CN114907299B - Salt form of key intermediate of tazistat, preparation method and intermediate thereof - Google Patents
Salt form of key intermediate of tazistat, preparation method and intermediate thereof Download PDFInfo
- Publication number
- CN114907299B CN114907299B CN202110172947.0A CN202110172947A CN114907299B CN 114907299 B CN114907299 B CN 114907299B CN 202110172947 A CN202110172947 A CN 202110172947A CN 114907299 B CN114907299 B CN 114907299B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- reaction
- reductive amination
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 183
- 150000003839 salts Chemical group 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 281
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 15
- 229940125773 compound 10 Drugs 0.000 claims abstract description 14
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 125
- 238000006243 chemical reaction Methods 0.000 claims description 101
- 238000006268 reductive amination reaction Methods 0.000 claims description 97
- 239000003960 organic solvent Substances 0.000 claims description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 47
- 229940125898 compound 5 Drugs 0.000 claims description 43
- 238000005859 coupling reaction Methods 0.000 claims description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 35
- 229940126214 compound 3 Drugs 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 32
- 229940125782 compound 2 Drugs 0.000 claims description 30
- 150000007524 organic acids Chemical class 0.000 claims description 29
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 25
- 238000006722 reduction reaction Methods 0.000 claims description 25
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 238000005893 bromination reaction Methods 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 20
- 238000005886 esterification reaction Methods 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- 239000012279 sodium borohydride Substances 0.000 claims description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 13
- 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 12
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 235000019253 formic acid Nutrition 0.000 claims description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 10
- VXWBQOJISHAKKM-UHFFFAOYSA-N (4-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)C=C1 VXWBQOJISHAKKM-UHFFFAOYSA-N 0.000 claims description 9
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- 239000011591 potassium Substances 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- UIGXGNUMMVHJKX-UHFFFAOYSA-N (4-formylphenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(C=O)C=C1 UIGXGNUMMVHJKX-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 5
- 229910017052 cobalt Inorganic materials 0.000 claims description 5
- 239000010941 cobalt Substances 0.000 claims description 5
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical group BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 11
- 230000031709 bromination Effects 0.000 claims 1
- 238000003908 quality control method Methods 0.000 abstract description 8
- 238000001953 recrystallisation Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000002994 raw material Substances 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000010517 secondary reaction Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- -1 iron amine Chemical class 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 4
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QPFDUULIDNELSE-UHFFFAOYSA-N [4-(morpholin-4-ylmethyl)phenyl]boronic acid Chemical compound C1=CC(B(O)O)=CC=C1CN1CCOCC1 QPFDUULIDNELSE-UHFFFAOYSA-N 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- PKAUVIXBZJUYRV-UHFFFAOYSA-N methane;hydroiodide Chemical compound C.I PKAUVIXBZJUYRV-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000011946 reduction process Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OSXFATOLZGZLSK-UHFFFAOYSA-N 6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine Chemical compound C=12C=C(OC)C(OC)=CC2=NC(N2CCN(C)CCC2)=NC=1NC(CC1)CCN1CC1=CC=CC=C1 OSXFATOLZGZLSK-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 201000005231 Epithelioid sarcoma Diseases 0.000 description 1
- 108010016918 Histone-Lysine N-Methyltransferase Proteins 0.000 description 1
- 102000000581 Histone-lysine N-methyltransferase Human genes 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 229950004774 tazemetostat Drugs 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel salt form of a key intermediate of tazistat, a preparation method thereof and an intermediate thereof. Compared with the compound 8, the novel salt type compound 9 of the key intermediate of the tazistat is prepared directly, the compound 8 is converted into the compound 9 and then the compound 10 is prepared, and the purity is improved under the condition that the yield is ensured, so that the purity of the tazistat prepared by the subsequent hydrolysis can be further improved; in addition, the compound 9 is salified and solidified, so that a solid with better properties can be obtained, and quality control can be performed through recrystallization, thereby being beneficial to quality control of medicines. The invention also provides a preparation method of the novel salt type compound 9 of the key intermediate of the tazistat and the intermediate thereof, and the preparation method of the novel salt type compound 9 of the key intermediate of the tazistat is low in cost, high in yield and suitable for industrial production.
Description
Technical Field
The invention relates to a novel salt form of a key intermediate of tazistat, a preparation method thereof and an intermediate thereof.
Background
Tazestat (Tazemetostat) is an oral EZH2 inhibitor originally developed by Epizyme corporation and shown in structural formula 1. EZH2 is a histone lysine methyltransferase, which, if abnormally activated, will cause deregulation of genes that control cell proliferation, thereby causing unrestricted rapid growth of non-hodgkin's lymphoma (NHL) and other various solid tumor cells. Tazestat can exert an antitumor effect by inhibiting the activity of the enzyme EZH 2.
Tazistat was approved for epithelioid sarcoma indication in month 1 2020. The tumors of the two refractory follicular lymphomas (1) which are mainly treated are confirmed by FDA-approved detection methods as EZH2 mutation positive, recurrent or refractory FL adult patients who have previously received at least 2 systemic therapies, are marketed again in 6 months 2020; (2) Recurrent or refractory FL adult patients with no satisfactory alternative treatment options.
In several clinical experiments of the medicine, the tazistat has the characteristics of good tolerance and low incidence rate of adverse events related to treatment, and has clinically significant and durable single medicine activity on patients and obvious curative effect on EZH2 activation mutant patients.
The current synthetic route for tazistat is as follows:
route one: (see CN104080769, CN104768555, CN105440023, CN 109745316)
In the route, the methyl esterification reaction uses the iodine methane with higher price, the dosage is four times equivalent relative to A2, and the industrialization cost is increased; the process of A3 to A4 adopts the elimination process iron amine reduction method which is definitely regulated by the national Committee for improvement in 2005, and the reduction process of iron powder can cause the problem of three wastes; the reaction process of synthesizing A5 from A4 and A6 from A5 and synthesizing tazistat from A9 uses a column passing means for purification, which is not suitable for industrialized operation; as the Suzuki coupling reaction uses a palladium catalyst, the residual palladium element is possibly caused, and the quality control requirement on the final product is higher. In route one, the cost of the pinacol 4- (4-morpholinomethyl) phenylboronic acid used in the Suzuki coupling reaction is relatively expensive. The overall route yield was 27.2%.
Route two: (refer to CN105829302, CN108358899, CN 104603130A)
Compared with the first route, the method advances the Suzuki coupling reaction step, so that the Pd element residue of the final product is reduced, and the pressure of the final product on the quality control of heavy metal residue is reduced. There are also some problems: the methyl esterification reaction uses the iodine methane with higher price, the dosage is four times equivalent relative to the B2, and the industrialization cost is increased. The reduction process of the iron powder can cause the problem of three wastes; the two steps of reductive amination post-treatment processes of B4 to B5 and B5 to B6 are both purified by using a column passing method, so that the method is not suitable for industrial production, and the column passing yield of B4 to B5 is lower and is 69%; the 4- (4-morpholinomethyl) phenylboronic acid pinacol used in the Suzuki reaction has higher price, 4-formylphenylboronic acid and pinacol are required to react and then undergo reductive amination reaction with morpholine, and the yield of the Suzuki reaction after column chromatography is 71%.
B7 in the patent is orange oily compound with yield of 164%, possibly including impurities and solvents, and lacks a quality control link. B8 was a solid in 80% yield. The total route yield cannot be accurately calculated.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the raw material cost is high, the route yield is low, and the method is not suitable for being applied to one or more of the problems of industrial production and the like in a synthetic route of the tazistat, therefore, the invention provides a novel salt type compound 9 of a key intermediate of the tazistat, compared with the method for directly preparing the compound 10 from the compound 8, the method converts the compound 8 into the compound 9 and then prepares the compound 10, and the purity is improved under the condition of ensuring the yield, so that the purity of the tazistat prepared by the subsequent hydrolysis can be further improved; in addition, the compound 9 is salified and solidified, so that a solid with better properties can be obtained, and quality control can be performed through recrystallization, thereby being beneficial to quality control of medicines. The invention also provides a preparation method of the novel salt type compound 9 of the key intermediate of the tazistat and the intermediate thereof, and the preparation method of the novel salt type compound 9 of the key intermediate of the tazistat is low in cost, high in yield and suitable for industrial production.
