CN114105980B - 卢美哌隆中间体化合物的制备方法及卢美哌隆中间体化合物 - Google Patents
卢美哌隆中间体化合物的制备方法及卢美哌隆中间体化合物 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 title description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 230000009467 reduction Effects 0.000 claims abstract description 18
- 229940125782 compound 2 Drugs 0.000 claims abstract description 16
- 230000031709 bromination Effects 0.000 claims abstract description 14
- 238000005893 bromination reaction Methods 0.000 claims abstract description 14
- 238000005859 coupling reaction Methods 0.000 claims abstract description 13
- 230000008878 coupling Effects 0.000 claims abstract description 12
- 238000010168 coupling process Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- 238000007256 debromination reaction Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 229940125898 compound 5 Drugs 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000007126 N-alkylation reaction Methods 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- IPQWXJDRMKGSFI-UHFFFAOYSA-N 3,5-diamino-4-methylbenzenesulfonic acid Chemical compound CC1=C(N)C=C(S(O)(=O)=O)C=C1N IPQWXJDRMKGSFI-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 8
- 230000000996 additive effect Effects 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 150000001879 copper Chemical class 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229960001270 d- tartaric acid Drugs 0.000 claims description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- ZPATUOFYXSBHMN-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [H+].[H+].[H+].[Br-].[Br-].[Br-].C1=CC=NC=C1 ZPATUOFYXSBHMN-UHFFFAOYSA-N 0.000 claims description 3
- LBVZINOLAFTARU-UHFFFAOYSA-N 2-bromo-n-methylacetamide Chemical compound CNC(=O)CBr LBVZINOLAFTARU-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims description 2
- 229930182820 D-proline Natural products 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000006887 Ullmann reaction Methods 0.000 claims description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
- QVGHRPSUYBFXLH-UHFFFAOYSA-M benzyl(tributyl)azanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 QVGHRPSUYBFXLH-UHFFFAOYSA-M 0.000 claims description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 150000001408 amides Chemical class 0.000 abstract description 9
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052802 copper Inorganic materials 0.000 abstract description 4
- 239000010949 copper Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000001212 derivatisation Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 35
