CN1361771A - 制备取代的苯并异噻唑的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910021529 ammonia Inorganic materials 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000908 ammonium hydroxide Substances 0.000 claims description 9
- 150000003863 ammonium salts Chemical class 0.000 claims description 9
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- 239000000203 mixture Substances 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- YCNIBOIOWCTRCL-UHFFFAOYSA-N azane;2,2,2-trifluoroacetic acid Chemical group [NH4+].[O-]C(=O)C(F)(F)F YCNIBOIOWCTRCL-UHFFFAOYSA-N 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
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- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- -1 heteroaryl isothiazole compounds Chemical class 0.000 description 6
- 239000000047 product Substances 0.000 description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 4
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
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- AMSQDPBABYOYNA-UHFFFAOYSA-N (2-acetyl-4-amino-5-fluorophenyl) thiocyanate Chemical compound CC(=O)C1=CC(N)=C(F)C=C1SC#N AMSQDPBABYOYNA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
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- FLLADTZDHSRDAJ-UHFFFAOYSA-N ethyl 2-(5-amino-4-fluoro-2-thiocyanatophenyl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CC(N)=C(F)C=C1SC#N FLLADTZDHSRDAJ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
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- 238000004949 mass spectrometry Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
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- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- VVHJMBAIRRDVEL-UHFFFAOYSA-N 6-fluoro-3-(3-methylpyridin-2-yl)-1,2-benzothiazol-5-amine Chemical compound CC1=CC=CN=C1C1=NSC2=CC(F)=C(N)C=C12 VVHJMBAIRRDVEL-UHFFFAOYSA-N 0.000 description 1
