JP2023524262A - スルホンアミド中間体の合成 - Google Patents
スルホンアミド中間体の合成 Download PDFInfo
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- JP2023524262A JP2023524262A JP2022566652A JP2022566652A JP2023524262A JP 2023524262 A JP2023524262 A JP 2023524262A JP 2022566652 A JP2022566652 A JP 2022566652A JP 2022566652 A JP2022566652 A JP 2022566652A JP 2023524262 A JP2023524262 A JP 2023524262A
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- sodium
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- 239000000543 intermediate Substances 0.000 title abstract description 22
- 230000015572 biosynthetic process Effects 0.000 title description 21
- 238000003786 synthesis reaction Methods 0.000 title description 16
- 229940124530 sulfonamide Drugs 0.000 title description 9
- 150000003456 sulfonamides Chemical class 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 200
- 238000000034 method Methods 0.000 claims abstract description 115
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000012453 solvate Substances 0.000 claims abstract description 16
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- 239000002585 base Substances 0.000 claims description 83
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 63
- 238000002156 mixing Methods 0.000 claims description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- 230000000269 nucleophilic effect Effects 0.000 claims description 46
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 35
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 claims description 34
- 239000003960 organic solvent Substances 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 26
- 238000007254 oxidation reaction Methods 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 25
- 230000003647 oxidation Effects 0.000 claims description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 claims description 20
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 20
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 19
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 18
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 16
- 239000012038 nucleophile Substances 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 235000017281 sodium acetate Nutrition 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- 239000001632 sodium acetate Substances 0.000 claims description 12
- -1 alkali metal cation Chemical group 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical group [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 6
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- OWBTYPJTUOEWEK-IMJSIDKUSA-N (S,S)-butane-2,3-diol Chemical compound C[C@H](O)[C@H](C)O OWBTYPJTUOEWEK-IMJSIDKUSA-N 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- QPDJILZPDAMLFH-UHFFFAOYSA-N lithium;2-methylbutan-2-olate Chemical compound [Li]OC(C)(C)CC QPDJILZPDAMLFH-UHFFFAOYSA-N 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- ZMJJCODMIXQWCQ-UHFFFAOYSA-N potassium;di(propan-2-yl)azanide Chemical compound [K+].CC(C)[N-]C(C)C ZMJJCODMIXQWCQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229940087562 sodium acetate trihydrate Drugs 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- 229910020667 PBr3 Inorganic materials 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 150000004820 halides Chemical group 0.000 claims description 2
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 claims description 2
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 claims description 2
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims 2
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 claims 1
- HZALVOVUCVCATF-UHFFFAOYSA-N (hydroxyamino)oxy hydrogen sulfate Chemical compound ONOOS(O)(=O)=O HZALVOVUCVCATF-UHFFFAOYSA-N 0.000 claims 1
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 claims 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims 1
- 229910004354 OF 20 W Inorganic materials 0.000 claims 1
- 239000012973 diazabicyclooctane Substances 0.000 claims 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims 1
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 abstract description 24