The invention provides a compound shown as a formula 9:
The invention provides a preparation method of a compound shown as a formula 9, which comprises the following steps: in an organic solvent, carrying out salt forming reaction on the compound 8 and hydrogen chloride to obtain a compound shown as a formula 9;
In the salt forming reaction, the organic solvent is conventional in the art, preferably one or more of methanol, ethanol, isopropanol, isopropyl ether, methyl tert-butyl ether, acetone and ethyl acetate, more preferably methanol, ethyl acetate, isopropyl ether or methyl tert-butyl ether.
In the salification reaction, the volume-mass ratio of the organic solvent to the compound 8 is conventional in the art, preferably 0.7-1.2mL/g, for example 0.8mL/g, 0.91mL/g, 0.98mL/g or 1.0mL/g.
In the salt-forming reaction, the molar ratio of the hydrogen chloride to the compound 8 is conventional in the art, preferably (1.5-1): 1, for example, 1:1.
The temperature of the salt forming reaction is conventional in the art, preferably from 0℃to 60 ℃.
The salification reaction is preferably carried out by the following steps: and (3) reacting the mixed solution of the compound 8, the hydrogen chloride and the organic solvent under stirring, and filtering and drying after the reaction is finished.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, carrying out reductive amination reaction on the compound 7 and morpholine in the presence of organic acid and borohydride to obtain a compound 8;
In the reductive amination reaction, the organic acid is conventional in the art, preferably one or more of formic acid, acetic acid and benzoic acid, more preferably formic acid or acetic acid.
The molar ratio of said organic acid to said borohydride is conventional in the art, preferably (10-40): 1, for example 30:1.
In the reductive amination reaction, the borohydride is conventional in the art, preferably sodium borohydride and/or potassium borohydride, more preferably sodium borohydride.
The molar ratio of borohydride to compound 7 in the reductive amination reaction is conventional in the art, and is preferably (1-5): 1, for example, 2.98:1.
In the reductive amination reaction, the molar ratio of morpholine to compound 7 is conventional in the art, preferably (1-10): 1, for example 1.2:1.
In the reductive amination reaction, the organic solvent is conventional in the art, preferably one or more of dichloromethane, methanol, ethanol and toluene, more preferably dichloromethane or ethanol.
In the reductive amination reaction, the volume to mass ratio of the organic solvent to the compound 7 is conventional in the art, preferably 5 to 20mL/g, for example 7.6mL/g.
The temperature of the reductive amination reaction is conventional in the art, preferably from 0 ℃ to 60 ℃, for example, room temperature.
The time for the reductive amination reaction may be measured by conventional detection means until the reaction is completed, preferably 5 to 30 hours, for example 9 hours or 22 hours.
The reductive amination reaction is preferably carried out by the steps of: in the first system, in an organic solvent, the compound 7 reacts with the morpholine; in a second system, adding the borohydride into an organic solvent and reacting with the organic acid; the first system is added to the second system, preferably the borohydride is added to the solvent and the organic acid in portions under ice bath conditions, and more preferably the first system is added to the second system in a dropwise manner.
The reductive amination reaction preferably further comprises the following post-treatment steps: after the reaction is finished, adding an organic solvent and an aqueous hydrochloric acid solution for extraction, washing with an alkali solution, drying and concentrating the organic phase, wherein the alkali solution is preferably a saturated sodium bicarbonate solution, and the organic solution is preferably dichloromethane.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent and water, in the presence of a catalyst and alkali, carrying out a coupling reaction on the compound 6 and 4-formylphenyl boric acid to obtain a compound 7;
In the coupling reaction, the catalyst is conventional in the art, preferably a palladium catalyst such as one or more of palladium acetate, tetrakis triphenylphosphine palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and tris (dibenzylideneacetone) dipalladium, more preferably tetrakis triphenylphosphine palladium.
In the coupling reaction, the mass ratio of the catalyst to the compound 6 is conventional in the art, preferably (0.008-0.10): 1, for example, 0.009:1, 0.011:1, 0.015:1 or 0.048:1.
In the coupling reaction, the base is conventional in the art, preferably sodium carbonate and/or potassium carbonate, more preferably sodium carbonate.
The molar ratio of base to compound 6 in the coupling reaction is conventional in the art, preferably (0.5-2): 1, e.g. 2:1.
In the coupling reaction, the ratio of the volume mass of the water to the compound 6 is conventional in the art, preferably 1-2mL/g, for example 1mL/g.
In the coupling reaction, the molar ratio of the 4-formylphenylboronic acid to the compound 6 is conventional in the art, and preferably (1-2): 1, for example, 1:1.
In the coupling reaction, the organic solvent is conventional in the art, preferably one or more of ethanol, 1, 4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene and N, N-dimethylformamide, more preferably ethanol, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide or ethylene glycol dimethyl ether.
In the coupling reaction, the volume to mass ratio of the organic solvent to the compound 6 is conventional in the art, preferably 1 to 5mL/g, for example 3mL/g.
The temperature of the coupling reaction is conventional in the art, preferably from 0℃to 100 ℃.
The coupling reaction may be carried out for a period of time up to the completion of the reaction by conventional detection means, preferably 1 to 15 hours, for example 6 hours, 3 hours or 10 hours.
The coupling reaction is preferably carried out by the steps of: at room temperature, the compound 6, the 4-formylphenylboronic acid, the base, the catalyst, the organic solvent and the water are reacted under the protection of inert gas, preferably nitrogen.
The coupling reaction preferably further comprises the following post-treatment steps: after the reaction is finished, adding an organic solvent, carrying out suction filtration, washing with water, washing a water layer with the organic solvent, combining organic phases, washing with water, drying, filtering and concentrating.
The coupling reaction, preferably, further comprises the following purification steps: after the reaction is completed, the mixture is recrystallized from methanol/water or isopropyl acetate, more preferably from methanol/water.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, carrying out reductive amination reaction on the compound 5 and acetaldehyde in the presence of organic acid and borohydride to obtain a compound 6;
In the reductive amination reaction, the organic acid is conventional in the art, preferably one or more of formic acid, acetic acid and benzoic acid, more preferably formic acid or acetic acid.
In the reductive amination reaction, the molar ratio of the organic acid to the borohydride is conventional in the art, preferably (3-6): 1, for example 5:1.
In the reductive amination reaction, the borohydride is conventional in the art, preferably sodium borohydride and/or potassium borohydride, more preferably sodium borohydride.
The molar ratio of borohydride to compound 5 in the reductive amination reaction is conventional in the art, and is preferably (1-3): 1, e.g., 2:1.
The molar ratio of acetaldehyde to compound 5 in the reductive amination reaction is conventional in the art, preferably (1-10): 1, e.g. 10:1.
In the reductive amination reaction, the organic solvent is conventional in the art, preferably one or more of dichloromethane, methanol and toluene, more preferably dichloromethane or methanol.
In the reductive amination reaction, the volume to mass ratio of the organic solvent to the compound 5 is conventional in the art, preferably 5 to 20mL/g, for example 10mL/g.
The reductive amination reaction is carried out at a temperature conventional in the art, preferably from 0℃to 60℃and preferably at room temperature.
The time for the reductive amination reaction may be measured by conventional detection means until the reaction is completed, preferably 20 to 30 hours, for example 22 hours.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, carrying out reductive amination reaction on a compound 4 and tetrahydropyranone in the presence of organic acid and borohydride to obtain a compound 5;
The molar ratio of tetrahydropyranone to compound 4 in the reductive amination reaction is conventional in the art, preferably (1-2): 1, for example 1.5:1.
