HRP960082A2 - Process for producing thietanones - Google Patents

Description

The invention relates to a process for the production of thietanones of the general formula I

[image]

R1-R4 independently of each other, the same or different, H,

C1-C6-alkyl, C3-C6-cycloalkyl, aryl and arylalkyl,

whereby residues R1-R4 can be, where possible and permissible, linear or branched, substituted by halogen and/or substituted by heteroatom N, O, S, and

whereby always two of the residues R1-R4 can be connected in a ring.

Thietanones of the general formula In addition to being used in mechanistic or physicochemical studies, they are used as precursors for substances that are added to dipeptide sweeteners (US-PS 4,692,512, EP-A 168 112, IL-A 63 396, EP-A 128 654 , US-PS 4,411,925; US-PS 4,399,163, EP-A 69 811, EP-A 34 876, EP-A 325 485, J. Med. Chem. 1990, 33, 1052).

Thus, for example, simple reduction of compounds of general formula I leads to the corresponding alcohols (a). Reductive amination gives, starting from thietanones of the general formula I, the corresponding amines (b). As ester or amide constituents of dipeptides, compounds (a) and (b) give them extreme seeding power. In the event that all the residues R1-R4 are methyl, the constituent substance for Alitam is obtained with amine (b), which has approx. 2000 times more sweetening power than sugar (ACS Symp. Ser. 1991, 4 50, 57 - 67).

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Processes for the production of thietanones of the general formula I already belong to the state of the art.

So from Tetrahedron Lett. 1985, 26, 5187 known production variant for the compound of general formula I with R1-R4 = methyl, where this compound is produced by the addition of a carbene to a cyclic disulfide. Admittedly, the utilization of this variant is extremely low.

Somewhat better yields are obtained in the production of compounds of general formula I by dibromination of ketones of general formula III

[image]

and then by cyclization with hydrogen sulfide in the presence of base or with NaHS or Na2S (Arkiv Kemi 1963, 21, 295; J. Chem. Soc. Perkin Trans I, 1975, 2513, ibid 1976, 2590; J. Ara. Chem. Soc. 1976 , 98, 6696; Chem. Ber. 1980, 113, 2255; Chem. Ber. 1991, 124, 1747; J. Am. Chem. Soc. 1976, 98, 7081; Chem. Ber. 1984, 117, 277; J. Am. . Chem. Soc. Perkin Trans I 1984, 2457; Tetrahedron 1986, 42, 5301; US-PS 4,851,548).

The shortcoming of these known methods, however, is that bromine is applied, and the bromide compound accumulates as a waste product, which must be processed or properly disposed of. Another disadvantage is the use of highly toxic hydrogen sulfide. Both aspects are critical in terms of safety measures at work and endangering the environment.

Bearing in mind the state of the art stated and considered here, the task of the invention is to provide a process for the production of thietanone of the general formula I, which on the one hand far-reachingly avoids the use of expensive or technically hazardous substances in the application, and on the other hand allows the production of the desired end product of high purity with the highest possible utilization.

These and further tasks, not specified in detail, are solved by the process at the beginning of the mentioned method with the features that characterize claim 1.

Modifications of the process of the invention which show advantages are the subject of subclaims related to claim 1.

Thus, β-oxosulfenyl and general formulas II

[image]

where

R1-R4 have the meaning given by formula I, a

X stands for Cl, Br, J, are cyclized under the influence of a base in an organic solvent, it became possible in a predictable manner to significantly increase the utilization rates stated in the literature. Furthermore, it was possible to particularly conveniently avoid the use of generally very toxic hydrogen sulfide, which is normally used for the cyclization of the dibromine compound of the general formula (d).

[image]

This can be followed by cyclization of oxosulphenyl compounds of the general formula II in an inert organic solvent. Solvents that are particularly suitable according to the invention include, for example, ethers, such as THF, diethyl ether, diisopropyl ether or tertiary butyl ether, (C1-C6) alcohols, such as methanol, ethanol, isopropanol, n-propanol, tert. butanol, n-butanol, n-pentanol or n-hexanol, as well as aliphatic or aromatic hydrocarbons, such as for example n-hexane, cyclohexane or toluene or a mixture of the mentioned solvents, and alkanes; solvents such as methanol, ethanol, isopropanol, butanol and tetrahydrofuran, diethyl ether, di isopropyl ether, tertiary butyl methyl ether are particularly recommended within the scope of the invention.

A large number of substances can be used as a base for the cyclization reaction within the scope of the invention. Recommended compounds include potassium carbonate, sodium hydride, and alkaline alcoholates. It is particularly recommended to use KOtBu when using ether as a solvent, as well as when using alcohol, the use of the appropriate sodium alcoholate.

