EP1891025A1 - Verfahren zur herstellung von substituierten azolen - Google Patents
Verfahren zur herstellung von substituierten azolenInfo
- Publication number
- EP1891025A1 EP1891025A1 EP06743081A EP06743081A EP1891025A1 EP 1891025 A1 EP1891025 A1 EP 1891025A1 EP 06743081 A EP06743081 A EP 06743081A EP 06743081 A EP06743081 A EP 06743081A EP 1891025 A1 EP1891025 A1 EP 1891025A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- optionally substituted
- phenyl
- alkoxy
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 150000003851 azoles Chemical class 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- -1 hydroxymethylene Chemical group 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 239000000203 mixture Chemical class 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 239000012039 electrophile Substances 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- LSDPWZHWYPCBBB-UHFFFAOYSA-N methyl mercaptane Natural products SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 4
- INBDPOJZYZJUDA-UHFFFAOYSA-N methanedithiol Chemical compound SCS INBDPOJZYZJUDA-UHFFFAOYSA-N 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 125000003441 thioacyl group Chemical group 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- IPILPUZVTYHGIL-UHFFFAOYSA-M tributyl(methyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](C)(CCCC)CCCC IPILPUZVTYHGIL-UHFFFAOYSA-M 0.000 claims description 3
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 claims description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 claims description 2
- SNNIPOQLGBPXPS-UHFFFAOYSA-M tetraoctylazanium;chloride Chemical compound [Cl-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC SNNIPOQLGBPXPS-UHFFFAOYSA-M 0.000 claims description 2
- UMMDBKGUDMBUSR-UHFFFAOYSA-M tris-decyl(methyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCC[N+](C)(CCCCCCCCCC)CCCCCCCCCC UMMDBKGUDMBUSR-UHFFFAOYSA-M 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims 1
- 230000002349 favourable effect Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 29
- 125000003545 alkoxy group Chemical group 0.000 description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000004663 dialkyl amino group Chemical group 0.000 description 24
- 125000004414 alkyl thio group Chemical group 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 21
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- 125000004423 acyloxy group Chemical group 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 18
- 125000004438 haloalkoxy group Chemical group 0.000 description 18
- 125000001188 haloalkyl group Chemical group 0.000 description 18
- 125000004995 haloalkylthio group Chemical group 0.000 description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000011737 fluorine Substances 0.000 description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- AQBHAXPSOCMLGV-UHFFFAOYSA-N 1-benzyltetrazole Chemical compound C1=NN=NN1CC1=CC=CC=C1 AQBHAXPSOCMLGV-UHFFFAOYSA-N 0.000 description 5
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical class C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 4
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000006138 lithiation reaction Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- LIADNJWRJNOJEO-UHFFFAOYSA-N 1-octyltetrazole Chemical compound CCCCCCCCN1C=NN=N1 LIADNJWRJNOJEO-UHFFFAOYSA-N 0.000 description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical class C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 3
- NYICCYZMQSKXFR-UHFFFAOYSA-N 5-iodo-1-octyltetrazole Chemical compound CCCCCCCCN1N=NN=C1I NYICCYZMQSKXFR-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 2
- YIUFUEBPZBUERK-UHFFFAOYSA-N 1-benzyl-5-iodotetrazole Chemical compound IC1=NN=NN1CC1=CC=CC=C1 YIUFUEBPZBUERK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005190 thiohydroxy group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- UZLRVNYNUJHVFB-UHFFFAOYSA-N (1-benzyltetrazol-5-yl)-cyclohexylmethanol Chemical compound N=1N=NN(CC=2C=CC=CC=2)C=1C(O)C1CCCCC1 UZLRVNYNUJHVFB-UHFFFAOYSA-N 0.000 description 1
- MIBWEPPNBSXNHN-UHFFFAOYSA-N (1-benzyltetrazol-5-yl)-phenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=NN=NN1CC1=CC=CC=C1 MIBWEPPNBSXNHN-UHFFFAOYSA-N 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- ODJQFWLXWRQLSQ-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]tetrazole Chemical class C1=CC(OC)=CC=C1CN1N=NN=C1 ODJQFWLXWRQLSQ-UHFFFAOYSA-N 0.000 description 1
- JEUFVIDEBOFLAA-UHFFFAOYSA-N 1-benzyl-5-bromotetrazole Chemical compound BrC1=NN=NN1CC1=CC=CC=C1 JEUFVIDEBOFLAA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- OEZWQDDZWWFYKO-UHFFFAOYSA-N amino(methyl)carbamic acid Chemical class CN(N)C(O)=O OEZWQDDZWWFYKO-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- VBWIZSYFQSOUFQ-UHFFFAOYSA-N cyclohexanecarbonitrile Chemical compound N#CC1CCCCC1 VBWIZSYFQSOUFQ-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Definitions
- the present invention relates to a novel process for the preparation of substituted azoles, in particular substituted 1H-tetrazoles and substituted 1H-triazoles.