In the reductive amination reaction, the borohydride is conventional in the art, preferably sodium borohydride and/or potassium borohydride, more preferably sodium borohydride.
The molar ratio of borohydride to compound 4 in the reductive amination reaction is conventional in the art, preferably (1-3): 1, e.g., 2:1
In the reductive amination reaction, the organic acid is conventional in the art, preferably formic acid and/or acetic acid.
In the reductive amination reaction, the molar ratio of the organic acid to the borohydride is conventional in the art, preferably (3-6): 1, for example 3:1 or 4:1.
In the reductive amination reaction, the organic solvent is conventional in the art, preferably dichloromethane and/or methanol.
In the reductive amination reaction, the volume to mass ratio of the organic solvent to the compound 4 is conventional in the art, preferably 5 to 20mL/g, for example 20mL/g.
The temperature of the reductive amination reaction is conventional in the art, preferably from 0 ℃ to 50 ℃.
The time for the reductive amination reaction may be measured by conventional detection means until the reaction is completed, preferably 1 to 5 hours, for example 2 hours or 3 hours.
The reductive amination reaction preferably further comprises the following purification steps: recrystallizing with ethanol.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, carrying out reduction reaction on the compound 3 in the presence of a catalyst and hydrogen to obtain a compound 4;
In the reduction reaction, the catalyst is conventional in the art, preferably one or more of Raney nickel, palladium carbon and Raney cobalt, more preferably Raney nickel or Raney cobalt.
In the reduction reaction, the mass ratio of the catalyst to the compound 3 is conventional in the art, preferably (0.03-0.3): 1, for example, 0.09:1, 0.3:1 or 0.045:1.
In the reduction reaction, the organic solvent is conventional in the art, preferably, one or more of methanol, ethanol and isopropanol, more preferably, methanol.
In the reduction reaction, the volume/mass ratio of the organic solvent to the compound 3 is conventional in the art, preferably 5 to 15mL/g, for example 10mL/g.
The temperature of the reduction reaction is conventional in the art, preferably 20℃to 50 ℃.
The time of the reduction reaction may be measured by a conventional measuring means until the completion of the reaction, and is preferably 4 to 10 hours, for example 8 hours.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in an organic solvent, in the presence of thionyl chloride, performing methyl esterification reaction on the compound 2 and methanol to obtain a compound 3;
In the methyl esterification reaction, the organic solvent is conventional in the art, preferably methanol and/or tetrahydrofuran, more preferably methanol.
In the methyl esterification reaction, the volume/mass ratio of the organic solvent to the compound 2 is conventional in the art, preferably 1 to 20mL/g, for example 1.6mL/g.
In the methyl esterification reaction, the molar ratio of the thionyl chloride to the compound 2 is conventional in the art, preferably (1-3): 1, for example, 1.5:1.
The methyl esterification reaction temperature is conventional in the art, preferably from 0 ℃ to 100 ℃, and preferably at room temperature.
The time of the methyl esterification reaction may be measured by a conventional measuring means until the reaction is completed, and is preferably 4 to 7 hours, for example, 7 hours.
The preparation method of the compound shown in the formula 9 can further comprise the following steps: in the presence of acid, carrying out bromination reaction on the compound 1 and a brominating reagent to obtain a compound 2;
in the bromination reaction, the acid is conventional in the art, preferably sulfuric acid, such as concentrated sulfuric acid.
In the bromination reaction, the volume to mass ratio of the acid to the compound 1 is conventional in the art, preferably 1 to 5mL/g, for example 4mL/g.
In the bromination reaction, the brominating reagent is conventional in the art, preferably dibromohydantoin.
In the bromination reaction, the molar ratio of the brominating reagent to the compound 1 is conventional in the art, preferably (0.3-1): 1, for example, 0.6:1.
The bromination reaction is conventional in the art, preferably at 0 ℃ to 60 ℃, for example at room temperature.
The time of the bromination reaction can be measured by a conventional measuring means until the reaction is completed, and is preferably 1 to 8 hours, for example, 6 hours.
The invention also provides a preparation method of the compound 10, which comprises the following steps: in an organic solvent, carrying out hydrolysis reaction on the compound 9 in the presence of alkali to obtain a compound 10;
In the hydrolysis reaction, preferably, the organic solvent is conventional in the art, preferably, methanol.
In the hydrolysis reaction, the ratio of the volume mass of the organic solvent to the compound 9 is preferably conventional in the art, preferably 6 to 10mL/g, for example 8mL/g.
In the hydrolysis reaction, the base is preferably conventional in the art, preferably NaOH.
In the hydrolysis reaction, the molar ratio of the base to the compound 9 is preferably conventional in the art, and preferably (3-8): 1, for example 4:1 or 6:1.
In the hydrolysis reaction, it is preferable to perform the steps of: and (3) reacting the compound 9 with the alkali in the organic solvent, adjusting the pH to be neutral after the reaction is finished, extracting, concentrating and drying.
In the hydrolysis reaction, the temperature of the hydrolysis reaction is preferably 0 to 60 ℃, for example 60 ℃.
The invention also provides a compound shown as a formula 7:
the invention also provides a preparation method of the compound 7, which comprises the following steps: in an organic solvent and water, in the presence of a catalyst, carrying out a coupling reaction on the compound 6 and 4-formylphenylboric acid to obtain a compound 7;
In the preparation method of the compound 7, the reaction conditions of the coupling reaction can be as described above.
The process for preparing compound 7 may further comprise the step of preparing compound 6 according to the process described above.
The invention also provides a preparation method of the compound 8, which comprises the following steps: in an organic solvent, carrying out reductive amination reaction on the compound 7 and morpholine in the presence of organic acid and borohydride to obtain a compound 8;
In the preparation method of the compound 8, the reaction conditions of the reductive amination reaction can be as described above.
The process for preparing compound 8 may further comprise the step of preparing compound 7 according to the process described above.
The invention provides a preparation method of a compound 5, which comprises the following steps: in an organic solvent, carrying out reductive amination reaction on a compound 4 and tetrahydropyranone in the presence of organic acid and borohydride to obtain a compound 5;
In the preparation method of the compound 5, the reaction conditions of the reductive amination reaction can be as described above.
The process for preparing compound 5 may further comprise the step of preparing compound 5 according to the process described above.
The invention also provides a preparation method of the compound 4, which comprises the following steps: in an organic solvent, carrying out reduction reaction on the compound 3 in the presence of a catalyst and hydrogen to obtain a compound 4;
In the preparation method of the compound 4, the reaction conditions of the reductive amination reaction can be as described above.
The process for preparing compound 4 may further comprise the step of preparing compound 4 according to the process described above.
The invention provides a preparation method of a compound 3, which comprises the following steps: in an organic solvent, in the presence of thionyl chloride, performing methyl esterification reaction on the compound 2 and methanol to obtain a compound 3;
in the preparation method of the compound 3, the reaction conditions of the reductive amination reaction can be as described above.
The process for preparing compound 3 may further comprise the step of preparing compound 3 according to the process described above.
The invention provides a preparation method of a compound 2, which can further comprise the following steps: in the presence of acid, carrying out bromination reaction on the compound 1 and a brominating reagent to obtain a compound 2;
In the preparation method of the compound 2, the reaction conditions of the reductive amination reaction can be as described above.
The room temperature in the invention is 15-35 ℃.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention can achieve one or more of the following technical effects:
(1) According to the invention, the compound 8 oily matter is salified and solidified to obtain the compound 9, so that a solid with better properties can be conveniently obtained, and the quality of the solid can be controlled by recrystallization, thereby being beneficial to the quality control of medicines;
(2) In the process of preparing the compound 10, the compound 9 is used as a raw material, so that the purity is improved under the condition of ensuring the yield, and the purity of the tazistat prepared by the subsequent hydrolysis is improved;
(3) The synthetic route of the invention improves the yield of the preparation of the tazistat, and the total yield of the first route is 27.24%, the total yield of the second route is 29.04%, and the total yield of the invention is 46.41% through calculation; compound 10 was prepared in a total yield of 41.48% for route two and 66.3% for the present invention.
