JP2020536861A - ボロン酸誘導体およびその合成 - Google Patents
ボロン酸誘導体およびその合成 Download PDFInfo
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- JP2020536861A JP2020536861A JP2020518813A JP2020518813A JP2020536861A JP 2020536861 A JP2020536861 A JP 2020536861A JP 2020518813 A JP2020518813 A JP 2020518813A JP 2020518813 A JP2020518813 A JP 2020518813A JP 2020536861 A JP2020536861 A JP 2020536861A
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- Prior art keywords
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- 230000015572 biosynthetic process Effects 0.000 title abstract description 24
- 238000003786 synthesis reaction Methods 0.000 title abstract description 20
- 150000001642 boronic acid derivatives Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 246
- 238000000034 method Methods 0.000 claims abstract description 116
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims description 160
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 154
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 142
- 239000003054 catalyst Substances 0.000 claims description 140
- -1 di-tert-butylphosphino Chemical group 0.000 claims description 127
- 239000003446 ligand Substances 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 125000000623 heterocyclic group Chemical group 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 34
- 125000002947 alkylene group Chemical group 0.000 claims description 34
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 32
- 239000002585 base Substances 0.000 claims description 31
- 125000004429 atom Chemical group 0.000 claims description 30
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 28
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 27
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical class C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 23
- BOUYBUIVMHNXQB-UHFFFAOYSA-N dicyclohexyl(2-dicyclohexylphosphanylethyl)phosphane Chemical compound C1CCCCC1P(C1CCCCC1)CCP(C1CCCCC1)C1CCCCC1 BOUYBUIVMHNXQB-UHFFFAOYSA-N 0.000 claims description 20
- 229910052759 nickel Inorganic materials 0.000 claims description 20
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 18
- 239000012018 catalyst precursor Substances 0.000 claims description 17
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 17
- 239000002168 alkylating agent Substances 0.000 claims description 16
- 229940100198 alkylating agent Drugs 0.000 claims description 16
- 230000003301 hydrolyzing effect Effects 0.000 claims description 16
- 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 15
