CN105017251A - Preparation method of NK-1 receptor antagonist and intermediate thereof - Google Patents
Preparation method of NK-1 receptor antagonist and intermediate thereof Download PDFInfo
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- CN105017251A CN105017251A CN201510378729.7A CN201510378729A CN105017251A CN 105017251 A CN105017251 A CN 105017251A CN 201510378729 A CN201510378729 A CN 201510378729A CN 105017251 A CN105017251 A CN 105017251A
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- compound
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- benzyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 71
- 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 abstract description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 claims abstract description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 129
- -1 carbobenzoxy-(Cbz) Chemical class 0.000 claims description 102
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 68
- 239000002585 base Substances 0.000 claims description 67
- 239000004305 biphenyl Substances 0.000 claims description 63
- 235000010290 biphenyl Nutrition 0.000 claims description 63
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 63
- 239000000377 silicon dioxide Substances 0.000 claims description 61
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 60
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 49
- 239000001301 oxygen Substances 0.000 claims description 49
- 229910052760 oxygen Inorganic materials 0.000 claims description 49
- 239000003153 chemical reaction reagent Substances 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 28
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 22
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 238000006722 reduction reaction Methods 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 14
- 230000000903 blocking effect Effects 0.000 claims description 14
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 14
- 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 14
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 14
- 238000010511 deprotection reaction Methods 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
- 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 10
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 10
- 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
- 150000002466 imines Chemical group 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 125000006278 bromobenzyl group Chemical group 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
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 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
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical group CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- 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 4
- 150000001336 alkenes Chemical class 0.000 claims description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 4
- 229940073608 benzyl chloride Drugs 0.000 claims description 4
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 4
- 238000005649 metathesis reaction Methods 0.000 claims description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 4
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000105 potassium hydride Inorganic materials 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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 230000031709 bromination Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 235000010755 mineral Nutrition 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- UXTFKIJKRJJXNV-UHFFFAOYSA-N 1-$l^{1}-oxidanylethanone Chemical compound CC([O])=O UXTFKIJKRJJXNV-UHFFFAOYSA-N 0.000 claims description 2
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical group CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 32
- 238000007086 side reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- 239000012074 organic phase Substances 0.000 description 51
- 238000003756 stirring Methods 0.000 description 40
- 239000000243 solution Substances 0.000 description 35
- 238000001035 drying Methods 0.000 description 34
- 150000002576 ketones Chemical class 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 238000005406 washing Methods 0.000 description 31
- 239000000203 mixture Substances 0.000 description 29
- 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- 230000008030 elimination Effects 0.000 description 23
- 238000003379 elimination reaction Methods 0.000 description 23
- 239000003960 organic solvent Substances 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 17
- 239000008346 aqueous phase Substances 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 125000003368 amide group Chemical group 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000008213 purified water 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
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 238000003809 water extraction Methods 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
- 238000002386 leaching Methods 0.000 description 6
- 239000000126 substance Substances 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
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000002024 ethyl acetate extract Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound 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
- 239000002253 acid Substances 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 229940125810 compound 20 Drugs 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
- 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
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-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
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- VXIKDBJPBRMXBP-UHFFFAOYSA-N 3H-pyrrole Chemical class C1C=CN=C1 VXIKDBJPBRMXBP-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- LOESDOAIWSCMKM-UHFFFAOYSA-N NC(CCCO)=O Chemical compound NC(CCCO)=O LOESDOAIWSCMKM-UHFFFAOYSA-N 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 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
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- 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
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- 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
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- 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
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- 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
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Abstract
The invention relates to a preparation method of an NK-1 receptor antagonist and an intermediate thereof. The invention provides a preparation method of (5S, 8s)-8-{[1-(3, 5-bis-(trifluoromethyl)phenyl)-ethoxy]methyl}-8-phenyl-1, 7-diaza-spiro[4, 5]dec-2-one (formula I compound), which is prepared from a formula II compound, and also provides the formula II compound and a preparation method thereof. The method provided by the invention has the advantages of simple operation, mild reaction condition, high safety factor, little side reaction, high yield and high purity, lowers the production cost and operation risk, and is very suitable for large-scale industrial production. (formula II as shown in the specification).
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of nk 1 receptor antagonist (5S, 8S)-8-[{ (1R)-1-[3,5-pair-(trifluoromethyl) phenyl] oxyethyl group }-methyl]-8-phenyl-1, the preparation method of 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone, also relates to key intermediate in the method and preparation method thereof.
Background technology
CN1606545A discloses a kind of chemistry (5S by name, 8S)-8-[{ (1R)-1-[3,5-pair-(trifluoromethyl) phenyl] oxyethyl group }-methyl]-8-phenyl-1, the compound of 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone, its structural formula is as shown in the formula shown in I, be neurokinine-1 (NK-1) receptor antagonist, can be used for the various diseases such as treatment vomiting, melancholia, anxiety and cough.
At present, the preparation method about formula I mainly contains following three kinds:
CN1606545A discloses a kind of preparation method of formula I, route 1 specific as follows, this preparation method is using commercially available starting material phenylglycine as raw starting material, have passed through 17 process steps just obtained formula I, and a lot of steps in the method need isolated or purified before for next operation steps, technique final step also needs to be separated by chirality preparative chromatography, seriously constrains industrial scale.Visible, the method operation steps is long, and separating step is many, and process overall yields is lower, and adopt this route to carry out the difficulty of industrial amplification production comparatively greatly, production cost is higher.
CN101679257A discloses the preparation method of another kind of formula I, route 2 specific as follows, this preparation method adopts compound 7 in above-mentioned route 1 as raw starting material, through the obtained formula I of 5 step reaction, compared with route 1, this route operation steps is shorter, and the chiral compound 20 of the method adopting into salt-pepper noise splits, and technique is more succinct.But because this route is in the process preparing compound 20, generation be isomer mixture, need to remove isomer wherein by splitting, process recovery ratio significantly reduced.
CN102203062A discloses the preparation method of another kind of formula I, route 3 specific as follows, and this preparation method adopts compound 3 in above-mentioned route 1 as raw starting material, through the obtained formula I of 7 steps reaction.In route 3, the preparation of compound 3 is by the preparation method of the respective compound in above-mentioned route 1, and this preparation method has related to the non-natural S-2-phenylglycocoll of use, needs to be produced by the method for chemical resolution method or asymmetric chemistry synthesis.Utilize the compound 3 in this compound syntheti c route 3 to need very low temperature (– 78 DEG C) under carry out, need a large amount of energy consumptions, need the equipment of special substance simultaneously, the operation easier of very low temperature reaction is comparatively large, and danger is larger.Need in route 3 to adopt the acid (as Hydrogen bromide, hydrofluoric acid etc.) of severe corrosive to remove Cbz protecting group, produce a large amount of acid waste water and waste liquid, be unfavorable for environment protection.In addition, in route 3, compound 27 obtains formula I, in this reaction through the method for catalytic hydrogenation, the side reaction of two (trifluoromethyl) benzyl of 1-(1-methyl)-3,5-can be removed, make to introduce impurity in product, and make process recovery ratio reduce, cost improves.Meanwhile, namely this route introduces two (trifluoromethyl) benzyl of R-1-(1-methyl)-3,5-in the route initial stage, and process costs can raise.
Summary of the invention
For the defect that prior art exists, the present invention aims to provide a kind of simple, efficient, low cost, is applicable to the preparation (5S of suitability for industrialized production, 8S)-8-{ [1-(3,5-pair-(trifluoromethyl) phenyl)-oxyethyl group]-methyl }-8-phenyl-1, the method of 7-diaza-spiro [4,5]-2-ketone in the last of the ten Heavenly stems (formula I).
Contriver is through a large amount of experimental studies, and the wonderful new preparation method finding a kind of formula I, it is prepared by formula II compound, provides the preparation method of formula II compound simultaneously.The present invention is based on this find and complete, the method is easy and simple to handle, reaction conditions is gentle, safety coefficient is high, side reaction is few, yield is high, purity is high, reduces cost and operational risk, is highly suitable for large-scale industrialization and produces.
First aspect present invention provides one (5S, 8S)-8-{ [1-(3,5-pair-(trifluoromethyl) phenyl)-oxyethyl group]-methyl }-8-phenyl-1,7-diaza-spiro [4,5] preparation method in-2-ketone in the last of the ten Heavenly stems (formula I), comprises the following steps:
E (), by deprotection reaction, makes the blocking group R in formula VII compound be removed, production VIII compound;
F (), under alkaline reagents exists, makes formula VIII compound and two (trifluoromethyl) benzene of S-1-(1-bromotrifluoromethane)-3,5-react, obtained formula I;
Wherein, R is hydroxy-protective group, is selected from C
1-4alkyl, benzyl, trityl, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), preferable methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl, trityl, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl is silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), more preferably benzyl, pivaloyl group, benzoyl, silica-based to chlorobenzene formacyl, tert-butyl diphenyl, most preferably benzyl, pivaloyl group, silica-based to chlorobenzene formacyl, tert-butyl diphenyl,
R
1be selected from hydrogen, benzyl, the benzyl of replacement, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); The benzyl of preferred hydrogen, benzyl, replacement, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, ethoxy carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl (Boc), carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); More preferably hydrogen, benzyl, ethanoyl, propionyl, tert-butoxycarbonyl, pivaloyl group, carbobenzoxy-(Cbz), trifluoroacetyl group; Most preferably hydrogen, benzyl, trifluoroacetyl group.
