DE1568302B - Rhodanine derivatives and process for their preparation - Google Patents

Description

Rhodunindcrivuie of the general form
X ₁ - Ν - Ο

X ₁ JJ s- _s U

III

-NH,

either

a) with thiophosgene / u phenylseniols of the allizeminen formula

X ₁ - ^; · -NCS

unc this then with a u-Mercapiofcttsüurc the general formula

H SCHRCOOH

to compounds of general formula I or

b) with carbon disulfide in the presence of an organic or inorganic base / u a dithioearbamic acid derivative the general formula

x, - ^J

NH

s - ■■ c

(Uli

in which A means an inorganic cation or a basir.ch.es organic radical, umsct / t and these compounds either
with an alkali salt of an - »- llaloginfcttsäurc of the general formula

HaICHRCOOII

brings to reaction and the resulting carboxymethyldithiocarbamic acid derivative of the general formula

h2 | by alkylation into the dithiocarbamic acid S-alk> l ester the general formula

_I5 χ.-

X ₁ -

X ₂ -L.

--HN HO-C = O - NH

S = C

in which Xi and X, each a chlorine atom and X ₂ also denotes a bromine atom and R denotes a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, show excellent molluseacide. anthelmintic or ascaricidal properties.

These compounds are prepared by using aniline derivatives of the general formula S.

S C

CHR

(IVi

heated or converted into a l'hcnyl mustard oil with lead or zinc salts and this as under a) further processed or

in which B is an alkyl group, converted and these compounds with a <i-mercaptofenic acid of the general formula

HSCHRCOOH

at 150 to 250 C or

b3) by reacting with lead or zinc salts in on Phenyl mustard derivative transferred and this how further processed under a).

The bases for process variant a) are /. B ammonium hydroxide. Alkali hydroxide, such as sodium hydroxide. Potassium hydroxide. , .'-dimethylaminoethanol or N-ethylpiperidine. used. The reactiv. is suitably at a temperature between 25 and 40 (preferably, at 30 to 35 C. in small; performed · excess of carbon disulfide by some Pnzenten and Jas reaction mixture IIk allowed to stand overnight to ensure a complete Reakn ■■■ ;;...

The i; vthiocarbamic acid derivatives of the general formula obtained in this addition reaction; '■] are new and also show anthelmintic u, ..: molluseacid properties.

As the alkali salt of a Ί-halo acid. the - ;, - _: from iLt Fissig-. Propionic. Butter or Valcriansa: u derives, according to process variant bll »o; vu . ■ wise the potassium or sodium salt is reacted with a compound of the general formula III - optionally without isolating it beforehand. [) The reaction is carried out in aqueous or organic Me.l · - iim. like ethanol. Methanol. Dimethylformam ■■ [ carried out and takes a few hours.;, After acidification, the corresponding.!.

N - (3.4 - Dihalophynyl) - S - carboxymcthyhluhi. carbamic acid derivatives of the formula | V. Extract the loader reaction mixture with ether. and also have anthelmintic and molluseacid I jl'.h shafts.

The ring closure of these connections is successful! \ .τ-zugswcisc in the presence of a dilute mine 'acid, e.g. B. hydrochloric or phosphoric acid, or a strong organic acid, e.g. B. acetic acid. The reaction is expediently carried out in an apolar organic solvent (for example benzene or toluene , and the water formed during the reaction is removed by azeotropic distillation.

According to a preferred procedure, from the reaction of the dithiocarbamic acid

<*> derivatives of the general formula III with the alkali salt of the ii-halogen fatty acids obtained reaction mixture, the rhodanine derivative of the general formula I is prepared immediately by heating after acidification. Any existing impurities Carboxymethyldithiocarbamic acid derivatives of the formula IV can be obtained from the rhodanine derivatives of the formula I by washing with ether remove.

According to process variable b2), the dithiocarbamic acid derivatives of the general formula III, optionally without isolation - in the form of their salts are alkylated in an alcoholic medium. e.g. with dimethyl sulfate. Diethyl sulfate. Methyl, fcromid or ethyl bromide. The obtained dithiotarbamic acid S-alkyl ester general formula V also has anthelmintic and molluscacid effects.

