JP4708012B2 - 第四級アンモニウム塩の製造法 - Google Patents
第四級アンモニウム塩の製造法 Download PDFInfo
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- JP4708012B2 JP4708012B2 JP2004362562A JP2004362562A JP4708012B2 JP 4708012 B2 JP4708012 B2 JP 4708012B2 JP 2004362562 A JP2004362562 A JP 2004362562A JP 2004362562 A JP2004362562 A JP 2004362562A JP 4708012 B2 JP4708012 B2 JP 4708012B2
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- JP
- Japan
- Prior art keywords
- group
- formula
- methyl
- isoindole
- quaternary ammonium
- Prior art date
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- 150000003242 quaternary ammonium salts Chemical class 0.000 title claims description 43
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- -1 1,2-benzisothiazol-3-yl group Chemical group 0.000 claims description 92
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 90
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 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 17
- 238000000034 method Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- KRDOFMHJLWKXIU-UHFFFAOYSA-N ID11614 Chemical compound C1CNCCN1C1=NSC2=CC=CC=C12 KRDOFMHJLWKXIU-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- JIHKCHWEXXZTOU-UHFFFAOYSA-N [2-(methylsulfonyloxymethyl)cyclohexyl]methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1CCCCC1COS(C)(=O)=O JIHKCHWEXXZTOU-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 3
- 150000003949 imides Chemical group 0.000 claims 1
- 125000003003 spiro group Chemical group 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000006227 byproduct Substances 0.000 description 27
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 125000003545 alkoxy group Chemical group 0.000 description 16
- 125000005586 carbonic acid group Chemical group 0.000 description 14
- 125000004430 oxygen atom Chemical group O* 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 12
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 238000004811 liquid chromatography Methods 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 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 description 7
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 125000004450 alkenylene group Chemical group 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000005156 substituted alkylene group Chemical group 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229910001873 dinitrogen Inorganic materials 0.000 description 5
- 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 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- RIVOBMOBWMOLDJ-UHFFFAOYSA-N 6713-41-3 Chemical compound C1CC2C3C(=O)NC(=O)C3C1C2 RIVOBMOBWMOLDJ-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 4
