CN114380763A - Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one - Google Patents
Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one Download PDFInfo
- Publication number
- CN114380763A CN114380763A CN202011109641.2A CN202011109641A CN114380763A CN 114380763 A CN114380763 A CN 114380763A CN 202011109641 A CN202011109641 A CN 202011109641A CN 114380763 A CN114380763 A CN 114380763A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- reaction
- mmol
- sodium
- 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.)
- Pending
Links
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 238000005917 acylation reaction Methods 0.000 claims abstract description 11
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 11
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims abstract description 10
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims abstract description 10
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- 238000010189 synthetic method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 148
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 101
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 30
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 18
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000005660 chlorination reaction Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 7
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 5
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 claims description 5
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- UXBLSWOMIHTQPH-UHFFFAOYSA-N 4-acetamido-TEMPO Chemical compound CC(=O)NC1CC(C)(C)N([O])C(C)(C)C1 UXBLSWOMIHTQPH-UHFFFAOYSA-N 0.000 claims description 4
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003810 Jones reagent Substances 0.000 claims description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 4
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 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 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 4
- 229960002218 sodium chlorite Drugs 0.000 claims description 4
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 4
- 239000001119 stannous chloride Substances 0.000 claims description 4
- 235000011150 stannous chloride Nutrition 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 3
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 239000012320 chlorinating reagent Substances 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 8
- 230000010933 acylation Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- CAFAOQIVXSSFSY-UHFFFAOYSA-N 1-ethoxyethanol Chemical class CCOC(C)O CAFAOQIVXSSFSY-UHFFFAOYSA-N 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 82
- 239000000243 solution Substances 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000002699 waste material Substances 0.000 description 7
- HUTXVUPGARJNHM-UHFFFAOYSA-N 1-(2-chloroethoxy)ethanol Chemical compound CC(O)OCCCl HUTXVUPGARJNHM-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 235000010265 sodium sulphite Nutrition 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000005457 optimization Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 208000005374 Poisoning Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical class C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 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
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a synthesis method of Ribose intermediate 4- (4-aminophenyl) morpholine-3-one (CAS:438056-69-0) shown in formula (f), which is characterized in that 2-halogenated ethoxy ethanol is used as a raw material, and the Ribose intermediate 4- (4-aminophenyl) morpholine-3-one is synthesized through five steps of oxidation, acylation, condensation, ring closure and reduction. The synthetic method has the advantages of high yield, simple and convenient operation, low cost, less uncontrollable generated impurities, suitability for industrial production and the like. The structure of the Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one is as follows:
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of a Ribose intermediate 4- (4-aminophenyl) morpholine-3-one.
Background
Rizhua sand ban (CAS: 366789-02-8, trade name is Bytritol) is a famous novel anticoagulant drug which can be orally taken, is jointly developed by Germany Bayer and America, is approved to be on the market in Canada and European Union respectively in 2008 and 9 and 10 months, is approved to be on the market in 7 months in 2011, and is approved to be on the market in 29 countries including China at present, so that the market demand is wide; and 4- (4-aminophenyl) morpholine-3-one (CAS:438056-69-0) is a key intermediate for synthesizing Ribose.
At present, a plurality of relevant patents or documents exist in the process of synthesizing 4- (4-aminophenyl) morpholine-3-one. Taking (WO2019138362a1, Heterocycles,2007, vol.74, # cp.437-445) as an example, the routes have more or less defects such as poor process stability, tedious operation, low yield, more three wastes, serious environmental pollution, uncontrollable impurity generation and the like, so that the production risk is large, the cost is high, and the method is not suitable for industrial production.
Specifically, the method comprises the following steps: the synthesis of 4- (4-aminophenyl) morpholin-3-one from the compounds p-nitroaniline and 2-chloroethoxyethanol by oxidation, acylation, ring closure and reduction is described in patent document (WO2019138362a1) and is shown in scheme (B):
the obvious drawbacks are: 1. the phenylboronic acid used in the reaction in the step 2 is expensive, the source of goods is limited, and the capacity is limited; 2. the solvent adopted in the step 3 is acetonitrile, and is mutually soluble with water in the post-treatment process, so that the treatment difficulty, treatment capacity and treatment cost of three wastes are obviously increased.
Disclosure of Invention
The invention provides a novel industrial synthesis method of Rizhamaban intermediate 4- (4-aminophenyl) morpholine-3-ketone. The synthesis method of the invention takes the compound of the formula a as a raw material, and synthesizes the Ribose intermediate 4- (4-aminophenyl) morpholine-3-ketone through oxidation, chlorination, acylation, ring closing and reduction reactions in sequence. The method has the advantages of high process stability, simple operation, economy, environmental protection, suitability for industrial production and the like.
The invention provides a synthesis method of Rizhushaban intermediate 4- (4-aminophenyl) morpholine-3-ketone, the synthesis process is shown in a route (A),
wherein X is halogen, etc.;
preferably, X is chlorine.
The invention relates to a synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one, which comprises the following steps:
1) in a solvent, under the action of an oxidant, carrying out an oxidation reaction on the compound shown in the formula a to obtain a compound shown in the formula b;
2) in a solvent, under the action of a chlorination reagent, performing chlorination reaction on the compound shown in the formula b to obtain a compound shown in the formula c;
3) in an organic solvent, under the action of a catalyst, the compound of the formula c and p-nitroaniline are subjected to acylation reaction to obtain a compound of a formula d;
4) in an organic solvent, under the action of alkali, the compound of the formula d undergoes a ring closure reaction to obtain a compound of the formula e;
5) and (3) in an organic solvent, under the action of a catalyst, carrying out reduction reaction on the compound of the formula e under the action of a reducing agent to obtain a compound of the formula f.
In the step 1), the oxidant is one or more of sodium hypochlorite, sodium periodate, sodium chlorite, NBS, NCS, hydrogen peroxide, TCCA, Jone reagent, potassium permanganate, TEMPO, 4-hydroxy-TEMPO, 4-acetamido-TEMPO and the like; preferably, sodium hypochlorite.
