DE2148204A1 - Process for the production of organic see thioacetates - Google Patents

Description

Process for the production of organic thioacetates

The invention relates to a. Method of making a organic thioacetate by reacting an organic halide with a Thioessigsciuresalz replacing the Halogen atoms through thioacetoxy groups.

It is known that organic thioacetates are replaced by the reaction of organic halides with potassium thioacetate of the halogen atoms can be produced by thioacetoxy groups (cf. e.g. J. Chem. Soc., 248, 1949). This However, the process has the disadvantage that the desired product is only obtained in relatively low yields so that it is not suitable for large-scale implementation.

The object of the invention is to provide an improved process for the preparation of organic thioacetates in which the desired products can be obtained in higher yield, so that it is also suitable for large-scale implementation suitable.

It has now been found that organic thioacetates are essential Higher yields can be obtained by mixing an organic halide with a tetraalkylammonium thioacetate

in iirusetzL. In this process the _{respective halogen atoms contained in the organic iu'ilo t} ', eriid are replaced by thioaceto ^ ygr.ippeii, with the corresponding j (. ·.' -rc · .- IkylaniTüoiiiumhalogenid being formed "

', cr' / - n5; Laiid de.rj! rf: iiidun ^r ; is a method of manufacture

2 0 9 8 1 h / 1 7 8 1

BATH ORIGINAL

of an organic thioacetate by reacting an organic halide with a thioacetic acid salt Replacement of the halogen atoms by thioacetoxy groups, which is characterized in that the reaction is uncer Use of a tetraalkylammonium thioacetate as thioacetic acid salt with an at least stoichiometric Amount of tefccaalkylammonium thioacetate for a sufficient length of time carried out until the reaction is complete and the thioacetate formed from the reaction mixture obtained separates in a manner known per se.

The method of the invention has the advantage that the desired Products are obtained in significantly higher yields than in the previously known processes is the case, so that it can also be carried out on an industrial scale.

The process of the invention is illustrated by the following general equation, in which R is an alkyl radical, preferably having 1 to 8, in particular 1 to 4 carbon atoms, R _{1 is} an organic radical and X is a halogen atom, preferably a chlorine or bromine atom;

0 0

(R) ₄ NSCCH + R ₁ - X -> R ₁ - SCCH ₀ + (R) ₄ II - X

Tetraalkyl- Organic- Organic Tetraalkylammonium Thioacetate ammonium

thioacetate halide ha Io genie. "

The organic thioacetates obtained in the process of the invention give on hydrolysis in non-aqueous L. ^ cii i-.i '> -

20981 5/178 1

BATH

-rf *

solvents thiols without the sulfides being formed.

The tetraalkylammonium thioacetates useful in the process of the invention can be prepared by neutralizing the respective tetraalkylammonium hydroxide Thioacetic acid. This implementation is explained by the following equation:

0 0

V-J

+ CH ₃ CSH> (R) ₄ NSCCH ₃ + H ₂ O

Each of the four alkyl groups used in the process of the invention usable Tetraall ^ lammoniumthioacetats can have 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, contain. All alkyl groups can be the same or it two or more different alkyl groups can be present, typical examples for those which can be used according to the invention Tetraalkylammonium thioacetates are tetramethylammonium thioacetate, Tetraethylammonium thioacetate / and tetrabutylammonium thioacetate.

Examples of starting materials used in the process of the invention Organic halides which can be used are acyclic or cyclic aliphatic compounds or aromatic compounds or heterocyclic compounds, provided that they contain one or more substitutable halogen atoms, the are bound to a carbon atom, typical classes for Such organic halides which can be used in the process of the invention are e.g. B. the alkylhalo-

2 Π 9 8 1 B / 1 7 8 1

2H8204 - r-

genides, allyl halides, acyl halides, polymethylene halides, Aryl halides and alkyl aryl halides.

The reaction of the organic halide with the tetraalkylammonium thioacetate according to the process of the invention is preferably using an inert organic solvent carried out. Examples of preferably usable solvents are tetrahydrofuran and short-chain ones aliphatic ketones such as acetone, 2-butanone, methyl-npropy! ketone, Methyl isopropyl ketone and diethyl ketone.