- WLDMPODMCFGWAA-UHFFFAOYSA-N 3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1CCCC2C(=O)NC(=O)C21 WLDMPODMCFGWAA-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 238000011088 calibration curve Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- SVGOMVDLLKZDBF-UHFFFAOYSA-N O=C1C2C(C3)CCC3C2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=NC=CC=N1 Chemical compound O=C1C2C(C3)CCC3C2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=NC=CC=N1 SVGOMVDLLKZDBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 125000005368 heteroarylthio group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- IACVNURSTUDTFC-UHFFFAOYSA-N (2-hydroxy-3-methylsulfonyloxypropyl) methanesulfonate Chemical compound CS(=O)(=O)OCC(O)COS(C)(=O)=O IACVNURSTUDTFC-UHFFFAOYSA-N 0.000 description 1
- WLDMPODMCFGWAA-OLQVQODUSA-N (3as,7ar)-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1CCC[C@@H]2C(=O)NC(=O)[C@@H]21 WLDMPODMCFGWAA-OLQVQODUSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MKIIBHAVKKVAKM-UHFFFAOYSA-N 1,2-bis(bromomethyl)cyclohexane Chemical compound BrCC1CCCCC1CBr MKIIBHAVKKVAKM-UHFFFAOYSA-N 0.000 description 1
- GRZUMRMUCBCYHV-UHFFFAOYSA-N 1,2-bis(bromomethyl)cyclopentane Chemical compound BrCC1CCCC1CBr GRZUMRMUCBCYHV-UHFFFAOYSA-N 0.000 description 1
- KIHQZLPHVZKELA-UHFFFAOYSA-N 1,3-dibromopropan-2-ol Chemical compound BrCC(O)CBr KIHQZLPHVZKELA-UHFFFAOYSA-N 0.000 description 1
- DEWLEGDTCGBNGU-UHFFFAOYSA-N 1,3-dichloropropan-2-ol Chemical compound ClCC(O)CCl DEWLEGDTCGBNGU-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 description 1
- ROUYUBHVBIKMQO-UHFFFAOYSA-N 1,4-diiodobutane Chemical compound ICCCCI ROUYUBHVBIKMQO-UHFFFAOYSA-N 0.000 description 1
- PYUFUUDEYQJLPV-UHFFFAOYSA-N 1-(1-benzofuran-5-yl)piperazine Chemical compound C1CNCCN1C1=CC=C(OC=C2)C2=C1 PYUFUUDEYQJLPV-UHFFFAOYSA-N 0.000 description 1
- KFVKNZPFYQDNAE-UHFFFAOYSA-N 1-(1-benzofuran-7-yl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=C1OC=C2 KFVKNZPFYQDNAE-UHFFFAOYSA-N 0.000 description 1
- VNICFCQJUVFULD-UHFFFAOYSA-N 1-(1-naphthalenyl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=CC=CC=C12 VNICFCQJUVFULD-UHFFFAOYSA-N 0.000 description 1
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 1
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 1
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 description 1
