JP6464098B2 - ボルチオキセチンの製造方法 - Google Patents
ボルチオキセチンの製造方法 Download PDFInfo
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- JP6464098B2 JP6464098B2 JP2015558446A JP2015558446A JP6464098B2 JP 6464098 B2 JP6464098 B2 JP 6464098B2 JP 2015558446 A JP2015558446 A JP 2015558446A JP 2015558446 A JP2015558446 A JP 2015558446A JP 6464098 B2 JP6464098 B2 JP 6464098B2
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- piperazine
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- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title claims description 53
- 229960002263 vortioxetine Drugs 0.000 title claims description 35
- 238000004519 manufacturing process Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 48
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 23
- -1 5 - cyclopentadienyl iron (II) hexafluorophosphate Chemical compound 0.000 claims description 20
- 230000008569 process Effects 0.000 claims description 19
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Substances ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006303 photolysis reaction Methods 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
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- AMNLXDDJGGTIPL-UHFFFAOYSA-N 2,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C(C)=C1 AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
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- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 5
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- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
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- 125000003944 tolyl group Chemical group 0.000 claims description 2
- WEYVCQFUGFRXOM-UHFFFAOYSA-N perazine Chemical compound C1CN(C)CCN1CCCN1C2=CC=CC=C2SC2=CC=CC=C21 WEYVCQFUGFRXOM-UHFFFAOYSA-N 0.000 claims 1
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- RMVRSNDYEFQCLF-UHFFFAOYSA-N phenyl mercaptan Natural products SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 5
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
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- 125000003118 aryl group Chemical group 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- QHSYAVQHEZLRFL-UHFFFAOYSA-N 1-[2-(3,5-dimethylphenyl)sulfanylphenyl]piperazine Chemical compound CC1=CC(C)=CC(SC=2C(=CC=CC=2)N2CCNCC2)=C1 QHSYAVQHEZLRFL-UHFFFAOYSA-N 0.000 description 2
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- RBUCAPSNRDZVKR-UHFFFAOYSA-N [Fe+]C1C=CC=C1 Chemical compound [Fe+]C1C=CC=C1 RBUCAPSNRDZVKR-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001500 aryl chlorides Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229940018557 citraconic acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-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
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/02—Iron compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Compounds Of Unknown Constitution (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
および式III
また、本願は、特許請求の範囲に記載の発明に関するものであるが、他の態様として以下も包含し得る。
(1)ボルチオキセチンまたはその薬学的に許容できる塩の製造のための方法であって、式I
および式III
(2)Halがクロロを表す、上記(1)に記載の方法。
(3)R’が水素を表す、上記(1)または(2)に記載の方法。
(4)RがHを表す、上記(1)〜(3)のいずれか一項に記載の方法。
(5)Rが保護基を表す、上記(1)〜(3)のいずれか一項に記載の方法。
(6)Rが、Boc、Fmoc、BnおよびCbzから選択される保護基を表す、上記(5)に記載の方法。
(7)X − が、PF 6 − 、AlCl 4 − 、ClO 4 − 、BF 4 − 、[B[3,5−(CF 3 ) 2 C 6 H 3 ] 4 ] − 、B(C 6 F 5 ) 4 − およびAl(OC(CF 3 ) 3 ) 4 − から選択される、上記(1)〜(6)のいずれか一項に記載の方法。
(8)X − がPF 6 − である、上記(7)に記載の方法。