- 238000006722 reduction reaction Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005040 ion trap Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- HOIIHACBCFLJET-SFTDATJTSA-N 4-((6br,10as)-3-methyl-2,3,6b,9,10,10a-hexahydro-1h-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7h)-yl)-1-(4-fluorophenyl)-1-butanone Chemical compound C([C@@H]1N2CCN(C=3C=CC=C(C2=3)[C@@H]1C1)C)CN1CCCC(=O)C1=CC=C(F)C=C1 HOIIHACBCFLJET-SFTDATJTSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 238000010668 complexation reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- LHAPOGAFBLSJJQ-GUTACTQSSA-N iti007 Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C([C@@H]1N2CCN(C=3C=CC=C(C2=3)[C@@H]1C1)C)CN1CCCC(=O)C1=CC=C(F)C=C1 LHAPOGAFBLSJJQ-GUTACTQSSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- PHCYUJRYSFMJMG-UHFFFAOYSA-N (2-bromophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=CC=C1Br PHCYUJRYSFMJMG-UHFFFAOYSA-N 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 alkoxy amide Chemical class 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229950003467 lumateperone Drugs 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 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 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- LUBGFMZTGFXIIN-UHFFFAOYSA-N ethyl 4-oxopiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(=O)CC1 LUBGFMZTGFXIIN-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 2
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- FGSHJLJPYBUBHO-UHFFFAOYSA-N 2-chloroethyl(methyl)azanium;chloride Chemical compound [Cl-].C[NH2+]CCCl FGSHJLJPYBUBHO-UHFFFAOYSA-N 0.000 description 1
- HYTIPJFUWHYQON-UHFFFAOYSA-N 3,4-dihydro-1h-quinoxalin-2-one Chemical compound C1=CC=C2NC(=O)CNC2=C1 HYTIPJFUWHYQON-UHFFFAOYSA-N 0.000 description 1
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- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
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- 229910000510 noble metal Inorganic materials 0.000 description 1
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/16—Peri-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明适用于药物合成技术领域,提供了卢美哌隆中间体化合物的制备方法及卢美哌隆中间体化合物;本发明利用Ir‑ZhaoPhos不对称氢化构建手性化合物2,对映体选择性高、转化效率高(S/C=5000‑10000),收率高,反应条件温和,有利于降低成本;通过对所得手性化合物2a进行进一步的衍生化,苯环溴化处理、铜催化C‑N偶联、脱溴、酰胺还原得到卢美哌隆关键中间体7,而由化合物2b、2c、2d合成卢美哌隆关键中间体7不包含溴化和脱溴步骤,经济环保。
Description
技术领域
本发明属于药物合成技术领域,尤其涉及卢美哌隆中间体化合物的制备方法及卢美哌隆中间体化合物。
背景技术
卢美哌隆(通用名:Lumateperone tosylate,商品名为Caplyta),化学名为: 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one,4-methylbenzene-sulfonate。卢美哌隆甲磺酸盐的分子量:393.50;CAS登记号:1187020-80-9(Lumateperonetosylate),313368-91-1 (Lumateperone);结构式为式I所示:
抗精神病药卢美哌隆Lumateperone由生物制药企业Intra-Cellular Therapies开发,2019 年12月获美国食品药物监督管理局(FDA)批准上市,用于成人精神分裂症的治疗。卢美哌隆Lumateperone是精神分裂症治疗领域的首创新药,可协同作用于5-羟色胺、多巴胺及谷氨酸能系统,其独特的作用机制使得该药不仅能改善精神分裂症患者的阳性症状,亦对阴性症状及抑郁症状有效,常见的不良反应有镇静、头痛、腹泻、口干等。
