CN1898245B - 三唑嘧啶的制备方法 - Google Patents
三唑嘧啶的制备方法 Download PDFInfo
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- CN1898245B CN1898245B CN200480038604XA CN200480038604A CN1898245B CN 1898245 B CN1898245 B CN 1898245B CN 200480038604X A CN200480038604X A CN 200480038604XA CN 200480038604 A CN200480038604 A CN 200480038604A CN 1898245 B CN1898245 B CN 1898245B
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- -1 alkyloxycarbonyl isothiocyanate Chemical class 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000003905 agrochemical Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 150000001733 carboxylic acid esters Chemical group 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
- NXPHCVPFHOVZBC-UHFFFAOYSA-N hydroxylamine;sulfuric acid Chemical compound ON.OS(O)(=O)=O NXPHCVPFHOVZBC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- BDTDECDAHYOJRO-UHFFFAOYSA-N ethyl n-(sulfanylidenemethylidene)carbamate Chemical compound CCOC(=O)N=C=S BDTDECDAHYOJRO-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 2
- VGYYSIDKAKXZEE-UHFFFAOYSA-L hydroxylammonium sulfate Chemical compound O[NH3+].O[NH3+].[O-]S([O-])(=O)=O VGYYSIDKAKXZEE-UHFFFAOYSA-L 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- NKFLEFWUYAUDJV-UHFFFAOYSA-N pyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN=C1 NKFLEFWUYAUDJV-UHFFFAOYSA-N 0.000 description 2
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 150000005006 2-aminopyrimidines Chemical class 0.000 description 1
- WNNUCBYVVRCGSE-UHFFFAOYSA-N 2-propoxypyrimidine Chemical compound CCCOC1=NC=CC=N1 WNNUCBYVVRCGSE-UHFFFAOYSA-N 0.000 description 1
- MWLFJSYZFRVWBS-UHFFFAOYSA-N 4,6-diethoxypyrimidin-2-amine Chemical compound CCOC1=CC(OCC)=NC(N)=N1 MWLFJSYZFRVWBS-UHFFFAOYSA-N 0.000 description 1
- FFYYHFMMWZGEMB-UHFFFAOYSA-N 4,6-dimethoxypyridin-2-amine Chemical compound COC1=CC(N)=NC(OC)=C1 FFYYHFMMWZGEMB-UHFFFAOYSA-N 0.000 description 1