In the step 1), the solvent is one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, acetone, acetonitrile, water and the like; preferably, the solvent is a mixed solvent of water and dichloromethane.
In the step 1), the molar ratio of the compound of the formula a to the oxidant is 1: (1-5); preferably, 1: 3.
in the step 1), the temperature of the oxidation reaction is 0-60 ℃; preferably, it is 25 ℃.
In the step 1), the time of the oxidation reaction is 1-24 h; preferably, it is 2 h.
In the step 2), the solvent is one or more of dichloromethane, 1, 2-dichloroethane, toluene, xylene, tetrahydrofuran, dioxane, acetonitrile and the like; preferably, dichloromethane.
In the step 2), the chlorinated reagent is one or more of thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, oxalyl chloride and the like; preferably, oxalyl chloride.
In the step 2), the mol ratio of the compound of the formula b to the chlorinated reagent is 1: (1-10); preferably, 1: 2.5.
in the step 2), the temperature of the chlorination reaction is 0-110 ℃; preferably, it is 30 ℃.
In the step 2), the time of the chlorination reaction is 3-24 h; preferably, it is 8 h.
In the step 3), the organic solvent is one or more of toluene, xylene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, DMF and the like; preferably, dichloromethane.
In the step 3), the catalyst is one or more of DMAP, triethylamine, pyridine, DBU, DBN and the like; preferably, DMAP.
In the step 3), the molar ratio of the compound of the formula c, the p-nitroaniline and the catalyst is (1-10): 1: (0.1-5); preferably, 1: 1: 0.5.
in the step 3), the temperature of the acylation reaction is 0-150 ℃; preferably, it is 40 ℃.
In the step 3), the acylation reaction time is 1-16 h; preferably, it is 3 h.
In the step 4), the organic solvent is one or more of toluene, xylene, isopropanol, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, DMF, acetone, methyl ethyl ketone and the like; preferably, dichloromethane.
In the step 4), the alkali is one or more of pyridine, triethylamine, DIPEA, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate and the like; preferably, triethylamine.
In the step 4), the molar ratio of the compound of the formula d to the base is 1: (1-10); preferably, 1: 3.
in the step 4), the temperature of the ring closing reaction is 0-150 ℃; preferably, it is 40 ℃.
In the step 4), the time of the ring closing reaction is 1-20 h; preferably, it is 15 h.
In the step 5), the organic solvent is one or more of methanol, ethanol, isopropanol, ethyl acetate, DMF, 1, 2-dichloroethane, tetrahydrofuran and the like; preferably, it is methanol.
In the step 5), the catalyst is one or more of palladium carbon, platinum carbon, Raney nickel and the like; preferably, palladium on carbon.
In the step 5), the reducing agent is one or more of hydrogen, formic acid, ammonium formate, sodium hydrosulfite, stannous chloride, sodium sulfide and the like; preferably, it is hydrogen.
In the step 5), the molar ratio of the compound of the formula e to the catalyst to the reducing agent is 1: (0.01-1): (1-10); preferably, 1: 0.1: 4.
in the step 5), the temperature of the reduction reaction is 0-100 ℃; preferably, it is 40 ℃.
In the step 5), the time of the reduction reaction is 1-20 h; preferably, it is 4 h.
In the route of the invention, the reaction stability is high, the operation is simple, the three wastes are less, and the cost has obvious advantages.
The process for obtaining the compound of formula f according to the invention has the following advantages: 1) wherein the oxidation reaction is green and environment-friendly, the yield is high (about 90 percent), the pollution is less, and the treatment cost is low; 2) and the chlorination reaction is simple and convenient to operate, and the reaction solution of the compound of the formula c is concentrated to dryness and can be directly put into the next reaction. 3) The acylation and ring closure reaction steps are mild in condition, the yield is quite high (the total yield of the three steps is about 72%), the purity is good (about 98%), and the obtained reaction liquid of the compound shown in the formula d is directly put into the next reaction without being processed to prepare the compound shown in the formula e; 4) and concentrating the reaction solution of the compound shown in the formula e, adding water, pulping, and filtering to obtain the compound shown in the formula e. 5) The compound of the formula e is subjected to palladium-carbon hydrogenation, the reaction solution is directly filtered and concentrated to obtain the compound of the formula f, the method is green and environment-friendly, the concentrated solvent can be directly recycled, and the product yield is high (about 90%).
The invention also provides a Ribose intermediate 4- (4-aminophenyl) morpholine-3-ketone prepared by the method, and the structure of the Ribose intermediate is shown as the formula (f):
the invention is different from the prior art or has the innovation points that:
the method for synthesizing Ribosban intermediate 4- (4-aminophenyl) morpholine-3-ketone has the following remarkable advantages compared with the existing synthetic method: (1) in the step 1, sodium hypochlorite is used as an oxidant for reaction, so that the environmental pollution is less, the treatment cost is low, and the problems of heavy environmental pollution, high wastewater treatment cost and the like caused by the use of a heavy metal oxidant can be solved; (2) the chlorination reagent such as oxalyl chloride adopted in the step 2 can avoid the palladium-carbon poisoning of the catalyst in the step 5, while other chlorination reagents in the prior art have the risk of poisoning the palladium-carbon catalyst in the step 5; (3) the reaction solution in the step 2 can be directly concentrated and then put into the next reaction, and is continuously put into the same reaction kettle with the step 3 and the step 4, so that the post-treatment time is saved, and the operation is simple and convenient; (4) and step 5, palladium carbon is adopted as a catalyst for hydrogenation, the obtained product is directly filtered and concentrated, the method is economic and environment-friendly, the concentrated solvent can be directly recycled, new impurities are generated in the reaction system of the platinum carbon and the Raney nickel, the purification is not facilitated, and the purification cost is increased.
In one embodiment, the industrial synthetic route for the Ribose intermediate 4- (4-aminophenyl) morpholin-3-one of formula (f) is as follows:
the invention has the beneficial effects that: the method has the advantages of high process stability, simple operation, less three wastes, high yield, less uncontrollable impurities and low production cost, is suitable for industrial mass production, and has obvious economic benefit.
