CN105017251B - A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist - Google Patents
A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist Download PDFInfo
- Publication number
- CN105017251B CN105017251B CN201510378729.7A CN201510378729A CN105017251B CN 105017251 B CN105017251 B CN 105017251B CN 201510378729 A CN201510378729 A CN 201510378729A CN 105017251 B CN105017251 B CN 105017251B
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- formula
- tert
- benzyl
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 74
- 239000002464 receptor antagonist Substances 0.000 title abstract description 5
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 5
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title description 3
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- -1 3,5 bis- (trifluoromethyl) phenyl Chemical group 0.000 claims abstract description 89
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000004519 manufacturing process Methods 0.000 claims abstract description 22
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 75
- 239000000758 substrate Substances 0.000 claims description 68
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 64
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 claims description 45
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 41
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 34
- 239000003153 chemical reaction reagent Substances 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 23
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 16
- 229910052710 silicon Inorganic materials 0.000 claims description 16
- 239000010703 silicon Substances 0.000 claims description 16
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 claims description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 14
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 14
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 12
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 230000000903 blocking effect Effects 0.000 claims description 11
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- 239000011987 hoveyda–grubbs catalyst Substances 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 10
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 238000006722 reduction reaction Methods 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 150000002466 imines Chemical group 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000006083 1-bromoethyl group Chemical group 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000012445 acidic reagent Substances 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- XXZOEDQFGXTEAD-UHFFFAOYSA-N 1,2-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1C(F)(F)F XXZOEDQFGXTEAD-UHFFFAOYSA-N 0.000 claims description 4
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 238000005865 alkene metathesis reaction Methods 0.000 claims description 4
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000011984 grubbs catalyst Substances 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
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 4
- LUAMIGOADJTNQF-UHFFFAOYSA-N [Mg].[Cl-].C(=C)[N+]1=CNC=C1 Chemical compound [Mg].[Cl-].C(=C)[N+]1=CNC=C1 LUAMIGOADJTNQF-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- XJWOWXZSFTXJEX-UHFFFAOYSA-N phenylsilicon Chemical compound [Si]C1=CC=CC=C1 XJWOWXZSFTXJEX-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract description 2
- 125000003003 spiro group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 239000012074 organic phase Substances 0.000 description 48
- 239000000243 solution Substances 0.000 description 35
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 238000003756 stirring Methods 0.000 description 31
- 239000000203 mixture Substances 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 238000001035 drying Methods 0.000 description 28
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 239000003960 organic solvent Substances 0.000 description 21
- 238000005406 washing Methods 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 235000010290 biphenyl Nutrition 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 239000012071 phase Substances 0.000 description 17
- 125000003368 amide group Chemical group 0.000 description 16
- 239000004305 biphenyl Substances 0.000 description 16
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 230000006837 decompression Effects 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000004519 grease Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- VLUVSBVLPIEGCP-SSDOTTSWSA-N (2R)-2-ethenyl-5-oxo-1H-pyrrole-2-carbaldehyde Chemical compound O=C1C=C[C@@](N1)(C=O)C=C VLUVSBVLPIEGCP-SSDOTTSWSA-N 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- 125000006278 bromobenzyl group Chemical group 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical class OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 4
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000011017 operating method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000003809 water extraction Methods 0.000 description 3
- ULQLVELTQDGZEP-UHFFFAOYSA-N 2-ethenyl-5-methyl-1h-pyrrole Chemical compound CC1=CC=C(C=C)N1 ULQLVELTQDGZEP-UHFFFAOYSA-N 0.000 description 2
- JCOUEUSHQNDXNG-UHFFFAOYSA-N 2-phenylethenoxymethylbenzene Chemical class C=1C=CC=CC=1COC=CC1=CC=CC=C1 JCOUEUSHQNDXNG-UHFFFAOYSA-N 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical class CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical class CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- TYHOSUCCUICRLM-UHFFFAOYSA-N 1,3-oxazole-2-carbaldehyde Chemical compound O=CC1=NC=CO1 TYHOSUCCUICRLM-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- MZNSQRLUUXWLSB-UHFFFAOYSA-N 2-ethenyl-1h-pyrrole Chemical compound C=CC1=CC=CN1 MZNSQRLUUXWLSB-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- XSKCDKCFMZSAIZ-UHFFFAOYSA-N C(=O)Cl.ClC1=CC=CC=C1 Chemical compound C(=O)Cl.ClC1=CC=CC=C1 XSKCDKCFMZSAIZ-UHFFFAOYSA-N 0.000 description 1
- FIVSJYGQAIEMOC-ZGNKEGEESA-N C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)OC[C@](CC1)(c2ccccc2)NC[C@]1(CC1)NC1=O Chemical compound C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)OC[C@](CC1)(c2ccccc2)NC[C@]1(CC1)NC1=O FIVSJYGQAIEMOC-ZGNKEGEESA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/06—Sulfinamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- 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
- C07C45/64—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 introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
The present invention relates to a kind of Preparation Method And Their Intermediates of 1 receptor antagonists of NK.The present invention provides one kind (5S, 8S) 8 { [1 (3,5 bis- (trifluoromethyl) phenyl) ethyoxyl] methyl } 8 phenyl 1,7 diaza spiros [4,5] preparation method of 2 ketone of the last of the ten Heavenly stems (compound of formula I), it is prepared by Formula II compound, while provides Formula II compound and preparation method thereof.The method of the present invention is easy to operate, reaction condition is mild, safety coefficient is high, side reaction is few, high income, purity are high, reduces production cost and operational risk, is highly suitable for scale industrial production.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of nk 1 receptor antagonist (5S, 8S) -8- [{ (1R) -1-
[3,5- bis--(trifluoromethyl) phenyl] ethyoxyl }-methyl] -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone preparation side
Method further relates to key intermediate in this method and preparation method thereof.
Background technology
CN1606545A disclose a kind of entitled (5S, the 8S) -8- of chemistry [(1R) -1- [3,5- is bis--(trifluoromethyl) benzene
Base] ethyoxyl-methyl] -8- phenyl -1,7- diaza-spiro [4.5] decyl- 2- ketone compound, structural formula such as following formula I institute
Show, be neurokinine-1 (NK-1) receptor antagonist, available for a variety of diseases such as treatment vomiting, melancholia, anxiety and coughs.
At present, mainly there are following three kinds about the preparation method of compound of formula I:
CN1606545A discloses a kind of preparation method of compound of formula I, and route 1 specific as follows, the preparation method is with city
Raw material phenylglycine is sold as raw starting material, 17 process steps is have passed through and compound of formula I is just made, and in this method
Many steps isolated or purified is needed before for next operating procedure, technique final step also needs to prepare color by chirality
Spectrum is detached, and seriously constrains production scale.As it can be seen that this method operating procedure is long, separating step is more, process overall yields compared with
Low, the difficulty that industrial amplification production is carried out using the route is larger, and production cost is higher.
CN101679257A discloses the preparation method of another compound of formula I, route 2 specific as follows, the preparation method
Using the compound 7 in above-mentioned route 1 as raw starting material, reacted by 5 steps and compound of formula I is made, compared with route 1
Compared with the route operating procedure is shorter, and using being split into the chiral compound 20 of method that salt crystallizes, technique is more simple
It is clean.But since the route is during prepare compound 20, generation is isomer mixture, needs to remove it by splitting
In isomers, significantly reduce process recovery ratio.
CN102203062A discloses the preparation method of another compound of formula I, route 3 specific as follows, the preparation method
Using the compound 3 in above-mentioned route 1 as raw starting material, reacted by 7 steps and compound of formula I is made.Compound in route 3
3 preparation method prepared through the respective compound in above-mentioned route 1, the preparation method have been related to using non-natural S-
2- phenylglycines need to produce by chemical resolution method or asymmetric chemistry synthetic method.Utilize the compound
Compound 3 in preparation route 3 needs to carry out under ultralow temperature (- 78 DEG C), needs a large amount of energy consumption, while need special substance
Equipment, the operation difficulty of ultralow temperature reaction is larger, dangerous larger.Acid (such as hydrogen bromine using strong corrosive is needed in route 3
Acid, hydrofluoric acid etc.) removing Cbz protecting groups, a large amount of acid waste water and waste liquid are generated, is unfavorable for environmental protection.In addition, route 3
Compound of formula I is made in middle method of the compound 27 through catalytic hydrogenation, in the reaction, it may occur that removing 1- (1- methyl) -3,5- is bis-
The side reaction of (trifluoromethyl) benzyl makes to introduce impurity in product, and reduce process recovery ratio, and cost improves.Meanwhile the road
Line introduces bis- (trifluoromethyl) benzyls of R-1- (1- methyl) -3,5- in the route incipient stage, and process costs can increase.
Invention content
In view of the defects existing in the prior art, the present invention is intended to provide it is a kind of simple, efficiently, low cost, suitable for industry
Preparation (5S, 8S) -8- { [1- (3,5- bis--(trifluoromethyl) phenyl)-ethyoxyl]-methyl } -8- phenyl -1,7- two of metaplasia production
The method of aza-spiro [4,5] decyl- 2- ketone (compound of formula I).
Inventor passes through a large amount of experimental study, in accordance with the present invention it has now surprisingly been found that the new preparation method of compound of formula I a kind of,
It is prepared by Formula II compound, while provides the preparation method of Formula II compound.It finds and completes the present invention is based on this,
This method is easy to operate, reaction condition is mild, safety coefficient is high, side reaction is few, high income, purity are high, reduces cost and behaviour
Make risk, be highly suitable for large-scale industrial production.
First aspect present invention provides one kind (5S, 8S) -8- { [1- (3,5- bis--(trifluoromethyl) phenyl)-ethoxies
Base]-methyl -8- phenyl -1,7- diaza-spiro [4,5] decyl- 2- ketone (compound of formula I) preparation method, include the following steps:
(e) by deprotection reaction, it is removed the blocking group R in Formula VII compound, production VIII compounds;
(f) in the presence of alkaline reagent, make Formula VIII compound and bis- (trifluoromethyl) benzene of S-1- (1- bromoethyls) -3,5-
Compound of formula I is made in reaction;
Wherein, R is hydroxy-protective group, selected from C1-4Alkyl, benzyl, trityl, C1-5Alkyl-carbonyl, C1-4Alkoxy
Carbonyl, benzyloxycarbonyl group (Cbz), benzoyl (Bz), to chlorobenzene formacyl, mesyl, trifyl, tolysulfonyl
Base, trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9- fluorenes
Methoxycarbonyl group (Fmoc);It is preferred that methyl, ethyl, isopropyl, tertiary butyl, benzyl, trityl, formoxyl, acetyl group, propionyl
Base, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group (Cbz), benzene first
Acyl group (Bz), to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, triethyl group silicon
Base, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc);More preferable benzyl
Base, pivaloyl group, benzoyl, to chlorobenzene formacyl, tert-butyl diphenyl silicon substrate;Most preferably benzyl, pivaloyl group, to chlorobenzene
Formoxyl, tert-butyl diphenyl silicon substrate;
R1Selected from hydrogen, benzyl, the benzyl of substitution, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, benzyloxycarbonyl group, trifluoroacetyl
Base, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl
(Fmoc);It is preferred that hydrogen, benzyl, the benzyl of substitution, formoxyl, acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, ethyoxyl
Carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl group, trifluoroacetyl group, benzoyl, to chlorobenzoyl
Base, mesyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc);More preferable hydrogen, benzyl, acetyl
Base, propiono, tert-butoxycarbonyl, pivaloyl group, benzyloxycarbonyl group, trifluoroacetyl group;Most preferably hydrogen, benzyl, trifluoroacetyl group.
Specifically, (e) is removed the blocking group R in Formula VII compound, production VIII by deprotection reaction
Compound;
Wherein, when the blocking group R described in the step (e) is selected from benzyl, the benzyl of substitution, benzyloxycarbonyl group, it is preferred to use
Formula VIII compound is made in the method deprotection that hydro-reduction is carried out using palladium charcoal, platinum charcoal etc. as catalyst;When the protecting group
Group R is selected from C1-5Alkyl-carbonyl (such as acetyl group, pivaloyl group), C1-4Alkoxy carbonyl, trifluoroacetyl group, benzoyl, it is right
When chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, it is preferred to use basic hydrolysis (such as NaOH or KOH
Solution hydrolyzes) method deprotection Formula VIII compound is made;When the blocking group R is selected from trimethyl silicon substrate, triethyl group silicon
When base, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, it is preferred to use in tetrabutyl ammonium fluoride etc.