- 229910052751 metal Inorganic materials 0.000 claims description 14
- 239000002184 metal Substances 0.000 claims description 14
- 229960002179 ephedrine Drugs 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 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 claims description 11
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical group CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000005271 boronizing Methods 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000001414 amino alcohols Chemical class 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 claims description 6
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000008300 phosphoramidites Chemical class 0.000 claims description 5
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 5
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 claims description 4
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 4
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- DLNKOYKMWOXYQA-CBAPKCEASA-N (-)-norephedrine Chemical compound C[C@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-CBAPKCEASA-N 0.000 claims description 3
- LYHOBZAADXPPNW-UHFFFAOYSA-N (r)-xylyl-phanephos Chemical compound CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C=3CCC4=CC=C(C(=C4)P(C=4C=C(C)C=C(C)C=4)C=4C=C(C)C=C(C)C=4)CCC(=CC=3)C=2)=C1 LYHOBZAADXPPNW-UHFFFAOYSA-N 0.000 claims description 3
- SAYJSSIMFYICKR-UHFFFAOYSA-N 1,3-bis(1-adamantyl)imidazol-1-ium Chemical compound C1C(C2)CC(C3)CC2CC13[N+](C=C1)=CN1C(C1)(C2)CC3CC2CC1C3 SAYJSSIMFYICKR-UHFFFAOYSA-N 0.000 claims description 3
- LSMWOQFDLBIYPM-UHFFFAOYSA-N 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-2h-imidazol-1-ium-2-ide Chemical compound CC1=CC(C)=CC(C)=C1N1[C-]=[N+](C=2C(=CC(C)=CC=2C)C)CC1 LSMWOQFDLBIYPM-UHFFFAOYSA-N 0.000 claims description 3
- MXBZSBSKUMTJDH-UHFFFAOYSA-N 1,3-ditert-butylimidazol-1-ium Chemical compound CC(C)(C)N1C=C[N+](C(C)(C)C)=C1 MXBZSBSKUMTJDH-UHFFFAOYSA-N 0.000 claims description 3
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 3
- SXXPTCXIFIOPQF-UHFFFAOYSA-N 3-bis(2-methoxyphenyl)phosphanylpropyl-bis(2-methoxyphenyl)phosphane Chemical compound COC1=CC=CC=C1P(C=1C(=CC=CC=1)OC)CCCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1OC SXXPTCXIFIOPQF-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 3
- XJJVPYMFHXMROQ-UHFFFAOYSA-N [4-[5-bis(3,5-dimethylphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C(=C3OCOC3=CC=2)C=2C(=CC=C3OCOC3=2)P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)=C1 XJJVPYMFHXMROQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 150000004985 diamines Chemical class 0.000 claims description 3