- Azoles in particular the 5-substituted 1H-triazoles and -tetrazoles, are used inter alia as pharmaceutically active substances in medicine or are used, for example, in the protection of plants and technical materials as biocides.
- lithiation is the method of choice for derivatization of the 5-position, for example by halogens, the low temperature, the use of air-sensitive and less-expensive metallating reagents such as n-BuLi and especially the complete instability of the metallated intermediate at temperatures above -78 ° C are very disadvantageous.
- the object of the present invention was thus to provide an improved process for the preparation of substituted azoles.
- the present invention relates to a process for the preparation of substituted azoles of the general formula (I), and / or their salts and / or their acid addition compounds,
- A is N, CH or CR 3 ,
- B is N, CH or CR 4 ,
- R 1 is hydrogen or in each case optionally substituted alkyl, alkenyl, alkynyl or phenyl,
- R 2 is F, Cl, Br, I, OH, SH, CN, SCN, or in each case optionally substituted alkyl, cycloalkyl, phenethyl, benzyl, acyl, thioacyl, hydroxymethylene, or methylene thiol,
- Each R 3 is optionally substituted alkyl, alkenyl, alkynyl, phenyl or phenethyl, and
- R 4 is in each case optionally substituted alkyl, alkenyl, alkynyl, phenyl or phenethyl,
- the process according to the invention preferably serves for the preparation of compounds of the general formula (I) in which
- R 1 is hydrogen or straight-chain or branched C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkyl, each of which is optionally mono- to polysubstituted by identical or different substituents by halogen; nitro; cyano; hydroxy; C r C 6 alkoxy which is optionally substituted from 1 to 9 times, identically or differently, by halogen; C 1 -C 6 -alkylthio which is optionally substituted by 1 to 9 times, the same or different by halogen; amino; Monoalkylamino having straight-chain or branched QC 6 -alkyl radicals; Dialkylamino having the same or different, straight-chain or branched C 1 -C 6 -alkyl radicals; Phenyl which is optionally monosubstituted to polysubstituted by the same or different halogen, nitro, cyano, alkyl, halo
- R 1 is phenyl which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino,
- R 2 is F, Cl, Br, I, OH, SH, CN, SCN, straight-chain or branched C 1 -C 8 -alkyl or Q-cyclo-cycloalkyl,
- phenethyl or benzyl which is in each case optionally mono- to polysubstituted by identical or different substituents by halogen; nitro; cyano; hydroxy; C r C 6 alkoxy which is optionally substituted from 1 to 9 times, identically or differently, by halogen; C 1 -C 6 -alkylthio which is optionally 1 to 9 times, identical or different
- Halogen is substituted; amino; Monoalkylamino having straight-chain or branched C 1 -C 6 -alkyl radicals; Dialkylamino having the same or different, straight-chain or branched C 1 -C 6 -alkyl radicals; Phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino,
- acyl or thioacyl each of which is optionally substituted by hydroxy; thiohydroxy; straight or branched C r -C 8 -alkyl which is optionally substituted 1-fold 9-bis, or equal to different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, Monoalkylamino, dialkylamino substituted; Q-
- C 1 -C 10 cycloalkyl which is optionally substituted by 1 to 9 times, same or different by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino, dialkylamino; Phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy,
- hydroxymethylene or methylenethiol each of which is optionally substituted by straight-chain or branched C r -C 8 -alkyl which is optionally substituted 1-fold to 9 identical or different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy,
- Halogen nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio,
- A is N, CH or CR3,
- R 3 is straight-chain or branched C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl, each of which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy , Alkylthio, alkoxy, amino, and
- B is N, CH or CR4,
- R 4 represents straight-chain or branched CpCg-alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl, which is in each case optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy, alkylthio, Alkoxy, amino,
- R 1 represents hydrogen or straight-chain or branched, which to tetrasubstituted by identical or different substituents in each case optionally monosubstituted by fluorine; Chlorine; Bromine; nitro; cyano; hydroxy; Ci-C 4 alkoxy which optionally 1 to 5-fold, same or different by fluorine, chlorine or
- Bromine is substituted; C 1 -C 4 -alkylthio which is optionally substituted by 1 to 5 times, the same or different, by fluorine, chlorine or bromine; amino; Monoalkylamino having straight-chain or branched C 1 -C 4 -alkyl radicals; Dialkylamino having the same or different, straight-chain or branched C 1 -C 4 -alkyl radicals; Phenyl, which optionally one to four times, identically or differently by fluorine, chlorine. Bromine. nitro,
- Cyano hydroxy, C 1 -C 4 -alkyl.