现有技术文献:非专利文献(J.Med.Chem.2014,57,2670-2682),报道以3,4-二氢-1H-2- 喹喔啉酮为原料,经亚硝化、还原、Fischer吲哚反应构建含六氢-γ-咔唑四环结构,然后经氰基硼氢化钠还原、酰胺甲基化、酰胺还原、酰胺水解得到消旋的顺式四环母核,然后与卤代酮N-烷基化反应,得到消旋体卢美哌隆,最后经手性HPLC拆分得到目标产物卢美哌隆 (Scheme 1,路线一)。该路线原料昂贵,路线长,使用大量潜在的剧毒试剂氰基硼氢化钠作为还原剂,废液对环境有影响,最后的步骤使用手性拆分得到目标产物,产率低,利用率低。路线二以盐酸邻溴苯肼伪原料,经Fisher吲哚反应、硅氢还原、N-酰化反应、钯催化C-N键偶联反应、N-烷基化反应、亚胺水解和酰胺化反应、酰胺烷基化、酰胺还原、烷氧酰胺水解得到四元环母核,然后经手性HPLC制备得到手性的四元环母核,最后与烷基酮N-烷基化反应得到目标产物卢美哌隆。该路线同样路线长,使用大量的还原剂,使用贵金属钯催化偶联,最后使用手性HPLC拆分得到关键母核,同样产率低、产品利用率低(Scheme 1,路线二)。以上路线都不具有工业应用价值。
路线一:
专利(WO 2008112280)技术路线如Scheme 2所示。同样以2-溴苯肼盐酸盐与4-哌啶酮盐酸盐为原料合成邻溴六氢-γ-咔唑,接着硅氢化还原、(S)-(+)-扁桃酸成盐拆分得到光学纯的邻溴八氢-γ-咔唑,然后哌啶环N-烷氧羰基化,氢化吲哚环N上烷基化、铜催化Ullman偶联构建四元环,最后硼氢化还原酰胺,得到卢美哌隆关键中间体。
专利(CN 113024554 A)报道的技术路线,通过2-溴苯肼盐酸盐与4-哌啶酮盐酸盐一水化合物反应得到6-溴-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚盐酸盐,随后通过三氟乙酸和三乙基硅氢还原得到相应的消旋化合物6-溴-2,3,4,4a,5,9b-六氢-1H-吡啶并[4,3-b]吲哚盐酸盐,接着通过 (S)-(+)-扁桃酸拆分得到手性的(4aS,9bR)-6-溴-2,3,4,4a,5,9b-六氢-1H-吡啶并[4,3-b]吲哚(S)-(+)- 扁桃酸盐。然后与氯甲酸乙酯反应得到相应的(4aS,9bR)-6-溴-2,3,4,4a,5,9b-六氢-2H-吡啶并 [4,3-b]吲哚-2-羧酸乙酯,最后与2-氯-N-甲基乙胺盐酸盐反应,通过CuI偶联得到卢美哌隆关键中间体。(Scheme 3)
专利(WO 2020112941 A)的技术路线如Scheme 4所示。该路线与J.Med.Chem.路线的不同之处在于四氢吡啶环上N保护基换成苄氧羰基,使用钯催化C-N偶联构建四环结构,然后再钯碳催化氢化还原和脱苄氧羰基后得到消旋体,再与L-(-)-对甲基二苯甲酰酒石酸成盐拆分、游离,得到光学纯的化合物。该路线使用昂贵的钯催化偶联,拆分步骤过于靠后,造成物料的浪费。
专利(CN 112062767A)报道的技术路线如Scheme 5所示,以邻溴六氢-γ-咔唑为底物,经 Ru/JosiphosSL-J505-1不对称氢化,酒石酸结晶得到手性的邻溴八氢-γ-咔唑,经Boc2O保护, N-烷基化反应,CuI催化Ullmann偶联,酰胺还原,脱Boc反应,还原胺化,格氏加成反应得到卢美哌隆。该技术路线关键步骤利用不对称氢化、酒石酸结晶合成手性的邻溴八氢-γ- 咔唑,使用的手性配体JosiphosSL-J505-1价格昂贵,且不对称催化转化数(S/C=1000)不高,工业应用价值有限。
由此可见,现有的卢美哌隆中间体的制备方法存在成本高昂、工艺复杂、环境友好性差以及收率低的问题。
发明内容
本发明实施例提供一种卢美哌隆中间体化合物2的制备方法,旨在解决现有的卢美哌隆中间体的制备方法存在成本高昂、工艺复杂、环境友好性差以及收率低的问题。
本发明实施例是这样实现的,一种卢美哌隆中间体化合物2的制备方法,其特征在于,包括:
在化合物1中加入酸添加剂、反应溶剂以及催化剂,于反应温度为0~50℃以及氢气压力为0.1~8.0Mpa的条件下进行Ir-ZhaoPhos催化不对称氢化处理,得到手性化合物2,反应如下:
所述R为H、F、Cl、Br中的一种;
其中,所述酸添加剂为对甲苯磺酸、甲磺酸、盐酸、硫酸、D-樟脑磺酸、L-樟脑磺酸、D-酒石酸、L-酒石酸中的一种;
所述反应溶剂为二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、甲苯中的一种;
所述催化剂为Ir-ZhaoPhos,金属前体为[Ir(COD)Cl]2、Ir(COD)2BF4中的一种,配体为 (S,RFc)-ZhaoPhos。
本发明实施例还提供了若干卢美哌隆中间体化合物,结构如下:
本发明实施例还提供一种卢美哌隆中间体化合物7的制备方法,包括:
将手性化合物2在碱性条件下与N-甲基-2-氯乙酰胺进行N-烷基化处理,得到化合物3,反应如下:
当R为H时,所述化合物3为化合物3a,将化合物3a进行苯环溴化处理,得到化合物4,反应如下:
将所述化合物4在铜盐催化下进行C-N乌尔曼偶联处理,得到化合物5,反应如下:
将所述化合物5进行脱溴处理,得到化合物6,反应如下:
将所述化合物6进行还原处理,得到卢美哌隆中间体7,反应如下:
本发明实施例利用Ir-ZhaoPhos不对称氢化构建手性化合物2,对映体选择性高、转化效率高(S/C=5000-10000),收率高,反应条件温和,有利于降低成本;以及通过对所得手性化合物2a进行进一步的衍生化,苯环溴化处理、铜催化C-N偶联、脱溴、酰胺还原得到卢美哌隆关键中间体7,而由化合物2b、2c、2d合成卢美哌隆关键中间体7不包含溴化和脱溴步骤,经济环保。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明实施例提供了一种卢美哌隆中间体化合物2的制备方法,包括:
在化合物1中加入酸添加剂、反应溶剂以及催化剂,于反应温度为0~50℃以及氢气压力为0.1~8.0Mpa的条件下进行Ir-ZhaoPhos催化不对称氢化处理,得到手性化合物2,反应如下:
所述R为H、F、Cl、Br中的一种。
其中,所述酸添加剂为对甲苯磺酸、甲磺酸、盐酸、硫酸、D-樟脑磺酸、L-樟脑磺酸、D-酒石酸、L-酒石酸中的一种。
其中,所述反应溶剂为二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、甲苯中的一种。
其中,所述催化剂为Ir-ZhaoPhos,金属前体为[Ir(COD)Cl]2、Ir(COD)2BF4中的一种,配体为(S,RFc)-ZhaoPhos。
