WO2014146275A1

WO2014146275A1 - Method for synthesizing thiadiazole sulfoxide compound

Info

Publication number: WO2014146275A1
Application number: PCT/CN2013/072991
Authority: WO
Inventors: 苏叶华; 蔡国平; 刘维; 杨政和; 陈邦池
Original assignee: 浙江省诸暨合力化学对外贸易有限公司
Priority date: 2013-03-21
Filing date: 2013-03-21
Publication date: 2014-09-25

Abstract

The present invention relates to a method for synthesizing a thiadiazole sulfoxide compound. Steps thereof comprise: thiadiazole thioether reacting in an organic solvent or mixed liquor of an organic solvent and water, by using a specific oxidizing agent, and at a proper temperature, so as to thiadiazole sulfoxide. A catalyst can be added into the reaction to improve the reaction performance, and a phase transfer catalyst can be added to improve the reaction speed. The present invention has simple reaction operations, a safe process, rapid reaction, a high yield, and is suitable for industrialized production.

Description

Method for synthesizing thiadiazole sulfoxide compounds

The invention belongs to the field of organic synthesis of sulfoxides. More specifically, the invention relates to the use of thiophenes

A synthetic method for preparing thiadiazole sulfoxide by selective oxidation of a raw material.

BACKGROUND OF THE INVENTION Thiacazole sulfoxide compounds have the structural formula

^(|) is an important class of intermediates widely used in the synthesis of various drugs and pesticide compounds. Sulfoxide group as a good leaving group, this kind of sulfoxide intermediate can be used for organic unit reaction such as carbon-carbon coupling, carbon-oxygen coupling, carbon-nitrogen coupling, molecular rearrangement and other functional group conversion. At present, the most important synthetic method for the preparation of sulfoxide is selective oxidation by thioether. The disclosed oxidants include: hydrogen peroxide, nitric acid and nitrate, chromium trioxide, molybdenum trioxide, m-chloroperoxybenzoic acid and t-butyl peroxidation. Hydrogen, etc.

Hydrogen peroxide is a green oxidant, and the price is low. The product of the oxidant reaction is water, which has attracted the attention of researchers. In 1908, Grazdar and Smiles used hydrogen peroxide at room temperature to oxidize thioether with acetone as a solvent, but the oxidation time was very long and it took 10 days to complete the reaction. Because of the low activity of hydrogen peroxide and the long reaction time, it is generally necessary to add a catalyst to increase the reactivity and selectivity of hydrogen peroxide. Tetrahedron Letters 53, 4328-4331 discloses the use of hydrogen peroxide as an oxidizing agent to selectively oxidize thioether to synthesize sulfoxide in the presence of a zinc salt, but this method requires the addition of an organic ligand with a low yield. Hydrogen peroxide and acetic acid systems can also selectively oxidize thioethers. Hydrogen peroxide is first reacted with acetic acid to obtain peroxyacetic acid, and peroxyacetic acid is used to oxidize thioether to obtain sulfoxide. However, this method has poor selectivity and is easily peroxidized into by-product sulfone. And a large amount of peracid wastewater is produced. In order to improve the selectivity and activity of the reaction, it is necessary to add a vanadium salt, a titanium salt or a molybdate as a catalyst, which increases the cost, and the addition of the metal catalyst may cause product separation and wastewater treatment difficulties. Question.

US 4,994,485 discloses a synthesis method of another sulfoxide compound, which is obtained by selective oxidation of m-sulfoxide at 0-5 ° C with m-chloroperoxybenzoic acid as an oxidizing agent. The yield of the method is not high, the cost is high, and the oxidizing agent By-products are not easily removed.

U.S. Patent No. 6,437,189 discloses the use of peroxyborate or peroxycarbonate as an oxidizing agent for the selective oxidation of sulfoxide. The synthesis scheme is: 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole is selectively oxidized with sodium peroxoperate (or sodium percarbonate), during the reaction, the monitoring system The pH value of the system is maintained at 0.5-1. After the addition is completed, the temperature is raised to 70-75 °C to continue the reaction. After the reaction is stopped, the organic phase is separated at a high temperature, and after removing the solvent, 2-methylsulfoxide-5-trifluoromethyl-1,3,4-thiadiazole is obtained, which is effective for controlling peroxidation. The yield is high, but the acidity is maintained during the reaction. It is necessary to continuously monitor the pH value and add HC1. The high temperature separation of the organic phase has certain safety hazards.

