JP2018507170A - ジアリールチオヒダントイン化合物の調製方法 - Google Patents
ジアリールチオヒダントイン化合物の調製方法 Download PDFInfo
- Publication number
- JP2018507170A JP2018507170A JP2017532818A JP2017532818A JP2018507170A JP 2018507170 A JP2018507170 A JP 2018507170A JP 2017532818 A JP2017532818 A JP 2017532818A JP 2017532818 A JP2017532818 A JP 2017532818A JP 2018507170 A JP2018507170 A JP 2018507170A
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- JP
- Japan
- Prior art keywords
- compound
- vii
- chloride
- methylamine
- halide
- 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
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 141
- 238000000034 method Methods 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 112
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 80
- 229910052763 palladium Inorganic materials 0.000 claims description 58
- 239000003054 catalyst Substances 0.000 claims description 47
- -1 β-naphthyl Chemical group 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- 239000003446 ligand Substances 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 28
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 27
- 239000011574 phosphorus Substances 0.000 claims description 27
- 229910052698 phosphorus Inorganic materials 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 17
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 16
- 150000004791 alkyl magnesium halides Chemical class 0.000 claims description 14
- 239000012298 atmosphere Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 229910052744 lithium Inorganic materials 0.000 claims description 12
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 11
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- 150000004820 halides Chemical class 0.000 claims description 10
- 239000003586 protic polar solvent Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- JFWWQYKSQVMLQU-UHFFFAOYSA-M magnesium;pentane;chloride Chemical compound [Mg+2].[Cl-].CCCC[CH2-] JFWWQYKSQVMLQU-UHFFFAOYSA-M 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- 239000012973 diazabicyclooctane Substances 0.000 claims description 7
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 claims description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 7