(4) The synthetic route of the invention reduces the cost of preparing the tazistat, and the cost of the second route is 3901.77 yuan/g and the cost of the invention is 271.154 yuan/g after calculation to prepare the compound 10 and neglecting common solvents and reagents in laboratories.
(5) The 4-formylphenylboronic acid is directly connected with the compound 6, the yield of the suzuki step column chromatography can reach 93 percent, which is far higher than the yield of the patent CN104603130, and the recrystallization of the system of methanol/water or isopropyl acetate is used for replacing the complicated column chromatography which is not easy to amplify, and the recrystallization yield can reach 89 percent;
(6) The reaction condition is controlled in the process of synthesizing the compound 8 from the compound 7, the yield can reach 98%, the total yield of the two steps is superior to that of the patent route, and the total synthesis step is shortened by one step;
(7) In the preparation process of the compound 3, thionyl chloride with the quantity close to the theoretical quantity (namely, the equimolar quantity with the compound 2) is used for replacing excessive and expensive methyl iodide, methanol is used as a solution and a reagent, and crystallization is separated out after the reaction is finished, so that the treatment is convenient;
(8) In the preparation process of the compound 4, the hydrogen normal temperature and normal pressure reduction method is used for the reduction reaction to replace the iron amine reduction method, so that the operation is simpler and more convenient, and the three wastes caused by the iron amine reduction method are avoided;
(9) In the preparation process of the compound 5, recrystallization can be used for purifying instead of a column in the post-treatment step, so that the method is more suitable for industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The purity test in the examples used an HPLC method under the following conditions:
Chromatographic conditions:
column: welch Xtimate C8 (5 μm, 4.6X1250 mm)
Mobile phase: 25mM/L KH 2PO4 (pH adjusted to 4.0 with H 3PO4) in water-acetonitrile gradient
Gradient elution conditions are as in table 1:
TABLE 1
Time (min) | 25MM/L KH 2PO4 aqueous solution (%) | Acetonitrile (%) |
0 | 90 | 10 |
10 | 90 | 10 |
15 | 50 | 50 |
30 | 50 | 50 |
31 | 90 | 10 |
40 | 90 | 10 |
Flow rate: 1ml/min
Column temperature: 35 DEG C
Detection wavelength: 254nm
Sample injection amount: 10 microliters
Example 1 preparation of Compound 10
Using the compound 8 obtained in example 10 as a starting material, compound 8 (3 g,6.65 mmol), naOH (1.064 g, 26.6 mmol), 24ml of methanol, 6ml of water were added to a reaction flask at 60℃and after the reaction was completed, pH was adjusted to about 7 in an ice bath at 0-5℃and extracted 4 times with methylene chloride containing 5% methanol, the organic phases were combined and dried over anhydrous magnesium sulfate to give the objective compound 10,2.81g of a white solid in 96.3% yield and 97.91% purity.
Example 2 preparation of Compound 10
Using the compound 9 (hydrochloride) obtained in example 7 as a starting material, compound 9 (3.25 g,6.65 mmol), naOH (1.596 g, 39.9 mmol), methanol (24 ml), water (6 ml) were added to a reaction flask at 60℃and after the completion of the reaction, the pH was adjusted to about 7 by ice bath at 0-5℃and extracted 4 times with methylene chloride containing 5% methanol, the organic phases were combined and dried over anhydrous magnesium sulfate to give the objective compound 10,3.16g as a solid in 97.2% yield and 99.52% purity.
Example 3 preparation of Compound 10
The phosphate of the compound 8 obtained in example 9 was used as a raw material, phosphate (2.97 g,5.4 mmol) of the compound 8, naOH (1.298 g, 32.4 mmol), 24ml of methanol and 6ml of water were added to a reaction flask at 60℃and the pH was adjusted to about 7 in an ice bath at 0-5℃after the completion of the reaction, the mixture was extracted 4 times with methylene chloride containing 5% methanol, the organic phases were combined and dried over anhydrous magnesium sulfate to give the objective compound 10,2.22g of a solid in a yield of 93.7% and a purity of 95.3%.
Example 4 preparation of Compound 10
The sulfate salt of Compound 8 obtained in example 8 was used as a starting material, sulfate salt (3 g,5.4 mmol) of Compound 8, naOH (1.298 g, 32.4 mmol), 24ml of methanol and 6ml of water were added to a reaction flask at 60℃and reacted for 7 hours, after the completion of the reaction, the pH was adjusted to about 7 by ice bath at 0-5℃and extracted 4 times with methylene chloride containing 5% methanol, the organic phases were combined and dried over anhydrous magnesium sulfate to give the objective compound 10,2.27g of a white solid in 95.7% yield and 96.8% purity.
Example 5 preparation of Compound 9
Using the compound 8 obtained in example 10 as a starting material, compound 8 (3 g,6.65 mmol), a methanol solution of HCl (2.243 g, W HCl/W Solution =10%) was added to a reaction flask at room temperature, and stirred for 2 hours. The hydrochloride of the target compound 9 is obtained by suction filtration and drying, the yield is 98.71 percent, and the purity is 97.66 percent.
EXAMPLE 6 preparation of Compound 9
Using the compound 8 obtained in example 10 as a starting material, compound 8 (3 g,6.65 mmol) was added to a reaction flask, and an ethyl acetate solution of HCl (2.243 g, W HCl/W Solution =10%) was stirred for 2h. The hydrochloride of the target compound 9 is obtained by suction filtration and drying, and the yield is 98.71 percent.
EXAMPLE 7 preparation of Compound 9
Using the compound 8 obtained in example 10 as a starting material, a solution of compound 8 (3 g,6.65 mmol) in methyl tert-butyl ether (2.243 g, W HCl/W Solution =10%) of HCl was added to a reaction flask and stirred for 2h. The hydrochloride of the target compound 9 is obtained by suction filtration and drying, and the yield is 98.71 percent.
EXAMPLE 8 preparation of sulfate salt of Compound 8
Using the compound 8 obtained in example 10 as a starting material, compound 8 (3 g,6.65 mmol), 0.666g of concentrated sulfuric acid was added to a reaction flask, and stirred for 7 hours. The sulfate of the target compound 9 is obtained by suction filtration and drying, and the yield is 93 percent and the purity is 97.2 percent.
Example 9 preparation of phosphate salt of Compound 8
Using the compound 8 obtained in example 10 as a starting material, compound 8 (3 g,6.65 mmol), 0.698g of phosphoric acid was added to a reaction flask, and stirred overnight. The sulfate of the target compound 9 is obtained by suction filtration and drying, the yield is 87%, and the purity is 95.9%.
EXAMPLE 10 preparation of Compound 8
Using the compound 7 obtained in example 12 as a starting material, compound 7 (27 g,71.1 mmol), morpholine (7.2 g,84.6 mmol) and 270mL of methylene chloride were added to a secondary reaction flask under reflux, and the mixture was reacted for 2 hours. 270mL of methylene chloride and acetic acid (382.5 g,6.27 mol) are added into a main reaction bottle, sodium borohydride (8.01 g, 212.22 mmol) is added in portions under the ice bath condition, the reaction solution is moved to room temperature for reaction for 2H, the reaction solution of a secondary reaction bottle is dripped into the main reaction bottle for reaction for 7H at room temperature, and no raw material remains after TLC monitoring. The reaction solution was added to 500mL of methylene chloride, washed twice with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 32.11g of the objective compound 8 in a yield of 99.8% and a purity of 97.12%.1H NMR(CDCl3,400MHz)δ7.82(d,1H),7.58(d,2H),7.54(d,2H),7.50(d,1H),3.98(d,2H),3.94(s,3H),3.87(s,4H),3.76(s,2H),3.36(td,2H,J=12Hz),3.12-3.17(m,2H),3.01-3.07(m,1H),2.68(s,3H),2.56(s,3H),1.68-1.79(m,5H),0.94(t,3H).