Davis (TETRAHEDRON 45, 5703-5742) found that the oxaziridine compound is a good and specific choice for the oxidation of thioether to sulfoxide. However, how the reactivity of such oxidants in the thiadiazole system has not been reported.

Disclosure of invention

There are many problems in the prior art techniques for preparing thiadiazole sulfoxides, such as long reaction time, expensive transition metal catalysts, difficult catalyst preparation, poor safety, cumbersome operation, easy peroxidation, low selectivity, and low yield. Wait. Therefore, an economically safe and efficient method for synthesizing thiadiazole sulfoxides is urgently needed.

The invention provides a method for synthesizing a thiadiazole sulfoxide compound, wherein the thiadiazole sulfoxide compound

R ¹ is hydrogen, a decyl group of dC ₆ , an aryl group of C ₆ -C ₁₄ or a hetero atom aryl group containing nitrogen, oxygen or sulfur, ^ is a fluorenyl group, a C ₆ -C ₁₄ aryl group or a a hetero atom aryl group of nitrogen, oxygen or sulfur, characterized in that:

N~N

Ho first to thiadiazole disulfide as raw materials, thiadiazole sulfide of the general formula: R is the same in ^{^{R1 ^ S ^ SR 2 ( "}} ) of the general formula II in the formula R ¹ I ¹ and, on R ² in the formula II is the same as R ^{2 in the} formula I, and the volume ratio of the raw material of the formula II to the solution is 1:1 to 20, wherein the solution is an organic solvent or water, or is an organic solvent and water. Mixing the solution; second, at 0 ° C - 60 ° C, adding an oxidizing agent, the molar ratio of the oxidizing agent to the raw material of the formula II is 1:1 to 1:2, wherein the oxidizing agent is hypochlorite, hypobromite One or more of hypoiodate, chlorate, bromate, iodate, oxaridinium compound, persulfate or hydrogen persulfate; third, after adding oxidant, Stirring the reaction until the reaction is completed to obtain the thiadiazole sulfoxide of the formula I. The reaction is carried out in a solvent in the presence of a specific oxidizing agent. The reaction can be added to the catalyst to improve the reaction performance, and the phase transfer catalyst can be added to increase the reaction rate. R in formula I and formula II ¹ is (C _r C ₆₎ - alkyl with the aryl group (C ₆ -C ₁₄₎ aryl group or a hetero atom (nitrogen Oxygen, sulfur), preferably (C _r C ₆₎ - the embankment group, and more preferably dC ₆₎ - alkyl with halo, most preferably a trifluoromethyl group according to general formula I and on. R ² in formula II is a (C _r C ₆ ) -fluorenyl group, an aryl group (C ₆ -C ₁₄ ) or a hetero atom-containing aryl group (nitrogen, oxygen, sulfur), preferably (C _r C ₆ ) - a mercapto group, more preferably a hypochlorite, a hypobromite, a hypoiodate, a chlorate, a bromate, an iodate, an oxaziridine compound, Oxidizing agents such as sulfate or hydrogen persulfate are sodium hypochlorite, sodium hypobromite, sodium hypoiodate, sodium chlorate, sodium bromate, sodium iodate, potassium hypochlorite, potassium hypobromite, potassium hypoiodate, potassium chlorate, potassium bromate, iodine. Potassium acid, sodium persulfate, sodium persulfate, potassium persulfate or potassium persulfate, preferred oxygen The agent is sodium persulfate, sodium hydrogen persulfate, potassium persulfate or potassium persulfate, and most preferred is sodium persulfate or potassium persulfate. When thioether is oxidized by peroxyacid, the sulfur atom has a partial negative charge, and the peroxyacid has good oxidation effect under acidic conditions, and the speed is fast. The sodium persulfate or potassium persulfate itself is acidic, and its oxidation by-product sulfuric acid Potassium hydrogen also has a strong acidity, which allows the reaction system to remain oxidized under acidic conditions.