- KXMMNJQMGILZDB-UHFFFAOYSA-N 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one Chemical compound O=C1C=CC=CN1C(=S)N1C(=O)C=CC=C1 KXMMNJQMGILZDB-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- WMJMABVHDMRMJA-UHFFFAOYSA-M [Cl-].[Mg+]C1CCCCC1 Chemical group [Cl-].[Mg+]C1CCCCC1 WMJMABVHDMRMJA-UHFFFAOYSA-M 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000001569 carbon dioxide Substances 0.000 claims description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- HJMZMZRCABDKKV-UHFFFAOYSA-M cyanoformate Chemical compound [O-]C(=O)C#N HJMZMZRCABDKKV-UHFFFAOYSA-M 0.000 claims description 4
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- YNLPNVNWHDKDMN-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CC[CH-]C YNLPNVNWHDKDMN-UHFFFAOYSA-M 0.000 claims description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 4
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 4
- GBRJQTLHXWRDOV-UHFFFAOYSA-M magnesium;hexane;chloride Chemical compound [Mg+2].[Cl-].CCCCC[CH2-] GBRJQTLHXWRDOV-UHFFFAOYSA-M 0.000 claims description 4
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 2
- IKYOVSVBLHGFMA-UHFFFAOYSA-N dipyridin-2-yloxymethanethione Chemical compound C=1C=CC=NC=1OC(=S)OC1=CC=CC=N1 IKYOVSVBLHGFMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims 4
- 229910052749 magnesium Inorganic materials 0.000 claims 4
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims 2
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 claims 1
- ZRXHYHZENMJKMG-UHFFFAOYSA-N bis(benzotriazol-1-yl)methanethione Chemical compound N1=NC2=CC=CC=C2N1C(=S)N1C2=CC=CC=C2N=N1 ZRXHYHZENMJKMG-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 3
- 206010060862 Prostate cancer Diseases 0.000 abstract description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 2
- 238000011835 investigation Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 239000000047 product Substances 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
- 230000009466 transformation Effects 0.000 description 3
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102100021391 Cationic amino acid transporter 3 Human genes 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 108091006230 SLC7A3 Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 238000005910 aminocarbonylation reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FNAIXFLDEJRUFR-UHFFFAOYSA-N CNC(c(ccc(N(C1(CCC1)C(N1c(cc2C(F)(F)F)cnc2C#N)=O)C1=S)c1)c1F)O Chemical compound CNC(c(ccc(N(C1(CCC1)C(N1c(cc2C(F)(F)F)cnc2C#N)=O)C1=S)c1)c1F)O FNAIXFLDEJRUFR-UHFFFAOYSA-N 0.000 description 1