- XTMOKVUSLXWZAR-UHFFFAOYSA-N 1-[[2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]cyclohexyl]methyl]-4,4-dimethylpiperidine-2,6-dione Chemical compound O=C1CC(C)(C)CC(=O)N1CC1C(CN2CCN(CC2)C=2C3=CC=CC=C3SN=2)CCCC1 XTMOKVUSLXWZAR-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- HPEIDXNJCQFWBG-UHFFFAOYSA-N 2-[4-(4-phenylpiperazin-1-yl)butyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound O=C1C2CCCCC2C(=O)N1CCCCN(CC1)CCN1C1=CC=CC=C1 HPEIDXNJCQFWBG-UHFFFAOYSA-N 0.000 description 1
- CKWYMRLGBVPIHJ-UHFFFAOYSA-N 2-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound COC1=CC=CC=C1N1CCN(CCCCN2C(C3CCCCC3C2=O)=O)CC1 CKWYMRLGBVPIHJ-UHFFFAOYSA-N 0.000 description 1
- MEIAMUDAJQPLSA-UHFFFAOYSA-N 2-[[2-[(4-isoquinolin-3-ylpiperazin-1-yl)methyl]cyclohexyl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1=CC=C2C=NC(N3CCN(CC3)CC3CCCCC3CN3C(=O)C4CCCCC4C3=O)=CC2=C1 MEIAMUDAJQPLSA-UHFFFAOYSA-N 0.000 description 1
- TVHSSDWTXQPROI-UHFFFAOYSA-N 2-[[2-[(4-naphthalen-1-ylpiperazin-1-yl)methyl]cyclohexyl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1=CC=C2C(N3CCN(CC3)CC3CCCCC3CN3C(=O)C4CCCCC4C3=O)=CC=CC2=C1 TVHSSDWTXQPROI-UHFFFAOYSA-N 0.000 description 1
- KDXGOAOXIFWEPO-UHFFFAOYSA-N 2-[[2-[(4-pyrimidin-2-ylpiperazin-1-yl)methyl]cyclohexyl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound O=C1C2CCCCC2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=NC=CC=N1 KDXGOAOXIFWEPO-UHFFFAOYSA-N 0.000 description 1
- IAQORBQEZAJTET-UHFFFAOYSA-N 2-[[2-[(4-quinolin-8-ylpiperazin-1-yl)methyl]cyclohexyl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1=CN=C2C(N3CCN(CC3)CC3CCCCC3CN3C(=O)C4CCCCC4C3=O)=CC=CC2=C1 IAQORBQEZAJTET-UHFFFAOYSA-N 0.000 description 1
- IYXSIWARVWPCRS-UHFFFAOYSA-N 2-[[2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]-3-bicyclo[2.2.1]heptanyl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1=CC=C2C(N3CCN(CC3)CC3C4CCC(C4)C3CN3C(=O)C4CCCCC4C3=O)=NSC2=C1 IYXSIWARVWPCRS-UHFFFAOYSA-N 0.000 description 1
- PTASJEULJZADAB-UHFFFAOYSA-N 2-[[2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-5-en-3-yl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1=CC=C2C(N3CCN(CC3)CC3C4OC(C=C4)C3CN3C(=O)C4CCCCC4C3=O)=NSC2=C1 PTASJEULJZADAB-UHFFFAOYSA-N 0.000 description 1
- DFOATGAIVVNLEX-UHFFFAOYSA-N 2-[[2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]cyclohexyl]methyl]-3a,4,5,6,7,7a-hexahydro-octahydro-1h-4,7-epoxyisoindole-1,3-dione Chemical compound C1=CC=C2C(N3CCN(CC3)CC3CCCCC3CN3C(=O)C4C5CCC(O5)C4C3=O)=NSC2=C1 DFOATGAIVVNLEX-UHFFFAOYSA-N 0.000 description 1
- UIGJVYSDOODTJR-UHFFFAOYSA-N 2-[[2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]cyclohexyl]methyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1=CC=C2C(N3CCN(CC3)CC3CCCCC3CN3C(=O)C4CCCCC4C3=O)=NSC2=C1 UIGJVYSDOODTJR-UHFFFAOYSA-N 0.000 description 1