Corresponding full-name corresponding table used for short names in the specification
| Entry | Abbreviations | Full scale |
| 1 | DCM | Methylene dichloride |
| 2 | TEMPO | 2,2,6, 6-tetramethylpiperidine oxide |
| 3 | TCCA | Trichloroisocyanuric acid |
| 4 | DMAP | 4-dimethylaminopyridine |
| 5 | DMF | N, N-dimethylformamide |
| 6 | DIPEA | N, N-diisopropylethylamine |
| 7 | DBU | 1, 8-diazabicycloundec-7-enes |
| 8 | DBN | 1, 5-diazabicyclo [4.3.0 ]]Non-5-ene |
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
Synthesis of Compound b:
scheme 1:
under the protection of nitrogen, dichloromethane (60mL, 10V) and water (5mL, 1V) are added into a 250mL reaction kettle, then 2-chloroethoxyethanol (5g, 40.14mmol), TEMPO (0.88g, 5.6mmol), sodium chloride (0.5g) and sodium bromide (0.2g) are added, sodium hypochlorite (64g, 120.42mmol) is added dropwise at 0 ℃, after the addition is finished, the reaction is carried out for 2 hours at 25 ℃, HPLC or TLC detection is carried out, and the reaction is finished. The temperature was reduced to 10 ℃, sodium sulfite solid (10g, 80.28mmol) was added, the mixture was allowed to stand for liquid separation, the aqueous phase was extracted twice with dichloromethane (15mL, 3V), the organic phases were combined, washed with saturated brine solution (5mL, 1V), and the organic phase was directly charged to the next reaction (90% of theoretical yield to the next step).
1H NMR(400MHz,CHLOROFORM-d)δppm 3.64-3.75(m,2H)，3.80-3.94(m,2H)，4.24(s,2H)，8.73(br.s.,1H)。
According to the scheme, after the sodium hypochlorite oxidation reaction is finished and the solution is directly separated, the obtained organic phase saturated saline solution is washed by water to obtain the dichloromethane solution of the compound shown in the formula b, namely the dichloromethane solution can be directly fed into the next step, the yield is high (fed into the next step according to 90% of the theoretical yield), the operation process is simple and convenient, the reaction safety is high, uncontrollable impurities are not generated, and the generated three wastes are less.
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
adding dichloromethane (60mL, 10V) or 1, 2-dichloroethane (60mL, 10V) or tetrahydrofuran (60mL, 10V) or dioxane (60mL, 10V) or acetone (60mL, 10V) or acetonitrile (60mL, 10V) into a 250mL reaction kettle under the protection of nitrogen, adding 2-chloroethoxyethanol (5g, 40.14mmol), TEMPO (0.88g, 5.6mmol), sodium chloride (0.5g), sodium bromide (0.2g), dropwise adding sodium hypochlorite (64g, 120.42mmol) at 0 ℃, completely adding sodium sulfite, reacting at 25 ℃ for 2 hours, detecting by HPLC or TLC, cooling to 10 ℃, adding sodium sulfite solid (10g, 80.28mmol), standing for liquid separation, extracting the aqueous phase twice with dichloromethane (15mL, 3V), combining the organic phases, washing with saturated saline solution (5mL, 1V), and concentrating the organic phase to dryness to obtain the compound of the formula b.
Compound of formula b obtained in dichloromethane system (5g, 36.13 mmol); 1, 2-dichloroethane system (4.45g, 32.13 mmol); compound of formula b obtained in tetrahydrofuran system (4.17g, 30.13 mmol); compound of formula b obtained from dioxane system (4.31g, 31.13 mmol); the compound of formula b obtained in the acetone system (4.64g, 33.5 mmol); acetonitrile system (3.53g, 25.5 mmol);
the reaction solvent defined in this embodiment is therefore preferably a mixed system of dichloromethane and water.
Schemes 1-2:
under the protection of nitrogen, dichloromethane (60mL, 10V), water (5mL, 1V) are added into a 250mL reaction kettle, 2-chloroethoxyethanol (5g, 40.14mmol), TEMPO (0.88g, 5.6mmol), sodium chloride (0.5g), sodium bromide (0.2g) are added, sodium hypochlorite (64g, 120.42mmol) or sodium chlorite (13.6g, 120.42mmol) or sodium periodate (25.76g, 120.42mmol) or NBS (21.4g, 120.42mmol) or NCS (16.1g, 120.42mmol) or hydrogen peroxide (13.65g, 120.42mmol) or TCCA (27.96g, 120.42mmol) or Jone reagent (82.3g, 120.42mmol) or potassium permanganate (19.0g, 120.42mmol) or 4-hydroxy-TEMPO (20.7g, 120.42mmol) or 4-acetamido-TEMPO (69 g, 5869 g, 25.582 h), TLC or HPLC is added, the temperature is reduced to finish the reaction, sodium sulfite solid (10g, 80.28mmol) was added, the mixture was allowed to stand for liquid separation, the aqueous phase was extracted twice with dichloromethane (15mL, 3V), the organic phases were combined, washed with saturated brine solution (5mL, 1V), and the organic phase was concentrated to dryness to give the compound of formula b.
Sodium hypochlorite aqueous system to give compound of formula b (5g, 36.13 mmol); the compound of formula b obtained in the aqueous sodium chlorite system (4.25g, 30.7 mmol); compound of formula b obtained from sodium periodate system (4.11g, 29.7 mmol); NBS system gave compound of formula b (3.62g, 26.13 mmol); NCS system (3.56g, 25.7 mmol); a compound (3.9g, 28.13mmol) of the formula b obtained by a hydrogen peroxide system; TCCA system gave compound of formula b (4g, 28.9 mmol); jone reagent system gave compound of formula b (4g, 28.9 mmol); a compound of formula b (2.87g, 20.7mmol) obtained from a potassium permanganate system; compound of formula b obtained with 4-hydroxy-TEMPO system (2.79g, 20.13 mmol); 4-acetamido-TEMPO system (2.59g, 18.7 mmol).
