DE1445784A1 - Process for the preparation of thiazolidiones - Google Patents

Description

FARBENFABRIKEN BAYER AG LEVERKUSEN - *, «™ * £ 8. QKt. 198 * Patent Dept.

Reu / Hü

Process for the preparation of thiazolidinones

The invention relates to a process for the preparation of new thiazolidinones by reacting unsaturated amines with sulfur and isocyanates.

It has been found that enamines whose ß-carbon atom is substituted by alkyl radicals with Convert sulfur and isocyanates to thiazolidinones. The surprising course of the reaction is the implementation as an example of isobutenylmorpholine with sulfur and phenyl isocyanate explained:

C ⁵ : + S + ^^ -N = CO

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In general, the reaction is carried so that it, preferably in an organic solvent initially the sulfur or compounds which easily give off sulfur, such as Trimetiiylaminpolysulfide, xanthate polysulfides, between -10 ° and 150 ⁰ C at between 20 and 60 C. the enamim adds. Dialky / formamides such as dimethylformamide have proven to be particularly suitable solvents. However, you can also work in pyridine, acetone, chloroform or in solvent mixtures. When the addition of sulfur has ended, the isocyanate is added dropwise or the isocyanate is introduced into the solution. The 'thiszolidinones' are formed in a mostly exothermic reaction and precipitate in crystalline form on cooling.

In some cases it is also possible to add first the isocyanate to the enamine and then at an elevated temperature - to soak the sulfur (100 ° 150 ⁰ C). Finally, the thiazolidinones are also formed by direct combination of the three components in one of the solvents indicated above.

The net Ihiazolidinone correspond to the general formula

Xi ■ ^ ^m w XX ^^^^^^

Le k 9072 8 0 980 9 / -1.128

where E ₁ denotes an alkyl "-" aryl, cycloalkyl, aroyl or an arylsulfonyl group, Rp and IU denote an alkyl group, where R ₂ and R, together as ring members, can also form a hydrocarbon ring and R ^. and R, - are alkyl groups, where R and Rj- as ring members a with the nitrogen atom can form a ring which can additionally contain heteroatoms.

For example, the following thiazolidinones are those of the above lormel correspond to the procedure accessible:

3-phenyl-4-pyrrolidino-5,5-dimethyl-thiazolidin (2) one, 3- (4) chlorophenyl-4-py _i rrplidino-5,5-dimethyl-thiazolidine2) one, 3- (3 * 4) -Dichorpfaenyl-4-pyrrolidino-5,5-dimethyl-thiazolidin (2) one, 3-H) nitrophenyl-4- "PyIrOlIdino-5,5-dimethyl-thiazolidini2) one, 3-benzoyl-4 ~ pyrrolidino-5, 5-dimethylthiazolidine2) one, ^ -Toluenesulfonyl-4-pyrrolidino-5,5 ~ dimethyl-thiazolidine2) one, 3-naphthyl (1) -4-pyrrolidino-5,5-diiethyl-thiazolidine2) one, 3-methyl-4 -pyrrolidino-5,5-dimethyl-thiazolidine2) one, 3-ithyl-4-pyrrolidino-5,5-dimethyl-

n, 3-Cyclohexyl-4-pyrrolidino-5,5-dimethyl-thia-οη, 3-methoxymethyl-4-pyrrolidino-5,5-dimethyl-thi £ ^ o-, 3-phenyl-4-pyrrolidino-5, 5- (3-pentene) -thiazolidin- (2) oa, 1,4 * -Bisr- (4'-pyrrolidiiio-5,5-dimethyl-thia2olidinonyl) -phenyl.ezty. 1, 6 ^ -5ä _t & - (4-pyrrolidino-5,5-dimethyl-thiazolidinonyl) -n-hexane. Dasai die *, eatepreoliead compounds, which instead of pyrrolidine contain Hoxpholiöf, Bipericlin, N-Methylpeperazin und Dialkylamin ,,, ijriie be4 «i> iüea.®ireiae IT, K ¹ - (3-Phenyl-5,5-dimethyl-thiazolidinonyl) -

128

Preferred for the process according to the invention Coming enamines are isobutenylmorpholine, isobutenylpiperidine, isobutenyl-N-methylpiperazine, isobutenyl-di-n-butylamine and isobutenyl-di-n-isopropylamine. Furthermore, the enamines can be derived from hexahydrobenzaldehyde, tetrahydrobenzaldehyde and letrahydrotolylaldehyde with secondary amines, preferably di-n-pfopylamine, Di-isopropylamine, di-n-butylamine, di-isobutylamine, piperidine, ot *, ß- or γ-pipeeolin, hexamethyleneimine, morpholine, N-methylpiperazine find use as starting products. Also with bis-enamines the reaction can be carried out, e.g. with diisobutenylpiperazine.

