CN107033124A - 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
- Publication number
- CN107033124A CN107033124A CN201710263665.5A CN201710263665A CN107033124A CN 107033124 A CN107033124 A CN 107033124A CN 201710263665 A CN201710263665 A CN 201710263665A CN 107033124 A CN107033124 A CN 107033124A
- Authority
- CN
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- Prior art keywords
- morpholine
- phenyl
- piperidin
- bases
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 166
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 10
- 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
- -1 cyanophenylamino Chemical group 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000460 chlorine Substances 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- FOLRKRMAFDGZRR-UHFFFAOYSA-N tert-butyl 2,2-dichloroacetate Chemical class CC(C)(C)OC(=O)C(Cl)Cl FOLRKRMAFDGZRR-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000002585 base Substances 0.000 claims description 95
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 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 22
- 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
- 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
- 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
- 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
- 150000003839 salts Chemical class 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
- 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 5
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical class CC(C)C=O AMIMRNSIRUDHCM-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
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 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
- 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
- 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
- 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
- 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
- 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
- 229910019213 POCl3 Inorganic materials 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
- 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
- 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
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004246 zinc acetate Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 2
- 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
- 239000001142 4-methyl-2-oxopentanoic acid Substances 0.000 claims 1
- 229910015900 BF3 Inorganic materials 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 150000001299 aldehydes Chemical class 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 5
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical class CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 abstract 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000002390 rotary evaporation Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000376 reactant Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 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
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- 239000000463 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
- 238000005406 washing Methods 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
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-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
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects 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
- 239000002547 new drug Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride 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
- 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
- APYLNYCULQUSLG-UHFFFAOYSA-N 9h-carbazole-3-carbonitrile Chemical compound C1=CC=C2C3=CC(C#N)=CC=C3NC2=C1 APYLNYCULQUSLG-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- JCADXTLJQSQBQA-UHFFFAOYSA-N CCc1ccc(C(C)(C)C(OCC)=O)cc1N(CC1)CCC1N1CCOCC1 Chemical compound CCc1ccc(C(C)(C)C(OCC)=O)cc1N(CC1)CCC1N1CCOCC1 JCADXTLJQSQBQA-UHFFFAOYSA-N 0.000 description 1
- IZXIEGQJATXOJQ-UHFFFAOYSA-N CCc1ccc(C(C)(C)C=O)cc1N(CC1)CCC1N1CCOCC1 Chemical compound CCc1ccc(C(C)(C)C=O)cc1N(CC1)CCC1N1CCOCC1 IZXIEGQJATXOJQ-UHFFFAOYSA-N 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027336 Menstruation delayed 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
- ZGBSOTLWHZQNLH-UHFFFAOYSA-N [Mg].S(O)(O)(=O)=O Chemical compound [Mg].S(O)(O)(=O)=O ZGBSOTLWHZQNLH-UHFFFAOYSA-N 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-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
- 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
- 229940049706 benzodiazepine Drugs 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
- 229910052799 carbon Inorganic materials 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
- 229940079593 drug Drugs 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
- 238000000605 extraction Methods 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
- 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
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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 class CCCC(=O)C(=O)OC MBNLVYPIKSWXCT-UHFFFAOYSA-N 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
- 150000004885 piperazines Chemical class 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the preparation method that a kind of Ai Le replaces Buddhist nun.2 { 4 ethyl 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } 2 methylpropanoates are carried out reduction reaction by this method；Obtain 2 { 4 ethyl 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } 2 butylic aldehydes and the 2,2 dichloroacetic acid tert-butyl esters are subjected to addition rearrangement reaction；The obtained oxopentanoate of 3 chlorine 4 { 4 ethyl 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } 4 methyl 2 and m-aminophenyl formonitrile HCN are subjected to substitution reaction；The oxopentanoate of obtain 3 (3 cyanophenylamino) 4 { 4 ethyl 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } 4 methyl 2 is subjected to cyclization and hydrolysis；The carboxylic acid of 6 obtained cyano group 2 { 2 [4 ethyl 3 (4 (base of morpholine 4) piperidinyl-1 base) phenyl] the third 2 base } 1H indoles 3 is subjected to cyclization, Ai Le is obtained for Buddhist nun.This method operation simplifies, and cost is relatively low, is a kind of environmental protection process, it is adaptable to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of Ai Le replaces the preparation method of Buddhist nun.
