DE2259222A1 - NEW, 1,1-DIOXOTHIAZOLIDIN-4-ONE AND THE METHOD FOR THE PREPARATION - Google Patents

Description

New l, l-dioxothiazolidin-4-ones and processes for their preparation

The present invention relates to new i, l-dioxothiazolidin-4-ones as well as a new process for their production

It is known from the literature that by reacting compounds which contain a ^^, C = N group with α-Halocarboxylic acid halides in organic solvents and azetidinones are formed in the presence of an organic base.

It has now been found that, surprisingly, when sulfur dioxide is used as a solvent, new 1,1-dioxothiazolidin-4-ones can be obtained.

The present invention therefore relates to new 1,1-dioxothiazolidin-4-ones of the formula I.

^R 2

π 2 ₃ NR ₃ (I),

SO ₉ C = 0 M ^{2 4} /

A-

R ₄ R ₅

ft

in which '

R. and R2 independently of one another are hydrogen, one

30982S / 1132

CIBA-GEIGYAG 2

aliphatic or araliphatic hydrocarbon radical, mean an aryl radical or a 5-membered heterocycle containing 0 and / or S atoms or

R ₁ and R "together with the ring carbon atom to which they are attached form a cycloaliphatic ring with a total of 5 to 8 carbon atoms,

R _{3 is} an aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, an aryl radical or a heterocycle connected directly or via 1 to 3 methylene groups to the ring nitrogen atom, in particular a 5- or 6-membered heterocycle and

R, and R ₁ . each a halogen atom or
R, hydrogen, an alkyl radical with 1 to 5

Carbon atoms or an aryl radical and R ₁ - represent a halogen atom, as well as a new process for the preparation of the compounds of the formula I by adding a compound of the formula II R,

^ C = N-R- (II),

where R ,, R «and R _{3 have} the meaning given under formula I, in liquid sulfur dioxide and in counter

309825/1132

CIBA-GEIGYAG

wart a tertiary organic base and optionally an inert organic solvent with a α-halocarboxylic acid halide of the formula III

R,

^ - CO - Y (III),

where Y is chlorine or bromine and for R, and R ₁ . what is stated under formula I applies,

converts, the compounds of formula II and III and the tertiary organic base in at least molar Quantities are used.

Preferably at least one of R 1, R 1 and R-j represents an aryl radical. -

_{Particularly suitable aliphatic hydrocarbon radicals represented by R 1} , R 1 and / or R 3 are saturated or unsaturated, unsubstituted or substituted alkyl groups with 1 to 8 carbon atoms in the main chain. In the case of R 1 and R 1 it is preferably a matter of saturated unsubstituted alkyl groups having 1 to 8 carbon atoms, while Ro is also unsaturated or by an alkoxy or alkylthio group with 1 to 4 carbon atoms each

Alkyl part or an -N group substituted alkyl

2
residues with 1 to 8 carbon atoms in the main chain

309825/1132

CIBA-GEIGYAG

can represent, where X- and X «are independent of one another denote an alkyl radical having 1 to 8 carbon atoms, an allyl or benzyl radical, or X and X ″ together with the nitrogen atom to which they are bound, optionally including a further hetero atom, a cycloaliphatic ring with 4 to 7 carbon atoms, especially a piperidine, 4-methylpiperazine or morpholine ring.

Examples of such alkyl radicals are: methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, n-amyl, n-hexyl, n-octyl, Allyl, methoxyethyl, ethoxyethyl, n-butoxyethyl, methylthioethyl, n-butylthioethyl, dimethylaminoethyl, Di-n-hexylaminoiithyl, di-n-octylaminoethyl, dibenzylaminomethyl, Dicyclohexylaminoethyl, diallylaminoethyl, piperidinoethyl, 4-methylpiperazinyl-l-n-propyl- and morpholino-n-propyl groups.

Places R ,, R_ and / or R "araliphatic Hydrocarbon residues are, for example the phenethyl radical, but especially the benzyl radical.

By R ,, R ₂ »R q / R aryl radicals represented and or, may be unsubstituted or substituted. In general, preference is given to substituents which have a negative influence on the aryl radical, such as

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CIBA-GEIGYAG

2253222

Halogen atoms, trifluoromethyl, nitro, cyano, alkyl sulf onyl or phenylsulfonyl groups. R-, .R "and / or Ro represent in particular unsubstituted or halogen atoms, such as chlorine, bromine or fluorine, trifluoromethyl Nitro, cyano, phenylsulfonyl, alkylsulfonyl, alkyl, alkoxy or alkylthio groups, each with 1 to 4 carbon atoms in the alkyl part represent substituted phenyl radicals or unsubstituted α- or ß-naphthyl radicals, while the aryl radical R, especially the unsubstituted phenyl radical, comes into consideration. R, as an alkyl radical with 1 up to 5 carbon atoms is e.g. methyl, ethyl, isopropyl, n-propyl, η-butyl, sec-butyl, tert-butyl or n-amyl group.

If R, and R ^ each mean a halogen atom, so
it is especially chlorine, bromine or fluorine; if R ₁ and R 1 - are not identical, R ₁ - as a halogen atom is preferably chlorine or bromine.

As represented by R ^ and / or R ~ 5-membered Heterocycles containing O and / or S atoms may be mentioned: the 1,2-Oxäthiolanrest, in particular but unsubstituted thienyl and furyl radicals, such as the 2-thienyl and 2-furyl radical.

If R- represents a cycloaliphatic radical, it is primarily a question of cycloalkyl radicals with 5

309-825 / 11 32.

up to 8 carbon atoms, especially the cyclohexyl radical.

For R ₃ meaning a heterocycle connected directly or via 1 to 3 methylene groups to the ring nitrogen atom, there are above all unsaturated N, O and / or S atoms containing, optionally condensed, but especially 5- or 6-membered, heterocycles in Consider, for example, thienyl, benzothienyl, furyl, pyrazolyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, benzthiazolyl and oxazolyl radicals, for example by halogen atoms, especially chlorine or bromine, trifluoromethyl -, nitro, alkyl or alkoxy groups with 1 to 4 carbon atoms each can be substituted. As a heterocycle as defined, R ^ is advantageously an unsubstituted thienyl or furyl radical or an unsubstituted pyridyl, pyrimidinyl or triazinyl radical connected to the ring nitrogen atom directly or via a methylene group.