The following isocyanates can be used: aryl isocyanates and Arylene diisocyanates, the. by Allqzb-, Alkoxy-, Garb oxy alkyl-, Halogen or nitro groups can be substituted, alkyl isocyanates, Alkylene diisocyanates, cycloalkyl isocyanates, arylsulfonyl isocyanates and benzoyl isocyanates. The following compounds are preferably used: alkyl isocyanates, their alkyl group Has 1-6 carbon atoms methyl and ethyl isocyanate and phenyl isocyanates, such as bienyl isocyanate, chlorophenyl isocyanate and Toluene isocyanate *

The new compounds resulting from the process can for the manufacture of pharmaceuticals and pesticides · ■ be used.

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Beiapiel 18

/ -χ / ^0H 3

( Ti-CH

( Ti

η
O

a), 69.5 g of isobutenylpiperidine are added together with 16 g of sulfur in 4-0 ecm of dimethylformamide and stirred for 3 hours. Then 38.5 g of methyl is ο cy ana t are poured in. The temperature rises gradually to 60 °. The mixture is then stirred for half an hour. The reaction mixture cools down to room temperature and the contents of the flask solidify. After suctioning off and drying, 95 g of a compound are obtained which, after dissolving in white spirit, melts at 114 ° -116 °. C ₁₁ H ₂₀ N ₂ OS (228)

Ber. C 57.8 H 8.78 N 12.26 S H.05 Found 57.8 8.9 12.2 14.0

b) The components specified under a) are combined with stirring . The temperature rises very slowly to 40 °. After stirring for 5 hours, 70 g of a compound have become

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deposited which show no melting point depression with the substance prepared according to a).

Example 2i

CH, II-CH C

'I IV,

If you work analogously to Example 1 with 62.5 g of isobutenylpyrolidine, 75 g of the above pyrolidine compound are obtained, which according to the Dissolve from light petrol at 88 - 90 ° melts.

Ber. C 56.2 H 8.42 N 13.08 3 14.94 Found 56.2 8.7 13.1 15.2

Example 3 *

CH- H CH, 5s / 3

N-C C

' II ^x

CH, CH,

N 1

στ

25 g of N-dimethyl isobutenylamine and 8 g of sulfur are stirred in 20 ecm of dimethylformamide at 40 ° -45 °. In these

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Solution is allowed to drop in 30 g of phenyl isocyanate and, by occasional cooling, ensures that the temperature does not reach 70 ° exceeds. When cooling down you get a crisp connection, which is first digested with 70 ecm of methanol. To the substance is recrystallized from methanol after suction, yield 32 g, m.p. » 108-110 °.

V- _v

C ₁₃ H ₁₈ H ₂ OS (250)

Ber.t G 62.4 H 7.25 N 11.2 S 12.8 Found i 62.2 7.4 11.1 12.8

Example 4V

) 70.5 g of isobutenylmorpholine and 16 g of sulfur are in 60 ecm Dimethylformamide for 2 hours. Stirred at 30 °. 60 g of phenoxy cyanate are then added dropwise. During the dropping, the increases Temperature to 52 °. On cooling, a crystalline precipitate forms, which is sucked off after adding 50 ecm of methanol will. The piltrate is mixed with water and the resulting precipitate is suctioned off. In total you get 88g

. a bond, which after the umlosen from methanol at 165 ° melts.

809809/1128

Γ \ TJ
O Λ f — Xi 20 ¹ J ₂ O 2 ^S 1 , 7 (292.4) N 9 , 59 S. 1 ο, 95 Ber. ί C. 61 , 7 H 6.89 9 , 5 1 1, 2 ffef. 61 7.2

b) The reaction described under a) can also be carried out in acetonitrile carry out. The sulfur is added to the enamine at 80 ° and the phenyl isocyanate is then added dropwise at 70 °. the The resulting compound shows no melting point depression with that obtained according to a).

c) 60 g of phenyl isocyanate, 16 g of sulfur and 70.5 g of isobutenylmorpholine are in 40 ecm of dimethylformamide with stirring for one hour Heated to 70 °. This creates a clear solution. After the reaction mixture has cooled down, 50 ecm of petroleum ether are added. To For a few hours, the compound which has crystallized out is filtered off with suction and washed with methanol. One receives 60 g of a colorless one Substance which does not show any melting point depressions with the compounds prepared according to a) and b).

