) enzoic acid _i 3- (2 »-Methylbenzylsulfinyl) -5-nitrobenzoic acid ₉

3_ (3 »_ trifluoromethylbenzylsulfinyl) -5-.nitrobenzoic acid,

3- (i |. «- Brorabenzylsulfinyl} -5-nitroben7.oeBäur ₈ 3- (2» -iletroxybenzylsulfynyl) ^{-5-nitrobenzoic acid, 2- (3 l} -ethoxybenzylsulfinyl) -5-chlorobenzoic acid 2- (li Chlorobenzyl8ulfinyl) -5-chlorobenzoe Bourej

2- (3 "-TrIf luormethylbenzylßulf ir" vl) -S-chlorben ^ o ^ p ^ ure, 2- (ii -'- trifluoromethyl isulfonylbenzylsulfynyl) -5-bromobenzoic acid,

2- (3 * -Kethylbenzylsulphinyl) -5-bromobenzoic acid, P-benzylsulphinyl-5-fluorobenzoic acid, 2- (3-nitrobenzylsulphinyl) - »5-fluorobenzoic acid, 4- (3'-methylbenzylsulphinyl) -3-methoxybenzoic acid , ^ - (2 ⁱ -Hethoxyben2ylsulfinyl) -3-raethoxybenzoic acid, i | .- (if «« Cb1 orbenzylsulfynyl} -3-

3- (l |. «_ Hethylbensy1 sulfynyl) -5-t

3- (if «-Trif luormethy lsulfonylbenzylsulfinyl ^ -5-trifluorme t ^ oxybenzoic acid, j

3- (U ^l -Kitroben? YLS "lfinyl) -5-trlfluorinethyl8ulfonylbenzorsyurp, ⁱ 3- ^(3-l -Broiribenzyl8tilfinyl5-5 trifluormethylsulfonylbenzoef = äure, 3- (2 -Met ^{5 l} ^ ioxyb nj'ylsulfi ^T iy3) -5 ? -trifluorniethylsulfonylbenzoeF acid, 3 "| - -5-trifluormethylBulfonylbenroeF ^ acid, (i 'Jod'bennylsul * ^m ynyl.)

2-Ben "ylsnlfinyl-5-direthylsulf ^r mylbenzoesäure,

2- (3 · -Tr i fluorine thy Ibensylpulfinyl) -5-dinethylsulf ^ rny 1-bä

2- (3 * -Kethylber. Zyl sulfynyl) - 5-di -n-hex2 ^r lsulf pmyTben? ο ^ s ^ ure ₉

909044/177 9

2- (4'-Chlorobenzylsulfinyl) -5-di-n-hexylsulfamy! Benzoic acid,? -. (3i_IIet '"oxybeneylsulfynyl) -5- <3-yn-hexylsulfamylberjzoic acid, 2- (2'-methylbe: nzylsulfynyl) -5-M-ethylsulfamylbenzoic acid, 2- (3'-fluorobenzylsulfinyl) -5-N-phenylsulfamylbenzoic acid, 2- (4'-nitrobenzylsulfinyl) -5-N-benzylsulfamyrbenzoic acid, 2- (o6, naphthylmethylene sulfynyl) - 5-methylbenzoic acid, 2- (β-N-phthylmethylene sulfinyl) -4-methylbenzoic acid, 2- (tfC-thienylmethylene sulfinyl) -5-methoxybenzoic acid, 3- (β-thienylmethylene sulfinyl) -5-trifluoromethoxybenzoic acid ₈ 2-benzylsulfynyl-5 -ä.in-hexadecylsulfamy! benzoic acid,

3- (3 «_Trif luorme methylbenzylsulfynyl) -5-a-iphenylsulf amylbenzoic acid,

4- (4 ^l -Chlortensylsulfin3 ^r l) -3-dibenzylsulfamylbenzoP acid,

4- (2'-Methoxybenzyl-sulfinyl) -3-N-phenyl-N-äthylsulfßmylbenzoic acid, ■. ■

2- (2 ^! -Methylbenzylsulfynyl) -5-W »n-Ethylenesulfamylbenzoescäiire,

3- (4'-Nitrobenzylsulfinyl) -5-N, N-dodecamethylene sulfamylbenzoic acid, ;

4 - (? '- Pluobenzylsulfinyl) -2-N, N- (2'-methyl) -tetramethylene sulfamylbenzoic acid

SO

Position- the arylalkyl-

5-CH,
5-Cl "