Form R, and R „together with the ring carbon atom to which they are bound, a cycloaliphatic ring with a total of 5 to 8 carbon atoms, so it is preferably the cyclohexyl radical.

1,1-Dioxothiazolidin-4-ones of the formula I in which R _{1 is} hydrogen, R "is a un-

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substituted or by halogen atoms, trifluoromethyl or alkyl groups with 1 to 4 carbon atoms substituted phenyl radical, Ro is an unsubstituted one or by an alkoxy group substituted alkyl radical with a total of 1 to 4 carbon atoms or one unsubstituted or by halogen atoms, trifluoromethyl * - or alkyl groups with 1 to 4 carbon atoms substituted phenyl radical and R, and R- each chlorine, bromine or fluorine or R, hydrogen and R, - represent chlorine.

According to a further preference, R is hydrogen, R _nd R ₃ independently represent an unsubstituted or Halögenatome or Trifluormethyigruppen substituted phenyl and R, and R ₅ are each chlorine,

The compounds of formula II are known., Or can be prepared in manner known per se by reacting corresponding aldehydes or ketones with appropriate primary amines ^1.

CIBA-GEIGV AG

Examples of suitable compounds of the formula II include:

N-benzylidenemethylamine, N-benzylidene-n-propylamine, N-benzylidene-isopropylamine, N-benzylidene-n-butylamine, N-benzylidene-sec-butylamine, N-benzylidene-tert-butylamine, N-benzylidene-n-pentyl-, -n-hexyl- and -n-octylamine, N-benzylidenecyclohexylamine, N-Benzylidenallylamine, N-Benzylidenebenzylamine, N-benzylidene-ß-phenylethylamine, N-benzylidene aniline, N-benzylidene-4-chloroaniline, N-benzylidene-S.S-dichloroaniline, N-benzylidene-S-trifluoromethyl-A-chloroaniline, N-benzylidene-4-fluoroaniline, N-benzylidene-3-methylaniline, N-benzylidene-4-methoxyaniline, N-benzylidene-2-methylthioaniline, N-benzylidene-4-nitroaniline, N-benzylidene-3-trifluoromethylaniline, N-benzylidene-3,5-bis-trifluoromethylaniline,

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CIdA-GEIGYAG

N-benzylidene-2-methoxyethylamine, N-benzylidene-2-ethoxyethylamine, N-benzylidene-2-methylthioethylamine, N-benzylidene-2-dimethylaminoethylamine, N-benzylidene-2-di-n-hexylaminoethylamine, N-benzylidene-dlbenzylaminomethylamine, - N-benzylidene-2-dicyclohexylaminoäthylamin, N-benzylidene-diallylaminomethylamin, N-benzylidene-2- (piperidino) ethylamine, N-benzylidene-2- (4-methyl-piperazinyl-1 ^{f 1)} n-propylarain, N -Benzylidene-2-thienylamine, N-benzylidene-2-furylamine,

N-benzylidene-2-thienylmethylamine (N-benzylidene-2-thenylamine), N-benzylidene-furfurylamine, N-benzylidene-pyridyl-2-, -3- or -4-amine, N-benzylidene-pyrimidinyl-2-amine , N-benzylidene-s-triazinyl-2-atnine, N- (3 ', 4' -dichlorobenzylidene) -aniline, N- (3 '^ 4'-dichlorobenzylidene) -2-methoxyaniline, N- (2', 6 '-Dichlorobenzylidene) -isopropylamine, N- (4 ¹ -nitrobenzylidene) -aniline, N- (3 ¹ -trifluoromethylbenzylidene) -aniline, N- (4 * -methylbenzylidene) -aniline, N- (4'-methoxybenzylidene) -aniline , ^λ:

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N- (3'-methylthiobenzylidene) aniline, N-isobutylidene-2,6-diethylaniline,

N-ethylidene-aniline,

N-n-heptylidene aniline,

N- (α- or ß-napthylmethylene) aniline, N- (α-naphthylmethylene) benzylamine, N- (2'-thenylidene) -ß-naphthylamine,

N- (2 ¹ -henylidene) -a-naphthylamine,

N- (2'-furfurylidene) aniline,

N-cyclohexylidene-aniline,

N- (phenethylidene) aniline,

N- (benzhydrylidene) methylamine,

N- (α-methylbenzylidene) -3-trifluoromethylaniline.

The α-halocarboxylic acid halides of the formula III used in the process according to the invention are also known or can in a known manner by halogenation of the corresponding carboxylic acid halides can be obtained.

Suitable compounds are, for example: dichloroacetic acid chloride, dibromoacetic acid chloride, difluoroacetic acid chloride, Dibrornacetic acid bromide, chloroacetic acid chloride, Chloroacetic acid bromide, a-chloropropionic acid chloride, α-chloro-n-caproic acid chloride, α-chloroiso-caproic acid chloride, α-chloro-n-valeric acid chloride

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and α-chloro-α-phenylacetic acid chloride.

Preference is given to using dihalocarboxylic acid chlorides in the process according to the invention, such as dibromo- and difluoroacetic acid chloride and especially dichloroacetic acid chloride, or chloroacetic acid chloride *

Tertiary organic bases which can be used in the process according to the invention are above all tertiary Amines into consideration, especially trialkylaminesj Ν, Ν-dialkylanilines and triphenylamine, such as trimethylamine, Triethylamine, tri-n-propylamine, tri-n-butylamine, triisopentylamine, Ν, Ν-dimethylaniline, Ν, Ν-diethylaniline, and heterocyclic systems with tertiary nitrogen atoms, such as 1-aza-bicyclo [2,2,2joctane, 1,4-diaza-2.2.2J octane, pyridine and alkyl pyridines. Pyridine and very particularly triethylamine are preferred.

