DE10394213B4 - Process for the synthesis of bis (4-substituted quinolyl) disulphides - Google Patents

Abstract

The present invention relates to a process for the synthesis of bis (4-substituted quinolyl) disulfides.

Description

Territory of invention

The The present invention relates to a process for the synthesis of bis (4-substituted Quinolyl) disulphides.

background the invention

substituted Bis-quinolyl disulfides are for their activity known against malaria and some of them are called analysis agencies used. Recent research has found that these Compounds a selective and effective antibacterial activity against bacteria, that belong to the Helicobacter, and also for the treatment or prevention of the occurrence of peptic ulcer and chronic gastritises which are accompanied by infection by H-bacteria are.

It Reference may be made to Japanese Patent, JP Appl. 95 / 14,233, 31. January 1995, PCT International Application WO96 23,774 (Cl C07D215 / 36), August 8, 1996, CA: 125,247631h; (Japan) wherein quinoline-4 (1H) -thione oxidized to a disulfide using potassium ferricyanide has been. This process has the disadvantage of producing thione and the use of expensive potassium ferricyanide.

It is referred to Latv. PSR interest rate. Acad. Vestis, Kim. Ser. 1979 (9), 181 (Russ), CA: 91.39289c and Latv. PSR interest rate. Acad. vestis, Kim. Ser. 1979, (3), 282 (Russ), CA: 91, 193129j, in which a chlorosulfonyl derivative of quinoline is converted to the thiol by reduction, according to the oxidation gave a disulfide. This method has the disadvantage the use of dangerous and corrosive chlorosulfonic on.

It is also referred to Latv. PSR interest rate. Acad. Vestis, Kim. Ser. 1980, (4) 489 (Russ), CA: 94,15526, which discloses the diazotization of a Aminchinolins, followed by the reaction with thiourea, thereby a thiol is obtained. The oxidation of the thiol gives the disulfide. In this process, the critical diazotization reaction requires strict precautions.

It Reference is also made to Pharmazine 1978, 33 (9), 572, CA: 89, 215199v, which involves the reaction of chloroquinoline with thioacetamide or thiourea to form thiol derivatives, which after further oxidation give the disulfide. This special method has the disadvantage the use of higher Temperatures up.

• 1. Die Handhabung von gefährlicher und ätzender Chlorsulfonsäure ist schwierig.
• 2. Die Diazotierungsreaktion erfordert beträchtliche Vorsichtsmaßnahmen.
• 3. Die Isolierung eines Thiols aus einem wässrigen Medium ist beschwerlich.
• 4. Es ist ein zusätzlicher Oxidationsschritt erforderlich.
• 5. Es ist eine höhere Reaktionstemperatur erforderlich.
• 6. Die Anzahl der beteiligten Schritte ist höher.

All prior methods include the use of caustic and hazardous chlorosulfonic acid, critical diazotization, and higher reaction temperature. Moreover, the isolation of a thiol from an aqueous medium is difficult. Although all of these methods are feasible in the laboratory, they are barely usable on a commercial scale in terms of the steps involved, the cost, the handling of hazardous reagents and wastewater. Thus, the existing processes for the preparation of bis (quinolyl) disulfides have the following disadvantages:

• 1. The handling of dangerous and corrosive chlorosulfonic acid is difficult.
• 2. The diazotization reaction requires considerable precautions.
• 3. The isolation of a thiol from an aqueous medium is cumbersome.
• 4. An additional oxidation step is required.
• 5. It is a higher reaction temperature required.
• 6. The number of steps involved is higher.

Tasks of invention

The The main object of the present invention is to provide a Process for the preparation of bis (4-substituted quinolyl) disulfide using 4-substituted Halogen quinolines and the sodium, potassium or ammonium salts the dithiocarbamic acid, the above Disadvantages avoids.

Another object of the present invention is the development of a process for bis (4-sub substituted quinolyl) disulfides without the use of hazardous chlorosulfonyl derivatives and additional oxidizing reagents.

A Another object of the invention is the circumvention of critical diazotization and isolating the thiol from an aqueous medium.

A Another object of the invention is the use of a favorable, not dangerous Salt of dithiocarbamic acid, which reduces the number of steps and wastewater on a large scale minimized.

A Another object of the invention is to provide a method for the preparation of bis (4-substituted quinolyl) disulfide, wherein Disubstituted thiourea as a by-product also as a value-added Product is usable, reducing the cost-effectiveness of the process is improved.