Hypochlorite, hypobromite, hypoiodate, chlorate, bromate, iodate, xanthene, persulphate or persulphate are good oxidants, safe, Easy to store and use, raw materials are cheap and easy to get. We have found that thiadiazole thioether is slowly added to the above oxidizing agent at 0-60 ° C, and thiadiazole sulfoxide can be obtained with high selectivity. The amount of the oxidizing agent added and the addition of the N-sulfonimide compound can further increase the selectivity of oxidation and effectively inhibit the formation of the thiadiazole sulfone as a by-product of oxidation. Oxidizer Oxidation reaction is an exothermic process. By controlling the feed rate to maintain the optimum reaction temperature, the adiabatic reaction can be realized in production. The adiabatic reaction is the most energy-saving and temperature-controlled reaction operation in production, and it is easy to realize industrial production. In laboratory and industrial production, it is necessary to control the feed rate according to the temperature of the reaction system, so that the reaction temperature does not exceed 60 °C, otherwise the by-products will increase, that is, the oxidant feed rate can be increased at a lower reaction temperature, at approximately 60 ° C. Slows down the oxidant feed rate.

The added solution may be completely water, or may be completely an organic solvent, or a mixed solution of the two, wherein the organic solvent is preferably a water-miscible organic solvent, and the water-miscible organic solvent is DMF, DMSO, Methanol, ethanol, tetrahydrofuran, preferably methanol, ethanol, tetrahydrofuran, the most preferred solvent is tetrahydrofuran or methanol.

The reaction temperature is from 0 ° C to 60 ° C, and the preferred reaction temperature is from 5 ° C to 50 ° C.

The catalyst is N-sulfonylimide, preferably N-arylmethylene aryl sulfonamide, most preferably N-benzylidene benzene sulfonamide. In one embodiment of the invention, an N-benzylidenebenzenesulfonamide catalyst is added which selectively oxidizes the thioether to obtain a sulfoxide. By adding a catalyst before the oxidizing agent, the oxidizing agent can first oxidize N-benzylidenebenzenesulfonamide to obtain N-phenylmethylbenzenesulfonyloxapyridine, which can specifically oxidize the thioether to obtain sulfoxide and oxidize. This intermediate is then returned to N-benzylidenebenzenesulfonamide and continues to participate in the reaction. Catalysts such as hypochlorite, hypobromite, hypoiodate, chlorate, bromate, iodate or persulphate, which are slower to oxidize thioether under neutral or weakly alkaline, - The benzylidenebenzenesulfonamide catalyst can accelerate the oxidation rate and improve the reaction performance.

The phase transfer catalysts are quaternary ammonium salts, quaternary phosphonium salts, crown ethers and polyethers, preferably quaternary ammonium salts, most preferably benzyltriethylammonium chloride or tetrabutyl bromide. Ammonium.

In the embodiment of the present invention, the molar ratio of the oxidizing agent to the starting compound used is preferably 1:1 to 2, preferably 1:1 to 1.8, and most preferably 1:1 to 1.5.

The starting material thiadiazole sulfide of the present invention can be prepared by a variety of methods, and the synthetic scheme disclosed in U.S. Patent 5,162,539 can be referred to in the prior art.

The invention uses thiadiazole sulfide as raw material to selectively oxidize and synthesize thiadiazole sulfoxide under a specific oxidizing agent, and has many advantages, mainly embodied in: simple reaction operation, safe process, rapid reaction, high yield, Suitable for industrial production.

DRAWINGS

Figure 1 is a spectrum of ifi-NMR in Example 1.

Figure 2 is a mass spectrum of Example 1.

