CN107033124B - A kind of Ai Le replaces the preparation method of Buddhist nun - Google Patents
A kind of Ai Le replaces the preparation method of Buddhist nun Download PDFInfo
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- CN107033124B CN107033124B CN201710263665.5A CN201710263665A CN107033124B CN 107033124 B CN107033124 B CN 107033124B CN 201710263665 A CN201710263665 A CN 201710263665A CN 107033124 B CN107033124 B CN 107033124B
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- Prior art keywords
- base
- ethyl
- piperidin
- morpholine
- phenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 160
- -1 3- cyanophenylamino Chemical group 0.000 claims abstract description 21
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 9
- NJXPYZHXZZCTNI-UHFFFAOYSA-N 3-aminobenzonitrile Chemical compound NC1=CC=CC(C#N)=C1 NJXPYZHXZZCTNI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- FOLRKRMAFDGZRR-UHFFFAOYSA-N tert-butyl 2,2-dichloroacetate Chemical compound CC(C)(C)OC(=O)C(Cl)Cl FOLRKRMAFDGZRR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 95
- 238000006243 chemical reaction Methods 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000003377 acid catalyst Substances 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- 150000003839 salts Chemical group 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 239000011968 lewis acid catalyst Substances 0.000 claims description 5
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims description 5
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 4
- 239000001142 4-methyl-2-oxopentanoic acid Substances 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloro-acetic acid Natural products OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 3
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 2
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 2
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims description 2
- 239000004246 zinc acetate Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 2
- RJOWHRLIQNKYKW-UHFFFAOYSA-N 2-methyl-2-phenylpropanal Chemical compound O=CC(C)(C)C1=CC=CC=C1 RJOWHRLIQNKYKW-UHFFFAOYSA-N 0.000 claims 1
- KDVFRMMRZOCFLS-UHFFFAOYSA-N 2-oxopentanoic acid Chemical compound CCCC(=O)C(O)=O KDVFRMMRZOCFLS-UHFFFAOYSA-N 0.000 claims 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims 1
- ICXXXLGATNSZAV-UHFFFAOYSA-N butylazanium;chloride Chemical compound [Cl-].CCCC[NH3+] ICXXXLGATNSZAV-UHFFFAOYSA-N 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000009979 protective mechanism Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000002390 rotary evaporation Methods 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine Chemical compound C1CNCCC1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QLFNUXTWJGXNLH-UHFFFAOYSA-N bis(2-methoxyethoxy)alumane Chemical class COCCO[AlH]OCCOC QLFNUXTWJGXNLH-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- FOIXQDWOJWQMEF-UHFFFAOYSA-N 1h-indole;phenylhydrazine Chemical compound NNC1=CC=CC=C1.C1=CC=C2NC=CC2=C1 FOIXQDWOJWQMEF-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- NGGGZUAEOKRHMA-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)CC(O)=O NGGGZUAEOKRHMA-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MBNLVYPIKSWXCT-UHFFFAOYSA-N methyl 2-oxopentanoate Chemical compound CCCC(=O)C(=O)OC MBNLVYPIKSWXCT-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- FZGRPBJBMUNMQH-UHFFFAOYSA-N trimethyl-$l^{3}-chlorane Chemical compound CCl(C)C FZGRPBJBMUNMQH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses the preparation methods that a kind of Ai Le replaces Buddhist nun.2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester is carried out reduction reaction by this method；Obtained 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal and the 2,2- dichloroacetic acid tert-butyl ester are subjected to addition rearrangement reaction；The chloro- 4- of obtained 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate and m-aminophenyl formonitrile HCN are subjected to substitution reaction；Obtained 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate is subjected to cyclization and hydrolysis；Obtained 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indole -3-carboxylic acid is subjected to cyclization, obtains Ai Le for Buddhist nun.This method operation simplifies, and it is a kind of environmentally protective process that cost is relatively low, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of Ai Le replaces the preparation method of Buddhist nun.