5- (GH-OGH ₉ CH ₉ :

5-OCP ₃ = - = -. ^: - ■

5-Br - "

3 4

* 2 2

, -KSOo 2

CH,

3'-CF ₃ C ₆ H ₄₁ 4 · -

0 1 2 3

3'-Cl 4'-Er 4'-F

, C ₆ K ₄ 2'-CH ₃ OC ₆ H ₂ , 3 3'-I

3'-ToIyI 3'-NO ₉ C ₆ H ^ 2

3'-CP

909644/177 9

^ '- CH ₀ O

2 3'-CP _? S0 ₂

Position of the aryl ?, alkylsulfinyl group

2 2

^C 6 ^H ₅
G ₂ H,

H-

1
3

2'-CH, ^ '-NO,

3 2'-F

CO ₉ H

so-

I.,

CH = OR

Position of the cinnamylsul-

:: o

4- (CH ₃ OTi ₀ CH _g ) ₉ WSO ₂ 2 ' ¹ J-TO ₉ 2

^ -OCF ₃

H
GH

6 ^H 13

5
4'-ToUyI

° 6 ^H 5

CH ₃
^C 6 ^H 5

3'-F 4'-Br 3'-CF. 4 · -Cor

H
, 4'-CI

p; according to the present invention.

"^" - p riiiroh Orti. <3: ° tion of the Pen ^ ylaulfiriylbenzoesöuren or the ÄUvsylt- ^ i above ^ oeR. ^ Urpn hR ^ e ^o t ⁰ l? t. / ms Zviecklichkeitsprrnnden Pvo - "- 7U'jt iir-m the manufacturer of these connections from the last f) named Au ^ fran ^ Pin-T.

6.1 g (0.024 mol) of 2-benzene-3yltnio-5-diethylbenzene acid are added to about 200 ml of 97% formic acid. The mixture will

warmed up on a water bath to about 54 ° C, during which 15 ml of res hydrogen peroxide are added over a period of 2.5 minutes. After finished. The addition is heated to about 3 more degrees to 54.degree. The heating equipment is then cooled to temperature and overnight

The formic acid is removed under reduced pressure, and the same solid residue becomes 2 Sturwien, long ·> over phosphorus pentoxy ^ sretrorlroet, D ^ n ^ wire? sr with about 300 ml of v / ater triturated, filtered and dried in a VPkuunexikator ■ over phosphorus pentoxide, to viobei _'t f> [p- {^ e ^ IFOL nusbeube) of 2-benzylsulfonyl-5-niethyl-bRn2oef? · fiure of Sohrael55T ) u; ikt 198-201 ⁰ C received.

In an analogous vfeise vmrder · the following compounds from the en ^ ^c pr ° ohe _J ide "made from - ^ r.vy ^ r teri π Tier ¹ :

BADORIGiNAU

co

co 00

VerbinAun; ·

7 '.- (T-III.trobenzylsulfnnyl) -5-rc ^p thy! Benzoic acid? .- (τ' -Tr: if 1 norm * · til · 'iber ^ vT gulf onyl i-'i-methyl- »

2- (3 · -Tr if l fliAorrne ^

Tiylmii hair dryer ¹ *!

-y] sulfonyl) -5-tri-

lf onyl benzoic acid, 3-B-nzylsulfonyl-5-fluorine-methyl-benzoic acid 713-216

I56-I59 Sint.

184-186 Sint.

2 Wj - 2 24.6 171-172.5

Slementaran ^ Iy s β

r »Gef,

HC

? 23-225 51.35 4.80 51.54 4.94 192-1Q? ^ ₉ 61 2.44 'i-6.80 2.29 180-181.5 64.11 " 3.57 54.39 3.6iL 1 ^ 4-ΐρς 48.71 ' '2.92 48.44 2.74 214-215 AO, 87 4.38 60.65 ■ 4,511 184.5-185.5 52.32 3.22 52.53 3.26

In addition, the following compounds avz the corresponding benzylthiobenzoic acids were formed by the above process:

2-2-3-3. 3-2-2-2-

3-3-

Ben ^ ylsulfony! Benzoic acid,
sulf ony! benzoic acid,

4-

( 3'-fluorobenzylsulfonyl) -5-methylbenzoic acid, (i + 1 -chlorobenzylsulfonyl) -5-methylbenzoic acid, (3 · -M ^ thy! Benzylsulfonyl) -5-methy] benzoic acid, (3 i- Trifluormethylbenzylsulfony]) -5-methylbenzoevSäure, (k * -Nitrobpnzylsulfonyl) -5-met} iylbenzoesäure, (2 '-Methoxybenzylsnlfonyl) -5-rr.etbylbenzoesäure, (k' -Hethylbenzylsulfonyl) -5- trifluoromethyl luorrnethy benzoic acid, (3! ^1- methoxybenzyl-sulfonyl) -5-trifluoromethylbenzoic acid, (4- ^liter- brorabenzylsulfonyl) -5-trifluoromethylbenzoic acid,

(3 ^l -trifluoromethylsulfonylbenzylsulfonyl) -5-trifluoromethyl *. benzoic acid,

Benzylsulfonj ^r l-5-nitrobenzoe.9äure, (2'-methylbenzylidene] sulfonyl) -5-nitrobenzoic acid, (3 ^l -Tr'ifluormethylbenzylsulfonyl) ^{-5-nitrobenzoei:} äure, (^ • -Brcmbenzylsulfonyl) -5-N5T ^ Topzoic acid, (2'-methylbenzylsulfcnyl) -5-nitrobenzoic acid, (3'-methoxybenzylsulfonyl) -5-chlorobenzoic acid, (4'-chlorobenz "! sulfonyl) -5-chlorobenzoic acid, (3 '-trifluoromethy'-lbRn ^ ylf'iilfonyi -. ^ - chlorohenzoic acid, (4 '-Tri fluorine thy lfeeHeyiRulfonylbenzylsulfonyl) -5-bromobenzoe

? (3 '-Methylbenzy] sulf ^ ONJ l) -5-bromben ^ oesäure Benzj ^r lsulfonyl-5-f] uorbenzoeFMure (3,' -lütrobenzylsulfonyl) -5-f luorbenzop <nure, - (3 '-i' -et ^ \ ^r lbenzylsulfonyl) -3-methoxybenzoic acid, (?. '-Iiethorybenzylsulfonyl) -3-nethoryberjroesäure, (^' - chlorobenzylsulfonyl) -3-rr! et ^ oxyb O '-trif luorraethylbenzylsulfonyl) ^ -

^ -E

3- '

J sulfonyl) -f-

ben ^ oes acid,

) -5-trifluorometnoxy-

909844/1779

BATH ORIGINAL

3- (4'-Nibrobenzylsulfonyl) -5-trifluorraethylsulfonylber 3- (3 '

3_ (i). »_ J _o dbenzylsulfonyl) -5-trifluormet-.v ₁ ylRiafonylbenzoeByure, 2-benzylsulfonyl-5-dimethylsulf'imy! Benzoic acid, 2- (3 ^l -.TrifluormethylbenzylBulfonyl) -5-din! Ethylsulfupiylbenzoe-

_ (3 "_i: nthylbenzylcilfonyl) -5-di-n-hexylsulf '. my! benzoic acid,

(T -Methoxybenzyisnlf onyl) -5-cl i-n-he-ylsulf arpylbensoes ^ üre, ' (2'-I - "'- t'-iylben ^ vlsiilfonyl) - ^ ~ N-Mbhvl sulf ^ ni ^ lb ^ n ^ oenraire,

■ (3 '-Pluorben ^ ylsulf oryl) -5-H-phe ^ ylFmlf ^ mylbenzoesau.ro,

• ('·! -' -I ' ^f it crude ^ vlsulf onyl) -nWb ^ -i ζγ lsulfr-iny! Benzoic acid,. (OT ^ H``p ^v ! ^{KV 1} .; / "Lnet ' ¹ ^ ylensiiIf r»' ty3J-J -! - ^ t ^^ 'lberi'io-'ic acid,

■ (Γί - ^ - phthylpie "", '■' ylensii If nnyl) _ $ U_ne bhy! Benzoic acid,

• (ÖC-thio-nylrno ^L% vlensulfon.yl) -5-niet'.ioxybenzoesfiure,

■ (Ί? -! R>: i '- L.ylrn3 h; --ylonsuTf onyl) -5-trif luorme tlioxybenzoesaur-j ",

