JP2022532875A - Cracチャネル阻害剤の合成 - Google Patents
Cracチャネル阻害剤の合成 Download PDFInfo
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- JP2022532875A JP2022532875A JP2021566157A JP2021566157A JP2022532875A JP 2022532875 A JP2022532875 A JP 2022532875A JP 2021566157 A JP2021566157 A JP 2021566157A JP 2021566157 A JP2021566157 A JP 2021566157A JP 2022532875 A JP2022532875 A JP 2022532875A
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- 230000015572 biosynthetic process Effects 0.000 title claims description 9
- 238000003786 synthesis reaction Methods 0.000 title claims description 9
- 108091022898 Calcium release-activated calcium channel Proteins 0.000 title abstract description 18
- 102000020167 Calcium release-activated calcium channel Human genes 0.000 title abstract description 18
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 243
- 150000001875 compounds Chemical class 0.000 claims description 204
- 239000003054 catalyst Substances 0.000 claims description 115
- 229910052763 palladium Inorganic materials 0.000 claims description 88
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 239000002585 base Substances 0.000 claims description 75
- 238000000034 method Methods 0.000 claims description 75
- 239000002798 polar solvent Substances 0.000 claims description 73
- 230000008569 process Effects 0.000 claims description 66
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 62
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 50
- 150000002367 halogens Chemical class 0.000 claims description 50
- 238000005859 coupling reaction Methods 0.000 claims description 46
- 238000002360 preparation method Methods 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 41
- 239000002253 acid Substances 0.000 claims description 39
- 230000008878 coupling Effects 0.000 claims description 39
- 238000010168 coupling process Methods 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 37
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 36
- 150000003512 tertiary amines Chemical class 0.000 claims description 34
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 33
- 101150003085 Pdcl gene Proteins 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 31
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 30
- 238000005984 hydrogenation reaction Methods 0.000 claims description 30
- 235000011056 potassium acetate Nutrition 0.000 claims description 30
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 29
- 150000001266 acyl halides Chemical class 0.000 claims description 28
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- -1 t-butoxycarbonyl Chemical group 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- 239000003586 protic polar solvent Substances 0.000 claims description 17
- KRRTXVSBTPCDOS-UHFFFAOYSA-N 5-bromopyrazin-2-amine Chemical compound NC1=CN=C(Br)C=N1 KRRTXVSBTPCDOS-UHFFFAOYSA-N 0.000 claims description 13
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 13
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 13
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 13
- YQHJFPFNGVDEDT-UHFFFAOYSA-N 2-tert-butyl-1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(N(C)C)=NC(C)(C)C YQHJFPFNGVDEDT-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 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 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 229910052751 metal Inorganic materials 0.000 description 40
- 239000002184 metal Substances 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 27
- 230000009467 reduction Effects 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 239000011575 calcium Substances 0.000 description 19
