JP6594351B2 - 新規中間体を含むアルキル化アリールピペラジン及びアルキル化アリールピペリジン化合物の製造方法 - Google Patents
新規中間体を含むアルキル化アリールピペラジン及びアルキル化アリールピペリジン化合物の製造方法 Download PDFInfo
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- JP6594351B2 JP6594351B2 JP2016572799A JP2016572799A JP6594351B2 JP 6594351 B2 JP6594351 B2 JP 6594351B2 JP 2016572799 A JP2016572799 A JP 2016572799A JP 2016572799 A JP2016572799 A JP 2016572799A JP 6594351 B2 JP6594351 B2 JP 6594351B2
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- 150000001875 compounds Chemical class 0.000 title claims description 52
- 238000000034 method Methods 0.000 title claims description 33
- 239000000543 intermediate Substances 0.000 title description 7
- -1 [e] [1,3,2] dioxathiepine-3,3-dioxide Chemical compound 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 claims description 10
- 229960001432 lurasidone Drugs 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000920 calcium hydroxide Substances 0.000 claims description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 4
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 4
- 239000001095 magnesium carbonate Substances 0.000 claims description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 4
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 4
- 239000000347 magnesium hydroxide Substances 0.000 claims description 4
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- OQYOVYWFXHQYOP-UHFFFAOYSA-N 1,3,2-dioxathiane 2,2-dioxide Chemical compound O=S1(=O)OCCCO1 OQYOVYWFXHQYOP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Chemical group 0.000 claims description 3
- MSZUCXVGSQLRIL-HGPDSQILSA-N (1S,2R,6S,7R)-4-[[(1R,2R)-2-(hydroxymethyl)cyclohexyl]methyl]-4-azatricyclo[5.2.1.02,6]decane-3,5-dione Chemical compound O=C([C@H]1[C@@H](C2=O)[C@]3([H])CC[C@]1(C3)[H])N2C[C@@H]1CCCC[C@H]1CO MSZUCXVGSQLRIL-HGPDSQILSA-N 0.000 claims description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 2
- RIVOBMOBWMOLDJ-RNGGSSJXSA-N (3ar,4s,7r,7as)-hexahydro-1h-4,7-methanoisoindole-1,3(2h)-dione Chemical compound O=C1NC(=O)[C@@H]2[C@H]1[C@]1([H])C[C@@]2([H])CC1 RIVOBMOBWMOLDJ-RNGGSSJXSA-N 0.000 claims 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- KRDOFMHJLWKXIU-UHFFFAOYSA-N ID11614 Chemical compound C1CNCCN1C1=NSC2=CC=CC=C12 KRDOFMHJLWKXIU-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 239000011575 calcium Chemical group 0.000 claims 1
- 229910052791 calcium Chemical group 0.000 claims 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 229910052708 sodium Chemical group 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 125000003118 aryl group Chemical group 0.000 description 44