Formula VIII compound is made in catalysis deprotection in the presence of reagent;
(f) exist in alkaline reagent and under room temperature, make Formula VIII compound and S-1- (1- bromoethyls) -3,5- bis-
(trifluoromethyl) benzene is reacted in organic reagent again, and compound of formula I is made;
Wherein, alkaline reagent described in step (f) is selected from sodium tert-butoxide, potassium tert-butoxide, sodium hydride, hydrofining, calcium hydride
In it is one or more;The organic solvent is selected from tetrahydrofuran, N,N-dimethylformamide, N, N- diethylformamides, N-
It is one or more in methyl pyrrolidone;The room temperature has meaning well known in the art, has and refers to 15~35 DEG C, preferably
20~30 DEG C, more preferable 20~25 DEG C.
A kind of preparation method for compound of formula I that first aspect present invention provides, further comprises the steps:
(c) in the presence of ring closing metathesis catalyst, make Formula V compound that Intra-molecular condensation, production VI chemical combination occur
Object;
(d) by reduction reaction, Formula IV compound is converted into Formula VII compound;
Wherein, R, R1With meaning same as before.
Specifically, (c) in the presence of ring closing metathesis catalyst, in the organic solvent selected from toluene, dichloromethane and 50
At~70 DEG C, make Formula V compound that Intra-molecular condensation, production VI compounds occur;
Wherein, ring closing metathesis catalyst described in step (c) is selected from Grubbs catalyst, Hoveyda-Grubbs is catalyzed
Agent, preferably Hoveyda-Grubbs catalyst;Preferably 50~60 DEG C, 60~70 DEG C or 65~70 DEG C of the temperature range;
(d) in the presence of the catalyst such as palladium charcoal, platinum charcoal, selected from methanol, ethyl alcohol, toluene, dimethylbenzene organic solvent in,
It is reacted by hydro-reduction, Formula IV compound is converted into Formula VII compound;
Wherein, when the blocking group R in Formula IV compound described in step (d) is selected from benzyl, the benzyl of substitution, benzyloxy carbonyl
During base, Formula VIII compound can be directly made in step (d).
A kind of preparation method for compound of formula I that first aspect present invention provides, still further comprises following steps:
(a) Formula II compound is made to be reacted with formula III compound, production IV group with imine moiety;
(b) 1. work as R1During for hydrogen, formula IV compound restores to obtain Formula V compound through go back original reagent;Alternatively, 2. work as R1It is not
During hydrogen, formula IV compound after go back original reagent restores, then with R1Formula V compound is obtained by the reaction in-X;
Wherein, R, R1With meaning same as before;X is leaving group, preferably hydrogen, halogen, substituted or unsubstituted C1-4
Acyloxy, more preferable bromine, chlorine, iodine, acetyl group oxygroup, trifluoroacetyl group oxygroup;In the preferred technical solution of the present invention, R1-X
Selected from acetic anhydride, trifluoroacetic anhydride, benzyl bromide (i.e. bromobenzyl), benzyl chloride.
Specifically, (a) under the organic solvent and counterflow condition selected from toluene, dimethylbenzene, Formula II compound and formula III
Close object reaction, production IV group with imine moiety;
(b) 1. work as R1During for hydrogen, at organic solvent and -10~20 DEG C, formula IV compound restores to obtain through go back original reagent
Formula V compound;Alternatively, 2. work as R1When not being hydrogen, at organic solvent and -10~20 DEG C, formula IV compound is through go back original reagent
After reduction, then with R1Formula V compound is obtained by the reaction in-X;
Wherein, go back original reagent described in step (b) is selected from sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride
In one kind;The organic solvent is in toluene, ethyl alcohol, methanol, acetonitrile, dichloromethane, ethyl acetate, isopropyl acetate
It is one or more of;Preferably -5~10 DEG C, more preferable 0~10 DEG C of the temperature range.
A kind of preparation method for compound of formula I that first aspect present invention provides, process route are as follows:
Wherein, R, R1With meaning same as before.
In the preferred technical solution of the present invention, a kind of preparation method for compound of formula I that first aspect present invention provides,
Include the following steps:
(a) Formula II compound is made to be reacted with formula III compound, production IV group with imine moiety;
(b) 1. work as R1During for hydrogen, formula IV compound restores to obtain Formula V compound through go back original reagent;Alternatively, 2. work as R1It is not
During hydrogen, formula IV compound after go back original reagent restores, then with R1Formula V compound is obtained by the reaction in-X;
(c) in the presence of ring closing metathesis catalyst, by intramolecular olefin metathesis reaction, Formula V compound is made to occur to divide
Ring closure reaction in son, production VI compounds;
(d) by reduction reaction, Formula IV compound is converted into Formula VII compound;
(e) by deprotection reaction, it is removed the blocking group R in Formula VII compound, production VIII compounds;
(f) in the presence of alkaline reagent, make Formula VIII compound and bis- (trifluoromethyl) benzene of S-1- (1- bromoethyls) -3,5-
Compound of formula I is made in reaction;
Wherein, go back original reagent described in step (b) is selected from sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride
In one kind;
Ring closing metathesis catalyst described in step (c) is selected from Grubbs catalyst, Hoveyda-Grubbs catalyst, preferably
Hoveyda-Grubbs catalyst;
Alkaline reagent described in step (f) is selected from sodium tert-butoxide, potassium tert-butoxide, sodium hydride, hydrofining, and one in calcium hydride
Kind is a variety of.
Specifically, a kind of preparation method for compound of formula I that first aspect present invention provides, includes the following steps:
(a) under the organic solvent and counterflow condition selected from toluene, dimethylbenzene, Formula II compound and formula III compound are anti-
Should, production IV group with imine moiety;
(b) 1. work as R1During for hydrogen, at organic solvent and -10~20 DEG C, formula IV compound restores to obtain through go back original reagent
Formula V compound;Alternatively, 2. work as R1When not being hydrogen, at organic solvent and -10~20 DEG C, formula IV compound is through go back original reagent
After reduction, then with R1Formula V compound is obtained by the reaction in-X;
Wherein, go back original reagent described in step (b) is selected from sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride
In one kind;The organic solvent is in toluene, ethyl alcohol, methanol, acetonitrile, dichloromethane, ethyl acetate, isopropyl acetate
It is one or more of;Preferably -5~10 DEG C, more preferable 0~10 DEG C of the temperature range;
(c) in the presence of ring closing metathesis catalyst, in the organic solvent selected from toluene, dichloromethane and 50~70 DEG C
Under, by intramolecular olefin metathesis reaction (olefin metathesis), make Formula V compound that Intra-molecular condensation occur,
Production VI compounds;
Wherein, ring closing metathesis catalyst described in step (c) is selected from Grubbs catalyst, Hoveyda-Grubbs is catalyzed
Agent, preferably Hoveyda-Grubbs catalyst;Preferably 50~60 DEG C, 60~70 DEG C or 65~70 DEG C of the temperature range;
(d) in the presence of the catalyst such as palladium charcoal, platinum charcoal, methanol, ethyl alcohol, toluene, dimethylbenzene organic solvent in, pass through
Hydro-reduction reacts, and Formula IV compound is converted into Formula VII compound;
Wherein, the blocking group R in Formula IV compound described in step (d) is selected from benzyl, substituted benzyl or benzyloxy carbonyl
During base, Formula VIII compound can be directly made in step (d);
(e) by deprotection reaction, it is removed the blocking group R in Formula VII compound, production VIII compounds;
Wherein, when the blocking group R described in the step (e) is selected from benzyl, the benzyl of substitution, benzyloxycarbonyl group, it is preferred to use
Formula VIII compound is made in the method deprotection that hydro-reduction is carried out using palladium charcoal, platinum charcoal etc. as catalyst;When the protecting group
Group R is selected from C1-5Alkyl-carbonyl (such as acetyl group, pivaloyl group), C1-4Alkoxy carbonyl, trifluoroacetyl group, benzoyl, it is right
When chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, it is preferred to use basic hydrolysis (such as NaOH or KOH
Solution hydrolyzes) method deprotection Formula VIII compound is made;When the blocking group R is selected from trimethyl silicon substrate, triethyl group silicon
When base, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, it is preferred to use in tetrabutyl ammonium fluoride etc.
Formula VIII compound is made in catalysis deprotection in the presence of reagent;
(f) in the presence of alkaline reagent, in organic solvent and under room temperature, make Formula VIII compound and S-1- (1- bromines
Ethyl) bis- (trifluoromethyl) the benzene reactions of -3,5-, compound of formula I is made;
Wherein, alkaline reagent described in step (f) is selected from sodium tert-butoxide, potassium tert-butoxide, sodium hydride, hydrofining, calcium hydride
In one kind;It is or a variety of;The organic solvent is selected from tetrahydrofuran, N,N-dimethylformamide, N, N- diethylformamides, N-
It is one or more in methyl pyrrolidone;The room temperature has meaning well known in the art, has and refers to 15~35 DEG C, preferably
20~30 DEG C, more preferable 20~25 DEG C.
Second aspect of the present invention provides the compound such as following formula:
Wherein, R is hydroxy-protective group, selected from C1-4Alkyl, benzyl, trityl, C1-5Alkyl-carbonyl, C1-4Alkoxy
Carbonyl, benzyloxycarbonyl group (Cbz), benzoyl (Bz), to chlorobenzene formacyl, mesyl, trifyl, tolysulfonyl
Base, trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9- fluorenes
Methoxycarbonyl group (Fmoc);It is preferred that methyl, ethyl, isopropyl, tertiary butyl, benzyl, trityl, formoxyl, acetyl group, propionyl
Base, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group (Cbz), benzene first
Acyl group (Bz), to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, triethyl group silicon
Base, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc);More preferable benzyl
Base, pivaloyl group, benzoyl, to chlorobenzene formacyl, tert-butyl diphenyl silicon substrate;Most preferably benzyl, pivaloyl group, to chlorobenzene
Formoxyl, tert-butyl diphenyl silicon substrate;
R1Selected from hydrogen, benzyl, the benzyl of substitution, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, benzyloxycarbonyl group, trifluoroacetyl
Base, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl
(Fmoc);It is preferred that hydrogen, benzyl, the benzyl of substitution, formoxyl, acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, ethyoxyl
Carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl group, trifluoroacetyl group, benzoyl, to chlorobenzoyl
Base, mesyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc);More preferable hydrogen, benzyl, acetyl
Base, propiono, tert-butoxycarbonyl, pivaloyl group, benzyloxycarbonyl group, trifluoroacetyl group;Most preferably hydrogen, benzyl, trifluoroacetyl group.