3- (3 '- ^' iflur

ι- (4 ι -ChlorbenzyltHilfon, l) -3-dibe.nr:ylsulf ^; ; niylbenoic acid,

2- (2 '-I -5 (-. ¹ OyIh -.-;

uilf onyl) -5-N, N-Ethylenesulf-iray! benzoic acid, If onyl) -5-iy, ri-dodec ^ n-i-hylensulfaraylbenzoe

lf onyl ) - '> - * _r _ \ - (2 ' ~: ne il yl) -tetramethyleh-

'9

) i rs t

90 984A / 177

3 5- (CtL ₅ OCH,

5-CF ₃ SO ₂

₅ 4-n-CH ₃ G, H ^ N-5 Cv,

- «& - CHo ₁ 3 • 7
- H' i. 191 1 539 H - Position of
Aryl? Lkylsul-
fcnyleruppe y * Γ ^{1 T} - ~ ^{G: i} 3 VH _? 2 '-Cl TJ C ^ H ₂ G <K, 3 '-H
3 '- ^Ώ Ο • -? R 3 3'-CF ₀ 'jO ,, ·' F. r> ty Ι 3 ¹ -F Ii ^ —C ', -j
1 yi R.
R. 2 al 3'-I 3 V -Toi 3 ^zl ι -'η
'"3 O ₁ -.-. Γ »U" ¹ -ClUi ? c I τ- ^ O C-ti- ° 2 ^C 6 ^H i O · '; I. 3
-F 9 τ ~ I ?. T? '

_S oc - β ^

atelluB L ^ L ·. al .i i Γ ft
™. t 3 '-F -upoe CH ₃ C 5 -CH ₃ 2 6 13 ?; - ^ ^F 3
^ -'- KC ₂
; hv 5-GF ₃ 3 - -. ■, ■ - -I ^ ^K - 3-CF ₃ SO ₂
4- (CH ₃ OCH ₂ CH ₂
5-OGF ₃ ) ₉ NS0 _o i?
2
3 TT 3-sulfyno-5-trifluoromethylbenzoic acid Example 10 1. Manufacturing and the

In a mixture of 150 ml of water and 250 ml of tetrahydrofuran 0.10 FoI 3-amino-5'-trifluorinethylben2oef5äure seaquake. the

The resulting solution is cooled to approximately 18 ° C aJ3P; e), δεπη vxercien

9 0 8 8 4 U / 1 7 7 9

BAD ORSGiNAt

1η.η ·· ^{Γ 80ΠΓ} 50 ml of concentrated sulfuric acid is zuweiset · During represents addition, the T ^ö mpentur de ~ mixtures u 'terlr.ilfc about 30 G ■ ehalten, liach ended Zuynbe vrird the' V-mis ^ h to approximately -2 C abrekühlt, then we added a solution of 8.15 * iuten e- N ^ triumnitrit in sth. ^r r 120 ml Wap.w "nder stirring slowly i 'Vei'3''Uf of approximately 4 * 5 Hj> - .. During this Zueabe the temperature of the mixture is dislocated below ETVr * 5 ⁰ G '·?

The mixture is then stirred for 1 hour and a half minutes at -2 ° C, then about 0.63 Kill of sulfur dioxide are added in the course of 5 minutes. For the accessories of the fiappp, the temperature of the eye will be at about 0 ° G p: ehT.lten. Portions of 2.5 ff finely divided copper are added at intervals of 10 minutes, so that the inP [resanite in the course of 1 1 /? Hours 2 * 5 "· copper introduced xf ^ r'len. Then again ¹ ^ f ⁰ Mioxyd..about 1 hour 1" nc a ^ leads, until the total addition of the component amounts to about 1.26 KoI. V / ähr-nc of the above will ^ ie Temper · door dep Re;? Ktions; enisohs unterte ^ aH-. 3 ° cooling. N '\ ch finished S ^ h ^ ef ^ ldioxvdziuabe is increased l ^ n'-em to 10 ⁰ C. D'uin leaves the rencture for about sixteen hours with roughness. The cheese is separated from the organic layer, the latter i - is bew-nd ^ lt with decolorizing charcoal. D ^ nn confused ¹ einf - een °: t and with chloro-; form ver? * et "t, D-vf r ^oc " ultierf-n ^ «T ^ misch wi-r ^ at pressure arvr <! T; pft to öA · * r ^ nult ^{; <} -r'.nde Kr-iQ-i- ^ i'-is on fttw lB ° C a ": xokühlt ur. · 'Filtered. The 3-sulf ino-5-trifluorotiethylben'roep ^ ure obtained in this way is rocketed with Gt: 3oroform \ tut p-ew *!? Chen vrid at ettvi 50 C.

