JPWO2013129021A1 - Process for producing 5-substituted-2-aryl-2H-tetrazole - Google Patents
Process for producing 5-substituted-2-aryl-2H-tetrazole Download PDFInfo
- Publication number
- JPWO2013129021A1 JPWO2013129021A1 JP2014502083A JP2014502083A JPWO2013129021A1 JP WO2013129021 A1 JPWO2013129021 A1 JP WO2013129021A1 JP 2014502083 A JP2014502083 A JP 2014502083A JP 2014502083 A JP2014502083 A JP 2014502083A JP WO2013129021 A1 JPWO2013129021 A1 JP WO2013129021A1
- Authority
- JP
- Japan
- Prior art keywords
- group
- tetrazole
- mmol
- aryl
- substituted
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 37
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- -1 halide copper complex Chemical class 0.000 claims description 93
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 24
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 125000005110 aryl thio group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 150000001543 aryl boronic acids Chemical class 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 54
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 229910000027 potassium carbonate Inorganic materials 0.000 description 27
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 21
- 239000013078 crystal Substances 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000010949 copper Substances 0.000 description 8
- VVXKYYDFGPZSOZ-UHFFFAOYSA-L chlorocopper;n,n,n',n'-tetramethylethane-1,2-diamine;dihydrate Chemical compound O.O.[Cu]Cl.[Cu]Cl.CN(C)CCN(C)C.CN(C)CCN(C)C VVXKYYDFGPZSOZ-UHFFFAOYSA-L 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 150000003536 tetrazoles Chemical group 0.000 description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- MARUHZGHZWCEQU-UHFFFAOYSA-N 5-phenyl-2h-tetrazole Chemical compound C1=CC=CC=C1C1=NNN=N1 MARUHZGHZWCEQU-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- MWVKLRSIDOXBSE-UHFFFAOYSA-N 5-(1-piperidin-4-ylpyrazol-4-yl)-3-(6-pyrrolidin-1-yl-1,3-benzoxazol-2-yl)pyridin-2-amine Chemical compound NC1=NC=C(C2=CN(N=C2)C2CCNCC2)C=C1C(OC1=C2)=NC1=CC=C2N1CCCC1 MWVKLRSIDOXBSE-UHFFFAOYSA-N 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 2
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- BEXZJJQVPWJPOA-VOTSOKGWSA-N [(e)-hept-2-enyl] 6-methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCCC\C=C\COC(=O)C1=C(C)NC(=O)NC1C1=CC=C([N+]([O-])=O)C=C1 BEXZJJQVPWJPOA-VOTSOKGWSA-N 0.000 description 2
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 150000004699 copper complex Chemical class 0.000 description 2
- 125000005520 diaryliodonium group Chemical group 0.000 description 2
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PLVCYMZAEQRYHJ-UHFFFAOYSA-N (2-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Br PLVCYMZAEQRYHJ-UHFFFAOYSA-N 0.000 description 1
- AFSSVCNPDKKSRR-UHFFFAOYSA-N (3-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Br)=C1 AFSSVCNPDKKSRR-UHFFFAOYSA-N 0.000 description 1
- VUTJHOWRPUPHIG-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1Cl VUTJHOWRPUPHIG-UHFFFAOYSA-N 0.000 description 1
- YTJUYWRCAZWVSX-UHFFFAOYSA-N (3-chloro-4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1Cl YTJUYWRCAZWVSX-UHFFFAOYSA-N 0.000 description 1
- OBQRODBYVNIZJU-UHFFFAOYSA-N (4-acetylphenyl)boronic acid Chemical compound CC(=O)C1=CC=C(B(O)O)C=C1 OBQRODBYVNIZJU-UHFFFAOYSA-N 0.000 description 1
- QBLFZIBJXUQVRF-UHFFFAOYSA-N (4-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Br)C=C1 QBLFZIBJXUQVRF-UHFFFAOYSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 1
- DMJHEIDWSIAXCS-UHFFFAOYSA-N (4-phenylmethoxyphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1OCC1=CC=CC=C1 DMJHEIDWSIAXCS-UHFFFAOYSA-N 0.000 description 1
- XPEIJWZLPWNNOK-UHFFFAOYSA-N (4-phenylphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1C1=CC=CC=C1 XPEIJWZLPWNNOK-UHFFFAOYSA-N 0.000 description 1
- FCERNNLMTCOKHX-UHFFFAOYSA-N 1,5-diphenyltetrazole Chemical compound C1=CC=CC=C1C1=NN=NN1C1=CC=CC=C1 FCERNNLMTCOKHX-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- OJPYZWGULWNRSE-UHFFFAOYSA-N 2,5-diphenyltetrazole Chemical compound C1=CC=CC=C1C1=NN(C=2C=CC=CC=2)N=N1 OJPYZWGULWNRSE-UHFFFAOYSA-N 0.000 description 1
- IIFFFBSAXDNJHX-UHFFFAOYSA-N 2-methyl-n,n-bis(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)CC(C)C IIFFFBSAXDNJHX-UHFFFAOYSA-N 0.000 description 1
- PKZCRWFNSBIBEW-UHFFFAOYSA-N 2-n,2-n,2-trimethylpropane-1,2-diamine Chemical compound CN(C)C(C)(C)CN PKZCRWFNSBIBEW-UHFFFAOYSA-N 0.000 description 1
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 1
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 description 1
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 229940049937 Pgp inhibitor Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012955 diaryliodonium Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DSVGMNRERUUNAT-UHFFFAOYSA-N ethyl 2-phenyltetrazole-5-carboxylate Chemical compound N1=C(C(=O)OCC)N=NN1C1=CC=CC=C1 DSVGMNRERUUNAT-UHFFFAOYSA-N 0.000 description 1
- JBEHAOGLPHSQSL-UHFFFAOYSA-N ethyl 2h-tetrazole-5-carboxylate Chemical compound CCOC(=O)C=1N=NNN=1 JBEHAOGLPHSQSL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000002748 glycoprotein P inhibitor Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JMZFEHDNIAQMNB-UHFFFAOYSA-N m-aminophenylboronic acid Chemical compound NC1=CC=CC(B(O)O)=C1 JMZFEHDNIAQMNB-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 description 1
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003643 water by type Substances 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本発明は、医薬化合物を製造するための中間体として有用な5−置換−2−アリール−2H−テトラゾールの製造法であって、アリール基を2位に選択的に導入する方法に関する。The present invention relates to a method for producing a 5-substituted-2-aryl-2H-tetrazole useful as an intermediate for producing a pharmaceutical compound, in which an aryl group is selectively introduced at the 2-position.
Description
本発明は、医薬化合物を製造するための中間体として有用な5−置換−2−アリール−2H−テトラゾールの新規な製造方法に関するものである。より詳細には、5−置換−1H−テトラゾールの2位へのアリール置換基の選択的な導入方法に関するものである。 The present invention relates to a novel process for producing 5-substituted-2-aryl-2H-tetrazole useful as an intermediate for producing a pharmaceutical compound. More specifically, the present invention relates to a method for selectively introducing an aryl substituent at the 2-position of 5-substituted-1H-tetrazole.
薬理活性を有するテトラゾール化合物では2位にアリール置換基を有するものが数多く知られている。
例えば、日本特許第4303109号(特許文献1)には、代謝共役型グルタミン酸受容体サブタイプ5調節剤である、2位にアリール置換基を有する5−置換−2H−テトラゾールが記載されている。Many tetrazole compounds having pharmacological activity have an aryl substituent at the 2-position.
For example, Japanese Patent No. 4303109 (Patent Document 1) describes 5-substituted-2H-tetrazole having an aryl substituent at the 2-position, which is a metabotropic glutamate receptor subtype 5 modulator.
日本特表2009−536211号(特許文献2)には、代謝調節型グルタミン酸受容体に活性を示す、2位にアリール置換基を有する5−置換−2H−テトラゾールが記載されている。
日本特許第4481992号(特許文献3)には、p−糖蛋白質阻害剤として作用する、2位にアリール置換基を有する5−置換−2H−テトラゾールが記載されている。JP-T-2009-536211 (Patent Document 2) describes 5-substituted-2H-tetrazole having an aryl substituent at the 2-position, which shows activity at a metabotropic glutamate receptor.
Japanese Patent No. 4481992 (Patent Document 3) describes 5-substituted-2H-tetrazole having an aryl substituent at the 2-position, which acts as a p-glycoprotein inhibitor.
日本特許第4493341号(特許文献4)には、代謝型グルタメートサブタイプ5のモジュレータである、2位にアリール置換基を有する5−置換−2H−テトラゾールが記載されている。
国際公開第2010/106106号(特許文献5)には、ニコチン性アセチルコリン受容体のモジュレータである、2位にアリール置換基を有する5−置換−2H−テトラゾールが記載されている。
日本特表2011−500673号(特許文献6)には、代謝調節型グルタミン酸受容体の調節因子としての、2位にアリール置換基を有する5−置換−2H−テトラゾールが記載されている。Japanese Patent No. 4493341 (Patent Document 4) describes a 5-substituted-2H-tetrazole having an aryl substituent at the 2-position, which is a modulator of metabotropic glutamate subtype 5.