- 239000000203 mixture Substances 0.000 description 40
- 125000000623 heterocyclic group Chemical group 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 32
- 125000001072 heteroaryl group Chemical group 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 125000004122 cyclic group Chemical group 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 239000001301 oxygen Chemical group 0.000 description 14
- 229910052717 sulfur Chemical group 0.000 description 14
- 239000011593 sulfur Chemical group 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000012458 free base Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000002837 carbocyclic group Chemical group 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- TZJUVVIWVWFLCD-UHFFFAOYSA-N 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one Chemical compound O=S1(=O)C2=CC=CC=C2C(=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 TZJUVVIWVWFLCD-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 229950003599 ipsapirone Drugs 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229960003162 iloperidone Drugs 0.000 description 4
- XMXHEBAFVSFQEX-UHFFFAOYSA-N iloperidone Chemical compound COC1=CC(C(C)=O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- XUEIXBTXKMJFLK-UHFFFAOYSA-N 1-[3-(3-hydroxypropoxy)-4-methoxyphenyl]ethanone Chemical compound OCCCOC=1C=C(C=CC=1OC)C(C)=O XUEIXBTXKMJFLK-UHFFFAOYSA-N 0.000 description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 3
- JBMFHJZAZFFGGM-UHFFFAOYSA-N 3-(5-acetyl-2-methoxyphenoxy)propyl methanesulfonate Chemical compound CS(=O)(=O)OCCCOC1=C(C=CC(=C1)C(C)=O)OC JBMFHJZAZFFGGM-UHFFFAOYSA-N 0.000 description 3
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZTHQBROSBNNGPU-UHFFFAOYSA-N Butyl hydrogen sulfate Chemical compound CCCCOS(O)(=O)=O ZTHQBROSBNNGPU-UHFFFAOYSA-N 0.000 description 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- LFLBHTZRLVHUQC-UHFFFAOYSA-N butyl methanesulfonate Chemical compound CCCCOS(C)(=O)=O LFLBHTZRLVHUQC-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthene Chemical compound C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IZOQUTLQUZLEHF-YUMQZZPRSA-N (5aR,9aR)-1,5,5a,6,7,8,9,9a-octahydrobenzo[e][1,3,2]dioxathiepine 3,3-dioxide Chemical compound C1OS(OC[C@H]2[C@H]1CCCC2)(=O)=O IZOQUTLQUZLEHF-YUMQZZPRSA-N 0.000 description 2