Example 5 *

Qf

69.5 g isobutenylpiperidine and 16g sulfur are in 40 ecm Dimethylformamide stirred at 30 ° for 1 hour. 60 g are now added dropwise

Phenyl isocyanate is added and occasional cooling ensures that the temperature does not rise above 50 °. The contents of the basket solidify when the mixture is stirred. After redissolving from methanol, 114 g of a compound which melts from £ 12 to 127 are obtained. C ₁₆ H ₂₂ U ₂ OS (290.4)

Ber.i C 66.2 H 7.65 N 9.65 S 11.07

Gtef.i 66.7 7.7 9.7 11.0

b) The reaction described under a) can also be carried out in a completely analogous manner perform in acetone or pyridine. The resulting V " Compounds show no melting point depression with the substance obtained according to a).

c) To a solution of 60 g of phenyl isocyanate in 100 cc iicetone 16 g of sulfur and 70 g of isobutenylpiperidine are added. The mixture is then heated to the boil for 20 minutes while stirring. The cooled solution is mixed with 500 ecm of light petrol. Which separating crystals are suctioned off. 78 g of a compound are obtained which are obtained with the substances prepared according to a) and b) show no melting point depressions.

d) To a solution of 70 g of isobutenylpiperidine in 40 ecm of dimethylformamide 60 g of phenyl isocyanate are added dropwise with stirring. The temperature rises to 57 during this process. The mixture is subsequently stirred for 30 minutes and then enters 16g of sulfur. The reaction mixture is now heated to 115 °. This creates a clear solution. The contents of the flask solidify on cooling. After vacuuming and washing with a little methanol, 100 g of a compound is obtained which does not melt with the substances prepared according to a), b) and c)

Shows point depression.

Example 6f

D -? - j. '

^ s

a) 31 g of isobutenyl pyrolidine and 8 g of sulfur are in 50 ocm Dimethylformamide stirred for 6 hours at 25 °. Then you drip g phenyl isocyanate with cooling, so that the temperature does not rise above 50 °. When tracking you get one Crystal slurry, which is filtered off with suction and washed with methanol. Man receives 42 g of a compound which melts from 117 ° to 118 ° after dissolving from ethanol.

The reaction can also be carried out in N-methylpyrolidone, chloroform, chlorobenzene or benzene under analogous conditions. C ₁₅ H ₂₀ H ₂ OS (276.4) Calcd .: 0 65.3 H 7.28 N 10.15 S 11.62 Found s 65.4 7.3 10.1 11.6

In a mixture of 60 g phenyl isocyanate, 16 g sulfur and 100 ecm of dimethylformamide are left with 62.5 g of isobutenylpyrolidine while stirring to drip in. You keep them by cooling

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Temperature at 35 °. A clear solution is formed during the reaction. The contents of the flask solidify when the mixture is stirred. Der-Kri £ fcallbrei is triturated with methanol and filtered off with suction. 100 g of a substance are obtained which are prepared with that under a) Compound shows no melting point depression.

Example 7 *

62.5 g of isobutenylpyrolidine are in 40 ecm of dimethylformamide stirred together with 16g sulfur for 2 hours. Then you let in drop in 77.5 g of p-chlorophenyl isocyanate with cooling. the The temperature should not rise above 60 °. The contents of the flask solidify when the mixture is stirred. After suction and dissolving 90 g of a compound which van 129 melts up to 130 °.

C ₁₅ H 29 ^Ä 2 ° 1 ^p 1 ^G1 1 (31 0.5) N 9 , 5 S. 10, 25th Ber. ι C 57 ·? H 6 , 12 _; 8th 10, 2 Found ι 57 »9 6th , 4 Le A 9072

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Example 8?

r - v σ "
Il / GH, C. O λ I. CH _x S. Cl Cl ' N-CH-
1 1 II

62.5 g of isobutenyl pyrolidine are added together with 16 g of sulfur Stirred for 1.5 hours in 150 ecm dimethylformamide at 35 ° 200 ecm of acetone are then added to this solution and 112 g are then added 3,4-dichlorophenyl isocyanate. The Do not increase the temperature above 60 °. Disfigured when stirring a thick crystal slurry, which is redissolved after suction from methanol / acetone (1 * 1). 88 g of a compound are obtained which melts from I65 to 164.

₁₅₁₈₂₂ (345)
Ber.j C 52.5 H 5.25 N 8> 1 S 9.3

Found i 52.2 5.3 8.2 8.1

Example 9?

C CH

70 g and 16 g Isöbiitenylpi'peridin sulfur 4NC öoa pear formamide 10 min. Untei · Bühren 80 ^he erhitit * Hsxm

42 g of hexamethylene diisocyanate are added dropwise. It increases the temperature to 85 °. The mixture is stirred for 4 hours at 85 °, the dimethylformamide is distilled off in vacuo and digested the residue with a little methanol. The suctioned off product is washed with methanol and then with petroleum ether. 27 g of a compound are obtained, which after dissolving Methanol melts between 164 ° and 179 ° with decomposition.