WO 2010/106106 (Patent Document 5) describes a 5-substituted-2H-tetrazole having an aryl substituent at the 2-position, which is a modulator of a nicotinic acetylcholine receptor.
Japanese Special Table 2011-500673 (Patent Document 6) describes 5-substituted-2H-tetrazole having an aryl substituent at the 2-position as a regulator of a metabotropic glutamate receptor.
一方、5−置換−1H−テトラゾールの2位にアリール置換基を導入する方法として、次の方法が知られている。
すなわち、Tetrahedron Letters 39 (1998) 2941-2944(非特許文献1)には、Cu(OAc)2の存在下、ArB(OH)2による方法が記載されており、Tetrahedron Letters 40 (1999) 2747-2748(非特許文献2)には、Cu(OAc)2の存在下、Ar3Bi(OAc)2による方法が記載されている。
さらに、Tetrahedron Letters 43 (2002) 6221-6223(非特許文献3)には、パラジウムと銅を触媒として用い、ジアリールヨードニウム塩により5−置換−1H−テトラゾールの2位にアリール置換基を導入する方法が記載されている。On the other hand, the following method is known as a method for introducing an aryl substituent into the 2-position of 5-substituted-1H-tetrazole.
That is, Tetrahedron Letters 39 (1998) 2941-2944 (Non-patent Document 1) describes a method using ArB (OH) 2 in the presence of Cu (OAc) 2 , and Tetrahedron Letters 40 (1999) 2747- 2748 (Non-Patent Document 2) describes a method using Ar 3 Bi (OAc) 2 in the presence of Cu (OAc) 2 .
Furthermore, Tetrahedron Letters 43 (2002) 6221-6223 (Non-patent Document 3) uses palladium and copper as catalysts and introduces an aryl substituent at the 2-position of 5-substituted-1H-tetrazole with a diaryliodonium salt. Is described.
しかしながら、非特許文献1に記載の方法では、Cu(OAc)2が過剰(1.5当量)に使用され、しかも収率が低いという欠点を有している。
非特許文献2に記載の方法では、Cu(OAc)2の使用量は0.2当量と少ないが、アリール置換基導入試薬であるAr3Bi(OAc)2のArが1つしか有効に使用されず、残りの2つのArが無駄になるという欠点を有している。
また、非特許文献3に記載の方法でも、アリール置換基導入試薬であるジアリールヨードニウム塩の入手や調製が難しいため、導入できるアリール置換基の種類が限定される上、Arが1つしか有効に使用されず、残りの1つのArが無駄になるという欠点を有している。However, the method described in Non-Patent Document 1 has the disadvantage that Cu (OAc) 2 is used in excess (1.5 equivalents) and the yield is low.
In the method described in Non-Patent Document 2, the amount of Cu (OAc) 2 used is as low as 0.2 equivalent, but only one Ar of Ar 3 Bi (OAc) 2 that is an aryl substituent introduction reagent is effectively used. The remaining two Ars are wasted.
In addition, even in the method described in Non-Patent Document 3, since it is difficult to obtain and prepare a diaryl iodonium salt that is an aryl substituent introduction reagent, the types of aryl substituents that can be introduced are limited, and only one Ar is effective. It has the disadvantage that it is not used and the remaining one Ar is wasted.
さらに、上記の非特許文献1および2に記載の方法では、出発物質である5−置換−1H−テトラゾールの5位の置換基がフェニル基である例が示されているだけであって、それ以外の置換基を有する化合物については示されていない。
また、非特許文献3に記載の方法でも、Table 2およびその表題「Palladium- and copper-catalyzed selective arylation of 5-aryltetrazoles by diaryliodonium salts」から明らかなように、出発物質である5−置換−1H−テトラゾールの5位の置換基がピリジル基を含むアリールのみである。
したがって、上記の非特許文献1〜3に記載の方法は、いずれも5−置換−1H−テトラゾールの5位の置換基がアリールに限定された方法であり、汎用性に乏しい。Further, in the methods described in Non-Patent Documents 1 and 2 above, only an example in which the substituent at the 5-position of 5-substituted-1H-tetrazole as a starting material is a phenyl group is shown. Compounds having substituents other than are not shown.
Further, in the method described in Non-Patent Document 3, as shown in Table 2 and the title “Palladium- and copper-catalyzed selective arylation of 5-aryltetrazoles by diaryliodonium salts”, the starting material 5-substituted-1H— The substituent at the 5-position of tetrazole is only aryl containing a pyridyl group.
Therefore, all of the methods described in Non-Patent Documents 1 to 3 are methods in which the substituent at the 5-position of 5-substituted-1H-tetrazole is limited to aryl, and is not versatile.
本発明は、医薬化合物を製造するための中間体として有用な5−置換−2−アリール−2H−テトラゾールの新規な製造方法であって、アリール基を2位に選択的に導入する方法を提供するものである。 The present invention provides a novel method for producing a 5-substituted-2-aryl-2H-tetrazole useful as an intermediate for producing a pharmaceutical compound, wherein the aryl group is selectively introduced at the 2-position. To do.
本発明者らは、上記の課題を解決するため、鋭意研究を重ねた結果、一般式(II):
で表される5−置換−1H−テトラゾールを、塩基およびジ−μ−ヒドロキソ−ビス[(N,N,N’,N’−テトラメチルエチレンジアミン)銅(II)]ハライド銅錯体の存在下に、酸化性雰囲気下で、一般式(III):
で表されるアリールボロン酸と反応させることにより、一般式(I):
で表される5−置換−2−アリール−2H−テトラゾールが得られることを見出して、本発明を完成した。In order to solve the above-mentioned problems, the present inventors have conducted intensive studies, and as a result, the general formula (II):
In the presence of a base and a di-μ-hydroxo-bis [(N, N, N ′, N′-tetramethylethylenediamine) copper (II)] halide copper complex. In an oxidizing atmosphere, the general formula (III):
Is reacted with an arylboronic acid represented by the general formula (I):
The present invention was completed by finding that a 5-substituted-2-aryl-2H-tetrazole represented by the following formula was obtained.
本発明による製造方法を反応式で表すと次の通りである。
以下、本発明の製造方法を詳細に説明する。 Hereinafter, the production method of the present invention will be described in detail.
本明細書では、出発物質として用いられるテトラゾール化合物を、次の一般式(II):
本明細書中で用いられる各置換分について以下に説明する。
アルキル基およびアルキルチオ基におけるアルキル部分としては、C1−C6の低級アルキル基およびC7−C20の高級アルキル基が含まれる。
アルコキシ基、ならびにアリールアルコキシ基、フェニルアルコキシ基およびアルコキシカルボニル基におけるアルコキシ部分としては、C1−C6の低級アルコキシ基およびC7−C20の高級アルコキシ基が含まれる。
アルカノイル基には、C1−C6の低級アルカノイル基およびC7−C20の高級アルカノイル基が含まれる。
具体的には、低級アルキル基および低級アルキルチオ基における低級アルキル部分としては、直鎖または分枝鎖状のC1−C6アルキル、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert-ブチル、ペンチル、エチルプロピル、ヘキシルなどが挙げられ、これらの中ではメチルが特に好ましい。Each substitution used in the present specification will be described below.
The alkyl moiety in the alkyl group and the alkylthio group includes a C 1 -C 6 lower alkyl group and a C 7 -C 20 higher alkyl group.
Alkoxy group, and aryl alkoxy group, the alkoxy moiety in the phenylalkoxy group and alkoxycarbonyl group includes a higher alkoxy groups of lower alkoxy groups and C 7 -C 20 of C 1 -C 6.
Alkanoyl groups include C 1 -C 6 lower alkanoyl groups and C 7 -C 20 higher alkanoyl groups.
Specifically, the lower alkyl moiety in the lower alkyl group and the lower alkylthio group includes linear or branched C 1 -C 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. , Pentyl, ethylpropyl, hexyl, etc., among which methyl is particularly preferred.
低級アルコキシ基、ならびにアリール低級アルコキシ基、フェニル低級アルコキシ基および低級アルコキシカルボニル基における低級アルコキシ部分としては、直鎖または分枝鎖状のC1−C6アルコキシ、例えばメトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、tert-ブトキシ、ペンチルオキシ、エチルプロピルオキシ、ヘキシルオキシなどが挙げられ、これらの中ではメトキシおよびエトキシが好ましい。The lower alkoxy group and the lower alkoxy moiety in the aryl lower alkoxy group, phenyl lower alkoxy group and lower alkoxycarbonyl group include linear or branched C 1 -C 6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy , Butoxy, isobutoxy, tert-butoxy, pentyloxy, ethylpropyloxy, hexyloxy and the like, among which methoxy and ethoxy are preferred.
