WO2018010163A1 - 一种1,2,4-三唑-3-硫酮化合物的合成方法及其中间体 - Google Patents

一种1,2,4-三唑-3-硫酮化合物的合成方法及其中间体 Download PDF

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WO2018010163A1
WO2018010163A1 PCT/CN2016/090129 CN2016090129W WO2018010163A1 WO 2018010163 A1 WO2018010163 A1 WO 2018010163A1 CN 2016090129 W CN2016090129 W CN 2016090129W WO 2018010163 A1 WO2018010163 A1 WO 2018010163A1
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compound
group
acid
hydrogen
aryl
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French (fr)
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张志明
杜晓栋
盛秋菊
史界平
王君良
陈邦池
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泸州东方农化有限公司
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Priority to EP16908488.6A priority Critical patent/EP3486235A4/en
Priority to CN201680084812.6A priority patent/CN109311823B/zh
Priority to PCT/CN2016/090129 priority patent/WO2018010163A1/zh
Publication of WO2018010163A1 publication Critical patent/WO2018010163A1/zh
Priority to US16/212,705 priority patent/US10781186B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing a 1,2,4-triazole-3-thione compound and an intermediate thereof.
  • 1,2,4-Triazole-3-thione compound 1 is a class of substances having important biological activities.
  • 1,2,4-triazole-3-thione 1 was found to have antibacterial activity (WO2010142779, WO2010146113, WO2010146111, WO2010146112, WO2010040717, WO2014167008, WO2010040718, WO9706152, W9638423, WO9616048, WO9641798, WO9741107, WO2010149758, EP2746260, WO2010146029, WO2009077471, IN193553, WO2009077500, WO2014108288), antiviral activity (WO2010149758, WO2010122169, WO2010142779, WO2010149414, WO2010122167), antitumor activity (WO2010149758, WO2010122169, WO2010142779, WO2010149414, WO2010122167), and other biological activities (WO2013047308, WO2013084770, WO2011125317) and so on.
  • the strategy for preparing 1,2,4-triazole-3-thione compound 1 is divided into two broad categories depending on the construction of the triazole ring.
  • the first class produces a triazolethione target product by ring closure of thiosemicarbazide and formic acid or a formic acid derivative.
  • thiosemicarbazide thiosemicarbazide
  • formic acid a formic acid derivative.
  • 2-methyl-1,2,4-triazole-3-thione product Justus Liebigs Annalen der Chemie , 643, 128-35; 1961.
  • This type of method has a good ring formation reaction, but the preparation of compound 2 is very challenging, and regioselectivity is usually a problem.
  • the second type of strategy for the preparation of 1,2,4-triazole-3-thione compound 1 is by modification of the triazole ring which has been constructed.
  • This reaction requires the use of an organic strong base in the hydrogen extraction process, and requires anhydrous and oxygen-free operation, and the regioselectivity of the hydrogen extraction reaction is also a problem.
  • No. 6,593,317 discloses a process for the preparation of 1,2,4-triazole-3-thione by dehydrogenation of triazole 5 with FeCl 3 .
  • the raw material 5 of the method is unstable, is not easy to prepare, and the treatment of iron-containing waste is an environmental problem.
  • the present invention provides a method for synthesizing a 1,2,4-triazole-3-thione compound and an intermediate thereof in view of the deficiencies in the prior art.