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 18
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 18
- 235000019798 tripotassium phosphate Nutrition 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 125000001153 fluoro group Chemical group F* 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- 239000001632 sodium acetate Substances 0.000 description 17
- 235000017281 sodium acetate Nutrition 0.000 description 17
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 229910052708 sodium Inorganic materials 0.000 description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 125000001309 chloro group Chemical group Cl* 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 229910052759 nickel Inorganic materials 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 229940125400 channel inhibitor Drugs 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229910052791 calcium Inorganic materials 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 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 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 10
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 10
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 10
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 10
- 239000000920 calcium hydroxide Substances 0.000 description 10
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 10
- 235000011116 calcium hydroxide Nutrition 0.000 description 10
- 229910052744 lithium Inorganic materials 0.000 description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 10
- 235000011118 potassium hydroxide Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 230000002194 synthesizing effect Effects 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 9
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 9
- 239000000908 ammonium hydroxide Substances 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- 229910052796 boron Inorganic materials 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- AVPBPSOSZLWRDN-UHFFFAOYSA-M chloropalladium(1+);methanidylbenzene;triphenylphosphane Chemical compound [Pd+]Cl.[CH2-]C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 AVPBPSOSZLWRDN-UHFFFAOYSA-M 0.000 description 9
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 9
- 229910052805 deuterium Inorganic materials 0.000 description 9
- 125000001624 naphthyl group Chemical group 0.000 description 9
- OTYPIDNRISCWQY-UHFFFAOYSA-L palladium(2+);tris(2-methylphenyl)phosphane;dichloride Chemical compound Cl[Pd]Cl.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C OTYPIDNRISCWQY-UHFFFAOYSA-L 0.000 description 9
- 239000011736 potassium bicarbonate Substances 0.000 description 9
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 9
- 235000015497 potassium bicarbonate Nutrition 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 9
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 9
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 9
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 229910052792 caesium Inorganic materials 0.000 description 8
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 5
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 5
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 5
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 5
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 5
- WDRFYIPWHMGQPN-UHFFFAOYSA-N 2-chloroisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Cl)C(=O)C2=C1 WDRFYIPWHMGQPN-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 108091006146 Channels Proteins 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 5