高級アルキル基および高級アルキルチオ基における高級アルキル部分としては、直鎖または分枝鎖状のC7−C20アルキル、例えばヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル、ヘキサデシル、ヘプタデシル、オクタデシル、ノナデシル、エイコシル、メチルヘプチル、メチルオクチル、メチルノニル、メチルデシル、エチルヘプチル、エチルオクチル、エチルノニル、エチルデシルなどが挙げられる。The higher alkyl moiety in the higher alkyl group and higher alkylthio group includes linear or branched C 7 -C 20 alkyl, such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, Examples include heptadecyl, octadecyl, nonadecyl, eicosyl, methylheptyl, methyloctyl, methylnonyl, methyldecyl, ethylheptyl, ethyloctyl, ethylnonyl, ethyldecyl and the like.
高級アルコキシ基、ならびにアリール高級アルコキシ基、フェニル高級アルコキシ基および高級アルコキシカルボニル基における高級アルコキシ部分としては、直鎖または分枝鎖状のC7−C20アルコキシ、例えばヘプチルオキシ、オクチルオキシ、ノニルオキシ、デシルオキシ、ウンデシルオキシ、ドデシルオキシ、トリデシルオキシ、テトラデシルオキシ、ペンタデシルオキシ、ヘキサデシルオキシ、ヘプタデシルオキシ、オクタデシルオキシ、ノナデシルオキシ、エイコシルオキシ、メチルヘプチルオキシ、メチルオクチルオキシ、メチルノニルオキシ、メチルデシルオキシ、エチルヘプチルオキシ、エチルオクチルオキシ、エチルノニルオキシ、エチルデシルオキシなどが挙げられる。The higher alkoxy group and the higher alkoxy moiety in the aryl higher alkoxy group, the phenyl higher alkoxy group and the higher alkoxycarbonyl group include linear or branched C 7 -C 20 alkoxy such as heptyloxy, octyloxy, nonyloxy, Decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, eicosyloxy, methylheptyloxy, methyloctyloxy, methylnonyloxy, Examples thereof include methyldecyloxy, ethylheptyloxy, ethyloctyloxy, ethylnonyloxy, ethyldecyloxy and the like.
アリール基、ならびにアリールオキシ基、アリールチオ基およびアリールアルコキシ基におけるアリール部分としては、例えばフェニル、ナフチル、フェナントレニル、アントラセニルなどが挙げられ、これらの中ではフェニルおよびナフチルが好ましい。
アロイル基としては、ベンゾイル、ナフトイルなどが挙げられる。Examples of the aryl moiety in the aryl group and the aryloxy group, arylthio group, and arylalkoxy group include phenyl, naphthyl, phenanthrenyl, anthracenyl, and the like. Among these, phenyl and naphthyl are preferable.
Examples of aroyl groups include benzoyl and naphthoyl.
ヘテロアリール基としては、窒素、酸素、硫黄から選択されるヘテロ原子を含む芳香族複素環式基(例えば、フリル、チエニル、ピリジルなど)が挙げられ、これらの中では特にピリジルが好ましい。 Examples of the heteroaryl group include aromatic heterocyclic groups containing a hetero atom selected from nitrogen, oxygen, and sulfur (for example, furyl, thienyl, pyridyl, etc.). Among these, pyridyl is particularly preferable.
ハロゲン原子としては、フッ素、塩素、臭素またはヨウ素が挙げられ、これらの中ではフッ素、塩素および臭素が好ましい。
アシル基としては、低級アルカノイル(例えば、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイルなど)および高級アルカノイル(例えば、ラウロイル、ミリストイル、パルミトイル、ステアロイルなど)を含むアルカノイル、低級アルコキシカルボニル(例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、t-ブトキシカルボニルなど)および高級アルコキシカルボニル(例えば、ヘプチルオキシカルボニル、オクチルオキシカルボニル、ノニルオキシカルボニル、デシルオキシカルボニル、ウンデシルオキシカルボニル、ドデシルオキシカルボニル、トリデシルオキシ、テトラデシルオキシ、ペンタデシルオキシ、ヘキサデシルオキシカルボニル、ヘプタデシルオキシカルボニル、オクタデシルオキシカルボニル、ノナデシルオキシカルボニル、エイコシルオキシカルボニル、メチルヘプチルオキシカルボニル、メチルオクチルオキシカルボニル、メチルノニルオキシカルボニル、メチルデシルオキシカルボニル、エチルヘプチルオキシカルボニル、エチルオクチルオキシカルボニル、エチルノニルオキシカルボニル、エチルデシルオキシカルボニルなど)を含むアルコキシカルボニル、アロイル(例えば、ベンゾイル、ナフトイルなど)が挙げられ、これらの中ではアセチル、メトキシカルボニルおよびエトキシカルボニルが好ましい。Examples of the halogen atom include fluorine, chlorine, bromine or iodine. Among these, fluorine, chlorine and bromine are preferable.
Acyl groups include alkanoyl, lower alkoxycarbonyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.) and higher alkanoyl (eg, lauroyl, myristoyl, palmitoyl, stearoyl, etc.). For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.) and higher alkoxycarbonyl (eg, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxy) Carbonyl, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxyca Bonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, eicosyloxycarbonyl, methylheptyloxycarbonyl, methyloctyloxycarbonyl, methylnonyloxycarbonyl, methyldecyloxycarbonyl, ethylheptyloxycarbonyl, ethyloctyloxycarbonyl , Ethylnonyloxycarbonyl, ethyldecyloxycarbonyl and the like), and aroyl (for example, benzoyl, naphthoyl and the like), among which acetyl, methoxycarbonyl and ethoxycarbonyl are preferred.
R1における、置換されていてもよいアルキル基、アリール基、ヘテロアリール基、アルコキシ基、アルキルチオ基、アリールオキシ基もしくはアリールチオ基は、本発明の反応に悪影響を与えない置換分で置換されていてもよい。
そのような置換分としては、例えばハロゲン原子、アルキル、アリール、アシルなどが挙げられる。
R1における、置換されていてもよいアルキル基、アリール基、ヘテロアリール基、アルコキシ基、アルキルチオ基、アリールオキシ基もしくはアリールチオ基の中で、好ましくはアリールで置換されていてもよいアルキル基、ハロゲン原子もしくはアルキルで置換されていてもよいアリール基、およびアルキルで置換されていてもよいヘテロアリール基、より好ましくはフェニルで置換されていてもよいアルキル基、ハロゲン原子もしくはアルキルで置換されていてもよいフェニル基、およびピリジル基である。The optionally substituted alkyl group, aryl group, heteroaryl group, alkoxy group, alkylthio group, aryloxy group or arylthio group in R 1 is substituted with a substituent that does not adversely affect the reaction of the present invention. Also good.
Examples of such a substituent include a halogen atom, alkyl, aryl, acyl and the like.
In R 1, an optionally substituted alkyl group, an aryl group, a heteroaryl group, an alkoxy group, an alkylthio group, in the aryloxy group or arylthio group, preferably an alkyl group which may be substituted by aryl, halogen An aryl group optionally substituted with an atom or alkyl, and a heteroaryl group optionally substituted with alkyl, more preferably an alkyl group optionally substituted with phenyl, a halogen atom or an alkyl substituted Good phenyl and pyridyl groups.
上記の反応が行われる酸化性雰囲気下とは、反応系中に気体の酸素が存在する状態を意味し、大気中、不活性気体と酸素の混合気体中、酸素雰囲気下などが挙げられ、中でも酸素雰囲気下が特に好ましい。
酸素は、本願発明の方法の反応により還元される銅錯体の銅を酸化して、元の銅錯体を再生するために役立つと考えられる。The oxidizing atmosphere in which the above reaction is performed means a state in which gaseous oxygen is present in the reaction system, and includes the air, a mixed gas of inert gas and oxygen, an oxygen atmosphere, and the like. An oxygen atmosphere is particularly preferable.
It is believed that oxygen is useful for regenerating the original copper complex by oxidizing the copper of the copper complex that is reduced by the reaction of the method of the present invention.
塩基としては、例えば、水酸化アルカリ金属塩もしくはアルカリ土類金属塩、炭酸アルカリ金属塩もしくはアルカリ土類金属塩、酢酸アルカリ金属塩もしくはアルカリ土類金属塩、リン酸アルカリ金属塩もしくはアルカリ土類金属塩などの無機塩基、およびアルカリ金属アルコキシドもしくはアルカリ土類金属アルコキシドを含む金属アルコキシド、N,N-ジイソプロピルエチルアミン、トリエチルアミン、トリプロピルアミン、トリイソプロピルアミン、トリブチルアミン、トリイソブチルアミン、トリペンチルアミン、トリヘキシルアミンを含むトリ(低級アルキル)アミン、ピリジン、ルチジン、ジメチルアミノピリジン、ジアザビシクロウンデセンなどの有機塩基が挙げられ、それらの中でも無水の炭酸アルカリ金属塩が特に好ましい。
上記の塩基を構成するアルカリ金属としては、ナトリウム、カリウムまたはセシウムなどが挙げられ、アルカリ土類金属としては、カルシウム、マグネシウムなどが挙げられる。Examples of the base include alkali metal hydroxide or alkaline earth metal salt, alkali metal carbonate or alkaline earth metal salt, alkali metal acetate or alkaline earth metal salt, alkali metal phosphate or alkaline earth metal phosphate Inorganic bases such as salts, and metal alkoxides including alkali metal alkoxides or alkaline earth metal alkoxides, N, N-diisopropylethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, tripentylamine, Organic bases such as tri (lower alkyl) amines including hexylamine, pyridine, lutidine, dimethylaminopyridine, diazabicycloundecene and the like, and among them, anhydrous alkali metal carbonates are particularly preferable.