Concrete, (e), by deprotection reaction, makes the blocking group R in formula VII compound be removed, production VIII compound;
Wherein, when the R of blocking group described in step (e) be selected from benzyl, replacement benzyl, carbobenzoxy-(Cbz) time, preferably adopt the method deprotection carrying out hydro-reduction using palladium charcoal, platinum charcoal etc. as catalyzer to obtain formula VIII compound; When described blocking group R is selected from C
1-5-alkyl-carbonyl (as ethanoyl, pivaloyl group), C
1-4-alkoxy carbonyl, trifluoroacetyl group, benzoyl, during to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, the method deprotection of alkaline hydrolysis (as NaOH or KOH solution hydrolysis) is preferably adopted to obtain formula VIII compound; When described blocking group R be selected from trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl time, preferably adopt catalysis deprotection under the reagent such as tetrabutyl ammonium fluoride exist to obtain formula VIII compound;
F () to exist and under room temperature condition at alkaline reagents, formula VIII compound and S-1-(1-bromotrifluoromethane)-3,5-pairs of (trifluoromethyl) benzene are reacted in organic reagent again, obtains formula I;
Wherein, alkaline reagents described in step (f) is selected from one or more in sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, potassium hydride KH, hydrolith; Described organic solvent be selected from tetrahydrofuran (THF), DMF, N, N-diethylformamide, N-Methyl pyrrolidone one or more; Described room temperature has implication well known in the art, has and refers to 15 ~ 35 DEG C, preferably 20 ~ 30 DEG C, more preferably 20 ~ 25 DEG C.
The preparation method of a kind of formula I that first aspect present invention provides, further comprising the steps:
C (), under ring closing metathesis catalyzer exists, makes formula V compound generation Intra-molecular condensation, production VI compound;
D formula VI converting compounds, by reduction reaction, is formula VII compound by ();
Wherein, R, R
1there is aforementioned identical implication.
Particularly, (c), under ring closing metathesis catalyzer exists, in the organic solvent being selected from toluene, methylene dichloride and at 50 ~ 70 DEG C, makes formula V compound generation Intra-molecular condensation, production VI compound;
Wherein, the catalyzer of ring closing metathesis described in step (c) is selected from Grubbs catalyzer, Hoveyda-Grubbs catalyzer, preferred Hoveyda-Grubbs catalyzer; Described temperature range preferably 50 ~ 60 DEG C, 60 ~ 70 DEG C or 65 ~ 70 DEG C;
D (), under the catalyzer such as palladium charcoal, platinum charcoal exist, in the organic solvent being selected from methyl alcohol, ethanol, toluene, dimethylbenzene, being reacted by hydro-reduction, is formula VII compound by formula VI converting compounds;
Wherein, when the blocking group R in the compound of formula VI described in step (d) be selected from benzyl, replacement benzyl, carbobenzoxy-(Cbz) time, step (d) directly can obtain formula VIII compound.
The preparation method of a kind of formula I that first aspect present invention provides, also further comprising the steps:
A () makes formula II compound and formula III compound react, production IV group with imine moiety;
B () 1. works as R
1during for hydrogen, formula IV compound obtains formula V compound through going back original reagent reduction; Or, 2. work as R
1when not being hydrogen, formula IV compound through go back original reagent reduction after, then with R
1-X is obtained by reacting formula V compound;
Wherein, R, R
1there is aforementioned identical implication; X is leavings group, preferred hydrogen, halogen, substituted or unsubstituted C
1-4acyloxy, more preferably bromine, chlorine, iodine, ethanoyl oxygen base, trifluoroacetyl group oxygen base; In the preferred technical solution of the present invention, R
1-X is selected from diacetyl oxide, trifluoroacetic anhydride, bromotoluene (i.e. bromobenzyl), benzyl chloride.
Particularly, (a) is being selected under toluene, the organic solvent of dimethylbenzene and reflux conditions, and formula II compound and formula III compound react, production IV group with imine moiety;
B () 1. works as R
1during for hydrogen, at organic solvent and – 10 ~ 20 DEG C, formula IV compound obtains formula V compound through going back original reagent reduction; Or, 2. work as R
1for for hydrogen time, at organic solvent and – 10 ~ 20 DEG C, formula IV compound through go back original reagent reduction after, then with R
1-X is obtained by reacting formula V compound;
Wherein, go back original reagent described in step (b) and be selected from one in sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride; Described organic solvent is selected from one or more in toluene, ethanol, methyl alcohol, acetonitrile, methylene dichloride, ethyl acetate, isopropyl acetate; Described temperature range preferably-5 ~ 10 DEG C, more preferably 0 ~ 10 DEG C.
The preparation method of a kind of formula I that first aspect present invention provides, its operational path is as follows:
Wherein, R, R
1there is aforementioned identical implication.
In the preferred technical solution of the present invention, the preparation method of a kind of formula I that first aspect present invention provides, comprises the following steps:
A () makes formula II compound and formula III compound react, production IV group with imine moiety;
B () 1. works as R
1during for hydrogen, formula IV compound obtains formula V compound through going back original reagent reduction; Or, 2. work as R
1when not being hydrogen, formula IV compound through go back original reagent reduction after, then with R
1-X is obtained by reacting formula V compound;
C (), under ring closing metathesis catalyzer exists, by molecule internal olefin replacement(metathesis)reaction, makes formula V compound generation Intra-molecular condensation, production VI compound;
D formula VI converting compounds, by reduction reaction, is formula VII compound by ();
E (), by deprotection reaction, makes the blocking group R in formula VII compound be removed, production VIII compound;
F (), under alkaline reagents exists, makes formula VIII compound and two (trifluoromethyl) benzene of S-1-(1-bromotrifluoromethane)-3,5-react, obtained formula I;
Wherein, go back original reagent described in step (b) and be selected from one in sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride;
The catalyzer of ring closing metathesis described in step (c) is selected from Grubbs catalyzer, Hoveyda-Grubbs catalyzer, preferred Hoveyda-Grubbs catalyzer;
Alkaline reagents described in step (f) is selected from sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, potassium hydride KH, one or more in hydrolith.
Concrete, the preparation method of a kind of formula I that first aspect present invention provides, comprises the following steps:
A () is being selected under toluene, the organic solvent of dimethylbenzene and reflux conditions, formula II compound and formula III compound react, production IV group with imine moiety;
B () 1. works as R
1during for hydrogen, at organic solvent and – 10 ~ 20 DEG C, formula IV compound obtains formula V compound through going back original reagent reduction; Or, 2. work as R
1for for hydrogen time, at organic solvent and – 10 ~ 20 DEG C, formula IV compound through go back original reagent reduction after, then with R
1-X is obtained by reacting formula V compound;
Wherein, go back original reagent described in step (b) and be selected from one in sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride; Described organic solvent is selected from one or more in toluene, ethanol, methyl alcohol, acetonitrile, methylene dichloride, ethyl acetate, isopropyl acetate; Described temperature range preferably-5 ~ 10 DEG C, more preferably 0 ~ 10 DEG C;
C () is under ring closing metathesis catalyzer exists, in the organic solvent being selected from toluene, methylene dichloride and at 50 ~ 70 DEG C, by molecule internal olefin replacement(metathesis)reaction (olefin metathesis), make formula V compound generation Intra-molecular condensation, production VI compound;
Wherein, the catalyzer of ring closing metathesis described in step (c) is selected from Grubbs catalyzer, Hoveyda-Grubbs catalyzer, preferred Hoveyda-Grubbs catalyzer; Described temperature range preferably 50 ~ 60 DEG C, 60 ~ 70 DEG C or 65 ~ 70 DEG C;
D (), under the catalyzer such as palladium charcoal, platinum charcoal exist, in the organic solvent of methyl alcohol, ethanol, toluene, dimethylbenzene, being reacted by hydro-reduction, is formula VII compound by formula VI converting compounds;
Wherein, the blocking group R in the compound of formula VI described in step (d) is selected from benzyl, the benzyl of replacement, or during carbobenzoxy-(Cbz), step (d) directly can obtain formula VIII compound;
E (), by deprotection reaction, makes the blocking group R in formula VII compound be removed, production VIII compound;
Wherein, when the R of blocking group described in step (e) be selected from benzyl, replacement benzyl, carbobenzoxy-(Cbz) time, preferably adopt the method deprotection carrying out hydro-reduction using palladium charcoal, platinum charcoal etc. as catalyzer to obtain formula VIII compound; When described blocking group R is selected from C
1-5-alkyl-carbonyl (as ethanoyl, pivaloyl group), C
1-4-alkoxy carbonyl, trifluoroacetyl group, benzoyl, during to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, the method deprotection of alkaline hydrolysis (as NaOH or KOH solution hydrolysis) is preferably adopted to obtain formula VIII compound; When described blocking group R be selected from trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl time, preferably adopt catalysis deprotection under the reagent such as tetrabutyl ammonium fluoride exist to obtain formula VIII compound;
F (), under alkaline reagents exists, under organic solvent and room temperature condition, makes formula VIII compound and two (trifluoromethyl) benzene of S-1-(1-bromotrifluoromethane)-3,5-react, obtained formula I;
Wherein, alkaline reagents described in step (f) is selected from the one in sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, potassium hydride KH, hydrolith; Or it is multiple; Described organic solvent be selected from tetrahydrofuran (THF), DMF, N, N-diethylformamide, N-Methyl pyrrolidone one or more; Described room temperature has implication well known in the art, has and refers to 15 ~ 35 DEG C, preferably 20 ~ 30 DEG C, more preferably 20 ~ 25 DEG C.