Her ^ t Z.r.v.T ~ arg j-Benzylsilfon;, 'l-5-tri acidic zy le ^ te rs

0.50 »Ό! ^ -Sulfino-S-trifluorinnethylben ^ O '-. N ^ .ure, 1 ] oil Triäthylair.in nr · - ⁴ 1 "· Ό1? Er." Ylchjoriö vrerden in a liter- w ^! -free acetoritrile dissolved, d - 'nn we ^ the solution 16 hours long; am Eückfüu ^ -eko ^^ i .. D '= cooled after vir ^ r-rxf 8 ⁰ C and d ^ s Di-

l ^^ iä -i-rird abf73tr1ert ^r ürid mit

9098U / 1779 ^{ßA £} >

• - 56 -

va ^ ohen. The filtrate is evaporated under reduced pressure, then about 600 ml of 5% hydrochloric acid are added to the residue. ^l \. The resulting mixture is extracted six times with 1/2 1 ether each time, the Evtr ^Q kte were combined and twice with 0.6 1 Was ρ er p.-ewa ε chen, treated with decolorizing charcoal and concentrated to a volume of 500 ml . One liter of η-hexane is added to this mixture and the resulting slurry is cooled to about 5 °. Dap mixture we ^ filtered, ben with lter to Fe _{W C} and dried at pp R ^ umtemperatur in the air, wherein n in the obinen-benzyl ester is obtained.

3. Preparation of 3-benzy-sulfonyl-5-trifluoromethybenzoic acid

0.10 folic 3- ^{Rf = 'r'} '' ylsulfonyl-5-trifluoromethyl-benzoesäurebenzj ^r lefter vterö.rn i "lO ^ i-rer sulfur acid solution ppi'ocht one hour at reflux. Then the reaction mixture, cooled with urine hydride, made alkaline and extracted with ether, the -wäcprice Fh --- pe is acidified and extracted with ether. The extracts are dried over sodium sulphate and steamed, whereby the 3-benzylsulphonyl-5-trifluoromethybenzoic acid from Benno] zrmnkt 1.8ii-18.5 ° C receives.

Using the corresponding A, minobenzoic acids, the fenzyl sulfonylbene acids listed in connection with Example 9 can also be produced according to the above process,

Example 13

0.10 KoI? .- Eprr-yltrio-5-tr ^: iflurr'npi; hyl-benzoic acid are dissolved in 500 ml of ethanol ei ^ j -.- p.br ^ ht, which contains J.% hydrochloric acid. The mixture is 3 Stu ^ af-n l - '\ r; on Rüokfluii z <-. \ ^ it, diluted it ro water and with H "triumhydroxyd alkaline gePtellt The alkalis solution with" .HER, the extracts are riumsulfpt over anhydrous] <--- ^ e-etrocknet urd eingedap- pft. De ^ ^ i _J de "2-Benzylt> - i ^ - ¹ i-tT'ifluorir ^ t ^^ l-ber. ^ oeppuremej- ^ ylerter existing residue is obtained by distillation at reduced pressure. ^r --erp-i ': irt.

9098 4 ^ / 177 9

; BADORJGtNAL ..

Kit n-propanol or n-butanol can use the corresponding Propyl and butyl esters are prepared by the above process. Using this procedure, the methyl, n-propyl and n-butyl esters of those mentioned in Examples 1 to 10 * Connections made. .

Example 12

0.10 mol of 2-benzylthio-5-trifliormethyl-benzoic acid methyl T-ester are added to 500 ml of an ammonia-hiethanol mixture, and the mixture is kept at room temperature for 5 hours touched. After dilution with water, the 2-benzylthio-S-trifluoromethyl-benzamide separates out of the solution and becomes

The corresponding benzamides of the compounds of the examples 1 to 10 are prepared analogously from their diethyl esters. ■ ■

At 3T) each 13

0.10 mol of 2-benzylthia-5_trifl \ .iormethyl-benzoese'ure are added to 500 ml of an aqueous solution of 0.10 foil hydroxide with stirring. Soba.M everything is resolved _v becomes öie r e- _; sultie'renrie solution lyophilized, whereby 0.10 mol of the sodium salt of the ausrawic acid is obtained.