- ZCVIMNDSJRRGRK-YUMQZZPRSA-N (5aR,9aR)-1,5,5a,6,7,8,9,9a-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide Chemical compound C1OS(OC[C@H]2[C@H]1CCCC2)=O ZCVIMNDSJRRGRK-YUMQZZPRSA-N 0.000 description 2
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 2
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 0 O=C(*1)c(cccc2)c2S1(=O)=O Chemical compound O=C(*1)c(cccc2)c2S1(=O)=O 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960004372 aripiprazole Drugs 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229960002495 buspirone Drugs 0.000 description 2
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- WDECIBYCCFPHNR-UHFFFAOYSA-N chrysene Chemical compound C1=CC=CC2=CC=C3C4=CC=CC=C4C=CC3=C21 WDECIBYCCFPHNR-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VPUGDVKSAQVFFS-UHFFFAOYSA-N coronene Chemical compound C1=C(C2=C34)C=CC3=CC=C(C=C3)C4=C4C3=CC=C(C=C3)C4=C2C3=C1 VPUGDVKSAQVFFS-UHFFFAOYSA-N 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 229960000647 gepirone Drugs 0.000 description 2
- QOIGKGMMAGJZNZ-UHFFFAOYSA-N gepirone Chemical compound O=C1CC(C)(C)CC(=O)N1CCCCN1CCN(C=2N=CC=CN=2)CC1 QOIGKGMMAGJZNZ-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
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- 238000005292 vacuum distillation Methods 0.000 description 1
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- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 description 1
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- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- WFPIAZLQTJBIFN-DVZOWYKESA-N zuclopenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(Cl)=CC=C2SC2=CC=CC=C2/1 WFPIAZLQTJBIFN-DVZOWYKESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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Description
本出願は、2014年6月16日に出願された米国仮特許出願第62/012701号の優先権を主張するものであり、この開示は、全ての目的のためにそれらの全体を出典明示により援用する。
式中、R1及びR2は、個別に、水素、非置換アルキル、及び置換アルキルから選択されるか、又はR1及びR2は、結合され、5−8個の炭素環式環を形成し、nは0、1、又は2であり、Yは、NR3R4、OR5、又はSR5であり、このR3及びR4は、個別に、アシル又はスルホニルから選択され、R3及びR4は、結合され、置換又は非置換の環式又は二環式環を形成してもよく、R5は、アリール若しくはヘテロアリール、又は複素環であり、Arは、アリール又はヘテロアリール基である。
別途指定のない限り、本明細書及び特許請求の範囲を含む本出願で使用される以下の用語は、以下に提供された定義を有する。本明細書及び添付の特許請求の範囲において使用されるとき、単数形「a」、「an」、及び「the」は、文脈上他の意味を明確に指示しない限り、複数指示物を含む点に留意しなければならない。
本発明は、それらの中間体及び誘導体を含む、アリールピペラジン及びアリールピペリジン化合物を製造するための方法を提供する。より具体的には、本発明は、それぞれ、一般式(I)及び(VII)の様々なアルキル化アリールピペラジン及びアルキル化アリールピペリジン化合物を製造するための方法又は方法(methods)を提供する。
式中、R1及びR2は、個別に、水素、非置換アルキル、及び置換アルキルから選択されるか、又はR1及びR2は、結合され、5−8個の炭素環式環を形成し、nは0、1、又は2であり、Yは、NR3R4、OR5、又はSR5であり、このR3及びR4は、個別に、アシル又はスルホニルから選択され、R3及びR4は、結合され、置換又は非置換の環式又は二環式環を形成してもよく、R5は、アリール若しくはヘテロアリール、又は複素環であり、Arは、アリール又はヘテロアリール基である。