(9)前記溶媒が、トルエン、THF(テトラヒドロフラン)、MTBE(メチル第三級ブチルエーテル)、水、エタノール、2−プロパノール、NMP(N−メチル−2−ピロリドン)、DMF(ジメチルホルムアミド)、MIBK(メチルイソブチルケトン)、TEA(トリエチルアミン)、DIPEA(N,N−ジイソプロピルエチルアミン)、DCM(ジクロロメタン)、酢酸エチル、酢酸イソプロピルおよびこれらの組合せから選択される、上記(1)〜(8)のいずれか一項に記載の方法。
(10)R’’がHを表す、上記(1)〜(9)のいずれか一項に記載の方法。
(11)前記脱錯体化工程が光分解を含む、上記(1)〜(10)のいずれか一項に記載の方法。
(12)1当量の式Iの化合物が、式IIの化合物(1〜5当量)および式IIIの化合物(1〜5当量)と、溶媒中で、必要に応じて塩基(0.5当量超)と一緒に混合されて、式IVの化合物が得られ、その後、脱錯体化および必要に応じて前記ピペラジンにおける保護基の除去により、1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンが得られる、上記(1)に記載の方法。
(13)1当量の式Iの化合物が、塩基(0.5〜20当量)、ピペラジン(1〜5当量)および2,4−ジメチルチオフェノール(1〜5当量)と、溶媒中で混合されて、式IVの化合物が得られ、その後、脱錯体化により、1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンが得られる、上記(1)に記載の方法。
(14)1当量のη 6 −1,2−ジクロロベンゼン−η 5 −シクロペンタジエニル鉄(II)ヘキサフルオロホスフェートが、1〜5当量の塩基、1〜3当量の2,4−ジメチルチオフェノールおよび1〜3当量のピペラジンと、溶媒中で、10℃〜50℃で混合されて、下式
(15)前記得られた1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンが、好適な酸と反応されて、当量の薬学的に許容できる塩が得られる、上記(1)〜(14)のいずれか一項に記載の方法。
(16)上記(1)〜(15)のいずれか一項に記載の方法で得られる1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンおよびその薬学的に許容できる塩。
[実施例]
η6−1,2−ジクロロベンゼン−η5−シクロペンタジエニル鉄(II)ヘキサフルオロホスフェート(25g、61mmol)、炭酸カリウム(16.7g、121mmol)およびピペラジン(10.3g、120mmol)を、THF(200mL)と水(50mL)との混合物に溶解させた。反応混合物を周囲温度で1時間撹拌した。反応混合物に、2,4−ジメチルチオフェノール(8.8g、63.7mmol)を加え、一晩、撹拌し続けた。
Al 1ppm、Fe 401ppm、Na 291ppm、P 2453ppm(ICP−AESによって測定した際)。
純度:面積%:ボルチオキセチン99.73、1−[2−(3,5−ジメチル−フェニルスルファニル)−フェニル]−ピペラジン0.08%、未知試料(unknown)0.19(GCによって測定した際)。
1H NMR(DMSO−d6):8.84(bs,2H)、7.34(d,1H、7.7hz)、7.26(s,1H)、7.16(m,2H)、7.11(dd,1H、7.8および1.7hz)、6.97(dd,1H、7.8および1.7hz)、6.41(dd,1H、7.8および1.3hz)、3.26(bm,4H)、3.20(bm,4H)、2.33(s,3H)、2.25(s,3H)。
結晶形:β−形態(XRPDによって測定した際)。ボルチオキセチンHBrのα−形態およびβ−形態の定義については、国際公開第2007/144005号パンフレットを参照されたい。
含水量:<0.1%(Karl Fisherによって測定した際)および<0.2%(熱重量分析によって測定した際)。
元素分析C18H23N2SBrは、C56.99 H6.11 N7.38を必要とし、実測値C57.10、H6.12、N7.26であった。
1,2−ジクロロベンゼン(158.4g、1.08mol)、フェロセン(40.6g、218mmol)、三塩化アルミニウム(13.8g、104mmol)およびアルミニウム微粉末(7.0g、26mmol)を混合し、110℃で6時間加熱した。反応混合物を25℃に冷却し、25分間にわたって氷(240g)とn−ヘプタン(100mL)との混合物にゆっくりと加えた。(注:水による未反応の三塩化アルミニウムの処理は、発熱性が高い)。
Al 6ppm、Fe 18ppm、Na 3ppm、P 7ppm(ICP−AESによって測定した際)
純度:面積%:ボルチオキセチン99.96、1−[2−(3,5−ジメチル−フェニルスルファニル)−フェニル]−ピペラジン0.04、未知試料0%(GCによって測定した際)
1H NMR(DMSO−d6):8.86(bs,2H)、7.34(d,1H、7.7hz)、7.26(s,1H)、7.16(m,2H)、7.11(d,1H、7.9)、6.97(dd,1H、7.8および1.8hz)、6.41(dd,1H、7.7および1.4hz)、3.27(bm,4H)、3.21(bm,4H)、2.33(s,3H)、2.25(s,3H)。
結晶形:α−形態とβ−形態との混合物(XRPDによって測定した際)。
含水量:0.14%(Karl Fisherによって測定した際)および<0.2%(熱重量分析によって測定した際)。
元素分析C18H23N2SBrは、C56.99 H6.11 N7.38を必要とし、実測値C56.94、H6.09、N7.31であった。
Claims (12)
- ボルチオキセチンまたはその薬学的に許容できる塩の製造のための方法であって、式I
および式III
- Halがクロロを表す、請求項1に記載の方法。
- R’が水素を表す、請求項1または2に記載の方法。
- X−が、PF6 −、AlCl4 −、ClO4 −、BF4 −、[B[3,5−(CF3)2C6H3]4]−、B(C6F5)4 −およびAl(OC(CF3)3)4 −から選択される、請求項1〜3のいずれか一項に記載の方法。
- X−がPF6 −である、請求項4に記載の方法。
- 前記溶媒が、トルエン、THF(テトラヒドロフラン)、MTBE(メチル第三級ブチルエーテル)、水、エタノール、2−プロパノール、NMP(N−メチル−2−ピロリドン)、DMF(ジメチルホルムアミド)、MIBK(メチルイソブチルケトン)、TEA(トリエチルアミン)、DIPEA(N,N−ジイソプロピルエチルアミン)、DCM(ジクロロメタン)、酢酸エチル、酢酸イソプロピルおよびこれらの組合せから選択される、請求項1〜5のいずれか一項に記載の方法。
- R’’がHを表す、請求項1〜6のいずれか一項に記載の方法。
- 前記脱錯体化工程が光分解を含む、請求項1〜7のいずれか一項に記載の方法。
- 1当量の式Iの化合物が、式IIの化合物(1〜5当量)および式IIIの化合物(1〜5当量)と、溶媒中で、必要に応じて塩基(0.5当量超)と一緒に混合されて、式IVの化合物が得られ、その後、脱錯体化により、1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンが得られる、請求項1に記載の方法。
- 1当量の式Iの化合物が、塩基(0.5〜20当量)、ピペラジン(1〜5当量)および2,4−ジメチルチオフェノール(1〜5当量)と、溶媒中で混合されて、式IVの化合物が得られ、その後、脱錯体化により、1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンが得られる、請求項1に記載の方法。
- 1当量のη6−1,2−ジクロロベンゼン−η5−シクロペンタジエニル鉄(II)ヘキサフルオロホスフェートが、1〜5当量の塩基、1〜3当量の2,4−ジメチルチオフェノールおよび1〜3当量のピペラジンと、溶媒中で、10℃〜50℃で混合されて、下式
- 前記得られた1−[2−(2,4−ジメチル−フェニルスルファニル)−フェニル]−ピペラジンが、好適な酸と反応されて、当量の薬学的に許容できる塩が得られる、請求項1〜11のいずれか一項に記載の方法。
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