- LVFRCHIUUKWBLR-UHFFFAOYSA-N 4,6-dimethoxypyrimidin-2-amine Chemical compound COC1=CC(OC)=NC(N)=N1 LVFRCHIUUKWBLR-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- LBFAAYMITJMZOC-UHFFFAOYSA-N methyl n-(sulfanylidenemethylidene)carbamate Chemical compound COC(=O)N=C=S LBFAAYMITJMZOC-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- LQBVARDGLYXGHF-UHFFFAOYSA-N triazolo[4,5-d]pyrimidin-2-amine Chemical compound C1=NC=NC2=NN(N)N=C21 LQBVARDGLYXGHF-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Plant Pathology (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及制备未取代的或取代的2-氨基-[1，2，4]三唑嘧啶的方法，包括使A)2-氨基-嘧啶或其衍生物与烷氧羰基异硫氰酸盐或芳氧羰基异硫氰酸盐以及B)羟铵盐和碱结合，其中反应在40到150℃的温度范围内的极性非质子有机溶剂中进行。
Description
三唑嘧啶衍生物在药物或农业化学品的合成中，如杀菌剂、杀虫剂或除草剂的合成中是有利的结构单元。
WO 02/36595 A2(Dow Agrosciences LLC)描述了2-氨基-5，7-二甲氧基[1，2，4]-三唑[1，5-a]嘧啶通过2-氨基-4，6-二甲氧基嘧啶和乙氧羰基异硫氰酸盐的反应的合成路线。
后一反应在室温下在四氢呋喃(THF)中进行，并且分离中间体。然后在室温下使中间体与羟胺氢氯化物和二异丙胺在乙醇中反应以生成2-氨基-5，7-二甲氧基[1，2，4]-三唑[1，5-a]嘧啶。
这个两步骤方法的产率不令人满意，并且合成对如满足商业目的来说也不够简单。
本发明的目的是提供一种简单方法来产生高产率的2-氨基-三唑嘧啶，其可以在农业化学品合成中，如杀菌剂、杀虫剂或除草剂中用作结构单元。
因此找到了如权利要求定义的方法以及这个方法在制备包含2-氨基[1，2，4]-三唑[1，5-a]嘧啶结构的农业化学品或药品中的应用。
本发明方法的阶段A是结合取代的或未取代的2-氨基-嘧啶和烷氧羰基异硫氰酸盐或芳氧羰基异硫氰酸盐。
优选的未取代的或取代的2-氨基-嘧啶如通式I：
其中变量如下定义：
E＝独立地相同或不同为O、S、N、P；
R＝独立地相同或不同为C1-10-烷基；C6-20芳基；C7-20芳烷基；C7-20烷芳基，以上这些中的每个可以由一种或多种以下基团取代：F、Cl、Br、I、C1-20烷氧基、C6-20芳氧基、未取代的或优选取代的氨基；F、Cl、Br、I；
n＝0或1；
m＝1，当E＝O、S；
m＝2，当E＝N、P；
p＝0、1、2或3。
优选的基团R是直链或支链C1-6烷基如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、新戊基、正戊基、正己基，或C7-20芳烷基如苄基或二苯基甲基。
优选的基团E是氧(O)或氮(N)。
优选E为O，p是1或2，并且ER-基团彼此为间位。
最优选R是C1-6烷基，E是O，p是2，并且ER-基团彼此为间位。
通式I的适合化合物为2-氨基-嘧啶；2-氨基-4，6-二甲氧基-嘧啶；2-氨基-4，6-二乙氧基-嘧啶；2-氨基-4，6-二-正丙氧基-嘧啶；2-氨基-4，6-二-正丁氧基-嘧啶。
本发明的烷氧羰基或芳氧羰基异硫氰酸盐优选具有以下通式II：
其中R具有针对通式I的化合物中的定义相同的定义，包括优选定义。
通式II的合适化合物是甲氧羰基异硫氰酸盐，乙氧羰基异硫氰酸盐。
通式II的化合物在文献中是公知的，并且可以通过已知方法制得，如通过相应的有机氯甲酸酯与碱金属(K、Na、Rb、Cs)或碱土金属(如Ca、Ba、Sr)硫氰酸盐在有机溶剂中反应制得，(见例如，J.Heterocycl.Chem.5，837(1968)；J.Org.Chem.55(18)，5230-5231(1990)；US 4160037；US 4778921；US 5194673)。有机溶剂优选是可以进行本发明的反应的有机溶剂。
上述结合产生通式III的N-嘧啶-2-基-N’-烷氧羰基(或芳氧基)硫脲：
其中变量具有如通式I的化合物中的定义相同的定义，包括优选定义。