Third aspect present invention provides a kind of preparation method of Formula II compound, and process route is as follows:
Wherein, R is hydroxy-protective group, selected from C1-4Alkyl, benzyl, trityl, C1-5Alkyl-carbonyl, C1-4Alkoxy
Carbonyl, benzyloxycarbonyl group (Cbz), benzoyl (Bz), to chlorobenzene formacyl, mesyl, trifyl, tolysulfonyl
Base, trimethyl silicon substrate, triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9- fluorenes
Methoxycarbonyl group (Fmoc);It is preferred that methyl, ethyl, isopropyl, tertiary butyl, benzyl, trityl, formoxyl, acetyl group, propionyl
Base, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group (Cbz), benzene first
Acyl group (Bz), to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, triethyl group silicon
Base, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc);More preferable benzyl
Base, pivaloyl group, benzoyl, to chlorobenzene formacyl, tert-butyl diphenyl silicon substrate;Most preferably benzyl, pivaloyl group, to chlorobenzene
Formoxyl, tert-butyl diphenyl silicon substrate;
Third aspect present invention provides a kind of preparation method of Formula II compound, includes the following steps:
(1) in the presence of alkaline reagent, Formula IX compound carries out hydroxyl protection, obtains the compound of Formula X;
(2) in the presence of dehydrating agent, Formula X compound is made to be reacted with R- t-butyl sulfonamides, to form Formula XI imidization
Close object;
(3) Formula XI compound is made to be reacted with vinylimidazolium chloride magnesium or vinyl magnesium bromide, to form Formula XII compound;
(4) in the presence of acid reagent, Formula XII compound is made to remove terf-butylsulfinyl, Formula II compound is made;
Wherein, alkaline reagent described in step (1) be selected from organic base, such as triethylamine, imidazoles, pyridine in one kind or
One kind in inorganic base, such as potassium carbonate, sodium carbonate;
Dehydrating agent described in step (2) is tetraisopropyl titanate;
The one kind of acid reagent in hydrochloric acid, phosphoric acid, acetic acid described in step (4);
Specifically, a kind of preparation method for Formula II compound that third aspect present invention provides, includes the following steps:
(1) in the presence of alkaline reagent, in organic solvent, Formula IX compound is with being selected from benzyl chloride, bromobenzyl, substituted chlorine
Benzyl, substituted bromobenzyl, C1-4Alkyl acyl chloride, C1-4Alkoxy acyl chlorides, benzyloxy acyl chlorides, trifluoro-acetyl chloride, chlorobenzoyl chloride, to chlorine
Chlorobenzoyl chloride, mesyl chloride, trifluoromethanesulfchloride chloride, paratoluensulfonyl chloride, trim,ethylchlorosilane, chlorotriethyl silane, three isopropyls
Base chlorosilane, tert-butyl diphenyl chlorosilane, a kind of in tert-butyl chloro-silicane are reacted, and protect Formula IX compound
Hydroxyl in molecule forms the compound of Formula X;
Wherein, alkaline reagent described in step (1) be selected from organic base, such as triethylamine, imidazoles, pyridine in one kind or
One kind in inorganic base, such as potassium carbonate, sodium carbonate;The organic solvent is selected from chloroform, dichloromethane, N, N- bis-
One kind in methylformamide, tetrahydrofuran;
(2) in the presence of dehydrating agent, at organic solvent and 60~90 DEG C, make Formula X compound and R- tertiary butyl sulfenyls
Amine reacts, and forms Formula XI group with imine moiety;
Wherein, dehydrating agent described in step (2) is tetraisopropyl titanate;The organic solvent is selected from normal heptane, tetrahydrochysene furan
It mutters, the one or more in methyltetrahydrofuran, toluene;Preferably 70~80 DEG C of the temperature range;
(3) at the organic solvent selected from tetrahydrofuran, dichloromethane and -30~0 DEG C, make Formula XI compound and vinyl
Magnesium chloride or the reaction of vinyl magnesium bromide, form Formula XII compound;
Wherein, preferably -20~-15 DEG C of temperature range described in step (3);
(4) in the presence of acid reagent, in the organic solvent selected from methanol, ethyl alcohol and under room temperature, make Formula XII chemical combination
Object removes terf-butylsulfinyl, and Formula II compound is made;
Wherein, the one kind of acid reagent in hydrochloric acid, phosphoric acid, acetic acid described in step (4);The room temperature has ability
Meaning well known to domain has and refers to 15~35 DEG C, preferably 20~30 DEG C, more preferable 20~25 DEG C.
The present invention provides synthesis (5S, 8S) -8- [{ (1R) -1- [3,5- bis--(trifluoromethyl) phenyl] ethyoxyl }-first
Base] -8- phenyl -1,7- diaza-spiro [4.5] decyl- 2- ketone (compound of formula I) method, this method is various with reporting before
The method of synthetic compound of formula i compares, and has the advantage that:
1st, compound of formula I is made using chiral synthetic method in the route, and it is simply easy respectively to walk operation in preparation process
Row does not need to ultralow temperature reaction, and reaction temperature is not less than -25 DEG C, easy to operate without special installation, safe;And work
Mild condition when skill final step introduces R-1- (1- methyl) -3,5- bis- (trifluoromethyl) benzyls avoids the acid of strong corrosive
The use of property substance, the safer environmental protection of technique are more suitable for industrialized production;
2nd, the circuit is first by Formula IV compound by catalytic hydrogenation formula VII compounds, in technique final step
Bis- (trifluoromethyl) benzyls of R-1- (1- methyl) -3,5- are re-introduced into, final step in the route 3 reported before is avoided and is catalyzed hydrogen
The side reaction of removing bis- (trifluoromethyl) benzyls of 1- (1- methyl) -3,5- occurs when changing reaction and introduces impurity;
3rd, the route respectively walks good reaction selectivity, and high conversion rate, process recovery ratio is high, and gained intermediate and product purity are high,
The purifying difficulty of each intermediate and product is reduced, is conducive to industrialized production;
4th, compared with the route 3 reported before, the route final step just introduce the R-1- (1- methyl) of higher price-
3,5- bis- (trifluoromethyl) benzyls, make the cost of raw material effectively be reduced.
Specific embodiment
The specific embodiment of form by the following examples does further specifically the above of the present invention
It is bright, but the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all above-mentioned interior based on the present invention
Hold realized technology to all belong to the scope of the present invention.The present invention carries out the material and test method that are arrived used in experiment
General and/or specific description.It will be apparent to those skilled in the art that hereinafter, if not specified, the present invention is carried out
Operation be this field routine progress under room temperature.
It should be pointed out that if no special instruction is made, the dosage of the reaction dissolvent and related reagent is the routine of reaction
Dosage, those skilled in the art can determine according to the prior art;The reagent that the present invention uses is conventional reagent, Ke Yitong
It crosses market to be commercially available, starting material and reactant used can be prepared by the prior art or disclosed existing literature
It arrives, compound 2- hydroxy acetophenones can be bought from Lianyun Harbour Qun Sheng Chemical Co., Ltd.s and obtain, and tetraisopropyl titanate can be from
Shanghai nation buys into Chemical Co., Ltd. and obtains, 3- (1,1- dimethyl ethyl) dihydro -1,5- dioxy-(3R, 7 α R) -1H, 3H-
- 7 α (5H) of pyrroles [1,2-C] oxazole-formaldehyde can be obtained from the purchase of Wujiang consonance pharmaceutcal corporation, Ltd, vinyl magnesium bromide
Auspicious chemical Science and Technology Ltd.'s purchase can be won from Shanghai to obtain, R- (+)-t-butyl sulfonamide can be from Shanghai Gao Lang chemical industry
Science and Technology Ltd.'s purchase obtains, Hoveya-Grubbs 2ndCatalyst can be from Shanghai Ke Qin Chemical Industry Science Co., Ltd
Purchase obtains.
The preparation of 1 following formula of embodiment (S) -1- (tert-butyl diphenyl siloxy) -2- phenyl butyl- 3- alkene -2- amine
2- hydroxy acetophenones (200.0g, 1.47mol) are weighed, sequentially add 2000ml dichloromethane and tert-butyl diphenyl
Chlorosilane (445.3g, 1.62mol) makes the temperature of mixture be down to 0-10 DEG C under stirring, be added dropwise triethylamine (180.0g,
1.78mol), it being added dropwise, reacts complete to the conversion of 2- hydroxy acetophenones at room temperature, water is added to extract, liquid separation obtains organic phase,
Anhydrous sodium sulfate drying is added in, filters off drier after drying, filtrate decompression concentration obtains grease.
In the grease of acquisition add in 5500ml toluene, sequentially added under stirring tetraisopropyl titanate (829.7g,
2.94mol) with (R)-(+)-t-butyl sulfonamide (213.3g, 1.76mol), mixture is warming up at 70-80 DEG C and is reacted.
After reaction, room temperature is down to, 3000ml saturated salt solutions are added in into mixture, is stirred, extraction separates organic phase, organic
Saturated common salt water washing is mutually used, anhydrous sodium sulfate is dried, after drying, and elimination drier, concentrating filter liquor, obtained (R, Z)-
N- [2- (tert-butyl diphenyl siloxy) -1- phenyl-ethylenes] -2- methylpropane -2- sulfonamide 640.6g, yield:
91.2%.
Weigh (R, Z)-N- [2- (tert-butyl diphenyl siloxy) -1- phenyl-ethylenes] -2- methylpropane -2- sulfonamide
(500.0g, 1.05mol) adds in 5000ml dichloromethane, system is cooled to -20~-15 DEG C under nitrogen protection, is delayed into system
Slowly vinyl magnesium bromide (1mol/L in THF, 1250ml) is added dropwise to, after reaction, the hydrochloric acid 500ml for adding in 0.5M is quenched
Reaction, layering, organic phase are dried with anhydrous sodium sulfate, filter off drier after drying, and (R)-N- is made in concentrating filter liquor
[(S) -1- (tert-butyl diphenyl siloxy) -2- phenyl butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamide 511.6g,
Yield:92.5%.
1H NMR(CDCl3, 600MHz) and δ 7.59 (d, J=6.8Hz, 2H);7.52 (d, J=6.4Hz, 2H);7.45-7.28
(m,11H);5.95 (dd, J=10.8,17.6Hz, 1H);5.35-5.26(m,2H);4.47(s,NH,1H);3.96 (d, J=
9.6Hz,1H);3.55 (d, J=4.8Hz, 1H);1.25(s,9H);0.98(s,9H).
Weigh (R)-N- [(S) -1- (tert-butyl diphenyl siloxy) -2- phenyl butyl- 3- alkene -2- bases] -2- methyl-propyls -
2- sulfenamides (380.0g, 0.75mol), add in 2000ml methanol, and 2mol/L hydrochloric acid 1500ml stir lower reaction, reaction knot
Shu Hou, the pH that mixture is adjusted with saturated sodium bicarbonate solution is 7-8, adds in the extraction of 3000ml dichloromethane, liquid separation, and water phase is used
Dichloromethane solution extracts, and merges organic phase, with saturated common salt water washing, separates organic phase, dried with anhydrous sodium sulfate, dry
It finishes, filters off drier, (S) -1- (tert-butyl diphenyl siloxy) -2- phenyl butyl- 3- alkene -2- amine is made in filtrate decompression concentration
295.5g yield 98.1%.It is detected through high performance liquid chromatography (HPLC), purity:99.46%.
1H NMR(CDCl3, 600MHz) and δ 7.59 (d, J=6.8Hz, 2H);7.51 (d, J=6.8Hz, 2H);7.44-7.23
(m,11H);5.95 (dd, J=10.8,17.2Hz, 1H);5.27-5.19(m,2H);3.67 (t, J=5.6Hz, 1H);3.58
(t, J=5.6Hz, 1H);1.0 (s, 9H) .EI-MS are C26H32NOSi+[the M+H calculated+]:401.2, measured value:401.1.
The preparation of 2 following formula of embodiment (S) -1- benzyloxies -2- phenyl-butyl- 3- alkene -2- amine
2- hydroxy acetophenones (150.0g, 1.10mol) are weighed, 1500ml tetrahydrofurans is added in, 0-5 is cooled under stirring
DEG C and bromobenzyl (226.0g, 1.32mol), the temperature of mixture is made to be down to 0-10 DEG C under stirring, add in sodium tert-butoxide (126.9g,
1.32mol), it is added dropwise, reacts complete to the conversion of 2- hydroxy acetophenones, add in 200ml water, be concentrated under reduced pressure and remove tetrahydrochysene furan
It mutters, adds in the extraction of 1000ml dichloromethane, liquid separation obtains organic phase, adds in anhydrous sodium sulfate drying, filters off after drying dry
Drying prescription, filtrate decompression concentration obtain grease.
In the grease of acquisition add in 2000ml toluene, sequentially added under stirring tetraisopropyl titanate (622.3g,
2.21mol) with (R)-(+)-t-butyl sulfonamide (200.4g, 1.65mol), mixture is warming up at 70-80 DEG C and is reacted.
After reaction, room temperature is down to, 3000ml saturated salt solutions are added in into mixture, is stirred, extraction separates organic phase, organic
Saturated common salt water washing is mutually used, anhydrous sodium sulfate is dried, after drying, and elimination drier, concentrating filter liquor, obtained (R, Z)-
N- (2- benzyloxy -1- phenyl-ethylenes) -2- methylpropane -2- sulfonamide 269.6g, yield:81.6%.