  • the method comprises the following steps:
  • Step 1 Compound 6 or Compound 6' is reacted with Compound 7 or Compound 7' to give Compound 8 or Compound 8', which is represented by the following formula:
  • R is a C1-C18 alkyl group, a C6-C18 aryl group, and a C5-C6 oxygen, nitrogen or thiaheteroaryl group;
  • R 1 , R 2 are selected from hydrogen or C1-C6 alkyl; or R 1 , R 2 are taken together to form a dimethylene, trimethylene, tetramethylene or pentamethylene ring;
  • n 0.5, 1 or 2;
  • the HX is a hydrohalic acid, sulfuric acid or phosphoric acid
  • the M is hydrogen, an alkali metal or NR 3 R 4 R 5 R 6 , wherein R 3 , R 4 , R 5 , R 6 are selected from hydrogen, C1-C18 alkyl, C6-C18 aryl;
  • Step 2 Compound 8 or Compound 8' is reacted with thiocyanate M'SCN to obtain 1,2,4-triazole-3-thione compound 1, which is represented by the following reaction formula:
  • R is a C1-C18 alkyl group, a C6-C18 aryl group, and a C5-C6 oxygen, nitrogen or thiaheteroaryl group;
  • the M is hydrogen, an alkali metal or NR 3 R 4 R 5 R 6 , wherein R 3 , R 4 , R 5 , R 6 are selected from hydrogen, C1-C18 alkyl, C6-C18 aryl;
  • the M' is an alkali metal or NR 3 R 4 R 5 R 6 , wherein R 3 , R 4 , R 5 , R 6 are selected from hydrogen, C1-C18 alkyl, C6-C18 aryl;
  • the HX is a hydrohalic acid, sulfuric acid or phosphoric acid
  • the step 1 may be carried out in a solvent or solvent-free condition, and the solvent is preferably a mixture of one or more of water, acetonitrile, tert-butanol, dichloromethane, DMF, DMSO, and toluene.
  • the molar ratio of the compound 6 or the compound 6' to the compound 7 (or the compound 7') is preferably 1:1 to 10; the reaction temperature of the step 1 is preferably 0 to 40 °C.
  • the step 2 is preferably carried out under the action of an acid, which may be used as a catalyst or as a solvent.
  • the acid is preferably an organic acid such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid.
  • the molar ratio of the acid to the compound 8 or the compound 8' is preferably from 0.01 to 100:1.
  • the molar ratio of the compound 8 or the compound 8' to the thiocyanate in the step 2 is preferably 1:1 to 5; the reaction temperature in the step 2 is preferably 50 to 80 °C.
  • Steps 1 and 2 can be carried out in a stepwise or "one-pot" manner.
  • the 4-triazole-3-thione compound 1 is represented by the following reaction formula:
  • R is a C1-C18 alkyl group, a C6-C18 aryl group, and a C5-C6 oxygen, nitrogen or thiaheteroaryl group;
  • the M is hydrogen, an alkali metal or NR 3 R 4 R 5 R 6 , wherein R 3 , R 4 , R 5 , R 6 are hydrogen, C1-C18 alkyl, C6-C18 aryl;
  • the M' is an alkali metal or NR 3 R 4 R 5 R 6 , wherein R 3 , R 4 , R 5 , R 6 are hydrogen, C1-C18 alkyl, C6-C18 aryl;
  • the HX is a hydrohalic acid, sulfuric acid or phosphoric acid
  • the reaction is preferably carried out under the action of an acid which can be used both as a catalyst or as a solvent, preferably an organic acid such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid.
  • an acid which can be used both as a catalyst or as a solvent
  • an organic acid such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid.
  • the molar ratio of the acid to the compound 8 or the compound 8' is preferably from 0.01 to 100:1.
  • the molar ratio of the compound 8 or the compound 8' to the thiocyanate is preferably 1:1 to 5; and the reaction temperature is preferably 50 to 80 °C.
  • R is a C1-C18 alkyl group, a C6-C18 aryl group, and C5-C6 is an oxygen, nitrogen or thiaheteroaryl group, but R is not a methyl group, a phenyl group or a benzyl group;
  • the M is hydrogen, an alkali metal or NR 3 R 4 R 5 R 6 , wherein R 3 , R 4 , R 5 , R 6 are each hydrogen, C1-C18 alkyl, C6-C18 aryl;
  • R is a C1-C18 alkyl group, a C6-C18 aryl group, and C5-C6 is an oxygen, nitrogen or thiaheteroaryl group, but R is not a methyl group, a phenyl group or a benzyl group;
  • the HX is a hydrohalic acid, sulfuric acid or phosphoric acid.