Background technique
Novel anaplastic lymphoma kinase (ALK) inhibitor Ai Le replaces entitled ethyl -6 9- of chemistry of Buddhist nun (Alectinib),
6- dimethyl -8- [4- (morpholine -4- base) piperidin-1-yl] -11- oxo -6,11- dihydro -5H- benzo [b] carbazole -3- formonitrile HCN,
Its chemical structural formula are as follows:
The original new drug that Ai Le invents for the branch company Chugai Pharmaceutical that Buddhist nun is company, Roche Group,
The breakthrough therapeutic agent recognition of qulifications of U.S. FDA is obtained, accelerates examination & approval as oral anti-lung cancer new drug, for treating ALK
Advanced stage (metastatic) non-small cell lung cancer (NSCLC) of gene mutation, or the treatment of the patient to (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine tolerance.
A kind of synthetic route for preparing Ai Le and replacing Buddhist nun disclosed in patent US20130143877 and WO2012023597A1: with
7- methoxyl group -3,4- dihydro -2- naphthalenone be starting material, by double methylations and bromination reaction, then with the Fischer of phenylhydrazine
Indole synthesis carries out cyclization reaction, is then passed through oxidation and introduces 11- carbonyl, then is carried out by the hydroxyl that methoxy hydrolysis obtains
It is triflated, it is condensed with 4- (4- piperidyl) morpholine, last 9- bromo is replaced by acetenyl, then obtains through reduction reaction
Ai Le replaces Buddhist nun, and process route is as follows:
Since entire synthetic route step is longer, cumbersome, higher cost, is unfavorable for amplification production and industrialization pushes away
Extensively.
Ai Le disclosed in patent US20120083488 replaces the synthetic route of Buddhist nun, with iodo- 4 second of mono-tert-butyl malonate and 3-
Base tert-butyl benzene is starting material, and by the condensation of condensation, cyclization and 4- (4- piperidyl) morpholine, last cyclization obtains Ai Le
For Buddhist nun, process route is as follows:
Ai Le disclosed in patent CN104402862A is as follows for the synthetic route of Buddhist nun, wherein needing to use indoles parent nucleus
Compound is as starting raw material:
Above two be combined into route starting material it is more expensive, be not easy to obtain, thus need be synthetically prepared；Due to two
It is combined into the midbody product of route and final products is impure and by-product is more, thus purifying is needed using a large amount of solvents,
Cumbersome, yield is lower, is unfavorable for industrialization production popularization, it is therefore necessary to explore that process flow is short, easy to operate, cost
Ai Le that is cheap and using suitable industrialized production replaces the preparation method of Buddhist nun.
Summary of the invention
The preparation method of Buddhist nun is replaced the present invention is directed to overcome the deficiencies of the prior art and provide a kind of Ai Le.
In order to achieve the above object, technical solution provided by the invention are as follows:
The Ai Le includes the following steps: for the preparation method of Buddhist nun
(1) 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal is prepared: by 2- { 4- second
Base -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester in the system that reducing agent and solvent form into
Row reduction reaction obtains 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal, reaction equation are as follows:
(2) the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxo penta is prepared
Tert-butyl acrylate: by 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal and 2,2- dichloroacetic acid
The tert-butyl ester carries out addition rearrangement reaction in the system that base reagent, phase transfer catalyst and solvent form, and obtains the chloro- 4- { 4- of 3-
Ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, reaction equation are as follows:
(3) 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- is prepared
Methyl -2- oxopentanoate: by the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- first
Base -2- oxopentanoate is replaced in the system that acid binding agent alkali, inorganic salts and solvent form with m-aminophenyl formonitrile HCN
Reaction, obtains 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate, reaction equation are as follows:
(4) 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl }-is prepared
1H- indole -3-carboxylic acid: by 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -
4- methyl -2- oxopentanoate carries out cyclization under the action of acid catalyst and lewis acid catalyst, then into
Row hydrolysis obtains 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -
1H- indole -3-carboxylic acid, reaction equation are as follows:
(5) preparation Ai Le replaces Buddhist nun: by 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl]
Propyl- 2- yl } -1H- indole -3-carboxylic acid carries out cyclization in the system that acid catalyst and solvent form, obtain Ai Le for Buddhist nun,
Reaction equation are as follows:
Preferably, reducing agent described in step (1) is diisobutyl aluminium hydride or bis- (2- methoxy ethoxy) aluminum hydrides
Sodium；The solvent is tetrahydrofuran, methyl tertiary butyl ether(MTBE), toluene or 1,4- dioxane；Wherein, 2- { 4- ethyl -3- [4-
(morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, the molar ratio between reducing agent be 1.0: (1.2~1.6),
Solvent is the medium of reaction, is not involved in reaction, is not required to limit the molar ratio of itself and reactant and reagent.