- RSJBEKXKEUQLER-UHFFFAOYSA-N dicyclohexyl(3-dicyclohexylphosphanylpropyl)phosphane Chemical compound C1CCCCC1P(C1CCCCC1)CCCP(C1CCCCC1)C1CCCCC1 RSJBEKXKEUQLER-UHFFFAOYSA-N 0.000 claims description 3
- OWFLJHJHQKHZJR-UHFFFAOYSA-N dicyclohexyl(dicyclohexylphosphanylmethyl)phosphane Chemical compound C1CCCCC1P(C1CCCCC1)CP(C1CCCCC1)C1CCCCC1 OWFLJHJHQKHZJR-UHFFFAOYSA-N 0.000 claims description 3
- HPFGZHCWLVSVKJ-UHFFFAOYSA-N dicyclohexyl-[2-(2-dicyclohexylphosphanylphenoxy)phenyl]phosphane Chemical compound C1CCCCC1P(C=1C(=CC=CC=1)OC=1C(=CC=CC=1)P(C1CCCCC1)C1CCCCC1)C1CCCCC1 HPFGZHCWLVSVKJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002009 diols Chemical class 0.000 claims description 3
- SFCNPIUDAIFHRD-UHFFFAOYSA-N ditert-butyl-[[2-(ditert-butylphosphanylmethyl)phenyl]methyl]phosphane Chemical compound CC(C)(C)P(C(C)(C)C)CC1=CC=CC=C1CP(C(C)(C)C)C(C)(C)C SFCNPIUDAIFHRD-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- JCYWCSGERIELPG-UHFFFAOYSA-N imes Chemical compound CC1=CC(C)=CC(C)=C1N1C=CN(C=2C(=CC(C)=CC=2C)C)[C]1 JCYWCSGERIELPG-UHFFFAOYSA-N 0.000 claims description 3
- AXVOAMVQOCBPQT-UHFFFAOYSA-N triphos Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 AXVOAMVQOCBPQT-UHFFFAOYSA-N 0.000 claims description 3
- CMLWFCUAXGSMBB-UHFFFAOYSA-N tris(2,6-dimethoxyphenyl)phosphane Chemical compound COC1=CC=CC(OC)=C1P(C=1C(=CC=CC=1OC)OC)C1=C(OC)C=CC=C1OC CMLWFCUAXGSMBB-UHFFFAOYSA-N 0.000 claims description 3
- UYUUAUOYLFIRJG-UHFFFAOYSA-N tris(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 UYUUAUOYLFIRJG-UHFFFAOYSA-N 0.000 claims description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 2
- DTGKSKDOIYIVQL-QXFUBDJGSA-N (-)-borneol Chemical compound C1C[C@]2(C)[C@H](O)C[C@H]1C2(C)C DTGKSKDOIYIVQL-QXFUBDJGSA-N 0.000 claims description 2
- 229930006703 (-)-borneol Natural products 0.000 claims description 2
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 claims description 2
- ULSIYEODSMZIPX-QMMMGPOBSA-N (1r)-2-amino-1-phenylethanol Chemical compound NC[C@H](O)C1=CC=CC=C1 ULSIYEODSMZIPX-QMMMGPOBSA-N 0.000 claims description 2
- PONXTPCRRASWKW-ZIAGYGMSSA-N (1r,2r)-1,2-diphenylethane-1,2-diamine Chemical compound C1([C@@H](N)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-ZIAGYGMSSA-N 0.000 claims description 2
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 claims description 2
- GEJJWYZZKKKSEV-KBPBESRZSA-N (1s,2s)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KBPBESRZSA-N 0.000 claims description 2