The tetraalkylammonium thioacetate is used in the process of the invention preferably used in at least stoichiometric amounts, i.e. in such an amount that the molar ratio of tetraalkylammonium thioacetate to organic halide at least equal to the number of those in the organic halide existing Ilalogenatome is. As a rule, a small excess of tetraalkylammonium thioacetate is advantageous.

The method of the invention becomes more convenient at one Temperature from about 20 to about 80 C with reaction times on the order of about 15 minutes to about two hours carried out. The organic thioacetate formed during the reaction can easily be separated off from the reaction mixture by pouring them into various volumes of water, or by adding the tetraalkylammonium halide oil product removed by filtration and distilling off the solvent under reduced pressure and the remaining reaction product, if it is liquid, purifies it by distillation or, if it is solid, purifies it by crystallization.

209815/1781

2H8204 5

The invention is illustrated in more detail by the following examples.

example 1

To a solution of 500 g (1.37 mol) of tetramethylammonium hydroxide in 2000 g of methanol, 104 g (1.37 mol) of thioacetic acid were slowly added at a temperature of 20 to 30 ° C. with stirring and external cooling with water. All of the thioacetic acid was added and the mixture was stirred for an additional 5 to 10 minutes and then evaporated to near dryness without heating under reduced pressure. The product thus obtained consisted of yellow-brown colored crystals, these were collected, washed with acetone and then with ethyl ether and dried. Upon heating, the crystals changed their crystal shape at 133 ° C. and melted with decomposition at 205 ° C. They were identified as tetramethylammonium thioacetate by infrared analysis. The yield was 100 g, which corresponds to 54 % of the theoretical amount of 185 g.

To a solution of 11 g (0.033 mol) 1,4-dibromo-2,3-butylene diacetate 10 g (0.074 mol) of tetramethylammonium thioacetate were added to 25 ml of warm, dry acetone in the manner described above admitted. The resulting mixture was heated with constant stirring and occurred at about 40 ° C slightly exothermic reaction with the formation of a voluminous precipitate of tetramethylammonium bromide. At this , The reaction mixture was made by adding 50 ml of acetone diluted, stirred for a short time and then poured into a large volume

209815/1781

Poured water. The product that was deposited was with Ethyl ether extracted, the extracts were dried and the ethyl ether was reduced by distillation The pressure was removed and impure dithiothreitol tetraacetate was obtained. The implementation can be given by the following equation being represented:

0 0 Ii

H _Q CCO OCCH, 3, | 3

BrCH ₂ CHCIICH ₂ Br

0 H

1,4-dibromo-2,3-butylene diacetate

Tetramethylammonium thioacetate

0 N C

0 I.

N I

H ₃ CCO OCCH ₃

CH ₃ CSCH ₂ CHCHCH ₂ S

Ch

Dithiothreitol tetraacetate

2 (CH ₃ ) ₄ NBr

Tetramethyl

ammonium-

bromide

The impure dithiothreitol tetraacetate was recrystallized from methanol and gray-white crystals were obtained melted at 70 to 72 C. The yield was 5 g, which corresponds to 47% of the theoretical amount of 10.7 g. the Conversion of dithiothreitol tetraacetate into dithiothreitol, one for the maintenance of protein sulphydryl groups

209815/1781

2U8204

in the reduced state biochemically important reagent, can easily be carried out by putting it in a 1 η methanolic hydrochloric acid solution under reflux boils, the ethanol evaporates and the product recrystallized.

In contrast to the above results was at an identical experiment, but in which, instead of Tetramethylammoniumthioacetat potassium thioacetate and instead of acetone ethanol were used (the reason for the use of ethanol was that potassium thioacetate in ethanol is better soluble than in acetone) the yield of dithiothreitol tetraacetate was only 1 g, which corresponds to 9.3% of the theoretical amount of 10.7 g.