  • the synthesis method of a 1,2,4-triazole-3-thione compound and an intermediate provided by the invention has the following advantages:
  • the raw material of the invention is easy to obtain, the reaction zone is selective, the by-products are small, and the yield is high;

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

提供了一种1,2,4-三唑-3-硫酮化合物的合成方法及其中间体。该方法以肼为原料与乙醛酸反应得到亚肼基乙酸中间体，后者再与硫氰酸盐反应得到目标产物。该方法原料易得，反应区域选择性专一，副产物少，收率高；对设备没有特别要求，不需高真空高温或无水无氧操作；工艺简单，三废少，适合工业化生产。

Description

一种1,2,4-三唑-3-硫酮化合物的合成方法及其中间体 技术领域
本发明属于有机合成领域，具体涉及一种1,2,4-三唑-3-硫酮化合物的合成方法及其中间体。
背景技术
1,2,4-三唑-3-硫酮化合物1是一类具有重要生物活性的物质。
Figure PCTCN2016090129-appb-000001
例如，1,2,4-三唑-3-硫酮1被发现具有抗菌活性(WO2010142779，WO2010146113，WO2010146111，WO2010146112，WO2010040717，WO2014167008，WO2010040718，WO9706152，W9638423，WO9616048，WO9641798，WO9741107，WO2010149758，EP2746260，WO2010146029，WO2009077471，IN193553，WO2009077500，WO2014108288)，抗病毒活性(WO2010149758，WO2010122169，WO2010142779，WO2010149414，WO2010122167)，抗肿瘤活性(WO2010149758，WO2010122169，WO2010142779，WO2010149414，WO2010122167)，和其它生物活性(WO2013047308，WO2013084770，WO2011125317)等。
制备1,2,4-三唑-3-硫酮化合物1的策略根据三唑环的构建不同分为两大类。第一类通过氨基硫脲和甲酸或甲酸衍生物关环生成三唑硫酮目标产物。例如，N-氨基-N-甲基硫脲(化合物2，R＝甲基)与甲酸反应得2-甲基-1,2,4-三唑-3-硫酮产物(Justus Liebigs Annalen der Chemie,643,128-35；1961)。这类方法成环反应效果好，但化合物2的制备很具挑战性，区域选择性通常是个问题。
Figure PCTCN2016090129-appb-000002
第二类制备1,2,4-三唑-3-硫酮化合物1的策略是通过对已构建好的三唑环进行修饰。例如，N-苯基三唑(化合物3，R＝苯基)通过叔丁基氧化锂拔氢后再和硫磺反应得目标产物(Journal of Organic Chemistry,74(21),8309-8313；2009)。该反应在拔氢过程中需要使用有机强碱，并且需要无水无氧操作，同时拔氢反应的区域选择性也是个问题。
Figure PCTCN2016090129-appb-000003
Heteroatom Chemistry,14(1),50-55；2003报道了用化合物4经真空高温裂解(FVP)制备1,2,4-三唑-3-硫酮1的方法。此方法不仅需要高温反应条件，同时会产生大量副产物。
Figure PCTCN2016090129-appb-000004
US6559317公开了用FeCl3氧化三唑5脱氢制备1,2,4-三唑-3-硫酮的方法。该方法的原料5不稳定，不容易制备，且含铁三废处理是一环保问题。
Figure PCTCN2016090129-appb-000005
发明内容
本发明针对现有技术中的不足，提供了一种1,2,4-三唑-3-硫酮化合物及其中间体的合成方法。该方法包括下述步骤：
步骤1:化合物6或化合物6’与化合物7或化合物7’反应，得到化合物8或化合物8’，用反应式表示如下：
Figure PCTCN2016090129-appb-000006
其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基；
所述的R1,R2选自氢或C1-C6烷基；或R1,R2合并一起成为二亚甲基、三亚甲基、四亚甲基、五亚甲基环；
所述的n＝0.5，1或2；