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- 125000005341 metaphosphate group Chemical group 0.000 description 1
- ITYJDNHFRZSTJY-UHFFFAOYSA-N methanesulfonyl bromide Chemical compound CS(Br)(=O)=O ITYJDNHFRZSTJY-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 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
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- 239000003279 phenylacetic acid Chemical group 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000018767 positive regulation of catalytic activity Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000012925 reference material Substances 0.000 description 1
- 230000021014 regulation of cell growth Effects 0.000 description 1
- 230000025053 regulation of cell proliferation Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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 Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
Description
本出願は、2019年5月6日に出願された米国仮出願第62/843,822号の利益を主張するものであり、この文献は参照によって全体として本明細書に組み込まれる。
R2とR3は、出現するたびに、ハロゲンと、ハロゲン、-OR’、-CN、-N(R’)2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択され、
あるいは、R1が両方とも独立してC1-C3アルキルである場合、2つのR1基は、それらが結合している原子と一体となって、炭素環を形成し、
nは0、1、2、または3であり、
mは0、1、2、3、4、または5であり、ならびに、
R’は、出現するたびに、水素と、各々がハロゲン、-CN、-NO2、-OH、-NH2、およびOCH3から出現するたびに独立して選択される1つ以上の置換基で随意に置換される、C1-6アルキルと、C2-6アルケニルと、C2-6アルキニルとから独立して選択され、
ここで、上記プロセスは、3級アミン塩基と非プロトン性極性溶媒の存在下において、式(I-A)の化合物
本明細書に記載されるすべての公開物、特許、および特許出願は、それぞれの個々の公開物、特許、および、特許出願が参照によって組み込まれるように具体的かつ個別にあたかも指定されているような程度で、参照により本明細書に組み込まれるものとする。
他に定義されない限り、本明細書で使用されるすべての技術用語および科学用語は、請求される主題が属する技術分野において一般に理解されるものと同じ意味を有する。本明細書の用語に複数の定義がある場合、この表題の定義が優先される。本明細書で引用される特許、特許出願、公報、および公開されたヌクレオチド配列とアミノ酸配列(例えば、GenBankなどのデータベースで入手可能な配列)はすべて、参照により引用される。URLまたは他のそのような識別子またはアドレスについて言及される場合、こうした識別子を変更することができ、インターネット上の特定の情報は現れたり消えたりする場合があるが、同等な情報はインターネット検索により見つけられることを理解されたい。これらに対する言及は、そのような情報の利用可能性と公共上の広まりを裏付けるものである。
本明細書に記載される1つの態様は、CRACチャネル阻害剤を合成するプロセスである。いくつかの実施形態では、CRACチャネル阻害剤は、式(I)の化合物
R1は、出現するたびに、水素と、ハロゲンと、ハロゲン、-OR’、-CN、-N(R’)2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択され、
R2とR3は、出現するたびに、ハロゲンと、ハロゲン、-OR’、-CN、-N(R’)2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択され、
あるいは、R1が両方とも独立してC1-C3アルキルである場合、2つのR1基は、それらが結合している原子と一体となって、炭素環を形成し、
nは0、1、2、または3であり、
mは0、1、2、3、4、または5であり、ならびに、
R’は、出現するたびに、水素と、各々がハロゲン、-CN、-NO2、-OH、-NH2、およびOCH3から出現するたびに独立して選択される1つ以上の置換基で随意に置換される、C1-6アルキルと、C2-6アルケニルと、C2-6アルキニルとから独立して選択される。
5-ブロモピラジン-2-アミン(1.1)(3.9kg、22.41モル)を、DCM(23~24L)に添加した。室温で溶液を撹拌し、3.6kgのトリエチルアミン(Et3N)(35.57mol)を、ヘッドタンクを介して添加した。反応混合物を0~10℃に冷却し、HDPEドラム中のDCM(11~13L)中のトリフェニルメチルクロリド(7.0g、25.11mol)の溶液を、0~20℃を超えずに、ヘッドタンクを介してゆっくりと添加した。反応は15~20℃で5~9時間進行した。完了すると、反応物を水(~4L)でクエンチし、10~25℃で40~60分間撹拌した。層を分離し、5%のNaCl(aq)(~4L)を有機層に添加した。混合物を40~60間撹拌し、層を分離した。溶液を4~5Xに濃縮し、メチルターシャリ-ブチルエーテル(MTBE)(15~20kg)を添加し、溶液を4~5Xに再濃縮した。このプロセスを3回繰り返した。このプロセスの3回目の反復後、その後の混合物を10~20℃で10~20分間撹拌した。結果として生じる固形物を濾過して、ウェットケーキを生成した。上記ケーキを40~50℃で16~20時間乾燥させた。収率=8.33kg。純度=96.8%。
1,4-ジオキサン(28~30L)を、5-ブロモ-N-トリチルピラジン-2-アミン(1.2)(6.8kg、16.33モル)、ビス(ピナコラート)ジボロン(4.95kg、19.5モル)、および酢酸カリウム(KOAc)(2.4kg)に添加した。室温で、溶液を窒素で3回パージした。Pd(dppf)Cl2(1.17kg、1.66モル)を添加し、溶液を窒素で3回パージした。反応は80~90℃で16~20時間進行した。完了後、反応物を20~30℃に冷まし、溶液を濾過し、2X~4Xに濃縮した。その溶液を、さらに精製することなく、直ちに次の工程に移した。
5-クロロ-2,2-ジフルオロベンゾ[d][1,3]ジオキソール(2.1)(3.0kg、15.58モル)をMeCN(~2.6L)に添加した。その溶液に、10~20℃で、N-ブロモスクシンアミド(NBS)(2.8~3.2kg、17~19モル)を添加した。~6.5kgのトリフルオロ酢酸(TFA)を10~20℃でゆっくり添加し、その後、10~20℃で~6.7kgの硫酸(H2SO4)をゆっくりと添加した。反応は15~20℃で24~36時間進行した。第2のバッチのNBS(~0.35kg)を添加し、反応は15~20℃で24~36時間進行した。第3のバッチのNBS(~0.35kg)を添加し、反応は15~20℃で24~36時間進行した。第4のバッチのNBS(~0.35kg)を添加し、反応は15~20℃で24~36時間進行した。完了間近に、水(~5.8L)を添加し、溶液を0~5℃に冷却した。メチルターシャリ-ブチルエーテル(MTBE)(~5kg)を添加し、生成物をMTBEで3回抽出した。0~15℃で内部温度を維持しながら、有機層を10%のNaOH(aq)(~5kg)で塩基性化して、pH~10-12にした。その後の混合物を0~15℃で40~60分間撹拌した。それらの層を分離し、その後の有機層を水(~4L)で洗浄した。30℃未満の温度を維持しながら、有機層を減圧下で2X~6Xに濃縮した。収率=3.54Kg。純度=87.8%。