Example 2

In a 250 ml flask. with 12.2 g (0.05 mol) 1,4-di-

chloro-2,3-buLylendiacetr.t dissolved in 75 cm acetone. The solution was heated to reflux and 15 g (0.1 Hol) of tetranethyliinimonium thioacetate were added and the mixture was refluxed at 56 ° C. for 15 minutes. During this time, a song made of tetramethylammoTiiumchlorid formed. The mixture was cooled to room temperature and poured into 2 volumes of water and that was

3 ·· separating oily product was extracted with 100 cm ether. The ethereal layer was separated over anhydrous sodium sulfate dried, filtered, and the filtrate evaporated in vacuo to give lithiothreitol tetraacetate as a solid that melted at 55 to 60 ° C. laugh

^209815/1781

2U8204

Recrystallization of the crude product from methanol gave white crystals melting at 73 to 75 ° C. The yield of dithiothre / tetraacetate was 6.5 g, which corresponds to 40 % of the theoretical yield of 16.1 g. The implementation described in this example can be represented by the following equation x

0 0 Il I

H ₀ GCO OGCH,

I I

GICh ₂ CHCHCH ₂ GI

2 (ClO ₄ NSCCH ₃

^, 3-butylene diacetate

Tetramethylammonium thioacetate

0 0 H ₀ CCO OC

CH

CH ₀ CSCH ₀ GHCHGh ₀ SCCH _{0 3 |} 2 2 H 3

0 0

2 (CH ₃ ) ₄ HC1

Dithiothreitol tetraacetate

Tetramethylammonium chloride

When carrying out a corresponding experiment in a larger device (22 liter apparatus) in which one of 16.8 mol of 1,4-dichloro-2,3-butylene diacetate and 34 IjoI Tetramethylammonium thioacetate ran out, 32OÜ g were obtained Dithiothreitol tetraacetate, which corresponds to 64% of the theoretical text of 5040 <r.

209815/1781

2H82Q4

Example 3

In one put on a steam bath and with one A stirrer, a reflux condenser and a thermometer provided 500 ml three-necked flask, 15.9 g (0.1 mol) 1.4-

3
Dichloro-2,3-butanediol dissolved in 400 cm dry tetrahydrofuran. 30 g (0.2 mol) of tetramethylammonium thioacetate were added to this solution. The slurry was stirred and refluxed on the steam bath for 20 hours. During this time it was found that the character of the solid changed from a granular to a fine white suspension, indicating that a reaction had taken place and that the solid was now tetramethylammonium chloride. The mixture was cooled to room temperature and filtered, the solids washed on the funnel with ether. The ether wash water was added to the tetrahydrofuran filtrates. The solid was dried and weighed. 21.6 g of solid were obtained (theoretical amount of tetramethylammonium chloride »21.9 g). The filtrates containing the product were concentrated under reduced pressure to remove the solvent, leaving the product dithiothreitol-S, S'-diacetate.

3 ··
The crude product was dissolved in 100 cm of ethyl ether, with ent-

(Nuchar) +)

firing activated carbon / treated, filtered through Supereel and the clear, colorless filtrates were concentrated under reduced pressure and dithiothreitol-S, S'-diacetate was obtained in the form of a colorless oil identified by infrared spectrum. The yield obtained was 22 g, which corresponds to 92.5% of the theoretical yield of 23.8 g. The implementation described in this example can be implemented by the following Equation to be represented;

⁺⁾ an ORIGINAL INSPECTED diatom filter aid

2H8204

2 (CHo) ₄ NSCCH ₃ .

1.4 dichloro-2,3-tetramethylammonium

butanediol thioacetate

0 0

CH CSCH ₂ CHOHCHOHCH ₂ SCCh ₃ + 2 (CH ₃ ) ^ Cl

Dithiothreitol-S, S * -diacetate Tetramethylammonium-

chloride

Example 4

16.9 g (0.1 mol) of 2-chlorobenzene were added to a 250 ml flask.

3
thiazole was dissolved in 100 cm of acetone and 16 g (0.11 mol) of tetramethylammonium thioacetate were added to the solution. An exothermic reaction occurred and the temperature rose to 38 ° C., at the same time tetramethylammonium chloride precipitated. The mixture was refluxed (56 ° C) for 30 minutes then cooled to room temperature. The tetramethylammonium chloride was removed by filtration and the filtrate was evaporated under reduced pressure and with mild heating to remove the acetone, the product 2-benzothiazolethiol acetate being returned in the form of an oil.

3 ..
stayed. The oil was dissolved in 75 cm of ethyl ether, the solution was washed with water to remove the unreacted tetramethylammoium thioacetate and dried over anhydrous free sodium sulfate, the ether was distilled off under reduced pressure, the product remaining. Infrared analysis confirmed that the product was' 2-benzothiazolethiol acetate. The yield was 20 g, which corresponds to 96% of the theoretical yield of 20.9 g.