Second aspect present invention provide as shown in the formula compound:
Wherein, R is hydroxy-protective group, is selected from C
1-4alkyl, benzyl, trityl, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), preferable methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl, trityl, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl is silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), more preferably benzyl, pivaloyl group, benzoyl, silica-based to chlorobenzene formacyl, tert-butyl diphenyl, most preferably benzyl, pivaloyl group, silica-based to chlorobenzene formacyl, tert-butyl diphenyl,
R
1be selected from hydrogen, benzyl, the benzyl of replacement, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); The benzyl of preferred hydrogen, benzyl, replacement, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, ethoxy carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl (Boc), carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); More preferably hydrogen, benzyl, ethanoyl, propionyl, tert-butoxycarbonyl, pivaloyl group, carbobenzoxy-(Cbz), trifluoroacetyl group; Most preferably hydrogen, benzyl, trifluoroacetyl group.
Third aspect present invention provides a kind of preparation method of formula II compound, and its operational path is as follows:
Wherein, R is hydroxy-protective group, is selected from C
1-4alkyl, benzyl, trityl, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), preferable methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl, trityl, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl is silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), more preferably benzyl, pivaloyl group, benzoyl, silica-based to chlorobenzene formacyl, tert-butyl diphenyl, most preferably benzyl, pivaloyl group, silica-based to chlorobenzene formacyl, tert-butyl diphenyl,
Third aspect present invention provides a kind of preparation method of formula II compound, comprises the following steps:
(1) under alkaline reagents exists, formula IX compound carries out hydroxyl protection, obtains the compound of formula X;
(2) under dehydrating agent exists, formula X compound and R-t-butyl sulfonamide are reacted, to form formula XI group with imine moiety;
(3) formula XI compound and vinylimidazolium chloride magnesium or vinyl bromination reactive magnesium is made, to form formula XII compound;
(4) under acid reagent exists, formula XII compound is made to remove terf-butylsulfinyl, obtained formula II compound;
Wherein, described in step (1), alkaline reagents is selected from organic bases, such as, one in triethylamine, imidazoles, pyridine, or is selected from mineral alkali, such as, one in salt of wormwood, sodium carbonate;
Described in step (2), dehydrating agent is titanium isopropylate;
Described in step (4), acid reagent is selected from the one in hydrochloric acid, phosphoric acid, acetic acid;
Concrete, the preparation method of a kind of formula II compound that third aspect present invention provides, comprises the following steps:
(1) alkaline reagents exist under, in organic solvent, formula IX compound be selected from benzyl chloride, bromobenzyl, the benzyl chloride of replacement, the bromobenzyl of replacement, C
1-4-alkyl acyl chloride, C
1-4-alkoxyl group acyl chlorides, benzyloxy acyl chlorides, trifluoroacetyl chloride, Benzoyl chloride, parachlorobenzoyl chloride, methylsulfonyl chloride, trifluoromethanesulfchloride chloride, Tosyl chloride, trimethylchlorosilane, chlorotriethyl silane, tri isopropyl chlorosilane, tert-butyl diphenyl chlorosilane, the one in TERT-BUTYL DIMETHYL CHLORO SILANE is reacted, hydroxyl in protection IX compound molecule, forms the compound of formula X;
Wherein, described in step (1), alkaline reagents is selected from organic bases, such as, one in triethylamine, imidazoles, pyridine, or is selected from mineral alkali, such as, one in salt of wormwood, sodium carbonate; Described organic solvent is selected from the one in trichloromethane, methylene dichloride, DMF, tetrahydrofuran (THF);
(2) under dehydrating agent exists, at organic solvent and 60 ~ 90 DEG C, formula X compound and R-t-butyl sulfonamide are reacted, forms formula XI group with imine moiety;
Wherein, described in step (2), dehydrating agent is titanium isopropylate; Described organic solvent is selected from one or more in normal heptane, tetrahydrofuran (THF), methyltetrahydrofuran, toluene; Described temperature range preferably 70 ~ 80 DEG C;
(3) be selected from tetrahydrofuran (THF), the organic solvent of methylene dichloride and – 30 ~ 0 DEG C, making formula XI compound and vinylimidazolium chloride magnesium or vinyl bromination reactive magnesium, form formula XII compound;
Wherein, temperature range described in step (3) preferably-20 ~-15 DEG C;
(4) under acid reagent exists, being selected under methyl alcohol, the organic solvent of ethanol and room temperature condition, formula XII compound is made to remove terf-butylsulfinyl, obtained formula II compound;
Wherein, described in step (4), acid reagent is selected from the one in hydrochloric acid, phosphoric acid, acetic acid; Described room temperature has implication well known in the art, has and refers to 15 ~ 35 DEG C, preferably 20 ~ 30 DEG C, more preferably 20 ~ 25 DEG C.
The invention provides synthesis (5S, 8S)-8-[{ (1R)-1-[3,5-pair-(trifluoromethyl) phenyl] oxyethyl group }-methyl]-8-phenyl-1, the method of 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (formula I), the method and the Measures compare of the various synthetic compound of formula i reported before, have following advantage:
1, this route adopts the method for chiral synthesize to obtain formula I, and in preparation process, each step operation is simple, and do not need very low temperature to react, temperature of reaction is not less than-25 DEG C, and without the need to specific installation, easy to operate, security is high; And mild condition during technique final step introducing R-1-(1-methyl)-3,5-two (trifluoromethyl) benzyl, avoid the use of the acidic substance of severe corrosive, the safer environmental protection of technique, is more suitable for suitability for industrialized production;
2, this circuit first passes through catalytic hydrogenation preparation formula VII compound by formula VI compound, R-1-(1-methyl)-3 is introduced again in technique final step, two (trifluoromethyl) benzyl of 5-, remove the side reaction of two (trifluoromethyl) benzyls of 1-(1-methyl)-3,5-in the route 3 reported before avoiding during final step catalytic hydrogenation and introduce impurity;
3, this route respectively walks good reaction selectivity, and transformation efficiency is high, and process recovery ratio is high, gained intermediate and product purity high, reduce the purifying difficulty of each intermediate and product, be conducive to suitability for industrialized production;
4, compared with the route 3 reported before, this route in the end step just introduces two (trifluoromethyl) benzyl of the higher R-1-of price (1-methyl)-3,5-, and material cost is effectively reduced.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment.All technology realized based on foregoing of the present invention all belong to scope of the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.It will be apparent to those skilled in the art that hereinafter, if not specified, the operation that the present invention carries out carries out under the room temperature condition of this area routine.
It is pointed out that as do not made specified otherwise, the consumption of described reaction solvent and related reagent is the conventional amount used of reaction, and those skilled in the art can determine according to prior art, the reagent that the present invention uses is conventional reagent, can be bought by market and obtain, starting raw material used and reactant all can be prepared by prior art or disclosed existing document, compound 2-hydroxy acetophenone can be bought from Lianyun Harbour Qun Sheng Chemical Co., Ltd. and obtain, titanium isopropylate can be bought from Shanghai Bang Cheng Chemical Co., Ltd. and obtain, 3-(1, 1-dimethyl ethyl) dihydro-1, 5-dioxy-(3R, 7 α R)-1H, 3H-pyrroles [1, 2-C] oxazole-7 α (5H)-formaldehyde can coordinate from Wujiang pharmaceutcal corporation, Ltd buy obtain, vinyl magnesium bromide can be won the purchase of auspicious chemical Science and Technology Ltd. and be obtained from Shanghai, R-(+)-t-butyl sulfonamide can be bought from Shanghai Gao Lang Chemical Industry Science Co., Ltd and obtain, Hoveya-Grubbs 2
ndcatalyst can buy from Shanghai Ke Qin Chemical Industry Science Co., Ltd and obtain.