Preferably, base reagent described in step (2) is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropylate
Or tert-pentyl alcohol potassium；The phase transfer catalyst is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, the tetrabutyl
Ammonium hydrogen sulfate, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, methyl tricapryl ammonium chloride, trimethyl chlorine
Change ammonium or tetradecyl trimethyl ammonium chloride；The solvent be tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile or
1,4- dioxane；Wherein, 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal, 2,2- bis-
Chloroacetic acid tert-butyl ester, base reagent, the molar ratio between phase transfer catalyst are 1.0: (1.2~1.4): (1.2~1.4): (0.02
~0.10), solvent is the medium of reaction, is not involved in reaction, is not required to limit the molar ratio of itself and reactant and reagent.
Preferably, acid binding agent alkali described in step (3) is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or hydroxide
Potassium；The inorganic salts are potassium iodide, potassium bromide, sodium chloride, potassium chloride, sodium bromide or sodium iodide；The solvent is N, N-
Dimethylformamide, methyl tertiary butyl ether(MTBE), methylene chloride, 1,2- dichloroethanes, chloroform, chlorobenzene or 1,4- dioxane；Wherein,
The chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, amino
Benzonitrile, acid binding agent alkali, the molar ratio between inorganic salts are 1.0: (1.2~1.4): (1.2~1.4): (0.2~0.6), solvent
For reaction medium, be not involved in reaction, be not required to limit the molar ratio of itself and reactant and reagent.
Preferably, acid catalyst described in step (4) is trifluoroacetic acid, acetic acid, formic acid, oxalic acid, propionic acid, n-butyric acie or different
Butyric acid；The lewis acid catalyst be aluminium chloride, zinc chloride, titanium chloride, stannic chloride, iron chloride, magnesium chloride, copper chloride,
Aluminum sulfate, ferric sulfate, zinc acetate, boron trifluoride ether or fluoroform sulphonate；Wherein, 3- (3- cyanophenylamino) -4- { 4- second
Base -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, acid catalyst, lewis acid
Molar ratio between catalyst is 1.0: (20.0~40.0): (10.0~20.0).
Preferably, acid catalyst described in step (5) is trifluoroacetic acid, trifluoroacetic anhydride, acetic acid, acetic anhydride, formic acid, grass
Acid, oxalyl chloride, phosphorus pentoxide, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, phosphorus trichloride, polyphosphoric acids, to toluene sulphur
Acid, paratoluensulfonyl chloride, methanesulfonic acid or mesyl chloride；The solvent is toluene, N,N-dimethylformamide, N, N- dimethyl
Acetamide or 1,4- dioxane；Wherein, 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl]
Propyl- 2- yl } -1H- indole -3-carboxylic acid, the molar ratio between acid catalyst be 1.0: (2.0~10.0), solvent be the matchmaker reacted
It is situated between, is not involved in reaction, is not required to limit the molar ratio of itself and reactant and reagent.