Although the reaction components and the tertiary organic base also used in excess can be used, the compound of the formula II, the α-halocarboxylic acid halide of the formula III and the tertiary organic base preferably in a mutual oil ratio of 1: 1: 1 to about 1.2: 1: 1.2.

If an inert organic solvent is added to the reaction mixture, in particular

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CIBA-GEIGYAG

aprotic organic solvents such as optionally halogenated aromatic or aliphatic solvents Hydrocarbons, e.g. benzene, toluene, xylenes, chlorobenzene, methylene chloride, 1,2-dichloroethane, chloroform and carbon tetrachloride, N, N-dialkylamides of lower monocarboxylic acids, such as dimethylformamide and dimethylacetamide, also ethers and ethereal compounds such as diethyl ether, dioxane and tetrahydrofuran.

However, it has proven to be expedient to carry out the reaction in pure sulfur dioxide. The liquid sulfur dioxide is preferably used in at least a 5-fold molar excess, in particular an approximately 10 to 20-fold molar excess is used.

The reaction according to the invention can be carried out either under normal pressure or in an autoclave. Carried out at atmospheric pressure, the reaction temperatures preferably lie between -10 ⁰ C (boiling point of the sulfur dioxide) and some -80 ° C, depending on whether pure sulfur dioxide or a mixture is used of the latter with a definition according to the solvent.

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According to another embodiment of the Invention can also compounds of formula Ia

₁ - c ₍ R ₃ S0 "C = O

(Ia), H.

where -

R ,, R ₀ and Ro have the meaning given under formula I and R, 'represents a halogen atom, produce by a l, l-dioxothiazolidin-4-one of the formula

1 ν j ^AV 3 SO ₂ C = O

in which R _{1 , R 0} , Ro and R 1 - the meaning given under formula I and R 1 have the meaning given under formula Ia, subjected to a reduction.

The reduction is carried out in a manner known per se in an acidic medium, for example organic acids, such as Formic acid, acetic acid or propionic acid., Or one Mixture of a lower aliphatic alcohol,

09 825/113

special methanol or ethanol, and an ammonium salt, such as ammonium chloride, and in the presence of a suitable mild reducing agent such as iron filings or zinc powder.

The 1,1-dioxothiazolidin-4-ones prepared according to the invention of the formula I can be isolated and purified in a customary manner, for example by Removal of the sulfur dioxide or sulfur dioxide / solvent mixture, dissolving the residue in one suitable solvent, such as chloroform or methylene chloride, extraction with water and subsequent recrystallization, for example from ethanol.

1,1-Dioxothiazolidin-4-ones obtained according to the invention of the formula Ia can by filtering off the excess reducing agent and pouring in the Residue in water and, if appropriate, subsequent extraction with a suitable solvent, such as Diethyl ether ^ or recrystallization, e.g. from ethanol, isolated and purified.

The new l, l-dioxothiazolidin-4-ones of the formula I and Ia are white to yellowish white crystallines or viscous substances. They can be converted into known compounds by reduction in a conventional manner of formula Ic

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CiBA-GEIGY AG

O 9 E Q 9 O O - 15 -

II ■ ³

^S <2 ^ = ⁰ (ic),

^R 4 ^R 5

wherein

E ,, R ^ and R «have the meaning given under formula I. have and

R, "and RJ 'each hydrogen or
R / ^{1 is} an alkyl radical with 1 to 5 carbon atoms or

an aryl radical corresponding to the meaning of R, and Re "represent hydrogen,

To be transferred. Suitable reducing agents are in addition to those mentioned above, e.g. also Raney nickel, Raney cobalt, magnesium, mercury or Tributyl tin hydride. The reduction is preferably carried out in anhydrous acetic acid and using zinc powder.

The compounds of the formula Ic can be used as active ingredients in pharmaceutical preparations, e.g. anticonvulsants Means, called anesthetics or anesthetics or used to enhance the sedative effect of other substances. .

The inventive method makes first-

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4058

maize the valuable intermediates of formula I or, Ia accessible; Furthermore, it proceeds with good to very good yields, and easily accessible starting products can be used be used.

The following examples illustrate the preparation of some 1,1-dioxothiazoldin-4-ones according to the invention and also the reduction to compounds of the formula Ia or Ic. The temperatures are in degrees Celsius indicated.

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Example 1

Cl- / ~~ S-CH N- CH ₀ CH ₀ OCHo

Λ_ /, I 2 2 3

_{c {} SC, C = O

C]

Gaseous, via conc. Sulfuric acid and calcium chloride, dried sulfur dioxide, is condensed in a 750 ml flask at -70 to -80 °. 10.1 g (0.1 mol) of triethylamine, 23.2 g (0.1 mol) of N- (3 ', 4'-dichlorobenzylidene) -2-methoxyethylamine ( Bp 95 ° / 0.03 Torr; prepared from 3,4-dichlorobenzaldehyde and 2-methoxyethylamine using a molecular sieve) and 14.74 g (0.1 mol) of dichloroacetic acid chloride were added dropwise. The cooling is then removed and the resulting clear solution is kept under SO ₂ reflux (approx. -10 ° · dry ice reflux condenser) for 2 hours. After the reaction has ended, the sulfur dioxide is evaporated off, the residue is dissolved in methylene chloride and extracted three times with 100 ml of water each time. The organic phases are combined and, after removal of the solvent, the residue is dissolved in 50 ml of hot ethanol. After cooling to room temperature (approx. 20-25 °), 27.3 g (67% of theory) of the l, l-dioxo-2- (3 ¹ , 4'-dichlorophenyl) -3- (2 " -methoxyethyl) -5,5-dichlorothiazolidin-4-ones of the above formula in the form of white crystals; m.p. 135-136 '

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IR (KBr): inter alia 5.63, 7.35, 8.56 µ; NMR (CDCl ₃ ) ItT = 3.3 ppm (s, 3H, -CH ₃ ); 2.8-4.3 ppm (m, 4H, -CH ₂ -CH ₂ -); 6.04 ppm (s, IH, -CH-); 7.2-7.7 ppm (m, 3H, arom.)