The dithioearbamic acid S-alkyl esters of the all-in-one Formula V can be - if appropriate without isolation - by reaction with expedient animal equimolar amount of the corresponding u-Mercapuv fatty acids with ring closure in the melt at a Temperature between 150 and 250 C. preferably i> at 200 ° C. into the rhodanine derivatives of the formula I. run over.

Ais preferred lead or zinc salts according to the process variant bl) or b3) are used for lead nitrate and zinc sulfate.

example 1

a) 162 g of 3,4-dichloroaniline are added to 200 ecm In absolute ethanol, the mixture is heated with stirring r.s / ur complete solution, then cools to 3d C 2s .! ■ ·. gives 165 ecm concentrated ammonia solution and i ι Ό ecm carbon disulfide too. being an exotherm Reaction instead of finv.ei. cools the reaction mixture obtained. mix slowly and stir for 2 hours at ambient temperature. the ammonium salt of N- (3.4-di- the mixture with 100 ecm of water, stirred for another hour at room temperature and left that '. Stand lemically overnight at 0 to -5 C. The. '! ag from. washes it with carbon tetrachloride and r.icknct it. 180 g of the ammonium salt are obtained ..!:; · N - (3.4 - dichlorophenyl - dithiocarbamic acid. Vhmp. 93 to 94 C.

A solution of 47.5 g of monochloroacetic acid in 100% of water is mixed with a solution of. ¹ % of sodium hydroxide in 10% of water and the aqueous sodium hydroxide solution obtained is added to a suspension of 125.9 g of the ammonium salt of N- (3,4-dichlorophenyl) dithiocarbamic acid in t-2 (H)% of water. The resulting reaction mixture is stirred for 5 hours at room temperature, 250 μm of concentrated hydrochloric acid are added the following day with vigorous stirring, and the precipitate which has separated out is filtered off. washes it with water. v> solves it in 800 ecm Athcr. separates the water ah. the ethereal phase dries over anhydrous sodium sulphate and the ether is distilled off. Man ei hai; 125.6 g of N- (3,4-dichlorophenole S-carboymetin! -D; thiocarbamic acid (in air-dry statei. I), is s-product melts at 127 to 130 ° C, solidifies again with further heating and then melts at 156 to 158 ° C .

c) 89 g of the N- (3,4-Diehlorphenyll-S-carboxymethyldithiocarbamic acid thus obtained it is heated in f> o 800 cm of a 1: 1 dilute aqueous hydrochloric acid Boil for 30 minutes while stirring, then cool ah. the deposited precipitate is filtered off and washed him with 500 ecm of water. The precipitate obtained in this way is heated to the boil with 200 ecm of ethanol. f> 5 cools the suspension obtained. the precipitate is filtered off. washes him with alcohol. him then in 250 ecm warm ether.

the suspension cools down and the precipitate obtained is filtered off. washes it with 100 ecm ether and dries him. 58 g of 3- (3 ', 4'-dichlorophenyl) rhodanine are obtained. M.p. 180 to 182 C. According to Finengen the alcoholic and ethereal mother liquor gives a further 4 g of the product.

Example 2

Fine solution of 0.5 g (0.1 Moll monochloroacetic acid 4 g of sodium hydroxide in 16 com of water are added to 20 ecm of water, and the sodium monodiloroacetate solution obtained is added with a solution of 25.51 g of aes ammonium salt obtained according to Example 1 a) the N- (3.4-dichlorophenyl) -dithiocarbamic acid mixed in 25 ecm of dimethylformamide. You get first a homogeneous solution that warms up slightly, and after about half an hour the precipitation of a crystalline precipitate begins. The reaction genius it is stirred for 2 hours, left to stand overnight, and 50 ecm more concentrated is added on the cowardly day Hydrochloric acid, heats it to the boil for 20 minutes, then cools it down. filtered off the precipitate and washes it with water. The precipitate is then heated to boiling with ~ 0ccm ethanol and then cooled away. filtered and suspended the precipitate obtained in 20 ecm of ether.

The deposited precipitate is filtered off and washed. 14.3 g of 3- (3'.4'-dichlorophenyl) rhodanine are obtained. Mp. 1X1 to 1 S3 C ". By concentrating the alcoholic and ethereal mother liquors. Filter. Washing with ether and drying of the precipitated product are a further 2.2 g of the product obtain

Example 3

Fin mixture of 7.4 g of the according to example Ib) obtained N- (3,4-dichlorophenyl-S-carboxymethyldithioearbamic acid and 30 ecm of acetic acid are heated to the boil for 20 minutes, initially a clear solution is obtained from which then a crystalline one Product precipitates, which is filtered off. with 5 ecm acetic acid washes, slurried in 25 ecm of ether and dries. 4.3 g of 3- (3'.4'-dichlorophenv ') rhodanine are obtained. Mp. 1X0 to IXl C The Mutler liquors deliver more Concentrate another 0.5 μ of the product.

