CN101137632A - 制备反式-1-((1r,3s)-6-氯-3-苯基茚满-1-基)-3,3-二甲基哌嗪的方法 - Google Patents
制备反式-1-((1r,3s)-6-氯-3-苯基茚满-1-基)-3,3-二甲基哌嗪的方法 Download PDFInfo
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- CN101137632A CN101137632A CNA2006800052071A CN200680005207A CN101137632A CN 101137632 A CN101137632 A CN 101137632A CN A2006800052071 A CNA2006800052071 A CN A2006800052071A CN 200680005207 A CN200680005207 A CN 200680005207A CN 101137632 A CN101137632 A CN 101137632A
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- China
- Prior art keywords
- compound
- alkali
- monovalent
- perhaps
- lithium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 64
- 239000012971 dimethylpiperazine Substances 0.000 title abstract 2
- 230000008569 process Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- 239000003513 alkali Substances 0.000 claims description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 43
- 229910052751 metal Inorganic materials 0.000 claims description 28
- 239000002184 metal Substances 0.000 claims description 28
- -1 4-methyl benzoic acid ester Chemical class 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000741 silica gel Substances 0.000 claims description 20
- 229910002027 silica gel Inorganic materials 0.000 claims description 20
- 229960001866 silicon dioxide Drugs 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 19
- 238000004587 chromatography analysis Methods 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000004808 supercritical fluid chromatography Methods 0.000 claims description 14
- 229920000856 Amylose Polymers 0.000 claims description 13
- 229920002472 Starch Polymers 0.000 claims description 13
- 230000006340 racemization Effects 0.000 claims description 13
- 239000008107 starch Substances 0.000 claims description 13
- 235000019698 starch Nutrition 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 10
- 229910052744 lithium Inorganic materials 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 229910052728 basic metal Inorganic materials 0.000 claims description 8
- 238000004811 liquid chromatography Methods 0.000 claims description 8
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
- 238000004176 ammonification Methods 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
- 230000004048 modification Effects 0.000 claims description 7
- 238000012986 modification Methods 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims description 5
- 150000004703 alkoxides Chemical class 0.000 claims description 5
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical compound [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 150000004704 methoxides Chemical class 0.000 claims description 5
- 230000000269 nucleophilic effect Effects 0.000 claims description 5
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
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- 230000000903 blocking effect Effects 0.000 claims description 2
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- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 239000003205 fragrance Substances 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluenecarboxylic acid Natural products CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 2
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- 239000002244 precipitate Substances 0.000 claims 2
- 239000000178 monomer Substances 0.000 claims 1
- BYPMJBXPNZMNQD-PZJWPPBQSA-N Zicronapine Chemical compound C1C(C)(C)N(C)CCN1[C@H]1C2=CC(Cl)=CC=C2[C@H](C=2C=CC=CC=2)C1 BYPMJBXPNZMNQD-PZJWPPBQSA-N 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 238000003756 stirring Methods 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 19
- 150000002576 ketones Chemical class 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
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- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 10
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- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
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- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 3