EXAMPLE 11 preparation of Compound 8
Using the compound 7 obtained in example 12 as a starting material, compound 7 (3 g,7.9 mmol), morpholine (0.8 g,9.4 mmol), 30mL of ethanol was added to a secondary reaction flask under reflux, and the mixture was reacted for 2 hours. 30mL of ethanol and formic acid (32.6 g,707.4 mmol) are added into a main reaction bottle, potassium borohydride (1.3 g, 23.6 mmol) is added in batches under the ice bath condition, the reaction is carried out for two hours at room temperature, the reaction liquid of a secondary reaction bottle is dripped into the main reaction bottle and then reacted for 20 hours, and no raw material remains by TLC monitoring. The reaction solution was added to 200mL of methylene chloride, washed twice with 200mL of water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.44g of the objective compound 8 in yield 96.2%.1H NMR(CDCl3,400MHz)δ7.82(d,1H),7.58(d,2H),7.54(d,2H),7.50(d,1H),3.98(d,2H),3.94(s,3H),3.87(s,4H),3.76(s,2H),3.36(td,2H,J=12Hz),3.12-3.17(m,2H),3.01-3.07(m,1H),2.68(s,3H),2.56(s,3H),1.68-1.79(m,5H),0.94(t,3H).
EXAMPLE 12 preparation of Compound 7
Using the compound 6 obtained in example 16 as a starting material, compound 6 (10 g,28 mmol), 4-formylphenylboronic acid (4.2 g 28 mmol), sodium carbonate (6.0 g 56 mmol), 0.15g [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 30mL of 1, 4-dioxane, 10mL of water, 3 times with nitrogen substitution were charged into a 500mL reaction flask, the temperature was raised to 60℃and the reaction was carried out for 6 hours, with no starting material remaining as monitored by TLC. The reaction solution was added to 500mL of dichloromethane, suction-filtered, washed once with 500mL of water, the aqueous layer was washed twice with dichloromethane, the organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from isopropyl acetate to give 7.8g of the objective compound 7 in 73% yield and melting point 106.5-107℃,1H NMR(CDCl3,400MHz)δ10.08(s,1H),δ7.98(s,2H),7.88(d,1H),7.75(d,2H),7.54(d,1H),4.0(dt,2H),3.96(d,3H),3.37(td,2H,J=12,4Hz),3.17(dd,2H,J=12,4Hz),3.02-3.10(m,1H),2.58(s,3H),1.68-1.79(m,5H),0.94(t,3H).
EXAMPLE 13 preparation of Compound 7
Using the compound 6 obtained in example 16 as a starting material, 500mL of the reaction flask was charged with compound 6 (10 g 28 mmol), 4-formylphenylboronic acid (4.2 g 28 mmol), potassium carbonate (7.6 g 56 mmol), 0.3g palladium acetate, 30mL of ethanol, 10mL of water, and nitrogen gas in place of air for 3 times, the temperature was raised to 100℃and the reaction was carried out for 3 hours, and TLC monitoring showed that no starting material remained. The reaction solution was added to 500mL of dichloromethane, suction-filtered, washed once with 500mL of water, the aqueous layer was washed twice with dichloromethane, the organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product is recrystallized by isopropyl acetate to obtain 9.80g of target compound 7 with yield 91.8%.1H NMR(CDCl3,400MHz)δ10.08(s,1H),δ7.98(s,2H),7.88(d,1H),7.75(d,2H),7.54(d,1H),4.0(dt,2H),3.96(d,3H),3.37(td,2H,J=12,4Hz),3.17(dd,2H,J=12,4Hz),3.02-3.10(m,1H),2.58(s,3H),1.68-1.79(m,5H),0.94(t,3H).
EXAMPLE 14 preparation of Compound 7
Using the compound 6 obtained in example 16 as a starting material, compound 6 (10 g 28 mmol), 4-formylphenylboronic acid (4.2 g 28 mmol), sodium carbonate (6.0 g 56 mmol), 0.3g of palladium tetraphenylphosphine, 30mL of ethylene glycol dimethyl ether, 10mL of water, and nitrogen gas were charged into a 500mL reaction vessel, and reacted at room temperature for 10 hours, with no substantial starting material remaining as monitored by TLC. The reaction solution was added to 500mL of dichloromethane, suction-filtered, washed once with 500mL of water, the aqueous layer was washed twice with dichloromethane, the organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallizing the crude product with methanol/water system to obtain 9.9g of target compound 7 with yield 92.7%.1H NMR(CHCl3-d6,400MHz)δ10.08(s,1H),δ7.98(s,2H),7.88(d,1H),7.75(d,2H),7.54(d,1H),4.0(dt,2H),3.96(d,3H),3.37(td,2H,J=12,4Hz),3.17(dd,2H,J=12,4Hz),3.02-3.10(m,1H),2.58(s,3H),1.68-1.79(m,5H),0.94(t,3H).
EXAMPLE 15 preparation of Compound 7
Using the compound 6 obtained in example 16 as a starting material, 500mL of the reaction flask was charged with compound 6 (10 g 28 mmol), 4-formylphenylboronic acid (4.2 g 28 mmol), sodium carbonate (6.0 g 56 mmol), 0.3g of tris (dibenzylideneacetone) dipalladium, 30mL of tetrahydrofuran, 10mL of water, and nitrogen gas in place of air for 3 times, and reacted at room temperature for 10 hours, and TLC monitoring showed substantially no starting material remained. The reaction solution was added to 500mL of dichloromethane, suction-filtered, washed once with 500mL of water, the aqueous layer was washed twice with dichloromethane, the organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallizing the crude product with isopropyl acetate to obtain 9.6g of target compound 7 with yield 89.3%.1H NMR(CDCl3,400MHz)δ10.08(s,1H),δ7.98(s,2H),7.88(d,1H),7.75(d,2H),7.54(d,1H),4.0(dt,2H),3.96(d,3H),3.37(td,2H,J=12,4Hz),3.17(dd,2H,J=12,4Hz),3.02-3.10(m,1H),2.58(s,3H),1.68-1.79(m,5H),0.94(t,3H).
EXAMPLE 16 preparation of Compound 6
Using the compound 5 obtained in example 18 as a starting material, compound 5 (98.5 g,0.3 mol) and 1L of methylene chloride (44.05 g,3 mol) were charged into a 5L reaction flask at room temperature and reacted for 2 hours. Into a 2L main reaction flask was charged dichloromethane, glacial acetic acid (180 g,3 mol), and sodium borohydride (22.7 g,0.6 mol) was added in portions under ice bath conditions and reacted at room temperature for two hours. The reaction liquid in the secondary reaction flask was dropped into the primary reaction flask and reacted for 20 hours, and TLC monitoring was carried out without raw material remaining. Regulating pH to 7-8 with saturated sodium carbonate solution, separating, washing water phase with dichloromethane for 2 times, mixing organic phases, washing with saturated common salt water for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 103.99g of target compound 6, with yield of 97.3%, directly feeding into the next step .1H NMR(CHCl3-d6,400MHz)δ7.71(s,1H),7.37(s,1H),3.96(d,2H),3.89(s,3H),3.33(td,2H,J=8,4Hz),3.03-3.06(m,2H),2.91-2.96(m,1H),2.45(s,3H),1.61-1.71(m,5H),1.26(t,1H).