- UNSKLGZBNPPGOW-UHFFFAOYSA-N C[N]C(c(ccc(N(C1(CCC1)C(N1c2cc(C(F)(F)F)c(C#N)nc2)=O)C1=S)c1)c1F)=O Chemical compound C[N]C(c(ccc(N(C1(CCC1)C(N1c2cc(C(F)(F)F)c(C#N)nc2)=O)C1=S)c1)c1F)=O UNSKLGZBNPPGOW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VQZPLPUKKLQUJM-UHFFFAOYSA-N N#Cc(c(C(F)(F)F)c1)ncc1N(C(C1(CCC1)N1c(cc2)cc(F)c2I)=O)C1=S Chemical compound N#Cc(c(C(F)(F)F)c1)ncc1N(C(C1(CCC1)N1c(cc2)cc(F)c2I)=O)C1=S VQZPLPUKKLQUJM-UHFFFAOYSA-N 0.000 description 1
- LYBRMBVNXMGBEU-UHFFFAOYSA-N N#Cc(nc1)c(C(F)(F)F)cc1N(C1OC1C1(CCC1)N1c(cc2)cc(F)c2C(O)=O)C1=S Chemical compound N#Cc(nc1)c(C(F)(F)F)cc1N(C1OC1C1(CCC1)N1c(cc2)cc(F)c2C(O)=O)C1=S LYBRMBVNXMGBEU-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- LXHANLQHAXWSIQ-UHFFFAOYSA-K [Cl-].[Li+].C(C)(C)[Mg]Cl.[Li+].[Cl-] Chemical compound [Cl-].[Li+].C(C)(C)[Mg]Cl.[Li+].[Cl-] LXHANLQHAXWSIQ-UHFFFAOYSA-K 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 238000007083 alkoxycarbonylation reaction Methods 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- QVQGTNFYPJQJNM-UHFFFAOYSA-N dicyclohexylmethanamine Chemical compound C1CCCCC1C(N)C1CCCCC1 QVQGTNFYPJQJNM-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Abstract
Description
本出願は、本明細書にその全容を参照により援用するところの2014年12月19日出願の米国仮特許出願第62/094425号に基づく優先権を主張するものである。
以下に述べる本発明の研究及び開発は、米連邦政府の支援によるものではない。
本発明は、化合物(X)の調製及びその合成における中間体に関する。より詳細には、本発明は、本明細書にその全容を参照により援用するところの2013年5月21日発行の米国特許第8,445,507号に開示される化合物(X)を調製するためのプロセスに関する。
(ii)化合物(VII)を、一酸化炭素雰囲気下、パラジウム触媒の存在下、1種類以上のリン配位子の存在下、有機塩基の存在下、水の存在下、有機溶媒中、約0℃〜約100℃の温度で反応させて、対応する化合物(1c)を生成し、次いで、
(ii)化合物(VII)を、適当なアルコキシカルボニル条件下、一酸化炭素雰囲気下、パラジウム触媒の存在下、1種類以上のリン配位子の存在下、塩基の存在下、C1〜6アルコール溶媒中、概ね室温〜約100℃の温度で反応させて、対応する式(1e)の化合物を生成し、次いで、
本発明の全体的なスキームは、下記に示されるスキームAに示される。
(i)化合物(VII)は、その対応するカルボン酸である化合物(1c)を経由して化合物(X)に変換することができるが、これは、化合物(VII)と、C1〜8アルキルマグネシウムハロゲン化物又はC5〜7シクロアルキルマグネシウムハロゲン化物から選択される有機マグネシウムハロゲン化物とを、塩化リチウム、臭化リチウム、又はヨウ化リチウムなどのハロゲン化リチウムの存在下又は非存在下で反応させた後、THF、2−MeTHF、MTBE、CPME、又はトルエンから選択される非プロトン性有機溶媒中、約0℃の温度で二酸化炭素ガスを添加して、対応するカルボン酸化合物(1c)を生成することにより行われる。