Analysis for C ₁₂ H ₁₁ Cl ₄ NO ₄ S (mol. Wt. 407.1): calculated C 35.41 1 H 2.721 N 3.447 »Cl 34.6% found C 35.14% H 2.707» N 3.45% Cl 34.87 ».

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Example 2

—CH- N CH

I j \ CH ₃ \ on r = n

ci ^ Si

A solution of 17.5 g (Ο, Ι, ΜοΙ) 2,6-dichlorobenzaldehyde and 6.0 g (0.1 mol) isopropylamine in 200 ml benzene is refluxed for 3 hours. The water formed during the reaction is removed continuously. The benzene is then drawn off, and 10.2 g (0.1 mol) of triethylamine in 200 ml of absolute chloroform are added to the remaining 21.6 g (0.1 mol) of N- (2 *, 6 * -dichlorobenzylidene) isopropylamine admitted. The reaction mixture is cooled to -70 to -80 °, whereupon 350 ml of dried sulfur dioxide are added with condensation. Finally, 14.74 g (0.1 mol) of dichloroacetic acid chloride are added dropwise with vigorous stirring. After stirring for 2 hours at -10 °, the sulfur dioxide is stripped off and the remaining chloroform solution is extracted three times with water. The organic phase is purified with activated charcoal and concentrated. Recrystallization of the residue from hot ethanol gives 27.7 g (71% of theory) of l, l-dioxo-2- {2 ¹ ', 6 ⁱ dichlorophenyl) -3-isopropyl-5,5-dichlorothiazolidine- 4-ones of the above formula in the form of white crystals;

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CBA-GEIGYAG

Mp 131-132 ° _F; IR (CHCl ₃ ): inter alia 5.81, 7.33, 8.54, 8 * 65 u; NMR (CDCl ₃ ): <Γ = 1.14 + 1.41 ppm (2 χ d, J = IlHz, 6Η, 2XCH ₃ ) j 4.38 ppm (q, IH, -N-CH-); 6.72 ppm (S, IH, Benzyl-CH) i 7.2-7.7 ppm (m, 3H, arom.),

Analysis for C ₁₂ H ₁₁ Cl ₄ NO ₃ S (Molge ^. 391.1):

calculated C 36.2O7p H 2.847 »Cl 36.227 _O N 3.597 _P S 8.22%

Found C 37.107 ₀ H _O Cl 2,89J 35.587 _D N 3 _f 627p ß S

$ 30,992 / 113?

Example 3

/ ~ \ _CH - Ν— AF SO ₀ C = O.

A 750 ml flask is charged with 27.9 g (0.2.75 mol) of triethylamine and 49.9 g (0.25 mol) of N-benzylidene-4-fluoroaniline (melting point 57 ° -59 °). 300 ml of dried sulfur dioxide are then condensed in with cooling to -70 ° to -80 °. The cooling is removed and at -10 ° (S0 ₂ reflux) a solution of 36.9 g (0.25 mol) of dichloroacetic acid chloride in ml of diethyl ether is added dropwise over 4 hours. After the solvents have been stripped off, the residue is dissolved in methylene chloride and extracted three times with water. The organic phase is purified with activated charcoal, the solvent is removed and the residue is recrystallized from ethanol. 72.5 g (78% of theory) of 1,1-dioxo-2-phenyl-3- (4'-fluorophenyl) -5,5-dichlorothiazolidin-4-one of the above formula are obtained in the form of white crystals ; M.p. 132-134 °; IR (KBr): 5.74, 7.35, 8.57 µ; NMR (GDCl ₃ ): o = 6.28 ppm (s, IH, -CH-); 6.8-7.4 ppm (m, 4H, arom.); 7.4 ppm (s, 5H, arom.).

Analysis for C ₁₅ H ₁₀ Cl ₂ FNO ₃ S (mol wt. 374.23): calculated C 48.60% H 2.70% Cl 19.0% F 5.08% N 3.74% found C 48.23 % II 2.72% Cl 18.96% F 5.14% N 3.82%.

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Example 4

^C 2 ^H 5 ^H 3 ^C V- \

HC CH N— / \

SO

Cl

^C 2 ^H 5

To a refluxed and vigorously stirred solution of 20.3 g (0.1 mol) of N-isobutylidene-2,6-diethylaniline (b.p. 80-83 ° / 0.2 Torr) and 8.25 g (0.105 mol ) Pyridine in 400 ml of sulfur dioxide are added dropwise 14.7 g (0.1 mol) of dichloroacetic acid chloride within 90 minutes. After the sulfur dioxide has been distilled off, the residue is dissolved in methylene chloride, extracted three times with water and the solvent is removed. After recrystallization of the reaction product from 50 ml of hot ethanol, 12.1 g (32% of theory) of 1,1-dioxo-2-isopropyl-3- (2 *, 6'-diethylphenyl) -5.5 are obtained -dichlorthiazolidin-4-ones of the above formula; M.p. 131-133 °; IR (KBr): inter alia 5.73, 7.33, 8.54 / j; NMR (CDCl.,) : S = 0.66 + 1.30 ppm (2xd, J = 7Hz, 6H, CH «in the isopropyl group); 1.22 ppm (t, J-7Hz, 6H, CHo in the ethyl group); about 2.2 ppm (nij IH, -CH (CH ₃ ) ₂ ); 2.50 + 2.62 ppm (2xq, J = 7Hz, 4H, CH «in the ethyl group); 4.96 (d, J = 8Hz, IH, N-CH-SO _2); 7.1-7.6 ppm (m, 3H, arom.). Analysis for C ₁₆ H ₂₁ Cl ₂ NO ₃ S (mol wt. 378.33): Calculated C 50.78% H 5.59% Cl 18.72% N 3.71% S 8.48% found C 50.76 % H 5.64% Cl 18.66% N 3.72% S 8.65%.