^C 26 ^H 46 ^H 4 ° 2 ^S 2 < ⁵¹¹ >

Ber.s C 61.1 H 9.1 N 11.0 S 12.6 Found: 61.1 9.3 11.3 12.3

Example 10i

O Q

CH; 7th

It Il

0 0

70 g of isobutenylpiperidine together with 16 g of sulfur in 40 ecm of dimethylformamide stirred for one hour. T5 g of phenylene diisocyanate Ci, 4) are then introduced into the reaction mixture. By While cooling, the temperature is not allowed to rise. Now you add 250 ecm of acetone and then carry the rest of the isocyanate (25 g). Thickening occurs when stirring Crystal pulp, after suction filtration and drying, 85 g are obtained. After dissolving from chlorobenzene, the compound melts below at 247 ° Decomposition.

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-H-

^K 4 ° 2 ^S 2 - ^(5O2) '
Ber.i C 62.2 H 7.65 -BT 11.2 S 12.8 Gef.i 62 _t 0 7.7 11.2 12.2

Example Its

19 * 5 g of Bi ^ isobutenylpiperazine together with 6.4 g of sulfur stirred in 15 ecm Mmethylformamid for one hour at 130 °. Of the Sulfur goes into solution and a thick syrup separates out. More than 75 ecm of pyridine are added. Then stir for 1 hour after and then allowed to drop in at 50 ° 24 g of phenyl isocyanate. At the. Tracking and cooling separate a crystalline one Refusal from. 9 g of a compound are obtained, which according to your OBLissolving from chlorobenzene melts at 268 with decomposition.

(497)

Ber. ϊ C 62.9 H 6.5 N 11.3 3 12.9 Sef.t 63.2 6.5 11.3 12.7

Example 12t

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77.5 g of tetrahydrobenzylidene morpholine and 16 g of sulfur are in 40 ecm dimethylformamide 45 min. Stirred at 35 °. For this purpose, 60 g of phenyl isocyanate are added dropwise with cooling in such a way that the Temperature does not rise above 55 °. The mixture is subsequently stirred at 55 ° for 1 hour. A thick slurry of crystals forms on cooling. Haeh that Suction gives 68 g of a compound which, after dissolving in methanol, melts at 168-170 °.

(314)

Calc .: C 65.4 H 6.7 N 8.5 3 9.7 Found i 65.5 6.8 8.8 9.5

Example 13i

C ^h i

C ^h i ^h

96 g of hydrotolylidene morpholine are used together with 40 cos

nBamid and 16 g sulfur 1 hour at room temperature and JäBxai can add drops to 59.5 g of phenyl isocyanate. By cooling, one ensures that the reaction temperature does not rise to 60 °. When the mixture is stirred and then cooled, a critical connection is formed. Sbn receives

β09809. / 1Ί28

60 g. The compound melts by dissolving it from toluene Clay 200 ^ - 203 ° l

C ₁₉ H ₂₄ F ₂ O ₂ S (328)

Ber.t G 66.2 H 7.03 F 8.14 S 9.31

Found: 66.0 7 * 1 8.2 8.9

Example 14t

31 g of isobutenylpyrolidine and 8 g of sulfur are dissolved in 60 ccifl of pyridine Stirred at 25 ° for 1 hour. 49 g of tosyl isocyanate are then instilled in » The temperature rises rapidly and is cooled by cooling held. The mixture is stirred for T / 2 hours and then distilled Pyridine in vacuo. The crystalline ^ residue is with methanol digested and then sucked off. 1 g of a compound is obtained which melts with decomposition at T44f.

Ber.t C 54 r 2 E 6 _r 25 ^ 1.9 S t 54 _r 0 6.2 '7.9 17.9

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Claims (2)

Claims t 1. A process for the preparation of thiazolidinones, characterized in that that one enamines with sulfur or sulfur-releasing compounds and isocyanates in an organic Reacts solvent at temperatures between 10 ° and 150 °. 2. Thiazolidinones of the formula ^E 4 CH- C- *
H / C. \ * "I. ι \ «Si I. S. ^Ε Γ " where R ₁ denotes an alkyl, aryl, aroyl, cycloalkyl or an arylsulfonyl group, IL, ^and an alkyl group, where R « and R3 can also together form a hydrocarbon ring as ring members and R ^ and Rc an alkyl group are, where R * and Rc as ring members can form a ring with the nitrogen atom. Le A 9072 80 98 09/1128