[(1R,2R)−シクロヘキサン−1,2−ジイル]ジメタノール(分子量144.21)を、アセトニトリルに添加し、懸濁液の形態の反応混合物を得る。この混合物を撹拌し、0−5℃に冷却する。塩化チオニルを、0−10℃の温度で、この混合物に添加し、澄んだ溶液を得る。この溶液を0−5℃で撹拌し、一定時間ごとにアッセイして、反応の完了を確認する。
アセトニトリルを、(5aR,9aR)−オクタヒドロベンゾ[e][1,3,2]ジオキサチエピン3,3−ジオキシド(分子量206.26、1当量)、(3aR,4s,7R,7aS−ヘキサヒドロ−1H−7,4−メタノイソインドール−1,3(2H)−ジオン(分子量165.19、1.2当量)、及び炭酸カリウム(2当量)の混合物に添加し、混合物を約75℃に加熱する。
実施例2の粗ルラシドン遊離塩基を、酢酸エチル(10容量)中でスラリー状にし、澄んだ溶液が得られるまで加熱する。溶液を50−55℃まで冷却し、濾過して、溶液中のいかなる粒子状物質も除去する。溶液を、およそ4−5容量までさらに蒸留し、次いで、およそ0−5℃まで冷却する。得られた固形沈殿物を濾過し、酢酸エチルで濯ぎ、次いで真空下で乾燥させ、結晶ルラシドン遊離塩基をもたらす。
実施例3のルラシドン遊離塩基を、イソプロパノール(15容量のイソプロパノールに対し1当量の塩基)中でスラリー状にする。次いで、スラリーを、澄んだ溶液が得られるまで加熱する。溶液を濾過し、溶液中のいかなる粒子状物質も除去する。前濾過したHCl水溶液の10%水溶液を次いで添加し、バッチを、結晶が沈殿し始めるまで、およそ45−70℃までゆっくりと冷却する。バッチをこの時点で数時間保持し、次いで、およそ0℃までさらに冷却する。得られた固形沈殿物を濾過し、次いでイソプロパノール(3×2容量)で洗浄する。沈殿物を乾燥させ、ルラシドン塩酸塩をもたらす。
アセトニトリル(220mL)中、1,3,2−ジオキサチアン2,2−ジオキシド(22.4g、160mmol、1当量)、1−(3−ヒドロキシ−4−メトキシフェニル)エタン−1−オン(26.9g、160mmol、1当量)、及び炭酸カリウム(44.8g、320mmol、2当量)の混合物を、ほぼ還流温度で加熱する。反応をHPLCによって監視する。完了時に、バッチを約20−25℃まで冷却する。反応混合物をセライトパッドを通して濾過し、パッドをアセトニトリル(180mL)で洗浄し、アセトニトリル中、カリウム3−(5−アセチル−2−メトキシフェノキシ)プロピルスルフェートの溶液を得て、これを次の工程で使用する。
3−(5−アセチル−2−メトキシフェノキシ)プロピルメタンスルホネート(3g、10mmol、1当量)、6−フルオロ−3−(ピペリジン−4−イル)ベンゾ[d]イソオキサゾール(2.42g、11mmol、1.1当量)、KHCO3(1.5g、15mmol、1.5当量)、H2O(6g)、及びトルエン(15mL)の混合物を、還流温度で12−16時間加熱する。反応が完了したら、バッチを約20−25℃に冷却し、次いでトルエン(15mL)、IPA(10mL)及び水(10mL)を添加する。二相性溶液を、約20−25℃で約15分間撹拌する。有機層を分離し、水(2×10mL)で洗浄する。バッチを、50℃未満において真空下で約3−4容量まで濃縮し、灰白色固形物を沈殿させる。イソプロパノール(20mL)を添加し、バッチを50℃未満にて、真空下で3−4容量まで濃縮する。イソプロパノール(20mL)を再び添加し、バッチを50℃未満にて、真空下で3−4容量まで濃縮する。イソプロパノール(10mL)をもう一度添加し、バッチを還流温度で1時間加熱し、次いで混合物を5−8℃に4時間にわたって冷却する。混合物を濾過し、ケーキをイソプロパノール(2×5mL)で洗浄し、乾燥させ、イロペリドン遊離塩基(3.1g、収率74%、HPLCによる98% AUC)を得る。
ベンゾ[d]イソチアゾール−3(2H)−オン1,1−ジオキシド(16.0g、87.3mmol、1.0当量)、1,3,2−ジオキサチエパン2,2−ジオキシド(15.3g、100.5mmol、1.2当量)、K2CO3(24.1g、174.6mmol、2.0当量)、及びACN(240mL)の混合物を還流温度で20時間加熱する。反応が完了した後、混合物を濾過し、真空下で濃縮して、油状生成物を得る。この残留物に、ACN(200mL)を添加し、固形物をすぐに沈殿させる。混合物を20−25℃で1時間撹拌し、次いで濾過する。カリウム4−(1,1−ジオキシド−3−オキソベンゾ[d]イソチアゾール−2(3H)−イル)ブチルスルフェートを白色固形物として回収する(11.4g、収率35%、HPLCによる98.5%のAUC)、LC−MS、M+:335.6(スルホン酸)。
H2O(2mL)中、H2SO4(0.8g、8.2mmol、0.5当量)の溶液を、ACN(90mL)及びH2O(5mL)中、カリウム4−(1,1−ジオキシド−3−オキソベンゾ[d]イソチアゾール−2(3H)−イル)ブチルスルフェート(6.1g、16.3mmol、1.0当量)の混合物に、滴下する。反応が、HPLC分析により完了したとみなされるまで、得られた混合物を、75−80℃で加熱する。混合物を濾過し、濾液をおよそ10mLまで濃縮する。この残留物に、ジクロロメタン及びDI水を添加する。層を分離し、有機層を、飽和NaHCO3溶液で洗浄し、硫酸ナトリウム上で乾燥させ、次いで濃縮して、HPLCによる94%の純度で粗生成物を得る。粗物質を、シリカゲルカラムクロマトグラフィー(石油エーテル:酢酸エチル4:1−3:1)によってさらに精製し、2−(4−ヒドロキシブチル)ベンゾ[d]イソチアゾール−3(2H)−オン1,1−ジオキシドを、(2.3g、収率55%、HPLCによる99% AUC);LC−MS、M+:255.8で、明黄色油状物として得る。