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- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical group OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- DMADELJYOZEJCQ-UHFFFAOYSA-N O=C1C2C(C3)CCC3C2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=CC=CC2=C1OC=C2 Chemical compound O=C1C2C(C3)CCC3C2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=CC=CC2=C1OC=C2 DMADELJYOZEJCQ-UHFFFAOYSA-N 0.000 description 1
- HYMWWRVZGXFNNY-UHFFFAOYSA-N O=C1C2C(C3)CCC3C2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=CC=CC=N1 Chemical compound O=C1C2C(C3)CCC3C2C(=O)N1CC1CCCCC1CN(CC1)CCN1C1=CC=CC=N1 HYMWWRVZGXFNNY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- JIHKCHWEXXZTOU-UWVGGRQHSA-N [(1r,2r)-2-(methylsulfonyloxymethyl)cyclohexyl]methyl methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H]1CCCC[C@H]1COS(C)(=O)=O JIHKCHWEXXZTOU-UWVGGRQHSA-N 0.000 description 1
- RPVVUZPLCARFKW-UHFFFAOYSA-N [2-(methylsulfonyloxymethyl)cyclopentyl]methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1CCCC1COS(C)(=O)=O RPVVUZPLCARFKW-UHFFFAOYSA-N 0.000 description 1
- QXQBWEJTOQIKJY-UHFFFAOYSA-N [6-(methylsulfonyloxymethyl)cyclohex-3-en-1-yl]methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1CC=CCC1COS(C)(=O)=O QXQBWEJTOQIKJY-UHFFFAOYSA-N 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 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
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- YRTHJMQKDCXPAY-UHFFFAOYSA-N azaspirodecanedione Chemical compound C1C(=O)NC(=O)CC11CCCC1 YRTHJMQKDCXPAY-UHFFFAOYSA-N 0.000 description 1
- OSNDUYDDOHEKEE-UHFFFAOYSA-N azepane-2,7-dione Chemical compound O=C1CCCCC(=O)N1 OSNDUYDDOHEKEE-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005921 isopentoxy group Chemical group 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
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 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
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 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
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 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
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000005484 neopentoxy group Chemical group 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
- 208000015238 neurotic disease Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 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
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- XCFVUJRNGIESJC-UHFFFAOYSA-N spiro[bicyclo[2.2.2]octane-3,3'-pyrrolidine]-2',5'-dione Chemical compound O=C1NC(=O)CC11C(CC2)CCC2C1 XCFVUJRNGIESJC-UHFFFAOYSA-N 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
で示される化合物に代表される式(5)