本发明实施例还提供了若干卢美哌隆新中间体化合物,结构如下:
本发明实施例还提供了一种卢美哌隆中间体化合物7的制备方法,所述卢美哌隆中间体为(6bR,10aS)-3-甲基-2,3,6b,9,10,10a-六氢-1H-吡啶并[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-8(7H)-羧酸乙酯7。其结构如式所示:
该卢美哌隆中间体化合物7的制备方法包括以下步骤:
步骤S1:将手性化合物2在碱性条件下与N-甲基-2-氯乙酰胺进行N-烷基化处理,得到化合物3,反应如下:
在本发明实施例中,所述步骤S1,具体为:
在手性化合物2中加入碱、催化剂、有机溶剂以及N-烷基化试剂,进行N-烷基化处理,得到化合物3。
其中,反应温度为70~100℃。
其中,所述碱为碳酸钾、碳酸钠、氢化钠、叔丁醇钠、叔丁醇钾、甲醇钠、乙醇钠、三乙胺、二异丙基乙胺、DABCO中的一种或几种。
其中,所述催化剂为碘化钾、碘化钠、苄基三丁基碘化铵中的一种或几种。
其中,所述有机溶剂为丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环中的一种或几种。
其中,所述N-烷基化试剂为N-甲基-2-氯乙酰胺或N-甲基-2-溴乙酰胺。
步骤S2:将所述化合物3a(R=H)进行苯环溴化处理,得到化合物4,反应如下:
在本发明实施例中,所述步骤S2,具体为:
在所述化合物3a中加入溴化试剂,进行苯环溴化处理,得到化合物4。
其中,所述溴化试剂为Br2/HBr、Br2/CH3CO2H、三溴化吡啶中的一种或几种。
在本发明实施例中,只有当R为H时,化合物3才需要进行苯环溴化处理,而当R为F、Cl、Br、I中的一种时即当化合物3的结构中包含卤素取代基时,无需再进行溴化以及脱溴处理,即由化合物2b、2c、2d合成中间体7不包含溴化和脱溴步骤。
步骤S3:将所述化合物4在铜盐催化下进行C-N乌尔曼偶联处理,得到化合物5,反应如下:
在本发明实施例中,所述步骤S3,具体为:
在所述化合物4中加入铜盐、碱、配体以及有机溶剂,进行C-N乌尔曼偶联处理,得到化合物5。
其中,反应温度为30~120℃。
其中,所述铜盐为碘化亚铜、溴化亚铜、氯化亚铜中的一种或几种。
其中,所述碱为碳酸钾、碳酸钠、叔丁醇钠、叔丁醇钾、三乙胺、二异丙基乙胺中的一种或几种。
其中,所述配体为D-脯氨酸、L-脯氨酸、1,10-菲咯啉、N,N-二甲基乙二胺中的一种。
其中,所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、乙腈、二氧六环中的一种或几种。
步骤S4:将所述化合物5进行脱溴处理,得到化合物6,反应如下:
在本发明实施例中,所述步骤S4,具体为:
在所述化合物5中加入催化剂以及碱,进行脱溴处理,得到化合物6;
其中,所述催化剂为Pd/C或Ru/C。
其中,所述碱为三乙胺、二异丙基乙胺、N-甲基吗啉中的一种或几种。
步骤S5:将所述化合物6进行还原处理,得到卢美哌隆中间体7,反应如下:
在本发明实施例中,所述步骤S5,具体为:
在所述化合物6中加入还原剂以及有机溶剂,进行还原处理,得到卢美哌隆中间体7;
其中,所述还原剂为硼烷四氢呋喃、ZnCl2/硼氢化钠中的一种;
其中,所述有机溶剂为四氢呋喃、叔丁基甲醚中的一种或两种。
具体地,以R为H为例,技术路线如Scheme 6所示:以苯肼盐酸盐和4-氧代-1-哌啶羧酸乙酯为起始原料,经Fisher吲哚反应合成1,3,4,5-四氢-2H-吡啶[4,3-b]吲哚-2-羧酸乙酯1a,然后经Ir-ZhaoPhos催化不对称氢化得到手性化合物2a,接着与2-氯乙酰胺进行N-烷基化反应得到化合物3a,然后溴化得到化合物4,铜催化C-N偶联得到分子内环化产物5,然后Pd/C 催化脱Br得到化合物6,然后硼烷还原得到卢美哌隆中间体化合物7。
以下给出本发明某些实施方式的实施例,其目的不在于对本发明的范围进行限定。
实施例1:
氮气氛围下,反应瓶中加入盐酸苯肼(2.9g,20mmol)和1-乙氧羰基-4-哌啶酮(3.4g,20 mmol),乙醇(50mL),90℃下回流4h,冷却至室温,浓缩,加水析出大量固体,抽滤,水洗,干燥,得到目标产物1a(4.5g,93%yield)。
1H NMR(600MHz,CDCl3)δ7.96(s,1H),7.46(d,J=7.8Hz,1H),7.31(d,J=7.8Hz,1H), 7.16(t,J=7.5Hz,1H),7.11(t,J=7.4Hz,1H),4.70(s,2H),4.22(q,J=7.1Hz,2H),3.88(s,2H),2.84(s,2H),1.31(t,J=7.1Hz,3H).
13C NMR(151MHz,CDCl3)δ156.3,134.7,133.0,126.8,124.1,120.9,116.8,108.5,104.4, 61.8,41.3,23.5,14.9.
MS(ESI):m/z 245.3[M+H]+.
实施例2:
氮气氛围下,在封口瓶中加入[Ir(cod)Cl]2(6.7mg,0.01mmol),(S,RFc)-ZhaoPhos(18.2mg, 0.021mL)和二氯甲烷(2mL),室温下搅拌15分钟,原位络合得到Ir-ZhaoPhos溶液[0.01M]。在安剖氢化瓶中加入化合物1a(1.22g,5mmol),对甲苯磺酸(904mg,5.25mmol),二氯甲烷(50mL),最后加入Ir-ZhaoPhos溶液(100μL,0.001mmol),氢气压力设置为50–65atm,室温下反应结束后,旋蒸除去二氯甲烷,加入乙酸乙酯和水溶解,分出有机相,水相再用乙酸乙酯萃取2次,水相调pH至7-8,二氯甲烷萃取,得到粗品2a(94%ee),经重结晶精制后得到光学纯化合物2a(1.1g,90%yield,>99%ee)。
1H NMR(400MHz,CDCl3)δ7.13(d,J=7.2Hz,1H),7.05(td,J=7.6,1.2Hz,1H),6.73(td, J=7.4,0.8Hz,1H),6.66(d,J=7.8Hz,1H),4.20–4.06(m,2H),3.97(dt,J=6.8,4.9Hz,1H),3.96–3.64(m,2H),3.63–3.53(m,1H),3.49–3.11(m,3H),1.90(ddt,J=14.1,9.3,4.6Hz,1H), 1.76(ddd,J=14.4,9.3,5.3Hz,1H),1.26(t,J=6.6Hz,3H).