Background technology
New anaplastic lymphoma kinase (ALK) inhibitor Ai Le replaces chemical entitled 9- ethyl -6 of Buddhist nun (Alectinib),
6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs,
Its chemical structural formula is：
Ai Le is the original new drug of the branch company Chugai Pharmaceutical inventions of company of Roche Group for Buddhist nun,
Through obtaining the breakthrough medicine recognition of qulifications of U.S. FDA, accelerate examination ＆ approval as oral anti-lung cancer new drug, for treating ALK
Late period (metastatic) non-small cell lung cancer (NSCLC) of gene mutation, or to (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine be resistant to patient treatment.
It is a kind of disclosed in patent US20130143877 and WO2012023597A1 to prepare the synthetic route that Ai Le replaces Buddhist nun：With
7- methoxyl group -3,4- dihydro -2- naphthalenones are initiation material, are methylated and bromination reaction by double, then with the Fischer of phenylhydrazine
Indole synthesis carry out ring-closure reaction, are then passed through oxidation and introduce 11- carbonyls, then the hydroxyl obtained by methoxy hydrolysis is carried out
It is triflated, it is condensed with 4- (4- piperidyls) morpholine, last 9- bromos are replaced by acetenyl, then are obtained through reduction reaction
Ai Le replaces Buddhist nun, and process route is as follows：
Because whole synthetic route step is longer, cumbersome, cost is higher, is unfavorable for amplification production and industrialization is pushed 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 initiation material, and by condensation, cyclization, the condensation with 4- (4- piperidyls) 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 used as starting raw material：
The above two is combined into the initiation material of route costly, is difficult to obtain, thus needs synthetically prepared；Due to two
The midbody product and final products for being combined into route are impure more with accessory substance, thus purifying needs to use a large amount of solvents,
Cumbersome, yield is relatively low, is unfavorable for industrialization production popularization, it is therefore necessary to explore that technological process is short, simple to operate, cost
Ai Le that is cheap and using suitable industrialized production replaces the preparation method of Buddhist nun.
The content of the invention
It is contemplated that overcoming the deficiencies in the prior art, there is provided the preparation method that a kind of Ai Le replaces Buddhist nun.
In order to achieve the above object, the technical scheme that provides of the present invention is：
The Ai Le comprises the following steps for the preparation method of Buddhist nun：
(1) 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal is prepared：By 2- { 4- second
Base -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester enters in the system that reducing agent and solvent are constituted
Row reduction reaction, obtains 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal, and reaction equation is：
(2) 3- chloro- 4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxos penta are prepared
Tert-butyl acrylate：By 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanals 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 are constituted, and obtains the chloro- 4- { 4- of 3-
Ethyl -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, reaction equation is：
(3) 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- is prepared
Methyl -2- oxopentanoates：By the chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- first
Base -2- oxopentanoates are replaced with m-aminophenyl formonitrile HCN in the system that acid binding agent alkali, inorganic salts and solvent are constituted
Reaction, obtains 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate, reaction equation is：
(4) prepare 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -
1H- indole -3-carboxylic acids：By 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -
4- methyl -2- oxopentanoates carry out cyclization in the presence of acid catalyst and lewis acid catalyst, then enter
Row hydrolysis, obtain 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -
1H- indole -3-carboxylic acids, reaction equation is：
(5) prepare Ai Le and replace Buddhist nun：By 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl]
Propyl- 2- yls } -1H- indole -3-carboxylic acids carry out cyclization in the system that acid catalyst and solvent are constituted, and obtain Ai Le for Buddhist nun,
Reaction equation is：
Preferably, the reducing agent described in step (1) is diisobutyl aluminium hydride or double (2- methoxy ethoxies) aluminum hydrides
Sodium；Described solvent is tetrahydrofuran, methyl tertiary butyl ether(MTBE), toluene or 1,4- dioxane；Wherein, 2- { 4- ethyl -3- [4-
(morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, the mol 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 itself and reactant and the molar ratio of reagent.