The oxidant identified in this embodiment is therefore preferably sodium hypochlorite.
Schemes 1-3:
under the protection of nitrogen, dichloromethane (60mL, 10V) and water (5mL, 1V) are added into a 250mL reaction kettle, then 2-chloroethoxyethanol (5g, 40.14mmol), TEMPO (0.88g, 5.6mmol), sodium chloride (0.5g) and sodium bromide (0.2g) are added, sodium hypochlorite (64g, 120.42mmol) or sodium hypochlorite aqueous solution (42.67g, 80.28mmol) or sodium hypochlorite aqueous solution (85.33g, 160.56mmol) are added dropwise at 0 ℃, after the reaction is finished, sodium hypochlorite solid (10g, 80.28mmol) is added dropwise at 25 ℃ for 2 hours, HPLC or TLC detection is carried out, the reaction is finished, the temperature is reduced to 10 ℃, sodium sulfite solid (10g, 80.28mmol) is added, liquid separation is carried out, the aqueous phase is extracted twice by dichloromethane (15mL, 3V), the organic phase is combined, saturated saline solution (5mL, 1V) is washed, and the organic phase is concentrated to be dry to obtain the compound of the formula b.
An aqueous sodium hypochlorite solution (64g, 120.42mmol) to give a compound of formula b (5g, 36.13 mmol); an aqueous sodium hypochlorite solution (42.67g, 80.28mmol) to give a compound of formula b (3.92g, 28.3 mmol); aqueous sodium hypochlorite (85.33g, 160.56mmol) to give compound of formula b (5g, 36.13 mmol).
The molar ratio oxidant/compound a is therefore tentatively 3: 1.
schemes 1-4:
under the protection of nitrogen, dichloromethane (60mL, 10V), water (5mL, 1V) are added into a 250mL reaction kettle, then 2-chloroethoxyethanol (5g, 40.14mmol), TEMPO (0.88g, 5.6mmol), sodium chloride (0.5g), sodium bromide (0.2g) are added, sodium hypochlorite (64g, 120.42mmol) is added dropwise at 0 ℃, after the addition is finished, the reaction is carried out for 2 hours at 25 ℃ or 0 ℃ or 40 ℃, HPLC or TLC detection is carried out, after the reaction is finished, sodium sulfite solid (10g, 80.28mmol) is added, standing and liquid separation are carried out, an aqueous phase is extracted twice by dichloromethane (15mL, 3V), an organic phase is combined, saturated saline solution (5mL, 1V) is washed, and the organic phase is concentrated to be dry to obtain the compound of the formula b.
The reaction was carried out at 0 ℃ for 2 hours with the starting material remaining and the compound of formula b obtained from the system (4.25g, 30.71 mmol); a compound of formula b (5g, 36.13mmol) obtained by reaction at 25 ℃ for 2 hours; the reaction was carried out at 40 ℃ for 2 hours to obtain a compound of formula b (5g, 36.13 mmol).
The optimum reaction temperature is therefore temporarily set to 25 ℃ in this case.
Example 2
Synthesis of compound of formula c:
scheme 1:
the organic phase containing the compound of formula b from the previous step (5g, 36.13mmol) was added to a 250mL reactor and oxalyl chloride (11.46g, 90.33mmol) was added dropwise at 30 deg.C, after which the reaction was terminated at 30 deg.C for 8 hours by HPLC or TLC. The reaction solution is directly concentrated to be dry and put into the next reaction (the reaction solution is put into the next step according to 100 percent of theoretical yield).
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
adding the organic phase (5g, 36.13mmol) containing the compound of the formula b in the previous step into a 250mL reaction kettle, dropwise adding oxalyl chloride (11.46g, 90.33mmol) or thionyl chloride (10.75g, 90.33mmol) or sulfuryl chloride (12.19g, 90.33mmol) or phosphorus trichloride (12.41g, 90.33mmol) or phosphorus pentachloride (18.81g, 90.33mmol) or triphosgene (26.81g, 90.33mmol) at 30 ℃, after adding, reacting at 30 ℃ for 8 hours, detecting by HPLC or TLC, and ending the reaction. Directly concentrating the reaction solution to dryness to obtain the compound of the formula c.
Oxalyl chloride system to give compound of formula c (5.67g, 36.09 mmol); compound of formula c obtained in thionyl chloride system (5.67g, 36.09 mmol); sulfonyl chloride system (5.67g, 36.09mmol) phosphorus trichloride system (4.88g, 31.1 mmol); phosphorus pentachloride system (5.10g, 32.5mmol), triphosgene system (4.72g, 30.09 mmol).
Since thionyl chloride and sulphuryl chloride contain sulphur, which poisons the catalyst palladium on carbon in step 5, the acylating agent identified in this scheme is preferably oxalyl chloride.
Schemes 1-2:
the organic phase containing the compound of formula b from the previous step (5g, 36.13mmol) was added dropwise at 30 ℃ to a 250mL reaction vessel, followed by addition of oxalyl chloride (11.46g, 90.33mmol) or oxalyl chloride (6.88g, 54.2mmol) or oxalyl chloride (16.05g, 126.46mmol), followed by reaction at 30 ℃ for 8 hours, HPLC or TLC detection, and reaction was complete. Directly concentrating the reaction solution to dryness to obtain the compound of the formula c.
Oxalyl chloride (6.88g, 54.2mmol) to obtain the compound of formula c (5.18g, 33 mmol); oxalyl chloride (11.46g, 90.33mmol) to give a compound of formula c (5.67g, 36.09 mmol); oxalyl chloride (16.05g, 126.46mmol) to give a compound of formula c (5.67g, 36.09 mmol).
The acylation agent/compound b molar ratio is therefore tentatively 2.5 in this case: 1.
schemes 1-3:
adding the organic phase (5g, 36.13mmol) containing the compound of the formula b in the previous step into a 250mL reaction kettle, dropwise adding oxalyl chloride (11.46g, 90.33mmol) at 30 ℃, reacting for 8 hours or 6 hours or 10 hours at 30 ℃ after the addition is finished, and detecting by HPLC or TLC to finish the reaction. Directly concentrating the reaction solution to dryness to obtain the compound of the formula c.