所述的HX为氢卤酸、硫酸或磷酸；
所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6选自为氢，C1-C18烷基，C6-C18芳基；
所述的m＝0或1；
步骤2:化合物8或化合物8’与硫氰酸盐M’SCN反应，得1,2,4-三唑-3-硫酮化合物1，用反应式表示如下：
Figure PCTCN2016090129-appb-000007
其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基；
所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6选自为氢，C1-C18烷基，C6-C18芳基；
所述的M’为碱金属或NR3R4R5R6，其中R3,R4,R5,R6选自为氢，C1-C18烷基，C6-C18芳基；
所述的m＝0或1；
所述的HX为氢卤酸、硫酸或磷酸；
具体地，步骤1可以在溶剂或无溶剂的条件下进行，所述的溶剂优选为水、乙腈、叔丁醇、二氯甲烷、DMF、DMSO、甲苯中的一种或多种混合。化合物6或化合物6’与化合物7(或化合物7’)的摩尔比优选为1:1-10；步骤1的反应温度优选为0-40℃。所述的步骤2优选在酸的作用下进行，酸既可以作催化剂也可以直接作溶剂，所述的酸优选为有机酸，如甲酸、乙酸、三氟乙酸、甲磺酸、对甲苯磺酸中的一种或多种混合，酸与化合物8或化合物8’的摩尔比优选为0.01-100:1。步骤2中化合物8或化合物8’与硫氰酸盐的摩尔比优选为1:1-5；步骤2的反应温度优选为50-80℃。
步骤1和步骤2可以采用分步或“一锅煮”的方式进行。
一种1,2,4-三唑-3-硫酮化合物1的合成方法，其特征在于，该方法是将化合物8或化合物8’与硫氰酸盐M’SCN反应，得1,2,4-三唑-3-硫酮化合物1，用反应式表示如下：
Figure PCTCN2016090129-appb-000008
其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基；
所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢，C1-C18烷基，C6-C18芳基；
所述的M’为碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢，C1-C18烷基，C6-C18芳基；
所述的m＝0或1；
所述的HX为氢卤酸、硫酸或磷酸；
具体地，该反应优选在酸的作用下进行，酸既可以作催化剂也可以直接作溶剂，所述的酸优选为有机酸，如甲酸、乙酸、三氟乙酸、甲磺酸、对甲苯磺酸中的一种或多种混合，酸与化合物8或化合物8’的摩尔比优选为0.01-100:1。化合物8或化合物8’与硫氰酸盐的摩尔比优选为1:1-5；反应温度优选为50-80℃。
一种化合物8，其结构式如下：
Figure PCTCN2016090129-appb-000009
其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基，但R不为甲基、苯基、苄基；
所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6分别为氢，C1-C18烷基，C6-C18芳基；
或化合物8’，
Figure PCTCN2016090129-appb-000010
其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基，但R不为甲基、苯基、苄基；
所述的m＝0或1；
所述的HX为氢卤酸、硫酸或磷酸。
本发明提供的一种1,2,4-三唑-3-硫酮化合物和中间体的合成方法具有以下优点：
(1)本发明原料易得，反应区域选择性专一，副产物少，收率高；
(2)对设备没有特别要求，不需高真空高温或无水无氧操作；
(3)工艺简单，三废少，适合工业化生产。
具体实施方式
下面的实施例进一步举例说明了本发明的一些特征，但本发明所申请保护的内容和范围并不受下述实施例的限制。
实施例1：2-(2-苯基亚肼基)乙酸的合成
在500mL反应瓶中加入28.9g盐酸苯肼，300mL水和75mL乙腈，滴加29.6g 50％乙醛酸溶液，室温搅拌，反应结束后过滤，水洗，烘干得到29.0g固体产物(收率88％)。1H NMR(δ,DMSO-d6):11.125(m,1H),7.283-7.252(m,2H),7.157(s,1H),7.123-7.107(d,2H),6.896-6.866(t,1H)；MS：m/z＝165.1([M+1]+)。
实施例2：2-(2-苯基亚肼基)乙酸的合成
在500mL反应瓶中加入43.4g盐酸苯肼和350mL水，滴加57.6g 50％乙醛酸钠溶液，室温搅拌，反应结束后过滤，水洗，烘干得到45.3g固体产物(收率92％)。
