WO2014146275A1 - Procédé de synthèse d'un composé thiadiazole sulfoxyde - Google Patents

Procédé de synthèse d'un composé thiadiazole sulfoxyde Download PDF

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Publication number
WO2014146275A1
WO2014146275A1 PCT/CN2013/072991 CN2013072991W WO2014146275A1 WO 2014146275 A1 WO2014146275 A1 WO 2014146275A1 CN 2013072991 W CN2013072991 W CN 2013072991W WO 2014146275 A1 WO2014146275 A1 WO 2014146275A1
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WIPO (PCT)
Prior art keywords
thiadiazole
synthesizing
formula
reaction
compound according
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PCT/CN2013/072991
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English (en)
Chinese (zh)
Inventor
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
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Priority to PCT/CN2013/072991 priority Critical patent/WO2014146275A1/fr
Publication of WO2014146275A1 publication Critical patent/WO2014146275A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical

Definitions

  • 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 is described.
  • Thiacazole sulfoxide compounds have the structural formula (
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • thioether 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.
  • 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.
  • the adiabatic reaction 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.
  • 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 organic solvent is preferably a water-miscible organic solvent
  • 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.
  • an N-benzylidenebenzenesulfonamide catalyst is added which selectively oxidizes the thioether to obtain a sulfoxide.
  • 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.
  • 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.
  • 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.
  • Figure 1 is a spectrum of ifi-NMR in Example 1.
  • Figure 2 is a mass spectrum of Example 1.
  • Example 1 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 Example 1:
  • 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%).
  • 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%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

La présente invention concerne un procédé de synthèse d'un composé thiadiazole sulfoxyde. Les étapes associées comprennent : la réaction d'un thioéther thiadiazole dans un solvant organique ou liqueur mixte d'un solvant organique et de l'eau, à l'aide d'un agent d'oxydation spécifique et à une température adéquate, afin de produire du thiadiazole sulfoxyde. Un catalyseur peut être ajouté à la réaction pour améliorer la performance de réaction, et un catalyseur de transfert de phase peut être ajouté pour améliorer la vitesse de réaction. La présente invention concerne des opérations de réaction simples, un procédé sûr, une réaction rapide, un rendement élevé, et est appropriée pour une production industrialisée.
PCT/CN2013/072991 2013-03-21 2013-03-21 Procédé de synthèse d'un composé thiadiazole sulfoxyde WO2014146275A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6437189B1 (en) * 1997-12-12 2002-08-20 Bayer Corporation Synthesis of sulfoxides via selective oxidation of sulfides with a perborate or a percarbonate
CN1377878A (zh) * 2001-04-04 2002-11-06 中国医学科学院药物研究所 一种亚砜基前体氧化工艺
CN101466666A (zh) * 2006-04-06 2009-06-24 武田药品工业株式会社 有机氧化物的制备方法
CN103288776A (zh) * 2013-03-21 2013-09-11 浙江省诸暨合力化学对外贸易有限公司 一种2-亚砜基-5-(三氟甲基)-1，3，4-噻二唑类化合物的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6437189B1 (en) * 1997-12-12 2002-08-20 Bayer Corporation Synthesis of sulfoxides via selective oxidation of sulfides with a perborate or a percarbonate
CN1377878A (zh) * 2001-04-04 2002-11-06 中国医学科学院药物研究所 一种亚砜基前体氧化工艺
CN101466666A (zh) * 2006-04-06 2009-06-24 武田药品工业株式会社 有机氧化物的制备方法
CN103288776A (zh) * 2013-03-21 2013-09-11 浙江省诸暨合力化学对外贸易有限公司 一种2-亚砜基-5-(三氟甲基)-1，3，4-噻二唑类化合物的合成方法

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