Examples of the alkali metal that constitutes the base include sodium, potassium, and cesium, and examples of the alkaline earth metal include calcium and magnesium.
ジ−μ−ヒドロキソ−ビス[(N,N,N’,N’−テトラメチルエチレンジアミン)銅(II)]ハライドとしては、ジ−μ−ヒドロキソ−ビス[(N,N,N’,N’−テトラメチルエチレンジアミン)銅(II)]クロリド([Cu(OH)TMEDA]2Cl2)が好ましい。
この化合物の使用量は触媒量でよく、その量は具体的には、出発物質のテトラゾールに対する当量よりも少ない量、好ましくは出発物質のテトラゾールに対して10〜20モル%、より好ましくは11〜13モル%であり、特に好ましくは12モル%である。Di-μ-hydroxo-bis [(N, N, N ′, N′-tetramethylethylenediamine) copper (II)] halide includes di-μ-hydroxo-bis [(N, N, N ′, N ′. - tetramethylethylenediamine) copper (II)] chloride ([Cu (OH) TMEDA] 2 Cl 2) is preferred.
The amount of the compound used may be a catalytic amount, and specifically, the amount is less than the equivalent amount of the starting material to tetrazole, preferably 10 to 20 mol%, more preferably 11 to 12%, based on the starting material tetrazole. 13 mol%, particularly preferably 12 mol%.
上記の反応で用いられる塩基の量は、出発物質のテトラゾールに対して1〜1.5当量が好ましく、より好ましくは出発物質のテトラゾールに対して1〜1.3当量、特に好ましくは1.1当量である。
反応溶媒は、反応に悪影響を及ぼさない有機溶媒であれば特に限定されず、中でも塩化メチレンが特に好ましい。
反応温度は特に限定されず、通常、室温または加熱下で反応が行われる。
なお、上記の反応は、添加剤として例えば塩化リチウムのような無機塩を加えて行ってもよい。The amount of the base used in the above reaction is preferably 1 to 1.5 equivalents relative to the starting tetrazole, more preferably 1 to 1.3 equivalents relative to the starting tetrazole, particularly preferably 1.1. Is equivalent.
The reaction solvent is not particularly limited as long as it is an organic solvent that does not adversely affect the reaction, and methylene chloride is particularly preferable.
The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature or under heating.
The above reaction may be performed by adding an inorganic salt such as lithium chloride as an additive.
上記の反応により生成する5−置換−2−アリール−2H−テトラゾールは、溶媒抽出、粉末化、結晶化、再結晶、カラムクロマトグラフィー、再沈殿などの慣用の分離・精製手段により、反応混合物から単離され得る。 The 5-substituted-2-aryl-2H-tetrazole produced by the above reaction is separated from the reaction mixture by conventional separation / purification means such as solvent extraction, pulverization, crystallization, recrystallization, column chromatography, and reprecipitation. Can be isolated.
本願発明の方法によれば、5位の置換基がアリールに限定されない5−置換−1H−テトラゾールにおいて、テトラゾールの1位がAr(ここで、Arは前記で定義されたとおりである)で置換された5−置換−1−Ar−1H−テトラゾールを生じないか、またはほとんど生じることなく、2位がAr(ここで、Arは前記で定義されたとおりである)で置換された5−置換−2−Ar−2H−テトラゾールを選択的に得ることができる。 According to the method of the present invention, in the 5-substituted-1H-tetrazole in which the substituent at the 5-position is not limited to aryl, the 1-position of the tetrazole is substituted with Ar (wherein Ar is as defined above) 5-substituted in which the 2-position is substituted with Ar (where Ar is as defined above) with little or no resulting 5-substituted-1-Ar-1H-tetrazole -2-Ar-2H-tetrazole can be selectively obtained.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
以下の実施例において、
1H NMRは、JEOL(日本電子)JNM-AL400を用いた。
13C NMRは、JEOL(日本電子)JNM-AL400を用いた。
高分解能MASS(HRMS)は、Waters LCT Premier XE(ESI法)を用いて測定した。
また、反応で得られた化合物が1位置換体であるか2位置換体であるかは、導入したアリール置換基のオルト位の1H NMRのケミカルシフト、およびテトラゾールの13C NMRケミカルシフトを公知化合物の1位置換体および2位置換体のそれらと比較することにより決定した。EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
In the following examples:
For 1 H NMR, JEOL (JEOL) JNM-AL400 was used.
For 13 C NMR, JEOL (JEOL) JNM-AL400 was used.
High resolution MASS (HRMS) was measured using Waters LCT Premier XE (ESI method).
Whether the compound obtained by the reaction is a 1-position substituent or a 2-position substituent is determined based on the 1 H NMR chemical shift of the ortho position of the introduced aryl substituent and the 13 C NMR chemical shift of tetrazole. By comparing with those of the 1- and 2-position substitutes.
実施例1
フェニルボロン酸を用いた5-置換-1H-テトラゾールの2,5-ジ置換テトラゾールの一般的合成手順
室温下、5-置換-1H-テトラゾールの塩化メチレン溶液 (0.1-0.2 mol/L)に無水炭酸カリウム (110 mol%)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (12 mol%)、フェニルボロン酸 (160-300 mol%)を加え、系内を酸素置換した。酸素雰囲気下、室温で16-17時間撹拌後、10 %アンモニア水溶液を加え、塩化メチレンで抽出し、10 %塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をカラムクロマトグラフィー(シリカゲル60N(球状,中性)、n-ヘキサン/塩化メチレン)で精製して目的の化合物を得た。
目的の化合物を得た後、極性溶媒で溶出したカラムクロマトグラフィー内の残渣を高分解能Massで測定し、5-置換-1-フェニル-1H-テトラゾールが生成していないか、またはほとんど生成していないことを確認した。Example 1
General procedure for the synthesis of 2,5-disubstituted tetrazole of 5-substituted-1H-tetrazole using phenylboronic acid anhydrous at room temperature in methylene chloride solution of 5-substituted-1H-tetrazole (0.1-0.2 mol / L) Potassium carbonate (110 mol%), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] chloride (12 mol%), phenylboronic acid (160-300 mol%) was added, and the inside of the system was replaced with oxygen. After stirring at room temperature for 16-17 hours in an oxygen atmosphere, 10% aqueous ammonia solution was added, extracted with methylene chloride, washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 60N (spherical, neutral), n-hexane / methylene chloride) to obtain the desired compound.
After obtaining the desired compound, the residue in column chromatography eluted with a polar solvent was measured with high resolution Mass, and 5-substituted-1-phenyl-1H-tetrazole was not produced or almost not produced. Confirmed that there is no.
上記の手順にしたがって、以下の化合物1a〜8を得た。
(1)化合物1a:2,5-ジフェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物1a (180.4 mg, 81 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.28-8.19 (4H, m), 7.61-7.49 (6H, m);
13C NMR (100 MHz, CDCl3) δ: 165.2, 137.0, 130.6, 129.7, 129.6, 129.0, 127.2, 127.1, 119.9;
HRMS (ESI) C13H11N4 [M+H]+ に対する計算値223.0984, 実測値223.0984The following compounds 1a-8 were obtained according to the above procedure.