- WAPNOHKVXSQRPX-SSDOTTSWSA-N (R)-1-phenylethanol Chemical group C[C@@H](O)C1=CC=CC=C1 WAPNOHKVXSQRPX-SSDOTTSWSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 2
- GTIXSUJKFAATAE-UHFFFAOYSA-N (r)-c3-tunephos Chemical compound C=12C(C(=CC=C3)P(C=4C=CC=CC=4)C=4C=CC=CC=4)=C3OCCCOC2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 GTIXSUJKFAATAE-UHFFFAOYSA-N 0.000 claims description 2
- PSXWGNIMIRRWRB-LURJTMIESA-N 2-[(2s)-pyrrolidin-2-yl]propan-2-ol Chemical compound CC(C)(O)[C@@H]1CCCN1 PSXWGNIMIRRWRB-LURJTMIESA-N 0.000 claims description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 2
- HVVNJUAVDAZWCB-RXMQYKEDSA-N D-prolinol Chemical compound OC[C@H]1CCCN1 HVVNJUAVDAZWCB-RXMQYKEDSA-N 0.000 claims description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- BARUNXKDFNLHEV-UHFFFAOYSA-N [3-diphenylphosphanyl-2-(diphenylphosphanylmethyl)-2-methylpropyl]-diphenylphosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CC(CP(C=1C=CC=CC=1)C=1C=CC=CC=1)(C)CP(C=1C=CC=CC=1)C1=CC=CC=C1 BARUNXKDFNLHEV-UHFFFAOYSA-N 0.000 claims description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 2
- PVRATXCXJDHJJN-QWWZWVQMSA-N dimethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound COC(=O)[C@H](O)[C@@H](O)C(=O)OC PVRATXCXJDHJJN-QWWZWVQMSA-N 0.000 claims description 2
- QKZWXPLBVCKXNQ-ROJLCIKYSA-N dipamp Chemical compound COC1=CC=CC=C1[P@@](C=1C=CC=CC=1)CC[P@@](C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-ROJLCIKYSA-N 0.000 claims description 2
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 claims description 2
- LJOQGZACKSYWCH-WZBLMQSHSA-N hydroquinine Chemical compound C1=C(OC)C=C2C([C@@H](O)[C@@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-WZBLMQSHSA-N 0.000 claims description 2
- 229960004251 hydroquinine Drugs 0.000 claims description 2
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 claims description 2
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical compound COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 claims description 2
- 229960000948 quinine Drugs 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- HRJABHWZEQHPFS-UHFFFAOYSA-N [1-[2-(12,14-dioxa-13-phosphapentacyclo[13.8.0.02,11.03,8.018,23]tricosa-1(15),2(11),3,5,7,9,16,18,20,22-decaen-13-yloxy)naphthalen-1-yl]naphthalen-2-yl]-diphenylphosphane Chemical compound O1C=2C=CC3=CC=CC=C3C=2C(C2=CC=CC=C2C=C2)=C2OP1OC1=CC=C2C=CC=CC2=C1C(C1=CC=CC=C1C=C1)=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 HRJABHWZEQHPFS-UHFFFAOYSA-N 0.000 claims 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 2