EXAMPLE 17 preparation of Compound 6
Using the compound 5 obtained in example 18 as a starting material, compound 5 (98.5 g,0.3 mol), anhydrous acetaldehyde (44.05 g,3 mol) was added to 1L of methanol in a 5-liter reaction flask at room temperature, and the mixture was reacted for 2 hours. To a 2L main reaction flask was added 1L of methanol, formic acid (138.1 g,3 mol), and potassium borohydride (32.4 g,0.6 mol) was added in portions under ice bath conditions, and the reaction was carried out at room temperature for two hours. The reaction liquid in the secondary reaction flask was dropped into the primary reaction flask and reacted for 20 hours, and TLC monitoring was carried out without raw material remaining. Regulating pH to 7-8 with saturated sodium carbonate solution, separating, washing water phase with dichloromethane for 2 times, mixing organic phases, washing with saturated common salt water for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 98.01g of target compound 6 with yield of 91.7%, and directly feeding into next step .1H NMR(CHCl3-d6,400MHz)δ7.71(s,1H),7.37(s,1H),3.96(d,2H),3.89(s,3H),3.33(td,2H,J=8,4Hz),3.03-3.06(m,2H),2.91-2.96(m,1H),2.45(s,3H),1.61-1.71(m,5H),1.26(t,1H).
EXAMPLE 18 preparation of Compound 5
Using the compound 4 obtained in example 20 as a starting material, compound 4 (97 g,0.397 mol), tetrahydropyranone (59.68 g,0.596 mol), 1L of methylene chloride was charged into a 2L reaction flask at room temperature, and reacted for 2 hours. To a 5L main reaction flask were added 1L of methylene chloride and acetic acid (190.72 g of 3.176 mol), and sodium borohydride (30.04 g of 0.794 mol) was added under ice bath conditions, and the mixture was reacted at room temperature for 2 hours after the addition. The reaction liquid of the secondary reaction bottle is dripped into the main reaction bottle to react for 2 hours, the TLC detection raw material is basically disappeared, the pH value is adjusted to 7-8 by saturated sodium bicarbonate solution, the liquid is separated, the water phase is washed by methylene dichloride for 2 times, the organic phases are combined, saturated common salt water is washed, and anhydrous sodium sulfate is dried, thus 132g of crude product is obtained. Ethanol recrystallization gives 117.27g of white solid with a yield of 90%, melting point 139-140℃,1H NMR(CDCl3,400MHz)δ7.23(s,1H),6.84(s,1H),4.01(dt,2H,J=8Hz),3.88(s,3H),3.65(s,1H),3.55(td,2H,J=8Hz),3.51(s,1H),2.23(s,3H),2.05(d,2H,J=8Hz),1.48-1.55(m,2H).
Example 19 preparation of Compound 5
Using the compound 4 obtained in example 20 as a starting material, compound 4 (97 g,0.397 mol), tetrahydropyranone (59.62 g,0.595 mol), 1L of methanol was charged into a 2L reaction flask at room temperature, and reacted for 2 hours. To a 5L main reaction flask, 1L of methanol and formic acid (190.72 g 3.176 mol) were added, and potassium borohydride (42.83 g 0.794 mol) was added under ice bath conditions, and the reaction was carried out at room temperature for 1 hour after the addition. Dropping the reaction liquid of the secondary reaction bottle into the main reaction bottle, reacting for 2 hours, detecting the substantial disappearance of the raw material by TLC, adjusting the pH value to 7-8 by using saturated sodium bicarbonate solution, separating liquid, washing the water phase by dichloromethane for 2 times, combining the organic phases, washing by using saturated common salt water, and drying by using anhydrous sodium sulfate. Ethanol recrystallization gives 113.36g of white solid with a yield of 87% and a melting point 139-140℃,1H NMR(CDCl3,400MHz)δ7.23(s,1H),6.84(s,1H),4.01(dt,2H,J=8Hz),3.88(s,3H),3.65(s,1H),3.55(td,2H,J=8Hz),3.51(s,1H),2.23(s,3H),2.05(d,2H,J=8Hz),1.48-1.55(m,2H).
EXAMPLE 20 preparation of Compound 4
To the flask was added compound 3 (11 g,40.5 mmol), 110mL of isopropanol, 1g of Raney cobalt, and the mixture was reacted at room temperature for 8 hours under hydrogen atmosphere. Suction filtration and concentration of the filtrate under reduced pressure gave 9.2g of the title compound in 93.2% yield. 1H NMR(CHCl3 D6,400 MHz) δ7.29 (s, 1H), 6.88 (s, 1H), 3.85 (s, 3H), 2.23 (s, 3H).
Example 21 preparation of Compound 4
To the reaction flask was added compound 3 (111 g,405 mmol), 1.11L methanol, 33.3g Raney nickel, and reacted at room temperature for 8 hours under hydrogen atmosphere. Suction filtration and concentration of the filtrate under reduced pressure gave 97.4g of the title compound in 98.6% yield. 1H NMR(CHCl3 D6,400 MHz) δ7.29 (s, 1H), 6.88 (s, 1H), 3.85 (s, 3H), 2.23 (s, 3H).
Example 22 preparation of Compound 4
To the flask was added compound 3 (11 g,40.5 mmol), 110mL ethanol, 0.5g palladium on carbon, and the mixture was reacted at room temperature for 8 hours under a hydrogen atmosphere. After suction filtration and concentration of the filtrate under reduced pressure, the compound was purified by column chromatography by petroleum ether: ethyl acetate was eluted to provide the desired compound to give 5.4g of the title compound in 55% yield. 1H NMR(CDCl3 400 MHz) delta 7.70 (d, 1H), 7.61 (d, 1H), 7.40 (t, 1H), 3.84 (s, 3H), 2.45 (s, 3H).
EXAMPLE 23 preparation of Compound 3
To a reaction flask was added compound 2 (130 g,500 mmol) and methanol (160 g,5000 mmol) dropwise thionyl chloride (89 g,750 mmol) as in the example. The reaction is carried out at room temperature for 7 hours, the TLC detection raw material is basically disappeared, the temperature is reduced to room temperature, 126.1g of solid is obtained by suction filtration and drying, and the yield is 93.1%. Melting point 49-50 ℃. 1H NMR(CDCl3 400 MHz) delta 8.14 (s, 1H), 7.99 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H).
EXAMPLE 24 preparation of Compound 2
Compound 1 (200 g,1104 mmol) and 800mL of concentrated sulfuric acid are added into a reaction bottle, dibromohydantoin (176.8 g,618.2 mmol) is added under the ice bath condition, the reaction is carried out for 6 hours after the addition, the TLC detection raw material is basically disappeared, the reaction liquid is poured into 1L ice water, stirring and suction filtration are carried out, a filter cake is washed with 1L ice water for 3 times, 285.6g of solid is obtained after drying, and the yield is 99.5%. Melting point 182-183 ℃. 1H NMR(CDCl3 400 MHz) delta 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
Comparative example 1 preparation of Compound 3
To the reaction flask were added compound 2 (13 g,50 mmol), 130mL DMF, methyl iodide (28.4 g,200 mmol) and sodium carbonate (21.2 g,200 mmol). The reaction is carried out for 5h at 60 ℃, the TLC detection raw material is basically disappeared, the temperature is reduced to the room temperature, 12.7g of solid is obtained after suction filtration and drying, and the yield is 93 percent. Melting point 49-50 ℃. 1 H NMR (CHCl 3-d6,400 MHz) delta 8.14 (s, 1H), 7.99 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H).