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 abstract description 24
- 239000003112 inhibitor Substances 0.000 abstract description 16
- 239000000243 solution Substances 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000004076 pyridyl group Chemical group 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000007800 oxidant agent Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 241000534944 Thia Species 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000012455 biphasic mixture Substances 0.000 description 5
- 230000031709 bromination Effects 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000051485 Bcl-2 family Human genes 0.000 description 3
- 108700038897 Bcl-2 family Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000006735 epoxidation reaction Methods 0.000 description 3
- 150000002440 hydroxy compounds Chemical class 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000002924 oxiranes Chemical class 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- KSXVDBSINBXKGA-BQBZGAKWSA-N (2S,3S)-3-methylhex-5-en-2-ol Chemical compound C[C@H]([C@H](C)O)CC=C KSXVDBSINBXKGA-BQBZGAKWSA-N 0.000 description 2
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- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- UAENTLSAGQVMDD-UHNVWZDZSA-N [(2S,3R)-3-bromobutan-2-yl] acetate Chemical compound C(C)(=O)O[C@@H](C)[C@@H](C)Br UAENTLSAGQVMDD-UHNVWZDZSA-N 0.000 description 1
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- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
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- 125000004429 atom Chemical group 0.000 description 1
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- 229960004106 citric acid Drugs 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 231100000722 genetic damage Toxicity 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
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- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
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- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
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- CYSFUFRXDOAOMP-UHFFFAOYSA-M magnesium;prop-1-ene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C=C CYSFUFRXDOAOMP-UHFFFAOYSA-M 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 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
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical class OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- KBLZDCFTQSIIOH-UHFFFAOYSA-M tetrabutylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC KBLZDCFTQSIIOH-UHFFFAOYSA-M 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
- C07C29/103—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers
- C07C29/106—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes of cyclic ethers of oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/11—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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Abstract
Description
本出願は、2020年5月6日に出願された米国仮特許出願第63/020,951号明細書の利益を主張するものであり、この明細書は、あたかも本明細書に完全に記載されているかの如く、あらゆる目的のためにその全体が参照により本明細書に組み込まれる。
(a)(2S,3S)-ブタン-2,3-ジオール、臭化物源、及び酢酸を混合して、化合物I
(b)化合物I、及び非求核塩基を混合して、化合物J
(c)化合物J、及びアリル求核試薬を混合して、化合物K
(d)化合物K、脱離基試薬、及びアミン塩基を混合して、化合物L
(e)化合物L、非求核塩基、及びAr1-SHを混合して、化合物M
(f)化合物Mを酸化させて、化合物N
(g)化合物N、塩基、及びヒドロキシルアミン-O-スルホン酸を混合して、化合物Zを形成することを含む方法である。
本開示の方法は、化合物Iを得るための2S,3S-ブタン-ジオールの臭素化及びアセチル化を含み、この臭素化及びアセチル化は、2S,3S-ブタン-ジオール、臭化物源、及び酢酸を混合することを含む。
本開示の方法は、化合物Jを得るための化合物Iのエポキシ化を含み得る。本明細書の方法は、化合物I及び非求核塩基を混合して化合物Jを形成することにより化合物Jを合成することを含み得る。本明細書で提供される場合、化合物Jは、
本開示の方法は、化合物Kを得るための化合物Jへのアリル付加を含む。本明細書の方法は、化合物J及びアリル求核試薬を混合して化合物Kを形成することにより化合物Kを合成することを含み得る。本明細書で提供される場合、化合物Kは、
本開示の方法は、化合物Lを得るための化合物Kへの脱離基(LG)付加を含む。本明細書の方法は、化合物K、脱離基試薬、及びアミン塩基を混合して化合物Lを形成することにより化合物Lを合成することを含み得る。本明細書で提供される場合、化合物Lは、
本開示の方法は、化合物Mを得るための化合物Lの求核置換を含む。本明細書の方法は、化合物L、非求核塩基、及びAr1-SHを混合して化合物Mを形成することにより化合物Mを合成することを含む。本明細書で提供される場合、化合物Mは、
本開示の方法は、化合物Nを得るための化合物Mの酸化を含む。この酸化は、化合物M及び酸化剤を混合して化合物Nを形成することを含む。本明細書で提供される場合、化合物Nは、
本開示の方法は、化合物Zを得るための化合物Nスルホンアミド化を含む(工程(g))。このスルホンアミド化は、化合物N、塩基、及びヒドロキシルアミン-O-スルホン酸を混合して化合物Zを形成することを含む。本明細書で提供される場合、化合物Zは、
1H NMR(300MHz,CDCl3)δ 2.64-2.58(m,2H),1.19-1.15(m,6H).