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
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- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
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- 239000003480 eluent Substances 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
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- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
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- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
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- VMOWKUTXPNPTEN-UHFFFAOYSA-N n,n-dimethylpropan-2-amine Chemical compound CC(C)N(C)C VMOWKUTXPNPTEN-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 206010036067 polydipsia Diseases 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940018489 pronto Drugs 0.000 description 1
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- 238000011555 rabbit model Methods 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Classifications
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- 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
- C07D295/06—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 halogen atoms or nitro radicals
- C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- 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
- C07D295/06—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 halogen atoms or nitro radicals
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/36—Opioid-abuse
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- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
- C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
柱 | Rs | ||||
名称 | 尺寸a | 甲醇 | 乙醇 | 异丙醇 | 乙腈 |
ChiralpakAD-H | 4.6,250,5 | 17.1 | 10.0 | 2.0 | 19.1 |
ChiralpakAS-H | 4.6,250,5 | 3.5 | 4.0 | 4.9 | 3.6 |
ChiralcelOD-H | 4.6,250,5 | 4.0 | 3.2 | 2.8 | |
ChiralcelOJ-H | 4.6,250,5 | 0.7 | 0.0 | 0.0 | |
ChiralpakIA | 4.6,250,5 | 5.4 | 2.8 | 0.6 | 2.6 |
(R,R)-Whelk-O1 | 4.6,250,5 | 1.0 | 1.1 | 1.7 |
条目 | 碱1的当-量 | 碱1 | 碱2的当量 | 碱2 | 时间1)hr | 粗产物纯度% | ee2)% |
1 | 2.25 | LDA3) | N/A | N/A | 2.5 | 91 | 2 |
2 | 2.25 | KOtBu | N/A | N/A | 2.5 | 38 | -10 |
3 | 2.25 | BuLi | N/A | N/A | 2.5 | 39 | 5 |
4 | 2.25 | tBuLi | N/A | N/A | 2.5 | 40 | -13 |
5 | 1.25 | LDA4) | 1.25 | BuLi | 2.5 | 83 | 1 |
6 | 1.25 | LDA4) | 1 | KOtBu | 2.5 | 88 | 0 |
7 | 1.25 | LDA4) | 1.25 | tBuLi | 2.5 | 88 | -4 |
8 | 1.25 | LiHMDS | 1 | KOtBu | 2.5 | 86 | 1 |
9 | 1.25 | LiOtBu | 1 | KOtBu | 2.5 | 93 | 0 |
10 | 1.25 | LDA5) | 1 | BuLi | 0.5 | 82 | 2 |
11 | 1.25 | LDA5) | 1 | BuLi | 1 | 93 | 2 |
12 | 1.25 | LDA5) | 1 | BuLi | 2.5 | 90 | -3 |
136) | 1.25 | LDA5) | 1 | BuLi | 0.5 | 85 | 2 |
146) | 1.25 | LDA5) | 1 | BuLi | 1 | 85 | 2 |
156) | 1.25 | LDA5) | 1 | BuLi | 2.5 | 86 | -1 |
条目 | 碱1的当量 | 碱1 | 碱2的当量 | 碱2 | 时间1)hr | 产率% | 纯度% | ee2)% |
1 | 2.25 | LDA3) | N/A | N/A | 2.5 | 53 | 97 | -3 |
2 | 1.25 | LDA4) | 1.25 | BuLi | 2.5 | 60 | 97 | -1 |
3 | 1.25 | LDA4) | 1 | KOtBu | 2.5 | 76 | 87 | 0 |
4 | 1.25 | LiOtBu | 1 | KOtBu | 2.5 | 70 | 79 | -2 |
5 | 1.25 | LDA5) | 1 | BuLi | 2.5 | 70 | 97 | 0 |
66) | 1.25 | LDA6) | 1.25 | BuLi | 1/2 | 59 | 96 | 0 |
Claims (39)
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US65342805P | 2005-02-16 | 2005-02-16 | |
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PCT/DK2006/000086 WO2006086984A1 (en) | 2005-02-16 | 2006-02-14 | Process for making trans-1-((1r, 3s)-6-chloro-3-phenylindan-1-yl)-3, 3-dimethylpiperazine |
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US (2) | US8569499B2 (zh) |
EP (1) | EP1853574A1 (zh) |
JP (1) | JP5148289B2 (zh) |
KR (1) | KR101364365B1 (zh) |
CN (1) | CN101137632B (zh) |
AR (1) | AR054735A1 (zh) |
AU (1) | AU2006215955B2 (zh) |
BR (1) | BRPI0607438A2 (zh) |
CA (1) | CA2597615C (zh) |
EA (1) | EA018059B1 (zh) |
HK (1) | HK1123544A1 (zh) |
IL (1) | IL184553A (zh) |
MX (1) | MX2007009814A (zh) |
MY (1) | MY148242A (zh) |
NO (1) | NO20074642L (zh) |
NZ (1) | NZ556517A (zh) |
TW (1) | TWI453198B (zh) |
UA (1) | UA106191C2 (zh) |