Comparative example 2 preparation of Compound 5
To the reaction flask was added compound 4 (2.3 g,9.4 mol), tetrahydropyranone (1.42 g,14.12 mol), 50mL dichloromethane, and the reaction was carried out for 2h. Sodium triacetoxyborohydride (7.9 g, 37.4 mol) was added in portions to the flask in ice bath, and the mixture was reacted at room temperature for 5 hours after the addition. TLC detection of substantial disappearance of starting material, adjustment to pH 7-8 with saturated sodium bicarbonate solution, separation of the liquid, washing of the aqueous phase with dichloromethane 2 times, combining the organic phases, saturated brine, drying over anhydrous sodium sulfate, purification of the crude product by column chromatography (200-300 mesh silica gel), purification with petroleum ether: ethyl acetate to give the desired compound in 2.2g, yield 70%, melting point 139-140℃,1H NMR(CHCl3-d6,400MHz)δ7.23(s,1H),6.84(s,1H),4.01(dt,2H,J=8Hz),3.88(s,3H),3.65(s,1H),3.55(td,2H,J=8Hz),3.51(s,1H),2.23(s,3H),2.05(d,2H,J=8Hz),1.48-1.55(m,2H)
Comparative example 3 preparation of Compound 7
To the reaction flask was added compound 7 (5 g,14 mmol), 4- (morpholinomethyl) phenylboronic acid (3.1 g 14 mmol), sodium carbonate (3.0 g 28 mmol), 0.15g [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 15mL 1, 4-dioxane, 5mL water, nitrogen sparge air 3 times, heat up to 60 ℃, react for 5h, TLC monitored no starting material remained. The reaction solution was added to 200mL of dichloromethane, suction-filtered, washed once with 200mL of water, the aqueous layer was washed twice with dichloromethane, the organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The impurities are removed, and the yield is increased 52%.1H NMR(CDCl3,400MHz)δ10.08(s,1H),δ7.98(s,2H),7.88(d,1H),7.75(d,2H),7.54(d,1H),4.0(dt,2H),3.96(d,3H),3.37(td,2H,J=12,4Hz),3.17(dd,2H,J=12,4Hz),3.02-3.10(m,1H),2.58(s,3H),1.68-1.79(m,5H),0.94(t,3H).
Comparative example 4 preparation of Compound 8
In a reaction flask was added compound 7 (3 g,7.9 mmol), morpholine (0.8 g,9.4 mmol), 60mL dichloromethane, after 2h reaction sodium triacetoxyborohydride (5.022 g,23.7 mmol) was added in portions under ice-bath conditions, the reaction was moved to room temperature for 5h, tlc detected the substantial disappearance of starting material, adjusted to pH 7-8 with saturated sodium bicarbonate solution, separated, dichloromethane washed the aqueous phase 2 times, the organic phases combined, saturated brine wash, dried over anhydrous sodium sulfate, the crude product purified by column chromatography (200-300 mesh silica gel) using petroleum ether: ethyl acetate was eluted to give 2.145g of the desired compound in 60% yield.
1H NMR(CDCl3,400MHz)δ7.82(d,1H),7.58(d,2H),7.54(d,2H),7.50(d,1H),3.98(d,2H),3.94(s,3H),3.87(s,4H),3.76(s,2H),3.36(td,2H,J=12Hz),3.12-3.17(m,2H),3.01-3.07(m,1H),2.68(s,3H),2.56(s,3H),1.68-1.79(m,5H),0.94(t,3H).
Claims (27)
1. A process for the preparation of compound 10, comprising the steps of: in an organic solvent, carrying out hydrolysis reaction on the compound 9 in the presence of alkali to obtain a compound 10;
The organic solvent is methanol;
After the hydrolysis reaction is finished, regulating the pH value to be neutral;
In the hydrolysis reaction, the molar ratio of the alkali to the compound 9 is (3-8): 1;
in the hydrolysis reaction, the volume-mass ratio of the organic solvent to the compound 9 is 6-10mL/g.
2. The method of claim 1, wherein,
In the hydrolysis reaction, the alkali is NaOH;
And/or, the hydrolysis reaction is carried out by the following steps: the compound 9 and the alkali react in the organic solvent, and after the reaction is finished, the pH is regulated to be neutral, and the mixture is extracted, concentrated and dried;
and/or the temperature of the hydrolysis reaction is 0-60 ℃.
3. The process according to claim 2, wherein the molar ratio of the base to the compound 9 in the hydrolysis reaction is 4:1 or 6:1;
And/or, in the hydrolysis reaction, the volume-mass ratio of the organic solvent to the compound 9 is 8mL/g;
and/or the temperature of the hydrolysis reaction is 60 ℃.
4. A method of preparation according to any one of claims 1 to 3, comprising the steps of: in an organic solvent, carrying out salt forming reaction on the compound 8 and hydrogen chloride to obtain a compound shown as a formula 9;
5. The method according to claim 4, wherein the organic solvent is one or more of methanol, ethanol, isopropanol, isopropyl ether, methyl tert-butyl ether, acetone and ethyl acetate;
and/or, in the salification reaction, the volume-mass ratio of the organic solvent to the compound 8 is 0.7-1.2mL/g;
and/or, in the salification reaction, the molar ratio of the hydrogen chloride to the compound 8 is (1.5-1): 1;
and/or, the temperature of the salifying reaction is 0-60 ℃;
and/or, the salification reaction is carried out by the following steps: and (3) reacting the mixed solution of the compound 8, the hydrogen chloride and the organic solvent, filtering out the solid after the reaction is finished, and drying.
6. The preparation method according to claim 4, wherein the preparation method of the compound 8 comprises the steps of: in an organic solvent, carrying out reductive amination reaction on a compound 7 and morpholine in the presence of organic acid and borohydride to obtain a compound 8;
7. The process according to claim 6, wherein in the process for producing the compound 8, the organic acid is one or more of formic acid, acetic acid and benzoic acid;
and/or, in the preparation method of the compound 8, the molar ratio of the organic acid to the borohydride in the reductive amination reaction is (10-40): 1;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the borohydride is sodium borohydride and/or potassium borohydride;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the molar ratio of the borohydride to the compound 7 is (1-5): 1;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the molar ratio of the morpholine to the compound 7 is (1-10): 1;
and/or in the preparation method of the compound 8, in the reductive amination reaction, the organic solvent is one or more of dichloromethane, methanol, ethanol and toluene;
and/or in the preparation method of the compound 8, in the reductive amination reaction, the volume-mass ratio of the organic solvent to the compound 7 is 5-20mL/g;
and/or, in the preparation method of the compound 8, the temperature of the reductive amination reaction is 0-60 ℃;
and/or, in the preparation method of the compound 8, the reductive amination reaction time is 5-30h;
and/or, in the preparation method of the compound 8, the reductive amination reaction is carried out by the following steps: in the first system, in an organic solvent, the compound 7 reacts with the morpholine; in a second system, adding the borohydride into an organic solvent and reacting with the organic acid; adding the first system into the second system;
And/or, in the preparation method of the compound 8, the reductive amination reaction further comprises the following post-treatment steps: after the reaction is finished, adding an organic solvent and a hydrochloric acid aqueous solution for extraction, washing with an alkali solution, and drying and concentrating the organic phase.
8. The process according to claim 7, wherein in the process for producing compound 8, the molar ratio of the organic acid to the borohydride in the reductive amination reaction is 30:1;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the borohydride is sodium borohydride;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the molar ratio of the borohydride to the compound 7 is 2.98:1;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the molar ratio of the morpholine to the compound 7 is 1.2:1;
And/or, in the preparation method of the compound 8, the organic solvent is dichloromethane or ethanol in the reductive amination reaction;
And/or, in the preparation method of the compound 8, in the reductive amination reaction, the volume-mass ratio of the organic solvent to the compound 7 is 7.6mL/g;
And/or, in the preparation method of the compound 8, the temperature of the reductive amination reaction is room temperature;
And/or, in the preparation method of the compound 8, the reductive amination reaction time is 9 hours or 22 hours;
and/or, in the preparation method of the compound 8, the reductive amination reaction is carried out by the following steps: in the first system, in an organic solvent, the compound 7 reacts with the morpholine; in a second system, adding the borohydride into an organic solvent and reacting with the organic acid; adding the first system into the second system; wherein the borohydride is added to the solvent and the organic acid in portions under ice bath conditions; the first system is added into the second system in a dropwise manner;
And/or, in the preparation method of the compound 8, the reductive amination reaction further comprises the following post-treatment steps: after the reaction is finished, adding an organic solvent and a hydrochloric acid aqueous solution for extraction, washing with an alkali solution, and drying and concentrating the organic phase; wherein the alkali solution is saturated sodium bicarbonate solution, and the organic solution is dichloromethane.