- VZVKLQRLCVYZOV-UHFFFAOYSA-N 6-fluoro-3-methyl-1,2-benzothiazol-5-amine Chemical compound FC1=C(N)C=C2C(C)=NSC2=C1 VZVKLQRLCVYZOV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GEHMBYLTCISYNY-UHFFFAOYSA-N Ammonium sulfamate Chemical compound [NH4+].NS([O-])(=O)=O GEHMBYLTCISYNY-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- YXSDXAFWTYSITI-UHFFFAOYSA-N ethyl 2-(3-amino-4-fluorophenyl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CC=C(F)C(N)=C1 YXSDXAFWTYSITI-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
由硫氰酸2-酰基苯基酯制备式(I)苯并异噻唑的一步法。式(I)苯并异噻唑可在除草活性化合物的制备中用作关键中间体。
Description
发明领域
取代的苯并异噻唑除草剂描述在U.S.5,484,763和WO 99/14216以及许多其它出版物中,并且是良好杀虫方案的非常理想的农作物选择性组分。所述取代的苯并异噻唑除草剂是用苯并异噻唑和杂芳基异噻唑化合物制备的。
制备苯并异噻唑和杂芳基异噻唑化合物(“异噻唑”)的方法是文献中已知的。然而,唯一已知的一步法需要严格的反应条件,并且最大产率仅为38%。当杂芳基异噻唑环是取代的环时,该低产率会显著下降(《加拿大化学杂志》(Canadian Journal of Chemistry),1973,51,1741)。这样的产率和反应条件不能为大规模制备或生产条件所接受。
所述异噻唑的两步合成需要分离中间体,导致不适当的溶剂浪费,并影响环境。此外,这些合成需要严格的反应条件,使用昂贵的试剂,并且其产率仅勉强令人接受,即使对于相对未取代的异噻唑也是如此(Journal of Chemical Research,Synop.,1979,395和Journal of the Chemical Society,Perkin II,1977,1114)。
因此,本发明的目的是提供能进行大规模制备的制备取代的苯并异噻唑化合物的一步法。
本发明的另一目的是提供在较温和的反应条件下由易得原料和试剂以良好产率获得取代的苯并异噻唑化合物的方法。
本发明的再一目的是提供用于制备重要的取代苯并异噻唑除草剂的取代的苯并异噻唑中间体的有利于环境的商业来源。
发明简述
本发明提供了制备式I苯并异噻唑化合物的方法其中Y是氢或卤素;R是CO2R3;任选被一个或多个卤素、C1-C6烷氧基、CO2R1或COR2基团取
代的C1-C6烷基;或任选被一个或多个卤素、CN、NO2、C1-C6烷基、C1-C6卤代烷基、C1-C6
烷氧基或C1-C6卤代烷氧基取代的6-元杂环;以及R1、R2和R3分别独立地为氢、C1-C6烷基或NH2,该方法包括在溶剂存在下使式II化合物与氨源反应,其中Y和R如上所定义。
本发明还提供了在制备具有除草活性的取代的苯并异噻唑农药的方法中使用式I化合物的方法。
发明详述
本发明提供了由适当硫氰酸2-酰基苯基酯前体一步制备取代的苯并异噻唑化合物的方法。所述苯并异噻唑化合物可在重要的除草剂例如在U.S.5,484,763和WO 99/14216中描述的除草剂的制备中用作关键中间体。这样的除草剂对于全球的粮食供应的生产和质量是非常重要的。以有利于环境的方式有效率地制备这样的除草活性化合物一直是个挑战。
本发明方法提供了式I化合物的一步制备,其中式I如上所述,所述制备是在比较温和的条件下由易得原料进行的,并且能够进行有效的大规模商业生产。通过本发明方法制得的优选的式I化合物是其中R是C1-C6烷基或CO2R3,且R3是C1-C6烷基的式I化合物。更优选的式I化合物是其中Y是氢或F,且R是C1-C6烷基或CO2R3的式I化合物。