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CIBA-GEIGY AG ". 2 2, V V> C. 2 Example 5

ι ^Λ - =

In a refluxed and very stirred solution of 18.1 g (0.1 mol) of N-benzylidene aniline and 10.1 g (0.1 mol) of triethylamine in 350 ml of silicon dioxide, a solution of 17 g is obtained within 60 minutes Φ Λ mol), ct-Chlprcapronsäurechlorid (bp j84t $ 9 ^Q / 45 Tprj prepared by ßljlorierung yon Caprons.änFeGh | or | Pi -4-t SulfuryUchlprid in the presence of catalytically _£:.? is, chen amounts Jo4) zugetrqpft in piäthyläther . After eggs Abglrgheji the solvents, the residue is taken up in §rid Methylenßh! And four exjtrahiert with water ,. 0ie organic phase \ ^ ir4 forth Magfiesiumsulfat dried, concentrated and purified on a silica gel chrpir ·· matographiert, Purch eluted with benzene to obtain first 10.2 gl _i 4-piphenyl-3-n-butyl-3-chlorazetidin - 2- pni m.p. 115-11% IE (CHGl ₃ ); et al. 5.62, 7.22 yui; and then 12.2 g (32.5% of theory) of the!, l-Dipxp - ^^ rdiphenyl-rS-nrbutyl-5-chlorophiazolidine-4-pniS of the above formula ^ mp. 133-134 ° (from Aetha | iol) j IR {CHClo): u _f a _? 5.70, 7.40, 8.60 «| (): 6 ^ O, 83 ppm <t, 3H, CH ^); 1.0-2.6 ppm (m,; 6.27 ppm (s, IH, -CH-); 7.1-7.4 ppm (m, 10H, arom.)

CIBA-GEIGYAG

- 24 -

Analysis for C ₁₉ H ₂₀ ClNO ₃ S (molar weight 377.89):

calculated C 60.48% H 5.31% N 3.71% Cl 9.39% S 8.48%

found C 60.64% H 5.33% N 3.82% Cl 9.48% S 8.64%.

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"eyelet

In the following table I further l, l-dioxotbiazolidin-4-ones according to the invention are listed, which were prepared according to the methods described in the preceding examples.

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example
No. * - Table I. organ.
base 1,1-dioxo-thiazoli-
din-4-on yield
Yo d.Th. M.p. ° C 22592 6th Compound of formula
^R l \ - ■ Tri-
ethyl-
amine l, l-dioxo-2,3-di-
phenyl-5,5-dichloro
thiazolidin-4-one 81 129-
130 NJ
NJ 7th N-benzylidene aniline Compound of formula
_P ⁴ "^ CH - COY do. l, l-dioxo-2-phenyl-
3- (3 ¹ , 5'-dichloro
phenyl) -5,5-di-
chlorothiazolidine-4-
on 74 162-3 8th N-benzylidene-3,5-
dichloroaniline Dichloroacetic acid
chloride Pyri-
din l, l-dioxo-2,3-di-
phenyl-5-chlorothia-
zolidin-4-one 65 127-9 co
O 9 N-benzylidene aniline Dichloroacetic acid
chloride Tri-
ethyl-
amine 1, l-dioxo-2-phenyl-
3- (3 ^f , 5'-dichloro-
phenyl) -5-chlorothia-
zolidin-4-one 76 61 9826 / 10 N-benzylidene-3,5-
dichloroaniline Chloroacetic acid
chloride do. l, l-dioxo-2-phenyl-
3- (3'-trifluorom-
ethylphenyl) -5,5-di-
chlorothiazolidine-4-
on 80 136-7 IO 11 N-benzylidine-3-tri-
fluoromethylaniline Chloroacetic acid
chloride do. 1, l-dioxo-2-phenyl-
3- (4'-chlorophenyl) -
5,5-dichlorthiazo-
lidin-4-one 80 158-9 N-benzylidene-4-
chloraniline Dichloroacetic acid
chloride Dichloroacetic acid
chloride

Table I continued

example

Connection or formula
R.

■ Compound of the formula ⁴ ^ - GÖY

base

2, Ι-Ώ! Oxo-thiazo11- din - & - ön

Yield d.Tfa.

M.p. ^ C

N-Benzylidene-3-trifluorme thy 1r-4-chloroaniline

N- (3 ^f , 4'-dichlorobenzylidene) aniline

N- (α-methylbenzylidene) -3-trifluoromethylaniline

N-benzylidene aniline

N- (α-naphthylmethylene) benzylamine

N-benzylidene aniline

N- (benzhydrylidene) ■
methylamine

Dichlores s igs acid chloride

Dichloroacetic acid chloride

Dichloroacetic acid chloride

Dibromoacetic acid chloride

Dichlorous acid chloride

a-chior-a-phenylacetic Mure chloride

Dichloroacetic acid chloride

Triethyl amine

1,1-Dioxo-2-phenyl-3- (3'-tri-fluoromethyl-4'-chlorophenyl) -5,5-dichlorothiazolidin-4-one

l, l-dioxo-2- (3 _'i ^f 4-dichloro phenyl) - 3-phenyl-5,5-dichloro ■ thiazolidin-4-on

1, l-DioKO ~ 2-methyl-2-phenyl-3- (3'-trif Iu ormethylphenyl) ■ 5, »5-dichlorothiazplidine-4-ση

l, l-Dioxo-2,3-diphenyl-5., 5-dibromothiazolidin-4-one

1,1-Dioxo-2- (a-naphthyl) -3-benzyl-5,5-dichlorothiazolidine-4-ση

1,1-Dioxo-2,3-triphenyl-5-chlorothia zolidin-4-one

l ₎ l-Dioxo-2,2-diphenyl-3-methyl-5,5-dichlorothiazolin-4-one

44

38

25th

67

21

14th

76

59-9

160-2

116-8

137-139 160.5-161

184-185.5 171-172

CLBA-GEIGY AG

- 28 -

Example 19

N-f "> /> CH

I N = / V - = / j

j I N = / V - = / j I

_{so c} _o so c = o so "

Vr / \ r V

Cl ^ tI IT ^X C1 H ^X H

35.6 g (0.1 mol) of the 1,1-dioxo-2,3-diphenyl-5,5-dichlorothiazolidin-4-one prepared according to Example 6 (A) are dissolved in 300 ml of anhydrous acetic acid at 50 °. After adding 60 g of iron filings, the reaction mixture is during Stirred for 45 minutes at this temperature. The reducing agent is then filtered off and the filtrate under added dropwise to 2 liters of water with vigorous stirring. The precipitated white crystals are then filtered off and dried in vacuo and purified by silica gel chromatography. By elution with a benzene / ethyl acetate mixture (9: 1) initially 4.7 g (13% of theory) of the compound of formula A (starting material) are obtained, then 24.3 g (75.5% of theory) l, l-Dioxo-2,3-diphenyl-5-chlorothiazolidin-4-one (compound of formula B) and finally 2.9 g (10.1% d, th *) l, l-Dioxo-2,3-diphenylthiazolidin-4-one (compound of formula C).