Preferably, the temperature of reduction reaction described in step (1) is -78~-68 DEG C, and the reaction time is 1~3 hour；Step
Suddenly the temperature of addition rearrangement reaction described in (2) is 20~40 DEG C, and the reaction time is 12~24 hours；Step takes described in (3)
The temperature of generation reaction is 50~70 DEG C, and the reaction time is 12~18 hours；The temperature of cyclization described in step (4) be 90~
110 DEG C, the reaction time is 6~12 hours；The temperature of the hydrolysis is 50~70 DEG C, and the reaction time is 2~4 hours；
The temperature of cyclization described in step (5) is 100~120 DEG C, and the reaction time is 12~20 hours.
A kind of Ai Le of the present invention replaces the preparation method of Buddhist nun, first with 2- { 4- ethyl -3- [4- (morpholine -4- base) piperazine
Pyridine -1- base] phenyl } -2 Methylpropionic acid ethyl ester is that raw material is reduced to aldehyde, and then by being added with 2, the 2- dichloroacetic acid tert-butyl ester
At rearrangement reaction, the chloro- 4- of obtained 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxo
Pentanoate and m-aminophenyl formonitrile HCN carry out substitution reaction, are related to aniline alkylating, and then molecule inner ring condensation prepares indoles mother
Core, reaction condition is mild, finally by hydrolyzing and being cyclized again, Ai Le is prepared for Buddhist nun, route methods design is rationally only
It arrives, raw material is cheap and easy to get, and reaction condition is easy effectively control.
Technical solution provided by the invention is had following technical effect that first, only making after being completed due to the reaction of each step normal
Without column chromatography, impurity is less, controllable, can directly carry out next step reaction, therefore for the post-processing and purifying of rule property
Operation is simplified, while each step can obtain higher yield；Second, process route starting material of the invention and used
Reagent is easy to get, and the technical solution of synthetic reaction is reasonable, and the use demand of bulk pharmaceutical chemicals can be met with mass production, is suitable for industry
Metaplasia produces；Third, since pollutant will not be generated during the preparation process, thus environmentally protective effect can be embodied.
Specific embodiment
Embodiment 1
A 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal) is prepared:
2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (5.0g,
It 12.9mmol) is dissolved in tetrahydrofuran (80mL), is cooled to -78 DEG C, the four of diisobutyl aluminium hydride (18.0mmol) are slowly added dropwise
Hydrogen tetrahydrofuran solution, -78 DEG C of heat preservation are stirred to react 2 hours, and vacuum rotary steam is added dilute hydrochloric acid and is adjusted to neutrality to doing, ethyl acetate
Extraction, washing and drying, for vacuum rotary steam to doing, recrystallisation from isopropanol obtains 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidines -
1- yl] phenyl } -2 methyl propanal, light yellow solid (4.1g), yield 92%.
B the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxo penta) is prepared
Tert-butyl acrylate:
2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal (4.0g, 11.6mmol) and
2, the 2- dichloroacetic acid tert-butyl esters (2.8g, 15.1mmol) are dissolved in tetrahydrofuran (80mL), and ice bath is cooling, are slowly added to sodium methoxide
(0.8g, 14.8mmol) warms naturally to 30 DEG C, is stirred to react 9 hours, be then added tetrabutylammonium chloride (0.2g,
0.72mmol), it is stirred for reaction 9 hours at room temperature, dilute hydrochloric acid is added and is adjusted to neutrality, concentrated by rotary evaporation to dry, addition acetic acid second
Ester extraction, washing and dry, magnesium sulfate drying, for concentrated by rotary evaporation to doing, recrystallizing methanol obtains the chloro- 4- of 3- { 4- ethyl -3- [4-
(morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, off-white powder (4.6g), yield 80%.