209815/1781

The implementation described in this example can be represented by the following equation

-Cl

0
(CHg) ₄ NSCCH ₃

2-chlorobenzothiazole

Te tr ame thy lammonium thioacetate

(CII ₃ ) ₄ NCL

2-benzothiazole thiol acetate

Tetramethylammonium chloride

Example 5

In a 250 ml flask, 13 g (0.103 mol) oc-chlorine

3
Toluene dissolved in 100 cm of acetone and 15.5 g (0.104 liol) of tetrahydrofuran lainmonium thioace were added to the solution. äs An exothermic reaction occurred on, rise vjobei the temperature at 45 C and at the same time, a precipitate of tetramethylammonium chloride was formed. The mixture was reduced to a 17; The steam bath was refluxed for 15 minutes: "- heated (56 C), then cooled to room temperature and the tetro-methylammonium chloride was removed by filtration.

2 0 9 8 15/1781

BAD QR {<2 | N _AL

The filtrate was concentrated under reduced pressure and with gentle heating to remove the acetone, whereby the product α-toluene thiol acetate in the form of an oil

3 ..

The oil was dissolved in 100 cm of ethyl ether and the solution was washed with water to remove the unreacted tetramethylammonium thioacetate and dried over anhydrous sodium sulfate. The solution was filtered and the ether was distilled off under reduced pressure, leaving the product. Infrared analysis confirmed that the product was α-toluene thiol acetate. The yield was 14 g, which corresponds to 83 % of the theoretical yield of 17.1 g. The implementation described in this example can be represented by the following equation:

/ Λ.

CH ₂ Cl

(CH ₃ ) ₄ NSCCH ₃

α-chlorotoluene

Te trame thy1ammonium thioacetate

0 A

- CH ₂ SCCH ₃

α-toluene thiol acetate

(CH) ₄ KC1

Tetramethylammonium chloride

209815/1781

Example 6

In a 250 ml flask, 16.3 g (0.1 mol) of bromocyclo-

3
hexane was dissolved in 75 cm of acetone and 16 pounds (0.11 mol) of tetramethylanimonium thioacetate were added to the solution. The mixture was refluxed (56 ° C) on a steam bath for two hours and a precipitate of tetramethylammonium bromide formed. After filtering, the tetramethylammonium bromide was obtained in an amount of 15 g compared with a theoretical amount of 15.4 g. The filtrate was poured into water

3 ..
poured, extracted with 100 cm of ethyl ether and the layer of leaves was separated, poured over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove the ether. The product identified by red analysis as cyclohexanethiol acetate. YTurde, remained in the form of an oil. It was obtained in a yield of 7.8 g, which corresponds to 50% of the theoretical yield of 15.8 g. The implementation described in this example can be represented by the following equation *

+ (CH,). NSCCH,

Cromcyclo-tetramethylhexane ammonium thio acetate

Example 7

(CH ₃ ) ₄ NBr

Cyclohexane tetramethylthiol acetate ammonium bromide

In a 500 ml flask, 18.1 g (0.1 mol) of 1-4-bis (chloromethyl) -cyclohcxun were added dissolved in 3.50 cm 2-butanone and added to the

209815/1781

ORfGtNAU INSPECTED

ΧΑ

Solution, 30 g (0.22 mol) of tetramethylammonium thioaceta.t admitted. The mixture was on a steam bath Heated under reflux (78 to 79 ° C.) for two hours, during which time a precipitate of tetramethylammonium chloride forms formed. The mixture was cooled to room temperature and by filtration there was obtained 20 g Tetramethylammonium chloride (92% of the theoretical amount) obtained. The filtrate was evaporated to dryness, whereby the product 1,4-cyclohexanebis (methylthioacetate) in the form

3 of an oil remained. The oil was dissolved in 75 cm of ethyl ether to remove the unreacted tetramethylammonium thioacetate washed with water, dried over what serfrei sodium sulfate and taken to remove the ether distilled under reduced pressure. Infrared analysis confirms that the product is 1,4-cyclohexanebis (methylthioacetate) acted. The yield was 19.5 g, which corresponds to 75% of the theoretical yield of 26 g. The one in this The implementation described in the example can be represented by the following equation:

ClCH ₂ -

-CH ₂ Cl

1,4-bis (chlorine thy I) cyclohexane

2 (CH_). NSCCH

Tetramethylammonium thioacetate

CH ₃ CSGH ₂

-O-

CH ₂ SCCH ₃ +

2 (CII ₃ ) ₄ NC1

1,4-cyclohexanebis (methy1-thioacetate)

Tetramethylammonium chloride

0 9 8 15/1781

2U8204

Example 8

4 kg (2.73 mol) of tetraethylammonium hydroxide were placed in a 5 liter flask (in the form of a 10% aqueous solution) and then 210 g (2.75 mol) of thioacetic acid were added with stirring admitted. The temperature of the mixture rose to 30 to 35 ° C and the thioacetic acid dissolved Formation of a clear, yellow, slightly acidic solution. The solution was made under reduced pressure on a steam bath concentrated and as soon as the volume was 1 to 1.2 liters, it was treated with decolorizing charcoal and filtered and then further concentrated to a thick syrup. Two fractions of the product were obtained from this syrup by filtering and drying in vacuo at 35 ° G. The product was an extremely hygroscopic, yellow-brown colored, waxy solid with a melting point of 34 to 39 C, which was identified as tetraethyl monium thioacetate by infrared analysis. The yield was 210 g, which corresponds to 37.5% of the theoretical yield of 561 g.

In a 250 ml flask, 16.3 g (0.1 mol) of bromocyclo-

3
hexane was dissolved in 75 cm of acetone and 21 g (0.1 mol) of the tetraethylammonium acetate prepared as above were added to the solution. The mixture was heated to reflux (56 ° C.) for 30 minutes on a sardampfbad and a precipitate of tetraethylammonium bromide formed. The tetra; Methylammonium bromide was removed by filtration, the filtrate was poured into water and extracted with 100 cm of ether. The ether layer was separated off, dried over anhydrous sodium sulfate, filtered and removed

2 0 9 8 15/1781
'\ BAD ORIGINAL

- Vf -

of the ether is distilled under reduced pressure, the product remaining in the form of an oil. The infrared spectrum of the product Cj ^ cIohexanthiolacetat was identical to the product obtained in Example 6, in which tetra-methylammonium thioacetate had been used, and it was obtained in a yield of 10.5 g, which corresponds to 66.5 % of the theoretical Yield of 15.8 g. The implementation described in this example can be represented by the following equation:

Br SGGIU

Bromocyclohexane

Tetraethyl

ammonium-

thioacetate

Cyclohexanethiol acetate

l'etraäthyl

ammonium-

broiuid

Example 9

In a 1 liter flask was 300 g (0.28 mol) of tetrabutylammonium hydroxide (in the form of a 25% solution in methanol). The solution was stirred and it became 22.8 g (0.30 mol) thioacetic acid added to form a pale orange, weakly acidic solution. The methanol formed during the reaction and water became under reduced pressure evaporated to form a hygroscopic, reddish colored, waxy solid with a melting point of 47 to 50 G, which by infrared analysis as tetrabutylammonium thioacetnt was identified. The yield was 91 g,

0 9 8 15/1781

this corresponds to 98 % of the theoretical yield of 92 g.

In a 250 ml flask, 16.3 g (0.1 mol) of Brorncyclo-

3
hexane was dissolved in 75 cm of acetone and 32 g of the tetrabutylammoniuriithioacetate prepared as described above were added to the solution. The mixture was refluxed (56 ° C) on a steam bath for one hour and then the acetone was allowed to evaporate from the boiling mixture for 30 to 45 minutes until the temperature reached 85 ° C. The mixture was then cooled to room temperature, poured into water and the oily product was with

3 ..