Using equivalent amounts of the corresponding j

Bases were made according to the above procedure! receive the following salts: |

Potassium, ammonium, calcium and magnesium salts of 2-benzylthio- j 5- tr if luorme thylbenzOes? 'Ure

Ή ^'1 ch obift-efi procedures are also the pharmaceutically ziiläs ^ in ^1-en ^ .hr.ium-, potassium, ammonium, calcium and Kagnesiumsalze Ö3V compounds of Examples 1 to 10 formed.

0.10 Hol crude 2-benzylthio-5-trifluoromethyl-benzoessure, Set up according to procedure 1, pour into one liter while stirring an aqueous solution of 0.05 mol Ba (OH) ^. 8HpO added. the

9.09844 / 1779

Solution is extracted with ether and lyophilized, whereby; man 0.05 mol of the bariura salt of the starting acid is obtained.

The barium salt is then added to water, the resulting solution is acidified and the purified 2-benzylthio.5-trifluoromethylbenzoic acid which separates out is isolated. The pharmaceutically acceptable salts of this acid can be prepared according to the procedure of Example 13 .

Using the equivalent kengen of the deprecated Bases become the cesium and strontium «= Iz of the above acid

fc produced analogously.

These salts are according to the above method in the example 13 mentioned pharmaceutically acceptable Seize transferred. Do According to the above process, the pharmaceutically unacceptable barium, strontium and cesium salts of the compounds can also be used Examples 1 to 10 are produced,

Example 15 .

Three groups of k · normal male Sprague-Dawley (Charles River ) rats each were fed a dish of 160 to 220 g each with Purina rescue food. One group, which serves as a comparison group, is fed only with rat chow. A second group 'will this? buttermit 0.25 Gev /, -? l 2-Bear ': ^r lthio-5-trifluorineth; / l-benzoic acid ver ^ "■ ^ dispenses, the third group contains the Gutter with .0.25 ~ Ge ^ r * '-%' ■■ "? " p-Chlorphenoxyisobutt ^ r ^ aure, a 'hypolipäniischen gown according to the state of the art,

The obiscus products are administered to the hats during two nightly feeding periods. On ΐοτζ ^ ο of the third day they are anesthetized and bled from the TJnterle ^ oseorta, ~

The total plasma cholesterol in the solidified blood is determined by the method of 7, J. Garr and IJ Drekter, Clin, Chem, 2 *, 353 (1956).

9 0 8 h θ 4 / \ ia * & ^ - ~ ^ t BAD

The cholesterol level in the group fed putter containing 2-benzylthio-5-trifluoromethylbenzoic acid was significantly below the level found in the animals fed a feed or additive; he further Ir t P ^- Unstiffer.als cholesterol Spie ^ el at the t ^ th, the putter with a known hyix>Lit> ämisehen the steps], namely r> -OhlorOhenoxvisobutterpäur ^»1, received.

Repeated irr>r> eye obigre Verfahrp.n with other-s compounds of Examples 1 bie 13 'so bowlers similar ErgebniF ^ e ER-

Two groups of 4 dogs each with a similar crew were treated as follows: One group was fed orally, susan with the usual dog food, twice with a thorn of 50 to 100 m «r / k: r administered 2-benzylthio-5-trifluoromethyl-benzoic acid, while the animals of the broad group leruirlic! ^{1 received} dog food.

The animals were on this VJ ^ ise two weeks, lanpr del t, -Each r'wide Tr.tr was the Serura-Cholp- ^ terln'-ehai t and-

The Ohol ^^ te ^ ijis ^ ie ^ -el we ^; e lvcli op "! ■> ■ *"? * ode by JJ, Carr and IJ Drekter, Glin. Chemical "P _-., ~ ^ (^ IQ), the TRLE Iy ¹ Oi ^ j-el na h ^ l'ethod of E. V" -n H ^ ^ nn l and ^). "P. ZiI-th, « ^T. LpI :. ^ C ^ä 5.n. Keä., ^ 0, 152 (I ³ 57l determined.

pterir- und Triclyceriö ^ev> ierel of the dogs, never had the 2-Boncyl t -'- io-f-örifluor ^ ethyl-baiiiioeE / ure, is essential ^ i "'' ^ ir" r alp b ^ i de- n sub-Vd = Ith animals.

More analogous 3r.-Ronis ^c e were evi-'t, vrenn m "n obi e? Procedures with the compounds according to Example 2e ^ 1-13 repeated.