It Another object of the invention is a method of preparation of bis (4-substituted Quinolyl) disulfide, which makes the use of hazardous and corrosive chlorosulfonic the for the diazotization required high and strict safety measures, the difficulty in isolating a thiol from an aqueous one Medium, the extra Oxidation step and the requirement of higher reaction temperature avoids.

Summary the invention

The present process is suitable for one stage production of Bis (4-substituted Quinolyl) disulfides using 4-substituted haloquinoline and a sodium, potassium or ammonium salt of dithiocarbamic acid in one aprotic solvents. Another objective of the method is to use caustic Chlorosulfonyl chloride or expensive oxidation reagents or the isolation to avoid unstable thiols. The essential feature of Invention is that disulfides are produced in one step, which makes the number of laborious Avoid steps and the use of hazardous, corrosive chemicals becomes. The yield of disulfides is also high.

Formel 1 bereit, wobei R1 aus der Gruppe bestehend aus Trifluor, Trichlor, Cyano und substituiertem Amid ausgewählt ist; R2 aus der Gruppe bestehend aus Alkyl, Alkoxy, Halogen, Alkylamino ausgewählt ist; umfassend das Umsetzen von 4-substituiertem Halogenchinolin mit einem Salz von Alkyl- oder Aryldithiocarbaminsäure in einem organischen Lösungsmittel, um das Bis(4-substituierte Chinolyl)disulfid der Formel 1 und den disubstituierten Thioharnstoff der Formel 2

Formel 2 zu erhalten.The present invention thus provides a one step process for the preparation of bis (4-substituted quinolyl) disulfide of formula 1

Formula 1 wherein R1 is selected from the group consisting of trifluoro, trichloro, cyano and substituted amide; R2 is selected from the group consisting of alkyl, alkoxy, halo, alkylamino; comprising reacting 4-substituted haloquinoline with a salt of alkyl or aryldithiocarbamic acid in an organic solvent to form the bis (4-substituted quinolyl) disulfide of formula 1 and the disubstituted thiourea of formula 2

Formula 2 to get.

In an embodiment The invention is the halogen in the 4-substituted haloquinoline selected from the group consisting of iodine, bromine, chlorine and fluorine.

In another embodiment of the invention are the substituents of quinoline at position 2 from the group consisting of trifluoromethyl, trichloromethyl, cyano and substituted amide.

In a further embodiment of the invention are the substituents of quinoline at the positions 5, 6, 7 or 8 from the group consisting of halogen, alkyl, alkoxy and alkylamino selected.

In a further embodiment The invention is the salt of alkyl or Aryldithiocarbaminsäure the group consisting of sodium, potassium and ammonium salts selected.

In a further embodiment The invention is the organic solvent from the group consisting of dimethylformamide, dimethyl sulfoxide, mixtures thereof and acetonitrile.

In a further embodiment the invention, the reaction at a temperature in the range of 20 ° C to 40 ° C performed.

In a further embodiment The invention provides the reaction for a period of time in the range carried out from 6 to 17 h.

In a further embodiment the invention, the yield of bis (4-substituted quinolyl) disulfide is the Formula 1 in the range of 70 to 80%.

Full Description of the invention

The present process is suitable for one-step preparation of bis (4-substituted quinolyl) disulfides using 4-substituted haloquinoline and a Sodium, potassium or ammonium salt of dithiocarbamic acid in one aprotic solvents. Another object of the method is to use caustic Chlorosulfonyl chloride or expensive oxidation reagents or the isolation to avoid unstable thiols. The essential feature of Invention is that disulfides are produced in one step, which makes the number of laborious Avoid steps and the use of hazardous, corrosive chemicals becomes. The yield of disulfides is also high.

Schema 1 R₁ = Trifluor, Trichlor, Cyano, substituiertes Amid
R₂ = Alkyl, Alkoxy, Halogen, Alkylamino
R₃ = Alkyl, C₁-C₄, Aryl
Z = Na, K oder NH₄ Scheme 1 depicts the preparation of bis (4-substituted quinolyl) disulfide.