C 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- first) is prepared
Base -2- oxopentanoate:
The chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -2- oxopentanoic acid
Ester (4.5g, 9.1mmol) is dissolved in n,N-Dimethylformamide (90mL), and m-aminophenyl formonitrile HCN (1.4g, 11.9mmol), carbon is added
Sour potassium (1.6g, 11.6mmol) and potassium iodide (0.6g, 3.6mmol), 60 DEG C of reaction mixture are stirred to react 15 hours, reaction solution
It is down to room temperature, is added water (60mL), is cooled to -10 DEG C of crystallizations 3 hours, filters, obtains 3- (3- cyanophenylamino) -4- { 4- ethyl -
3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, white solid (4.6g), yield
88%.
D 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H-) is prepared
Indole -3-carboxylic acid:
3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate (4.5g, 7.8mmol) is dissolved in trifluoroacetic acid (26.8g, 235.0mmol), and ice bath is cooling, is slowly added to chlorine
Change aluminium (15.7g, 117.7mmol), 100 DEG C of reaction mixture are stirred to react 9 hours, and reaction solution is down to 60 DEG C, and water is added
(50mL), insulation reaction 3 hours, concentrated by rotary evaporation to dry, addition saturated sodium bicarbonate solution neutralization, addition ethyl acetate extraction,
Magnesium sulfate is dry, and concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to doing, obtains 6- cyano -2- { 2- [4- second
Base -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indole -3-carboxylic acid, off-white powder (3.5g), receipts
Rate 89%.
E) preparation Ai Le replaces Buddhist nun:
6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indoles -
3- carboxylic acid (3.5g, 7.0mmol), trifluoroacetic acid (4.8g, 42.1mmol) are dissolved in toluene (40mL), and it is anti-to be heated to 110 DEG C of stirrings
It answers 16 hours, concentrated by rotary evaporation is added saturated sodium bicarbonate solution and neutralizes to doing, and ethyl acetate extraction, magnesium sulfate drying, rotation is added
Steaming is concentrated to dryness, and is recrystallized with ethyl acetate and n-hexane mixed solvent, and get Ai Le replaces Buddhist nun, off-white powder (3.1), yield
92%.
Embodiment 2
A 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal) is prepared:
2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (10.0g,
It 25.7mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (120mL), is cooled to -78 DEG C, bis- (2- methoxy ethoxy) aluminum hydrides are slowly added dropwise
Isosorbide-5-Nitrae-dioxane solution of sodium (41.0mmol), -75 DEG C of heat preservation are stirred to react 3 hours, vacuum rotary steam to dry, addition dilute hydrochloric acid
It is adjusted to neutrality, ethyl acetate extraction, washing and drying, for vacuum rotary steam to doing, recrystallisation from isopropanol obtains 2- { 4- ethyl -3-
[4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal, light yellow solid (8.0g), yield 90%.
B the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxo penta) is prepared
Tert-butyl acrylate:
2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal (8.0g, 23.2mmol) and
2, the 2- dichloroacetic acid tert-butyl esters (6.0g, 32.4mmol) are dissolved in tetrahydrofuran (130mL), and ice bath is cooling, are slowly added to the tert-butyl alcohol
Potassium (3.6g, 32.1mmol), warms naturally to 20 DEG C, is stirred to react 12 hours, be then added tetrabutylammonium iodide (0.17g,
0.46mmol), it is stirred for reaction 12 hours at room temperature, dilute hydrochloric acid is added and is adjusted to neutrality, concentrated by rotary evaporation to dry, addition acetic acid second
Ester extraction, washing and dry, magnesium sulfate drying, for concentrated by rotary evaporation to doing, recrystallizing methanol obtains the chloro- 4- of 3- { 4- ethyl -3- [4-
(morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, off-white powder (9.8g), yield 86%.