Preferably, the base reagent described in step (2) is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, sodium isopropylate
Or tert-pentyl alcohol potassium；Described phase transfer catalyst is tetrabutylammonium chloride, TBAB, 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；Described solvent be tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile or
1,4- dioxane；Wherein, 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal, 2,2- bis-
Mol ratio between chloroacetic acid tert-butyl ester, base reagent, phase transfer catalyst is 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 itself and reactant and the molar ratio of reagent.
Preferably, the acid binding agent alkali described in step (3) is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or hydroxide
Potassium；Described inorganic salts are KI, KBr, sodium chloride, potassium chloride, sodium bromide or sodium iodide；Described solvent is N, N-
Dimethylformamide, methyl tertiary butyl ether(MTBE), dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene or 1,4- dioxane；Wherein,
The chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, an amino
Mol ratio between benzonitrile, acid binding agent alkali, inorganic salts is 1.0: (1.2~1.4): (1.2~1.4): (0.2~0.6), solvent
For the medium of reaction, reaction is not involved in, is not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the acid catalyst described in step (4) is trifluoroacetic acid, acetic acid, formic acid, oxalic acid, propionic acid, n-butyric acie or different
Butyric acid；Described lewis acid catalyst be aluminium chloride, zinc chloride, titanium chloride, stannic chloride, iron chloride, magnesium chloride, copper chloride,
Aluminum sulfate, ferric sulfate, zinc acetate, BFEE or fluoroform sulphonate；Wherein, 3- (3- cyanophenylaminos) -4- { 4- second
Base -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, acid catalyst, lewis acid
Mol ratio between catalyst is 1.0: (20.0~40.0): (10.0~20.0).
Preferably, the acid catalyst described in step (5) is trifluoroacetic acid, TFAA, acetic acid, acetic anhydride, formic acid, grass
Acid, oxalyl chloride, phosphorus pentoxide, POCl3, thionyl chloride, phosphorus pentachloride, phosphorus trichloride, polyphosphoric acids, to toluene sulphur
Acid, paratoluensulfonyl chloride, methanesulfonic acid or mesyl chloride；Described solvent is toluene, N,N-dimethylformamide, N, N- dimethyl
Acetamide or 1,4- dioxane；Wherein, 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl]
Propyl- 2- yls } -1H- indole -3-carboxylic acids, the mol ratio between acid catalyst be 1.0: (2.0~10.0), solvent for reaction matchmaker
It is situated between, is not involved in reaction, is not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the temperature of the reduction reaction described in step (1) is -78~-68 DEG C, and the reaction time is 1~3 hour；Step
Suddenly the temperature of the addition rearrangement reaction described in (2) is 20~40 DEG C, and the reaction time is 12~24 hours；Taking described in step (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 described 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- ethyls -3- [4- (morpholine -4- bases) piperazines
Pyridine -1- bases] 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 esters
Into rearrangement reaction, the obtained chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxos
Pentanoate carries out substitution reaction with m-aminophenyl formonitrile HCN, is related to aniline alkylating, and then molecule inner ring condensation prepares indoles mother
Core, reaction condition is gentle, eventually passes hydrolysis and is cyclized again, prepares Ai Le for Buddhist nun, the route methods are reasonable in design solely
Arrive, raw material is cheap and easy to get, reaction condition is easily effectively controlled.
The technical scheme that the present invention is provided has following technique effect：First, only making after being completed due to the reaction of each step normal
The post processing and purifying of rule property are without column chromatography, and impurity is less, controllable, can directly carry out next step reaction, therefore
Operation is simplified, while each step can obtain higher yield；Second, the process route initiation material and used of the present invention
Reagent is easy to get, and the technical scheme of synthetic reaction rationally, can largely produce to meet the use demand of bulk drug, it is adaptable to industry
Metaplasia is produced；Third, due to pollutant will not be produced in preparation process, thus environmental protection effect can be embodied.