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Cited By (3)
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CN102471289A (zh) * | 2009-07-07 | 2012-05-23 | H.隆德贝克有限公司 | 4-((1r,3s)-6-氯-3-苯基-茚满-1-基)-1,2,2-三甲基-哌嗪和1-((1r,3s)-6-氯-3-苯基-茚满-1-基)-3,3-二甲基-哌嗪的制备 |
CN103209949A (zh) * | 2010-11-09 | 2013-07-17 | 株式会社钟化 | 卤化茚酮类及使用其的光学活性茚满酮类或光学活性茚满醇类的制造方法 |
CN103429577A (zh) * | 2011-01-07 | 2013-12-04 | H.隆德贝克有限公司 | 4-((1r,3s)-6-氯-3-苯基-茚满-1-基)-1,2,2-三甲基哌嗪和1-((1r,3s)-6-氯-3-苯基-茚满-1-基)-3,3-二甲基哌嗪的拆分方法 |
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AU2004265021B2 (en) | 2003-08-18 | 2010-05-27 | H. Lundbeck A/S | Succinate and malonate salt of trans-4-(IR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and the use as a medicament |
TWI453198B (zh) * | 2005-02-16 | 2014-09-21 | Lundbeck & Co As H | 製造反式-1-((1r,3s)-6-氯基-3-苯基茚滿-1-基) -3 , 3 -二甲基六氫吡與其鹽類之方法及製造4-((1r , 3s)-6 -氯基-3-苯基茚滿-1-基 )-1,2,2-三甲基六氫吡與其鹽類之方法 |
TWI376373B (en) | 2005-02-16 | 2012-11-11 | Lundbeck & Co As H | Crystalline base of a pharmaceutical compound |
TW200819426A (en) | 2006-08-31 | 2008-05-01 | Lundbeck & Co As H | Novel indane compounds |
LT2720989T (lt) * | 2011-06-20 | 2016-11-25 | H. Lundbeck A/S | Deuterinti 1-piperazin-3-fenilindanai, skirti šizofrenijos gydymui |
JP5838628B2 (ja) * | 2011-07-25 | 2016-01-06 | 東ソー株式会社 | N−アルキルピペラジン類の製造方法 |
AR094054A1 (es) | 2012-12-19 | 2015-07-08 | H Lundbeck As | 6-cloro-3-(fenil-d₅)-inden-1-ona y uso de la misma |
JP6786761B2 (ja) * | 2015-05-26 | 2020-11-18 | ディーエスエム アイピー アセッツ ビー.ブイ.Dsm Ip Assets B.V. | Sfcによるキラル異性体の分離 |
US20210395208A1 (en) | 2018-10-29 | 2021-12-23 | H. Lundeck A/S | Amorphous compounds of formula (i) and amorphous compounds of formula (i) salts |
WO2020114853A1 (en) | 2018-12-03 | 2020-06-11 | H. Lundbeck A/S | Prodrugs of 4-((1r,3s)-6-chloro-3-phenyl-2,3-dihydro-1h-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1/r,3s)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1h-inden-1-yl)-2,2-dimethy-1-(methyl-d3)piperazine |
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TWI453198B (zh) * | 2005-02-16 | 2014-09-21 | Lundbeck & Co As H | 製造反式-1-((1r,3s)-6-氯基-3-苯基茚滿-1-基) -3 , 3 -二甲基六氫吡與其鹽類之方法及製造4-((1r , 3s)-6 -氯基-3-苯基茚滿-1-基 )-1,2,2-三甲基六氫吡與其鹽類之方法 |
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- 2006-02-14 WO PCT/DK2006/000086 patent/WO2006086984A1/en active Application Filing
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102471289A (zh) * | 2009-07-07 | 2012-05-23 | H.隆德贝克有限公司 | 4-((1r,3s)-6-氯-3-苯基-茚满-1-基)-1,2,2-三甲基-哌嗪和1-((1r,3s)-6-氯-3-苯基-茚满-1-基)-3,3-二甲基-哌嗪的制备 |
CN103209949A (zh) * | 2010-11-09 | 2013-07-17 | 株式会社钟化 | 卤化茚酮类及使用其的光学活性茚满酮类或光学活性茚满醇类的制造方法 |
CN104496780A (zh) * | 2010-11-09 | 2015-04-08 | 株式会社钟化 | 卤化茚酮类及使用其的光学活性茚满酮类或光学活性茚满醇类的制造方法 |
CN103209949B (zh) * | 2010-11-09 | 2016-08-10 | 株式会社钟化 | 卤化茚酮类及使用其的光学活性茚满酮类或光学活性茚满醇类的制造方法 |
CN103429577A (zh) * | 2011-01-07 | 2013-12-04 | H.隆德贝克有限公司 | 4-((1r,3s)-6-氯-3-苯基-茚满-1-基)-1,2,2-三甲基哌嗪和1-((1r,3s)-6-氯-3-苯基-茚满-1-基)-3,3-二甲基哌嗪的拆分方法 |
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CA2597615A1 (en) | 2006-08-24 |
AU2006215955A1 (en) | 2006-08-24 |
CA2597615C (en) | 2014-05-27 |
JP2008530038A (ja) | 2008-08-07 |
TW200716582A (en) | 2007-05-01 |
US8569499B2 (en) | 2013-10-29 |
ZA200705984B (en) | 2009-01-28 |
US20100069676A1 (en) | 2010-03-18 |
EP1853574A1 (en) | 2007-11-14 |
MY148242A (en) | 2013-03-29 |
NZ556517A (en) | 2010-05-28 |
CN101137632B (zh) | 2013-06-19 |
JP5148289B2 (ja) | 2013-02-20 |
AU2006215955B2 (en) | 2011-09-08 |
BRPI0607438A2 (pt) | 2010-04-06 |
IL184553A0 (en) | 2007-10-31 |
KR20070103386A (ko) | 2007-10-23 |
TWI453198B (zh) | 2014-09-21 |
HK1123544A1 (en) | 2009-06-19 |
IL184553A (en) | 2014-05-28 |
MX2007009814A (es) | 2007-09-07 |
NO20074642L (no) | 2007-09-12 |
AR054735A1 (es) | 2007-07-11 |
WO2006086984A1 (en) | 2006-08-24 |
EA018059B1 (ru) | 2013-05-30 |
UA106191C2 (ru) | 2014-08-11 |
US20080153847A1 (en) | 2008-06-26 |
KR101364365B1 (ko) | 2014-02-21 |
EA200701738A1 (ru) | 2007-12-28 |
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