1H NMR(500MHz,DMSO-d6)δ 8.81(dd,J=1.2,5.1Hz,1H),8.18(ddd,J=1.2,7.9,8.2Hz,1H),8.08(d,J=7.9Hz,1H),7.77(dd,J=5.1,8.2Hz,1H),5.68(m,1H),5.05(m,2H),3.70(m,1H),2.26(m,1H),2.05(m,2H),1.09(d,J=7.2Hz,3H),0.98(d,J=7.2Hz,3H).LRMS(ESI):C12H17N1S1+Hについての計算値:208.3、実測値:208.3。IR(無溶媒)vmax 3086,2980,2966,2934,1450,1428,1304,1108,794,593,541。
1H NMR(500MHz,DMSO-d6)δ 6.69(s,2H),5.75(m,1H),5.06(m,2H),2.92(m,1H),2.31(m,1H),2.03(m,2H),1.17(d,J=7.2Hz,3H),0.92(d,J=7.2Hz,3H).LRMS(ESI):C7H15N1O2S1+Naについての計算値:200.1、実測値:200.1。IR(無溶媒)vmax 3323,3255,2980,2962,1556,1452,1312,1165,11137,900,593,548,511。
Claims (80)
- 化合物Z
(a)(2S,3S)-ブタン-2,3-ジオール、臭化物源、及び酢酸を混合して、化合物I
(b)化合物I、及び非求核塩基を混合して、化合物J
(c)化合物J、及びアリル求核試薬を混合して、化合物K
(d)化合物K、脱離基試薬、及びアミン塩基を混合して、化合物L
を形成すること;
(e)化合物L、非求核塩基、及びAr1-SHを混合して、化合物M
を形成すること;
(f)化合物Mを酸化させて、化合物N
並びに
(g)化合物N、塩基、及びヒドロキシルアミン-O-スルホン酸を混合して、化合物Zを形成すること
を含む方法。 - 前記臭化物源は、HBr、PBr3、又はこれらの組合せを含む、請求項1に記載の方法。
- HBrは、20w/w%~50w/w%の量で酢酸中に存在する、請求項2に記載の方法。
- HBrは、酢酸中に33w/w%溶液として存在する、請求項3に記載の方法。
- 工程(a)の前記混合を、-20℃~10℃の温度で行なう、請求項1~4のいずれか一項に記載の方法。
- 工程(a)の前記混合を、1時間~24時間にわたり行なう、請求項1~5のいずれか一項に記載の方法。
- 工程(a)の前記混合を、15時間~20時間にわたり行なう、請求項6に記載の方法。
- 工程(b)は、モノエチレングリコールをさらに含む、請求項1~7のいずれか一項に記載の方法。
- 工程(b)に関して、化合物Iと混合する前に、前記非求核塩基及びモノエチレングリコールを一緒に撹拌する、請求項8に記載の方法。
- 前記非求核塩基及びモノエチレングリコールを、25℃~40℃の温度で一緒に撹拌する、請求項9に記載の方法。
- 前記非求核塩基は、リチウム tert-ブトキシド、ナトリウム tert-ブトキシド、カリウム tert-ブトキシド、ナトリウム tert-アミレート、カリウムアミレート、又はこれらの組合せを含む、請求項1~10のいずれか一項に記載の方法。
- 前記非求核塩基は、カリウム tert-ブトキシドを含む、請求項11に記載の方法。
- 工程(b)の前記混合を、tert-ブチルメチルエーテル、2-メチルテトラヒドロフラン、シクロペンチルメチルエーテル、ジメトキシエタン、又はこれらの組合せを含む有機溶媒中で行なう、請求項1~12のいずれか一項に記載の方法。
- 前記有機溶媒は、tert-ブチルメチルエーテルを含む、請求項13に記載の方法。
- 工程(b)の前記混合を、10分~2時間にわたり行なう、請求項1~14のいずれか一項に記載の方法。
- 工程(b)の前記混合を、30分にわたり行なう、請求項15に記載の方法。
- 工程(b)の前記混合を、70℃~120℃の温度で行なう、請求項1~16のいずれか一項に記載の方法。
- Xは、Clである、請求項18に記載の方法。
- 工程(c)の前記混合を、テトラヒドロフラン、2-メチルテトラヒドロフラン、tert-ブチルメチルエーテル(MTBE)、シクロペンチルメチルエーテル、ジメトキシエタン、又はこれらの組合せを含む有機溶媒中で行なう、請求項1~19のいずれか一項に記載の方法。