Weigh (R, Z)-N- (2- benzyloxy -1- phenyl-ethylenes) -2- methylpropane -2- sulfonamide (262.5.0g,
0.80mol), 3000ml dichloromethane is added in, system is cooled to -20~-15 DEG C under nitrogen protection, is slowly added dropwise into system
Enter vinylimidazolium chloride magnesium (1mol/L in THF, 960ml), after reaction, reaction is quenched in the hydrochloric acid 400ml for adding in 0.5M, point
Layer, organic phase are dried with anhydrous sodium sulfate, filter off drier after drying, and (R)-N- [(S) -1- benzyls are made in concentrating filter liquor
Oxygroup) -2- phenyl-butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamide 256.2g, yield:89.6%.
1H NMR(CDCl3, 600MHz) and δ 7.33-7.28 (m, 10H);6.30 (dd, J=10.8,17.6Hz, 1H);5.00-
4.98(m,2H);4.46(s,NH,1H);4.63(s,2H);4.03(s,2H);1.32(s,9H).
Weigh (R)-N- [(S) -1- benzyloxies) -2- phenyl-butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamides
(210.0g, 0.59mol), adds in 2000ml methanol, and 2mol/L hydrochloric acid 1500ml stir lower reaction, after reaction, use saturation
The pH that sodium bicarbonate solution adjusts mixture is 7-8, adds in 3000ml dichloromethane and extracts, liquid separation, and water phase dichloromethane is molten
Liquid extracts, and merges organic phase, with saturated common salt water washing, separates organic phase, dried with anhydrous sodium sulfate, and drying finishes, and filters off
(S) -1- benzyloxies -2- phenyl -3 alkene -2- amine 143.6g of butyl-, yield 96.2% is made in drier, filtrate decompression concentration.Through height
Effect liquid phase chromatogram method (HPLC) detects, purity 99.23%.
1H NMR(CDCl3, 600MHz) and δ 8.61 (s, 2H);7.33-7.28(m,10H);6.30 (dd, J=10.8,
17.2Hz,1H);5.01-4.99(m,2H);4.04-3.79(m,2H);4.63 (s, 2H) .EI-MS are C26H32NOSi+It calculates
[M+H+]:254.3, measured value:254.2.
The preparation of 3 following formula of embodiment (S) -1- (4- chlorobenzene formacyls) oxygroup -2- phenyl-butyl- 3- alkene -2- amine
Weigh be prepared Following the procedure of Example 1 (R)-N- [(S) -1- (tert-butyl diphenyl siloxy) -2- phenyl -
Butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamides (10.1g, 0.02mol), 100ml tetrahydrofurans are added in, add in four fourths
Base ammonium fluoride (10.5g, 0.04mol), is stirred to react, and after reaction, water is added to extract, and separates organic phase, and anhydrous sodium sulfate is done
It is dry, drier is filtered off after drying, cools the filtrate to 0-5 DEG C, is added in triethylamine (4.0g, 0.04mol), is instilled to chlorobenzene
Formyl chloride (4.2g, 0.024mol) after the reaction was complete, adds in purified water extraction, and liquid separation, organic phase is dried over anhydrous sodium sulfate
Afterwards, drier is filtered off, (R)-N- [(S) -1- (4- chlorobenzene formacyls oxygroup) -2- phenyl-butyl- 3- is made in filtrate decompression concentration
Alkene -2- bases] -2- methyl-propyl -2- sulfenamide 6.33g, yield 77.8%.
Weigh (R)-N- [(S) -1- (4- chlorobenzene formacyls oxygroup) -2- phenyl-butyl- 3- alkene -2- bases] -2- methyl-propyls -
2- sulfenamides (6.0g, 0.015mol) add in 50ml methanol, and 2mol/L hydrochloric acid 10ml stir lower reaction, after reaction,
The pH that mixture is adjusted with saturated sodium bicarbonate solution is 7-8, adds in the extraction of 100ml dichloromethane, liquid separation, water phase dichloromethane
Alkane solution extracts, and merges organic phase, with saturated common salt water washing, separates organic phase, dried with anhydrous sodium sulfate, and drying finishes,
Drier is filtered off, (S) -1- (4- chlorobenzene formacyls) oxygroup -2- phenyl-butyl- 3- alkene -2- amine 4.0g are made in filtrate decompression concentration,
Yield 91.4%.It is detected through high performance liquid chromatography (HPLC), purity 99.17%.
1H NMR(CDCl3, 600MHz) and δ 7.89 (d, J=8.4Hz, 2H);7.61 (d, J=8.4Hz, 2H);7.33-7.28
(m,5H);6.27 (dd, J=10.8,17.2Hz, 1H);5.01-4.99(m,2H);4.92-4.76(m,2H);EI-MS is
C26H32NOSi+[the M+H calculated+]:302.7, measured value:302.5.
The preparation of 4 following formula of embodiment (S) -1- pivaloyl group oxygroup -2- phenyl-butyl- 3- alkene -2- amine
Weigh be prepared Following the procedure of Example 1 (R)-N- [(S) -1- (tert-butyl diphenyl siloxy) -2- phenyl -
Butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamides (10.1g, 0.02mol), 100ml tetrahydrofurans are added in, add in four fourths
Base ammonium fluoride (10.5g, 0.04mol), is stirred to react, and after reaction, water is added to extract, and separates organic phase, and anhydrous sodium sulfate is done
It is dry, drier is filtered off after drying, cools the filtrate to 0-5 DEG C, adds in triethylamine (4.0g, 0.04mol), instills pivaloyl
Chlorine (2.9g, 0.024mol) after the reaction was complete, adds in purified water extraction, and liquid separation after organic phase is dried over anhydrous sodium sulfate, is filtered
Drier is removed, (R)-N- [(S) -1- pivaloyl group oxygroup -2- phenyl-butyl- 3- alkene -2- bases] -2- first is made in filtrate decompression concentration
Base propyl -2- sulfenamide 6.45g, yield 91.8%.
Weigh (R)-N- [(S) -1- pivaloyl group oxygroup -2- phenyl-butyl- 3- alkene -2- bases] -2- methyl-propyl -2- Asias sulphur
Amide (6.0g, 0.017mol), adds in 60ml methanol, and 2mol/L hydrochloric acid 20ml stir lower reaction, after reaction, use saturation
The pH that sodium bicarbonate solution adjusts mixture is 7-8, adds in the extraction of 100ml dichloromethane, liquid separation, water phase dichloromethane solution
Extraction merges organic phase, with saturated common salt water washing, separates organic phase, dried with anhydrous sodium sulfate, and drying finishes, and filters off dry
(S) -1- pivaloyl group oxygroup -2- phenyl-butyl- 3- alkene -2- amine 4.02g, yield is made in drying prescription, filtrate decompression concentration:94.1%.
It is detected through high performance liquid chromatography (HPLC), purity 98.43%.
1H NMR(CDCl3, 600MHz) and δ 7.33-7.25 (m, 5H);5.95 (dd, J=10.8,17.2Hz, 1H);5.01-
4.99(m,2H);4.75-4.50(m,2H);1.27 (s, 9H) .EI-MS are C26H32NOSi+[the M+H calculated+]:248.3, actual measurement
Value:248.4.
5 following formula of embodiment (R) -5- { [(S) -1- (tert-butyl diphenyl silicon substrate oxygroup) -2- phenyl-butyl- 3- alkene -2- bases
Amido] methyl -5- vinyl pyrrole base -2- ketone preparation
(S) -1- (tert-butyl diphenyl siloxy) -2- phenyl butyl- 3- alkene -2- amine (280.0g, 0.70mol) is weighed, is added
Enter 1000ml toluene, be added with stirring (R) -5- oxo -2- vinyl pyrrole -2- formaldehyde (formula III compound) (116.9g,
0.84mol), back flow reaction after reaction, mixture is pressurizeed and is concentrated, obtains grease.
The concentrate is dissolved in absolute methanol, system temperature is made to be cooled to 0-10 DEG C, sodium borohydride is added in into system
(53.0g, 1.4mol), room temperature reaction after reaction, glacial acetic acid and water are added in into system, stirred 1 hour.Into system
Ethyl acetate is added in, layering, water phase extracts again with ethyl acetate, merges organic phase, successively with saturated sodium bicarbonate solution and full
And brine It, it is concentrated in vacuo and removes ethyl acetate, rapid column chromatography obtains (R) -5- { [(S) -1- (tert-butyl diphenyl silicon
Base oxygroup) -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- vinyl pyrrole base -2- ketone 317.0g, yield:86.3%.
It is detected through high performance liquid chromatography (HPLC), purity 99.27%.
1H NMR(CDCl3, 600MHz) and δ 7.50-7.45 (m, 4H);7.35-7.14(m,11H);6.10(s,NH);6.03
(dd, J=11.2,18.0Hz, 1H);5.74-5.69(m,1H);5.31-5.21(m,2H);5.14-5.04(m,2H);3.71-
3.59(m,2H);2.62 (d, J=6.8Hz, 1H);2.31-2.16(m,4H);1.85 (t, J=8.0Hz, 2H);0.93(s,
9H) .EI-MS is C33H41N2O2Si+[the M+H calculated+]:525.8, measured value:525.3.
6 following formula of embodiment (R) -5- { [(S) -1- benzyloxies -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- ethylene
The preparation of base pyrrole radicals -2- ketone
(S) -1- benzyloxy -2- phenyl butyl- 3- alkene -2- amine (17.7g, 0.07mol) is weighed, adds in 80ml toluene, stirring
Lower addition (R) -5- oxo -2- vinyl pyrrole -2- formaldehyde (formula III compound) (11.7g, 0.08mol), back flow reaction, instead
After answering, mixture is pressurizeed and is concentrated, obtain grease.
The concentrate is dissolved in absolute methanol, system temperature is made to be cooled to 0-10 DEG C, sodium borohydride is added in into system
(5.3g, 0.14mol), room temperature reaction after reaction, glacial acetic acid and water are added in into system, stirred 1 hour.Into system
Ethyl acetate is added in, layering, water phase extracts again with ethyl acetate, merges organic phase, successively with saturated sodium bicarbonate solution and full
And brine It, it is concentrated in vacuo and removes ethyl acetate, obtain (R) -5- { [(S) -1- benzyloxies -2- phenyl-butyl- 3- alkene -2-
Base amido] methyl } -5- vinyl pyrrole base -2- ketone 21.7g, yield:82.4%.It is detected through high performance liquid chromatography (HPLC),
Purity is 99.20%.
1H NMR(CDCl3, 600MHz) and δ 7.33-7.28 (m, 10H);6.31(m,1H);6.11(s,1H);5.83(m,
1H);5.23-5.19(m,2H);5.00-4.98(m,2H);4.63(s,2H);3.70-3.58(m,2H);2.87-2.62(m,
2H);2.61(m,1H);2.31-2.14 (m, 4H) .EI-MS is C24H29N2O2 +[the M+H calculated+]:377.5, measured value:
377.2。
7 following formula of embodiment (R) -5- { [(S) -1- (4- chlorobenzene formacyls) oxygroup -2- phenyl-butyl- 3- alkene -2- bases amido]
Methyl } -5- vinyl pyrrole base -2- ketone preparation
(S) -1- (4- chlorobenzene formacyls) oxygroup -2- phenyl butyl- 3- alkene -2- amine (21.1g, 0.07mol) is weighed, is added in
90ml toluene, be added with stirring (R) -5- oxo -2- vinyl pyrrole -2- formaldehyde (formula III compound) (11.7g,
0.08mol), back flow reaction after reaction, mixture is pressurizeed and is concentrated, obtains grease.
The concentrate is dissolved in absolute methanol, system temperature is made to be cooled to 0-10 DEG C, sodium borohydride is added in into system
(5.3g, 0.14mol), room temperature reaction after reaction, glacial acetic acid and water are added in into system, stirred 1 hour.Into system
Ethyl acetate is added in, layering, water phase extracts again with ethyl acetate, merges organic phase, successively with saturated sodium bicarbonate solution and full
And brine It, be concentrated in vacuo remove ethyl acetate, column chromatography obtain (R) -5- [(S) -1- (4- chlorobenzene formacyls) oxygroup -
2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- vinyl pyrrole base -2- ketone 24.7g, yield:82.9%.Through efficient liquid phase
Chromatography (HPLC) detects, purity 98.64%.