实施例3：2-(3-氯吡啶亚肼基)乙酸的合成
在100mL反应瓶中加入5.0g 3-氯-2-肼基吡啶和50mL水，滴加26g 50％乙醛酸溶液，室温搅拌，反应结束后过滤，水洗，烘干得到6.6g固体产物(收率95％)。1H NMR(δ,DMSO-d6):12.648(s,1H),11.092(s,1H),8.230-8.215(m,1H),7.855-7.832(m,1H),7.706(s,1H),7.003-6.972(m,1H)；MS：m/z＝200.02([M+1]+)。
实施例4：2-(2-苯基亚肼基)乙酸钠的合成
在100mL反应瓶中加入5.0g苯肼和50mL水，滴加8.9g 50％乙醛酸钠溶液，室温搅拌，反应结束后脱溶，烘干得到7.6g固体产物(收率100％)。
实施例5：2-(2-甲基亚肼基)乙酸的合成
在100mL反应瓶中加入5.0g甲基肼硫酸盐和50mL水，滴加入5.7g 50％乙醛酸溶液，室温搅拌，反应结束后过滤，水洗，烘干得到3.4g固体产物(收率95％)。1H NMR(δ,DMSO-d6):11.975(s,1H),6.463-6.461(d,1H),4.995(s,1H),2.835(s,3H)；MS：m/z＝103.0([M+1]+)。
实施例6：2-(2-苄基亚肼基)乙酸的合成
在250mL反应瓶中加入11.7g苄基肼二盐酸盐，100mL水和15mL乙腈，滴加入9.5g 50％乙醛酸溶液，室温搅拌，反应结束后过滤，水洗，烘干得到9.4g固体产物(收率88％)。1H NMR(δ,DMSO-d6):11.994(s,1H),7.370-7.333(t,2H),7.290-7.253(t,1H),7.2256-7.208(d,2H),6.397(s,1H),5.339(s,1H),4.700(s,2H)；MS：m/z＝179.1([M+1]+)。
实施例7：2-(2-苄基亚肼基)乙酸的合成
在50mL反应瓶中加入2.34g苄基肼二盐酸盐和20mL水，分批加入1.18g乙醛酸一水合物，室温搅拌，反应结束后过滤，水洗，烘干得到1.94g固体产物(收率91％)。
实施例8：2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟基丙基]亚肼基}乙酸的合成
在250mL反应瓶中加入13.7g 2-(1-氯环丙基)-1-(2-氯苯基)-3-肼基丙-2-醇和100mL水，分批 加入4.7g乙醛酸一水合物，室温搅拌，反应结束后过滤，水洗，烘干得到14.5g固体产物(收率88％)。
实施例9：2-(2-苯基亚肼基)乙酸钠的合成
在500mL反应瓶中加入50g 2-(2-苯基亚肼基)乙酸和300mL乙醇，滴加24.4g 50％氢氧化钠水溶液，室温搅拌，反应结束后浓缩，乙醇打浆，过滤，烘干得到56.1g固体产物(收率99％)。
实施例10：2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟基丙基]亚肼基}乙酸半硫酸盐的合成
在25mL反应瓶中加入1.37g 2-(1-氯环丙基)-1-(2-氯苯基)-3-肼基丙-2-醇和15mL乙腈，滴加0.96g 50％乙醛酸水溶液和0.25g浓硫酸，室温搅拌，反应结束后脱溶，冷冻干燥，得到1.89g固体产物(收率99％)。
实施例11：2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟基丙基]亚肼基}乙酸半硫酸盐的合成
在250mL反应瓶中加入3.3g 2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟基丙基]亚肼基}乙酸和10mL乙腈，滴加0.5g浓硫酸，室温搅拌，反应结束后脱溶，冷冻干燥，得到3.8g固体产物(收率99％)。
实施例12：2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟丙基]亚肼基}乙酸的合成
在250mL反应瓶中加入15.5g 2-(1-氯环丙基)-1-(2-氯苯基)-3-肼基丙-2-醇的盐酸盐，滴加75g50％乙醛酸水溶液，室温搅拌，反应结束后过滤，水洗，烘干得到16.4g固体产物(收率99％)。1H NMR(δ,CDCl3):7.456-7.437(m,1H),7.405-7.386(m,1H),7.271-7.252(m,1H),7.245-7.223(m,1H),6.971-6.899(t,1H),6.781(s,1H),3.906-3.898,3.878-3.869(dd,1H),3.547-3.519(d,1H),3.519-3.508,3.491-3.480(dd,1H),3.211-3.183(d,1H),2.506(s,2H),1.175-1.134(m,1H),0.964-0.852(m,3H)；MS：m/z＝330.9([M+1]+)。