Beta-oxosulfenyl compounds of the general formula II required for cyclization to thietanones can be produced according to procedures known in the literature. From Helv. Chem. Acta 1966, 49, 2344 and J. Prakt. Chem. 1979, 321, 1017, it is known that diisopropyl ketone can be converted with sulfur dichloride into the corresponding oxosulfenyl chloride of formula (c).

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At the same time, for example, in Helv. Chem. Acta 1966, 49, 2344 suggests that the reaction between sulfur dichloride and diisopropylketone is carried out by adding sulfur dichloride to a solution of diisopropylketone in chloroform at 50 to 60 °C with some aluminum chloride as a catalyst. According to the regulation stated in this source, the reaction mixture is distilled in fractions to isolate the reaction products after the evolution of hydrogen chloride is completed. The oxosulfenyl chloride of formula (c) is obtained with only approx. 50% utilization.

A further possibility for the production of sulfenyl chloride of formula (c) consists in the conversion of diisopropylketone with disulfur dichloride into bisdiisopropyldisulfide (Lit.: Helv. Chim. Acta 1966, 49, 2344. Utilization: 55 7.). Furthermore, it is known that disulfides can be converted with chlorine into the corresponding sulfenyl chlorides (Lit.: Houben Uley 1 "Methoden der organischen Chemie", vol. Eli, p. 72ff).

β-oxosulfenyl compounds of formula II can be obtained in a recommended way within the framework of the invention by reacting ketones of general formula III

[image]

where R1-R4 have the meaning given by formula I, with sulfur compounds of general formula IV

SX2 (IV)

where X stands for Cl, Br and/or J, excluding the addition of solvent and further Lewis acids.

Furthermore, (3-oxosul phenyl compounds of formula II can be obtained by reaction of ketones of general formula III

[image]

R1-R4 have the meaning given by formula I,

With compounds of general formula V

S2X2 (V)

where X stands for Cl, Br and/or J,

excluding the addition of solvent and further Lewis acids and the following reaction with

X2

where X has the above meaning.

In contrast to the methods known from the state of the art, the reaction for obtaining β-oxosulfenyl compounds of formula II can be carried out within the framework of the invention without solvents and without the addition of Lewis acid, which can significantly increase the yields stated in the literature. Furthermore, the fact that the reaction mixture that accumulates during the production of oxosulfenyl compounds of formula II according to the invention can be further processed without further complicated processing, simply by dissolving it in an organic compound suitable as a solvent, is of particular great advantage.

The process of the invention is particularly suitable for the production of 2, 2, 4, 4-tetramethyl thietanone. This compound, in which all the residues always stand for the methyl group, has, as already mentioned at the beginning, an important place as an intermediate product for the production of artificial sweeteners.

According to the invention, it is further recommended for the conversion of ketones of the general formula III to choose sulfur dichloride as the compound of the general formula IV, that is, disulfur dichloride of the general formula V and chlorine as the cleavage agent. These sulfur compounds are safe and easy to handle, and allow the production of β-oxosulfenyl compounds of formula II, which are cyclized in high yield according to the invention.

The following examples serve to clarify the invention:

Example 1

Production of 2-(2,4-dimethyl-3-oxo-pentyl)-sulfenyl chloride (R1-R4 in formula II = methyl, X = Cl)

428 ml (3 mol) of diisopropyl ketone is placed in a 1 L three-necked flask with a dropping funnel, a thermometer and a vacuum connection. Now slowly add 0.25 equivalents of sulfur dioxide. After the reaction has started (increase in temperature), the remaining 0.75 equivalents of sulfur dichloride are added while cooling with ice so that the temperature does not exceed 3.0 °C. After the decrease in the evolution of hydrogen chloride, it is stirred for another 30 min and then the remaining hydrogen chloride is removed at 20 mbar in a vacuum using a water pump. Sulphenyl chloride is obtained with a yield > 90%.

Example 2

Production of 2,2,4,4-tetramethylthiathanone (R1-R4 in formula I = methyl)

1.8 g (10 mmol) of the sulfenyl chloride obtained in example 1 is dissolved in 140 ml of tetrahydrofuran and, with ice cooling, added dropwise to a solution of 1.23 g (11 mmol) of potassium tertiary butylate in 50 ml of tetrahydrofuran. The mixture is left to mix for approx. 1 hour. Refinement follows by distilling tetrahydrofuran through a column with a cooler, until a mixture containing approx. 10 wt.%. ketones. The remaining ether phase was mixed with 20 ml of 1 N hydrochloric acid and the mixture was extracted 3 times with 30 ml of diethyl ether. The collected ether phases are dried over magnesium sulfate. After filtration, the yield of 91 V is determined by HPLC.

Example 3

Production of 1-cyclopropylcarbonyl-1-cyclopropylsulfenyl chloride (formula II, where R1, R2, R3 and R4 are C1-alkyl, and R1 with R2 as well as R3 with R4 are always connected in a ring).