(i)化合物(VII)はまた、その対応するC1〜6エステル(1e)を経由して化合物(X)に変換することもできるが、これは、化合物(VII)と、C1〜8アルキルマグネシウムハロゲン化物又はC5〜7シクロアルキルマグネシウムハロゲン化物から選択される有機マグネシウムハロゲン化物とを、塩化リチウム、臭化リチウム、又はヨウ化リチウムなどのハロゲン化リチウムの存在下又は非存在下、THF、2−MeTHF、トルエンなどから選択される非プロトン性有機溶媒中、約−50℃〜約22℃の温度で反応させた後、クロロギ酸C1〜6アルキル又はシアノギ酸C1〜6アルキルを添加して、対応する式(1e)のエステルを生成することにより行われる。
(i)化合物(VII)は、化合物(VII)を、ヘキサカルボニルモリブデンの存在下、場合により、ノルボルナジエン、テトラブチルアンモニウムブロミドなどの1種類以上の試薬、又はトリエチルアミン若しくはDABCOなどの塩基の存在下、ジグライム、ジオキサン、ブチロニトリル、プロピオニトリルなどから選択される有機溶媒中で反応させた後、約60℃〜約140℃の温度でメチルアミンを添加して、対応する化合物(X)を生成することにより、直接化合物(X)に変換することができる。
以下の実施例は、本発明の理解を助けるために記載するものであり、本明細書に付属する「特許請求の範囲」に記載される発明をいかなる意味においても限定することを目的としたものではなく、またそのように解釈されるべきではない。
改変触媒スラリーの調製
20mLのガラスビーカー中で、0.156g(0.129mL、50重量/重量%)のH3PO2を、1.00gの5%Pt/C触媒F101 R/W(EvonikAG社より販売される、約60%の水を含むもの)と4.0mLの脱イオン水のスラリーに添加した。マグネチックスターラーバーで15分攪拌した後、58mgのNH4VO3を添加し、スラリーを再び15分間攪拌した。
100mLのオートクレーブに、10.0gの化合物(III)(46.1mmol)を26.7mLのキシレン及び13.3mLのブチロニトリルに加えた溶液を入れた。この溶液に、2mLの脱イオン水を用いて改変触媒スラリーを添加した。オートクレーブを閉じてから窒素で10barに3回、水素で10barに3回加圧することによって不活化した。反応容器の圧力を5.0bar水素に設定し、攪拌を開始し(中空シャフトタービンスターラー、1200rpm)、混合物を70℃にまで50分以内に加熱した。70℃に達するとすぐに水素の取り込みが止まった。更に40分間攪拌した後、加熱を停止し、オートクレーブを冷却させた。スラリーをグラスファイバー製フィルターに通して濾過し、20〜23℃の40mLのキシレンにより少量ずつ洗浄した。ブチロニトリル溶媒を蒸溜して、溶液から化合物(IV)を結晶化させた。1H NMR(300MHz,DMSO−d6)δ 8.20(d,J=2.4Hz,1H),7.31(d,J=2.6Hz,1H),7.04(s,NH)。
Claims (50)
- 前記溶媒系が、酢酸である、請求項2に記載のプロセス。
- 前記溶媒系が、90%酢酸および10%エタノールである、請求項2に記載のプロセス。
- ステップ(1b)が、
- 前記チオカルボニル化剤が、1−(2−オキソピリジン−1−カルボチオイル)ピリジン−2−オンである、請求項5に記載のプロセス。
- 前記有機溶媒がDMAである、請求項6に記載のプロセス。
- 化合物(VII)と、C1〜8アルキルマグネシウムハロゲン化物及びC5〜7シクロアルキルマグネシウムハロゲン化物からなる群から選択される有機マグネシウムハロゲン化物とを、塩化リチウム、臭化リチウム、又はヨウ化リチウムからなる群から選択されるハロゲン化リチウムの存在下又は非存在下で反応させた後、THF、2−MeTHF、MTBE、CPME、及びトルエンからなる群から選択される非プロトン性有機溶媒中、約0℃の温度で二酸化炭素ガスを添加して、対応するカルボン酸化合物(1c)を生成することを含む、請求項8に記載のプロセス。
- 前記C1〜8アルキルマグネシウムハロゲン化物が、C1〜8アルキルマグネシウムクロリド又はC1〜8アルキルマグネシウムブロミドである、請求項9に記載のプロセス。
- 前記C1〜8アルキルマグネシウムハロゲン化物が、イソプロピルマグネシウムクロリド、sec−ブチルマグネシウムクロリド、n−ペンチルマグネシウムクロリド、ヘキシルマグネシウムクロリド、エチルマグネシウムクロリド、エチルマグネシウムブロミド、n−ブチルマグネシウムクロリド、及びイソプロピルマグネシウムクロリドからなる群から選択される、請求項10に記載のプロセス。
- 化合物(VII)とn−ペンチルマグネシウムクロリドとを、ハロゲン化リチウムの非存在下で反応させた後、THF中、約0℃の温度で二酸化炭素ガスを添加して、対応するカルボン酸化合物(1c)を生成することを更に含む、請求項11に記載のプロセス。
- 前記C5〜7シクロアルキルマグネシウムハロゲン化物が、C5〜7シクロアルキルマグネシウムクロリド又はC5〜7シクロアルキルマグネシウムブロミドである、請求項9に記載のプロセス。
- 前記C5〜7シクロアルキルマグネシウムハロゲン化物がシクロヘキシルマグネシウムクロリドである、請求項13に記載のプロセス。
- 前記パラジウム触媒が、dppfであるリン配位子と酢酸パラジウムであるパラジウム金属化合物とからなる、請求項15に記載のプロセス。