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 claims 1
- IJXJGQCXFSSHNL-QMMMGPOBSA-N (R)-(-)-2-Phenylglycinol Chemical compound OC[C@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-QMMMGPOBSA-N 0.000 claims 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims 1
- 229940035437 1,3-propanediol Drugs 0.000 claims 1
- GGOUXJDVUDDDIV-UHFFFAOYSA-N C(C)(C)C1=C(C(=CC=C1)C(C)C)N1C(N(CC1)C1=C(C=CC=C1C(C)C)C(C)C)=C1[N+](=[C-]N(C1)C1=C(C=CC=C1C(C)C)C(C)C)C1=C(C=CC=C1C(C)C)C(C)C Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)N1C(N(CC1)C1=C(C=CC=C1C(C)C)C(C)C)=C1[N+](=[C-]N(C1)C1=C(C=CC=C1C(C)C)C(C)C)C1=C(C=CC=C1C(C)C)C(C)C GGOUXJDVUDDDIV-UHFFFAOYSA-N 0.000 claims 1
- 239000012752 auxiliary agent Substances 0.000 claims 1
- LCSNDSFWVKMJCT-UHFFFAOYSA-N dicyclohexyl-(2-phenylphenyl)phosphane Chemical group C1CCCCC1P(C=1C(=CC=CC=1)C=1C=CC=CC=1)C1CCCCC1 LCSNDSFWVKMJCT-UHFFFAOYSA-N 0.000 claims 1
- 125000006501 nitrophenyl group Chemical group 0.000 claims 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims 1
- 239000001294 propane Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 abstract description 15
- 229940126062 Compound A Drugs 0.000 abstract description 13
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 13
- 159000000000 sodium salts Chemical class 0.000 abstract description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/74—Iron group metals
- B01J23/755—Nickel
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
Abstract
Description
任意の優先権出願への参照による援用
本願は、その開示全体が参照によって本明細書に組み込まれる、2017年10月11日出願のBoronic Acid Derivatives and Synthesis Thereofという名称の米国仮出願第62/571149号に対する利益を主張する。
連邦政府資金による研究開発についての記載
抗生物質は、この50年間、感染症の処置における有効なツールとなってきた。1980年代後期までの抗生物質治療の発展によって、先進国では細菌感染がほぼ完全に制御された。しかし、抗生物質使用の圧力に応答して、多重耐性機序が拡大しており、抗細菌治療の臨床的な有用性が脅かされている。抗生物質耐性株の増加は、大規模病院およびケアセンターで特によく見られるものになってきた。耐性株増加の結果には、罹患率および死亡率の上昇、患者の入院の長期化、ならびに処置費用の増大が含まれる。
したがって、β−ラクタマーゼ阻害剤(BLI)を合成する効率的な方法が必要である。
式(A−I)の化合物
有機ホウ素中間体を式(A−III)の化合物に変換するステップと
を含み、式中、R1は、カルボン酸保護基である、方法に関する。
式(A−III)の化合物を加水分解して、式(I)の化合物を形成するステップと
を含む、方法に関する。
式(A−II)の化合物
を含む、方法に関する。
式(A−V)の化合物
式(A−VI’)の化合物を式(A−I)の化合物に変換するステップと、
式(A−I)の化合物を加水分解して、式(A−I’)の化合物を形成するステップとを含み、
式中:
R1は、カルボン酸保護基である、方法に関する。一部の実施形態では、R1は、C1〜6アルキルである。
化合物Aおよび薬学的に許容されるその塩は、その全体が参照によって本明細書に組み込まれる国際出願PCT/US2017/039787に記載されている。化合物Aは、β−ラクタム抗生物質と組み合わせて使用される場合に、細菌感染を処置するのに有効なβ−ラクタマーゼ阻害剤である。
式(A−I)の化合物
有機ホウ素中間体を式(A−III)の化合物
式(A−III)の化合物を加水分解して、式(I)の化合物を形成するステップと
を含み、
式中:
R1は、カルボン酸保護基である、方法に関する。
式(A−III)の化合物を加水分解して、式(I)の化合物を形成するステップと
を含み、
式中:
R1は、カルボン酸保護基であり、
Raは、OHまたは必要に応じて置換されている−O−C1〜6アルキルである、方法に関する。