C 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- first) is prepared
Base -2- oxopentanoate:
The chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -2- oxopentanoic acid
Ester (9.0g, 18.3mmol) is dissolved in methyl tertiary butyl ether(MTBE) (150mL), and m-aminophenyl formonitrile HCN (3.0g, 25.4mmol), carbonic acid is added
Sodium (2.7g, 25.5mmol) and potassium bromide (1.3g, 10.9mmol), 50 DEG C of reaction mixture are stirred to react 12 hours, reaction solution
It is down to room temperature, is added water (40mL), is cooled to 0 DEG C of crystallization 6 hours, filters, obtains 3- (3- cyanophenylamino) -4- { 4- ethyl -3-
[4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, white solid (9.3g), yield
89%.
D 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H-) is prepared
Indole -3-carboxylic acid:
3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate (9.0g, 15.7mmol) is dissolved in formic acid (14.5g, 315.0mmol), and ice bath is cooling, is slowly added to chlorination
Titanium (59.4g, 313.2mmol), 90 DEG C of reaction mixture are stirred to react 12 hours, and reaction solution is down to 70 DEG C, are added water (80mL),
Insulation reaction 2 hours, concentrated by rotary evaporation was added saturated sodium bicarbonate solution and neutralizes to doing, and ethyl acetate extraction is added, and magnesium sulfate is done
Dry, concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to doing, obtains 6- cyano -2- { 2- [4- ethyl -3- (4-
(morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indole -3-carboxylic acid, off-white powder (6.9g), yield 88%.
E) preparation Ai Le replaces Buddhist nun:
6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indoles -
3- carboxylic acid (6.5g, 13.0mmol), trifluoroacetic anhydride (5.5g, 26.2mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (90mL), are heated to
100 DEG C are stirred to react 20 hours, concentrated by rotary evaporation to dry, addition saturated sodium bicarbonate solution neutralization, addition ethyl acetate extraction, sulphur
Sour magnesium is dry, and concentrated by rotary evaporation is recrystallized to doing with ethyl acetate and n-hexane mixed solvent, and get Ai Le replaces Buddhist nun, off-white powder
(5.8g), yield 92%.
Embodiment 3
A 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal) is prepared:
2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (2.3g,
It 5.9mmol) is dissolved in methyl tertiary butyl ether(MTBE) (30mL), is cooled to -78 DEG C, diisobutyl aluminium hydride (7.5mmol) is slowly added dropwise
T-butyl methyl ether solution, -68 DEG C of heat preservation are stirred to react 1 hour, and vacuum rotary steam is added dilute hydrochloric acid and is adjusted to neutrality to doing, second
Acetoacetic ester extraction, washing and drying, for vacuum rotary steam to doing, recrystallisation from isopropanol obtains 2- { 4- ethyl -3- [4- (morpholine -4-
Base) piperidin-1-yl] phenyl } -2 methyl propanal, light yellow solid (1.7g), yield 83%.
B the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxo penta) is prepared
Tert-butyl acrylate:
2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal (1.5g, 4.4mmol) and
2, the 2- dichloroacetic acid tert-butyl esters (1.0g, 5.4mmol) are dissolved in tetrahydrofuran (30mL), and ice bath is cooling, are slowly added to sodium tert-butoxide
(0.51g, 5.3mmol) warms naturally to 40 DEG C, is stirred to react 6 hours, be then added tetrabutylammonium bromide (0.14g,
0.43mmol), it is stirred for reaction 6 hours at room temperature, dilute hydrochloric acid is added and is adjusted to neutrality, concentrated by rotary evaporation to dry, addition acetic acid second
Ester extraction, washing and dry, magnesium sulfate drying, for concentrated by rotary evaporation to doing, recrystallizing methanol obtains the chloro- 4- of 3- { 4- ethyl -3- [4-
(morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, off-white powder (1.7g), yield 79%.
C 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- first) is prepared
Base -2- oxopentanoate:
The chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -2- oxopentanoic acid
Ester (1.5g, 3.0mmol) is dissolved in chloroform (25mL), be added m-aminophenyl formonitrile HCN (0.43g, 3.6mmol), cesium carbonate (1.2g,
3.7mmol) with sodium chloride (0.04g, 0.68mmol), 70 DEG C of reaction mixture are stirred to react 18 hours, and reaction solution is down to room temperature,
It is added water (20mL), is cooled to 0 DEG C of crystallization 4 hours, filter, obtain 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -
4- yl) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, white solid (1.6g), yield 92%.