DMF(~20L)を、新たに調製した5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-N-トリチルピラジン-2-アミン(1.3)に添加し、溶液を15~30分間撹拌した。この溶液を、5-ブロモ-6-クロロ-2,2-ジフルオロベンゾ[d][1,3]ジオキソール(2.2)MTBE溶液(2.28kg、12.44モル、1.0Xとしての正味量に添加した。CsF(~4kg)および水(~0.017kg)を添加し、溶液を窒素で3回脱気した。Pd(PPh3)4(0.94kg、0.81モル)を窒素下で添加し、窒素で3回脱気し、反応は80~90℃で1~2時間進行した。完了後、反応物を15~25℃に冷まし、水(~4L)を添加した。DCM()を添加し、混合物を15~25℃で30~60分間撹拌し、その後、層を分離した。有機層を集め、反応容器を水できれいにし、DCMで3回逆洗浄した。有機層を組み合わせて、13X~14Xに濃縮した。MeOHを添加して蒸発させることを3回繰り返して、固形物を得て、これを遠心分離した。母液を除去し、結果として生じる固形物をDCM(13X~14X)に溶解した。MeOHを添加して蒸発させるプロセスをさらに3回繰り返し、混合物を遠心分離した。母液を分離し、結果として生じる固形物を、40~50℃で5~10時間乾燥させた。固形物をDCMに溶解し、透明になるまで15~25℃で30~60分間撹拌し、溶液をシリカゲル(5X~8X)に通して2回濾過した。結果として生じる母液を13X~14Xに濃縮し、MeIH(10X~11X)で溶解し、10~20℃で30~60分間撹拌した。混合物を遠心分離し、母液を分離した。この遠心分離プロセスを繰り返し、結果として生じる固形物を、40~50℃で16~20時間乾燥させた。収率=3.64kg。純度=99%。
DCM(2.5X~3.0X)およびDMF(0.00019X~0.00020X)を、2-フルオロ-6-メチル安息香酸(3.1)(0.88kg、5.71モル)に添加した。20~25℃で、塩化オキサリル((COCl)2)(0.98kg、7.72モル)を溶液に添加した。反応は20~30℃で16~20時間進行した。第2のバッチのDMF(0.00019X~0.00020)を添加し、反応は20~30℃で10~12時間進行した。トルエン(5X~6Xkg)を添加し、40℃未満の内部温度を維持しながら、反応物を2~3Xに濃縮した。この工程を繰り返し、すぐに使えるよう維持した。
Claims (36)
- 式(I)の化合物
式中、
R1は、出現するたびに、水素と、ハロゲンと、ハロゲン、-OR’、-CN、-N(R’)2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択され、
R2とR3は、出現するたびに、ハロゲンと、ハロゲン、-OR’、-CN、-N(R’)2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択され、
あるいは、R1が両方とも独立してC1-C3アルキルである場合、2つのR1基は、それらが結合している原子と一体となって、炭素環を形成し、
nは0、1、2、または3であり、
mは0、1、2、3、4、または5であり、ならびに、
R’は、出現するたびに、水素と、各々がハロゲン、-CN、-NO2、-OH、-NH2、およびOCH3から出現するたびに独立して選択される1つ以上の置換基で随意に置換される、C1-6アルキルと、C2-6アルケニルと、C2-6アルキニルとから独立して選択され、
ここで、前記プロセスは、3級アミン塩基と非プロトン性極性溶媒の存在下において、式(I-A)の化合物
ここで、Xは、-Cl、-Br、-I、-CN、-N3、-OCH3、-OCH2CH3、-OC6H5、-OC6H4-4-NO2、-OC(O)CH3、-OC(O)C6H5、-O(SO2)CH3、または-O(SO2)C6H4-4-CH3である、プロセス。 - 3級アミン塩基は、ピリジン、トリエチルアミン、トリイソプロピルアミン、2-tert-ブチル-1,1,3,3-テトラメチルグアニジン、4-ジメチルアミノピリジン、N,N-ジイソプロピルエチルアミン、およびN-メチルモルホリンからなる群から選択される、請求項1に記載のプロセス。
- 非プロトン性極性溶媒は、クロロホルム、ジクロロメタン、およびそれらの混合物からなる群から選択される、請求項1または2に記載のプロセス。
- 酸は、トリフルオロ酢酸、硫酸、および塩酸からなる群から選択される、請求項4に記載のプロセス。
- カップリング触媒はパラジウム系触媒である、請求項7に記載のプロセス。
- パラジウム系触媒は、Pd(PPh3)4、Pd(dppf)Cl2、およびPdCl2(PPh3)4からなる群から選択される、請求項8に記載のプロセス。
- カップリングは約80℃~約90℃の温度で実施される、請求項7-9のいずれか1つに記載のプロセス。
- 第2のパラジウム系触媒はPd(dppf)Cl2である、請求項11に記載のプロセス。
- 塩基は酢酸カリウムである、請求項11または12に記載のプロセス。
- 式(I-F)の化合物は結晶性固体である、請求項14に記載のプロセス。
- ハロゲン化アシル調製剤は、塩化オキサリル、塩化チオニル、塩化ホスホリル、および三塩化リンからなる群から選択される、請求項16に記載のプロセス。
- R1は、出現するたびに、水素と、ハロゲンと、ハロゲン、-OH、-OCH3、-CN、-NH2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択され、ならびに、
R2とR3は、出現するたびに、ハロゲンと、ハロゲン、-OH、-OCH3、-CN、-NH2、および-NO2から出現するたびに独立して選択される1つ以上の置換基で随意に置換されたC1-C3アルキルとから独立して選択される、請求項1-17のいずれか1つに記載のプロセス。 - 3級アミン塩基は、ピリジン、トリエチルアミン、トリイソプロピルアミン、2-tert-ブチル-1,1,3,3-テトラメチルグアニジン、4-ジメチルアミノピリジン、N,N-ジイソプロピルエチルアミン、およびN-メチルモルホリンからなる群から選択される、請求項19に記載のプロセス。
- 非プロトン性極性溶媒は、クロロホルム、ジクロロメタン、およびそれらの混合物からなる群から選択される、請求項19または20に記載のプロセス。
- 酸は、トリフルオロ酢酸、硫酸、および塩酸からなる群から選択される、請求項22に記載のプロセス。
- カップリング触媒はパラジウム系触媒である、請求項25に記載のプロセス。
- パラジウム系触媒は、Pd(PPh3)4、Pd(dppf)Cl2、およびPdCl2(PPh3)4からなる群から選択される、請求項26に記載のプロセス。
- カップリングは約80℃~約90℃の温度で実施される、請求項25-27のいずれか1つに記載のプロセス。
- 第2のパラジウム系触媒はPd(dppf)Cl2である、請求項29に記載のプロセス。
- 塩基は酢酸カリウムである、請求項29または30に記載のプロセス。
- 極性溶媒は、1,4-ジオキサンである、請求項29-31のいずれか1つに記載のプロセス。
- 式(II-F)の化合物は結晶性固体である、請求項33に記載のプロセス。
- ハロゲン化アシル調製剤は、塩化オキサリル、塩化チオニル、塩化ホスホリル、および三塩化リンからなる群から選択される、請求項35に記載のプロセス。
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