实施例13：2-苯基-1,2,4-三唑-3-硫酮的合成
在250mL反应瓶中加入4.9g 2-(2-苯基亚肼基)乙酸，8.7g硫氰酸钾和50mL三氟乙酸，升温至50℃，反应结束后浓缩，加入甲苯，水洗，脱溶，得到4.4g固体产物(收率83％)。1H NMR(δ,DMSO-d6):14.193(s,1H),10.005(s,1H),7.826-7.810(d,2H),7.600-7.569(m,2H),7.492-7.463(m,1H)；MS：m/z＝178.0([M+1]+)。
实施例14：2-苄基-1,2,4-三唑-3-硫酮的合成
在250mL反应瓶中加入9g 2-(2-苄基亚肼基)乙酸，4g硫氰酸钠和100mL醋酸，升温至80℃，反应结束后浓缩，加入甲苯，水洗，脱溶，得到8.7g固体产物(收率91％)。1H NMR(δ,DMSO-d6):13.565(s,1H),8.355(s,1H),7.368-7.144(m,5H),5.297(s,2H)。
实施例15：2-(3-氯吡啶-2-基)-1,2,4-三唑-3-硫酮的合成
在250mL反应瓶中加入6.0g 2-(3-氯吡啶亚肼基)乙酸的盐酸盐，11.4g硫氰酸铵和50mL三氟乙酸，升温至80℃，反应结束后浓缩，加入甲苯，水洗，脱溶，得到5.0g固体产物(收率93％)。1H NMR(δ,DMSO-d6):7.904-7.889(m,1H),7.568-7.545(m,1H),6.564-6.533(m,1H),6.234(s,2H)；MS：m/z＝213.0([M+1]+)。
实施例16：2-甲基-1,2,4-三唑-3-硫酮的合成
在250mL反应瓶中加入9.2g 2-(2-甲基亚肼基)乙酸，14.6g硫氰酸钠和80mL醋酸，升温至80℃，反应结束后浓缩，加入甲苯，水洗，脱溶，得到9.3g固体产物(收率90％)。1H NMR(δ,DMSO-d6):8.733(s,1H),6.039(s,1H),3.631(s,3H)。
实施例17：2-苯基-1,2,4-三唑-3-硫酮的合成
在250mL反应瓶中加入16.8g 2-(2-苯基亚肼基)乙酸钠，14.6g硫氰酸钠，80mL醋酸和8.7g甲磺酸，升温至80℃，反应结束后浓缩，加入甲苯，水洗，脱溶，得到14.9g固体产物(收率93％)。
实施例18：2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟丙基]-1,2,4-三唑-3-硫酮的合成
在250mL反应瓶中加入16.5g 2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟丙基]亚肼基}乙酸，6.1g硫氰酸钠和80mL醋酸，升温至80℃，反应结束后浓缩，加入甲苯，水洗，脱溶，得到16.3g固体产物(收率95％)。1H NMR(δ,CDCl3):12.300(s,1H),7.856(s,1H),7.549-7.544,7.534-7.530(dd,1H),7.377-7.374,7.362-7.358(dd,1H),7.242-7.183(m,2H),4.802-4.773(d,1H),4.510-4.481(d,1H),4.212(s,1H),3.621-3.594(d,1H),3.193-3.166(d,1H),0.943-0.922(m,1H),0.885-0.767(m,3H)；MS：m/z＝343.9([M+1]+)。
实施例19：2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟基丙基]-1,2,4-三唑-3-硫酮的合成
在25mL反应瓶中加入1.89g 2-{2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟基丙基]亚肼基}乙酸半硫酸盐，0.62g硫氰酸钠和10mL乙酸，升温至50℃，反应结束后浓缩，加入甲苯溶解，水洗，脱溶，得到1.43g固体产物(收率83％)。
实施例20：2-[2-(1-氯环丙基)-3-(2-氯苯基)-2-羟丙基]-1,2,4-三唑-3-硫酮的合成
在100mL反应瓶中加入0.93g 2-(1-氯环丙基)-1-(2-氯苯基)-3-肼基丙-2-醇的盐酸盐，15mL乙腈，0.55g 50％的乙醛酸溶液和0.24g硫氰酸钠，升温至60℃，反应结束后加入10mL水，调pH＝2左右，分层，水相用甲苯萃取，合并有机相，脱溶，得到0.92g固体产物(收率89％)。

Claims (10)

  1. 一种1,2,4-三唑-3-硫酮化合物1的合成方法，其特征在于，该方法包括下述步骤：
    步骤1:化合物6或化合物6’与化合物7或化合物7’反应，得到化合物8或化合物8’，用反应式表示如下：
    Figure PCTCN2016090129-appb-100001