After 6 hours of reaction, the starting material remained, and the compound of formula c (4.71g, 30mmol) was obtained; the compound of formula c obtained after 8 hours of reaction (5.67g, 36.09 mmol); the reaction was carried out for 10 hours to obtain the compound of formula c (5.67g, 36.09 mmol).
The optimum reaction time is therefore temporarily set to 8 hours in this case.
Example 3
Synthesis of compounds of formula d:
scheme 1:
dichloromethane (50mL, 10V), paranitroaniline (4.99g, 36.13mmol) and DMAP (2.2g, 18.07mmol) were added to a 250mL reaction vessel, and a concentrated solution of the compound of formula c (5.67g, 36.13mmol) was added dropwise at 0 ℃ and, after completion of the addition, the reaction was carried out at 40 ℃ for 3 hours and then the reaction was terminated by HPLC or TLC. The reaction mixture was directly subjected to the next step (100% of theoretical yield was charged to the next step).
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
adding dichloromethane (50mL, 10V) or 1, 2-dichloroethane (50mL, 10V) or toluene (50mL, 10V) or xylene (50mL, 10V) or tetrahydrofuran (50mL, 10V) or dioxane (50mL, 10V) or ethyl acetate (50mL, 10V) or acetonitrile (50mL, 10V) or DMF (50mL, 10V), p-nitroaniline (4.99g, 36.13mmol), DMAP (2.2g, 18.07mmol), dropwise adding the concentrated solution (5.67g, 36.13mmol) of the compound of the formula c at 0 ℃, reacting at 40 ℃ for 3 hours, detecting by HPLC or TLC, finishing the reaction, and directly concentrating to dryness to obtain the crude compound of the formula d.
The 1, 2-dichloromethane system gave significant impurities and yielded compound of formula d (7.81g, 30.2 mmol); toluene system derived compound of formula d (8.55g, 33.05 mmol); dichloromethane system (9.35g, 36.13 mmol); xylene system (8.03g, 31.05 mmol); tetrahydrofuran system gave compound of formula d (5.7g, 22.05 mmol); compound of formula d obtained from dioxane system (6.48g, 25.05 mmol); ethyl acetate system to give compound of formula d (3.89g, 15.05 mmol); acetonitrile system (7.26g, 28.05 mmol); the compound of formula d obtained in DMF system (5.19g, 20.05 mmol);
the reaction solvent identified in this scheme is therefore preferably dichloromethane.
Schemes 1-2:
dichloromethane (50mL, 10V), p-nitroaniline (4.99g, 36.13mmol), DMAP (2.2g, 18.07mmol) or triethylamine (1.83g, 18.07mmol) or pyridine (1.43g, 18.07mmol) or DBU (2.75g, 18.07mmol) or DBN (2.24g, 18.07mmol) are added into a 250mL reaction kettle, and concentrated solution (5.67g, 36.13mmol) of the compound of formula c is added dropwise at 0 ℃, reacted for 3 hours at 40 ℃ after the addition is finished, detected by HPLC or TLC, and directly concentrated to dryness to obtain the crude compound of formula d.
DMAP system gave compound of formula d (9.35g, 36.13 mmol); compound of formula d obtained with triethylamine system (7.79g, 30.13 mmol); pyridine system to give compound of formula d (6.5g, 25.13 mmol); compound of formula d obtained from DBU system (8.05g, 31.13 mmol); DBN system gave compound of formula d (7.28g, 28.13 mmol).
The catalyst identified in this embodiment is therefore preferably DMAP.
Schemes 1-3:
adding dichloromethane (50mL, 10V), p-nitroaniline (4.99g, 36.13mmol), DMAP (2.2g, 18.07mmol) or DMAP (1.1g, 9.04mmol) or DMAP (3.3g, 27.12mmol) into a 250mL reaction kettle, dropwise adding a concentrated solution (5.67g, 36.13mmol) of the compound of the formula c at 0 ℃, reacting at 40 ℃ for 3 hours after the addition is finished, detecting by HPLC or TLC, finishing the reaction, and directly concentrating until the reaction is dry to obtain a crude compound of the formula d.
DMAP (1.1g, 9.04mmol) system and the starting material were not reacted to obtain the compound of formula d (8.28g, 32 mmol); DMAP (2.2g, 18.07mmol) to give a compound of formula d (9.35g, 36.13 mmol); DMAP (3.3g, 27.12mmol) to give a compound of formula d (9.35g, 36.13 mmol).
The molar ratio of catalyst/compound c is therefore tentatively 0.5 in this case: 1.
example 4
Synthesis of compound of formula e:
scheme 1:
triethylamine (10.95g) is added into the same 250mL reaction kettle, after the addition is finished, the temperature is raised to 40 ℃ for reaction for 15 hours, and HPLC or TLC detection is carried out to finish the reaction. The temperature is reduced to 25 ℃, the mixture is concentrated under reduced pressure, water (40mL) is added, and the solid obtained by pulping and filtering is the compound (5.85g, 26.34mmol) of the formula e.
1H NMR(400MHz,DMSO-d)δppm 3.78-3.90(m,2H)，3.94-4.04(m,2H)，4.26(s,2H)，7.76(d,J＝9.29Hz,2H)，8.26(d,J＝8.80Hz,2H)。
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
triethylamine (10.95g, 108.39mmol), pyridine (8.56g, 108.39mmol), DIPEA (14.01g, 108.39mmol), sodium carbonate (11.49g, 108.39mmol), sodium hydroxide (4.34g, 108.39mmol), potassium hydroxide (6.08g, 108.39mmol), cesium carbonate (35.32g, 108.39mmol) or potassium carbonate (14.96g, 108.39mmol) are added into the same 250mL reaction kettle, and after the addition is finished, the temperature is raised to 40 ℃ for reaction for 15 hours, HPLC or TLC detection is carried out, and the reaction is finished. Cooling to 25 deg.c, decompression concentrating the reaction liquid, adding water and filtering to obtain solid compound as the compound in the formula e.