式(A−II)の化合物
キラル錯体をシクロプロピル化剤と反応させて、式(III)の化合物
式(A−III)の化合物を加水分解して、式(I)の化合物を形成するステップと
をさらに含み、
式中:
R1は、カルボン酸保護基であり、
Raは、OHまたは必要に応じて置換されている−O−C1〜6アルキルであり、
RcおよびRdは、任意の介在する原子と共に、必要に応じて置換されている4〜7員のヘテロシクリル環を形成する。
キラル錯体をシクロプロピル化剤と反応させて、式(III)の化合物
式中:
R1は、カルボン酸保護基であり、
Raは、OHまたは必要に応じて置換されている−O−C1〜6アルキルである、方法に関する。
式(A−V)の化合物
式(A−VI’)の化合物を式(A−I)の化合物に変換するステップと、
式(A−I)の化合物を還元し、加水分解して、式(A−I’)の化合物を形成するステップとを含み、式中、R1は、カルボン酸保護基である、方法に関する。
定義
ら選択される。
保護基
エチル6−フルオロベンゾフラン−7−カルボキシレートの合成
ベンゾフラン1は、化合物Aを調製するための中間体であり、それを、スキーム1Aに示される通り3つのステップで合成した。メタンスルホン酸を用いるエタノール中6−フルオロ−サリチル酸(1a)のフィッシャーエステル化は、ゆっくり進行させて(2〜3日)、1bを優れた収率で得た。次に、フェノール基をDMF中t−BuOKの存在下で100℃においてブロモアセトアルデヒドジエチルアセタールでアルキル化して、ベンゾフラン前駆体1cを定量的収率で得た。次に、90℃におけるジクロロエタン中Amberlyst15(スルホン酸樹脂)で閉環を達成して、所望のベンゾフラン1を40〜45%の全収率で得た。
ベンゾフラン前駆体1c
ベンゾフラン1の合成
(実施例2)
(実施例3)
化合物Aの合成
化合物rac−3の異性体の分離
25%NaOH(2.3mL)を、エチルエステル3(760mg)のジオキサン(2.3mL)溶液に室温で添加した。反応混合物を室温で3日間撹拌し、その後HPLCは、出発材料が残っていないことを示す。透明なオレンジ溶液のpHを、6NのHClを用いて8.0に低減した。溶液をMTBEで抽出して、有機物を除去した。水層を濃縮乾固して、ジオキサンを除去した。残留物を水(5mL)に溶かし、シリンジフィルターを介して濾過した。透明なオレンジ色の濾液を濃縮乾固させた。残留物を水(2mL)に溶かし、ジオキサン(12mL)を添加した。二相性の不均一な混合物が得られた。室温で一晩撹拌した後、固体を濾過によって収集し、アセトンですすぎ、風乾させ、次に高真空下で乾燥させて、化合物Aを濁った白色の粉末452mg(収率52%)として得た。二相性の濾液を、週末にわたって室温で静置した。固体が見られ、それを収集し、次にジオキサンですすぎ、乾燥させて、第2の収穫物275mg(収率32%)を得た。
(実施例4)
(実施例5)
(実施例6)
(実施例7)
(実施例8)
(実施例9)
(実施例11)
(実施例12)
(実施例15)
(実施例16)
(実施例17)
(実施例18)
(実施例19)
(実施例20)
(実施例21)
(実施例22)
(実施例22)
(実施例23)
Claims (80)
- 式(I)の化合物または薬学的に許容されるその塩
式(A−I)の化合物
前記有機ホウ素中間体を、式(A−III)の化合物
前記式(A−III)の化合物を加水分解して、前記式(I)の化合物を形成するステップとを含み、
式中:
R1は、カルボン酸保護基である、方法。 - 前記有機ホウ素中間体が、式(A−II)
Raは、OHまたは必要に応じて置換されている−O−C1〜6アルキルである]
の構造を有する、請求項1に記載の方法。 - 前記有機ホウ素中間体が、1つまたは複数のキラル補助剤と組み合わされて、式(A−II’)
の構造を有するキラル錯体を形成する、請求項1に記載の方法。 - 前記ホウ素化剤が、(R2O)2B−B(OR2)2であり、式中、各R2が、独立に、H、必要に応じて置換されているC1〜6アルキルであるか、または、2つのR2が一緒になって、必要に応じて置換されているC2〜4アルキレン鎖になり、介在する原子と共に、必要に応じて置換されている5〜7員のヘテロシクリル環を形成する、請求項1から3のいずれか一項に記載の方法。
- 前記ホウ素化剤が、(HO)2B−B(OH)2、B2(Pin)2、B2(Cat)2、およびB2neop2からなる群から選択される、請求項1から4のいずれか一項に記載の方法。
- 前記ホウ素化剤が、B2(Pin)2である、請求項1から5のいずれか一項に記載の方法。
- 前記式(A−I)の化合物および前記ホウ素化剤の反応が、第1の触媒の存在下で実施される、請求項1から6のいずれか一項に記載の方法。
- 前記第1の触媒が、1つまたは複数のNi触媒前駆体および1つまたは複数の配位子配位子を含む、請求項7に記載の方法。
- 前記Ni触媒前駆体が、NiCl2、Ni(Acac)2、Ni(COD)2、NiCl2(PPh3)2、NiCl2(PCy2Ph)2、NiCl2(PPh2CH2CH2PPh2)、NiCl2(1,3−ビス(ジフェニルホスフィノ)プロパン)、およびNiCl2(1,3−ビス(ジフェニルホスフィノ)エタン)からなる群から選択される、請求項8に記載の方法。
- 前記Ni触媒前駆体が、NiCl2またはNi(Acac)2である、請求項8または9に記載の方法。
- 前記配位子が、単座または二座である、請求項8から10のいずれか一項に記載の方法。
- 前記配位子が、NHC配位子、ホスフィン、ホスファイト、ホスホラミダイト、アミン、アルコール、アミノアルコール、およびそれらの組合せからなる群から選択される、請求項8から11のいずれか一項に記載の方法。