在本申请说明书和权利要求书中使用的术语卤素是指氯、氟、溴或碘。术语卤代烷基是指含有一至2n+1个卤素原子的烷基CnH2n+1。术语6-元杂环是指经由碳原子连接的含有1个或2个选自O、N或S的杂原子的6-元芳环系。6-元杂环的实例包括:吡啶、嘧啶、吡喃、噻喃等。
依据本发明方法,式I苯并异噻唑可如下所述方便地制得:在溶剂、优选极性溶剂存在下,使式II适当取代的硫氰酸2-酰基苯基酯与氨源例如氨、氢氧化铵、铵盐如氯化铵、乙酸铵、三氟乙酸铵等或提供氨的任何常规手段反应。在反应方案I中解释了该反应,其中Y和R如上所述。
反应方案I
式II化合物可通过常规方法容易地制得,例如在溴和酸存在下用硫氰酸钠与式III适当取代的苯甲酰基化合物反应。下述反应方案II解释了该反应。
适用于本发明方法的溶剂包括极性溶剂例如水、醇、有机酸、酯和非质子传递溶剂例如二氧杂环己烷或乙腈。优选的溶剂是水,二氧杂环己烷或低级烷基醇例如甲醇、乙醇、丙醇、异丙醇等,或它们的混合物。
氨源可以是引入氨的任何常规手段,例如氨气、氢氧化铵、铵盐等,优选氢氧化铵或铵盐。可在本发明方法中使用的铵盐是在所用的具体溶剂中具有足够溶解度的铵盐。合适的铵盐的实例包括三氟乙酸铵、乙酸铵、硝酸铵、氨基磺酸铵、氯化铵、硫酸铵等,优选乙酸铵或三氟乙酸铵。
在本发明方法中,反应温度与反应速率直接相关,因此提高温度可提高反应速率。然而,过高的温度可导致不需要的副反应,并使产物的产率和纯度下降。合适的反应温度可以为约室温至所用特定溶剂的回流温度。
在实际实施时,在溶剂,优选极性溶剂,更优选水、二氧杂环己烷或低级烷基醇例如C1-C4烷基醇如甲醇或异丙醇或其混合物存在下,在约室温-溶剂的回流温度,用氨源、优选氢氧化铵或铵盐处理式II硫氰酸2-酰基苯基酯化合物。当反应完全时,使用常规方法例如萃取、过滤、色谱法等分离所需的式I苯并异噻唑产物。
在本发明方法中,从严格上来说氨源的量不是关键,并且可采用约1-5摩尔当量、优选约1-3摩尔当量的量。应当理解,可使用更大量的氨源,即大于5摩尔当量的量,然而,这样不会获得任何好处。
式I化合物可在取代的苯并异噻唑除草剂的制备中用作中间体。因此,在本发明一个实施方案中,在酸或碱的存在下,任选在溶剂存在下,可将如上所述由式II化合物制得的式I化合物与式IVa或IVb环状化合物反应其中R4和R5分别独立地为氢、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C3-C6卤代环烷基,或者R4和R5可以与它们所连接的原子一起形成环,其中R4R5代表可任选被1-3个卤素或甲基取代的5-元或6-元亚环烷基;R6和R7分别独立地为氢、卤素、或C1-C6卤代烷基;R8和R9分别独立地为C1-C4烷基,以生成式V或其中R10是氢的式VI化合物;并且对于VI,可进一步在碱存在下任选使VI与C1-C6烷基卤R11X反应,以生成其中R10是C1-C4烷基的式VI化合物。在反应方案III中解释了该反应,其中X是氯或溴。
在将式I化合物转化成式V和VI除草活性产物的已知方法当中,可提及的有在U.S.5,484,763和WO 99/14216中描述的方法。
提供下述实施例以更清楚地理解本发明。这些实施例仅是举例说明,不应当理解为以任何方式限制本发明的范围和实质。
术语NMR和HPLC分别是指核磁共振和高效液相色谱。除非另有说明,否则所有份数都是指重量份。
实施例1
在搅拌下,将2M溴在乙酸中的溶液(32.7ml,65.4mmol)滴加到4-乙酰基-2-氨基氟苯(5.0g,32.6mmol)和硫氰酸钠(7.94g,97.9mmol)在冰醋酸内的混合物中。将该反应混合物在室温搅拌1小时,倒入水中,并用乙酸乙酯萃取。合并萃取液,依次用水和盐水洗涤,用硫酸镁干燥,并真空浓缩,获得了本标题化合物,为橙色固体,4.68g,产率68%,1HNMR光谱和HPLC分析证实了该化合物。
实施例2
制备5-氨基-6-氟-3-甲基苯并异噻唑
将硫氰酸2-乙酰基-4-氨基-5-氟苯基酯(100mg,0.476mmol)在甲醇中的溶液用30%氢氧化铵(4ml)处理,并搅拌42小时。将该反应混合物倒入水中,并用乙酸乙酯萃取。合并萃取液,用盐水洗涤,用硫酸镁干燥,并真空浓缩,获得了油状物。通过色谱法(硅胶/己烷-乙酸乙酯洗脱剂)纯化,获得了本标题产物,为36.9mg,产率56%,1HNMR光谱和HPLC分析证实了该化合物。
实施例3
制备3-氨基-4-氟-6-硫氰酸基苯基2-(3-甲基吡啶基)酮