100 cm of ether extracted. The ether layer was separated,

dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove the ether, the product remaining in the form of an oil. With regard to its infrared spectrum, the product cyclohexanethiol acetate was identical to the product obtained in Example 6, in which i'etramethylammonium thioacetate had been used, and it was obtained in a yield of 11 g, which corresponds to 70 % of the theoretical yield of 15.8 g. The implementation described in this example can be represented by the following equation: ι-0

+ (C ₄ n ₉ ) ₄ N3CCn ₃

ijrorncyclo- tetrabutyl- cyclohexane-tetrabutyl-

hexane ammonium thiol acetate ammonium thioacetate. bromide

Example 10

In a 1 liter three-necked flask that is placed in a steam bath

2098 15/178 1

/ IS

set and with a stirrer, a reflux condenser and was fitted with a thermometer, with the 41.1 g (0.1 mol) Tetra-O-acetyl-a-D-glucopyranosyl bromide (acetobromoglucose) dissolved in 250 cm dry acetone. To the stirred solution was 15.0 g (0.1 mol) of tetramethylammonium thioacetate added and the suspension was heated to reflux. The reaction started immediately and was through a change in the nature of the suspended material from coarse crystals to a fine white suspension of Tetramethylammonium bromide. Do two hours the reaction was complete and the stirred mixture was allowed to cool to room temperature. The mixture was under strong Stir poured into 1 liter of cold tap water. The product was an oil first, then crystallized into a thick fluffy solid. The product was filtered with Washed with water until the filtrates were colorless, then squeezed under a rubber sheet.

The crude, moist solid was heated and stirred

3
dissolved in 150 cm of methanol. The hot solution was treated with decolorizing activated charcoal and filtered through a Supercel pad. The filtrate was cooled by concentration under reduced pressure without the application of heat until crystallization started, then it was left to stand and cooled externally with a water bath. The purified product crystallized out in the form of a thick layer of Iia.deIn. The product was filtered, squeezed under a Kaiicschuk plate and washed on a funnel with a small amount of cold methanol, then air dried. The filtrates were concentrated to half their volume and a second fraction was obtained which was made from ethanol as above

2098Ί 5/1781

BATH ORIGINAL

2U8204

- ee »-

/ 9

was recrystallized. The pure 1-thio-D-glucose-pentaacetate obtained in this way was in the form of white oil balls with a melting point of 120 to 122 ° C. The yield was 31 g, which corresponds to 76% of the theoretical Henge of 40.6 g.

10
The procedure described in this example / can be carried out by

the following equation can be represented:

H ₀ OCC

CH ₂ OCCH ₃

Il

H OCCH,

CU ₀ CO

OCCIL

CII ₀ CO

³ II 0 II

The l-thio-D-glucose-pentaacetate obtained in this way can be easily hydrolyzed to 1-thio-D-glucose and given the form of the liatric salt can be isolated. The gold salt of 1-thio-D-glucose, known as aurothioglucose, is used in gold therapy and used as a remedy for arthritis.

2 0 9 8 15/1781

Claims (5)

-Mr claims 1. A process for producing an organic thioacetate by reacting an organic halide with a thioacetic acid salt under _; . Replacement of the halogen atoms by thioacetoxy groups, characterized in that the reaction is carried out using a tetraalkylammonium thioacetate as thioacetic acid salt with an at least stoichiometric amount of tetcaalkylammonium thioacetate for a sufficient time until the reaction has ended and the thioacetate formed is separated off in a manner known per se from the reaction mixture obtained. 2. The method according to claim 1, characterized in that the tetraalkylammonium thioacetate is tetramethylammonium thioacetate, Tetraethylammonium thioacetate or tetrabutylammonium thioacetate used. 3. Process according to Claims 1 and 2, characterized in that the organic halide used is a 1,4-dihalo-2,3-butylene diacetate, in particular 1,4-dibromo-2,3-butylene diacetate or 1,4-dichloro-2,3-butylene diacetate, 1,4-dichloro-2,3-butanediol, 2-chlorobenzothiazole, oc-chlorotoluene, bromocyclohexane, 1,4-bis (chlorinethyl) cyclohexane or tetra-O-acetyl-a-D-glucopyranosyl bromide used. 4. Process according to Claims 1 to 3, characterized in that the reaction is carried out with a molar ratio of tetramethyl 209815/1781 2U8204 - H- U ammonium thioacetate to organic halide of at least Performs 2: 1. 5. Process according to claims 1 to 4, characterized in that that the reaction in the presence of tetrahydrofuran or in the presence of a short-chain aliphatic ketone performs as a solvent. 209815/1781