- 前記配位子または触媒が、ビス(ジ−シクロペンチルホスフィニウム)エチルテトラフルオロボレート、4,5−ビス(ジ−tert−ブチルホスフィノ)−9,9−ジメチルキサンテン、2,2’−ビス(ジシクロヘキシルホスファニル)−1,1’−ビフェニル、1,2−ビス((ジ−tert−ブチルホスファニル)メチル)ベンゼン、1,3−ビス(1−アダマンチル)イミダゾリウム、1,3−ジ−tert−ブチルイミダゾリウム、1,3−ビス(2,6−ジイソプロピル−フェニル)−4,5−ジヒドロイミダゾール−2−イリデン、1,3−ビス(2,6−ジイソプロピルフェニル)−1H−イミダゾール−3−イウム−2−イド、P(オクチル)3、Dppf、DiPrf、dcype、JosiPhos 9−1、(S,S,R,R)−TangPhos、(S,S,R,R)−DuanPhos、DavePhos、P(tBu)3、XantPhos、(tBu)XantPhos、(R)−SegPhos、(R)−DM−SegPhos、(R)−MeOBIPHEP、(R,S)−BinaPhos、Binaphane、ホスホラミダイト、(S)−SegphosRu(Oac)2、trans−PdCl2(Pcy3)2、[Rh(S,S)EtDuPhos(COD)]Otf、(S)−XylylPhanePhos、(R)−C3−TunePhos、(R)−DTBM−Garphos、(R)−DMM−Garphos、(R,R,R)−Xyl−SKP、Thio−XantPhos、TaniaPhos、SPANPhos、トリス(4−メトキシフェニル)ホスフィン、トリス(2,6−ジメトキシフェニル)ホスフィン、トリオクチルホスフィン、ビス(ジシクロヘキシルホスフィノ)メタン)、DCYPE、1,3−ビス(ジシクロヘキシルホスフィノ)プロパン、1,2−ビス(ジフェニルホスフィノ)エタン、(R,R)−Dipamp、ビス(ジシクロヘキシルホスフィノフェニル)エーテル、DPEPhos、ビス(2−ジフェニルホスフィノエチル)フェニルホスフィン、1,1,1−トリス(ジフェニルホスフィノメチル)エタン、DPPF、1,1’−フェロセンジイル−ビス(ジシクロヘキシルホスフィン)、DTBPF、DiPrF、1−ジフェニルホスフィノ−1’−(ジ−ブチルホスフィノ)フェロセン、HiersoPhos、iPr(NHC)、SIMes、IMes、および(1,3−ビス[ビス(o−メトキシフェニル)ホスフィノ]プロパンからなる群から選択される、請求項8から12のいずれか一項に記載の方法。
- 前記配位子が、P(オクチル)3、diPrf、またはdcypeである、請求項7から13のいずれか一項に記載の方法。
- 前記式(A−I)の化合物および前記ホウ素化剤の反応が、塩基系の存在下で実施される、請求項1から14のいずれか一項に記載の方法。
- 前記塩基系が、1つまたは複数の無機塩基を含む、請求項15に記載の方法。
- 前記塩基系が、K2CO3、Cs2CO3、Li2CO3、またはそれらの任意の組合せを含む、請求項15または16に記載の方法。
- 前記塩基系が、K2CO3およびCs2CO3の混合物を含み、K2CO3およびCs2CO3のモル比が、約5:1〜15:1の範囲である、請求項15から17のいずれか一項に記載の方法。
- 前記式(A−I)の化合物および前記ホウ素化剤の反応が、有機溶媒中で実施される、請求項1から18のいずれか一項に記載の方法。
- 前記有機溶媒が、トルエン、キシレン、またはTHFである、請求項19に記載の方法。
- 前記式(A−I)の化合物および前記ホウ素化剤の反応が、約70℃〜100℃の範囲の温度で実施される、請求項1から20のいずれか一項に記載の方法。
- 前記式(A−I)の化合物および前記ホウ素化剤の反応が、約90℃の温度で実施される、請求項1から21のいずれか一項に記載の方法。
- 前記有機ホウ素中間体を変換する前記ステップが、前記有機ホウ素中間体をシクロプロピル化剤と反応させることを含む、請求項1から22のいずれか一項に記載の方法。
- 前記有機ホウ素中間体を変換する前記ステップが、前記有機ホウ素中間体および1つまたは複数のキラル補助剤を組み合わせてキラル錯体を形成すること、および前記キラル錯体をシクロプロピル化剤と反応させることを含む、請求項1から22のいずれか一項に記載の方法。
- 前記シクロプロピル化剤が、カルベノイドまたはジアゾメタンを含む、請求項23または24に記載の方法。
- 前記シクロプロピル化剤が、ジアゾメタンを含む、請求項23から25のいずれか一項に記載の方法。
- 前記シクロプロピル化剤を用いる前記反応が、第2の触媒の存在下で実施される、請求項24から26のいずれか一項に記載の方法。
- 前記第2の触媒が、金属触媒を含む、請求項27に記載の方法。
- 前記金属触媒が、Pd触媒、Cu触媒、Zn触媒、Fe触媒、Mn触媒、またはRh触媒から選択される、請求項24に記載の方法。
- 第2の触媒が、Pd触媒である、請求項23から25のいずれか一項に記載の方法。
- 前記Pd触媒が、Pd(OAc)2である、請求項28に記載の方法。
- 前記キラル補助剤が、モノアルコール、ジオール、アミノアルコール、ジアミン、およびヒドロキシル酸、およびエステルからなる群から選択される、請求項24から31のいずれか一項に記載の方法。
- 前記キラル補助剤が、(R)−(+)−1−フェニルエタノール、L−メントール、(−)−ボルネオール、(4S,5S)−2,2−ジメチル−α,α,α’,α’−テトラフェニルジオキソラン−4,5−ジメタノール、(R)−(+)−1,1’−ビス(2−ナフトール)、(R)−(−)−2−フェニルグリシノール、(R)−(−)−2−アミノ−1−フェニルエタノール、(S,S)−(−)−2−アミノ−1,2−ジフェニルエタノール、(R)−(−)−2−ピロリジンメタノール、(R)−(+)−α,α,−ジフェニル−2−ピロリジンメタノール、(1R,2S)−(−)−エフェドリン、(1R,2R)−(+)−1,2−ジフェニルエチレンジアミン、(1R,2R)−(−)−N−p−トシル−1,2−ジフェニルエチレンジアミン、L−(+)−乳酸、(R)−(−)−マンデル酸、(−)−メチルL−ラクテート、L−(+)酒石酸、L−(+)−酒石酸ジメチルエステル、(1S,2S)−(+)−プソイドエフェドリン、(1R,2S)−(−)−ノルエフェドリン、(1R,2S)−(−)−N−メチルエフェドリン、(S)−2−(ピロリジン−2−イル)プロパン−2−オール、N−メチル−D−グルカミン、(1R,2R)−(−)−2−アミノ−1−(4−ニトロフェニル)−1,3−プロパンジオール、キニーネ、およびヒドロキニンからなる群から選択される、請求項24または32のいずれか一項に記載の方法。