Example 4

7.4g of the N- | 3.4-dichlorophenyl) obtained according to example lh) - S - carboxymethyl - dithioearbamic acid are heated to boiling in 50 ecm toluene for 2 hours, then the greater part of the toluene is distilled off, with that formed during the reaction Water au. ;! cr reaction is removed. The residue one cools off. liltricrt the precipitated crystals, muddy them in a small amount of ether aiii, Tütricrt again, washes the precipitate with it Ether and dry it. 5.2 g of 3- (3 ', 4'-dichlorophenyl) rhodanine are obtained. Mp. 172 to 175 ° C, the after recrystallization from ethanol to 179 to 181 ° C increases. Isolated from the toluene ether mother liquors one more 1.5 g of the product if left to stand overnight.

Example 5

A solution of 20.6 g of 3-chloro-4-bromaniline in 25 ecm of alcohol are mixed with a solution of 11.7 g of dimethylaminoethanol in 15 ecm of alcohol and then adds 7 ecm of carbon disulfide. the

568

Reaction decreases with slow heating approximately

3 hours to complete. Thereafter, it is 30 cc of an aqueous, neutralized with sodium hydroxide solution of ^l) .5 g of monochloroacetic acid at room temperature to iiihI riihri S hours hei room temperature. slow warming is observed. With continued stirring, 50 ml of concentrated acetic acid are added and the mixture is refluxed for 20 minutes, an ocher-yellow oil separating out. After the boiling has ended, add 200 ecm of water while stirring vigorously and place the mixture in the refrigerator for a few hours. The precipitate is then filtered off, washed with distilled water, dried and pulverized. 10.5 g of 3- (3'-ChIoM'-bromophenyl! -Rhodanine are obtained, the melting point of which, after purification by heating to boiling, is 50 ecm of alcohol. Filter off, wash the precipitate with alcohol and dry.

Example 6

a) A suspension of 25.5 g of the according to Example 1 al obtained ammonium salt of N- (3.4-Dichlorpheiwli-dithiocarbamic acid In 60 ecm of methanoi, 5 ecm of dimethyl sulfate are added under intensive stirring added dropwise from 15 minutes and the dropping funnel was washed with 15 ecm of methanol. One observes warm up slowly and stir the reaction mixture 3 hours at room temperature, then warms it to 40 C. It holds on for another 2 hours this temperature, treated it with activated charcoal and filtered. Then you put it under intense Stir with 400 ecm of distilled water, filter the obtained precipitate. washes it with distilled water and dries it. 19.75 g are obtained of the crude N- (3,4-dichlorophenyl; -dithiocarbamic acid-S-methyl ester. Mp. 122 to 125 C.

b) 25.2 g of the methyl ester obtained are heated with 11.5 g of XO'Oiger thioglycolic acid within 15 minutes to 200 ° C. and the mixture is kept at this temperature for 5 to 10 minutes, during which time it melts. f) then the mixture is cooled. admits 30 ecm of methanol. heated to boiling, filtered off the precipitate and recrystallized it from ethanol. 3- (3'.4'-dichlorophenyl) -rho- ** ■ danin is obtained. Mp. 177 to 179 C.

Example 7

A solution of 16.2 g of 3,4-dichloroaniline and 1.3 g N-Ethylpiperidin in 40 ecm ethanol is mixed with 7 ecm carbon disulfide. The reaction takes 3 his

4 hours to complete, and the mixture solidifies / u fincm Kristallbrci.