D 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H-) is prepared
Indole -3-carboxylic acid:
3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate (1.5g, 2.6mmol) is dissolved in acetic acid (6.2g, 103.3mmol), and ice bath is cooling, is slowly added to zinc chloride
(3.6g, 26.4mmol), 110 DEG C of reaction mixture are stirred to react 6 hours, and reaction solution is down to 50 DEG C, are added water (20mL), heat preservation
Reaction 4 hours, concentrated by rotary evaporation are added saturated sodium bicarbonate solution and neutralize to doing, addition ethyl acetate extraction, magnesium sulfate drying,
Concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to dry, obtain 6- cyano -2- 2- [4- ethyl -3- (4- (
Quinoline -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indole -3-carboxylic acid, off-white powder (1.2g), yield 92%.
E) preparation Ai Le replaces Buddhist nun:
6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indoles -
3- carboxylic acid (1.2g, 2.4mmol), acetic acid (1.4g, 23.3mmol) are dissolved in n,N-Dimethylformamide (30mL), are heated to 120
It DEG C is stirred to react 12 hours, concentrated by rotary evaporation is added saturated sodium bicarbonate solution and neutralizes, ethyl acetate extraction, sulfuric acid is added to dry
Magnesium is dry, and concentrated by rotary evaporation is recrystallized to doing with ethyl acetate and n-hexane mixed solvent, and get Ai Le replaces Buddhist nun, off-white powder
(1.0g), yield 86%.
Claims (7)
1. the preparation method that a kind of Ai Le replaces Buddhist nun, which is characterized in that described method includes following steps:
(1) 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal is prepared: by 2- { 4- ethyl -
3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester carries out in the system that reducing agent and solvent form
Reduction reaction obtains 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal；
(2) the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoic acid uncle is prepared
Butyl ester: by 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2 methyl propanal and the tertiary fourth of 2,2- dichloroacetic acid
Ester carries out addition rearrangement reaction in the system that base reagent, phase transfer catalyst and solvent form, and obtains 3- chloro- 4- { 4- ethyl-
3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate；
(3) 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl-is prepared
2- oxopentanoate: by the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxygen
Substitution reaction is carried out in the system that acid binding agent alkali, inorganic salts and solvent form for pentanoate and m-aminophenyl formonitrile HCN, is obtained
To 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- methyl -2- oxo penta
Tert-butyl acrylate；
(4) 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- Yin is prepared
Diindyl -3- carboxylic acid: by 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -4- first
Base -2- oxopentanoate carries out cyclization under the action of acid catalyst and lewis acid catalyst, then carries out water
Solution reaction, obtains 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- Yin
Diindyl -3- carboxylic acid；
(5) preparation Ai Le replaces Buddhist nun: by 6- cyano -2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl-
2- yl } -1H- indole -3-carboxylic acid carries out cyclization in the system that acid catalyst and solvent form, Ai Le is obtained for Buddhist nun.
2. the preparation method that a kind of Ai Le according to claim 1 replaces Buddhist nun, which is characterized in that reduction described in step (1)
Agent is diisobutyl aluminium hydride or bis- (2- methoxy ethoxy) sodium aluminum hydrides；The solvent is tetrahydrofuran, methyl- tert fourth
Base ether, toluene or 1,4- dioxane；Wherein, 2- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] phenyl } -2- methyl
Molar ratio between ethyl propionate, reducing agent is 1.0: (1.2~1.6).