在搅拌下,将2M溴在乙酸中的溶液(12ml,0.024mol)滴加到3-氨基-4-氟苯基2-(3-甲基吡啶基)酮(4.20g,0.017mol)和硫氰酸钠(4.15g,0.051mol)在冰醋酸内的混合物中,并在室温搅拌1小时。将该反应混合物倒入冷的氨水溶液中,并过滤。用硫酸钙将滤饼在真空烘箱中干燥,获得了本标题化合物,为黄色固体,4.19g,产率80%,1H、13C和19FNMR以及质谱分析证实了该化合物。
实施例4
制备5-氨基-6-氟-3-(3-甲基-2-吡啶基)苯并异噻唑
3-氨基-4-氟-6-硫氰酸基苯基2-(3-甲基吡啶基)酮(2.74g,0.01mol)与30%氢氧化铵在甲醇中的混合物于室温搅拌过夜,用等量甲醇和30%氢氧化铵溶液稀释10倍,并过滤。将滤饼干燥,获得了本标题化合物,为黄色固体,1.31g,产率51%,1H、13C和19FNMR以及质谱分析证实了该化合物。
实施例5
向(5-氨基-4-氟苯基)乙醛酸乙酯(90g,0.426mol)和硫氰酸钠(114g,1.41mol)在乙酸内的溶液中滴加2M溴在乙酸中的溶液(980ml,0.98mmol),并搅拌1小时。将该反应混合物倒入冰中,并用乙酸乙酯萃取。合并萃取液,依次用水和盐水洗涤,用硫酸镁干燥,并真空浓缩,获得了油状残余物。通过快速色谱法(硅胶/洗脱剂己烷-乙酸乙酯)纯化残余物,获得了本标题产物,为黄色固体,60g,产率52%,1HNMR分析证实了该化合物。
实施例6
在氮气氛下,将(5-氨基-4-氟-2-硫氰酸基苯基)乙醛酸乙酯(1.00g,3.73mmol)在二氧杂环己烷中的溶液用三氟乙酸铵(1.71g,13mmol)处理,并在回流温度下加热2小时。通过色谱法(硅胶/己烷-乙酸乙酯洗脱剂)纯化粗的反应混合物,获得了本标题产物,为浅绿色固体,0.59g,产率66%,1HNMR分析证实了该化合物。
实施例7
使用基本与上述相同的方法,并采用适当的硫氰酸2-酰基苯基酯,获得了如在表I中所示的化合物。
Claims (15)
2.权利要求1的方法,其中所述溶剂包括二氧杂环己烷。
3.权利要求1的方法,其中所述溶剂包括水或C1-C4烷基醇或它们的混合物。
4.权利要求1的方法,其中所述氨源是氢氧化铵或铵盐。
5.权利要求4的方法,其中所述铵盐是三氟乙酸铵或乙酸铵。
6.权利要求1的方法,其中在式I化合物中,Y是氢或F。
7.权利要求1的方法,其中在式I化合物中,R是C1-C6烷基或CO2R3;以及R3是C1-C4烷基。
8.权利要求5的方法,其中所述溶剂选自水、C1-C4烷基醇、水与C1-C4烷基醇的混合物和二氧杂环己烷。
9.权利要求8的方法,其中在式I化合物中,Y是氢或F。
10.权利要求9的方法,其中在式I化合物中,R是C1-C6烷基或CO2R3;以及R3是C1-C4烷基。
代的C1-C6烷基;或任选被一个或多个卤素、CN、NO2、C1-C6烷基、C1-C6卤代烷基、C1-C6
烷氧基或C1-C6卤代烷氧基取代的6-元杂环;以及R1、R2和R3分别独立地为氢、C1-C6烷基或NH2,R4和R5分别独立地为氢、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C3-C6卤代环烷基,或者R4和R5可以与它们所连接的原子一起形成环,其中R4R5代表可任选被1-3个卤素或甲基取代的5-元或6-元亚环烷基;R6和R7分别独立地为氢、卤素、或C1-C6卤代烷基;R8和R9分别独立地为C1-C4烷基;和R10是氢或C1-C4烷基,其中式V或式VI化合物的制备是如下进行的:在酸或碱存在下,任选在溶剂存在下,使式I化合物与式IVa或IVb化合物反应其中R4、R5、R6、R7、R8和R9如上所述,以生成所需的式V或其中R10是氢的式VI化合物,对于式VI化合物,可在碱存在下任选使其与C1-C4烷基卤R11X反应,其中R11是C1-C4烷基,且X是氯或溴,以生成其中R10是C1-C4烷基的式VI化合物。
12.权利要求11的方法,其中所述氨源是氢氧化铵、乙酸铵或三氟乙酸铵。
13.权利要求11的方法,其中所述溶剂是二氧杂环己烷、水、C1-C4烷基醇或水与C1-C4烷基醇的混合物。
14.权利要求11的方法,其中Y是F;R是C1-C6烷基或CO2R3;R3是C1-C4烷基;R6和R7分别独立地为氢或CF3;且R10是C1-C4烷基。
15.权利要求14的方法,其中是制备式VI化合物。
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