酢酸エチル(172mL、10容量)中、2−(4−ヒドロキシブチル)ベンゾ[d]イソチアゾール−3(2H)−オン1,1−ジオキシド(17.2g、67.4mmol、1.0当量)の混合物に、トリエチルアミン(13.6g、134.7mmol、2.0当量)を、5℃未満で添加し、その後、酢酸エチル(20mL)中、Ms2O(12.9g、74.1mmol、1.1当量)を5−15℃で滴加する。混合物を20−25℃で20時間撹拌し、HPLCによって、反応が完了したとみなす。混合物をH2Oで2回洗浄し、次いでNa2SO4上で乾燥させる。溶媒を減圧下で除去し、粗物質を得る。粗生成物を、シリカゲル上のカラムクロマトグラフィー(30×シリカゲル、石油エーテル:酢酸エチル[10:1]−石油エーテル:酢酸エチル[4:1])で精製し、4−(1,1−ジオキシド−3−オキソベンゾ[d]イソチアゾール−2(3H)−イル)ブチルメタンスルホネートを、白色固形物として得る(8.5g、収率38%、HPLCによる96% AUC)として得る;LC−MS、M+:355.6。
(1,1−ジオキシド−3−オキソベンゾ[d]イソチアゾール−2(3H)−イル)ブチルメタンスルホネート(4.6g、13.8mmol、1.0当量)、2−(ピペラジン−1−イル)ピリミジン(2.9g、17.9mmol、1.3当量)、KHCO3(2.1g、20.7mmol、1.5当量)、及びトルエン(46mL)の懸濁液を、95−100℃で22時間加熱する。脱イオン水(35mL)を添加し、有機相を分離する。水性相を酢酸エチル(2×30mL)で抽出する。有機相を合わせ、Na2SO4上で乾燥させる。溶媒を減圧下で除去し、粗生成物を得て、これをシリカゲル上のカラムクロマトグラフィーで、17−33%のEtOAc/石油エーテルで溶出することによって精製し、イプサピロン遊離塩基を、灰白色固形物(2g、収率27%、HPLCによる96% AUC)として得る。
Claims (7)
- ルラシドンを調製するための方法であって、
(i)(3aR,4S,7R,7aS)−ヘキサヒドロ−1H−4,7−メタノイソインドール−1,3(2H)−ジオンを、K2CO3の存在下で、(5aR,9aR)−オクタヒドロベンゾ[e][1,3,2]ジオキサチエピン−3,3−ジオキシドと反応させることによってアルキル化し、カリウム((1R,2R)−2−(((3aR,4S,7R,7aS)−1,3−ジオキソオクタヒドロ−2H−4,7−メタノイソインドール−2−イル)メチル)シクロヘキシル)メチルスルフェートを形成する工程と、
(ii)カリウム((1R,2R)−2−(((3aR,4S,7R,7aS)−1,3−ジオキソオクタヒドロ−2H−4,7−メタノイソインドール−2−イル)メチル)シクロヘキシル)メチルスルフェートを加水分解し、(3aR,4S,7R,7aS)−2−(((1R,2R)−2−(ヒドロキシメチル)シクロヘキシル)メチル)ヘキサヒドロ−1H−4,7−メタノイソインドール−1,3(2H)−ジオンを形成する工程と、
(iii)(3aR,4S,7R,7aS)−2−(((1R,2R)−2−(ヒドロキシメチル)シクロヘキシル)メチル)ヘキサヒドロ−1H−4,7−メタノイソインドール−1,3(2H)−ジオンをメタンスルホニルクロリドと反応させて、((1R,2R)−2−(((3aR,4S,7R,7aS)−1,3−ジオキソオクタヒドロ−2H−4,7−メタノイソインドール−2−イル)メチル)シクロヘキシル)メチルメタンスルホネートを形成する工程と、
(iv)3−(ピペラジン−1−イル)ベンゾ[d]イソチアゾールを((1R,2R)−2−(((3aR,4S,7R,7aS)−1,3−ジオキソオクタヒドロ−2H−4,7−メタノイソインドール−2−イル)メチル)シクロヘキシル)メチルメタンスルホネートと反応させて、(3aR,4S,7R,7aS)−2−(((1R,2R)−2−((4−(ベンゾ[d]イソチアゾール−3−イル)ピペラジン−1−イル)メチル)シクロヘキシル)メチル)ヘキサヒドロ−1H−4,7−メタノイソインドール−1,3(2H)−ジオン(ルラシドン)を形成する工程と
を含む方法。 - 式
(式中、
Yは、式
からなる群から選択される基であり、
Arは、式
からなる群から選択される基であり、
ただし、Yが、式
の基であるとき、Arは、式
の基であり、或いは
Yが、式
の基であるとき、Arは、式
の基であり、或いは
Yが式、
の基であるとき、Arは、式
の基である。)
の化合物を調製する方法であって、
(i)式
を有する1,3,2−ジオキサチアン2,2−ジオキシドで、式
の化合物を、炭酸カリウム、炭酸ナトリウム、炭酸マグネシウム、炭酸カルシウム、水酸化カリウム、水酸化ナトリウム、水酸化マグネシウム及び水酸化カルシウムからなる群から選択される塩基の存在下で、アルキル化し、式
(式中、nが1の場合、Qは、カリウム又はナトリウムであり、あるいは、nが2の場合、Qは、マグネシウム又はカルシウムである。)
の対応するアルキル化化合物を形成する工程と、
(ii)工程(i)のアルキル化化合物を硫酸溶液で加水分解し、式
(式中、Yは、式
からなる群から選択される基である。)
の対応するヒドロキシル化合物を得る工程と、
(iii)工程(ii)の式
の化合物を、式
(式中、LGは、アリールスルホネート又はアルキルスルホネートである。)
の化合物に変換する工程と、
(iv)工程(iii)の式
の化合物で、式
(式中、Arは、式
からなる群から選択される基であり、ただしYが、式
の基であるとき、Arは、式