13C NMR(151MHz,CDCl3)δ155.7,150.9,130.1,128.1,124.3,119.1,110.0,61.3,57.5, 43.9,41.0,39.8,28.1,14.8.
HRMS(ESI/ion trap)m/z:[M+H]+calcd for C14H19N2O2 +:247.1441,found:247.1442.
实施例3:
氮气氛围下,在封口瓶中加入[Ir(cod)Cl]2(6.7mg,0.01mmol),(S,RFc)-ZhaoPhos(18.2mg, 0.021mL)和二氯甲烷(2mL),室温下搅拌15分钟,原位络合得到Ir-ZhaoPhos溶液[0.01M]。在安剖氢化瓶中加入化合物1b(1.31g,5mmol),对甲苯磺酸(904mg,5.25mmol),二氯甲烷(50mL),最后加入Ir-ZhaoPhos溶液(100μL,0.001mmol),氢气压力设置为50–65atm,室温下反应结束后,旋蒸除去二氯甲烷,加入乙酸乙酯和水溶解,分出有机相,水相再用乙酸乙酯萃取2次,水相调pH至7-8,二氯甲烷萃取,得到粗品2b(77%ee),经重结晶精制后得到光学纯化合物2b(0.90g,72%yield,>99%ee)。
1H NMR(400MHz,CDCl3)δ6.90(d,J=7.3Hz,1H),6.82(dd,J=9.7,8.4Hz,1H),6.65(ddd,J=8.1,7.5,4.6Hz,1H),4.11(ddq,J=14.3,7.2,3.5Hz,2H),4.01(dt,J=6.8,4.9Hz,1H),3.97–3.66(m,2H),3.60–3.52(m,1H),3.48–3.38(m,1H),3.36–3.13(m,2H),1.90(ddt,J= 14.1,9.3,4.6Hz,1H),1.77(dt,J=14.2,4.6Hz,1H),1.24(t,J=6.7Hz,3H).
13C NMR(101MHz,CDCl3)δ155.6,149.4(d,J=240.4Hz),137.7(d,J=12.9Hz),133.9(d, J=7.5Hz),119.6(d,J=23.1Hz),114.7(d,J=17.5Hz),61.3,58.2,43.7,41.3,39.7,27.9,14.8.
19F NMR(376MHz,CDCl3)δ-135.5.
HRMS(ESI/ion trap)m/z:[M+H]+calcd for C14H18FN2O2 +:265.1347,found:265.1349.
实施例4:
氮气氛围下,在封口瓶中加入[Ir(cod)Cl]2(6.7mg,0.01mmol),(S,RFc)-ZhaoPhos(18.2mg, 0.021mL)和二氯甲烷(2mL),室温下搅拌15分钟,原位络合得到Ir-ZhaoPhos溶液[0.01M]。在安剖氢化瓶中加入化合物1c(1.39g,5mmol),对甲苯磺酸(904mg,5.25mmol),二氯甲烷(50mL),最后加入Ir-ZhaoPhos溶液(100μL,0.001mmol),氢气压力设置为50–65atm,室温下反应结束后,旋蒸除去二氯甲烷,加入乙酸乙酯和水溶解,分出有机相,水相再用乙酸乙酯萃取2次,水相调pH至7-8,二氯甲烷萃取,得到粗品2c(72%ee),经重结晶精制后得到光学纯化合物2c(0.97g,69%yield,>99%ee)。
1H NMR(400MHz,CDCl3)δ6.92(d,J=7.2Hz,1H),6.84(dd,J=9.6,8.4Hz,1H),6.68(ddd,J=8.2,7.6,4.8Hz,1H),4.16(ddq,J=14.2,7.2,3.6Hz,2H),4.08(dt,J=6.8,4.8Hz,1H),4.04–3.72(m,2H),3.63–3.55(m,1H),3.52–3.42(m,1H),3.40–3.17(m,2H),1.93(ddt,J= 14.0,9.2,4.4Hz,1H),1.81(dt,J=14.2,4.8Hz,1H),1.27(t,J=6.8Hz,3H).
13C NMR(101MHz,CDCl3)δ155.9,150.4,138.2,134.5,121.6,116.8,61.4,58.3,43.8,41.5, 39.8,27.9,14.8.