- Q-Gi-haloalkyl which 1- to 5-fold identical or substituted by fluorine, chlorine or bromine, Ci-C 4 alkoxy, C 1 -C 4 - halogenoalkoxy which is 1- to 5-fold identical or different substituents by fluorine, chlorine or bromine, C 1 -C 4 -AlkVItMo, G-Cd-haloalkylthio which is monosubstituted or disubstituted by one to five times by fluorine, chlorine or bromine, C 1 -Cn-AcVl.
- R 1 is phenyl which is optionally substituted one to four times, identically or differently by fluorine; Chlorine; Bromine; nitro; cyano; hydroxy; C r C 4 alkyl; C 1 -C 4 -haloalkyl which is monosubstituted or disubstituted by fluorine, chlorine or bromine; C 1 -C 4 -alkoxy; C] -C 4 -haloalkoxy which is monosubstituted or disubstituted by fluorine, chlorine or bromine; C 1 -C 4 -alkylthio; QC 4 - Halogenalkylthio which is 1 to 5 times the same or different by fluorine, chlorine or
- Bromine is substituted; Ci-C 4 acyl; QQ acyloxy; C 1 -C 4 alkoxycarbonyl; carboxyl; amino; Monoalkylamino having straight-chain or branched C 1 -C 4 -alkyl radicals, or Dialkylamino having the same or different, straight-chain or branched C 1 -C 4 -alkyl radicals,
- benzyl which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino,
- acyl or thioacyl which is optionally substituted by
- Q-Cg-alkyl which is optionally 1 to 9-fold, identical or different, by halogeno, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino , Dialkylamino is substituted; Q-Cio-cycloalkyl which optionally 1 to 9-fold, the same or different
- hydroxymethylene or methylene thiol which is in each case optionally substituted by straight-chain or quenched Q-Cg-alkyl which is optionally 1 to 9-fold, identical or different, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy,
- Phenyl which is optionally mono- to polysubstituted, identically or differently, by halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, Haloalkylthio, acyl, acyloxy, alkoxycarbonyl, carboxyl, amino, monoalkylamino or dialkylamino,
- A is N, CH or CR3,
- R 3 represents straight-chain or branched C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl, each of which is optionally mono- to polysubstituted by identical or different substituents by halogen, nitro, cyano, hydroxy , Alkylthio, alkoxy, amino
- B is N, CH or CR4,
- R4 represents straight-chain or branched Q-Cg-alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl which is in each case optionally mono- to polysubstituted identically or differently by halogen, nitro, cyano, hydroxyl, Alkylthio, alkoxy, amino,
- R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, Allyl, vinyl, propargyl, wherein said alkyl radicals are each optionally substituted one to four times, identically or differently by fluorine, chlorine, bromine, nitro, cyano, hydroxy, methoxy, ethoxy, n-
- R 1 is phenyl which is optionally monosubstituted to trisubstituted by fluorine, chlorine, bromine, nitro, cyano, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl , tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, methylthio, ethylthio, n-propylthio, isopropylthio, Trifluoromethylthio, formyl, acetyl, acetyloxy, methoxycarbonyl, ethoxycarbonyl, carboxy, amino, methylamines, ethylamino, n-propylamino, isoprop
- R 2 is F, Cl, Br, I, OH, SH, CN, SCN,
- Ci-Ci 0 - alkyl is benzyl, hydroxymethylene or methylene thiol which is optionally substituted by straight-chain or branched Ci-Ci 0 - alkyl which optionally
- Ci-Ci 0-cycloalkyl which is optionally substituted 1-fold to 9 identical or different halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, acyl,
- A is N or CH
- B is N or CH
- inventive method is also used for the preparation of salts and / or acid addition compounds of the compounds of formula (I), such as their hydrohalides, hydrophosphonates or hydrosulfates, for example, the corresponding salts and / or acid addition compounds of the formula (II) can be used.