Scheme 1 R ₁ = trifluoro, trichloro, cyano, substituted amide
R ₂ = alkyl, alkoxy, halogen, alkylamino
R ₃ = alkyl, C ₁ -C ₄ , aryl
Z = Na, K or NH ₄

Around those with the earlier Process for the preparation of bis (4-substituted quinolyl) disulfide linked To overcome difficulties The inventors of the present invention have described the process for Preparation of bis (4-substituted quinolyl) disulfides using of 4-substituted haloquinolines and the sodium, potassium and ammonium salt of alkyl or aryldithiocarbamic acid in one polar solvents uncovered. The Disulfidbildung took place in a step by Filtration or extraction was isolated.

example 1: bis (2,8-trifluoromethylquinolyl) disulfide A mixture of (2,8-trifluoromethyl) -4-bromoquinoline (0.1 mol) and the potassium salt of ethyldithiocarbamic acid (0.15 Mol) in dimethylformamide (300 ml) is stirred at 20 ° C for 10 h. This is poured into water and extracted with ether. After concentration, the product is used a mixture of hexane: ether (90:10) isolated. Yield 75%.

Example 2: Bis (2,8-trifluoromethylquinolyl) disulfide

2,8-Trifluoromethyl-4-iodoquinoline (0.1 mol) is dissolved in dimethylformamide (350 ml) and phenylammo Niumdithiocarbamat (0.15 mol) is added while maintaining the temperature at 15 ° C. It was further stirred for 9 h at 25 ° C, diluted with water and extracted with ether. After concentrating the solvent, the residue is extracted with toluene. Removal of the toluene gives the disulfide in 80% yield.

Example 3: Bis (2-trifluoromethyl-8-methylquinolyl) disulfide

To a solution of 2-trifluoromethyl-8-methyl-4-bromoquinoline (0.1 mol) in dimethyl sulfoxide (300 ml) is added portionwise a sodium salt of propyldithiocarbamic acid (0.15 Mol). It was for 13 h at 35 ° C further stirred and the solvent removed under vacuum. The residue was extracted with a mixture of toluene: hexane (60:40). The removal of the solvent gives a Disulfidausbeute of 76%.

Example 4: Bis (2-trifluoromethyl-8-chloroquinolyl) disulfide

A Mixture of 2-trifluoromethyl-8-chloro-4-bromoquinoline (0.1 mol) in Acetonitrile (400 ml) and the sodium salt of methyldithiocarbamic acid (0.18 Mole) is at 32 ° C for 17 h stirred. This is poured into water and extracted with ether. The removal of the solvent gives the crude product, from which the pure product by extraction with ether (4 × 100 ml) is obtained with a yield of 75%.

Example 5: Bis (2-trichloromethyl-8-trifluoromethyl-4-quinolyl) disulfide

Phenylammoniumdithiocarbamat (0.13 mol) is added portionwise to a cold solution of 2-trichloromethyl-8-trifluoromethyl-4-bromoquinoline (0.1 mol) in dimethylformamide (300 ml). Subsequently, will the mixture was stirred at room temperature for 11 h. The solvent is placed under vacuum removed and the residue is poured into water. The yield of isolated after extraction and crystallization Product was 77%.

Claims (9)

One step process for the preparation of bis (4-substituted quinolyl) disulfide of formula 1

Formula 1 wherein R1 is selected from the group consisting of trifluoro, trichloro, cyano and substituted amide; R2 is selected from the group consisting of alkyl, alkoxy, halo, alkylamino; comprising reacting 4-substituted haloquinoline with a salt of alkyl or aryldithiocarbamic acid in an organic solvent to form the bis (4-substituted quinolyl) disulfide of formula 1 and the disubstituted thiourea of formula 2

Formula 2 to get. The method of claim 1 wherein the halogen is in the 4-substituted haloquinoline selected from the group consisting of iodine, Bromine, chlorine and fluorine are selected is. The method of claim 1, wherein the substituents at position 2 of quinoline from the group consisting of trifluoromethyl, Trichloromethyl, cyano and substituted amide are selected. The method of claim 1, wherein the substituents at positions 5, 6, 7 or 8 of quinoline from the group selected from halogen, alkyl, alkoxy and alkylamino. Process according to claim 1, wherein the salt of the alkyl or aryldithiocarbamic acid from the group consisting of sodium, potassium and ammonium salts selected is. The method of claim 1, wherein the organic solvent from the group consisting of dimethylformamide, dimethyl sulphoxide, a mixture thereof and acetonitrile is selected. The method of claim 1, wherein the reaction in a temperature in the range of 20 ° C to 40 ° C is performed. The method of claim 1, wherein the reaction is for a period of time is carried out in the range of 6 to 17 h. Process according to claim 1, wherein the yield of the Product Bis (4-substituted Quinolyl) disulfide of formula 1 ranges from 70 to 80%.