适合的化合物III是E＝O，R＝C1-6烷基，m＝1，p＝1、2或3的化合物。优选的化合物III是E＝O，R＝C1-6烷基，m＝1，p＝2，其中ER基团彼此为间位的化合物。非常适合的化合物III如下：N-(4，6-二甲氧基嘧啶-2-基)-N’-乙氧羰基硫脲，N-(4，6-二乙氧基嘧啶-2-基)-N’-乙氧羰基硫脲。
本发明的阶段B是化合物III与羟铵盐在碱存在下结合，其中羟铵盐如硫酸羟胺、氯化羟胺、硝酸羟胺、磷酸羟胺，优选硫酸羟胺。
优选的碱是碱金属氢氧化物(如KOH、NaOH、RbOH、CsOH)。碱土金属氢氧化物(如Mg(OH)2、Ca(OH)2、Ba(OH)2、Sr(OH)2)和有机碱如胺—优选叔胺-吡啶和其它杂环有机碱，优选环胺碱。最优选的碱是碱氢氧化物，尤其是苛性钠(NaOH)。
优选地，将例如苛性钠的碱开始缓慢地加入来使反应混合物的pH值由1到7.5，然后保持在pH5到7.5，最好是pH6.5到7.0，直到反应完成。
上述反应顺序最终产生相应的2-氨基-[1，2，4]三唑嘧啶IV：
其中变量具有在通式I的化合物中的定义相同的定义，包括优选定义。
适合的化合物IV是E＝O，R＝C1-6烷基，m＝1，p＝1、2或3的化合物。优选的化合物IV是E＝O，R＝C1-6烷基，m＝1，p＝2，其中ER基团彼此为间位或者换言之其占据通式IV的三唑嘧啶环系统的5-和7-位(根据Chemical Abstract Nomenciature)。
非常适合的化合物IV是2-氨基-5，7-二甲氧基[1，2，4]三唑嘧啶，2-氨基-5，7-二乙氧基[1，2，4]三唑嘧啶，2-氨基-5，7-二正或二异丙氧基[1，2，4]三唑嘧啶，2-氨基-5，7-二正-或二叔或二异-丁氧基[1，2，4]三唑嘧啶，尤其是2-氨基-5，7-二甲氧基[1，2，4]三唑嘧啶。
通常在极性非质子溶剂中进行阶段A和B，该溶剂如腈(如乙腈)、醚(如thf，二甲氧基乙烷、二甲氧基甲烷、二乙氧基甲烷、二异丙基醚、1，4-二噁烷、甲基叔丁基醚(MTBE))，酮(如丙酮、二乙基酮、甲基异丁基酮)或优选在羧酸酯中进行阶段A和B，该羧酸酯如C1-20-羧酸-C1-10烷基酯或相应的C7-20烷芳基酯或C7-20芳烷基酯。
优选地，C1-20羧酸C1-10烷基酯用作溶剂。
上述溶剂的混合物也是适用的。
最优选地，阶段A的溶剂与阶段B的溶剂相同。
阶段A和/或阶段B中的最优选的溶剂是羧酸酯，如C1-20羧酸C1-10烷基酯，优选C1-6羧酸C1-6烷基酯，其中羧酸是直链脂肪族羧酸或苯甲酸，并且醇烷基部分是直链烷基；羧酸酯的合适例子是乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯，特别是乙酸乙酯。
优选阶段A和/或阶段B中的反应在40到150℃，优选60到100℃，最优选70到90℃的温度下进行。
最优选阶段A和阶段B中的反应在例如60到100℃，优选70到90℃温度下的相应溶剂的回流下进行。
有时，为了达到上述反应温度，必要地在压力下进行反应。
优选在本发明的方法中不分离中间体(一步式方法(one potprocedure))，尽管这个分离有可能容易地通过常用已知方法进行。
阶段A和B的整个反应时间通常为2到14小时，优选5到6小时。
反应产物IV通常是活跃的，用常用有机技术进行分离。
本发明的方法可以用于农用化学品或药物的合成，例如描述于WO02/36595 A2(DOW Agrosciences LLC或US 5,571,775(DOW Elanco)的农用化学品，其在此处并入作为参考。
例如通过本发明的方法得到的化合物IV可以与芳基-或杂芳基磺酰基卤化物Ar-SO2-Hal或(Hetaryl)-SO2-Hal反应以产生相应的N([1，2，4]三唑[1，5-a]嘧啶-2-基)芳基或杂芳基磺酰胺化合物V，如WO 02/36595A2(DOW Agrosciences LLC)所述。
其中变量具有与在通式I中定义相同的定义，并且R’独立地相同或不同为H或R，E1是CR’或N，优选N。
合适的化合物V是例如：
3-吡啶磺酰胺，N-(5，7-二甲氧基[1，2，4]三唑[1，5-a]嘧啶-2-基)-2-甲氧基-4-(三氟甲基)，如2002年7月Research Disclosure，1230-1231中所公开的；
3-吡啶磺酰胺，N-(5，7-二乙氧基[1，2，4]三唑[1，5-a]嘧啶-2-基)-2-甲氧基(三氟甲基)。
本发明的方法产生了一种简单，常用的一步式方法，以得到高产率的有用化合物IV，通常总产率高于85％，特别高于90％。
实施例
从2-氨基-4，6-二甲氧基嘧啶(ADP)合成2-氨基-5，7-二甲氧基[1，2，4]三唑嘧啶(ADTP)的一步式方法