- Suitable electrophiles for carrying out the process according to the invention are, for example, halogens such as fluorine, chlorine, bromine, iodine, aldehydes, e.g. benzaldehyde,
- Cyclohexane carbaldehyde nitriles such as cyclohexane carbonitrile or amides such as Weinrebamid.
- the electrophiles used are preferably chlorine, bromine, iodine and aldehydes or mixtures thereof.
- the electrophiles are generally used in amounts of 0.5 to 15 equivalents based on the azole (TT). Preference is given to using 1 to 5 equivalents and, in particular 1.1 to 3 equivalents of electrophile based on azole.
- the inventive method is generally conducted at temperatures between 0 0 C and 100 0 C, preferably between 15 0 C and 80 0 C, and particularly Favor performed between 20 0 C and 5O 0 C.
- Suitable solvents are all conventional organic solvents in question, which can not be affected or decomposed by the strongly basic environment such as, for example
- Petroleum ether Petroleum ether, n-octane, n-pentane, n-hexane, cyclohexane, n-pentane, toluene, benzene, THF,
- Phase is formed by the substrate. Preference is given to toluene, n-hexane, cyclohexane,
- Suitable bases for carrying out the process according to the invention are, for example, alkali metal hydroxides, phosphates, alcoholates and carbonates, and mixtures thereof. Particularly suitable are from the series of alkali hydroxides NaOH and KOH and from the series of carbonates Cs 2 CO 3 , CaCO 3 , MgCO 3 . Very particular preference is given to using aqueous solutions of NaOH and / or KOH, preferably 20% to 60% strength aqueous NaOH solution, more preferably aqueous 30% to 55% strength NaOH solution.
- the base will be in excess used to the substrate, preferably 1 to 100 equivalents, particularly preferably 10 to 60 equivalents per equivalent of substrate.
- phase transfer catalysts are 15-crown-5, 18-crown-6, tetrabutylammonium hydrogensulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraoctylammonium bromide, tetraoctylammonium chloride, methyltridecylammonium chloride, methyl trioctylammonium chloride (Aliquat 336) and methyl tributylammonium chloride. Preference is given to methyltrioctylammonium chloride (Aliquat 336) and methyl tributylammonium chloride or mixtures thereof.
- Examples of surface-active additives are molecular sieve, silica gel or alumina powder.
- the phase transfer catalyst can be used in an amount of 0.01 to 5 mol% based on the substrate, preferably 0.3 to 3 mol%.
- the reaction can also be advantageously carried out in an ultrasonic bath.
- the solution or suspension of the educt with the basic solution is advantageously stirred for some time, then the electrophile (possibly dissolved in a suitable solvent) is metered in at a suitable rate and stirred for some time.
- the optimum conditions depend on the substrate and its reactivity and solubility and must be determined, but are usually in the range of several minutes or hours.
- the procedure according to the invention has a number of advantages over previously used methods: it is possible to work in very inexpensive solvents. Depending on the substrate, the reaction does not require cooling or heating. Room temperature can be the most favorable temperature. The reaction is fast. The bases used are very inexpensive and readily available. The reagents used are readily available, such as bromine or iodine.
- Control and optimization of the reaction can be achieved by suitable dosage of the reactants and the choice of solvents.
- the reaction is easily transferable to a large scale.
- the product is produced in high yield and purity in some examples and does not require further purification.
- the following examples according to the invention may serve to illustrate:
- n-octyl-lH-tetrazole 0.50 g of n-octyl-lH-tetrazole are dissolved in 10 ml of THF, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 1.04 g of iodine dissolved in 10 ml of tetrahydrofuran is added dropwise within 15 minutes and stirred for one hour. After completion of the reaction is transferred to a separatory funnel and the aqueous phase washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After cleaning becomes 0.19 g pure product which crystallized after standing some (melting point 40 0 C, yield 22%).