Embodiment
Embodiment 1
A 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal) is prepared：
2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (5.0g,
Tetrahydrofuran (80mL) 12.9mmol) is dissolved in, -78 DEG C are cooled to, the four of diisobutyl aluminium hydride (18.0mmol) are slowly added dropwise
Hydrogen tetrahydrofuran solution, -78 DEG C of insulation stirring reaction 2 hours, vacuum rotary steam adds watery hydrochloric acid and adjusted to neutrality, ethyl acetate to dry
Extraction, washing and is dried, vacuum rotary steam to dry, recrystallisation from isopropanol, obtain 2- 4- ethyls -3- [4- (morpholine -4- bases) piperidines -
1- yls] phenyl } -2 methyl propanal, light yellow solid (4.1g), yield 92%.
B 3- chloro- 4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxos penta) are prepared
Tert-butyl acrylate：
2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanals (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 cooling is slowly added to sodium methoxide
(0.8g, 14.8mmol), warms naturally to 30 DEG C, stirring reaction 9 hours, then add tetrabutylammonium chloride (0.2g,
0.72mmol), reaction 9 hours is stirred at room temperature, is added watery hydrochloric acid and is adjusted to neutrality, concentrated by rotary evaporation adds acetic acid second to dry
Ester is extracted, washing and dry, magnesium sulfate drying, and concentrated by rotary evaporation is to doing, and recrystallizing methanol obtains the chloro- 4- of 3- { 4- ethyl -3- [4-
(morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, off-white powder (4.6g), yield 80%.
C 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- first) is prepared
Base -2- oxopentanoates：
The chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -2- oxopentanoic acids
Ester (4.5g, 9.1mmol) is dissolved in DMF (90mL), adds m-aminophenyl formonitrile HCN (1.4g, 11.9mmol), carbon
Sour potassium (1.6g, 11.6mmol) and KI (0.6g, 3.6mmol), 60 DEG C of reactant mixture stirring reaction 15 hours, reaction solution
Be down to room temperature, add water (60mL), be cooled to -10 DEG C of crystallizations 3 hours, filtering, obtain 3- (3- cyanophenylaminos) -4- 4- ethyls -
3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, white solid (4.6g), yield
88%.
D 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H-) is prepared
Indole -3-carboxylic acid：
3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate (4.5g, 7.8mmol) is dissolved in trifluoroacetic acid (26.8g, 235.0mmol), and ice bath cooling is slowly added to chlorine
Change aluminium (15.7g, 117.7mmol), 100 DEG C of reactant mixture stirring reaction 9 hours, reaction solution is down to 60 DEG C, adds water
(50mL), insulation reaction 3 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction,
Magnesium sulfate is dried, and concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to dry, obtains 6- cyano group -2- { 2- [4- second
Base -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids, off-white powder (3.5g), receipts
Rate 89%.
E) prepare Ai Le and replace Buddhist nun：
6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles -
3- carboxylic acids (3.5g, 7.0mmol), trifluoroacetic acid (4.8g, 42.1mmol) are dissolved in toluene (40mL), are heated to 110 DEG C of stirrings anti-
Answer 16 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, rotation
Steaming is concentrated to dryness, and is recrystallized with ethyl acetate and n-hexane mixed solvent, get Ai Le replaces Buddhist nun, off-white powder (3.1), yield
92%.
Embodiment 2
A 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal) is prepared：
2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (10.0g,
Isosorbide-5-Nitrae-dioxane (120mL) 25.7mmol) is dissolved in, -78 DEG C are cooled to, double (2- methoxy ethoxies) aluminum hydrides are slowly added dropwise
Isosorbide-5-Nitrae-dioxane solution of sodium (41.0mmol), -75 DEG C of insulation stirring reaction 3 hours, vacuum rotary steam adds watery hydrochloric acid to dry
Regulation to neutrality, ethyl acetate extraction is washed and dried, and vacuum rotary steam is to doing, and recrystallisation from isopropanol obtains 2- { 4- ethyls -3-
[4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal, light yellow solid (8.0g), yield 90%.