Compound of formula B:

M.p. 127-129 °; IR (KBr): including 5.82, 7.39, 8.53, 8.72 µ; NMR (CDCl ₃ ): Cf = 5.80 + 5.94 ppm (2x S, IH, benzyl-Η, di-

309825/1132

CLBA-GEIGY AG

- 29 - *

astereoisomers in the ratio approx. 4.5: 5.5); 6.38 + 6.52 ppm (2x s, 1H, CH-Cl); 7.3 ppm (m, 10H, arom). / Analysis for C ₁₅ H ₁₂ ClNO ₃ S (molar weight 321.5): calculated C 56.01% H 3.74% Cl 11.04% N 4.36% S 9.96% found C 55.75% H 4.02% Cl 10.95% N 4.18% S 9.76%. Compound of Formula C:

M.p. 184-185.5 °; IR (KBr): inter alia 5.96, 7.57, 8.79 p; NMR (dimethyl sulfoxide-d ₆ ): S = 4.57 ppm (s, 2H, CO-CH ₂ -SO ₂ ); 6.75 ppm (s, IH, benzyl-H); 7.1-7.7 ppm (m, 1OH, arom.). Analysis for C ₁₅ H ₁₃ NO S (mol wt. 287.34): Calculated C 62.70% H 4.57% N 4.88% S 11.15% found C 62.44% H 4.59% N 4 , 81% S 11.13%.

In the example above, if you use zinc powder instead of iron filings with otherwise the same working method, so the starting product (A) is reduced directly to the compound of formula C with 99% yield.

309825/1132

CLBA-GEIGY AG

- 30 -

Example 20

A suspension of 19.6 g (0.05 mol) of the gemMss Example 2 prepared 1,1-dioxo-2- (2 ', 6'-dichlorophenyl) -S-isopropyl-S, 5-dichlorothiazolidin-4-ones and 30 g of Raney nickel in 150 ml of 98% formic acid are stirred for 10 minutes at room temperature. After filtering the reaction solution is poured into 1.5 l of water. It 15.2 g (94.5% of theory) of l, l-dioxo-2- (2 \ 6'-dichlorophenyl) -3-isopropyl-thiazolidin-4-one fall of the above formula in the form of white crystals.

M.p. 176-8 °; IR (KBr): inter alia 5.84, 7.50, 7.60, 8.82, 12.72 p; NMR (CDCl ₃ ): S = 0.93 + 1.28 ppm (2 χ d, J-IlHz, 6H, 2xCH ₃ ); 3.96 + 4.01 ppm (2 χ s, 2H, -CH ₂ -); 4.67 ppm (q, IH, N-CH-); 6.54 ppm (s, IH, benzyl-CH); 7.2-7.7 ppm (m, 3H, arom.). Analysis for C ₁₂ H ₁₃ Cl ₂ NO ₃ S (molecular weight 322.21): Calculated C 44.73% H 4.07% Cl 22.01% N 4.35% S 9.94% found C 44.68 % H 4.03% Cl 21.92% N 4.44% S 10.02%.

In the above example, equivalents can also be used instead of 30 g of Raney nickel at reaction temperatures of 40-80 ° Amounts of zinc powder, magnesium, mercury, or Raney cobalt can be used.

309825/1132

CLBA-GEIGY AG Example 21

CH ₂ CH ₂ OCH ₃

20.35 g (0.05 mol) of the l, l-dioxo-2- (3 ' ₎ 4 ^l -dichlorophenyl) -3- (2 "-methoxyethyl) -5,5-dichlorothiazolidine-4- prepared according to Example 1 They are dissolved in 150 ml of anhydrous acetic acid at 30 ° -40 ° C. After adding 30 g of zinc powder, the reaction mixture is stirred at this temperature for 20 minutes, the reducing agent is then filtered off, the filtrate is concentrated and extracted with absolute diethyl ether extracted twice with water and dried over magnesium sulfate. After further concentration of the residue, 15.6 g (92% of theory) of pure l, l-dioxo-2- (3 ¹ , 4'-dichlorophenyl) -3- ( 2 "-methoxyethyl) -thiazolidin-4-one of the above formula as a yellowish viscous oil.

IR (CHCl ₃ ): inter alia 5.82, 7.42, 8.81, 8.93 µ; NMR (CDCl ₃ ): <T = 3.29 ppm (s, 3H, CH ₃ ); 2.8 to 4.4 ppm (m, 4H, - (CH ₂₎ - _2); 3.92 ppm (s, 2H ₅ -CH ₂ -); 5.90 ppm (s, IH, -CH-); 7.1-7.7 ppm (m, 3H, arom.).

Analysis for C ₁₂ H ₁₃ Cl ₂ NO ₄ S (molecular weight 338, 22): calculated C 42.59% H 3.87% N 4.15% S 9.48% found C 42.19% H 4.02 % N 4.03% S 9.30%.