(1) Compound 1a: 2,5-diphenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] Chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and phenylboronic acid (195.1 mg, 1.60 mmol) gave compound 1a (180.4 mg, 81%).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.28-8.19 (4H, m), 7.61-7.49 (6H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.2, 137.0, 130.6, 129.7, 129.6, 129.0, 127.2, 127.1, 119.9;
HRMS (ESI) Calculated for C 13 H 11 N 4 [M + H] + 223.0984, found 223.0984
(2)化合物2:5-(4-メチルフェニル)-2-フェニル-2H-テトラゾール
5-(4-メチルフェニル)-1H-テトラゾール (160.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物2 (187.6 mg, 79 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.21-8.13 (4H, m), 7.60-7.47 (3H, m), 7.33 (2H, d, J = 7.6 Hz), 2.44 (3H, s);
13C NMR (100 MHz, CDCl3) δ: 165.3, 140.8, 137.0, 129.7, 129.5, 127.0, 124.4, 119.9, 21.5;
HRMS (ESI) C14H13N4 [M+H]+ に対する計算値237.1140, 実測値237.1134(2) Compound 2: 5- (4-methylphenyl) -2-phenyl-2H-tetrazole
5- (4-Methylphenyl) -1H-tetrazole (160.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'- Compound 2 (187.6 mg, 79%) was obtained from tetramethylethylenediamine) copper (II)] chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.21-8.13 (4H, m), 7.60-7.47 (3H, m), 7.33 (2H, d, J = 7.6 Hz), 2.44 (3H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.3, 140.8, 137.0, 129.7, 129.5, 127.0, 124.4, 119.9, 21.5;
HRMS (ESI) Calculated for C 14 H 13 N 4 [M + H] + 237.1140, found 237.1134
(3)化合物3:5-(4-ブロモフェニル)-2-フェニル-2H-テトラゾール
5-(4-ブロモフェニル)-1H-テトラゾール (225.1 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物3 (228.2 mg, 75 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.21-8.12 (4H, m), 7.68-7.49 (5H, m);
13C NMR (100 MHz, CDCl3) δ: 164.4, 136.8, 132.2, 129.8, 129.7, 128.6, 126.1, 125.0, 119.9;
HRMS (ESI) C13H10BrN4 [M+H]+ に対する計算値301.0089, 実測値301.0085(3) Compound 3: 5- (4-Bromophenyl) -2-phenyl-2H-tetrazole
5- (4-Bromophenyl) -1H-tetrazole (225.1 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'- Compound 3 (228.2 mg, 75%) was obtained from tetramethylethylenediamine) copper (II)] chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.21-8.12 (4H, m), 7.68-7.49 (5H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 164.4, 136.8, 132.2, 129.8, 129.7, 128.6, 126.1, 125.0, 119.9;
Calculated for HRMS (ESI) C 13 H 10 BrN 4 [M + H] + 301.0089, found 301.0085
(4)化合物4:5-ベンジル-2-フェニル-2H-テトラゾール
5-ベンジル-1H-テトラゾール (160.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物4 (181.2 mg, 76 %)を得た。
無色油状物;
1H NMR (400 MHz, CDCl3) δ: 8.11-8.08 (2H, m), 7.55-7.23 (8H, m), 4.34 (2H, s); 13C NMR (100 MHz, CDCl3) δ: 165.8, 136.9, 136.6, 129.6, 129.5, 128.9, 128.7, 127.0, 119.9, 31.9;
HRMS (ESI) C14H13N4 [M+H]+ に対する計算値237.1140, 実測値237.1135(4) Compound 4: 5-benzyl-2-phenyl-2H-tetrazole
5-Benzyl-1H-tetrazole (160.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (4) Compound 4 (181.2 mg, 76%) was obtained from (II)] chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol).
Colorless oil;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.11-8.08 (2H, m), 7.55-7.23 (8H, m), 4.34 (2H, s); 13 C NMR (100 MHz, CDCl 3 ) δ: 165.8 , 136.9, 136.6, 129.6, 129.5, 128.9, 128.7, 127.0, 119.9, 31.9;
HRMS (ESI) Calculated for C 14 H 13 N 4 [M + H] + 237.1140, found 237.1135
(5)化合物5:4-(2-フェニル-2H-テトラゾール-5-イル)-ピリジン
5-(4-ピリジル)-1H-テトラゾール (147.1 mg, 1.00 mmol),無水炭酸カリウム (152.0 mg, 1.10 mmol),ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物5 (69.9 mg, 31 %)を得た。
淡黄色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.82 (2H, dd, J = 4.4, 1.6 Hz), 8.22-8.19 (2H, m), 8.13 (2H, dd, J = 4.4, 1.6 Hz), 7.63-7.53 (3H, m);
13C NMR (100 MHz, CDCl3) δ: 163.3, 150.8, 136.7, 134.5, 130.1, 129.8, 120.9, 120.0;
HRMS (ESI) C12H10N5 [M+H]+ に対する計算値224.0936, 実測値224.0925(5) Compound 5: 4- (2-Phenyl-2H-tetrazol-5-yl) -pyridine
5- (4-pyridyl) -1H-tetrazole (147.1 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetra Compound 5 (69.9 mg, 31%) was obtained from methylethylenediamine) copper (II)] chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol).
Pale yellow crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.82 (2H, dd, J = 4.4, 1.6 Hz), 8.22-8.19 (2H, m), 8.13 (2H, dd, J = 4.4, 1.6 Hz), 7.63 -7.53 (3H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 163.3, 150.8, 136.7, 134.5, 130.1, 129.8, 120.9, 120.0;
HRMS (ESI) calculated for C 12 H 10 N 5 [M + H] + 224.0936, found 224.0925
(6)化合物6:5-メチル-2-フェニル-2H-テトラゾール
5-メチル-1H-テトラゾール (84.1 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物6 (108.8 mg, 67 %)を得た。
無色油状物;
1H NMR (400 MHz, CDCl3) δ: 8.11-8.08 (2H, m), 7.57-7.45 (3H, m), 2.64 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 163.2, 136.9, 129.6, 129.5, 119.7, 11.0;
HRMS (ESI) C8H9N4 [M+H]+ に対する計算値161.0827, 実測値161.0825(6) Compound 6: 5-methyl-2-phenyl-2H-tetrazole
5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper Compound 6 (108.8 mg, 67%) was obtained from (II)] chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol).
Colorless oil;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.11-8.08 (2H, m), 7.57-7.45 (3H, m), 2.64 (3H, s); 13 C NMR (100 MHz, CDCl 3 ) δ: 163.2 , 136.9, 129.6, 129.5, 119.7, 11.0;
HRMS (ESI) Calculated for C 8 H 9 N 4 [M + H] + 161.0827, found 161.0825
(7)化合物7:5-メチルチオ-2-フェニル-2H-テトラゾール
5-(メチルチオ)-1H-テトラゾール (116.1 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物7 (120.5 mg, 62 %)を得た。
無色油状物;
1H NMR (400 MHz, CDCl3) δ: 8.10-8.07 (2H, m), 7.57-7.46 (3H, m), 2.76 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 165.7, 136.7, 129.7, 119.6, 14.5;
HRMS (ESI) C8H9N4S [M+H]+ に対する計算値193.0548, 実測値193.0546(7) Compound 7: 5-methylthio-2-phenyl-2H-tetrazole
5- (Methylthio) -1H-tetrazole (116.1 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine ) Copper (II)] chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol) gave compound 7 (120.5 mg, 62%).
Colorless oil;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.10-8.07 (2H, m), 7.57-7.46 (3H, m), 2.76 (3H, s); 13 C NMR (100 MHz, CDCl 3 ) δ: 165.7 , 136.7, 129.7, 119.6, 14.5;
HRMS (ESI) Calculated for C 8 H 9 N 4 S [M + H] + 193.0548, Found 193.0546
(8)化合物8:2-フェニル-2H-テトラゾール-5-カルボン酸エチルエステル
1H-テトラゾール-5-カルボン酸エチルエステル (1.00 g, 7.04 mmol)、無水炭酸カリウム (1.07 g, 7.74 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (0.39 g, 12 mol%)、無水塩化リチウム (0.15 g, 3.52 mmol)とフェニルボロン酸 (2.58 g, 21.12 mmol)から、化合物8 (0.82 g, 53 %)を得た。
黄色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.22-8.20 (2H, m), 7.62-7.53 (3H, m), 4.59 (2H, q, J = 7.2 Hz), 1.50 (3H, t, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3) δ: 157.8, 136.4, 130.7, 129.9, 120.4, 62.8, 14.2;
HRMS (ESI) C10H11N4O2 [M+H]+ に対する計算値219.0882, 実測値219.0886(8) Compound 8: 2-phenyl-2H-tetrazole-5-carboxylic acid ethyl ester
1H-tetrazole-5-carboxylic acid ethyl ester (1.00 g, 7.04 mmol), anhydrous potassium carbonate (1.07 g, 7.74 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethyl (Ethylenediamine) copper (II)] chloride (0.39 g, 12 mol%), anhydrous lithium chloride (0.15 g, 3.52 mmol) and phenylboronic acid (2.58 g, 21.12 mmol) to give compound 8 (0.82 g, 53%) Obtained.