(式中、Aは置換されていてもよい炭素数2〜4のアルキレン基または置換されていてもよい炭素数2〜4のアルケニレン基を表わし、Dはカルボニル基またはスルホニル基を表わす。Yは置換されていてもよい炭素数1〜2のアルキレン基を表わし、Zは置換されていてもよいメチレン基または置換されていてもよいイミノ基を表わす。)
で示されるイミド化合物は、例えば統合失調症、老年性精神疾患、躁鬱病、神経症等の治療薬の中間体として有用であり、式(3)
(式中、X−は対アニオンを表わし、YおよびZは上記と同一の意味を表わす。)
で示される第四級アンモニウム塩が、かかる式(5)で示されるイミド化合物の重要な合成中間体であることが知られている(例えば特許文献1参照。)。
(式中、Zは上記と同一の意味を表わす。)
で示される化合物と式(2)
(式中、Xは脱離して対アニオンを形成する基を表わし、Yは上記と同一の意味を表わす。)
で示される化合物とを、炭酸カリウムの存在下に反応させる方法が知られている(例えば特許文献1および2参照。)が、炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の生成が見られていた。かかる炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の多くは、次工程において、式(3)で示される第四級アンモニウム塩と同様の反応性を示し、式(3)で示される第四級アンモニウム塩の品質はもちろんのこと、次工程の目的生成物である上記式(5)で示されるイミド化合物の品質をも低下させる原因となり得るため、式(1)で示される化合物と式(2)で示される化合物との反応において、かかる炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の副生量をさらに抑制することが望まれていた。
で示される化合物(以下、化合物(1)と略記する。)の式中、Zは置換されていてもよいメチレン基または置換されていてもよいイミノ基を表わす。置換されていてもよいメチレン基の置換基としては、例えば低級アルキル基、低級アルコキシ基、低級アルキルチオ基、低級アルキリデン基、シクロアルキル基、シクロアルキルオキシ基、シクロアルキルチオ基、シクロアルケニル基、シクロアルケニルオキシ基、シクロアルケニルチオ基、アリール基、アリールオキシ基、アリールチオ基、ヘテロアリール基、ヘテロアリールオキシ基、ヘテロアリールチオ基等が挙げられる。
(式中、X、YおよびZは上記と同一の意味を表わす。)
で示される第四級アンモニウム塩(以下、第四級アンモニウム塩(3)と略記する。)を製造することができる。
(式中、Aは置換されていてもよい炭素数2〜4のアルキレン基または置換されていてもよい炭素数2〜4のアルケニレン基を表わし、Dはカルボニル基またはスルホニル基を表わす。)
で示される化合物(以下、化合物(6)と略記する。)とを、固体無機塩基の存在下に反応させることにより、式(5)
(式中、A、D、YおよびZは上記と同一の意味を表わす。)
で示されるイミド化合物(以下、イミド化合物(5)と略記する。)を製造することができる。
(1R,2R)−1,2−ビス(メタンスルホニルオキシメチル)シクロヘキサン16.4g、4−(1,2−ベンズイソチアゾール−3−イル)ピペラジン10gおよびトルエン162gの混合液に、攪拌しながら、比表面積が0.6m2/gである炭酸カリウム(旭硝子株式会社品;比表面積は窒素ガスを用いるBET吸着法(柴田科学製SA−1000を使用)により測定)3.8gを加えた。トルエン22gを留去した後、還流条件下で、6時間攪拌、反応させた。一旦内温約60℃に冷却した後、比表面積が0.6m2/gである炭酸カリウム(同上)1.9gおよび硫酸水素テトラ−n−ブチルアンモニウム0.62gを加え、還流条件下で、さらに16時間攪拌、反応させ、4’−(1,2−ベンゾイソチアゾール−3−イル)−(3aR,7aR)−オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]メタンスルホン酸塩を含む反応液を得た。反応液をLC分析したところ、4−(1,2−ベンズイソチアゾール−3−イル)ピペラジンの残存率(下記式(7)に従い算出)は、0.6%であった。
また、炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の副生率(下記式(8)に従い算出)は、1.8%であった。
前記実施例1で得られた4’−(1,2−ベンゾイソチアゾール−3−イル)−(3aR,7aR)−オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]メタンスルホン酸塩を含む反応液に、ヘキサヒドロ−(3aS,4R,7S,7aR)−4,7−メタノ−1H−イソインドール−1,3(2H)−ジオン11.3g、炭酸カリウム7.6gおよびトルエン22gを加えた。その後、トルエン22gを留去し、水0.4gを加え、還流条件下で、2時間反応させた。反応終了後、室温まで冷却し、水200gを加えて分液処理し、得られたトルエン層を2.3重量%食塩水175gで洗浄処理した。さらに活性炭0.9gを加え、1時間攪拌した後、活性炭を濾別し、2−[[(1R,2R)−2−[[4−(1,2−ベンゾイソチアゾール−3−イル)−1−ピペラジニル]メチル]シクロヘキシル]メチル]ヘキサヒドロ−(3aS,4R,7S,7aR)−4,7−メタノ−1H−イソインドール−1,3(2H)−ジオンを含むトルエン溶液288.8gを得た。2−[[(1R,2R)−2−[[4−(1,2−ベンゾイソチアゾール−3−イル)−1−ピペラジニル]メチル]シクロヘキシル]メチル]ヘキサヒドロ−(3aS,4R,7S,7aR)−4,7−メタノ−1H−イソインドール−1,3(2H)−ジオンの含量は、6.9重量%(LC絶対検量線法により算出)で、収率は、89.5%であった。また、炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の副生率(上記式(8)に従い算出)は、1.5%であった。