HRMS(ESI/ion trap)m/z:[M+H]+calcd for C14H18ClN2O2 +:281.1051,found:281.1047.
实施例5:
氮气氛围下,在封口瓶中加入[Ir(cod)Cl]2(6.7mg,0.01mmol),(S,RFc)-ZhaoPhos(18.2mg, 0.021mL)和二氯甲烷(2mL),室温下搅拌15分钟,原位络合得到Ir-ZhaoPhos溶液[0.01M]。在安剖氢化瓶中加入化合物1d(1.61g,5mmol),对甲苯磺酸(904mg,5.25mmol),二氯甲烷(50mL),最后加入Ir-ZhaoPhos溶液(100μL,0.001mmol),氢气压力设置为50–65atm,室温下反应结束后,旋蒸除去二氯甲烷,加入乙酸乙酯和水溶解,分出有机相,水相再用乙酸乙酯萃取2次,水相调pH至7-8,二氯甲烷萃取,得到粗品2d(66%ee),经重结晶精制后得到光学纯化合物2d(0.93g,62%yield,>99%ee)。
1H NMR(400MHz,CDCl3)δ7.21(d,J=8.0Hz,1H),7.06(d,J=7.2Hz,1H),6.58(t,J= 7.6Hz,1H),4.19–4.07(m,2H),3.97(dt,J=10.1,5.0Hz,1H),3.92–3.65(m,2H),3.62–3.13(m,4H),1.88(td,J=13.9,4.8Hz,1H),1.70(s,1H),1.27(brs,3H).
MS(ESI)m/z 325.0[M+H]+.
实施例6:
三口烧瓶中依次加入化合物2a(2.46g,10mmol),N-甲基-2-氯乙酰胺(1.29g,12mmol),碘化钾(0.83g,5mmol),碳酸钾(2.07g,15mmol),丙酮(30mL),70℃回流过夜,冷却至室温,过滤,滤液旋干,加入乙酸乙酯溶解,亚硫酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,滤液浓缩,加入正己烷析出白色固体,打浆,滤饼干燥,得到白色固体3a(3.01g, 95%yield)。
1H NMR(400MHz,CDCl3)δ7.14(dd,J=15.9,7.8Hz,2H),6.90–6.65(m,2H),6.46(d,J =7.8Hz,1H),4.08(s,2H),3.90–3.52(m,5H),3.45–3.09(m,3H),2.86(d,J=5.0Hz,3H),1.96–1.77(m,2H),1.31–1.11(m,3H).
13C NMR(151MHz,CDCl3)δ170.7,155.7,151.7,130.7,128.6,124.4,120.3,108.8,64.0, 61.5,52.8,44.4,39.9,26.1,14.8.
HRMS(ESI/ion trap)m/z:[M+H]+calcd for C17H24N3O3 +:318.1812,found:318.1811.
实施例7:
三口烧瓶中依次加入化合物2b(2.62g,10mmol),N-甲基-2-氯乙酰胺(1.29g,12mmol),碘化钾(0.83g,5mmol),碳酸钾(2.07g,15mmol),丙酮(30mL),70℃回流过夜,冷却至室温,过滤,滤液旋干,加入乙酸乙酯溶解,亚硫酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,滤液浓缩,得到粗品3b(3.3g)。
1H NMR(400MHz,CDCl3)6.92(d,J=7.2Hz,1H),6.84(dd,J=9.8,8.4Hz,1H),6.68(ddd, J=8.4,7.2,4.4Hz,1H),4.05(s,2H),3.88–3.50(m,5H),3.43–3.05(m,3H),2.83(d,J=5.0Hz,3H),1.91–1.75(m,2H),1.30–1.09(m,3H).
MS(ESI)m/z 336.3[M+H]+.
实施例8:
三口烧瓶中依次加入化合物2c(2.81g,10mmol),N-甲基-2-氯乙酰胺(1.29g,12mmol),碘化钾(0.83g,5mmol),碳酸钾(2.07g,15mmol),丙酮(30mL),70℃回流过夜,冷却至室温,过滤,滤液旋干,加入乙酸乙酯溶解,亚硫酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,滤液浓缩,得到粗品3c(3.5g)。
1H NMR(400MHz,CDCl3)7.08(d,J=7.3Hz,1H),6.91(dd,J=9.6,8.4Hz,1H),6.72(ddd, J=8.4,7.2,4.4Hz,1H),4.13(s,2H),3.95–3.55(m,5H),3.53–3.09(m,3H),2.89(d,J=5.1Hz,3H),1.97–1.80(m,2H),1.38–1.11(m,3H).
MS(ESI)m/z 352.1[M+H]+.