- n-octyl-1H-tetrazole 0.50 g of n-octyl-1H-tetrazole are dissolved in 10 ml of toluene, 10 ml of 50% strength sodium hydroxide solution are added, and the mixture is stirred well. 1.04 g of iodine suspended in 10 ml of toluene is added dropwise within 15 minutes and stirred for one hour. After completion of the reaction is transferred to a separatory funnel and the aqueous phase was washed with ethyl acetate, the collected organic
- n-octyl-1H-tetrazole 0.50 g of n-octyl-1H-tetrazole are dissolved in 10 ml of toluene, 10 ml of 50% strength sodium hydroxide solution and 0.02 ml of aliquat are added, and the mixture is stirred well. 1.04 g of iodine suspended in 10 ml of toluene is added dropwise within 15 minutes and stirred for one hour. After completion of the reaction is transferred to a separatory funnel and the aqueous phase washed with ethyl acetate, the collected organic phases washed with water, treated with brine and dried with sodium sulfate. After purification, 0.30 g of pure product is obtained, which crystallizes after standing for some time (melting point 40 ° C., yield 35%).
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005025992A DE102005025992A1 (de) | 2005-06-07 | 2005-06-07 | Verfahren zur Herstellung von substituierten Azolen |
| PCT/EP2006/005092 WO2006131228A1 (de) | 2005-06-07 | 2006-05-27 | Verfahren zur herstellung von substituierten azolen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1891025A1 true EP1891025A1 (de) | 2008-02-27 |
Family
ID=36869852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP06743081A Withdrawn EP1891025A1 (de) | 2005-06-07 | 2006-05-27 | Verfahren zur herstellung von substituierten azolen |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20090306397A1 (zh) |
| EP (1) | EP1891025A1 (zh) |
| JP (1) | JP2008542408A (zh) |
| KR (1) | KR20080019609A (zh) |
| CN (1) | CN101193873A (zh) |
| DE (1) | DE102005025992A1 (zh) |
| WO (1) | WO2006131228A1 (zh) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102006023242A1 (de) * | 2006-05-18 | 2007-11-22 | Lanxess Deutschland Gmbh | 5-Iodtetrazole zur Verwendung als Antimykotika |
| EP2822931B1 (en) | 2012-03-09 | 2017-05-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
| ES2660249T3 (es) | 2012-12-20 | 2018-03-21 | Inception 2, Inc. | Compuestos de tipo triazolona y sus usos |
| WO2015035059A1 (en) | 2013-09-06 | 2015-03-12 | Inception 2, Inc. | Triazolone compounds and uses thereof |
| EP3185684A1 (en) | 2014-08-29 | 2017-07-05 | E. I. du Pont de Nemours and Company | Herbicidal triazoles |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1695990A1 (de) * | 1967-04-24 | 1971-05-19 | Leuna Werke Veb | Verfahren zur Herstellung von halogensubstituierten 1,2,4-Triazolen |
| EP0117368A1 (en) * | 1982-12-31 | 1984-09-05 | Glaxo Group Limited | Guanidinoazolyl derivatives as histamine H2 antagonists |
-
2005
- 2005-06-07 DE DE102005025992A patent/DE102005025992A1/de not_active Withdrawn
-
2006
- 2006-05-27 US US11/921,252 patent/US20090306397A1/en not_active Abandoned
- 2006-05-27 WO PCT/EP2006/005092 patent/WO2006131228A1/de active Application Filing
- 2006-05-27 KR KR1020077028482A patent/KR20080019609A/ko not_active Application Discontinuation
- 2006-05-27 CN CNA2006800201131A patent/CN101193873A/zh active Pending
- 2006-05-27 EP EP06743081A patent/EP1891025A1/de not_active Withdrawn
- 2006-05-27 JP JP2008515092A patent/JP2008542408A/ja not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| CN101193873A (zh) | 2008-06-04 |
| JP2008542408A (ja) | 2008-11-27 |
| DE102005025992A1 (de) | 2007-01-11 |
| WO2006131228A1 (de) | 2006-12-14 |
| US20090306397A1 (en) | 2009-12-10 |
| KR20080019609A (ko) | 2008-03-04 |
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