Yellow crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.22-8.20 (2H, m), 7.62-7.53 (3H, m), 4.59 (2H, q, J = 7.2 Hz), 1.50 (3H, t, J = 7.2 Hz);
13 C NMR (100 MHz, CDCl 3 ) δ: 157.8, 136.4, 130.7, 129.9, 120.4, 62.8, 14.2;
HRMS (ESI) Calculated for C 10 H 11 N 4 O 2 [M + H] + 219.0882, measured 219.0886
(9)化合物9:5-ブロモ-2-フェニル-2H-テトラゾール
5-ブロモ-1H-テトラゾール (149.0 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]
クロリド (55.7 mg, 12 mol%)とフェニルボロン酸 (195.1 mg, 1.60 mmol)から、化合物9 (118.6 mg, 52 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.12-8.08 (2H, m), 7.60-7.51 (3H, m);
13C NMR (100 MHz, CDCl3) δ: 143.3, 136.4, 130.4, 129.8, 119.7;
HRMS (ESI) C7H6BrN4 [M+H]+ に対する計算値224.9776, 実測値224.9774(9) Compound 9: 5-bromo-2-phenyl-2H-tetrazole
5-Bromo-1H-tetrazole (149.0 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)]
Compound 9 (118.6 mg, 52%) was obtained from chloride (55.7 mg, 12 mol%) and phenylboronic acid (195.1 mg, 1.60 mmol).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.12-8.08 (2H, m), 7.60-7.51 (3H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 143.3, 136.4, 130.4, 129.8, 119.7;
HRMS (ESI) Calculated for C 7 H 6 BrN 4 [M + H] + 224.9776, found 224.9774
上記の結果をまとめたものを、以下の表1に示す。
実施例2
アリールボロン酸を用いた5-フェニル-1H-テトラゾールの2,5-ジ置換テトラゾールの一般的合成手順
室温下、5-フェニル-1H-テトラゾールの塩化メチレン溶液 (0.1-0.2 mol/L)に無水炭酸カリウム (110 mol%)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (12 mol%),無水塩化リチウム (50 mol%)、アリールボロン酸 (160 mol%)を加え、系内を酸素置換した。酸素雰囲気下、室温で16時間撹拌後、10 %アンモニア水溶液を加え、塩化メチレンで抽出し、10 %塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をカラムクロマトグラフィー(シリカゲル60N(球状,中性) 、n-ヘキサン/塩化メチレン)で精製した。
目的の化合物を得た後、極性溶媒で溶出したカラムクロマトグラフィー内の残渣を高分解能Massで測定し、5-フェニル-1-アリール-1H-テトラゾールが生成していないか、またはほとんど生成していないことを確認した。Example 2
General procedure for the synthesis of 2,5-disubstituted tetrazole of 5-phenyl-1H-tetrazole using arylboronic acid Anhydrous to methylene chloride solution of 5-phenyl-1H-tetrazole (0.1-0.2 mol / L) at room temperature Potassium carbonate (110 mol%), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] chloride (12 mol%), anhydrous lithium chloride (50 mol% ) And aryl boronic acid (160 mol%) were added, and the inside of the system was replaced with oxygen. After stirring at room temperature for 16 hours under an oxygen atmosphere, 10% aqueous ammonia solution was added, extracted with methylene chloride, washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 60N (spherical, neutral), n-hexane / methylene chloride).
After obtaining the desired compound, the residue in the column chromatography eluted with a polar solvent was measured with high resolution Mass, and 5-phenyl-1-aryl-1H-tetrazole was not produced or almost not produced. Confirmed that there is no.
上記の手順にしたがって、以下の化合物1b〜1pを得た。
(1)化合物1b:2-(4-メチルフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%),無水塩化リチウム (21.2 mg, 0.50 mmol)とp-メチルフェニルボロン酸 (217.5 mg, 1.60 mmol)から、化合物1b (187.0 mg, 79 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.24 (2H, m), 8.09-8.06 (2H, m), 7.59-7.47 (3H, m), 7.36 (2H, d, J = 8.4 Hz), 2.45 (3H, s);
13C NMR (100 MHz, CDCl3) δ: 165.1, 139.9, 134.8, 130.5, 130.2, 128.9, 127.3, 127.0, 119.8, 21.2;
HRMS (ESI) C14H13N4 [M+H]+ に対する計算値237.1140, 実測値237.1143According to the above procedure, the following compounds 1b to 1p were obtained.
(1) Compound 1b: 2- (4-methylphenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p-methylphenylboronic acid (217.5 mg, 1.60 mmol), compound 1b (187.0 mg, 79%) Obtained.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.24 (2H, m), 8.09-8.06 (2H, m), 7.59-7.47 (3H, m), 7.36 (2H, d, J = 8.4 Hz) , 2.45 (3H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.1, 139.9, 134.8, 130.5, 130.2, 128.9, 127.3, 127.0, 119.8, 21.2;
HRMS (ESI) Calculated for C 14 H 13 N 4 [M + H] + 237.1140, found 237.1143
(2)化合物1c:2-(4-メトキシフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とp-メトキシフェニルボロン酸 (243.1 mg, 1.60 mmol)から、化合物1c (180.6 mg, 71 %)を得た。
白色結晶; 1H NMR (400 MHz, CDCl3) δ: 8.26-8.23 (2H, m), 8.13-8.09 (2H, m), 7.55-7.47 (3H, m), 7.08-7.04 (2H, m), 3.90 (3H, s);
13C NMR (100 MHz, CDCl3) δ: 165.0, 160.5, 130.5, 130.4, 128.9, 127.3, 127.0, 121.4, 114.7, 55.7;
HRMS (ESI) C14H13N4O [M+H]+ に対する計算値253.1089, 実測値253.1083(2) Compound 1c: 2- (4-methoxyphenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p-methoxyphenylboronic acid (243.1 mg, 1.60 mmol), compound 1c (180.6 mg, 71%) Obtained.
White crystal; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.23 (2H, m), 8.13-8.09 (2H, m), 7.55-7.47 (3H, m), 7.08-7.04 (2H, m) , 3.90 (3H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.0, 160.5, 130.5, 130.4, 128.9, 127.3, 127.0, 121.4, 114.7, 55.7;
Calculated for HRMS (ESI) C 14 H 13 N 4 O [M + H] + 253.1089, found 253.1108
(3)化合物1d:2-(4-ベンジルオキシフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)と4-ベンジルオキシフェニルボロン酸 (364.9 mg, 1.60 mmol)から、化合物1d (258.3 mg, 78 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.25-8.23 (2H, m), 8.13-8.09 (2H, m), 7.55-7.34 (8H, m), 7.16-7.12 (2H, m), 5.16 (2H, s);
13C NMR (100 MHz, CDCl3) δ: 165.0, 159.7, 136.3, 130.7, 130.4, 128.9, 128.7, 128.3, 127.5, 127.3, 127.0, 121.4, 115.7, 70.4;
HRMS (ESI) C20H17N4O [M+H]+ に対する計算値329.1402, 実測値329.1394(3) Compound 1d: 2- (4-benzyloxyphenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and 4-benzyloxyphenylboronic acid (364.9 mg, 1.60 mmol), compound 1d (258.3 mg, 78%) Got.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.25-8.23 (2H, m), 8.13-8.09 (2H, m), 7.55-7.34 (8H, m), 7.16-7.12 (2H, m), 5.16 ( 2H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.0, 159.7, 136.3, 130.7, 130.4, 128.9, 128.7, 128.3, 127.5, 127.3, 127.0, 121.4, 115.7, 70.4;
Calculated value for HRMS (ESI) C 20 H 17 N 4 O [M + H] + 329.1402, measured value 329.1394
(4)化合物1e:2-(4-フルオロフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とp-フルオロフェニルボロン酸 (223.9 mg, 1.60 mmol)から、化合物1e (194.0 mg, 80 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.17 (4H, m), 7.56-7.48 (3H, m), 7.30-7.24 (2H, m);
13C NMR (100 MHz, CDCl3) δ: 165.4, 164.3, 161.8, 133.2, 133.2, 130.7, 129.0, 127.1, 121.9, 121.8, 116.8, 116.6;
HRMS (ESI) C13H10FN4 [M+H]+ に対する計算値241.0889, 実測値241.0892(4) Compound 1e: 2- (4-fluorophenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p-fluorophenylboronic acid (223.9 mg, 1.60 mmol), compound 1e (194.0 mg, 80%) Obtained.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.17 (4H, m), 7.56-7.48 (3H, m), 7.30-7.24 (2H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.4, 164.3, 161.8, 133.2, 133.2, 130.7, 129.0, 127.1, 121.9, 121.8, 116.8, 116.6;
HRMS (ESI) Calculated for C 13 H 10 FN 4 [M + H] + 241.0889, found 241.0892
(5)化合物1f:2-(4-クロロフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とp-クロロフェニルボロン酸 (250.2 mg, 1.60 mmol)から、化合物1f (202.8 mg, 79 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.23 (2H, m), 8.18-8.14 (2H, m), 7.57-7.49 (5H, m);
13C NMR (100 MHz, CDCl3) δ: 165.4, 135.5, 135.4, 130.7, 129.9, 129.0, 127.1, 126.9, 121.1;
HRMS (ESI) C13H10ClN4 [M+H]+ に対する計算値257.0594, 実測値257.0588(5) Compound 1f: 2- (4-chlorophenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] Chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p-chlorophenylboronic acid (250.2 mg, 1.60 mmol) gave compound 1f (202.8 mg, 79%) It was.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.23 (2H, m), 8.18-8.14 (2H, m), 7.57-7.49 (5H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.4, 135.5, 135.4, 130.7, 129.9, 129.0, 127.1, 126.9, 121.1;
HRMS (ESI) Calculated for C 13 H 10 ClN 4 [M + H] + 257.0594, Found 257.0588
(6)化合物1g:2-(4-ブロモフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とp-ブロモフェニルボロン酸 (321.3 mg, 1.60 mmol)から、化合物1g (242.3 mg, 80 %)を得た。
淡黄色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.23 (2H, m), 8.12-8.08 (2H, m), 7.73-7.70 (2H, m), 7.56-7.49 (3H, m);
13C NMR (100 MHz, CDCl3) δ: 165.4, 135.9, 132.9, 130.7, 129.0, 127.1, 126.9, 123.5, 121.3;
HRMS (ESI) C13H10BrN4 [M+H]+ に対する計算値301.0089, 実測値301.0086(6) Compound 1g: 2- (4-bromophenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p-bromophenylboronic acid (321.3 mg, 1.60 mmol), compound 1g (242.3 mg, 80%) Obtained.