1H NMR(CDCl3, 600MHz) and δ 7.88 (d, J=8.4Hz, 2H);7.61 (d, J=8.4Hz, 2H);7.33-7.28
(m,5H);6.31(m,1H);6.11(s,1H);5.83(m,1H);5.22-5.19(m,2H);5.01-4.98(m,2H);4.78-
4.54(m,2H);2.87-2.62(m,2H);2.61(m,1H);2.14(m,2H);1.92 (m, 2H) .EI-MS are C24H26ClN2O3 +[the M+H calculated+]:425.9, measured value:425.6.
8 following formula of embodiment (R) -5- { [(S) -1- pivaloyl group oxygroup -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -
The preparation of 5- vinyl pyrrole base -2- ketone
(S) -1- pivaloyl group oxygroup -2- phenyl butyl- 3- alkene -2- amine (17.3g, 0.07mol) is weighed, adds in 80ml first
Benzene is added with stirring (R) -5- oxo -2- vinyl pyrrole -2- formaldehyde (formula III compound) (11.7g, 0.08mol), reflux
Reaction after reaction, mixture is pressurizeed and is concentrated, obtains grease.
The concentrate is dissolved in absolute methanol, system temperature is made to be cooled to 0-10 DEG C, sodium borohydride is added in into system
(5.3g, 0.14mol), room temperature reaction after reaction, glacial acetic acid and water are added in into system, stirred 1 hour.Into system
Ethyl acetate is added in, layering, water phase extracts again with ethyl acetate, merges organic phase, successively with saturated sodium bicarbonate solution and full
And brine It, it is concentrated in vacuo and removes ethyl acetate, column chromatography obtains (R) -5- { [(S) -1- pivaloyl group oxygroup -2- benzene
Base-butyl- 3- alkene -2- bases amido] methyl } -5- vinyl pyrrole base -2- ketone 21.6g, yield:83.7%.Through high performance liquid chromatography
Method (HPLC) detects, purity 99.17%.
1H NMR(CDCl3, 600MHz) and δ 7.32-7.28 (m, 5H);6.31(m,1H);6.12(s,1H);5.81(m,1H);
5.23-5.20(m,2H);5.00-4.98(m,2H);4.65-4.39(m,2H);2.61(m,1H);2.14(m,2H);1.92(m,
2H);1.28 (s, 9H) .EI-MS are C22H31N2O3 +[the M+H calculated+]:371.5, measured value:371.2.
9 following formula N- of embodiment ((S) -1- ((tert-butyl diphenyl silicon substrate) oxygroup) -2- phenyl-butyl- 3- alkene -2- bases)-N-
The preparation of (((R) -5- oxo -2- vinyl pyrrole base -2- bases) methyl) trifluoroacetamide
Weigh (R) -5- { [(S) -1- (tert-butyl diphenyl silicon substrate oxygroup) -2- phenyl-butyl- 3- alkene -2- bases amido] first
Base } -5- vinyl pyrrole base -2- ketone (26.2g, 0.05mol), 130ml dichloromethane is added in, is added with stirring triethylamine
Mixture is down to 0-5 DEG C, instills trifluoroacetic anhydride (12.6g, 0.06mol), be added dropwise, continued by (7.6g, 0.075mol)
It reacts to (R) -5- { [(S) -1- (tert-butyl diphenyl silicon substrate oxygroup) -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- second
The conversion of alkenyl pyrrole radicals -2- ketone is complete, and purified water is added in into reaction mixture, extracts, separates organic phase, anhydrous sodium sulfate is done
It is dry, filter off drier after, filtrate through be concentrated under reduced pressure be made N- ((S) -1- ((tert-butyl diphenyl silicon substrate) oxygroup) -2- phenyl -
Butyl- 3- alkene -2- bases)-N- (((R) -5- oxo -2- vinyl pyrrole base -2- bases) methyl) trifluoroacetamide 27.7g, yield:
89.4%.It is detected through high performance liquid chromatography (HPLC), purity 98.08%.
1H NMR(CDCl3, 600MHz) and δ 7.50-7.45 (m, 4H);7.35-7.14(m,11H);6.10(s,NH);6.03
(dd, J=11.2,18.0Hz, 1H);5.74-5.69(m,1H);5.31-5.21(m,2H);5.14-5.04(m,2H);3.71-
3.59(m,2H);3.52(s,2H);2.31-2.16(m,4H);0.93 (s, 9H) .EI-MS is C35H40F3N2O3Si+[the M+ calculated
H+]:621.8, measured value:621.4.
10 following formula of embodiment (R) -5- { [benzyl ((S) -1- ((tert-butyl diphenyl silicon substrate) oxygroup) -2- phenyl-butyl- 3-
Alkene -2- bases) amino] methyl -5- vinyl pyrrole base -2- ketone preparation
Weigh (R) -5- { [(S) -1- (tert-butyl diphenyl silicon substrate oxygroup) -2- phenyl-butyl- 3- alkene -2- bases amido] first
Base } -5- vinyl pyrrole base -2- ketone (26.2g, 0.05mol), 130ml tetrahydrofurans are added in, stirring drops to 0-5 DEG C, adds in
Sodium tert-butoxide (5.8g, 0.06mol) after stirring 30 minutes, instills bromobenzyl (10.3g, 0.06mol), is added dropwise, the reaction was continued
To (R) -5- { [(S) -1- (tert-butyl diphenyl silicon substrate oxygroup) -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- vinyl
The conversion of pyrrole radicals -2- ketone is complete, and purified water is added in into reaction mixture, extracts, and separates organic phase, and anhydrous sodium sulfate is dried,
After filtering off drier, filtrate is through being concentrated under reduced pressure, column chromatography for separation, and (R) -5- { [benzyl ((S) -1- ((tert-butyl diphenyls are made
Silicon substrate) oxygroup) -2- phenyl-butyl- 3- alkene -2- bases) amino] methyl } -5- vinyl pyrrole base -2- ketone 23.1g, yield:
75.3%.It is detected through high performance liquid chromatography (HPLC), purity 98.47%.
1H NMR(CDCl3, 600MHz) and δ 7.50-7.45 (m, 4H);7.35-7.21(m,16H);6.10(s,NH);6.02
(dd, J=11.2,18.0Hz, 1H);5.73-5.69(m,1H);5.30-5.21(m,2H);5.13-5.04(m,2H);4.30-
4.05(m,2H);3.62(s,2H);(s,2H);3.52(s,2H);2.31-2.16(m,4H);0.93 (s, 9H) .EI-MS is
C40H47N2O2Si+[the M+H calculated+]:615.3, measured value:615.4.
11 following formula of embodiment (5R, 8S) -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -1,7- phenodiazines
The preparation of miscellaneous-spiral shell [4.5] decyl- 9- alkene -2- ketone
Weigh (R) -5- { [(S) -1- (tert-butyl diphenyl silicon substrate oxygroup) -2- phenyl-butyl- 3- alkene -2- bases amido] first
Base } -5- vinyl pyrrole base -2- ketone (310.0g, 0.59mol), it is dissolved in 3000ml toluene, adds in Hoveyda-Grubbs and urge
Agent (38.4g, 0.06mol) under nitrogen protection, is warming up at 50-60 DEG C and reacts.After the completion of reaction, saturation sulfurous is added in
Acid sodium solution makes mixture be cooled to room temperature, adds in saturated sodium bicarbonate solution (500ml).Biphase mixture stirring 1 is small at room temperature
When, water phase is separated off, organic phase is washed with saturated nacl aqueous solution, washing.Organic phase is filtered by Celite pad, concentration,
Column chromatography obtains product 243.2g, yield:83.0%.It is detected through high performance liquid chromatography (HPLC), purity 99.12%.
1H NMR(CDCl3, 600MHz) and δ 7.54 (d, J=6.6Hz, 2H);7.49 (d, J=7.8Hz, 2H);7.43-7.40
(m,4H);7.37-7.27(m,7H);6.17 (d, J=10.2Hz, 1H);5.82 (d, J=10.2Hz, 2H);3.70 (d, J=
12.6Hz,2H);2.90-2.75(m,2H);2.44-2.36(m,3H);1.92-1.89(m,2H);0.99 (s, 9H) .EI-MS is
C31H37N2O2Si+[the M+H calculated+]:497.3, measured value:497.1.
12 following formula of embodiment (5R, 8S) -8- benzyloxymethyls -8- phenyl -1,7- diaza-spiros [4.5] decyl- 9- alkene -2-
The preparation of ketone
Weigh (R) -5- { [(S) -1- benzyloxies -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- vinyl pyrroles
Base -2- ketone (22.6g, 0.06mol), is dissolved in 200ml toluene, adds in Hoveyda-Grubbs (3.84g, 0.006mol),
Under nitrogen protection, it is warming up at 60-70 DEG C and reacts.After the completion of reaction, saturated sodium bisulfite solution is added in, mixture is made to be cooled to room
Temperature adds in saturated sodium bicarbonate solution (150ml).It stirs 1 hour at room temperature, is separated off water phase, organic phase saturation chlorination
Sodium solution washs, washing.Organic phase is filtered by Celite pad, and concentration, column chromatography obtains product 17.8g, yield:85.1%.Through
High performance liquid chromatography (HPLC) detects, purity 99.36%.
1H NMR(CDCl3, 600MHz) and δ 7.35-7.28 (m, 10H);6.16 (d, J=10.2Hz, 1H);5.81 (d, J=
10.2Hz,2H);4.63(s,2H);3.90-3.68(m,2H);3.21-2.98(m,2H);2.44-2.36(m,3H);1.92-
1.89 (m, 2H) .EI-MS are C22H25N2O2 +[the M+H calculated+]:349.5, measured value:349.2.
13 following formula of embodiment (5R, 8S) -8- (4- chlorobenzene formacyls oxygroup) methyl -8- phenyl -1,7- diaza-spiros
[4.5] preparation of decyl- 9- alkene -2- ketone
Weigh (R) -5- { [(S) -1- (4- chlorobenzene formacyls) oxygroup -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5-
Vinyl pyrrole base -2- ketone (25.5g, 0.06mol), is dissolved in 220ml toluene, adds in Hoveyda-Grubbs catalyst
(3.84g, 0.006mol) under nitrogen protection, is warming up at 60-70 DEG C and reacts.After the completion of reaction, saturated sodium sulfite is added in
Solution makes mixture be cooled to room temperature, adds in saturated sodium bicarbonate solution (150ml).It stirs 1.5 hours, is separated off at room temperature
Water phase, organic phase are washed with saturated nacl aqueous solution, washing.Organic phase is filtered by Celite pad, and concentration, column chromatography obtains product
19.2g yield:80.6%.It is detected through high performance liquid chromatography (HPLC), purity 99.09%.
1H NMR(CDCl3, 600MHz) and δ 7.89 (d, J=8.4Hz, 2H);7.63 (d, J=8.4Hz, 2H);7.36-7.29
(m,5H);6.17 (d, J=10.2Hz, 1H);5.84 (d, J=10.2Hz, 2H);3.90-3.68(m,2H);3.21-2.98(m,
2H);2.43-2.37(m,3H);2.17-1.93 (m, 2H) .EI-MS is C22H22ClN2O3 +[the M+H calculated+]:397.9, actual measurement
Value:397.7.
14 following formula of embodiment (5R, 8S) -8- pivaloyl groups oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl-
The preparation of 9- alkene -2- ketone
Weigh (R) -5- { [(S) -1- pivaloyl group oxygroup -2- phenyl-butyl- 3- alkene -2- bases amido] methyl } -5- vinyl
Pyrrole radicals -2- ketone (22.2g, 0.06mol), is dissolved in 200ml toluene, addition Hoveyda-Grubbs catalyst (3.84g,
0.006mol), under nitrogen protection, it is warming up at 65-70 DEG C and reacts.After the completion of reaction, saturated sodium bisulfite solution is added in, is made
Mixture is cooled to room temperature, adds in saturated sodium bicarbonate solution (100ml).It stirs 1 hour at room temperature, is separated off water phase, it is organic
It is mutually washed, washed with saturated nacl aqueous solution.Organic phase is filtered by Celite pad, and concentration, column chromatography obtains product 12.3g, is received
Rate:84.2%.It is detected through high performance liquid chromatography (HPLC), purity 99.17%.