B 3- chloro- 4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxos penta) are prepared
Tert-butyl acrylate：
2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanals (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 cooling is slowly added to the tert-butyl alcohol
Potassium (3.6g, 32.1mmol), warms naturally to 20 DEG C, stirring reaction 12 hours, then add tetrabutylammonium iodide (0.17g,
0.46mmol), reaction 12 hours is stirred at room temperature, is added watery hydrochloric acid and is adjusted to neutrality, concentrated by rotary evaporation adds acetic acid second to dry
Ester is extracted, washing and dry, magnesium sulfate drying, and concentrated by rotary evaporation is to doing, and recrystallizing methanol obtains the chloro- 4- of 3- { 4- ethyl -3- [4-
(morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, off-white powder (9.8g), yield 86%.
C 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- first) is prepared
Base -2- oxopentanoates：
The chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -2- oxopentanoic acids
Ester (9.0g, 18.3mmol) is dissolved in methyl tertiary butyl ether(MTBE) (150mL), adds m-aminophenyl formonitrile HCN (3.0g, 25.4mmol), carbonic acid
Sodium (2.7g, 25.5mmol) and KBr (1.3g, 10.9mmol), 50 DEG C of reactant mixture stirring reaction 12 hours, reaction solution
It is down to room temperature, adds water (40mL), be cooled to 0 DEG C of crystallization 6 hours, filtering obtains 3- (3- cyanophenylaminos) -4- { 4- ethyls -3-
[4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, white solid (9.3g), yield
89%.
D 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H-) is prepared
Indole -3-carboxylic acid：
3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate (9.0g, 15.7mmol) is dissolved in formic acid (14.5g, 315.0mmol), and ice bath cooling is slowly added to chlorination
Titanium (59.4g, 313.2mmol), 90 DEG C of reactant mixture stirring reaction 12 hours, reaction solution is down to 70 DEG C, adds water (80mL),
Insulation reaction 2 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, and magnesium sulfate is done
Dry, concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to dry, obtains 6- cyano group -2- { 2- [4- ethyl -3- (4-
(morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids, off-white powder (6.9g), yield 88%.
E) prepare Ai Le and replace Buddhist nun：
6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles -
3- carboxylic acids (6.5g, 13.0mmol), TFAA (5.5g, 26.2mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (90mL), are heated to
100 DEG C of stirring reactions 20 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, sulphur
Sour magnesium is dried, and concentrated by rotary evaporation is recrystallized, get Ai Le replaces Buddhist nun, off-white powder to dry with ethyl acetate and n-hexane mixed solvent
(5.8g), yield 92%.
Embodiment 3
A 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal) is prepared：
2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (2.3g,
Methyl tertiary butyl ether(MTBE) (30mL) 5.9mmol) is dissolved in, -78 DEG C are cooled to, diisobutyl aluminium hydride (7.5mmol) is slowly added dropwise
T-butyl methyl ether solution, -68 DEG C of insulation stirring reaction 1 hour, vacuum rotary steam adds watery hydrochloric acid and adjusted to neutrality, second to dry
Acetoacetic ester is extracted, and is washed and is dried, and vacuum rotary steam is to doing, and recrystallisation from isopropanol obtains 2- { 4- ethyls -3- [4- (morpholine -4-
Base) piperidin-1-yl] phenyl } -2 methyl propanal, light yellow solid (1.7g), yield 83%.
B 3- chloro- 4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxos penta) are prepared
Tert-butyl acrylate：
2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanals (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 cooling is slowly added to sodium tert-butoxide
(0.51g, 5.3mmol), warms naturally to 40 DEG C, stirring reaction 6 hours, then add TBAB (0.14g,
0.43mmol), reaction 6 hours is stirred at room temperature, is added watery hydrochloric acid and is adjusted to neutrality, concentrated by rotary evaporation adds acetic acid second to dry
Ester is extracted, washing and dry, magnesium sulfate drying, and concentrated by rotary evaporation is to doing, and recrystallizing methanol obtains the chloro- 4- of 3- { 4- ethyl -3- [4-
(morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, off-white powder (1.7g), yield 79%.