The preparation of embodiment 1 following formula (S)-1-(tert-butyl diphenyl siloxy)-2-phenyl fourth-3-alkene-2-amine
Take 2-hydroxy acetophenone (200.0g, 1.47mol), add 2000ml methylene dichloride and tert-butyl diphenyl chlorosilane (445.3g successively, 1.62mol), the temperature of mixture is made to be down to 0-10 DEG C under stirring, drip triethylamine (180.0g, 1.78mol), dropwise, at room temperature react and transform completely to 2-hydroxy acetophenone, add water extraction, separatory obtains organic phase, add anhydrous sodium sulfate drying, drying terminates rear elimination siccative, and filtrate reduced in volume obtains oily matter.
5500ml toluene is added in the oily matter obtained, titanium isopropylate (829.7g is added successively under stirring, 2.94mol) with (R)-(+)-t-butyl sulfonamide (213.3g, 1.76mol), react at mixture being warming up to 70-80 DEG C.After reaction terminates, be down to room temperature, in mixture, add 3000ml saturated aqueous common salt, stir, extraction, separates organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, after drying terminates, elimination siccative, concentrating filter liquor, obtained (R, Z)-N-[2-(tert-butyl diphenyl siloxy)-1-phenyl-ethylene]-2-methylpropane-2-sulphonamide 640.6g, yield: 91.2%.
Take (R, Z)-N-[2-(tert-butyl diphenyl siloxy)-1-phenyl-ethylene]-2-methylpropane-2-sulphonamide (500.0g, 1.05mol), add 5000ml methylene dichloride, under nitrogen protection, system is chilled to-20 ~-15 DEG C, vinyl magnesium bromide (1mol/L in THF is slowly added dropwise in system, 1250ml), after reaction terminates, add the hydrochloric acid 500ml cancellation reaction of 0.5M, layering, organic phase anhydrous sodium sulfate drying, drying terminates rear elimination siccative, concentrating filter liquor, obtained (R)-N-[(S)-1-(tert-butyl diphenyl siloxy)-2-phenyl fourth-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine 511.6g, yield: 92.5%.
1H NMR(CDCl
3，600MHz)δ7.59(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).
Take (R)-N-[(S)-1-(tert-butyl diphenyl siloxy)-2-phenyl fourth-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine (380.0g, 0.75mol), add 2000ml methyl alcohol, 2mol/L hydrochloric acid 1500ml, stir lower reaction, after reaction terminates, the pH regulating mixture with saturated sodium bicarbonate solution is 7-8, add 3000ml dichloromethane extraction, separatory, aqueous phase dichloromethane solution extracts, merge organic phase, use saturated common salt water washing, separate organic phase, with anhydrous sodium sulfate drying, dry complete, elimination siccative, filtrate reduced in volume obtains (S)-1-(tert-butyl diphenyl siloxy)-2-phenyl fourth-3-alkene-2-amine 295.5g, yield 98.1%.Detect through high performance liquid chromatography (HPLC), purity: 99.46%.
1h NMR (CDCl
3, 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 is C
26h
32nOSi
+[the M+H calculated
+]: 401.2, measured value: 401.1.
The preparation of embodiment 2 following formula (S)-1-benzyloxy-2-phenyl-Ding-3-alkene-2-amine
Take 2-hydroxy acetophenone (150.0g, 1.10mol), add 1500ml tetrahydrofuran (THF), stir borehole cooling to 0-5 DEG C, with bromobenzyl (226.0g, 1.32mol), the temperature of mixture is made to be down to 0-10 DEG C under stirring, add sodium tert-butoxide (126.9g, 1.32mol), dropwise, react complete to the conversion of 2-hydroxy acetophenone, add 200ml water, concentrating under reduced pressure removing tetrahydrofuran (THF), add 1000ml dichloromethane extraction, separatory obtains organic phase, add anhydrous sodium sulfate drying, drying terminates rear elimination siccative, filtrate reduced in volume obtains oily matter.
2000ml toluene is added in the oily matter obtained, titanium isopropylate (622.3g is added successively under stirring, 2.21mol) with (R)-(+)-t-butyl sulfonamide (200.4g, 1.65mol), react at mixture being warming up to 70-80 DEG C.After reaction terminates, be down to room temperature, in mixture, add 3000ml saturated aqueous common salt, stir, extraction, separates organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, after drying terminates, elimination siccative, concentrating filter liquor, obtained (R, Z)-N-(2-benzyloxy-1-phenyl-ethylene)-2-methylpropane-2-sulphonamide 269.6g, yield: 81.6%.
Take (R, Z)-N-(2-benzyloxy-1-phenyl-ethylene)-2-methylpropane-2-sulphonamide (262.5.0g, 0.80mol), add 3000ml methylene dichloride, under nitrogen protection, system is cooled to-20 ~-15 DEG C, vinylimidazolium chloride magnesium (1mol/L in THF is slowly added dropwise in system, 960ml), after reaction terminates, add the hydrochloric acid 400ml cancellation reaction of 0.5M, layering, organic phase anhydrous sodium sulfate drying, drying terminates rear elimination siccative, concentrating filter liquor, obtained (R)-N-[(S)-1-benzyloxy)-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine 256.2g, yield: 89.6%.
1H NMR(CDCl
3，600MHz)δ7.33-7.28(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).
Take (R)-N-[(S)-1-benzyloxy)-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine (210.0g, 0.59mol), add 2000ml methyl alcohol, 2mol/L hydrochloric acid 1500ml, stir lower reaction, after reaction terminates, the pH regulating mixture with saturated sodium bicarbonate solution is 7-8, add 3000ml dichloromethane extraction, separatory, aqueous phase dichloromethane solution extracts, merge organic phase, use saturated common salt water washing, separate organic phase, with anhydrous sodium sulfate drying, dry complete, elimination siccative, filtrate reduced in volume obtains (S)-1-benzyloxy-2-phenyl-Ding-3 alkene-2-amine 143.6g, yield 96.2%.Detect through high performance liquid chromatography (HPLC), purity is 99.23%.
1h NMR (CDCl
3, 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 is C
26h
32nOSi
+[the M+H calculated
+]: 254.3, measured value: 254.2.
The preparation of embodiment 3 following formula (S)-1-(4-chlorobenzene formacyl) oxygen base-2-phenyl-Ding-3-alkene-2-amine
Take according to obtained (R)-N-[(S)-1-(tert-butyl diphenyl siloxy)-2-phenyl-Ding-3-alkene-2-the base]-2-methyl-propyl-2-sulfinyl amine (10.1g of the method for embodiment 1, 0.02mol), add 100ml tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (10.5g, 0.04mol), stirring reaction, after reaction terminates, add water extraction, separate organic phase, anhydrous sodium sulfate drying, drying terminates rear elimination siccative, filtrate is cooled to 0-5 DEG C, add triethylamine (4.0g, 0.04mol), instillation parachlorobenzoyl chloride (4.2g, 0.024mol), after reacting completely, add purified water extraction, separatory, organic phase is after anhydrous sodium sulfate drying, elimination siccative, filtrate reduced in volume, obtained (R)-N-[(S)-1-(4-chlorobenzene formacyl oxygen base)-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine 6.33g, yield 77.8%.
Take (R)-N-[(S)-1-(4-chlorobenzene formacyl oxygen base)-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine (6.0g, 0.015mol), add 50ml methyl alcohol, 2mol/L hydrochloric acid 10ml, stir lower reaction, after reaction terminates, the pH regulating mixture with saturated sodium bicarbonate solution is 7-8, add 100ml dichloromethane extraction, separatory, aqueous phase dichloromethane solution extracts, merge organic phase, use saturated common salt water washing, separate organic phase, with anhydrous sodium sulfate drying, dry complete, elimination siccative, filtrate reduced in volume obtains (S)-1-(4-chlorobenzene formacyl) oxygen base-2-phenyl-Ding-3-alkene-2-amine 4.0g, yield 91.4%.Detect through high performance liquid chromatography (HPLC), purity is 99.17%.
1h NMR (CDCl
3, 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 C
26h
32nOSi
+[the M+H calculated
+]: 302.7, measured value: 302.5.
The preparation of embodiment 4 following formula (S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-amine
Take according to obtained (R)-N-[(S)-1-(tert-butyl diphenyl siloxy)-2-phenyl-Ding-3-alkene-2-the base]-2-methyl-propyl-2-sulfinyl amine (10.1g of the method for embodiment 1, 0.02mol), add 100ml tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (10.5g, 0.04mol), stirring reaction, after reaction terminates, add water extraction, separate organic phase, anhydrous sodium sulfate drying, drying terminates rear elimination siccative, filtrate is cooled to 0-5 DEG C, add triethylamine (4.0g, 0.04mol), instillation pivaloyl chloride (2.9g, 0.024mol), after reacting completely, add purified water extraction, separatory, organic phase is after anhydrous sodium sulfate drying, elimination siccative, filtrate reduced in volume, obtained (R)-N-[(S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine 6.45g, yield 91.8%.