- 前記キラル補助剤が、エフェドリンまたはエフェドリン誘導体である、請求項24から33のいずれか一項に記載の方法。
- 前記キラル補助剤が、(1S,2S)−(+)−プソイドエフェドリンである、請求項34に記載の方法。
- 加水分解する前記ステップの前に、前記式(A−III)の化合物を精製するステップをさらに含む、請求項1から35のいずれか一項に記載の方法。
- 前記精製が、クロマトグラフィーまたは結晶化を使用して実施される、請求項35に記載の方法。
- 前記式(A−III)の化合物を加水分解する前記ステップが、塩基を使用して実施される、請求項1から37のいずれか一項に記載の方法。
- 前記塩基が、NaOHである、請求項38に記載の方法。
- R1が、C1〜6アルキルである、請求項1から39のいずれか一項に記載の方法。
- R1が、エチルである、請求項1から40のいずれか一項に記載の方法。
- 式(I)の化合物または薬学的に許容されるその塩
式(A−II)の化合物
前記式(A−III)の化合物を加水分解して、前記式(I)の化合物を形成するステップとを含み、
式中:
R1は、カルボン酸保護基であり、
Raは、OHまたは必要に応じて置換されている−O−C1〜6アルキルである、
方法。 - 前記式(A−II)の化合物を前記式(A−III)の化合物へ変換する前記ステップが、前記式(A−II)の化合物および1つまたは複数のキラル補助剤を組み合わせて、式(A−II’)
前記キラル錯体をシクロプロピル化剤と反応させることとを含み、式中、RcおよびRdは、任意の介在する原子と共に、必要に応じて置換されている4〜7員のヘテロシクリル環を形成する
、請求項42に記載の方法。 - 式(I)の化合物または薬学的に許容されるその塩
式(A−II’)
前記式(A−III)の化合物を加水分解して、前記式(I)の化合物を形成するステップとを含み、
式中:
R1は、カルボン酸保護基であり、
RcおよびRdは、任意の介在する原子と共に、必要に応じて置換されている4〜7員のヘテロシクリル環を形成する、方法。 - 式(A−II)の化合物
式(A−I)の化合物
式中:
R1は、カルボン酸保護基であり、
Raは、OHまたは必要に応じて置換されている−O−C1〜6アルキルである、方法。 - 前記式(I)の化合物を精製するステップをさらに含む、請求項1から41および45のいずれか一項に記載の方法。
- 前記式(A−I)の化合物が、
- 前記式(A−II)の化合物が、
- 前記式(A−III)の化合物が、
- 前記式(I)の化合物が、
- 前記式(I)の化合物または薬学的に許容されるその塩が、
- 式(A−I)の化合物
式(A−V)の化合物
前記式(A−VI)の化合物を前記式(A−I)の化合物に変換するステップとを含み、
式中:
R1は、カルボン酸保護基であり、
各R3は、独立に、必要に応じて置換されているC1〜6アルキルであるか、または2つのR3は一緒になって、必要に応じて置換されているC2〜3アルキレンになり、介在する原子と共に、必要に応じて置換されている5〜6員のヘテロシクリル環を形成する、方法。 - 前記アルキル化剤が、CH(OR3)2CH2Xであり、Xが、ハロゲンである、請求項52に記載の方法。
- 前記アルキル化剤が、CH(OEt)2CH2Brである、請求項52または53に記載の方法。
- 式(A−IV)の化合物
- 前記式(A−V)の化合物が、
- 前記式(A−VI)の化合物が、
- 前記式(A−I)の化合物が、
- 式(A−I’)の化合物
式(A−V)の化合物
前記式(A−VI’)の化合物を式(A−I)の化合物に変換するステップと、
前記式(A−I)の化合物を加水分解して、前記式(A−I’)の化合物を形成するステップとを含み、
式中:
R1は、カルボン酸保護基である、方法。 - 前記アルキル化剤が、COOR4CH2Xであり、式中、R4が、必要に応じて置換されているC1〜6アルキルであり、Xが、ハロゲンである、請求項59に記載の方法。
- 前記アルキル化剤が、COOMeCH2Clである、請求項59または60に記載の方法。
- 式(A−IV)の化合物
- 式(A−IV)の化合物
- 前記式(A−V)の化合物が、
- 前記式(A−VI’)の化合物が、
- 前記式(A−VI’)の化合物の前記式(A−I)の化合物への変換が、前記式(A−VI’)の化合物を式(A−VII’)の化合物
- 前記式(A−I)の化合物が、
- 式(A−VII’)の化合物が、
-
の構造を有する化合物。 -
-
の構造を有する化合物。 -
- 式(A−VI’)
の構造を有する化合物。 -
-
の構造を有する化合物。 -
-
の構造を有する化合物。 -
-
-
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METHYL 6-FLUORO-7-BENZOFURANCARBOXYLATE(RN 1427326-65-5), JPN7022004710, 5 April 2013 (2013-04-05), ISSN: 0005067077 * |
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