Best way to implement the invention

The technical solution of the present invention will be further described in detail below through specific embodiments. However, the scope of protection of the present invention is not limited to the implementation methods described below. Example 1:

Synthesis 2-Methylsulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

To a 250 mL three-necked flask equipped with a mechanical stirring and a thermometer, 21 g (0.1 mol) of 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole was added, and 60 mL of tetrahydrofuran and 60 mL of water were added. After stirring at 60 ° C, 35 g of potassium hydrogen persulfate was slowly added. After the addition was completed, the reaction was further stirred for 2 hours. The reaction mixture was filtered, and the filter cake was washed with tetrahydrofuran. The filtrate was combined and evaporated to dryness under reduced pressure. Toluene was then evaporated. The toluene phase was separated and washed with water. The toluene phase was separated and the solvent was removed to give 19.9 g of a solid product. The sulfoxide content is 98%). Ifi-NMR (CDC1 ₃ ) δ 3.21 (s, 3H); ¹³ C-NMR δ 3.21 (s, 3H); mass spectrum (ESI+) m/z2\l [C ₄ H ₄ F ₃ N ₂ OS ₂ + H requires 217]

Example 2:

Synthesis 2-Methylsulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

Add 21 g (0.1 mol) of 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole and O.lg tetrabutyl bromide to a 250 mL three-necked flask equipped with a mechanical stirrer and a thermometer. Ammonium chloride was added to 60 mL of methanol and 60 mL of water, and stirred at 0 ° C, and 51.8 g of potassium hydrogen persulfate was slowly added. After the addition was completed, the reaction was further stirred for 0.5 hour. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was combined, and the methanol was evaporated under reduced pressure. The toluene was extracted, and the toluene phase was separated and washed twice with water to remove the toluene phase. The solvent was removed to obtain 20.3 g of a solid product. 92% (sulfoxide content 98%).

Example 3:

Synthesis 2-Methylsulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

Into a 250 mL three-necked flask equipped with a mechanical stirrer and a thermometer, 21 g (0.1 mol) of 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole and O.lgbenzyltriethyl were added. The ammonium chloride was added, 120 mL of water was added, and the mixture was stirred at 0 ° C, and 70 g of potassium hydrogen persulfate was slowly added. After the addition was completed, the reaction was further stirred for 2 hours. Filter The reaction mixture was washed with toluene, the filtrate was combined, extracted with toluene, and the toluene phase was separated and washed twice with water. The toluene phase was separated, and the solvent was removed to obtain 21. 2 g of a solid product, yield 94% (sulfoxide content 96%) .

Example 4:

Synthesis 2-Methylsulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

To a 250 mL three-necked flask equipped with a mechanical stirrer and thermometer, 21 g (0.1 mol) of 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole and 0.5 g (0.002 mol) of N were added. -benzylidenebenzenesulfonamide, 60 mL of methanol and 60 mL of water were added, and the mixture was stirred at room temperature, and 38 g of potassium hydrogen persulfate was slowly added. After the addition was completed, the reaction was further stirred for 1 hour. The solid product is obtained. The yield is obtained. The product is obtained. The product is obtained. The product is obtained. 95% (sulfoxide content 99%).

Example 5:

Synthesis 2-Ethylsulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

Add 22.5g (O.lmol) 2-ethylthio-5-trifluoromethyl-1,3,4-thiadiazole to a 250mL three-necked flask equipped with a mechanical stirrer and thermometer. Add 100 mL of DMSO at room temperature. Stir, slowly join

After 35 g of potassium hydrogen persulfate was added, the reaction was stirred for 2 hours. The reaction mixture was filtered, and the filter cake was washed with DMS0. The filtrate was combined and evaporated to remove DMS0, and the toluene phase was separated, and the toluene phase was separated and washed with water. Next, the toluene phase was separated, and the solvent was removed to obtain 20.1 g of a solid product, yield 83% (yield 95%)

Example 6:

Synthesis of 2-methyl sulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

Add 21g (O.lmol) 2-A to a 250mL three-necked flask equipped with a mechanical stirrer and thermometer Thio-5-trifluoromethyl-1,3,4-thiadiazole and O. lg tetrabutylammonium bromide, add 60 mL of toluene and 60 mL of water, stir at 0 ° C, slowly add 18 g of hydrogen persulfate 5小时。 After stirring, the reaction was continued for 0.5 hours. The reaction mixture was filtered, and the filter cake was washed with toluene, and the toluene phase was separated and washed twice with water, and the toluene phase was separated, and the solvent was removed to give 20.9 g of a solid product (yield: 90%).