Take (R)-N-[(S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine (6.0g, 0.017mol), add 60ml methyl alcohol, 2mol/L hydrochloric acid 20ml, stir lower reaction, after reaction terminates, the pH regulating mixture with saturated sodium bicarbonate solution is 7-8, add 100ml dichloromethane extraction, separatory, aqueous phase dichloromethane solution extracts, merge organic phase, use saturated common salt water washing, separate organic phase, with anhydrous sodium sulfate drying, dry complete, elimination siccative, filtrate reduced in volume obtains (S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-amine 4.02g, yield: 94.1%.Detect through high performance liquid chromatography (HPLC), purity is 98.43%.
1h NMR (CDCl
3, 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 is C
26h
32nOSi
+[the M+H calculated
+]: 248.3, measured value: 248.4.
Embodiment 5 following formula (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl } preparation of-5-vinyl pyrrole base-2-ketone
Take (S)-1-(tert-butyl diphenyl siloxy)-2-phenyl fourth-3-alkene-2-amine (280.0g, 0.70mol), add 1000ml toluene, (R)-5-oxo-2-vinyl pyrrole-2-formaldehyde (formula III compound) (116.9g is added under stirring, 0.84mol), back flow reaction, after reaction terminates, by concentrated for mixture pressurization, obtain oily matter.
This enriched material is dissolved in anhydrous methanol, makes system temperature be chilled to 0-10 DEG C, in system, add sodium borohydride (53.0g, 1.4mol), room temperature reaction, after reaction terminates, in system, add glacial acetic acid and water, stir 1 hour.Ethyl acetate is added in system, layering, aqueous phase ethyl acetate extracts again, merge organic phase, use saturated sodium bicarbonate solution and saturated common salt water washing successively, vacuum concentration removing ethyl acetate, rapid column chromatography obtains (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone 317.0g, yield: 86.3%.Detect through high performance liquid chromatography (HPLC), purity is 99.27%.
1h NMR (CDCl
3, 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 C
33h
41n
2o
2si
+[the M+H calculated
+]: 525.8, measured value: 525.3.
Embodiment 6 following formula (R)-5-{ [(S)-1-benzyloxy-2-phenyl-Ding-3-alkene-2-base amido] methyl } preparation of-5-vinyl pyrrole base-2-ketone
Take (S)-1-benzyloxy-2-phenyl fourth-3-alkene-2-amine (17.7g, 0.07mol), add 80ml toluene, (R)-5-oxo-2-vinyl pyrrole-2-formaldehyde (formula III compound) (11.7g is added under stirring, 0.08mol), back flow reaction, after reaction terminates, by concentrated for mixture pressurization, obtain oily matter.
This enriched material is dissolved in anhydrous methanol, makes system temperature be chilled to 0-10 DEG C, in system, add sodium borohydride (5.3g, 0.14mol), room temperature reaction, after reaction terminates, in system, add glacial acetic acid and water, stir 1 hour.Ethyl acetate is added in system, layering, aqueous phase ethyl acetate extracts again, merge organic phase, use saturated sodium bicarbonate solution and saturated common salt water washing successively, vacuum concentration removing ethyl acetate, obtains (R)-5-{ [(S)-1-benzyloxy-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone 21.7g, yield: 82.4%.Detect through high performance liquid chromatography (HPLC), purity is 99.20%.
1h NMR (CDCl
3, 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 C
24h
29n
2o
2 +[the M+H calculated
+]: 377.5, measured value: 377.2.
Embodiment 7 following formula (R)-5-{ [(S)-1-(4-chlorobenzene formacyl) oxygen base-2-phenyl-Ding-3-alkene-2-base amido] methyl } preparation of-5-vinyl pyrrole base-2-ketone
Take (S)-1-(4-chlorobenzene formacyl) oxygen base-2-phenyl fourth-3-alkene-2-amine (21.1g; 0.07mol); add 90ml toluene; (R)-5-oxo-2-vinyl pyrrole-2-formaldehyde (formula III compound) (11.7g is added under stirring; 0.08mol), back flow reaction, after reaction terminates; by concentrated for mixture pressurization, obtain oily matter.
This enriched material is dissolved in anhydrous methanol, makes system temperature be chilled to 0-10 DEG C, in system, add sodium borohydride (5.3g, 0.14mol), room temperature reaction, after reaction terminates, in system, add glacial acetic acid and water, stir 1 hour.Ethyl acetate is added in system; layering; aqueous phase ethyl acetate extracts again; merge organic phase; use saturated sodium bicarbonate solution and saturated common salt water washing successively; vacuum concentration removing ethyl acetate, column chromatography obtains (R)-5-{ [(S)-1-(4-chlorobenzene formacyl) oxygen base-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone 24.7g, yield: 82.9%.Detect through high performance liquid chromatography (HPLC), purity is 98.64%.
1h NMR (CDCl
3, 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 is C
24h
26clN
2o
3 +[the M+H calculated
+]: 425.9, measured value: 425.6.
Embodiment 8 following formula (R)-5-{ [(S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-base amido] methyl } preparation of-5-vinyl pyrrole base-2-ketone
Take (S)-1-pivaloyl group oxygen base-2-phenyl fourth-3-alkene-2-amine (17.3g; 0.07mol); add 80ml toluene; (R)-5-oxo-2-vinyl pyrrole-2-formaldehyde (formula III compound) (11.7g is added under stirring; 0.08mol), back flow reaction, after reaction terminates; by concentrated for mixture pressurization, obtain oily matter.
This enriched material is dissolved in anhydrous methanol, makes system temperature be chilled to 0-10 DEG C, in system, add sodium borohydride (5.3g, 0.14mol), room temperature reaction, after reaction terminates, in system, add glacial acetic acid and water, stir 1 hour.Ethyl acetate is added in system; layering; aqueous phase ethyl acetate extracts again; merge organic phase; use saturated sodium bicarbonate solution and saturated common salt water washing successively; vacuum concentration removing ethyl acetate, column chromatography obtains (R)-5-{ [(S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone 21.6g, yield: 83.7%.Detect through high performance liquid chromatography (HPLC), purity is 99.17%.
1h NMR (CDCl
3, 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 is C
22h
31n
2o
3 +[the M+H calculated
+]: 371.5, measured value: 371.2.
The preparation of embodiment 9 following formula N-((S)-1-((tert-butyl diphenyl is silica-based) oxygen base)-2-phenyl-Ding-3-alkene-2-base)-N-(((R)-5-oxo-2-vinyl pyrrole base-2-base) methyl) trifluoroacetamide
Take (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone (26.2g, 0.05mol), add 130ml methylene dichloride, triethylamine (7.6g is added under stirring, 0.075mol), mixture is down to 0-5 DEG C, instillation trifluoroacetic anhydride (12.6g, 0.06mol), dropwise, continuing reaction to (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl } conversion of-5-vinyl pyrrole base-2-ketone is completely, purified water is added in reaction mixture, extraction, separate organic phase, anhydrous sodium sulfate drying, after elimination siccative, filtrate obtains N-((S)-1-((tert-butyl diphenyl is silica-based) oxygen base)-2-phenyl-Ding-3-alkene-2-base)-N-(((R)-5-oxo-2-vinyl pyrrole base-2-base) methyl) trifluoroacetamide 27.7g through concentrating under reduced pressure, yield: 89.4%.Detect through high performance liquid chromatography (HPLC), purity is 98.08%.
1h NMR (CDCl
3, 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 C
35h
40f
3n
2o
3si
+[the M+H calculated
+]: 621.8, measured value: 621.4.
Embodiment 10 following formula (R)-5-{ [benzyl ((S)-1-((tert-butyl diphenyl is silica-based) oxygen base)-2-phenyl-Ding-3-alkene-2-base) amino] methyl } preparation of-5-vinyl pyrrole base-2-ketone
Take (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone (26.2g, 0.05mol), add 130ml tetrahydrofuran (THF), stirring drops to 0-5 DEG C, add sodium tert-butoxide (5.8g, 0.06mol), stir after 30 minutes, instillation bromobenzyl (10.3g, 0.06mol), dropwise, continuing reaction to (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl } conversion of-5-vinyl pyrrole base-2-ketone is completely, purified water is added in reaction mixture, extraction, separate organic phase, anhydrous sodium sulfate drying, after elimination siccative, filtrate is through concentrating under reduced pressure, column chromatography for separation, obtained (R)-5-{ [benzyl ((S)-1-((tert-butyl diphenyl is silica-based) oxygen base)-2-phenyl-Ding-3-alkene-2-base) is amino] methyl }-5-vinyl pyrrole base-2-ketone 23.1g, yield: 75.3%.Detect through high performance liquid chromatography (HPLC), purity is 98.47%.
1h NMR (CDCl
3, 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 C
40h
47n
2o
2si
+[the M+H calculated
+]: 615.3, measured value: 615.4.