- 前記有機溶媒は、テトラヒドロフラン及びMTBEを含む、請求項20に記載の方法。
- 化合物Jを、1時間~5時間かけて前記アリル求核試薬に滴下する、請求項1~21のいずれか一項に記載の方法。
- 工程(c)の前記混合を、1時間~6時間にわたり行なう、請求項1~22のいずれか一項に記載の方法。
- 工程(c)の前記混合を、3時間にわたり行なう、請求項23に記載の方法。
- 工程(c)の前記混合を、-20℃~10℃の温度で行なう、請求項1~24のいずれか一項に記載の方法。
- 化合物J及び前記アリル求核試薬は、1:1.05~1:3のモル比で存在する、請求項1~25のいずれか一項に記載の方法。
- 脱離基は、F、Cl、Br、I、メシル、トシル、ノシル、又はトリフリルを含む、請求項1~26のいずれか一項に記載の方法。
- 前記脱離基は、メシルである、請求項27に記載の方法。
- 前記脱離基試薬は、塩化メシル、塩化トシル、塩化ノシル、メタンスルホン酸無水物、パラトルエンスルホン酸無水物、又はこれらの組合せを含む、請求項27又は28に記載の方法。
- 前記脱離基試薬は、塩化メシルである、請求項29に記載の方法。
- 工程(d)の前記混合を、ジクロロメタン、テトラヒドロフラン、2-メチルテトラヒドロフラン、tert-ブチルメチルエーテル、又はこれらの組合せを含む有機溶媒中で行なう、請求項1~30のいずれか一項に記載の方法。
- 前記有機溶媒は、テトラヒドロフランを含む、請求項31に記載の方法。
- 前記有機溶媒は、ジクロロメタンを含まない、請求項31又は32に記載の方法。
- 前記脱離基試薬を、化合物K及び前記アミン塩基を含む溶液に添加する、請求項1~33のいずれか一項に記載の方法。
- 前記脱離基試薬を、2時間~3時間かけて前記溶液に添加し、次いで10分~1時間にわたり撹拌する、請求項34に記載の方法。
- 工程(d)の前記アミン塩基は、トリメチルアミン、ピリジン、トリエチルアミン、アニリン、ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)、1,4-ジアザビシクロ[2.2.2]オクタン(DABCO)、2,6-ルチジン、又はこれらの組合せを含む、請求項1~35のいずれか一項に記載の方法。
- 前記アミン塩基は、トリエチルアミンを含む、請求項36に記載の方法。
- 工程(d)の前記混合を、-10℃~10℃の温度で行なう、請求項1~37のいずれか一項に記載の方法。
- 前記脱離基は、化合物Kを基準として、1.2~2モル当量で存在する、請求項1~38のいずれか一項に記載の方法。
- 前記アミン塩基は、化合物Kを基準として、1.8~3.3モル当量で存在する、請求項1~39のいずれか一項に記載の方法。
- 工程(e)に関して、化合物Lを、Ar1-SH及び前記非求核塩基を含む混合物に添加する、請求項1~40のいずれか一項に記載の方法。
- 化合物Lを、3~6時間かけて滴下する、請求項41に記載の方法。
- 工程(e)の前記非求核塩基は、リチウムヘキサメチルジシラジド(「HMDS」)、ナトリウムHMDS、カリウムHMDS、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウム tert-ブトキシド、ナトリウム tert-ブトキシド、カリウム tert-ブトキシド、リチウム tert-アミレート、ナトリウム tert-アミレート、カリウム tert-アミレート、又はこれらの組合せを含む、請求項1~42のいずれか一項に記載の方法。
- 前記非求核塩基は、ナトリウム tert-ブトキシド、カリウム tert-ブトキシド、又はナトリウム tert-アミレートを含む、請求項43に記載の方法。
- 化合物L及び工程(e)の前記非求核塩基は、1:1.1~1:4のモル比で存在する、請求項1~44のいずれか一項に記載の方法。
- 化合物L及びAr1-SHは、1:1.05~1:2.5のモル比で存在する、請求項1~47のいずれか一項に記載の方法。
- 化合物L、Ar1-SH、及び非求核塩基の工程(e)の前記混合を、3時間~5時間にわたり行なう、請求項1~48のいずれか一項に記載の方法。