C 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- first) is prepared
Base -2- oxopentanoates：
The chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -2- oxopentanoic acids
Ester (1.5g, 3.0mmol) is dissolved in chloroform (25mL), add 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 reactant mixture stirring reaction 18 hours, reaction solution is down to room temperature,
Add water (20mL), be cooled to 0 DEG C of crystallization 4 hours, filtering, obtain 3- (3- cyanophenylaminos) -4- 4- ethyls -3- [4- (morpholine -
4- yls) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates, white solid (1.6g), yield 92%.
D 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H-) is prepared
Indole -3-carboxylic acid：
3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2-
Oxopentanoate (1.5g, 2.6mmol) is dissolved in acetic acid (6.2g, 103.3mmol), and ice bath cooling is slowly added to zinc chloride
(3.6g, 26.4mmol), 110 DEG C of reactant mixture stirring reaction 6 hours, reaction solution is down to 50 DEG C, adds water (20mL), insulation
Reaction 4 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, and magnesium sulfate is dried,
Concentrated by rotary evaporation is recrystallized to dry with ethyl acetate and n-hexane mixed solvent, obtain 6- cyano group -2- 2- [4- ethyls -3- (4- (
Quinoline -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids, off-white powder (1.2g), yield 92%.
E) prepare Ai Le and replace Buddhist nun：
6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles -
3- carboxylic acids (1.2g, 2.4mmol), acetic acid (1.4g, 23.3mmol) are dissolved in DMF (30mL), are heated to 120
DEG C stirring reaction 12 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, sulfuric acid
Magnesium is dried, and concentrated by rotary evaporation is recrystallized, get Ai Le replaces Buddhist nun, off-white powder to dry with ethyl acetate and n-hexane mixed solvent
(1.0g), yield 86%.
Claims (7)
1. a kind of Ai Le replaces the preparation method of Buddhist nun, it is characterised in that methods described comprises the following steps：
(1) 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal is prepared：By 2- 4- ethyls-
3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } progress in the system that reducing agent and solvent are constituted of -2 Methylpropionic acid ethyl ester
Reduction reaction, obtains 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanal；
(2) 3- chloro- 4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoic acid uncles are prepared
Butyl ester：By 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 methyl propanals 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 are constituted, obtain 3- chloro- 4- 4- ethyls-
3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxopentanoates；
(3) prepare 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -
2- oxopentanoates：By the chloro- 4- of 3- { 4- ethyls -3- [4- (morpholine -4- bases) 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 are constituted for pentanoate and m-aminophenyl formonitrile HCN, is obtained
To 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -2- oxos penta
Tert-butyl acrylate；
(4) 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- Yin are prepared
Diindyl -3- carboxylic acids：By 3- (3- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- first
Base -2- oxopentanoates carry out cyclization in the presence of acid catalyst and lewis acid catalyst, then enter water-filling
Solution reaction, obtains 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- Yin
Diindyl -3- carboxylic acids；
(5) prepare Ai Le and replace Buddhist nun：By 6- cyano group -2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl-s
2- yls } -1H- indole -3-carboxylic acids carry out cyclization in the system that acid catalyst and solvent are constituted, and obtain Ai Le for Buddhist nun.
2. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the reduction described in step (1)
Agent is diisobutyl aluminium hydride or double (2- methoxy ethoxies) sodium aluminum hydrides；Described solvent is tetrahydrofuran, methyl- tert fourth
Base ether, toluene or 1,4- dioxane；Wherein, 2- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2- methyl
Mol ratio between ethyl propionate, reducing agent is 1.0: (1.2~1.6).
3. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the alkali examination described in step (2)
Agent is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, sodium isopropylate or tert-pentyl alcohol potassium；Described phase transfer catalyst is four
Butyl ammonium chloride, TBAB, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, the second of benzyl three
Base ammonium bromide, methyl tricapryl ammonium chloride, DTAC or tetradecyl trimethyl ammonium chloride；Described is molten
Agent is tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile or 1,4- dioxane；Wherein, 2- 4- ethyls -3- [4- (
Quinoline -4- bases) piperidin-1-yl] phenyl -2 methyl propanal, the 2,2- dichloroacetic acid tert-butyl ester, base reagent, between phase transfer catalyst
Mol ratio be 1.0: (1.2~1.4): (1.2~1.4): (0.02~0.10).
4. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that tie up acid described in step (3)
Agent alkali is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide；Described inorganic salts are KI, KBr, chlorine
Change sodium, potassium chloride, sodium bromide or sodium iodide；Described 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- ethyls -3- [4- (morpholine -4- bases)
Piperidin-1-yl] phenyl -4- methyl -2- oxopentanoates, 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. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the 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；Described 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- cyanophenylaminos) -4- { 4- ethyls -3- [4- (morpholine -4- bases) piperidin-1-yl] benzene
Base } -4- methyl -2- oxopentanoates, acid catalyst, the mol ratio between lewis acid catalyst be 1.0: (20.0~
40.0): (10.0~20.0).
6. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the acid described in step (5) is urged
Agent is trifluoroacetic acid, TFAA, acetic acid, acetic anhydride, formic acid, oxalic acid, oxalyl chloride, phosphorus pentoxide, POCl3, chlorine
Change sulfoxide, phosphorus pentachloride, phosphorus trichloride, polyphosphoric acids, p-methyl benzenesulfonic acid, paratoluensulfonyl chloride, methanesulfonic acid or mesyl chloride；
Described solvent is toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or 1,4- dioxane；Wherein, 6- cyano group-
2- { 2- [4- ethyls -3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids, acid catalyst
Between mol ratio be 1.0: (2.0~10.0).
7. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the 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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| CN110452215A (en) * | 2018-05-08 | 2019-11-15 | 新发药业有限公司 | A kind of Ai Le replaces the preparation method of Buddhist nun for Buddhist nun's intermediate and Ai Le |
| WO2020050241A1 (en) * | 2018-09-04 | 2020-03-12 | 中外製薬株式会社 | Method of producing tetracyclic compound |
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
| US11465999B2 (en) | 2017-07-05 | 2022-10-11 | Fresenius Kabi Oncology Ltd. | Process for preparing Alectinib or a pharmaceutically acceptable salt thereof |
| CN110452215A (en) * | 2018-05-08 | 2019-11-15 | 新发药业有限公司 | A kind of Ai Le replaces the preparation method of Buddhist nun for Buddhist nun's intermediate and Ai Le |
| CN110452215B (en) * | 2018-05-08 | 2020-07-17 | 新发药业有限公司 | Preparation method of erlotinib intermediate and erlotinib |
| WO2020050241A1 (en) * | 2018-09-04 | 2020-03-12 | 中外製薬株式会社 | Method of producing tetracyclic compound |
| CN112585126A (en) * | 2018-09-04 | 2021-03-30 | 中外制药株式会社 | Tetracyclic compounds |
| JPWO2020050241A1 (en) * | 2018-09-04 | 2021-08-30 | 中外製薬株式会社 | Method for producing tetracyclic compound |
| EP3848361A4 (en) * | 2018-09-04 | 2022-06-15 | Chugai Seiyaku Kabushiki Kaisha | Method of producing tetracyclic compound |
| JP7167171B2 (en) | 2018-09-04 | 2022-11-08 | 中外製薬株式会社 | Method for producing tetracyclic compound |
| US11939322B2 (en) | 2018-09-04 | 2024-03-26 | Chugai Seiyaku Kabushiki Kaisha | Method for producing tetracyclic compound |
| CN112585126B (en) * | 2018-09-04 | 2024-05-07 | 中外制药株式会社 | Process for preparing tetracyclic compounds |
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
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