前記実施例1において、比表面積が0.6m2/gである炭酸カリウム3.8gに代えて、比表面積が0.8m2/gである炭酸カリウム(旭硝子株式会社品;比表面積は窒素ガスを用いるBET吸着法(柴田科学製SA−1000を使用)により測定)3.8gを用いた以外は実施例1と同様にして、6時間反応させた。一旦内温約60℃に冷却した後、比表面積が0.8m2/gである炭酸カリウム(同上)1.9gおよび硫酸水素テトラ−n−ブチルアンモニウム0.62gを加え、還流条件下で、さらに8時間攪拌、反応させ、4’−(1,2−ベンゾイソチアゾール−3−イル)−(3aR,7aR)−オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]メタンスルホン酸塩を含む反応液を得た。反応液をLC分析したところ、4−(1,2−ベンズイソチアゾール−3−イル)ピペラジンの残存率(上記式(7)に従い算出)は、0.7%であった。また、炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の副生率(上記式(8)に従い算出)は、2.4%であった。
前記実施例1において、比表面積が0.6m2/gである炭酸カリウム3.8gに代えて、比表面積が1.8m2/gである炭酸カリウム(旭硝子株式会社品;比表面積は窒素ガスを用いるBET吸着法(柴田科学製SA−1000を使用)により測定)3.8gを用いた以外は実施例1と同様にして、7時間反応させた。一旦内温約60℃に冷却した後、比表面積が1.8m2/gである炭酸カリウム(同上)1.9gおよび硫酸水素テトラ−n−ブチルアンモニウム0.62gを加え、還流条件下で、さらに8時間攪拌、反応させ、4’−(1,2−ベンゾイソチアゾール−3−イル)−(3aR,7aR)−オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]メタンスルホン酸塩を含む反応液を得た。反応液をLC分析したところ、4−(1,2−ベンズイソチアゾール−3−イル)ピペラジンの残存率(上記式(7)に従い算出)は、0.8%であった。また、炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の副生率(上記式(8)に従い算出)は、4.5%であった。
前記実施例1において、比表面積が0.6m2/gである炭酸カリウム3.8gに代えて、比表面積が2.0m2/gである炭酸カリウム(旭硝子株式会社品;比表面積は窒素ガスを用いるBET吸着法(柴田科学製SA−1000を使用)により測定)3.8gを用いた以外は実施例1と同様にして、6時間反応させた。一旦内温約60℃に冷却した後、比表面積が2.0m2/gである炭酸カリウム(同上)1.9gおよび硫酸水素テトラ−n−ブチルアンモニウム0.62gを加え、還流条件下で、さらに8時間攪拌、反応させ、4’−(1,2−ベンゾイソチアゾール−3−イル)−(3aR,7aR)−オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]メタンスルホン酸塩を含む反応液を得た。反応液をLC分析したところ、4−(1,2−ベンズイソチアゾール−3−イル)ピペラジンの残存率(上記式(7)に従い算出)は、0.6%であった。また、炭酸カリウムとの反応由来の分子内に炭酸骨格を有する副生成物の副生率(上記式(8)に従い算出)は、9.2%であった。
Claims (12)
- Xが、メタンスルホニルオキシ基である、請求項1に記載の第四級アンモニウム塩の製造法。
- 式(2)で示される化合物が、1,2−ビス(メタンスルホニルオキシメチル)シクロヘキサンである、請求項1または2に記載の第四級アンモニウム塩の製造法。
- 式(3)で示される化合物が、4’−(1,2−ベンズイソチアゾール−3−イル)オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]のメタンスルホン酸塩である、請求項1〜3のいずれか一項に記載の第四級アンモニウム塩の製造法。
- 相間移動触媒の共存下に反応を実施する請求項1〜4のいずれか一項に記載の第四級アンモニウム塩の製造法。
- 比表面積が、0.2m2/g以上、1m2/g未満である炭酸カリウムを用いる請求項1〜5のいずれかに記載の第四級アンモニウム塩の製造法。
- 比表面積が、0.2m2/g以上、0.8m2/g以下である炭酸カリウムを用いる請求項6に記載の第四級アンモニウム塩の製造法。
- 式(6)で示される化合物が、ビシクロ[2.2.1]ヘプタン−2,3−ジ−エキソ−カルボキシイミドまたはビシクロ[2.2.1]ヘプタン−2,3−ジ−エンド−カルボキシイミドである請求項8に記載のイミド化合物の製造法。
- 式(5)で示される化合物が、2−[[2−[[4−(1,2−ベンズイソチアゾール−3−イル)−1−ピペラジニル]メチル]シクロヘキシル]メチル]ヘキサヒドロ−4,7−メタノ−1H−イソインドール−1,3(2H)−ジオンである請求項8または9に記載のイミド化合物の製造法。
- 水の共存下に反応を実施する請求項10に記載のイミド化合物の製造法。
- 有機溶媒中、4−(1,2−ベンズイソチアゾール−3−イル)ピペラジンと1,2−ビス(メタンスルホニルオキシメチル)シクロヘキサンとを、比表面積が0.2m2/g以上、1m2/g以下である炭酸カリウムの存在下に反応し、得られる4’−(1,2−ベンズイソチアゾール−3−イル)オクタヒドロ−スピロ[2H−イソインドール−2,1’−ピペラジニウム]メタンスルホン酸塩とビシクロ[2.2.1]ヘプタン−2,3−ジ−エキソ−カルボキシイミドまたはビシクロ[2.2.1]ヘプタン−2,3−ジ−エンド−カルボキシイミドとを反応させることを特徴とする2−[[2−[[4−(1,2−ベンズイソチアゾール−3−イル)−1−ピペラジニル]メチル]シクロヘキシル]メチル]ヘキサヒドロ−4,7−メタノ−1H−イソインドール−1,3(2H)−ジオンの製造法。
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