- 工程(e)の前記混合を、60℃~80℃の温度で行なう、請求項1~49のいずれか一項に記載の方法。
- 工程(f)の前記酸化の前に、化合物Mを、水酸化ナトリウム水溶液で3~5回洗浄する、請求項1~50のいずれか一項に記載の方法。
- 工程(f)の前記酸化が、化合物Mと、酸化触媒及び過酸化水素とを混合することを含む、請求項1~51のいずれか一項に記載の方法。
- 前記酸化触媒は、タングステン酸ナトリウム脱水和物、3-クロロ過安息香酸、又はこれらの組合せである、請求項52に記載の方法。
- 前記酸化触媒は、タングステン酸ナトリウム脱水和物である、請求項53に記載の方法。
- 化合物M及び前記酸化触媒は、1:0.05~1:0.5のモル比で存在する、請求項52~54のいずれか一項に記載の方法。
- 前記酸化が、酢酸を混合することをさらに含む、請求項52~55のいずれか一項に記載の方法。
- 化合物M及び過酸化水素は、1:1.3~1:5のモル比で存在する、請求項52~56のいずれか一項に記載の方法。
- 工程(f)の前記酸化を、溶媒中で行なう、請求項1~57のいずれか一項に記載の方法。
- 前記溶媒は、メタノール又はエタノールを含む、請求項58に記載の方法。
- 過酸化水素を添加する前に、化合物M、前記酸化触媒、及び酢酸を混合する、請求項52~59のいずれか一項に記載の方法。
- 過酸化水素を、3時間~5時間かけて添加する、請求項60に記載の方法。
- 工程(f)の前記酸化を、20℃~25℃の温度で行なう、請求項1~61のいずれか一項に記載の方法。
- 化合物N及び前記塩基の前記混合を、tert-ブチルメチルエーテル、メタノール、テトラヒドロフラン、2-メチルテトラヒドロフラン、又はこれらの組合せを含む溶媒中で行なう、請求項63に記載の方法。
- 前記溶媒は、tert-ブチルメチルエーテル及びメタノールを含む、請求項64に記載の方法。
- 化合物N及び前記塩基の前記混合を、25℃~50℃の温度で行なう、請求項63~65のいずれか一項に記載の方法。
- 前記塩基は、ナトリウムチオメトキシド、ナトリウムメトキシド、メタノール、及び炭酸カリウム、又はこれらの組合せを含む、請求項63~66のいずれか一項に記載の方法。
- 前記塩基は、ナトリウムチオメトキシドである、請求項67に記載の方法。
- ヒドロキシルアミン-O-スルホン酸を、酢酸ナトリウム、酢酸カリウム、ギ酸ナトリウム、ギ酸カリウム、又はこれらの組合せと共に、前記中間体化合物Oに添加する、請求項63~68のいずれか一項に記載の方法。
- ヒドロキシルアミン-O-スルホン酸を、酢酸ナトリウム三水和物と共に前記中間体化合物Oに添加する、請求項69に記載の方法。
- 前記中間体化合物O、ヒドロキシルアミン-O-スルホン酸、及び酢酸ナトリウムの前記混合を、tert-ブチルメチルエーテル、メタノール、テトラヒドロフラン、2-メチルテトラヒドロフラン、又はこれらの組合せを含む溶媒中で行なう、請求項70に記載の方法。
- 前記中間体化合物O、ヒドロキシルアミン-O-スルホン酸、及び酢酸ナトリウムの前記混合を、30分~4時間にわたり行なう、請求項63~71のいずれか一項に記載の方法。
- 前記中間体化合物O、ヒドロキシルアミン-O-スルホン酸、及び酢酸ナトリウムの前記混合を、2時間にわたり行なう、請求項72に記載の方法。
- 前記中間体化合物O、ヒドロキシルアミン-O-スルホン酸、及び酢酸ナトリウムの前記混合を、25℃~50℃の温度で行なう、請求項1~73のいずれか一項に記載の方法。
- 化合物Zを結晶化させることをさらに含む請求項1~74のいずれか一項に記載の方法。
- 前記結晶化が、化合物Zの溶液を40℃~45℃まで加熱すること、次いで、前記溶液を10℃~15℃まで冷却すること、及び前記冷却した溶液に結晶化溶媒を添加して化合物Zの結晶を形成することを含む、請求項75に記載の方法。
- 前記化合物Zの溶液は、tert-ブチルメチルエーテルを含み、前記結晶化溶媒は、ヘプタンを含む、請求項76に記載の方法。
- 前記化合物Zの溶液は、メタノールを含み、前記結晶化溶媒は、水を含む、請求項76に記載の方法。
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