1H NMR(CDCl3, 600MHz) and δ;7.32-7.28(m,5H);6.15 (d, J=10.2Hz, 1H);5.81 (d, J=
10.2Hz,2H);3.90-3.68(m,2H);3.21-2.98(m,2H);2.44-2.36(m,3H);1.92-1.89(m,2H);
1.27 (s, 9H) .EI-MS are C20H27N2O3 +[the M+H calculated+]:343.4, measured value:343.1.
15 following formula of embodiment (5R, 8S) -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -7- trifluoroacetyls
The preparation of base -1,7- diaza-spiros [4.5] decyl- 9- alkene -2- ketone
Weigh N- ((S) -1- ((tert-butyl diphenyl silicon substrate) oxygroup) -2- phenyl-butyl- 3- alkene -2- bases)-N- (((R) -5-
Oxo -2- vinyl pyrrole base -2- bases) methyl) trifluoroacetamide (24.8g, 0.04mol), it is dissolved in 250ml toluene, adds in
Hoveyda-Grubbs catalyst (2.56g, 0.004mol) under nitrogen protection, is warming up at 50-60 DEG C and reacts.It has reacted
Cheng Hou adds in saturated sodium bisulfite solution, and mixture is made to be cooled to room temperature, adds in saturated sodium bicarbonate solution (100ml), at room temperature
Mixture stirs 1 hour, is separated off water phase, and organic phase is washed with saturated nacl aqueous solution, washing.Organic phase passes through diatomite
Pad filtering, concentration, column chromatography obtain product 20.2g, yield:85.2%.It is detected through high performance liquid chromatography (HPLC), purity is
98.77%.
1H NMR(CDCl3, 600MHz) and δ 7.54 (d, J=6.6Hz, 2H);7.50 (d, J=7.8Hz, 2H);7.42-7.39
(m,4H);7.38-7.28(m,7H);6.17 (d, J=10.2Hz, 1H);5.82 (d, J=10.2Hz, 2H);3.70 (d, J=
12.6Hz,2H);2.90-2.75(s,2H);2.44-2.36(m,2H);1.92-1.89(m,2H);0.99 (s, 9H) .EI-MS is
C33H36N2O3Si+[the M+H calculated+]:593.7, measured value:593.4.
16 following formula of embodiment (5R, 8S) -7- benzyls -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -1,
The preparation of 7- diaza-spiros [4.5] decyl- 9- alkene -2- ketone
Weigh (R) -5- { [benzyls ((S) -1- ((tert-butyl diphenyl silicon substrate) oxygroup) -2- phenyl-butyl- 3- alkene -2- bases)
Amino] methyl } -5- vinyl pyrrole base -2- ketone (18.4g, 0.03mol), it is dissolved in 200ml toluene, adds in Hoveyda-
Grubbs catalyst (1.92g, 0.003mol) under nitrogen protection, is warming up at 55-65 DEG C and reacts.After the completion of reaction, add in
Saturated sodium bisulfite solution makes mixture be cooled to room temperature, adds in saturated sodium bicarbonate solution (100ml), mixture stirs at room temperature
It mixes 1 hour, is separated off water phase, organic phase is washed with saturated nacl aqueous solution, washing.Organic phase is filtered by Celite pad,
Concentration, column chromatography obtain product 14.9g, yield:84.7%.It is detected through high performance liquid chromatography (HPLC), purity 99.27%.
1H NMR(CDCl3, 600MHz) and δ 7.54 (d, J=6.6Hz, 2H);7.50 (d, J=7.8Hz, 2H);7.42-7.39
(m,4H);7.38-7.28(m,12H);6.17 (d, J=10.2Hz, 1H);6.12(s,1H);5.81 (d, J=10.2Hz, 1H);
3.70 (d, J=12.6Hz, 2H);3.62(s,2H);2.84-2.75(m,2H);2.44-2.36(m,2H);1.92-1.89(m,
2H);0.99 (s, 9H) .EI-MS is C38H43N2O2Si+[the M+H calculated+]:587.9, measured value:587.4.
17 following formula of embodiment (5S, 8S) -8- [(tert-butyl diphenyl siloxy) methyl] -8- phenyl -1,7- diazas -
The preparation of spiral shell [4.5] decyl- 2- ketone
Weigh (5R, 8S) -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -1,7- diaza-spiros [4.5]
Decyl- 9- alkene -2- ketone (240.0g, 0.48mol), is dissolved in 2500ml absolute methanols, and 10% Pd/C is added in into system
(24.0g).The system is passed through hydrogen, is reacted under 1.0-1.5MPa pressure.After reaction, reactant is filtered, no water beetle
Alcohol washs filter cake, and (5S, 8S) -8- [(tert-butyl diphenyl siloxy) methyl] -8- phenyl -1,7- phenodiazines are made in concentrating filter liquor
Miscellaneous-spiral shell [4.5] decyl- 2- ketone 235.6g, yield:98.4%.It is detected through high performance liquid chromatography (HPLC), purity 98.67%.
1H NMR(CDCl3, 600MHz) and δ 7.51 (d, J=6.6Hz, 2H);7.47 (d, J=7.8Hz, 2H);7.43-7.40
(m,4H);7.37-7.27(m,7H);5.82(s,1H);3.70 (d, J=12.6Hz, 2H);2.90-2.75(m,3H);2.44-
2.36(m,5H);1.92-1.89(m,2H);0.99 (s, 9H) .EI-MS is C31H39N2O2Si+[the M+H calculated+]:499.3, it is real
Measured value:499.1.
18 following formula of embodiment (5S, 8S) -8- [(tert-butyl diphenyl siloxy) methyl] -8- phenyl -1,7- diazas -
The preparation of spiral shell [4.5] decyl- 2- ketone
Weigh (5R, 8S) -7- benzyls -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -1,7- diazas -
Spiral shell [4.5] decyl- 9- alkene -2- ketone (11.7g, 0.02mol), is dissolved in 200ml absolute methanols, and 10% Pd/C is added in into system
(1.2g).The system is passed through hydrogen, is reacted under 1.0-1.5MPa pressure.After reaction, reactant is filtered, absolute methanol
Filter cake is washed, (5S, 8S) -8- [(tert-butyl diphenyl siloxy) methyl] -8- phenyl -1,7- phenodiazines are made in concentrating filter liquor
Miscellaneous-spiral shell [4.5] decyl- 2- ketone 9.2g, yield:93.0%.It is detected through high performance liquid chromatography (HPLC), purity 99.27%.
19 following formula of embodiment (5S, 8S) -8- (4- chlorobenzene formacyls) oxygroup methyl -8- phenyl -1,7- diaza-spiros
[4.5] preparation of decyl- 2- ketone
Weigh (5R, 8S) -8- (4- chlorobenzene formacyls) oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 9-
Alkene -2- ketone (15.9g, 0.04mol), is dissolved in 150ml absolute methanols, and 10% Pd/C (1.6g) is added in into system.The body
System is passed through hydrogen, is reacted under 1.0-1.5MPa pressure.After reaction, reactant is filtered, absolute methanol washing filter cake, filter
Liquid is concentrated to be made (5S, 8S) -8- (4- chlorobenzene formacyls) oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
15.6g yield:97.6%.It is detected through high performance liquid chromatography (HPLC), purity 99.54%.
1H NMR(CDCl3, 600MHz) and δ 7.89 (d, J=8.4Hz, 2H);7.64 (d, J=8.4Hz, 2H);7.37-7.27
(m,5H);5.83(s,1H);3.71(m,2H);3.02-2.76(m,3H);2.23-2.14(m,2H);2.11-1.88(m,2H);
1.85-1.53 (m, 4H) .EI-MS is C22H24ClN2O3 +[the M+H calculated+]:399.9, measured value:399.6.
20 following formula of embodiment (5S, 8S) -8- pivaloyl groups oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl-
The preparation of 2- ketone
Weigh (5R, 8S) -8- pivaloyl groups oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 9- alkene -2- ketone
(13.7g, 0.04mol) is dissolved in 150ml absolute methanols, and 10% Pd/C (1.4g) is added in into system.The system is passed through hydrogen
Gas reacts under 1.0-1.5MPa pressure.After reaction, reactant is filtered, absolute methanol washing filter cake, concentrating filter liquor
(5S, 8S) -8- pivaloyl group oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone 13.5g, yield is made:
97.8%.It is detected through high performance liquid chromatography (HPLC), purity 98.84%.
1H NMR(CDCl3, 600MHz) and δ 7.37-7.28 (m, 5H);5.84(s,1H);3.71(m,2H);3.02-2.76
(m,3H);2.24-2.14(m,2H);2.11-1.87(m,2H);1.85-1.52(m,4H);1.27 (s, 9H) .EI-MS are
C20H29N2O3 +[the M+H calculated+]:345.4, measured value:345.2.
21 following formula of embodiment (5R, 8S) -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -7- trifluoroacetyls
The preparation of base -1,7- diaza-spiros [4.5] decyl- 2- ketone
Weigh (5R, 8S) -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -7- trifluoroacetyl groups -1,7- two
Aza-spiro [4.5] decyl- 9- alkene -2- ketone (11.9g, 0.02mol), is dissolved in 100ml methanol, adds in 10% Pd/C (1.2g),
The system is passed through hydrogen, is reacted under 1.0-1.5MPa pressure.After reaction, reactant is filtered, absolute methanol washing filter
Cake, concentrating filter liquor be made (5R, 8S) -8- [(tert-butyl diphenyl silicon substrate oxygroup) methyl] -8- phenyl -7- trifluoroacetyl groups -
1,7- diaza-spiros [4.5] decyl- 2- ketone 11.0g, yield:92.4%.It is detected through high performance liquid chromatography (HPLC), purity is
99.61%.
1H NMR(CDCl3, 600MHz) and δ 7.53 (d, J=6.6Hz, 2H);7.49 (d, J=7.8Hz, 2H);7.42-7.39
(m,4H);7.38-7.28(m,7H);5.82(s,1H);3.70 (d, J=12.6Hz, 2H);2.90-2.75(m,3H);2.44-
2.36(m,5H);1.92-1.89(m,2H);0.99 (s, 9H) .EI-MS is C33H38N2O3Si+[the M+H calculated+]:595.8, it is real
Measured value:595.1.
22 following formula of embodiment (5S, 8S) -8- methylol -8- phenyl -7- trifluoroacetyl group -1,7- diaza-spiros [4.5]
The preparation of decyl- 2- ketone
Weigh (5S, 8S) -8- [(tert-butyl diphenyl siloxy) methyl] -8- phenyl -7- trifluoroacetyl group -1,7- phenodiazines
Miscellaneous-spiral shell [4.5] decyl- 2- ketone (8.9g, 0.015mol), adds in 100ml tetrahydrofurans, and stirring and dissolving adds in four fourths into system
Base ammonium fluoride (7.9g, 0.03mol), after reaction, into system, purified water and ethyl acetate extraction, separate organic phase, use
Saturated common salt water washing, anhydrous sodium sulfate drying, drying finish, and filter off drier, (5S, 8S) -8- hydroxyls are made in concentrating filter liquor
Methyl -8- phenyl -7- trifluoroacetyl groups -1,7- diaza-spiro [4.5] decyl- 2- ketone 4.9g, yield 91.0%.Through efficient liquid phase
Chromatography (HPLC) detects, purity 99.23%.
1H NMR (DMSO, 600MHz) δ 7.60-7.28 (m, 5H);6.61(s,NH)4.42(m,2H);4.31(s,1H);
3.70 (d, J=12.6Hz, 2H);2.23-1.86(m,6H);1.84-1.59 (m, 2H) .EI-MS is C17H20N2O3 +[the M calculated
+H+]:357.4, measured value:357.1.
The preparation of 23 following formula of embodiment (5S, 8S) -8- methylols -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
Weigh (5S, 8S) -8- [(tert-butyl diphenyl siloxy) methyl] -8- phenyl -1,7- diaza-spiros [4.5] decyl-
2- ketone (230.0g, 0.46mol), adds in 2500ml tetrahydrofurans, and stirring and dissolving adds in tetrabutyl ammonium fluoride into system
(240.5g, 0.92mol), after reaction, into system, purified water and ethyl acetate extraction, separate organic phase, are eaten with saturation
Salt water washing, anhydrous sodium sulfate drying, drying finish, and filter off drier, (5S, 8S) -8- methylols -8- is made in concentrating filter liquor
Phenyl -1,7- diaza-spiro [4.5] decyl- 2- ketone 106.1g, yield 88.6%.It is detected through high performance liquid chromatography (HPLC), it is pure
Spend is 99.54%.