の基であり、或いは
Yが、式
の基であるとき、Arは、式
の基であり、或いは
Yが、式
の基であるとき、Arは、式
の基である。)
の化合物を、炭酸カリウム、炭酸ナトリウム、炭酸マグネシウム、炭酸カルシウム、水酸化カリウム、水酸化ナトリウム、水酸化マグネシウム及び水酸化カルシウムからなる群から選択される塩基の存在下で、アルキル化する工程と
を含む、方法。 - 工程(i)及び(iv)の塩基が炭酸カリウムである、請求項2に記載の方法。
- LGがメチルスルホネートである、請求項2に記載の方法。
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WO2008019971A2 (en) | 2006-08-17 | 2008-02-21 | F. Hoffmann-La Roche Ag | Arylpiperazine derivatives and uses thereof |
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ES2527545T3 (es) | 2010-04-26 | 2015-01-26 | Sumitomo Dainippon Pharma Co., Ltd. | Un procedimiento de preparación de una sal de amonio cuaternario utilizando fosfato |
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US8258139B2 (en) | 2010-11-08 | 2012-09-04 | Dainippon Sumitomo Pharma Co., Ltd. | Method of treatment for mental disorders |
WO2012063246A1 (en) | 2010-11-11 | 2012-05-18 | Mapi Pharma Ltd. | Amorphous form of lurasidone hydrochloride |
WO2012107890A2 (en) | 2011-02-10 | 2012-08-16 | Ranbaxy Laboratories Limited | Crystalline forms of lurasidone hydrochloride |
WO2012123858A1 (en) | 2011-03-14 | 2012-09-20 | Ranbaxy Laboratories Limited | Amorphous lurasidone hydrochloride |
EP2694499A1 (en) | 2011-04-01 | 2014-02-12 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
WO2012158492A2 (en) | 2011-05-13 | 2012-11-22 | Dainippon Sumitomo Pharma Co., Ltd. | Treatment and management of cns disorders |
EP2736905A4 (en) | 2011-07-28 | 2015-07-29 | Mapi Pharma Ltd | INTERMEDIATE COMPOUNDS AND PROCESS FOR THE PREPARATION OF LURASIDONE AND SALTS THEREOF |
WO2013030722A1 (en) | 2011-08-26 | 2013-03-07 | Ranbaxy Laboratories Limited | Crystalline lurasidone hydrochloride |
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- 2015-06-12 SI SI201531384T patent/SI3154967T1/sl unknown
- 2015-06-12 WO PCT/US2015/035558 patent/WO2015195478A1/en active Application Filing
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US9790237B2 (en) | 2017-10-17 |
EP3154967B1 (en) | 2020-07-29 |
CA2951917C (en) | 2019-09-24 |
US20180099982A1 (en) | 2018-04-12 |
HRP20201638T1 (hr) | 2021-03-05 |
EP3154967A1 (en) | 2017-04-19 |
JP2017522284A (ja) | 2017-08-10 |
PL3154967T3 (pl) | 2021-01-11 |
US20150361099A1 (en) | 2015-12-17 |
WO2015195478A1 (en) | 2015-12-23 |
HUE052277T2 (hu) | 2021-04-28 |
SI3154967T1 (sl) | 2020-11-30 |
US20180312530A1 (en) | 2018-11-01 |
ES2826603T3 (es) | 2021-05-18 |
CA2951917A1 (en) | 2015-12-23 |
US9957283B1 (en) | 2018-05-01 |
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