实施例9:
两口瓶中加入化合物3a(1.58g,5mmol),二氯甲烷(20mL),搅拌至溶解,然后分批加入三溴化吡啶(3.52g,11mmol),室温反应1h,TLC检测反应完毕。加入二氯甲烷(20 mL)稀释,氢氧化钠(1M)调pH至7-8,分出有机相,饱和食盐水洗,无水硫酸钠干燥,滤液浓缩,加入正己烷打浆,过滤,滤饼干燥,得到淡黄色固体4(2.09g,88%yield,99%ee)。
1H NMR(600MHz,CDCl3)δ7.38(s,1H),7.16(s,1H),6.81(brs,1H),4.32–4.18(m,1H), 4.14–3.96(m,2H),3.89–3.12(m,7H),2.87(d,J=4.9Hz,3H),1.96–1.85(m,1H),1.83–1.72(m,1H),1.21(t,J=7.0Hz,3H).
13C NMR(151MHz,CDCl3)δ171.1,155.7,147.8,136.1,135.4,126.7,113.0,105.1,65.6, 61.7,54.6,43.5,41.1,39.9,26.2,25.0,14.7.
HRMS(ESI/ion trap)m/z:[M+H]+calcd for C17H22Br2N3O3 +:474.0022,found:474.002.
实施例10:
氮气氛围下,在反应瓶中依次加入化合物4(0.95g,2mmol),碘化亚铜(66.4mg,0.4mmol),N,N’-二甲基乙二胺(106mg,129uL,1.2mmol),碳酸钾(607mg,4.4mmol),除氧的1,4-二氧六环(4mL),加热至100℃回流反应24h,TLC跟踪至反应完全,冷却至室温,反应液经硅藻土过滤,滤液浓缩,加入正己烷析出固体,打浆,过滤,干燥,得到淡黄色固体化合物5(0.67g,85%yield)。
1H NMR(600MHz,CDCl3)δ7.00(s,1H),6.87(s,1H),4.22–4.07(m,3H),4.02(d,J=14.3 Hz,1H),4.03–3.80(m,2H),3.47–3.37(m,2H),3.29(s,3H),3.17–3.06(m,1H),2.84–2.58(m,1H),1.98–1.79(m,2H),1.27(t,J=7.1Hz,3H).
13C NMR(151MHz,CDCl3)δ164.8,155.5,138.0,127.6,122.0,115.7,115.4,112.4,66.6, 61.6,52.4,45.5,41.2,39.6,30.1,28.3,14.8.
HRMS(ESI/ion trap)m/z:[M+H]+calcd for C17H21BrN3O3 +:394.0716,found:.394.0718
实施例11:
在氢化釜中加入化合物5(0.59g,1.5mmol),加入5wt%Pd/C(10mol%),甲醇(3mL),三乙胺(152mg,1.5mmol),氢气置换3次,氢气加压至10atm,室温下反应14h后,过滤除去钯碳,滤液浓缩,乙酸乙酯/正己烷打浆得到目标化合物6(434mg,96%yield)。
1H NMR(CDCl3,600MHz)δ6.68(t,J=16.2Hz,1H),6.62(d,J=16.2Hz,1H),6.42(d,J=16.2Hz,1H),4.17(q,J=14.0Hz,2H),3.89-3.80(m,1H),3.77-3.54(m,2H),3.40-3.27(m,2H), 3.28-3.07(m,2H),2.92-2.79(m,5H),1.95-1.80(m,2H),1.80-1.71(m,1H),1.29(t,J=14.0Hz, 3H).
MS(ESI)m/z 302.4[M+H]+.
实施例12:
氮气氛围下,化合物6(301mg,1mmol)溶于无水四氢呋喃(5mL),缓慢加入1M硼烷四氢呋喃溶液(2mL),加热回流反应12-16小时。反应结束后冷却至0-5℃,加入甲醇淬灭反应,减压浓缩,加入甲醇水溶液,缓慢搅拌冷却析晶,过滤干燥得化合物7(260mg,91%yield)。
1H NMR(CDCl3,400MHz)δ6.69(t,J=10.8Hz,1H),6.63(d,J=10.7Hz,1H),6.44(d,J= 10.8Hz,1H),4.20(q,J=9.3Hz,2H),3.91-3.76(m,1H),3.82-3.55(m,2H),3.43-3.28(m,2H),3.29-3.07(m,2H),2.93-2.84(m,5H),1.96-1.77(m,2H),1.76-1.66(m,1H),1.29(t,J=9.2Hz, 3H).MS(ESI)m/z 302.3[M+H]+。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.卢美哌隆中间体化合物2的制备方法,其特征在于,包括:
在化合物1中加入酸添加剂、反应溶剂以及催化剂,于反应温度为0~50℃以及氢气压力为0.1~8.0Mpa的条件下进行Ir-ZhaoPhos催化不对称氢化处理,得到手性化合物2,反应如下:
所述R为H、F、Cl、Br中的一种;
其中,所述酸添加剂为对甲苯磺酸、甲磺酸、盐酸、硫酸、D-樟脑磺酸、L-樟脑磺酸、D-酒石酸、L-酒石酸中的一种;
所述反应溶剂为二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、甲苯中的一种;
所述催化剂为Ir-ZhaoPhos,金属前体为[Ir(COD)Cl]2、Ir(COD)2BF4中的一种,配体为(S,RFc)-ZhaoPhos。
2.卢美哌隆中间体化合物7的制备方法,其特征在于,包括:
在化合物1中加入酸添加剂、反应溶剂以及催化剂,于反应温度为0~50℃以及氢气压力为0.1~8.0Mpa的条件下进行Ir-ZhaoPhos催化不对称氢化处理,得到手性化合物2,反应如下:
所述R为H;
其中,所述酸添加剂为对甲苯磺酸、甲磺酸、盐酸、硫酸、D-樟脑磺酸、L-樟脑磺酸、D-酒石酸、L-酒石酸中的一种;
所述反应溶剂为二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、甲苯中的一种;
所述催化剂为Ir-ZhaoPhos,金属前体为[Ir(COD)Cl]2、Ir(COD)2BF4中的一种,配体为(S,RFc)-ZhaoPhos;
将手性化合物2在碱性条件下与N-甲基-2-氯乙酰胺进行N-烷基化处理,得到化合物3,反应如下:
当R为H时,所述化合物3为化合物3a,将化合物3a进行苯环溴化处理,得到化合物4,反应如下:
将所述化合物4在铜盐催化下进行C-N乌尔曼偶联处理,得到化合物5,反应如下:
将所述化合物5进行脱溴处理,得到化合物6,反应如下:
将所述化合物6进行还原处理,得到卢美哌隆中间体化合物7,反应如下:
3.如权利要求2所述的卢美哌隆中间体化合物7的制备方法,其特征在于,所述将手性化合物2在碱性条件下与N-甲基-2-氯乙酰胺进行N-烷基化处理,得到化合物3的步骤,包括:
在手性化合物2中加入碱、催化剂、有机溶剂以及N-烷基化试剂,进行N-烷基化处理,得到化合物3;
其中,所述碱为碳酸钾、碳酸钠、氢化钠、叔丁醇钠、叔丁醇钾、甲醇钠、乙醇钠、三乙胺、二异丙基乙胺、DABCO中的一种或几种;
所述催化剂为碘化钾、碘化钠、苄基三丁基碘化铵中的一种或几种;
所述有机溶剂为丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环中的一种或几种;
所述N-烷基化试剂为N-甲基-2-氯乙酰胺或N-甲基-2-溴乙酰胺。
4.如权利要求3所述的卢美哌隆中间体化合物7的制备方法,其特征在于,反应温度为70~100℃。
5.如权利要求2所述的卢美哌隆中间体化合物7的制备方法,其特征在于,所述将化合物3a进行苯环溴化处理,得到化合物4的步骤,包括:
在所述化合物3a中加入溴化试剂,进行苯环溴化处理,得到化合物4;
其中,所述溴化试剂为Br2/HBr、Br2/CH3CO2H、三溴化吡啶中的一种或几种。
6.如权利要求2所述的卢美哌隆中间体化合物7的制备方法,其特征在于,所述将所述化合物4在铜盐催化下进行C-N乌尔曼偶联处理,得到化合物5的步骤,包括:
在所述化合物4中加入铜盐、碱、配体以及有机溶剂,进行C-N乌尔曼偶联处理,得到化合物5;
其中,所述铜盐为碘化亚铜、溴化亚铜、氯化亚铜中的一种或几种;
所述碱为碳酸钾、碳酸钠、叔丁醇钠、叔丁醇钾、三乙胺、二异丙基乙胺中的一种或几种;
所述配体为D-脯氨酸、L-脯氨酸、1,10-菲咯啉、N,N-二甲基乙二胺中的一种;
所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、乙腈、二氧六环中的一种或几种。
7.如权利要求6所述的卢美哌隆中间体化合物7的制备方法,其特征在于,反应温度为30~120℃。
8.如权利要求2所述的卢美哌隆中间体化合物7的制备方法,其特征在于,所述将所述化合物5进行脱溴处理,得到化合物6的步骤,包括:
在所述化合物5中加入催化剂以及碱,进行脱溴处理,得到化合物6;
其中,所述催化剂为Pd/C或Ru/C;
所述碱为三乙胺、二异丙基乙胺、N-甲基吗啉中的一种或几种。
9.如权利要求2所述的卢美哌隆中间体化合物7的制备方法,其特征在于,所述将所述化合物6进行还原处理,得到卢美哌隆中间体化合物7的步骤,包括:
在所述化合物6中加入还原剂以及有机溶剂,进行还原处理,得到卢美哌隆中间体化合物7;
其中,所述还原剂为硼烷四氢呋喃、ZnCl2/硼氢化钠中的一种;
所述有机溶剂为四氢呋喃、叔丁基甲醚中的一种或两种。
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