1H NMR (DMSO, 600MHz) δ 7.58-7.26 (m, 5H);6.58(s,NH)4.42(m,2H);4.31(s,1H);
3.70 (d, J=12.6Hz, 2H);2.90-2.75(m,5H);1.92-1.89 (m, 4H) .EI-MS is C15H21N2O2 +[the M calculated
+H+]:261.2, measured value:261.1.
The preparation of 24 following formula of embodiment (5S, 8S) -8- methylols -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
Weigh (5R, 8S) -8- benzyloxymethyls -8- phenyl -1,7- diaza-spiros [4.5] decyl- 9- alkene -2- ketone (13.9g,
0.04mol), it is dissolved in 150ml absolute methanols, 10% Pd/C (1.4g) is added in into system.The system is passed through hydrogen,
1.0-1.5MPa it is reacted under pressure.After reaction, reactant is filtered, absolute methanol washing filter cake, concentrating filter liquor is made
(5S, 8S) -8- benzyloxies) methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone 9.3g, yield:89.4%.Through efficient
Liquid chromatography (HPLC) detects, purity 99.77%.
The preparation of 25 following formula of embodiment (5S, 8S) -8- methylols -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
Weigh (5S, 8S) -8- (4- chlorobenzene formacyls) oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
(12.0g, 0.03mol) adds in 35ml tetrahydrofurans, stirring and dissolving, the sodium hydroxide solution of addition 4mol/L into system
(15ml, 0.06mol), after reaction, into system, purified water and ethyl acetate extraction, separate organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate drying, drying finish, and filter off drier, (5S, 8S) -8- methylol -8- benzene is made in concentrating filter liquor
Base -1,7- diaza-spiro [4.5] decyl- 2- ketone 7.3g, yield 93.5%.It is detected through high performance liquid chromatography (HPLC), purity is
99.68%.
The preparation of 26 following formula of embodiment (5S, 8S) -8- methylols -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
Weigh (5S, 8S) -8- pivaloyl groups oxygroup methyl -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone
(10.3g, 0.03mol) adds in 30ml tetrahydrofurans, stirring and dissolving, the sodium hydroxide solution of addition 4mol/L into system
(15ml, 0.06mol), after reaction, into system, purified water and ethyl acetate extraction, separate organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate drying, drying finish, and filter off drier, (5S, 8S) -8- methylol -8- benzene is made in concentrating filter liquor
Base -1,7- diaza-spiro [4.5] decyl- 2- ketone 7.5g, yield 96.2%.It is detected through high performance liquid chromatography (HPLC), purity is
99.26%.
27 following formula of embodiment (5S, 8S) -8- [1- (R)-(3,5- bis--trifluoromethyl-phenyl)-ethoxyl methyl] -8- benzene
The preparation of base -1,7- diaza-spiros [4.5] decyl- 2- ketone (compound of formula I)
Weigh (5S, 8S) -8- (methylol) -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone (105.0g,
0.40mol), 1000mlN is added in, system is cooled to 0-5 DEG C by N- dimethylacetylamides under stirring, and 60% is added in into system
Sodium hydride (19.2g) is stirred to react 0.5 hour at 0 DEG C, and the bis- (fluoroforms of (S) -1- (1- bromoethyls) -3,5- are added in into system
Base) benzene (7.4g, 23.0mmol), it is warmed to room temperature that the reaction was continued after adding, after reaction, water quenching is added to go out, extracted with ethyl acetate
Take, wash organic phase, anhydrous sodium sulfate drying, filtering, filtrate is concentrated, using column chromatography be made (5S, 8S) -8- [1- (R) -
(3,5- bis--trifluoromethyl-phenyl)-ethoxyl methyl] -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone (Formulas I chemical combination
Object) 185.5g, yield:92.6%.It is detected through high performance liquid chromatography (HPLC), purity 99.87%.
1H NMR(CDCl3) 7.76~7.26 (m, 8H), 6.82 (s, NH), 5.30 (s, 1H), 4.37-4.35 (m, 2H),
3.38(s,1H),3.19–3.17(m,2H),2.74–2.68(m,2H),2.41–2.21(m,3H),1.81–1.27(m,4H),
1.38(s,3H).EI-MS is C25H27F6N2O2 +[the M+H calculated+]:501.2, measured value:501.1.
28 following formula of embodiment (5S, 8S) -8- [1- (R)-(3,5- bis--trifluoromethyl-phenyl)-ethoxyl methyl] -8- benzene
The preparation of base -1,7- diaza-spiros [4.5] decyl- 2- ketone (compound of formula I)
Weigh (5S, 8S) -8- (methylol) -8- phenyl -7- trifluoroacetyl group -1,7- diaza-spiros [4.5] decyl- 2- ketone
(3.5g, 0.01mol), adds in 20mlN, and system is cooled to 0-5 DEG C under stirring, is added in into system by N- dimethylacetylamides
60% sodium hydride (0.5g) is stirred to react 0.5 hour at 0 DEG C, and it is bis- that (S) -1- (1- bromoethyls) -3,5- is added in into system
(trifluoromethyl) benzene (7.4g, 23.0mmol), is warmed to room temperature that the reaction was continued after adding, after reaction, water quenching is added to go out, use acetic acid
Ethyl ester extracts, and washes organic phase, anhydrous sodium sulfate drying, and filtrate is concentrated, (5S, 8S) -8- is made using column chromatography by filtering
[1- (R)-(3,5- bis--trifluoromethyl-phenyl)-ethoxyl methyl] -8- phenyl -1,7- diaza-spiros [4.5] decyl- 2- ketone (formulas
Compound I) 4.5g, yield, 90.0%, it is detected through high performance liquid chromatography (HPLC), purity 99.83%.
The preparation of 29 following formula of embodiment (S) -2- amino -2- phenyl-butyl- 3- alkene acetic acid esters
Weigh be prepared Following the procedure of Example 1 (R)-N- [(S) -1- (tert-butyl diphenyl siloxy) -2- phenyl -
Butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamides (10.0g, 0.02mol), 100ml tetrahydrofurans are added in, add in four fourths
Base ammonium fluoride (10.5g, 0.04mol), is stirred to react, and after reaction, water is added to extract, and separates organic phase, and anhydrous sodium sulfate is done
It is dry, drier is filtered off after drying, cools the filtrate to 0-5 DEG C, adds in triethylamine (4.0g, 0.04mol), instills acetic anhydride
(2.5g, 0.024mol), N, N- dimethylamino naphthyridines (0.5g, 0.004mol) add in purified water extraction after the reaction was complete, point
Liquid after organic phase is dried over anhydrous sodium sulfate, filters off drier, and (R)-N- [(S) -1- acetyl oxygen is made in filtrate decompression concentration
Base -2- phenyl-butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamide 5.47g, yield 89.5%.
Weigh (R)-N- [(S) -1- acetoxyl groups -2- phenyl-butyl- 3- alkene -2- bases] -2- methyl-propyl -2- sulfenamides
(5.0g, 0.016mol), adds in 60ml methanol, and 2mol/L hydrochloric acid 20ml stir lower reaction, after reaction, use unsaturated carbonate
The pH that hydrogen sodium solution adjusts mixture is 7-8, adds in the extraction of 100ml dichloromethane, and liquid separation, water phase is extracted with dichloromethane solution
It takes, merges organic phase, with saturated common salt water washing, separate organic phase, dried with anhydrous sodium sulfate, drying finishes, and filters off drying
(S) -2- amino -2- phenyl-butyl- 3- alkene acetic acid esters 3.06g, yield is made in agent, filtrate decompression concentration:91.1%.Through efficient liquid
Phase chromatography (HPLC) detects, purity 98.11%.
1H NMR(CDCl3) 7.90 (s, 1H), 7.31-7.27 (m, 4H), 7.21-7.19 (m, 1H), 6.28 (dd, J=
11.4,18.0Hz, 1H), 5.19 (d, J=10.8Hz, 1H), 5.10 (t, J=6.0Hz, 1H), 5.07 (d, J=17.3Hz,
1H),3.80–3.69(m,2H),1.93(s,3H).EI-MS is C12H16NO2 +[the M+H calculated+]:206.1, measured value:
206.0.
30 following formula of embodiment (S) -2- { [(R) -5- oxo -2- vinyl pyrroles]-methyl amine } -2- phenyl butyl- 3- alkene second
The preparation of acid esters
(S) -2- amino -2- phenyl-butyl- 3- alkene acetic acid esters (3.0g, 14.6mmol) is weighed, adds in 30ml toluene, stirring
Lower addition (R) -5- oxo -2- vinyl pyrrole -2- formaldehyde (formula III compound) (3.9g, 17.5mmol), back flow reaction, instead
After answering, mixture is pressurizeed and is concentrated, obtain grease.
The concentrate is dissolved in absolute methanol, system temperature is made to be cooled to 0-10 DEG C, sodium borohydride is added in into system
(790mg, 20.8mmol), room temperature reaction after reaction, glacial acetic acid and water are added in into system, stirred 1 hour.To system
Middle addition ethyl acetate, layering, water phase extracts again with ethyl acetate, merges organic phase, successively with saturated sodium bicarbonate solution and
Saturated common salt water washing, is concentrated in vacuo and removes ethyl acetate, and rapid column chromatography obtains (S) -2- { [(R) -5- oxo -2- vinyl
Pyrroles]-methyl amine } -2- phenyl butyl- 3- alkene acetic acid esters 4.14g, yield:86.3%.It is examined through high performance liquid chromatography (HPLC)
It surveys, purity 98.07%.
1H NMR(CDCl3, 600MHz) and 7.50 (d, J=7.2Hz, 2H), 7.32 (t, J=7.2Hz, 2H), 7.22 (t, J=
7.2Hz, 1H), 6.15 (d, J=9.6Hz, 1H), 5.71-5.62 (m, 1H);5.30-5.21(m,2H);4.12 (d, J=
10.8Hz, 1H), 2.80 (d, J=13.2Hz, 1H), 2.67 (s, NH, 1H), 2.58 (d, J=12.0Hz, 1H), 2.21-2.11
(m, 2H), 1.94 (s, 3H), 1.83-1.70 (m, 2H) .EI-MS are C19H25N2O3 +[the M+H calculated+]:329.2, measured value:
329.1。
31 following formula of embodiment [(5R, 8S) -2- oxos -8- phenyl -1,7- diaza-spiros [4.5] decyl- 9- alkene -8- bases] first
The preparation of yl acetate
Weigh (S) -2- { [(R) -5- oxo -2- vinyl pyrroles]-methyl amine } -2- phenyl butyl- 3- alkene acetic acid esters
(4.0g, 12.2mmol) is dissolved in 100ml toluene, Hoveyda-Grubbs catalyst (458mg, 0.06mol) is added in, in nitrogen
Under gas shielded, it is warming up at 50-60 DEG C and reacts.After the completion of reaction, saturated sodium bisulfite solution is added in, mixture is made to be cooled to room
Temperature adds in saturated sodium bicarbonate solution (500ml).Biphase mixture stirs 1 hour at room temperature, is separated off water phase, organic phase
It is washed, washed with saturated nacl aqueous solution.Organic phase is filtered by Celite pad, and concentration, column chromatography obtains product 3.12g, yield:
85.0%.It is detected through high performance liquid chromatography (HPLC), purity 99.12%.
1H NMR(CDCl3) 7.94 (s, 1H), 7.51 (d, J=7.2Hz, 2H), 7.33 (t, J=7.2Hz, 2H), 7.24
(t, J=7.2Hz, 1H), 6.19 (d, J=9.6Hz, 1H), 5.84 (d, J=9.6Hz, 1H), 4.19 (d, J=11.4Hz, 1H),
4.10 (d, J=10.8Hz, 1H), 2.82 (d, J=13.2Hz, 1H), 2.77 (s, NH, 1H), 2.55 (d, J=12.0Hz, 1H),
2.26-2.15 (m, 2H), 1.94 (s, 3H), 1.83-1.70 (m, 2H) .EI-MS are C17H21N2O3 +[the M+H calculated+]:301.2,
Measured value:301.1.