309825/1132

CIBA-GEIGYAG

In the following table II further l, l-dioxo-thiazolidin-4-ones of the formula Ic are listed, the according to the processes described in Examples 20 and 21 from the corresponding compounds according to the invention of formula I:

309825/1132

Table II

example
No. Compound of formula I. Compound of formula Ic yield
% of th. M.p. ° C 22nd 1, l-Dioxo-2-phenyl-3- (3 ', 5' -
dichlorophenyl) -5,5-dichloro-
thiazolidin-4-one 1, l-Dioxo-2-phenyl-3- (3 ', 5'-
dichlorophenyl) thiazolidine
4-on 98 165-166 23 1, l-Dioxo-Z-phenyl-S- (3'-tri
fluoromethylphenyl) -5, 5-di-
chlorothiazolidine-4-ρη 1,1-dioxo-2-phenyl-3- (3'-tri
fluoromethylphenyl) thiazo
lidin-4-one 97 143-145 Ca) 24 1,1-Dioxo-2-phenyl-3- (4'-
chlorphenyl) -5,5-dichlorothia-
zolidin-4-one l, l-Dioxo-2-phenyl-3- (4'-
chlorophenyl) thiazolidine
4-on 99 169-170 0982 25th 1, l-Dioxo-2-phenyl-S- (3 '-tri *
fluoromethyl-4 ¹ -chlorphenyl) -
5,5-dichlorothiazolidin-4-one 1,1-Dioxo-2-phenyl-3- (3'-
trifluoromethyl-4 ¹ -chlorphe
nyl) -thiazolidin-4- ^ one 94 ■ 136-138 cn
_i 26th 1, l-dioxo-2- (3 ', 4'-dichloro
phenyl) -3-phenyl-5,5-dichloro
thiazolidin-4-one 1, l-dioxo-2- (3 ', 4'-dichloro
phenyl) -3-phenyl-thiazoli-
din-4-on 97 157-159 CO 27 l, l-Dioxo-2-methyl-2-phenyl-
3- (3'-trifluoromethylphenyl) -
5,5-dichlorothiazolidin-4-one 1, l-Dioxo ^ -methyl ^ -phenyl-
3- (3'-trifluoromethy! Phenyl) -
thiazolidin-4-one 99 152 28 l, l-Dioxo-2-phenyl-3- (4'-
fluorophenyl) -5,5-dichlorthia-
zolidin-4-one l, l-Dioxo-2-phenyl-3- (4'-
fluorophenyl) thiazolidin-4-one 98 138-140 29 l, l-Dioxo-2-isopropyl-3- (2 ',
6'-diethylphenyl) -5,5-dichloro-
thiazolidin-4-one l, l-Dioxo-2-is ^> propyl-3- (2 ',
6 'r-diethylphenyl) -thiazoli-
din-4-on 97 102-104

■ ro ro

Table II continued

example Compound of formula I. Compound of formula Ic yield M.p. ° C No. 7o d.Th. 30th 1, l-dioxo-2,3-diphenyl-5-n- 1, l-dioxo-2,3-diphenyl-5- 91 102-103 butyl-5-chlorothiazolidin-4-one n-butylthiazolidin-4-one 31 1,1-Dioxo-2- (a-naphthyl) -3- 1,1-Dioxo-2- (a-naphthyl) -3- 93 131 benzyl-5,5-dichlorothiazoli- benzylthiazolidin-4-one din-4-on 32 1, l-dioxo-2,3,5-triphenyl- 1, l-dioxo-2,3,5-triphenyl- 99 94-114 * 5-chlorothiazolidin-4-one thiazolidin-4-one co
ο 33 1, l-dioxo-2,2-diphenyl-3- 1, l-dioxo-2,2-diphenyl-3- 93 148-149 CD methyl-5,5-dichlorothiazoli- methylthiazolidin-4-one OO
NJ din-4-on

* 2.5 stereoisomeric mixture

CIBA-GEIGYAG Example 34

17.9 g (0.15 mol) of N-benzylidene-methylamine and 15.2 g (0.15 mol) of triethylamine are placed in a 1 liter flask submitted. 450 ml of dried sulfur dioxide are then condensed into the flask with cooling to -70 to -80 °. A solution of 22.1 g (0.15 mol) of dichloroacetic acid chloride is then added with vigorous stirring 400 ml of absolute diethyl ether were added dropwise. The reaction mixture is stirred for a further 2 hours at -10 ° * Then the sulfur dioxide and the diethyl ether are removed. The reaction product obtained is without Intermediate isolation dissolved in anhydrous acetic acid, 40 g zinc powder are added. and the reaction mixture is stirred for 20 minutes at 40 °. The reaction product is then filtered off, with 200 ml Diluted water and four times with 150 ml of diethyl ether each time extracted. The organic phases are combined, dried over magnesium sulfate and cleaned with activated charcoal. After removing the solvent, the residue is dissolved in hot ethanol. After cooling down 14.2 g (42% of theory) of 1,1-dioxo-2-phenyl-3-methylthiazolidin-4-one fall to room temperature the formula

O-CH N-GH, II ³

SO, C = O ^X CH ^

309825/1132

CLBA-GElGY AG oß

in the form of white needles. M.p. 123.5 °; IR (CHClO: among others 5.85, 7.46, 8.82, 14.39 μ ; NMR (CDCl ₃ ) :( T- 2.98 ppm (s, 3H, -CH ₃ ); 3.87 ppm ( s, 2H, -CHp; 5.55 ppm (s, IH, -CH-); 7.2-7.7 ppm (m, 5H, arom.). Analysis for C ₁₀ H ₁₁ NO ₃ S (molar weight. 225.27): calculated C 53.32% H 4.93% N 6.23% S 14.22% found C 53.38% H 5.00% N 6.29% S 14.09%.

3 (jy825 / 1 13?