Triethylamine system gave compound of formula e (5.85g, 26.34 mmol); pyridine system to give a compound of formula e (4.30g, 19.34 mmol); DIPEA system to give a compound of formula e (4.56g, 20.5 mmol); potassium carbonate system (4.84g, 21.8 mmol); sodium carbonate system gave compound of formula e (4.92g, 22.13 mmol); sodium hydroxide system (4.56g, 20.5 mmol); potassium hydroxide system (4.70g, 21.13 mmol); cesium carbonate system gave compound of formula e (4.04g, 18.17 mmol).
The base reagent identified in this scheme is therefore preferably triethylamine.
Schemes 1-2:
and adding triethylamine (10.95g, 108.39mmol) or triethylamine (7.30g, 72.26mmol) or triethylamine (14.60g, 144.52mmol) into the same 250mL reaction kettle, heating to 40 ℃ after the addition is finished, reacting for 15 hours, and detecting by HPLC or TLC to finish the reaction. Cooling to 25 deg.c, decompression concentrating the reaction liquid, adding water and filtering to obtain solid compound as the compound in the formula e.
Triethylamine (7.30g, 72.26mmol) system still had unreacted starting material to give the compound of formula e (4.72g, 21.24 mmol); triethylamine (10.95g, 108.39mmol) to give a compound of formula e (5.85g, 26.34 mmol); triethylamine (14.60g, 144.52mmol) gave a compound of formula e (5.85g, 26.34 mmol).
The molar ratio of basic reagent/compound d is therefore tentatively 3: 1.
schemes 1-3:
triethylamine (10.95g) is added into the same 250mL reaction kettle, after the addition is finished, the temperature is raised to 40 ℃ for reaction for 15 hours or reaction for 12 hours or reaction for 18 hours, HPLC or TLC detection is carried out, and the reaction is finished. Cooling to 25 deg.C, concentrating under reduced pressure, adding water, and directly filtering to obtain solid compound of formula e.
After 12 hours of reaction, the raw material remained, and the compound of formula e (4.89g, 22mmol) was obtained; the compound of formula e obtained after 15 hours reaction (5.85g, 26.34 mmol); reaction time 18 h gave compound of formula e (5.85g, 26.34 mmol).
The optimum reaction time is therefore temporarily set to 15 hours in this case.
Example 5
Synthesis of compounds of formula f:
scheme 1:
methanol (70mL, 12V), a compound of formula e (5.85g, 26.34mmol), palladium on carbon (0.5g, 0.1wt) were added to a 250mL reaction vessel, and after the addition, hydrogen was replaced, the system was heated to 40 ℃ for 4 hours, followed by HPLC or TLC detection, and the reaction was complete. The temperature was reduced to 25 ℃ and the reaction was filtered directly to give a filtrate which was concentrated directly to give the compound of formula f (4.56g, 23.71 mmol).
1H NMR(400MHz,DMSO-d)δppm3.55(t,J＝5.09Hz,2H)，3.88(t,J＝4.89Hz,2H)，4.02-4.14(m,2H)，5.13(br.s.,2H)，6.51(d,J＝8.61Hz,2H)，6.92(d,J＝8.61Hz,2H)。
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
adding methanol (70mL, 12V) or ethanol (70mL, 12V) or isopropanol (70mL, 12V) or DMF (70mL, 12V) or tetrahydrofuran (70mL, 12V) or 1, 2-dichloroethane (70mL, 12V), a compound of formula e (5.85g, 26.34mmol), palladium carbon (0.5g, 0.1wt), after the addition is finished, replacing hydrogen, heating the system to 40 ℃ for reaction for 4 hours, detecting by HPLC or TLC, and finishing the reaction. And (3) cooling to 25 ℃, directly filtering the reaction solution to obtain filtrate, and directly concentrating to obtain the compound of the formula f.
Methanol system (4.56g, 23.71 mmol); ethanol system gave compound of formula f (4.56g, 23.71 mmol); compound of formula f obtained from isopropanol system (4.56g, 23.71 mmol); compound of formula f obtained in DMF system (4.1g, 21.34 mmol); tetrahydrofuran system gave compound of formula f (4.1g, 21.34 mmol); 1, 2-dichloroethane system (3.72g, 19.34 mmol).
The reaction solvent identified in this scheme is preferably methanol, since methanol is less expensive than ethanol and isopropanol.
Schemes 1-2:
a250 mL reaction vessel was charged with methanol (70mL, 12V), a compound of formula e (5.85g, 26.34mmol), palladium on carbon (0.5g, 0.1wt) or platinum on carbon (0.5g, 0.1wt) or Raney nickel (0.5g, 0.1wt), after the addition was completed, hydrogen gas was replaced, the system was heated to 40 ℃ for 4 hours, and HPLC or TLC detection was performed to complete the reaction. And (3) cooling to 25 ℃, directly filtering the reaction solution to obtain filtrate, and directly concentrating to obtain the compound of the formula f.
Palladium on carbon system (4.56g, 23.71 mmol); the platinum carbon system gave impurities, giving a compound of formula f (4.1g, 21.34 mmol); raney nickel system also produced impurities, which gave compound of formula f (3.69g, 19.21 mmol).
The catalyst identified in this embodiment is therefore preferably palladium on carbon.
Schemes 1-3:
a250 mL reaction kettle is added with methanol (70mL, 12V), a compound of formula e (5.85g, 26.34mmol), palladium carbon (0.5g, 0.1wt) and hydrogen or formic acid (4.85g, 105.36mmol), or ammonium formate (6.64g, 105.36mmol), or sodium hydrosulfite (18.34g, 105.36mmol), or stannous chloride (19.98g, 105.36mmol), and the system is heated to 40 ℃ for reaction for 4 hours, HPLC or TLC detection is carried out, and the reaction is finished. Cooling to 25 ℃, and treating to obtain the compound of the formula f.