- 化合物(1c)とCDIであるカップリング剤とを、概ね室温で反応させ、その際、前記非プロトン性又はプロトン性溶媒がTHF又はトルエンであり、その後、メチルアミンを添加して、対応する化合物(X)を生成することを更に含む、請求項17に記載のプロセス。
- メチルアミンがTHF溶液として添加される、請求項18に記載のプロセス。
- メチルアミンがその気体状態で添加される、請求項18に記載のプロセス。
- メチルアミンがそのメチルアンモニウム塩として添加される、請求項18に記載のプロセス。
- ステップ(1e)が、化合物(VII)と、C1〜8アルキルマグネシウムハロゲン化物及びC5〜7シクロアルキルマグネシウムハロゲン化物からなる群から選択される有機マグネシウムハロゲン化物とを、塩化リチウム、臭化リチウム、又はヨウ化リチウムからなる群から選択されるハロゲン化リチウムの存在下又は非存在下、THF、2−MeTHF、又はトルエンから選択される非プロトン性有機溶媒中、約−50℃〜約22℃の温度で反応させた後、クロロギ酸C1〜6アルキル又はシアノギ酸C1〜6アルキルを添加して、対応する式(1e)のエステルを生成することを更に含む、請求項22に記載のプロセス。
- 前記C1〜8アルキルマグネシウムハロゲン化物が、C1〜8アルキルマグネシウムクロリド又はC1〜8アルキルマグネシウムブロミドである、請求項23に記載のプロセス。
- 前記C1〜8アルキルマグネシウムハロゲン化物が、イソプロピルマグネシウムクロリド、sec−ブチルマグネシウムクロリド、シクロヘキシルマグネシウムクロリド、n−ペンチルマグネシウムクロリド、ヘキシルマグネシウムクロリド、エチルマグネシウムクロリド、エチルマグネシウムブロミド、n−ブチルマグネシウムクロリド、及びイソプロピルマグネシウムクロリドからなる群から選択される、請求項24に記載のプロセス。
- 化合物(VII)を、n−ペンチルマグネシウムクロリドの存在下、ハロゲン化リチウムの非存在下、THF又は2−MeTHFである非プロトン性有機溶媒中、約−50℃〜約22℃の温度で反応させた後、クロロギ酸C1〜6アルキル又はシアノギ酸C1〜6アルキルを添加して、対応する式(1e)のエステルを生成することを更に含む、請求項25に記載のプロセス。
- 前記C5〜7シクロアルキルマグネシウムハロゲン化物が、C5〜7シクロアルキルマグネシウムクロリド又はC5〜7シクロアルキルマグネシウムブロミドである、請求項23に記載のプロセス。
- 前記C5〜7シクロアルキルマグネシウムハロゲン化物がシクロヘキシルマグネシウムクロリドである、請求項27に記載のプロセス。
- ステップ(1e)が、化合物(VII)を、一酸化炭素雰囲気下、パラジウム触媒の存在下、1種類以上のリン配位子の存在下、DIPEA、K2CO3、K3PO4、及びCy2NMeからなる群から選択される塩基の存在下、メタノール、エタノール、イソプロピルアルコール、n−ブチルアルコール、及びt−ブチルアルコールからなる群から選択されるC1〜4アルコール溶媒中、概ね室温〜約100℃の温度で反応させて、対応する式(1e)のエステルを生成することを更に含む、請求項29に記載のプロセス。
- 前記パラジウム触媒がPd(P(tBu3)2であり、前記塩基が1.2当量のDIPEAである、請求項30に記載のプロセス。
- 前記パラジウム触媒が、DIPEAの存在下、リン配位子dppfと、酢酸パラジウムであるパラジウム金属化合物とからなる、請求項30に記載のプロセス。
- 前記C1〜4アルコール溶媒が、メタノールである、請求項28に記載のプロセス。
- 前記プロトン性又は非プロトン性溶媒が、THF、DMF、DMA、及びエタノール、又はこれらの混合物からなる群から選択される、請求項35に記載のプロセス。
- メチルアミンがTHF溶液として添加される、請求項36に記載のプロセス。
- メチルアミンがMeOH溶液として添加される、請求項36に記載のプロセス。
- メチルアミンがその気体状態で添加される、請求項36に記載のプロセス。
- ノルボルナジエン、テトラブチルアンモニウムブロミド、及びDABCOが存在する、請求項40に記載のプロセス。
- 前記有機溶媒が、ブチロニトリル又はジグリムである、請求項41に記載のプロセス。
- ステップ(1g)が、化合物(VII)を、一酸化炭素雰囲気下、パラジウム触媒の存在下、1種類以上のリン配位子の存在下、DIPEA、K2CO3、K3PO4、Cy2NMe、及び過剰量のメチルアミンからなる群から選択される塩基の存在下、メチルアミンの存在下、有機溶媒中、概ね室温〜約100℃の温度で反応させて、対応する化合物(X)を生成することを更に含む、請求項43に記載のプロセス。
- 前記パラジウム触媒がPd(P(tBu3)2であり、前記塩基がDIPEAである、請求項44に記載のプロセス。
- メチルアミンがTHF溶液として添加される、請求項44に記載のプロセス。
- メチルアミンがMeOH溶液として添加される、請求項44に記載のプロセス。
- メチルアミンがその気体状態で添加される、請求項44に記載のプロセス。
- メチルアミンがそのメチルアンモニウム塩酸塩として添加される、請求項44に記載のプロセス。
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