The preparation of embodiment 11 following formula (5R, 8S)-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone
Take (R)-5-{ [(S)-1-(the silica-based oxygen base of tert-butyl diphenyl)-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone (310.0g; 0.59mol); be dissolved in 3000ml toluene; add Hoveyda-Grubbs catalyzer (38.4g; 0.06mol); under nitrogen protection, react at being warming up to 50-60 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (500ml).Under room temperature, biphase mixture stirs 1 hour, and be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 243.2g, yield: 83.0%.Detect through high performance liquid chromatography (HPLC), purity is 99.12%.
1h NMR (CDCl
3, 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 C
31h
37n
2o
2si
+[the M+H calculated
+]: 497.3, measured value: 497.1.
The preparation of embodiment 12 following formula (5R, 8S)-8-benzyloxymethyl-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone
Take (R)-5-{ [(S)-1-benzyloxy-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone (22.6g; 0.06mol); be dissolved in 200ml toluene; add Hoveyda-Grubbs (3.84g; 0.006mol); under nitrogen protection, react at being warming up to 60-70 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (150ml).Stirred at ambient temperature 1 hour, be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 17.8g, yield: 85.1%.Detect through high performance liquid chromatography (HPLC), purity is 99.36%.
1h NMR (CDCl
3, 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 is C
22h
25n
2o
2 +[the M+H calculated
+]: 349.5, measured value: 349.2.
The preparation of embodiment 13 following formula (5R, 8S)-8-(4-chlorobenzene formacyl oxygen base) methyl-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone
Take (R)-5-{ [(S)-1-(4-chlorobenzene formacyl) oxygen base-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone (25.5g; 0.06mol); be dissolved in 220ml toluene; add Hoveyda-Grubbs catalyzer (3.84g; 0.006mol); under nitrogen protection, react at being warming up to 60-70 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (150ml).Stirred at ambient temperature 1.5 hours, be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 19.2g, yield: 80.6%.Detect through high performance liquid chromatography (HPLC), purity is 99.09%.
1h NMR (CDCl
3, 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 C
22h
22clN
2o
3 +[the M+H calculated
+]: 397.9, measured value: 397.7.
The preparation of embodiment 14 following formula (5R, 8S)-8-pivaloyl group oxygen ylmethyl-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone
Take (R)-5-{ [(S)-1-pivaloyl group oxygen base-2-phenyl-Ding-3-alkene-2-base amido] methyl }-5-vinyl pyrrole base-2-ketone (22.2g; 0.06mol); be dissolved in 200ml toluene; add Hoveyda-Grubbs catalyzer (3.84g; 0.006mol); under nitrogen protection, react at being warming up to 65-70 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (100ml).Stirred at ambient temperature 1 hour, be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 12.3g, yield: 84.2%.Detect through high performance liquid chromatography (HPLC), purity is 99.17%.
1h NMR (CDCl
3, 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 is C
20h
27n
2o
3 +[the M+H calculated
+]: 343.4, measured value: 343.1.
The preparation of embodiment 15 following formula (5R, 8S)-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-7-trifluoroacetyl group-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone
Take N-((S)-1-((tert-butyl diphenyl is silica-based) oxygen base)-2-phenyl-Ding-3-alkene-2-base)-N-(((R)-5-oxo-2-vinyl pyrrole base-2-base) methyl) trifluoroacetamide (24.8g; 0.04mol); be dissolved in 250ml toluene; add Hoveyda-Grubbs catalyzer (2.56g; 0.004mol); under nitrogen protection, react at being warming up to 50-60 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (100ml), under room temperature, mixture stirs 1 hour, and be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 20.2g, yield: 85.2%.Detect through high performance liquid chromatography (HPLC), purity is 98.77%.
1h NMR (CDCl
3, 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 C
33h
36n
2o
3si
+[the M+H calculated
+]: 593.7, measured value: 593.4.
The preparation of embodiment 16 following formula (5R, 8S)-7-benzyl-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone
Take (R)-5-{ [benzyl ((S)-1-((tert-butyl diphenyl is silica-based) oxygen base)-2-phenyl-Ding-3-alkene-2-base) is amino] methyl }-5-vinyl pyrrole base-2-ketone (18.4g; 0.03mol); be dissolved in 200ml toluene; add Hoveyda-Grubbs catalyzer (1.92g; 0.003mol); under nitrogen protection, react at being warming up to 55-65 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (100ml), under room temperature, mixture stirs 1 hour, and be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 14.9g, yield: 84.7%.Detect through high performance liquid chromatography (HPLC), purity is 99.27%.
1h NMR (CDCl
3, 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 C
38h
43n
2o
2si
+[the M+H calculated
+]: 587.9, measured value: 587.4.
The preparation of embodiment 17 following formula (5S, 8S)-8-[(tert-butyl diphenyl siloxy) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5R, 8S)-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone (240.0g, 0.48mol), be dissolved in 2500ml anhydrous methanol, in system, add the Pd/C (24.0g) of 10%.This system passes into hydrogen, reacts under 1.0-1.5MPa pressure.After reaction terminates, reactant is filtered, anhydrous methanol washing leaching cake, concentrating filter liquor obtains (5S, 8S)-8-[(tert-butyl diphenyl siloxy) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 235.6g, yield: 98.4%.Detect through high performance liquid chromatography (HPLC), purity is 98.67%.
1h NMR (CDCl
3, 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 C
31h
39n
2o
2si
+[the M+H calculated
+]: 499.3, measured value: 499.1.
The preparation of embodiment 18 following formula (5S, 8S)-8-[(tert-butyl diphenyl siloxy) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5R, 8S)-7-benzyl-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone (11.7g, 0.02mol), be dissolved in 200ml anhydrous methanol, in system, add the Pd/C (1.2g) of 10%.This system passes into hydrogen, reacts under 1.0-1.5MPa pressure.After reaction terminates, reactant is filtered, anhydrous methanol washing leaching cake, concentrating filter liquor obtains (5S, 8S)-8-[(tert-butyl diphenyl siloxy) methyl]-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 9.2g, yield: 93.0%.Detect through high performance liquid chromatography (HPLC), purity is 99.27%.
The preparation of embodiment 19 following formula (5S, 8S)-8-(4-chlorobenzene formacyl) oxygen ylmethyl-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5R; 8S)-8-(4-chlorobenzene formacyl) oxygen ylmethyl-8-phenyl-1; 7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone (15.9g; 0.04mol); be dissolved in 150ml anhydrous methanol, in system, add the Pd/C (1.6g) of 10%.This system passes into hydrogen, reacts under 1.0-1.5MPa pressure.After reaction terminates, reactant is filtered, anhydrous methanol washing leaching cake; concentrating filter liquor obtains (5S; 8S)-8-(4-chlorobenzene formacyl) oxygen ylmethyl-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 15.6g, yield: 97.6%.Detect through high performance liquid chromatography (HPLC), purity is 99.54%.
1h NMR (CDCl
3, 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 C
22h
24clN
2o
3 +[the M+H calculated
+]: 399.9, measured value: 399.6.
The preparation of embodiment 20 following formula (5S, 8S)-8-pivaloyl group oxygen ylmethyl-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5R; 8S)-8-pivaloyl group oxygen ylmethyl-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone (13.7g, 0.04mol); be dissolved in 150ml anhydrous methanol, in system, add the Pd/C (1.4g) of 10%.This system passes into hydrogen, reacts under 1.0-1.5MPa pressure.After reaction terminates, filtered by reactant, anhydrous methanol washing leaching cake, concentrating filter liquor obtains (5S, 8S)-8-pivaloyl group oxygen ylmethyl-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 13.5g, yield: 97.8%.Detect through high performance liquid chromatography (HPLC), purity is 98.84%.
1h NMR (CDCl
3, 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 is C
20h
29n
2o
3 +[the M+H calculated
+]: 345.4, measured value: 345.2.
The preparation of embodiment 21 following formula (5R, 8S)-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-7-trifluoroacetyl group-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5R; 8S)-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-7-trifluoroacetyl group-1; 7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone (11.9g; 0.02mol); be dissolved in 100ml methyl alcohol; add the Pd/C (1.2g) of 10%, this system passes into hydrogen, reacts under 1.0-1.5MPa pressure.After reaction terminates; reactant is filtered; anhydrous methanol washing leaching cake; concentrating filter liquor obtains (5R; 8S)-8-[(the silica-based oxygen base of tert-butyl diphenyl) methyl]-8-phenyl-7-trifluoroacetyl group-1; 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 11.0g, yield: 92.4%.Detect through high performance liquid chromatography (HPLC), purity is 99.61%.
1h NMR (CDCl
3, 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 C
33h
38n
2o
3si
+[the M+H calculated
+]: 595.8, measured value: 595.1.