Palladium on carbon/hydrogen system (4.56g, 23.71 mmol); formic acid and ammonium formate system are free from the generation of compounds of formula f; the compound of formula f obtained from sodium hydrosulfite system (4.1g, 21.34 mmol); stannous chloride system to give compound of formula f (3.69g, 19.21 mmol); sodium sulfide system gave compound of formula f (3.69g, 19.21 mmol).
The reducing agent determined in the scheme is preferably hydrogen because other reducing agents generate three wastes in the post-treatment and purification processes of products and the yield is not high.
Scheme 2(WO2019138362a 1):
this patent document uses acetic acid and water as reaction solvent, and the compound of formula e as starting material, and reduces it under the action of palladium on carbon and hydrogen to give the compound of formula f (89% yield). Compared with methanol as a reaction solvent, the method has the defects that the solvent acetic acid and water must be distilled and removed under reduced pressure at high temperature, then isopropanol is added for crystallization at low temperature to obtain the compound of the formula f, the time consumption is long, the three wastes are more, and the cost is obviously increased.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (11)
1. A synthetic method of a Ribose intermediate 4- (4-aminophenyl) morpholine-3-one is characterized in that the synthetic process of the Ribose intermediate 4- (4-aminophenyl) morpholine-3-one is shown as the following scheme (A),
wherein X is halogen;
the method comprises the following specific steps:
1) in a solvent, under the action of an oxidant, carrying out an oxidation reaction on a compound shown in the formula a and the oxidant to obtain a compound shown in the formula b;
2) in a solvent, under the action of a chlorination reagent, the compound of the formula b is subjected to chlorination reaction to obtain a compound of a formula c
A compound;
3) in an organic solvent, under the action of a catalyst, the compound of the formula c and p-nitroaniline are subjected to acylation reaction to obtain a compound of a formula d;
4) in an organic solvent, under the action of alkali, the compound of the formula d undergoes a ring closure reaction to obtain a compound of the formula e;
5) and (3) in an organic solvent, under the action of a catalyst, carrying out a reduction reaction on the compound of the formula e under the action of a reducing agent to obtain a compound of the formula f.
2. The method of synthesis according to claim 1, wherein in step 1), the oxidizing agent is one or more of sodium periodate, sodium hypochlorite, sodium chlorite, NBS, NCS, hydrogen peroxide, TCCA, Jone reagent, potassium permanganate, TEMPO, 4-hydroxy-TEMPO, 4-acetamido-TEMPO; and/or the solvent is one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, acetone, acetonitrile and water.
3. The synthesis method according to claim 1, wherein in step 1), the molar ratio of the compound of formula a to the oxidant is 1: (1-5); and/or the temperature of the oxidation reaction is 0-60 ℃; and/or the time of the oxidation reaction is 1-24 h.
4. The synthesis method of claim 1, wherein in the step 2), the chlorinated reagent is one or more of thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene and oxalyl chloride; and/or the solvent is one or more of dichloromethane, 1, 2-dichloroethane, toluene, xylene, tetrahydrofuran, dioxane and acetonitrile.
5. The synthesis method according to claim 1, wherein in the step 2), the molar ratio of the compound of the formula b to the chlorinating reagent is 1: (1-10); and/or the temperature of the chlorination reaction is 0-110 ℃; and/or the time of the chlorination reaction is 3-24 h.
6. The synthetic method of claim 1 wherein in step 3), the organic solvent is one or more of toluene, xylene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, DMF; and/or the catalyst is one or more of DMAP, triethylamine, pyridine, DBU and DBN.
7. The synthesis method of claim 1, wherein in the step 3), the molar ratio of the compound of the formula c to the p-nitroaniline to the catalyst is (1-10): 1: (0.1-5); and/or, the temperature of the acylation reaction is 0-150 ℃; and/or the time of the acylation reaction is 1-16 h.
8. The method of claim 1, wherein in step 4), the organic solvent is one or more of toluene, xylene, isopropanol, dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, dioxane, acetone, ethyl acetate, DMF, and methyl ethyl ketone; and/or the alkali is one or more of pyridine, triethylamine, DIPEA, potassium carbonate, sodium hydroxide, potassium hydroxide and cesium carbonate.
9. The method of claim 1, wherein in step 4), the compound of formula d and the base are present in a molar ratio of 1: (1-10); and/or the temperature of the ring closing reaction is 0-150 ℃; and/or the time of the ring closing reaction is 1-20 h.
10. The synthesis method of claim 1, wherein in the step 5), the organic solvent is one or more of methanol, ethanol, isopropanol, ethyl acetate, 1, 2-dichloroethane, DMF and tetrahydrofuran; and/or the catalytic agent is one or more of palladium carbon, platinum carbon and Raney nickel; and/or the reducing agent is one or more of hydrogen, formic acid, ammonium formate, sodium hydrosulfite, stannous chloride and sodium sulfide.