Pale yellow crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.23 (2H, m), 8.12-8.08 (2H, m), 7.73-7.70 (2H, m), 7.56-7.49 (3H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.4, 135.9, 132.9, 130.7, 129.0, 127.1, 126.9, 123.5, 121.3;
HRMS (ESI) calculated for C 13 H 10 BrN 4 [M + H] + 301.0089, found 301.0086
(7)化合物1h:2-(3-ブロモフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とm-ブロモフェニルボロン酸 (321.3 mg, 1.60 mmol)から、化合物1h (220.9 mg, 73 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.40 (1H, t, J = 2.0 Hz), 8.27-8.24 (2H, m), 8.18 (1H, ddd, J = 8.4, 2.0, 0.8 Hz), 7.64 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.56-7.49 (3H, m), 7.46 (1H, t, J = 8.0 Hz);
13C NMR (100 MHz, CDCl3) δ: 165.5, 137.7, 132.6, 131.0, 130.8, 129.0, 127.1, 126.9, 123.3, 123.0, 118.4;
HRMS (ESI) C13H10BrN4 [M+H]+ に対する計算値301.0089, 実測値301.0081(7) Compound 1h: 2- (3-bromophenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and m-bromophenylboronic acid (321.3 mg, 1.60 mmol), compound 1h (220.9 mg, 73%) Obtained.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.40 (1H, t, J = 2.0 Hz), 8.27-8.24 (2H, m), 8.18 (1H, ddd, J = 8.4, 2.0, 0.8 Hz), 7.64 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.56-7.49 (3H, m), 7.46 (1H, t, J = 8.0 Hz);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.5, 137.7, 132.6, 131.0, 130.8, 129.0, 127.1, 126.9, 123.3, 123.0, 118.4;
Calculated for HRMS (ESI) C 13 H 10 BrN 4 [M + H] + 301.0089, found 301.0081
(8)化合物1i:2-(2-ブロモフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とo-ブロモフェニルボロン酸 (321.3 mg, 1.60 mmol)から、化合物1i (49.0 mg, 16 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.28-8.25 (2H, m), 7.83 (1H, dd, J = 8.0, 1.2 Hz), 7.65 (1H, dd, J = 7.6, 1.6 Hz), 7.57-7.45 (5H, m);
13C NMR (100 MHz, CDCl3) δ: 165.3, 136.8, 134.3, 132.0, 130.7, 129.0, 128.3, 128.0, 127.1, 127.0, 119.0;
HRMS (ESI) C13H10BrN4 [M+H]+ に対する計算値301.0089, 実測値301.0085(8) Compound 1i: 2- (2-bromophenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and o-bromophenylboronic acid (321.3 mg, 1.60 mmol), compound 1i (49.0 mg, 16%) Obtained.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.28-8.25 (2H, m), 7.83 (1H, dd, J = 8.0, 1.2 Hz), 7.65 (1H, dd, J = 7.6, 1.6 Hz), 7.57 -7.45 (5H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.3, 136.8, 134.3, 132.0, 130.7, 129.0, 128.3, 128.0, 127.1, 127.0, 119.0;
Calculated for HRMS (ESI) C 13 H 10 BrN 4 [M + H] + 301.0089, found 301.0085
(9)化合物1j:2-ビフェニル-4-イル-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)と4-ビフェニルボロン酸 (316.8 mg, 1.60 mmol)から、化合物1j (232.5 mg, 77 %)を得た。
淡黄色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.29-8.26 (4H, m), 7.81-7.78 (2H, m), 7.67-7.64 (2H, m), 7.57-7.39 (6H, m);
13C NMR (100 MHz, CDCl3) δ: 165.3, 142.6, 139.6, 136.0, 130.6, 129.0, 129.0, 128.3, 128.1, 127.2, 127.2, 127.1, 120.2;
HRMS (ESI) C19H15N4 [M+H]+ に対する計算値299.1297, 実測値299.1294(9) Compound 1j: 2-biphenyl-4-yl-5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] Chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and 4-biphenylboronic acid (316.8 mg, 1.60 mmol) gave compound 1j (232.5 mg, 77%). It was.
Pale yellow crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.29-8.26 (4H, m), 7.81-7.78 (2H, m), 7.67-7.64 (2H, m), 7.57-7.39 (6H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.3, 142.6, 139.6, 136.0, 130.6, 129.0, 129.0, 128.3, 128.1, 127.2, 127.2, 127.1, 120.2;
Calculated for HRMS (ESI) C 19 H 15 N 4 [M + H] + 299.1297, found 299.1294
(10)化合物1k:2-ナフタレン-1-イル-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)と1-ナフタレンボロン酸 (275.2 mg, 1.60 mmol)から、化合物1k (164.7 mg, 60 %)を得た。
淡褐色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.33-8.30 (2H, m), 8.11-8.08 (2H, m), 8.02-7.98 (1H, m), 7.91 (1H, dd, J = 7.6, 1.2 Hz), 7.66-7.50 (6H, m);
13C NMR (100 MHz, CDCl3) δ: 165.3, 134.3, 133.6, 131.2, 130.6, 129.0, 128.4, 128.2, 127.2, 127.2, 127.1, 124.9, 123.4, 122.8;
HRMS (ESI) C17H13N4 [M+H]+ に対する計算値273.1140, 実測値273.1133(10) Compound 1k: 2-naphthalen-1-yl-5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] Chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and 1-naphthaleneboronic acid (275.2 mg, 1.60 mmol) gave compound 1k (164.7 mg, 60%). It was.
Light brown crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.33-8.30 (2H, m), 8.11-8.08 (2H, m), 8.02-7.98 (1H, m), 7.91 (1H, dd, J = 7.6, 1.2 Hz), 7.66-7.50 (6H, m);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.3, 134.3, 133.6, 131.2, 130.6, 129.0, 128.4, 128.2, 127.2, 127.2, 127.1, 124.9, 123.4, 122.8;
HRMS (ESI) Calculated for C 17 H 13 N 4 [M + H] + 273.1140, found 273.1133
(11)化合物1l:3-(5-フェニルテトラゾール-2-イル)-フェニルアミン
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とm-アミノフェニルボロン酸 (219.1 mg, 1.60 mmol)から、化合物1l (93.1 mg, 39 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.23 (2H, m), 7.58-7.47 (5H, m), 7.32 (1H, t, J = 8.0 Hz), 6.79-6.76 (1H, m), 3.97 (2H, brs);
13C NMR (100 MHz, CDCl3) δ: 165.0, 147.7, 137.8, 130.5, 128.9, 127.3, 127.0, 116.0, 109.7, 106.0;
HRMS (ESI) C13H12N5 [M+H]+ に対する計算値238.1093, 実測値238.1085(11) Compound 1l: 3- (5-phenyltetrazol-2-yl) -phenylamine
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and m-aminophenylboronic acid (219.1 mg, 1.60 mmol), compound 1l (93.1 mg, 39%) Obtained.
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.23 (2H, m), 7.58-7.47 (5H, m), 7.32 (1H, t, J = 8.0 Hz), 6.79-6.76 (1H, m) , 3.97 (2H, brs);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.0, 147.7, 137.8, 130.5, 128.9, 127.3, 127.0, 116.0, 109.7, 106.0;
Calculated for HRMS (ESI) C 13 H 12 N 5 [M + H] + 238.1093, found 238.1085
(12)化合物1m:1-[4-(5-フェニルテトラゾール-2-イル)-フェニル]-エタノン
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とp-アセチルフェニルボロン酸 (262.4 mg, 1.60 mmol)から、化合物1m (29.2 mg, 11 %)を得た。
黄色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.35-8.32 (2H, m), 8.28-8.26 (2H, m), 8.20-8.16 (2H, m), 7.58-7.52 (3H, m), 2.69 (3H, s);
13C NMR (100 MHz, CDCl3) δ: 196.5, 165.6, 139.7, 137.6, 130.9, 130.0, 129.0, 127.2, 126.8, 119.8, 26.7;
HRMS (ESI) C15H13N4O [M+H]+ に対する計算値265.1089, 実測値265.1092(12) Compound 1m: 1- [4- (5-phenyltetrazol-2-yl) -phenyl] -ethanone
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p-acetylphenylboronic acid (262.4 mg, 1.60 mmol), compound 1m (29.2 mg, 11%) Obtained.