Claims (17)
- { [1- (3,5- bis--(trifluoromethyl) phenyl)-ethyoxyl]-the methyl } -8- phenyl -1,7- phenodiazines 1. one kind (5S, 8S) -8- The preparation method of the compound of formula I of miscellaneous-spiral shell [4,5] decyl- 2- ketone, which is characterized in that include the following steps:(a) Formula II compound is made to be reacted with formula III compound, production IV group with imine moiety;(b) 1. work as R1During for hydrogen, formula IV compound restores to obtain Formula V compound through go back original reagent;Alternatively, 2. work as R1When not being hydrogen, Formula IV compound after go back original reagent restores, then with R1Formula V compound is obtained by the reaction in-X;(c) in the presence of ring closing metathesis catalyst, by intramolecular olefin metathesis reaction, make Formula V compound that intramolecular occur Ring closure reaction, production VI compounds;(d) by reduction reaction, Formula IV compound is converted into Formula VII compound;(e) by deprotection reaction, it is removed the blocking group R in Formula VII compound, production VIII compounds;(f) in the presence of alkaline reagent, make Formula VIII compound and bis- (trifluoromethyl) benzene of S-1- (1- bromoethyls) -3,5- anti- Should, compound of formula I is made;Wherein, R is hydroxy-protective group, selected from C1-4Alkyl, benzyl, trityl, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, Benzyloxycarbonyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, Triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl;R1Selected from hydrogen, benzyl, the benzyl of substitution, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, benzyloxycarbonyl group, trifluoroacetyl group, benzene Formoxyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl;X is leaving group in step (b), selected from halogen, substituted or unsubstituted C1-4Acyloxy.
- 2. the preparation method of compound of formula I as described in claim 1, wherein R be selected from methyl, ethyl, isopropyl, tertiary butyl, Benzyl, trityl, acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tertiary fourth oxygen Base carbonyl, benzyloxycarbonyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, front three Base silicon substrate, triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9- fluorenes methoxy carbonyls Base;R1Selected from hydrogen, benzyl, the benzyl of substitution, acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, ethoxy carbonyl, isopropyl Epoxide carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifluoro Mesyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl;X is selected from bromine, chlorine, iodine, acetyl group oxygroup, trifluoroacetyl group oxygroup in step (b).
- 3. R in the preparation method of compound of formula I as described in claim 1, wherein step (b)1- X is selected from acetic anhydride, trifluoro second Acid anhydrides, benzyl bromide, benzyl chloride.
- 4. the preparation method of compound of formula I as claimed in claim 2, wherein R are selected from benzyl, pivaloyl group, benzoyl, right Chlorobenzene formacyl, tert-butyl diphenyl silicon substrate;R1Selected from hydrogen, benzyl, acetyl group, propiono, tert-butoxycarbonyl, pivaloyl group, benzyloxycarbonyl group, trifluoroacetyl group.
- 5. the preparation method of compound of formula I as claimed in claim 4, wherein R are selected from benzyl, pivaloyl group, to chlorobenzoyl Base, tert-butyl diphenyl silicon substrate;R1Selected from hydrogen, benzyl, trifluoroacetyl group.
- 6. the preparation method of compound of formula I as described in claim 1, which is characterized in that go back original reagent described in step (b) is selected One kind from sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride;Ring closing metathesis catalyst described in step (c) is selected from Grubbs catalyst, Hoveyda-Grubbs catalyst;The one kind of alkaline reagent described in step (f) in sodium tert-butoxide, potassium tert-butoxide, sodium hydride, hydrofining, calcium hydride.
- 7. the preparation method of compound of formula I as claimed in claim 6, ring closing metathesis catalyst described in step (c) is selected from Hoveyda-Grubbs catalyst.
- It is 8. a kind of such as the compound of following formula:Wherein, R is hydroxy-protective group, selected from C1-4Alkyl, benzyl, trityl, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, Benzyloxycarbonyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, Triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl;R1Selected from hydrogen, benzyl, the benzyl of substitution, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, benzyloxycarbonyl group, trifluoroacetyl group, benzene Formoxyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl.
- 9. compound as claimed in claim 8, wherein R be selected from methyl, ethyl, isopropyl, tertiary butyl, benzyl, trityl, Acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxy carbonyl Base, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, triethyl group Silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl;R1Selected from hydrogen, benzyl, the benzyl of substitution, acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, ethoxy carbonyl, isopropyl Epoxide carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group, trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifluoro Mesyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl.
- 10. compound as claimed in claim 9, wherein R be selected from benzyl, pivaloyl group, benzoyl, to chlorobenzene formacyl, Tert-butyl diphenyl silicon substrate;R1Selected from hydrogen, benzyl, acetyl group, propiono, tert-butoxycarbonyl, pivaloyl group, benzyloxycarbonyl group, trifluoroacetyl group.
- 11. compound as claimed in claim 10, wherein R are selected from benzyl, pivaloyl group, to chlorobenzene formacyl, tertiary butyl two Phenyl silicon substrate;R1Selected from hydrogen, benzyl, trifluoroacetyl group.
- 12. a kind of preparation method of Formula II compound, which is characterized in that its process route is as follows:Wherein, R is hydroxy-protective group, selected from C1-4Alkyl, benzyl, trityl, C1-5Alkyl-carbonyl, C1-4Alkoxy carbonyl, Benzyloxycarbonyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, trimethyl silicon substrate, Triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl.
- 13. the preparation method of Formula II compound as claimed in claim 12, wherein R is selected from methyl, ethyl, isopropyl, tertiary fourth Base, benzyl, trityl, acetyl group, propiono, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tertiary fourth Epoxide carbonyl, benzyloxycarbonyl group, benzoyl, to chlorobenzene formacyl, mesyl, trifyl, p-toluenesulfonyl, three Methylsilyl, triethyl group silicon substrate, triisopropylsilyl, tert-butyl diphenyl silicon substrate, t-Butyldimethylsilyl, 9- fluorenes methoxy carbonyls Base.
- 14. the preparation method of Formula II compound as claimed in claim 13, wherein R is selected from benzyl, pivaloyl group, benzoyl Base, to chlorobenzene formacyl, tert-butyl diphenyl silicon substrate.
- 15. the preparation method of Formula II compound as claimed in claim 14, wherein R is selected from benzyl, pivaloyl group, to chlorobenzene first Acyl group, tert-butyl diphenyl silicon substrate.
- 16. the preparation method of Formula II compound as claimed in claim 12, which is characterized in that include the following steps:(1) in the presence of alkaline reagent, Formula IX compound carries out hydroxyl protection, obtains the compound of Formula X;(2) in the presence of dehydrating agent, Formula X compound is made to be reacted with R- t-butyl sulfonamides, to form Formula XI group with imine moiety;(3) Formula XI compound is made to be reacted with vinylimidazolium chloride magnesium or vinyl magnesium bromide, to form Formula XII compound;(4) in the presence of acid reagent, Formula XII compound is made to remove terf-butylsulfinyl, Formula II compound is made.
- 17. the preparation method of Formula II compound as claimed in claim 16, which is characterized in that alkalinity examination described in step (1) The one kind of agent in organic bases triethylamine, imidazoles, pyridine or one kind in inorganic base potassium carbonate, sodium carbonate;Dehydrating agent described in step (2) is tetraisopropyl titanate;The one kind of acid reagent in hydrochloric acid, phosphoric acid, acetic acid described in step (4).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510378729.7A CN105017251B (en) | 2015-06-30 | 2015-06-30 | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510378729.7A CN105017251B (en) | 2015-06-30 | 2015-06-30 | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105017251A CN105017251A (en) | 2015-11-04 |
CN105017251B true CN105017251B (en) | 2018-06-29 |
Family
ID=54407599
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510378729.7A Active CN105017251B (en) | 2015-06-30 | 2015-06-30 | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105017251B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106866669A (en) * | 2017-04-19 | 2017-06-20 | 成都百特万合医药科技有限公司 | A kind of method for synthesizing the smooth intermediate of roller pyrrole |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20030762A1 (en) * | 2001-12-18 | 2003-09-05 | Schering Corp | HETEROCYCLIC COMPOUNDS AS NK1 ANTAGONISTS |
US7354922B2 (en) * | 2004-12-14 | 2008-04-08 | Schering Corporation | Bridged ring NK1 antagonists |
PL2004646T3 (en) * | 2006-04-05 | 2016-12-30 | Hydrochloride salt of 8-[{1-(3,5-bis-(trifluoromethyl) phenyl) -ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor | |
PE20080353A1 (en) * | 2006-04-05 | 2008-04-25 | Schering Corp | SALTS OF 8 - [{1- (3,5-BIS- (TRIFLUOROMETIL) PHENYL) -ETOXY} -METIL] -8-PHENYL-1,7-DIAZA-ESPIRO [4,5] DECAN-2-ONA AND PROCESS OF PREPARING THEM |
AR066191A1 (en) * | 2007-03-22 | 2009-08-05 | Schering Corp | PROCESS AND INTERMEDIARIES FOR THE SYNTHESIS OF COMPOUNDS 8- [(1- (3,5- BIS- (TRIFLUOROMETIL) PHENYL) - ETOXI) - METAL] - 8 PHENYL - 1,7- DIAZA - ESPIRO (4, 5) DECAN - 2 ONA |
EP2346823B1 (en) * | 2008-09-05 | 2015-08-19 | OPKO Health, Inc. | Intermediates for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds |
-
2015
- 2015-06-30 CN CN201510378729.7A patent/CN105017251B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN105017251A (en) | 2015-11-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107660206A (en) | For preparing the method and intermediate of { base of 1 (ethylsulfonyl) 3 [base of 4 (base of 7H pyrrolo-es [2,3 d] pyrimidine 4) 1H pyrazoles 1] azetidine 3 } acetonitrile | |
CN108947894A (en) | Novel biaryl structure chirality N- methylpyridoxal catalyst and its synthesis and application | |
CA2919317A1 (en) | Synthesis of biphenylalaninol via novel intermediates | |
CN117645636B (en) | Preparation method of adenine azide intermediate | |
CN107759577B (en) | GS5816 intermediate, preparation method and application | |
CN105017251B (en) | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist | |
CN106699604B (en) | One seed sand library is than bent and its intermediate preparation method | |
CN100532373C (en) | Fully-synthesizing method for (2R,3S)-epoxy-9-(aprylene-1-OL | |
CN109761884B (en) | Preparation method and application of chiral amine B | |
CN108424389A (en) | A kind of preparation method of Ivabradine impurity | |
CN106117204B (en) | The preparation method of the carboxylic acid of Lei Dipawei intermediates (1R, 3S, 4S) 2 Boc 2 azabicyclo [2.2.1] pentane 3 | |
CN106632275B (en) | The preparation method of Lei Dipawei a kind of and the intermediate for preparing Lei Dipawei | |
CN106977543A (en) | The preparation technology of improved Suo Feibuwei intermediates | |
CN107674016B (en) | Preparation method of telaprevir intermediate and intermediate thereof | |
CN105418477B (en) | The method for reducing diastereoisomer impurity content in Lei Dipawei intermediate | |
CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
CN109280055A (en) | The method of asymmetric synthesis of ergot alkaloid | |
CN109265385B (en) | Synthesis process of chiral catalyst | |
CN113754686A (en) | Synthesis method of biotin labeled matrine probe | |
WO2021100730A1 (en) | Method for producing pyrrolidine compound | |
CN108329332A (en) | A method of preparing Glecaprevir | |
CN110092802B (en) | Method for preparing trepetidine intermediate | |
CN110128363B (en) | Cyclosporine derivatives and process for preparing same | |
CN112939848B (en) | Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof | |
CN111072543B (en) | Preparation method and application of (3R,4S) -4-ethylpyrrolidine-3-carboxylic acid compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20201027 Address after: 570314 -A, Nanhai Avenue, national hi tech Development Zone, Hainan, Haikou, 273 Patentee after: QILU PHARMACEUTICAL (HAINAN) Co.,Ltd. Patentee after: Qilu Pharmaceutical Co.,Ltd. Address before: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 317 250100 Patentee before: Qilu Pharmaceutical Co.,Ltd. |