11. The synthesis method according to claim 1, wherein in the step 5), the molar ratio of the compound of formula e, the catalyst and the reducing agent is 1: (0.01-1): (1-10); and/or the temperature of the reduction reaction is 0-100 ℃; and/or the time of the reduction reaction is 1-20 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011109641.2A CN114380763A (en) | 2020-10-16 | 2020-10-16 | Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011109641.2A CN114380763A (en) | 2020-10-16 | 2020-10-16 | Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114380763A true CN114380763A (en) | 2022-04-22 |
Family
ID=81192596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011109641.2A Pending CN114380763A (en) | 2020-10-16 | 2020-10-16 | Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114380763A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115260117A (en) * | 2022-08-09 | 2022-11-01 | 江苏法安德医药科技有限公司 | Synthesis method of 4- (4-aminophenyl) morpholine-3-one |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101844978A (en) * | 2010-05-14 | 2010-09-29 | 南开大学 | Synthesis method of 2-(2-chloroethoxy) acetic acid |
| CN102464580A (en) * | 2010-11-17 | 2012-05-23 | 重庆华邦胜凯制药有限公司 | Preparation of haloethoxyacetic acid and esters thereof |
| CN102603665A (en) * | 2012-01-17 | 2012-07-25 | 北京贯虹科技集团有限公司 | Synthesis method of 4-(4-aminophenyl)-3-morpholone |
| CN103923079A (en) * | 2014-03-25 | 2014-07-16 | 沈阳中海药业有限公司 | Preparation method of apixaban intermediate |
| CN104098525A (en) * | 2013-04-01 | 2014-10-15 | 上海科胜药物研发有限公司 | Preparation method for 4-(4-aminophenyl)morpholine-3-one |
| CN104974105A (en) * | 2014-04-14 | 2015-10-14 | 北大方正集团有限公司 | Method of preparing 4-(4-aminophenyl)-3-morpholinone |
| CN109384738A (en) * | 2017-08-04 | 2019-02-26 | 新发药业有限公司 | A kind of preparation method of high-purity 4- (4- aminophenyl) morpholine -3- ketone |
| CN109651286A (en) * | 2017-10-12 | 2019-04-19 | 新发药业有限公司 | A kind of highly selective 4-(4- aminophenyl) morpholine -3- ketone synthetic method |
| WO2019138362A1 (en) * | 2018-01-12 | 2019-07-18 | Richter Gedeon Nyrt. | Process for the preparation of 4-(4-aminophenyl)morpholin-3-one |
| CN110746370A (en) * | 2018-07-23 | 2020-02-04 | 新发药业有限公司 | Preparation method of 4- (4-aminophenyl) morpholine-3-one |
-
2020
- 2020-10-16 CN CN202011109641.2A patent/CN114380763A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101844978A (en) * | 2010-05-14 | 2010-09-29 | 南开大学 | Synthesis method of 2-(2-chloroethoxy) acetic acid |
| CN102464580A (en) * | 2010-11-17 | 2012-05-23 | 重庆华邦胜凯制药有限公司 | Preparation of haloethoxyacetic acid and esters thereof |
| CN102603665A (en) * | 2012-01-17 | 2012-07-25 | 北京贯虹科技集团有限公司 | Synthesis method of 4-(4-aminophenyl)-3-morpholone |
| CN104098525A (en) * | 2013-04-01 | 2014-10-15 | 上海科胜药物研发有限公司 | Preparation method for 4-(4-aminophenyl)morpholine-3-one |
| CN103923079A (en) * | 2014-03-25 | 2014-07-16 | 沈阳中海药业有限公司 | Preparation method of apixaban intermediate |
| CN104974105A (en) * | 2014-04-14 | 2015-10-14 | 北大方正集团有限公司 | Method of preparing 4-(4-aminophenyl)-3-morpholinone |
| CN109384738A (en) * | 2017-08-04 | 2019-02-26 | 新发药业有限公司 | A kind of preparation method of high-purity 4- (4- aminophenyl) morpholine -3- ketone |
| CN109651286A (en) * | 2017-10-12 | 2019-04-19 | 新发药业有限公司 | A kind of highly selective 4-(4- aminophenyl) morpholine -3- ketone synthetic method |
| WO2019138362A1 (en) * | 2018-01-12 | 2019-07-18 | Richter Gedeon Nyrt. | Process for the preparation of 4-(4-aminophenyl)morpholin-3-one |
| CN110746370A (en) * | 2018-07-23 | 2020-02-04 | 新发药业有限公司 | Preparation method of 4- (4-aminophenyl) morpholine-3-one |
Non-Patent Citations (1)
| Title |
|---|
| 裴继诚等: "《植物纤维化学》", 中国轻工业出版社, pages: 199 - 200 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115260117A (en) * | 2022-08-09 | 2022-11-01 | 江苏法安德医药科技有限公司 | Synthesis method of 4- (4-aminophenyl) morpholine-3-one |
| CN115260117B (en) * | 2022-08-09 | 2024-05-28 | 江苏法安德医药科技有限公司 | Synthesis method of 4- (4-aminophenyl) morpholin-3-one |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106866553A (en) | A kind of synthetic method of Favipiravir | |
| AU2008237749B2 (en) | Process for the preparation of gefitinib | |
| CN107857743B (en) | Method for preparing roxatidine acetate hydrochloride and intermediate | |
| WO2017023123A1 (en) | Novel method for preparing chromanone derivative | |
| JP2018513205A (en) | Production method of ibrutinib | |
| CN114380763A (en) | Synthesis method of Ribosban intermediate 4- (4-aminophenyl) morpholine-3-one | |
| GR3022932T3 (en) | Process for the production of N-phenylmaleimide | |
| CN110818661A (en) | Preparation method of key intermediate 4-amino-5-halogenobenzofuran-7-carboxylic acid of 5-HT4 receptor agonist | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN114671859B (en) | Preparation method of rosuvastatin calcium and intermediate thereof | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN111675660B (en) | Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib | |
| CN115403555A (en) | Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid | |
| CN116063309B (en) | Synthesis method of ibrutinib | |
| CN113968842B (en) | Ibutinib intermediate compound | |
| CN115124530B (en) | Preparation method of evodiamine | |
| CN105017219B (en) | Synthetic method for p53-MDM2-binding inhibitor dyhydroxyl quinoline derivative | |
| CN111039838B (en) | Preparation method of 3-acetylmercapto-2-methylpropanoic acid | |
| CN1124265C (en) | Method for producing aromatic bisimides | |
| CN114805015A (en) | Synthesis process of 2, 4-dichloro-9, 9-dimethyl-9H-fluorene | |
| CN118619889A (en) | Synthesis method of 1,2, 3-triazole-4-ethyl formate | |
| CN115572224A (en) | Synthesis method of (S) - (-) -3-cyclohexenecarboxylic acid | |
| CN115785019A (en) | Synthesis method of ethyl-1-oxo-4-azaspiro [5.5] undecane-9-carboxylate | |
| CN113200986A (en) | Preparation method of ibrutinib intermediate | |
| KR820002153B1 (en) | Process for preparing heterocyclic compound contianing nitrogen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220422 |
|
| WD01 | Invention patent application deemed withdrawn after publication |