The preparation of embodiment 22 following formula (5S, 8S)-8-methylol-8-phenyl-7-trifluoroacetyl group-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5S, 8S)-8-[(tert-butyl diphenyl siloxy) methyl]-8-phenyl-7-trifluoroacetyl group-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (8.9g, 0.015mol), add 100ml tetrahydrofuran (THF), stirring and dissolving, tetrabutyl ammonium fluoride (7.9g is added in system, 0.03mol), after reaction terminates, purified water and extraction into ethyl acetate in system, separate organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, dry complete, elimination siccative, concentrating filter liquor obtains (5S, 8S)-8-methylol-8-phenyl-7-trifluoroacetyl group-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 4.9g, yield 91.0%.Detect through high performance liquid chromatography (HPLC), purity is 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 C
17h
20n
2o
3 +[the M+H calculated
+]: 357.4, measured value: 357.1.
The preparation of embodiment 23 following formula (5S, 8S)-8-methylol-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5S, 8S)-8-[(tert-butyl diphenyl siloxy) methyl]-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (230.0g, 0.46mol), add 2500ml tetrahydrofuran (THF), stirring and dissolving, tetrabutyl ammonium fluoride (240.5g is added in system, 0.92mol), after reaction terminates, purified water and extraction into ethyl acetate in system, separate organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, dry complete, elimination siccative, concentrating filter liquor obtains (5S, 8S)-8-methylol-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 106.1g, yield 88.6%.Detect through high performance liquid chromatography (HPLC), purity 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 C
15h
21n
2o
2 +[the M+H calculated
+]: 261.2, measured value: 261.1.
The preparation of embodiment 24 following formula (5S, 8S)-8-methylol-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5R, 8S)-8-benzyloxymethyl-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-2-ketone (13.9g, 0.04mol), be dissolved in 150ml anhydrous methanol, in system, add the Pd/C (1.4g) of 10%.This system passes into hydrogen, reacts under 1.0-1.5MPa pressure.After reaction terminates, filtered by reactant, anhydrous methanol washing leaching cake, concentrating filter liquor obtains (5S, 8S)-8-benzyloxy) methyl-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 9.3g, yield: 89.4%.Detect through high performance liquid chromatography (HPLC), purity is 99.77%.
The preparation of embodiment 25 following formula (5S, 8S)-8-methylol-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5S, 8S)-8-(4-chlorobenzene formacyl) oxygen ylmethyl-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (12.0g, 0.03mol), add 35ml tetrahydrofuran (THF), stirring and dissolving, sodium hydroxide solution (the 15ml of 4mol/L is added in system, 0.06mol), after reaction terminates, purified water and extraction into ethyl acetate in system, separate organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, dry complete, elimination siccative, concentrating filter liquor obtains (5S, 8S)-8-methylol-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 7.3g, yield 93.5%.Detect through high performance liquid chromatography (HPLC), purity is 99.68%.
The preparation of embodiment 26 following formula (5S, 8S)-8-methylol-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone
Take (5S, 8S)-8-pivaloyl group oxygen ylmethyl-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (10.3g, 0.03mol), add 30ml tetrahydrofuran (THF), stirring and dissolving, sodium hydroxide solution (the 15ml of 4mol/L is added in system, 0.06mol), after reaction terminates, purified water and extraction into ethyl acetate in system, separate organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, dry complete, elimination siccative, concentrating filter liquor obtains (5S, 8S)-8-methylol-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone 7.5g, yield 96.2%.Detect through high performance liquid chromatography (HPLC), purity is 99.26%.
The preparation of embodiment 27 following formula (5S, 8S)-8-[1-(R)-(3,5-pair-trifluoromethyl-phenyl)-ethoxyl methyl]-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (formula I)
Take (5S, 8S)-8-(methylol)-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (105.0g, 0.40mol), add 1000mlN, N-N,N-DIMETHYLACETAMIDE, under stirring, system is chilled to 0-5 DEG C, the sodium hydride (19.2g) of 60% is added in system, stirring reaction 0.5 hour at 0 DEG C, (S)-1-(1-bromotrifluoromethane)-3 is added in system, two (trifluoromethyl) benzene (7.4g of 5-, 23.0mmol), rise to room temperature after adding and continue reaction, after reaction terminates, add water cancellation, be extracted with ethyl acetate, washing organic phase, anhydrous sodium sulfate drying, filter, filtrate is concentrated, adopt the obtained (5S of column chromatography, 8S)-8-[1-(R)-(3, 5-pair-trifluoromethyl-phenyl)-ethoxyl methyl]-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (formula I) 185.5g, yield: 92.6%.Detect through high performance liquid chromatography (HPLC), purity is 99.87%.
1H NMR(CDCl
3)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 C
25h
27f
6n
2o
2 +[the M+H calculated
+]: 501.2, measured value: 501.1.
The preparation of embodiment 28 following formula (5S, 8S)-8-[1-(R)-(3,5-pair-trifluoromethyl-phenyl)-ethoxyl methyl]-8-phenyl-1,7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (formula I)
Take (5S, 8S)-8-(methylol)-8-phenyl-7-trifluoroacetyl group-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (3.5g, 0.01mol), add 20mlN, N-N,N-DIMETHYLACETAMIDE, under stirring, system is chilled to 0-5 DEG C, the sodium hydride (0.5g) of 60% is added in system, stirring reaction 0.5 hour at 0 DEG C, (S)-1-(1-bromotrifluoromethane)-3 is added in system, two (trifluoromethyl) benzene (7.4g of 5-, 23.0mmol), rise to room temperature after adding and continue reaction, after reaction terminates, add water cancellation, be extracted with ethyl acetate, washing organic phase, anhydrous sodium sulfate drying, filter, filtrate is concentrated, adopt the obtained (5S of column chromatography, 8S)-8-[1-(R)-(3, 5-pair-trifluoromethyl-phenyl)-ethoxyl methyl]-8-phenyl-1, 7-diaza-spiro [4.5]-2-in last of the ten Heavenly stems ketone (formula I) 4.5g, yield, 90.0%, detect through high performance liquid chromatography (HPLC), purity is 99.83%.
The preparation of embodiment 29 following formula (S)-2-amino-2-phenyl-Ding-3-alkene acetic ester
Take according to obtained (R)-N-[(S)-1-(tert-butyl diphenyl siloxy)-2-phenyl-Ding-3-alkene-2-the base]-2-methyl-propyl-2-sulfinyl amine (10.0g of the method for embodiment 1, 0.02mol), add 100ml tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (10.5g, 0.04mol), stirring reaction, after reaction terminates, add water extraction, separate organic phase, anhydrous sodium sulfate drying, drying terminates rear elimination siccative, filtrate is cooled to 0-5 DEG C, add triethylamine (4.0g, 0.04mol), instillation diacetyl oxide (2.5g, 0.024mol), N, N-Dimethylamino pyridine (0.5g, after 0.004mol) reacting completely, add purified water extraction, separatory, organic phase is after anhydrous sodium sulfate drying, elimination siccative, filtrate reduced in volume, obtained (R)-N-[(S)-1-acetoxyl group-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine 5.47g, yield 89.5%.
Take (R)-N-[(S)-1-acetoxyl group-2-phenyl-Ding-3-alkene-2-base]-2-methyl-propyl-2-sulfinyl amine (5.0g, 0.016mol), add 60ml methyl alcohol, 2mol/L hydrochloric acid 20ml, stir lower reaction, after reaction terminates, the pH regulating mixture with saturated sodium bicarbonate solution is 7-8, add 100ml dichloromethane extraction, separatory, aqueous phase dichloromethane solution extracts, merge organic phase, use saturated common salt water washing, separate organic phase, with anhydrous sodium sulfate drying, dry complete, elimination siccative, filtrate reduced in volume obtains (S)-2-amino-2-phenyl-Ding-3-alkene acetic ester 3.06g, yield: 91.1%.Detect through high performance liquid chromatography (HPLC), purity is 98.11%.
1H NMR(CDCl
3)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 C
12h
16nO
2 +[the M+H calculated
+]: 206.1, measured value: 206.0.
Embodiment 30 following formula (S)-2-{ [(R)-5-oxo-2-vinyl pyrrole]-methylamine } preparation of-2-phenyl fourth-3-alkene acetic ester
Take (S)-2-amino-2-phenyl-Ding-3-alkene acetic ester (3.0g, 14.6mmol), add 30ml toluene, (R)-5-oxo-2-vinyl pyrrole-2-formaldehyde (formula III compound) (3.9g is added under stirring, 17.5mmol), back flow reaction, after reaction terminates, by concentrated for mixture pressurization, obtain oily matter.
This enriched material is dissolved in anhydrous methanol, makes system temperature be chilled to 0-10 DEG C, in system, add sodium borohydride (790mg, 20.8mmol), room temperature reaction, after reaction terminates, in system, add glacial acetic acid and water, stir 1 hour.Ethyl acetate is added in system, layering, aqueous phase ethyl acetate extracts again, merge organic phase, use saturated sodium bicarbonate solution and saturated common salt water washing successively, vacuum concentration removing ethyl acetate ,-2-{ [(R)-5-oxo-2-vinyl pyrrole]-methylamine that rapid column chromatography obtains (S) }-2-phenyl fourth-3-alkene acetic ester 4.14g, yield: 86.3%.Detect through high performance liquid chromatography (HPLC), purity is 98.07%.