Yellow crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.35-8.32 (2H, m), 8.28-8.26 (2H, m), 8.20-8.16 (2H, m), 7.58-7.52 (3H, m), 2.69 ( 3H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 196.5, 165.6, 139.7, 137.6, 130.9, 130.0, 129.0, 127.2, 126.8, 119.8, 26.7;
HRMS (ESI) Calculated for C 15 H 13 N 4 O [M + H] + 265.1089, found 265.1092
(13)化合物1n:4-(5-フェニルテトラゾール-2-イル)-安息香酸メチルエステル
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)とp-(メトキシカルボニル)フェニルボロン酸 (288.0 mg, 1.60 mmol)から、化合物1n (81.6 mg, 29 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.32-8.25 (6H, m), 7.57-7.51 (3H, m), 3.98 (3H, s); 13C NMR (100 MHz, CDCl3) δ: 165.9, 165.6, 139.8, 131.3, 131.1, 130.8, 129.0, 127.2, 126.8, 119.6, 52.5;
HRMS (ESI) C15H13N4O2 [M+H]+ に対する計算値281.1039, 実測値281.1032(13) Compound 1n: 4- (5-phenyltetrazol-2-yl) -benzoic acid methyl ester
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and p- (methoxycarbonyl) phenylboronic acid (288.0 mg, 1.60 mmol), compound 1n (81.6 mg, 29 %).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.32-8.25 (6H, m), 7.57-7.51 (3H, m), 3.98 (3H, s); 13 C NMR (100 MHz, CDCl 3 ) δ: 165.9 , 165.6, 139.8, 131.3, 131.1, 130.8, 129.0, 127.2, 126.8, 119.6, 52.5;
HRMS (ESI) Calculated for C 15 H 13 N 4 O 2 [M + H] + 281.1039, found 281.1032
(14)化合物1o:2-(3-クロロ-4-メチルフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)と3-クロロ-4-メチルフェニルボロン酸 (272.6 mg, 1.60 mmol)から、化合物1o (216.7 mg, 80 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.24 (2H, m), 8.11 (1H, d, J = 2.4 Hz), 7.99 (1H, dd, J = 8.0, 2.4 Hz), 7.56-7.49 (4H, m), 2.52 (3H, s);
13C NMR (100 MHz, CDCl3) δ: 165.3, 138.0, 135.6, 135.2, 130.7, 130.2, 129.0, 127.1, 127.0, 122.0, 118.4, 20.3;
HRMS (ESI) C14H12ClN4 [M+H]+ に対する計算値271.0750, 実測値271.0753(14) Compound 1o: 2- (3-chloro-4-methylphenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and 3-chloro-4-methylphenylboronic acid (272.6 mg, 1.60 mmol), compound 1o (216.7 mg, 80%).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.24 (2H, m), 8.11 (1H, d, J = 2.4 Hz), 7.99 (1H, dd, J = 8.0, 2.4 Hz), 7.56-7.49 (4H, m), 2.52 (3H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.3, 138.0, 135.6, 135.2, 130.7, 130.2, 129.0, 127.1, 127.0, 122.0, 118.4, 20.3;
HRMS (ESI) calculated for C 14 H 12 ClN 4 [M + H] + 271.0750, found 271.0753
(15)化合物1p:2-(3-クロロ-4-メトキシフェニル)-5-フェニル-2H-テトラゾール
5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)、無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)と3-クロロ-4-メトキシフェニルボロン酸 (298.2 mg, 1.60 mmol)から、化合物1p (224.0 mg, 78 %)を得た。
白色結晶;
1H NMR (400 MHz, CDCl3) δ: 8.26-8.23 (3H, m), 8.08 (1H, dd, J = 8.8, 2.4 Hz), 7.56-7.49 (3H, m), 7.09 (1H, d, J = 8.8 Hz), 4.00 (3H, s);
13C NMR (100 MHz, CDCl3) δ: 165.2, 156.0, 130.6, 130.4, 129.0, 127.0, 123.6, 122.1, 119.3, 112.2, 56.6;
HRMS (ESI) C14H12ClN4O [M+H]+ に対する計算値287.0700, 実測値287.0701(15) Compound 1p: 2- (3-chloro-4-methoxyphenyl) -5-phenyl-2H-tetrazole
5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol), anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] From chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol) and 3-chloro-4-methoxyphenylboronic acid (298.2 mg, 1.60 mmol), compound 1p (224.0 mg, 78%).
White crystals;
1 H NMR (400 MHz, CDCl 3 ) δ: 8.26-8.23 (3H, m), 8.08 (1H, dd, J = 8.8, 2.4 Hz), 7.56-7.49 (3H, m), 7.09 (1H, d, J = 8.8 Hz), 4.00 (3H, s);
13 C NMR (100 MHz, CDCl 3 ) δ: 165.2, 156.0, 130.6, 130.4, 129.0, 127.0, 123.6, 122.1, 119.3, 112.2, 56.6;
HRMS (ESI) Calculated for C 14 H 12 ClN 4 O [M + H] + 287.0700, found 287.0701
上記の結果をまとめたものを、以下の表2に示す。
実施例3
室温下、5-フェニル-1H-テトラゾール (146.2 mg, 1.00 mmol)の塩化メチレン溶液 (0.2 mol/L)に無水炭酸カリウム (152.0 mg, 1.10 mmol)、ジ-μ-ヒドロキソ-ビス[(N,N,N',N'-テトラメチルエチレンジアミン)銅(II)]クロリド (55.7 mg, 12 mol%)、無水塩化リチウム (21.2 mg, 0.50 mmol)、フェニルボロン酸 (195.1 mg, 1.60 mmol)を加えた。空気中、室温で60時間撹拌後、10 %アンモニア水溶液を加え、塩化メチレンで抽出し、10 %塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をカラムクロマトグラフィー(シリカゲル60N(球状,中性) 、n-ヘキサン/塩化メチレン)で精製し、化合物1a:2,5-ジフェニル-2H-テトラゾール (129.3 mg, 58 %)を得た。
目的の化合物を得た後、極性溶媒で溶出したカラムクロマトグラフィー内の残渣を高分解能Massで測定し、1,5-ジフェニル-1H-テトラゾールの生成は認められなかった。Example 3
At room temperature, 5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol) in methylene chloride (0.2 mol / L) was added anhydrous potassium carbonate (152.0 mg, 1.10 mmol), di-μ-hydroxo-bis [(N, Add N, N ', N'-tetramethylethylenediamine) copper (II)] chloride (55.7 mg, 12 mol%), anhydrous lithium chloride (21.2 mg, 0.50 mmol), phenylboronic acid (195.1 mg, 1.60 mmol) It was. After stirring in air at room temperature for 60 hours, 10% aqueous ammonia solution was added, extracted with methylene chloride, washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 60N (spherical, neutral), n-hexane / methylene chloride) to obtain compound 1a: 2,5-diphenyl-2H-tetrazole (129.3 mg, 58 %).
After obtaining the target compound, the residue in the column chromatography eluted with a polar solvent was measured with high resolution Mass, and formation of 1,5-diphenyl-1H-tetrazole was not observed.
Claims (5)
で表される5−置換−1H−テトラゾールを、塩基およびジ−μ−ヒドロキソ−ビス[(N,N,N’,N’−テトラメチルエチレンジアミン)銅(II)]ハライド銅錯体の存在下に、酸化性雰囲気下で、一般式(III):
で表されるアリールボロン酸と反応させる、一般式(I):
で表される5−置換−2−アリール−2H−テトラゾールの製造方法。General formula (II):
In the presence of a base and a di-μ-hydroxo-bis [(N, N, N ′, N′-tetramethylethylenediamine) copper (II)] halide copper complex. In an oxidizing atmosphere, the general formula (III):
Is reacted with an aryl boronic acid represented by the general formula (I):
The manufacturing method of 5-substituted-2-aryl-2H-tetrazole represented by these.
前記アシル基が、アルカノイル基、アロイル基、アルコキシカルボニル基またはアリールオキシカルボニル基である請求項1に記載の製造方法。The optionally substituted alkyl group, aryl group or heteroaryl group in R 1 is substituted with an alkyl group optionally substituted with aryl, an aryl group optionally substituted with a halogen atom or alkyl, or alkyl. A heteroaryl group that may be
The production method according to claim 1, wherein the acyl group is an alkanoyl group, an aroyl group, an alkoxycarbonyl group, or an aryloxycarbonyl group.
前記Arが、ハロゲン原子、アルキル、アルコキシ、フェニル、フェニルアルコキシ、アミノ、アルカノイルおよびアルコキシカルボニルからなる群から選択される置換基で置換されていてもよいフェニル基またはナフチル基である請求項1または2に記載の製造方法。R 1 is a halogen atom, an alkyl group which may be substituted with phenyl, a phenyl group which may be substituted with a halogen atom or alkyl, a pyridyl group, an alkylthio group, or an alkoxycarbonyl group;
The Ar is a phenyl group or a naphthyl group which may be substituted with a substituent selected from the group consisting of a halogen atom, alkyl, alkoxy, phenyl, phenylalkoxy, amino, alkanoyl and alkoxycarbonyl. The manufacturing method as described in.
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