90Ö84A / 177

Claims (1)

Pe t escape 1. Connections of the formulas NS, X ₁ CO ₂ H SCH ₀ ¹ CO ₂ H * in those ■ H = CHo, CPo, or NO ₂ J and X = H, -CH ₃ , CH ₃ O-, -NO ₂ , 01, Br, P, I, -CP ₃ or CP, their amides, nip ^ ere alkyl esters and salts with bases. 2. Compound of formula • SO O H; in the . R = CH ₃ , CF ₃ , or NO ₂ J - X = H, 'CH ₃ CH ₃ O-, -FO ₂ , 01, Br, F, I, -CF ₃ , or CP ₃ SO ₂ J their amides, lower allyl esters and seize "with bases. 3. Connections of the formulas 9098A4 / 1 779 BADORfGINAI, ^l or NS. X, R CO ₀ H CO _? H "SO, γ = pt, -CT-L ,, CH ₃ O-, -ro _{? t} Br, Cl, P, I, -CP ₃ or CF ₃ SO ₂ -R ¹ = Cl, Br, F, -OCF .., - ⁰ HH ₃ , 'Ti ₃ SO ₂ -, (CH ₃ OCH ₉ CHp) ₂ - viobej R * "ii.ar] R-". ■ ie-'nils Wf - ^ - ^ ¹ ^? - ¹ - ^ toff, alkylP-groups nit Mr to 16 .iiFi'l'off. ° tonori, aryl- or -aralkyipruripen with up to 10 l ^ r- or alkylpoly- Γ "tomer, n ^ e · ¹ " zu.s \ rni-en
hylenß-run-npn. with hi "to check 15 carbon atoms, υη der» Γ-ϊί ^1. ^ CV ¹ I-IP, that R 'and R · not ^ leioh ^^ itia · hydrogen rler? n -Ämicie, - nieflpre Alkylertei. "" and Seize with bases, ^! 5'f ^a n der or CO. ^ CO _n rl 3 OH- ¹ 909844/1779 bath in which . R ^ = H, -CH. ,, -CP ₃ , -NO ₂ , Cl, Br, η ¹ , -CCH ₃ , C CP ₃ SO ₂ -, (GH ₃ CGHpCK ₂ ) _o ITSO ₂ - or (R ² R- ¹ JHSO ₂ -, R "and R- .ieiTPils V / qp ^ erstoff, alkyl c-groups with up to 16 Carbon atoms, aryl or aralkyl fruopes. with up to IC carbon atoms, or 3U3 ⁿ mrnen PoDymet ^ Tlen- or Alkylpol.ymethylengrmrreri with up to 15 carbon disguise d ^r r ~ share, imter der I-Ir..ßg- ^o be, d-'FR "and R" not both the same no oxygen, -CH _? -flf-i \ -phthyl, -ir " ₂ -ß-naphth; -l, -CHg-a-thi ^ ryl or - • IHg-ß-thienyl-, or'CP ₃ SO ₀ -J ';;''-''-'- η = 0-3 j ■: ■■■■ '■ R and R '' - / as.τ er? ^: -t off, iiioclere Alk ;, lyru ^ vsr- r: it up to 6 Kohlens boffatoKOi :: oö.t :? Zv .. ... t-- '. fet ¹ Γοΐ '"- ~ 1 i.iv; · .-- share, under the r-feß ^ c, ce, dr.fi Ώ ° urd Ξ 'not beiöe ;; & s- are hydrogen if η = 0, deran amides, lower alkyl esters and sal? e xr.it Easeaa. i - 5. 5-chloro-2- (p'-chlorobenzene ^ ylthioJ-ber ^ oesaü-re der Forirel 909Ö44 / 1779 '* - - .--. ,; . BATH ORIGINAL 6. 5 ~ C ^; '3or -: :-( o'-Chlorbenzyitliio) -benzoic acid -oe formula : o _c H Cl 7, 5_Trifluoromethyl-2 ~ (p ^t -Chlorbenzylthio ^ -ber - oe '-' acid of the formula CF 00 ,, Η Cl formula orne-U * iyi-.2- (in ^l -ChlQrb ⁱ 3 ^r izylthiG) - "t: sMure der; CF ^ nCO _? H S-IH, n.f-r For ι- ""! 909844/17 10. 5-Trifluoromethyl-2- (3 ', 4'-Dimethyl-benzylthio) -benzoene · acid of the formula 11. 5-Trifluoromethyl-2- (tf-methyl-benzylthio) - "benzoic acid the formula Ch ^r p .. Pfizer & Co., Ine, Ne-York, NY, V.St.A. 909844/17