A solution of ISg • -uromopropionic acid in 30 ecm of water is added to this crystal bridge. which is neutralized with 40% sodium hydroxide solution. Heat the reaction mixture on the water bath while stirring until a homogeneous solution forms, and let it react for half an hour. After the addition of 50 cc of concentrated hydrochloric acid, heating the mixture ⁰ ^ 20 minutes intensively at the boil to give a yellow oily phase separates. Then 350 ecm of distilled water are added. decanted off most of the aqueous phase. are again 350 cc of water and allowed to cool, the oil solidifies to a crystal mash ^fl. 5 If crystallization starts only with difficulty, the aqueous phase is decanted. add 100 ecm of methanol and cool the mixture with vigorous shaking in an ice-salt-water mixture. Under these conditions, the crystallization takes place in a short time. The crystalline reaction mixture is provided. Night in the refrigerator, then filtered off Jen precipitate. washes it three times with 10 ecm of methanol each time and dries it at room temperature. 20.5 g of 3- (3'.4-dichloroplienyU-5-methylrhodanine are obtained, which is purified by heating to boiling in methanol. Mp. 161 C.

Example p

The procedure is as in Example 7, but instead of ISg .i-bromopropionic acid 20g .i-bromo-n-butter- • 5 acid used. 22.6 g of 3- (3'.4'-dichlorophen \ l | - 5 - ethylrhodanine. which is purified by boiling in methanol. M.p. 130 C.

Example 9

2O The same as in Example 7 \, but instead of ISg ./-Bromopropionic acid, 21.6 g of w-bromo-n-valeric acid are used. 13.2 g of 3- (3'.4'-diclilorphen) l) -5-propvlrhodanine are obtained. which is cleaned by methanol treatment. M.p. 92 C.

Example IO

The procedure is as in Example 7, but instead of 16.2 g of 3,4-dichloroaniline, 20.7 g of 3-chloro-4-bromaniline were used. 2S.9 g of 3- (3-chloro-4-bromophenyl) -5-me (hylrhodanine are obtained. which melts at ISl C after purification in boiling methanol.

3> B e i s ρ i e I 11

Proceed as in example 7, but instead of 16.2 g of 3,4-dichloroaniline and IS g ./- bromopropionic acid c 20.7 g of 3 - ('chloro-4-bromoaniline and 20 g of n-bromon-butyric acid are used. 26.4 g of 3- (3-chloro-4'-bromophenyl) -5-ethylrhodanine are obtained. which melts at 157 C after purification in boiling methanol.

Claims (7)

Patent claims:
I. Rliodanine derivatives of the general formula X, N O in which X ₁ and X _{2 are} each a chlorine atom and X _: besides. represents a bromine atom and R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. 2. Process for the preparation of rhodanine derivatives according to Claim I, characterized in that that one aniline derivatives of the general formula X, - / ^N NH ₂ either with thiophosgene to phenyl mustard oils of the general formula NCS and this then with a fi-mercapto fatty acid of the general formula '° HSCHRCOOH to compounds of the general formula I or '5 ) with carbon disulfide in the presence of an organic or inorganic base a dithiocarbamic acid derivative of the general formula (MI) in which A is an inorganic cation or a basic organic radical and these connections either 1) with an alkali salt of a -halo fatty acid of the general formula HaICHRCOOH brings to reaction and the obtained Carr> oxymethyl - dithiocarbamic acid derivative of the general formula 35 HN HO-C = O S = C CHR (IV) 45 Phenyl mustard oil transferred and this as under a) further processed or b 2) by alkylation into the dithiocarbamic acid S-alkyl ester the general formula i NH SB heated or converted with lead or zinc salts into one in which B is an alkyl group and these compounds with an x-mercapto fatty acid the general formula HSCHRCOOH at 150 to 250 C or
b3) converted into a phenyl mustard oil derivative by reaction with lead or zinc salts and this is further processed as under a). 3. Expire according to claim 2, characterized in that that in process variant b) as the organic base ^ -dimethylaminoethanol or N-ethylpiperidine and used as inorganic base ammonium or sodium hydroxide. 4. The method according to claim 2 or 3, characterized in that the thermal ring closure according to process variant b 1) in an acidic medium, preferably at a temperature of 80 to 12OC. stirs. 5. The method according to claim 2 or 3, characterized in that the alkylation after of process variant b2) with dimethyl sulfate or diethyl sulfate in an alcoholic medium performs. 6. The method according to claim 2 or 3, characterized in that one is used as lead or zinc salts for process variants bl) and b3) lead nitrate or zinc sulfate is used. 7. The method according to claim 2, characterized in that that the reaction of the phenyl mustard oil derivatives according to process variant a) with a (i-mercapto fatty acid carried out in the melt.