Example 7:

Synthesis 2-butyl sulfoxide 5-5-(trifluoromethyl)-1,3,4-thiadiazole

Into a 250 mL three-necked flask equipped with a mechanical stirrer and a thermometer, 23 g (O.lmol) of 2-butylthio-5-trifluoromethyl-1,3,4-thiadiazole and 0.5 g (0.002 mol) of N were added. 5小时。 After the addition of the reaction was continued, the reaction was continued, the reaction was continued 0. 5 hours after the addition was completed, the reaction was continued. . 2克固体产物,的收率, Yield 2, 2g of solid product, yield, yield 93% (sulfoxide content 99%).

Example 8:

Synthesis 2-phenylsulfoxide-5-(trifluoromethyl)-1,3,4-thiadiazole

To a 250 mL three-necked flask equipped with a mechanical stirrer and a thermometer, 27.3 g (0.1 mol) of 2-phenylthio-5-trifluoromethyl-1,3,4-thiadiazole and 0.5 g (0.002 mol) were added. N-benzylidenebenzenesulfonamide was added to 60 mL of methanol and 60 mL of water, and stirred at room temperature, and 38 g of potassium hydrogen persulfate was slowly added. After the addition was completed, the reaction was further stirred for 0.5 hour. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was combined and evaporated to dryness under reduced pressure. Toluene was extracted with toluene. The toluene phase was separated and washed twice with water. The toluene phase was separated and the solvent was removed to give 24.8 g of a solid product. % (sulfoxide content 99%).

Claims

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A method for synthesizing a thiadiazole sulfoxide compound, wherein the thiadiazole sulfoxide compound has the following formula:

N~N

R ¹ SOR ² 0

N~N

Ho first to thiadiazole disulfide as raw materials, thiadiazole sulfide of the general formula: R is the same in ^{^{R1 ^ S ^ SR 2 ( "}} ) of the general formula II in the formula R ¹ I ¹ and, on R ² in the formula II is the same as R ^{2 in the} formula I, and the volume ratio of the raw material of the formula II to the solution is 1:1 to 20, wherein the solution is an organic solvent or water, or an organic solvent and water. Mixing the solution; second, at 0 ° C - 60 ° C, adding an oxidizing agent, the molar ratio of the oxidizing agent to the raw material of the formula II is 1: 1~2, wherein the oxidizing agent is selected from hypochlorite, hypobromite, One or more of hypoiodate, chlorate, bromate, iodate, oxaziridine, persulfate or hydrogen persulfate; third, after adding oxidant, continue The reaction is stirred until the reaction is complete to give the thiadiazole sulfoxide of formula I.

The method for synthesizing a thiadiazole sulfoxide compound according to claim 1, wherein R ¹ in the general formula I and the general formula II is a halogenated fluorenyl group of C _r C ₆ . The R ² in the general formula I and the general formula II is a hospital base of Ci-C6

The method for synthesizing a thiadiazol sulfoxide compound according to claim 1, wherein R ¹ in the above formula I and formula II is a trifluoromethyl group, and the formula I and R ² in the formula II is a methyl group.

The method for synthesizing a thiadiazol sulfoxide compound according to claim 1, wherein the The oxidizing agent is sodium hydrogen persulfate or potassium hydrogen persulfate.

The method for synthesizing a thiadiazol sulfoxide compound according to claim 1, wherein the reaction temperature in the second crucible is 5 ° C to 50 ° C.

The method for synthesizing a thiadiazole sulfoxide compound according to claim 1, wherein the molar ratio of the oxidizing agent to the starting compound is 1:1 to 1.5.

The method for synthesizing a thiadiazolsulfoxide compound according to claim 1, wherein a catalyst is simultaneously added to the first crucible.

The method for synthesizing a thiadiazol sulfoxide compound according to claim 7, wherein the catalyst is N-benzylidenebenzenesulfonamide.

The method for synthesizing a thiadiazolsulfoxide compound according to claim 1, wherein the organic solvent is tetrahydrofuran or methanol.

The method for synthesizing a thiadiazolsulfone compound according to claim 1, wherein a phase transfer catalyst capable of increasing the reaction rate is simultaneously added to the first crucible.

The method for synthesizing a thiadiazole sulfoxide compound according to claim 10, wherein the phase transfer catalyst is benzyltriethylammonium chloride or tetrabutylammonium bromide.