1h NMR (CDCl
3, 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 C
19h
25n
2o
3 +[the M+H calculated
+]: 329.2, measured value: 329.1.
The preparation of embodiment 31 following formula [(5R, 8S)-2-oxo-8-phenyl-1,7-diaza-spiro [4.5]-9-in last of the ten Heavenly stems alkene-8-base] methyl acetic acid ester
Take (S)-2-{ [(R)-5-oxo-2-vinyl pyrrole]-methylamine }-2-phenyl fourth-3-alkene acetic ester (4.0g; 12.2mmol); be dissolved in 100ml toluene; add Hoveyda-Grubbs catalyzer (458mg; 0.06mol); under nitrogen protection, react at being warming up to 50-60 DEG C.After having reacted, add saturated sodium bisulfite solution, make mixture be chilled to room temperature, add saturated sodium bicarbonate solution (500ml).Under room temperature, biphase mixture stirs 1 hour, and be separated removing aqueous phase, organic phase saturated nacl aqueous solution washs, washing.Organic phase is filtered by Celite pad, and concentrated, column chromatography obtains product 3.12g, yield: 85.0%.Detect through high performance liquid chromatography (HPLC), purity is 99.12%.
1h NMR (CDCl
3) 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 C
17h
21n
2o
3 +[the M+H calculated
+]: 301.2, measured value: 301.1.
Claims (10)
1. (a 5S, 8S)-8-{ [1-(3,5-pair-(trifluoromethyl) phenyl)-oxyethyl group]-methyl }-8-phenyl-1,7-diaza-spiro [4,5] preparation method in-2-ketone in the last of the ten Heavenly stems (formula I), it is characterized in that, comprise the following steps:
E (), by deprotection reaction, makes the blocking group R in formula VII compound be removed, production VIII compound;
F (), under alkaline reagents exists, makes formula VIII compound and two (trifluoromethyl) benzene of S-1-(1-bromotrifluoromethane)-3,5-react, obtained formula I;
Wherein, R is hydroxy-protective group, is selected from C
1-4alkyl, benzyl, trityl, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), preferable methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl, trityl, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl is silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), more preferably benzyl, pivaloyl group, benzoyl, silica-based to chlorobenzene formacyl, tert-butyl diphenyl, most preferably benzyl, pivaloyl group, silica-based to chlorobenzene formacyl, tert-butyl diphenyl,
R
1be selected from hydrogen, benzyl, the benzyl of replacement, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); The benzyl of preferred hydrogen, benzyl, replacement, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, ethoxy carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl (Boc), carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); More preferably hydrogen, benzyl, ethanoyl, propionyl, tert-butoxycarbonyl, pivaloyl group, carbobenzoxy-(Cbz), trifluoroacetyl group; Most preferably hydrogen, benzyl, trifluoroacetyl group.
2. preparation method as claimed in claim 1, is characterized in that, further comprising the steps:
C (), under ring closing metathesis catalyzer exists, by molecule internal olefin replacement(metathesis)reaction, makes formula V compound generation Intra-molecular condensation, production VI compound;
D formula VI converting compounds, by reduction reaction, is formula VII compound by ();
Wherein, R, R
1there is aforementioned identical implication.
3. preparation method as claimed in claim 1 or 2, is characterized in that, also further comprising the steps:
A () makes formula II compound and formula III compound react, production IV group with imine moiety;
B () 1. works as R
1during for hydrogen, formula IV compound obtains formula V compound through going back original reagent reduction; Or, 2. work as R
1when not being hydrogen, formula IV compound through go back original reagent reduction after, then with R
1-X is obtained by reacting formula V compound;
Wherein, R, R
1there is aforementioned identical implication; X is leavings group, preferred halogen, substituted or unsubstituted C
1-4alkoxy carbonyl, more preferably bromine, chlorine, iodine, ethanoyl oxygen base, trifluoroacetyl group oxygen base; In the preferred technical solution of the present invention, R
1-X is selected from diacetyl oxide, trifluoroacetic anhydride, bromotoluene (i.e. bromobenzyl), benzyl chloride.
4. (a 5S, 8S)-8-{ [1-(3,5-pair-(trifluoromethyl) phenyl)-oxyethyl group]-methyl }-8-phenyl-1,7-diaza-spiro [4,5] preparation method in-2-ketone in the last of the ten Heavenly stems (formula I), it is characterized in that, its operational path is as follows:
Wherein, wherein, R, R
1there is aforementioned identical implication.
5. preparation method as claimed in claim 4, is characterized in that, comprise the following steps:
A () makes formula II compound and formula III compound react, production IV group with imine moiety;
B () 1. works as R
1during for hydrogen, formula IV compound obtains formula V compound through going back original reagent reduction; Or, 2. work as R
1when not being hydrogen, formula IV compound through go back original reagent reduction after, then with R
1-X is obtained by reacting formula V compound;
C (), under ring closing metathesis catalyzer exists, by molecule internal olefin replacement(metathesis)reaction, makes formula V compound generation Intra-molecular condensation, production VI compound;
D formula VI converting compounds, by reduction reaction, is formula VII compound by ();
E (), by deprotection reaction, makes the blocking group R in formula VII compound be removed, production VIII compound;
F (), under alkaline reagents exists, makes formula VIII compound and two (trifluoromethyl) benzene of S-1-(1-bromotrifluoromethane)-3,5-react, obtained formula I.
6. preparation method as claimed in claim 5, is characterized in that, goes back original reagent and be selected from one in sodium borohydride, sodium cyanoborohydride, Sodium triacetoxyborohydride described in step (b);
The catalyzer of ring closing metathesis described in step (c) is selected from Grubbs catalyzer, Hoveyda-Grubbs catalyzer, preferred Hoveyda-Grubbs catalyzer;
Alkaline reagents described in step (f) is selected from sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, potassium hydride KH, the one in hydrolith.
7. one kind as shown in the formula compound:
Wherein, R is hydroxy-protective group, is selected from C
1-4alkyl, benzyl, trityl, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), preferable methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl, trityl, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl is silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), more preferably benzyl, pivaloyl group, benzoyl, silica-based to chlorobenzene formacyl, tert-butyl diphenyl, most preferably benzyl, pivaloyl group, silica-based to chlorobenzene formacyl, tert-butyl diphenyl,
R
1be selected from hydrogen, benzyl, the benzyl of replacement, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); The benzyl of preferred hydrogen, benzyl, replacement, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, ethoxy carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl (Boc), carbobenzoxy-(Cbz), trifluoroacetyl group, benzoyl, to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, 9-fluorenylmethyloxycarbonyl (Fmoc); More preferably hydrogen, benzyl, ethanoyl, propionyl, tert-butoxycarbonyl, pivaloyl group, carbobenzoxy-(Cbz), trifluoroacetyl group; Most preferably hydrogen, benzyl, trifluoroacetyl group.
8. a preparation method for formula II compound, is characterized in that, its operational path is as follows:
Wherein, R is hydroxy-protective group, is selected from C
1-4alkyl, benzyl, trityl, C
1-5alkyl-carbonyl, C
1-4alkoxy carbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl are silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), preferable methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl, trityl, formyl radical, ethanoyl, propionyl, tert-butyl carbonyl, pivaloyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, carbobenzoxy-(Cbz) (Cbz), benzoyl (Bz), to chlorobenzene formacyl, methylsulfonyl, trifyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, triisopropylsilyl, tert-butyl diphenyl is silica-based, t-Butyldimethylsilyl, 9-fluorenylmethyloxycarbonyl (Fmoc), more preferably benzyl, pivaloyl group, benzoyl, silica-based to chlorobenzene formacyl, tert-butyl diphenyl, most preferably benzyl, pivaloyl group, silica-based to chlorobenzene formacyl, tert-butyl diphenyl.
9. preparation method as claimed in claim 8, is characterized in that, comprise the following steps:
(1) under alkaline reagents exists, formula IX compound carries out hydroxyl protection, obtains the compound of formula X;
(2) under dehydrating agent exists, formula X compound and R-t-butyl sulfonamide are reacted, to form formula XI group with imine moiety;
(3) formula XI compound and vinylimidazolium chloride magnesium or vinyl bromination reactive magnesium is made, to form formula XII compound;
(4) under acid reagent exists, formula XII compound is made to remove terf-butylsulfinyl, obtained formula II compound.
10. preparation method as claimed in claim 9, it is characterized in that, described in step (1), alkaline reagents is selected from organic bases, such as, one in triethylamine, imidazoles, pyridine, or is selected from mineral alkali, such as, one in salt of wormwood, sodium carbonate;
Described in step (2), dehydrating agent is titanium isopropylate;
Described in step (4), acid reagent is selected from the one in hydrochloric acid, phosphoric acid, acetic acid.
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