    或，
    Figure PCTCN2016090129-appb-100002
    其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基；
    所述的R1,R2为氢或C1-C6烷基；或R1,R2合并一起成为二亚甲基、三亚甲基、四亚甲基、五亚甲基环；
    所述的n＝0.5，1或2；
    所述的HX为氢卤酸、硫酸或磷酸；
    所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢、C1-C18烷基或C6-C18芳基；
    所述的m＝0或1；
    步骤2:化合物8或化合物8’与硫氰酸盐M’SCN反应，得1,2,4-三唑-3-硫酮化合物1，用反应式表示如下：
    Figure PCTCN2016090129-appb-100003
    或，
    Figure PCTCN2016090129-appb-100004
    其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基；
    所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢、C1-C18烷基或C6-C18芳基；
    所述的M’为碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢、C1-C18烷基或C6-C18芳基；
    所述的m＝0或1；
    所述的HX为氢卤酸、硫酸或磷酸。
  2. 根据权利要求1所述的方法，其特征在于，所述的步骤1可以在溶剂或无溶剂的条件下进行；化合物6或化合物6’与化合物7或化合物7’的摩尔比优选为1:1-10；步骤1的反应温度优选为0-40℃。
  3. 根据权利要求2所述的方法，其特征在于，所述的溶剂优选为水、乙腈、叔丁醇、二氯甲烷、DMF、DMSO、甲苯中的一种或多种混合。
  4. 根据权利要求1所述的方法，其特征在于，步骤1和步骤2可以采用分步或“一锅煮”的方式进行。
  5. 一种1,2,4-三唑-3-硫酮化合物1的合成方法，其特征在于，该方法是将化合物8或化合物8’与硫氰酸盐M’SCN反应，得1,2,4-三唑-3-硫酮化合物1，用反应式表示如下：
    Figure PCTCN2016090129-appb-100005
    或，
    Figure PCTCN2016090129-appb-100006
    其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基；
    所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢、C1-C18烷基或C6-C18芳基；
    所述的M’为碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢、C1-C18烷基或C6-C18芳基；
    所述的m＝0或1；
    所述的HX为氢卤酸、硫酸或磷酸。
  6. 根据权利要求1或5所述的方法，其特征在于，化合物8或化合物8’与硫氰酸盐M’SCN的反应在酸的作用下进行；化合物8或化合物8’与硫氰酸盐的摩尔比优选为1:1-5；反应温度优选为50-80℃。
  7. 根据权利要求6所述的方法，其特征在于，所述的酸优选为有机酸；酸与化合物8或化合物8’摩尔比优选为0.01-100:1。
  8. 根据权利要求7所述的方法，其特征在于，所述的有机酸优选为甲酸、乙酸、三氟乙酸、甲磺酸、对甲苯磺酸中的一种或多种混合。
  9. 一种化合物8，其特征在于结构式如下：
    Figure PCTCN2016090129-appb-100007
    其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基，但R不为甲基、苯基、苄基；
    所述的M为氢、碱金属或NR3R4R5R6，其中R3,R4,R5,R6为氢、C1-C18烷基或C6-C18芳基；
  10. 一种化合物8’，其特征在于结构式如下：
    Figure PCTCN2016090129-appb-100008
    其中，所述的R为C1-C18烷基，C6-C18芳基，C5-C6含氧、氮、硫杂芳基，但R不为甲基、苯基、苄基；
    所述的m＝0或1；
    所述的HX为氢卤酸、硫酸或磷酸。
PCT/CN2016/090129 2016-07-15 2016-07-15 一种1,2,4-三唑-3-硫酮化合物的合成方法及其中间体 WO2018010163A1 (zh)

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