Claims (10)

ciBA-GEiGYAG i-2, Ο y Z 2, 2, Claims
l, l-Dioxothiazolidin-4-ones of the formula I. I ^{2 R} 4 ^R 5 wherein R ^ and R "independently of one another hydrogen, one aliphatic or araliphatic hydrocarbon radical, an aryl radical or a 5-membered one Mean heterocycle containing 0 and / or S atoms or R, and, R "together with the ring carbon atom to the they are bound to form a cycloaliphatic ring with a total of 5 to 8 carbon atoms, Ro is an aliphatic, cycloaliphatic or araliphatic Hydrocarbon radical, an aryl radical or one directly or via 1 to 3 methylene groups linked to the ring nitrogen atom, in particular 5- or 6-membered heterocycle and R, and R ₁ . each a halogen atom or R, hydrogen, an alkyl radical with 1 to 5 carbon atoms or an aryl radical and 3098 2B / 1132 CLBA-GEIGY AG Rr represent a halogen atom. 2. 1,1-Dioxothiazolidin-4-ones of the formula I according to claim 1, wherein at least one of R ₁ , R "and R ~ is an aryl radical. 3. 1, l-dioxothiazolidin-4-ones of the formula I according to claim 1, in which R * and R "independently of one another are hydrogen, a saturated one unsubstituted alkyl radical with 1 to 8 carbon atoms, a benzyl radical, an unsubstituted one or by halogen atoms, trifluoromethyl, nitro, cyano, phenylsulfonyl, alkylsulfonyl, Alkyl, alkoxy or alkylthio groups each having 1 to 4 carbon atoms in the alkyl part Phenyl radical, an unsubstituted α- or ß-naphthyl, thienyl or furyl radical or R- and R "together with the ring carbon atom to which they are bound, form a cyclohexyl radical, R "is an unsubstituted or by an alkoxy or Alkylthio group with 1 to 4 carbon atoms each / ^X l in the alkyl part or an -N group substituted 2nd alkyl radical with 1 to 8 carbon atoms in the main chain, where X, and X "independent of -309" 25/113 2 CLBA-GEIGY AG - 39 - represent each other an alkyl radical with 1 to 8 carbon atoms, an allyl or benzyl radical or X, and X ₂ together with the nitrogen atom to which they are bonded, optionally including a further hetero atom, a cycloaliphatic ring with a total of 4 to 7 carbon atoms, in particular form a piperidine, 4-methylpiperazine or morpholine ring; a cycloalkyl radical with 5 to 8 carbon atoms, an allyl or benzyl radical, an unsubstituted or halogen atom, trifluoromethyl, nitro, cyano, phenylsulfonyl, alkylsulfonyl, alkyl, alkoxy or alkylthio group with 1 to 4 carbon atoms in the alkyl part substituted phenyl radical, an unsubstituted α- or ß-naphthyl radical, an unsubstituted thienyl or furyl radical connected directly or via a methylene group to the ring nitrogen atom, an unsubstituted pyridyl, pyrimidinyl or triazinyl radical and R, and R, each chlorine, bromine or fluorine or R, hydrogen, an alkyl radical having 1 to 5 carbon atoms or an unsubstituted phenyl radical and
R ₁ . Represent chlorine or bromine. 309825/1132 '"" 4058 CLBA-GEIGY AG - 40 - 4. l, l-dioxothiazolidin-4-ones of the formula I according to claim 1, wherein R, hydrogen, R »is an unsubstituted or substituted by halogen atoms, trifluoromethyl or alkyl groups with 1 to 4 carbon atoms phenyl radical, R- is an unsubstituted or by a Alkoxy group-substituted alkyl radical with a total of 1 to 4 carbon atoms or an unsubstituted phenyl radical or a phenyl radical substituted by halogen atoms, trifluoromethyl or alkyl groups with 1 to 4 carbon atoms and R, and R ₅ each represent chlorine, bromine or fluorine or R, hydrogen and Rr chlorine. 5. 1,1-dioxothiazolidin-4-ones of the formula I according to claim 1, wherein R, hydrogen, R "and R ₃ independently of one another are an unsubstituted or substituted phenyl radical by halogen atoms or trifluoromethyl groups and R / and R ₁ -Je are chlorine. 6. Process for the preparation of 1,1-dioxothiazolidine 4-ones of the formula I. R ₂ SO ^R 5 3 U ¹ J 8? 5/1 1 3 / R, and R "independently of one another hydrogen, a aliphatic or araliphatic hydrocarbon radical, an aryl radical or a 5-membered one Heterocycle containing 0 and / or S atoms mean or R-, and Rp together with the ring carbon atom to which they are bound to form a cycloaliphatic ring with a total of 5 to 8 carbon atoms, Ro is an aliphatic, cycloaliphatic or araliphatic Hydrocarbon radical, an aryl radical , <or one directly or via 1 to 3 methylene groups linked to the ring nitrogen atom, in particular 5- or 6-membered heterocycle and R; and R, - each a halogen atom or> . R, hydrogen, an alkyl radical with 1 to 5 carbon atoms or an aryl radical and Rr represent a halogen atom, characterized in that one connects the Formula II ¹ J ^ C = N - R- (II), R ₂ in which R ,, R "and R" have the meaning given under formula I, in frlUssJ.gtmi sulfur dioxide and in the presence of a tertiary noise: ;; heu ίΊαν, α and: ^ a ^ eb CLBA-GElGY AG *. *, ·, - 42 - if an inert organic solvent with an α-halocarboxylic acid halide of the formula III ^R 4 CH-CO-Y (III), ^R 5 ^ where Y is chlorine or bromine and for R, and R ₁ . what is stated under formula I applies, converts, the compounds of formula II and III and the tertiary organic base in at least molar Quantities are used. 7. The method according to claim 6 for the preparation of compounds of formula Ia Vf η SO ₀ C = O ^{(Ia) t} «.4 H
wherein
R ₁ , R "and R-. have the meaning given under formula I and R, 'represents a halogen atom, characterized in that a 1,1-Dioxothiazoli · di.n-4-on of the formula Ib ι ■■ ', /! CLBA-GEIGY AG - 43 - ^R r - N- - ^R 3 C = O ^Xr 5 -c -
ι I. (Ib), wherein R ₁ , R «, R ^ and R ₁ . which under formula I and R, ^{1 have} the meaning given under formula la, subjected to a reduction. 8. The method according to claim 6, characterized in that the reaction is carried out in pure sulfur dioxide will. 9. The method according to claim 6 or 8, characterized in that the liquid sulfur dioxide in at least 5-fold molar excess is used. 10. The method according to claim 6, characterized in that that the compound of formula II, the α-halocarboxylic acid halide of formula III and the tertiary , organic base is used in a mutual molar ratio of 1: 1: 1 to about 1.2: 1: 1.2. 3Ό 9825/1 132 3i. yn »>. / i },].