将11.9g(0.075mol)ADP溶于68g乙酸乙酯。在78℃于20分钟内加入11g(0.0825mol)乙氧羰基异硫氰酸盐(无放热)。在回流(78-79℃)下搅拌混合物5小时。加入49.2g(0.075mol)硫酸羟胺(25％水溶液)，并将混合物加热到71℃(reflux aceotrope)。在1小时内加入50g(0.1mol)稀释的苛性钠(2mol/L)以使pH值从1.3升至6.5，并且保持在6.5到7.0(废气CO2和H2S，稍微放热)。在回流(71℃)下搅拌混合物过6小时以完成反应。冷却混合物过夜直至20℃。过滤产物(ADTP)，并且用每次25g的水洗涤3次来去除盐(第一次洗涤后Na含量为0.42％，第二次之后为0.20％，第三次之后为0.025％)。最后干燥固体ADTP。相对于ADP的产率为91.1％；纯度95.3％(定量HPLC分析)。
Claims (13)
1.制备2-氨基-[1，2，4]三唑嘧啶的方法，其包括结合A)2-氨基-嘧啶或其衍生物与烷氧羰基异硫氰酸盐或芳氧羰基异硫氰酸盐与B)羟铵盐和碱，其中反应在40到150℃的温度范围内的极性非质子有机溶剂中进行，
其中2-氨基-嘧啶或其衍生物如通式I所述：
并且2-氨基-[1，2，4]三唑嘧啶如通式IV所述：
其中变量如下定义：
E＝独立地相同或不同为O、S、N、P；
R＝独立地相同或不同为C1-10-烷基；C6-20芳基；C7-20芳烷基；C7-20烷芳基，以上这些中的每个由一种或多种以下基团取代：F、Cl、Br、I、C1-20烷氧基、C6-20芳氧基、氨基；F、Cl、Br、I；
n＝0或1；
m＝1，当E＝O、S；
m＝2，当E＝N、P；
p＝0、1、2或3。
2.根据权利要求1所述的方法，其中步骤B)的pH值随时间增加并且最终保持在5到7.5的范围内。
3.根据权利要求1或2所述的方法，其中羟铵盐是硫酸羟铵。
4.根据权利要求1或2所述的方法，其中极性非质子有机溶剂选自羧酸酯。
5.根据权利要求1或2所述的方法，其中基团R是直链或支链C1-6烷基或C7-20芳烷基。
6.根据权利要求5所述的方法，其中直链或支链C1-6烷基是甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、新戊基、正戊基、正己基，C7-20芳烷基是苄基或二苯基甲基。
7.根据权利要求1或2所述的方法，其中基团E是氧或氮。
8.根据权利要求1或2所述的方法，其中E为O，p是1或2，并且ER-基团彼此为间位。
9.根据权利要求1或2所述的方法，其中R是C1-6烷基，E是O，p是2，并且ER-基团彼此为间位。
10.根据权利要求1或2所述的方法，其中E为O，R为甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基，n＝1，m＝1，p＝2，其中ER-基团彼此为间位。
11.根据权利要求1或2所述的方法，其中所述方法在不分离中间体的情况下进行。
12.制备N-([1，2，4]三唑[1，5-a]嘧啶-基)芳基磺酰胺或N-([1，2，4]三唑[1，5-a]嘧啶-基)杂芳基磺酰胺的方法，其包括根据权利要求1-11任一项制备2-氨基-[1，2，4]三唑嘧啶随后使得到的2-氨基-[1，2，4]三唑嘧啶与芳基磺酰基卤化物Ar-SO2-Hal或杂芳基磺酰基卤化物Hetar-SO2-Hal反应。
13.根据权利要求1到11任一项所述的方法在合成包含N-([1，2，4]三唑[1，5-a]嘧啶-基)结构的农用化学品或药品中应用。
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| EP03029728.7 | 2003-12-23 | ||
| PCT/EP2004/014596 WO2005063753A1 (en) | 2003-12-23 | 2004-12-22 | Process for the preparation of triazolopyrimidines |
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| US5965490A (en) * | 1996-09-24 | 1999-10-12 | Dow Agrosciences Llc | N-([1,2,4]triazoloazinyl)benzenesulfonamide and pyridinesulfonamide compounds and their use as herbicides |
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