3. the preparation method that a kind of Ai Le according to claim 1 replaces Buddhist nun, which is characterized in that the examination of alkali described in step (2)
Agent is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropylate or tert-pentyl alcohol potassium；The phase transfer catalyst is four
Butyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, three second of benzyl
Base ammonium bromide, methyl tricapryl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride；Described is molten
Agent is tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile or 1,4- dioxane；Wherein, 2- 4- ethyl -3- [4- (
Quinoline -4- base) piperidin-1-yl] phenyl -2 methyl propanal, the 2,2- dichloroacetic acid tert-butyl ester, base reagent, between phase transfer catalyst
Molar ratio be 1.0: (1.2~1.4): (1.2~1.4): (0.02~0.10).
4. the preparation method that a kind of Ai Le according to claim 1 replaces Buddhist nun, which is characterized in that step ties up acid described in (3)
Agent alkali is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide；The inorganic salts are potassium iodide, potassium bromide, chlorine
Change sodium, potassium chloride, sodium bromide or sodium iodide；The solvent is N,N-dimethylformamide, methyl tertiary butyl ether(MTBE), dichloromethane
Alkane, 1,2- dichloroethanes, chloroform, chlorobenzene or 1,4- dioxane；Wherein, the chloro- 4- of 3- { 4- ethyl -3- [4- (morpholine -4- base)
Piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoate, m-aminophenyl formonitrile HCN, acid binding agent alkali, rubbing between inorganic salts
You are than being 1.0: (1.2~1.4): (1.2~1.4): (0.2~0.6).
5. the preparation method that a kind of Ai Le according to claim 1 replaces Buddhist nun, which is characterized in that acid described in step (4) is urged
Agent is trifluoroacetic acid, acetic acid, formic acid, oxalic acid, propionic acid, n-butyric acie or isobutyric acid；The lewis acid catalyst is chlorination
Aluminium, zinc chloride, titanium chloride, stannic chloride, iron chloride, magnesium chloride, copper chloride, aluminum sulfate, ferric sulfate, zinc acetate, boron trifluoride second
Ether or fluoroform sulphonate；Wherein, 3- (3- cyanophenylamino) -4- { 4- ethyl -3- [4- (morpholine -4- base) piperidin-1-yl] benzene
Base } -4- methyl -2- oxopentanoate, acid catalyst, the molar ratio between lewis acid catalyst be 1.0: (20.0~
40.0): (10.0~20.0).
6. the preparation method that a kind of Ai Le according to claim 1 replaces Buddhist nun, which is characterized in that acid described in step (5) is urged
Agent is trifluoroacetic acid, trifluoroacetic anhydride, acetic acid, acetic anhydride, formic acid, oxalic acid, oxalyl chloride, phosphorus pentoxide, phosphorus oxychloride, chlorine
Change sulfoxide, phosphorus pentachloride, phosphorus trichloride, polyphosphoric acids, p-methyl benzenesulfonic acid, paratoluensulfonyl chloride, methanesulfonic acid or mesyl chloride；
The solvent is toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or 1,4- dioxane；Wherein, 6- cyano-
2- { 2- [4- ethyl -3- (4- (morpholine -4- base) piperidin-1-yl) phenyl] propyl- 2- yl } -1H- indole -3-carboxylic acid, acid catalyst
Between molar ratio be 1.0: (2.0~10.0).
7. the preparation method that a kind of Ai Le according to claim 1 replaces Buddhist nun, which is characterized in that reduction described in step (1)
The temperature of reaction is -78~-68 DEG C, and the reaction time is 1~3 hour；The temperature of addition rearrangement reaction described in step (2) is 20
~40 DEG C, the reaction time is 12~24 hours；The temperature of substitution reaction described in step (3) is 50~70 DEG C, and the reaction time is
12~18 hours；The temperature of cyclization described in step (4) is 90~110 DEG C, and the reaction time is 6~12 hours；Described
The temperature of hydrolysis is 50~70 DEG C, and the reaction time is 2~4 hours；The temperature of cyclization described in step (5) is 100
~120 DEG C, the reaction time is 12~20 hours.
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