330 g (3 mol) of dicyclopropylketone are placed in a three-necked 1 L flask with a dropping funnel, a thermometer and a vacuum connection. Now add 0.25 equivalents of sulfur dichloride slowly. After the reaction has started (increase in temperature), the remaining 0.75 equivalents of sulfur dichloride are added while cooling with ice so that the temperature does not exceed 30°C. After the decrease in the evolution of hydrogen chloride, it is stirred for another 30 minutes, and then the remaining hydrogen chloride is removed in a vacuum using a water pump. Sulphenyl chloride is obtained with a yield > 90%.

Example 4

Production of thietanones of the general formula I with R1-R2 = CH2 and linked in a cyclopropyl, as well as R3 and R4 = CH2, also linked in a cyclopropyl residue.

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1.76 g (10 mmol) of the sulfenyl chloride obtained in example 3 is dissolved in 140 ml of tetrahydrofuran and, with ice cooling, added dropwise to a solution of 1.23 g (11 mmol) of potassium tertiary butylate in 50 ml of tetrahydrofuran. The mixture is left to mix for approx. 1 hour. Refinement is followed by distillation of tetrahydrofuran through a column with a cooler, until a mixture containing approx. 10 wt.-%. ketones. The remaining ester phase is mixed with 20 ml of 1 N hydrochloric acid and the mixture is extracted 3 times with 30 ml of diethyl ether. The collected ether phases are dried over magnesium sulfate. After filtration, a yield of 91% was determined by HPLC.

Example 5

Production of 2-(2,4-dimethyl-3-oxo-pentyl) sulfenyl chloride (R1-R4 in formula II = methyl, X = Cl)

4 equivalents of DIPK are placed in a three-necked flask of 1 l equipped with a dropping funnel and a thermometer as well as a distillation attachment. At < 10 °C, add 1 equiv. S2Cl2. After the reaction has started, excess DIPK is removed under vacuum, and then chlorine is introduced until saturation. Easily volatile compounds are then removed in vacuo, and sulfenyl chloride can be used in the next reaction.

Example 6

Production of 2,2,4,4-tetramethylthiethanone (R1-R4 in formula I = methyl)

Sulphenyl chloride from example 5 is added dropwise to a solution of 1.5 equiv. (relative to sulfenyl chloride) of sodium methylate in methanol. It is then heated for 3-4 hours under reflux. It is added to hot 1/5 volume of water, allowed to cool and filtered. The ketone is obtained as a colorless solid that smells like camphor, with a yield > 80%.

Further advantages and ways of carrying out the invention derive from the following patent claims.

Claims (9)

1. Process for the production of thietanones of the general formula I [image] where are they R1-R4 independent of each other, equal or different, C1-C6-alkyl, C3-C6-cycloalkyl, aryl and arylalkyl, where the residues R1-R4 can be, where possible and permissible, linear or branched, substituted by halogen and/or substituted by a heteroatom N, O, S, And whereby always two of the residues R1-R4 can be connected in a ring, characterized by, that β-oxosulfenyl and general formulas II [image] where R1-R4 have the meaning given by formula I, and X stands for Cl, Br, J, they are cyclized in an organic solvent under the influence of a base. 2. The method according to claim 1, characterized by the fact that ether is used as an organic solvent, and potassium-tert is used as a base. butylate. 3. The method according to claim 1, characterized by the fact that a (C1-C6)-alcohol is used as a solvent, and a suitable alkaline alcoholate is used as a base. 4. The method according to claim 3, characterized by the fact that methanol is used as a solvent, and sodium methanolate is used as a base. 5. The process according to one of the previous claims, characterized by the fact that β-oxosulfenic compounds of formula II are obtained by reaction of ketones of general formula III [image] where R1-R4 have the meaning indicated by formula I, with compounds of general formula IV SX2 (IV) where X stands for Cl, Br and/or J, excluding the addition of solvents and further Lewis acids. 6. The process according to one of the previous claims, characterized in that β-oxosulfenyl compounds of formula II are obtained by the reaction of ketones of general formula III [image] R 1 - R 4 have the meaning given by formula I, with compounds of general formula V S2X2 (V) where X stands for Cl, Br and/or J, excluding the addition of solvent and further Lewis acids, and the following reaction with X2 where X has the above meaning. 7. Process according to claim 5 or 6, characterized in that, according to claim 5 or 6, the resulting β-oxosulfenyl compounds of formula II are cyclized without further processing, dissolved in ether and with one base, while retaining the thiethanone according to formula I. 8. The method according to one of the previous claims, characterized by the fact that compounds react, in which all residues R1-R4 always stand for a methyl group. 9. The method according to one of the previous claims, characterized in that the compounds, in which X stands for Cl, react.