9. The preparation method according to claim 6, wherein the preparation method of the compound 7 comprises the steps of: in an organic solvent and water, in the presence of a catalyst and alkali, carrying out a coupling reaction on the compound 6 and 4-formylphenyl boric acid to obtain a compound 7;
10. the preparation method according to claim 9, wherein the preparation method of the compound 6 comprises the steps of: in the presence of organic acid and borohydride, carrying out reductive amination reaction on the compound 5 and acetaldehyde to obtain a compound 6;
11. The preparation method according to claim 10, wherein the preparation method of the compound 5 comprises the steps of: in the presence of organic acid and borohydride, carrying out reductive amination reaction on a compound 4 and tetrahydropyranone to obtain a compound 5;
12. The preparation method according to claim 11, wherein the preparation method of the compound 4 comprises the steps of: in an organic solvent, carrying out reduction reaction on the compound 3 in the presence of a catalyst and hydrogen to obtain a compound 4;
13. the preparation method according to claim 12, wherein the preparation method of the compound 3 comprises the steps of: in an organic solvent, in the presence of thionyl chloride, performing methyl esterification reaction on the compound 2 and methanol to obtain a compound 3;
14. the preparation method according to claim 13, wherein the preparation method of the compound 2 comprises the steps of: in the presence of acid, carrying out bromination reaction on the compound 1 and a brominating reagent to obtain a compound 2;
15. the process according to claim 9, wherein in the process for producing the compound 7, the catalyst in the coupling reaction is a palladium catalyst;
and/or, in the preparation method of the compound 7, the mass ratio of the catalyst to the compound 6 in the coupling reaction is (0.008-0.10): 1;
And/or, in the preparation method of the compound 7, the alkali is sodium carbonate and/or potassium carbonate in the coupling reaction;
And/or, in the preparation method of the compound 7, the molar ratio of the alkali to the compound 6 in the coupling reaction is (0.5-2) 1;
And/or, in the preparation method of the compound 7, in the coupling reaction, the volume-mass ratio of the water to the compound 6 is 1-2mL/g;
and/or, in the preparation method of the compound 7, the molar ratio of the 4-formylphenyl boric acid to the compound 6 in the coupling reaction is (1-2): 1;
And/or in the preparation method of the compound 7, in the coupling reaction, the organic solvent is one or more of ethanol, 1, 4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene and N, N-dimethylformamide;
And/or, in the preparation method of the compound 7, in the coupling reaction, the volume-mass ratio of the organic solvent to the compound 6 is 1-5mL/g;
And/or, in the preparation method of the compound 7, the temperature of the coupling reaction is 0-100 ℃;
And/or, in the preparation method of the compound 7, the coupling reaction time is 1-15h;
And/or, in the preparation method of the compound 7, the coupling reaction is performed by the following steps: at room temperature, the compound 6, the 4-formylphenyl boric acid, the alkali, the catalyst, the organic solvent and the water react under the protection of inert gas;
and/or, in the preparation method of the compound 7, the coupling reaction further comprises the following post-treatment steps: after the reaction is finished, adding an organic solvent, carrying out suction filtration, washing with water, washing a water layer with the organic solvent, merging organic phases, washing with water, drying, filtering and concentrating;
and/or, in the preparation method of the compound 7, the coupling reaction further comprises the following purification steps: after the reaction, it is recrystallized from methanol/water or isopropyl acetate.
16. The process according to claim 10, wherein in the process for producing the compound 6, the organic acid is one or more of formic acid, acetic acid and benzoic acid;
And/or, in the preparation method of the compound 6, in the reductive amination reaction, the molar ratio of the organic acid to the borohydride is (3-6): 1;
And/or, in the preparation method of the compound 6, in the reductive amination reaction, the borohydride is sodium borohydride and/or potassium borohydride;
and/or, in the preparation method of the compound 6, in the reductive amination reaction, the molar ratio of the borohydride to the compound 5 is (1-3): 1;
and/or, in the preparation method of the compound 6, the mol ratio of the acetaldehyde to the compound 5 in the reductive amination reaction is (1-10): 1;
and/or in the preparation method of the compound 6, in the reductive amination reaction, the organic solvent is one or more of dichloromethane, methanol and toluene;
And/or in the preparation method of the compound 6, in the reductive amination reaction, the volume-mass ratio of the organic solvent to the compound 5 is 5-20mL/g;
and/or, in the preparation method of the compound 6, the temperature of the reductive amination reaction is 0-60 ℃;
and/or, in the preparation method of the compound 6, the reductive amination reaction time is 20-30h.
17. The method of claim 11, wherein,
In the preparation method of the compound 5, the molar ratio of the tetrahydropyranone to the compound 4 in the reductive amination reaction is (1-2) 1;
And/or, in the preparation method of the compound 5, in the reductive amination reaction, the borohydride is sodium borohydride and/or potassium borohydride;
And/or, in the preparation method of the compound 5, in the reductive amination reaction, the molar ratio of the borohydride to the compound 4 is (1-3): 1;
And/or, in the preparation method of the compound 5, in the reductive amination reaction, the organic acid is formic acid and/or acetic acid;
and/or, in the preparation method of the compound 5, in the reductive amination reaction, the molar ratio of the organic acid to the borohydride is (3-6): 1;
and/or, in the preparation method of the compound 5, the organic solvent is dichloromethane and/or methanol in the reductive amination reaction;
and/or in the preparation method of the compound 5, in the reductive amination reaction, the volume-mass ratio of the organic solvent to the compound 4 is 5-20mL/g;
And/or, in the preparation method of the compound 5, the temperature of the reductive amination reaction is 0-50 ℃;
And/or, in the preparation method of the compound 5, the reductive amination reaction time is 1-5h;
And/or, in the preparation method of the compound 5, the reductive amination reaction further comprises the following purification steps: recrystallizing with ethanol.
18. The method of claim 12, wherein,
In the preparation method of the compound 4, in the reduction reaction, the catalyst is one or more of Raney nickel, palladium carbon and Raney cobalt;
And/or, in the preparation method of the compound 4, the mass ratio of the catalyst to the compound 3 in the reduction reaction is (0.03-0.3): 1;
and/or in the preparation method of the compound 4, in the reduction reaction, the organic solvent is one or more of methanol, ethanol and isopropanol;
and/or in the preparation method of the compound 4, in the reduction reaction, the volume-mass ratio of the organic solvent to the compound 3 is 5-15mL/g;
and/or, in the preparation method of the compound 4, the temperature of the reduction reaction is 20-50 ℃;
And/or, in the preparation method of the compound 4, the time of the reduction reaction is 4-10h.
19. The method of claim 13, wherein,
In the preparation method of the compound 3, in the methyl esterification reaction, the organic solvent is methanol and/or tetrahydrofuran;
And/or in the preparation method of the compound 3, in the methyl esterification reaction, the volume-mass ratio of the organic solvent to the compound 2 is 1-20mL/g;
And/or, in the preparation method of the compound 3, in the methyl esterification reaction, the molar ratio of the thionyl chloride to the compound 2 is (1-3): 1;
And/or, in the preparation method of the compound 3, the temperature of the methyl esterification reaction is 0-100 ℃;
and/or, in the preparation method of the compound 3, the methyl esterification reaction time is 4-7h.
20. The method of claim 14, wherein,
In the preparation method of the compound 2, in the bromination reaction, the acid is sulfuric acid;
And/or, in the preparation method of the compound 2, in the bromination reaction, the volume-mass ratio of the acid to the compound 1 is 1-5mL/g;
And/or, in the preparation method of the compound 2, in the bromination reaction, the brominating reagent is dibromohydantoin;
And/or, in the preparation method of the compound 2, the mol ratio of the brominating reagent to the compound 1 in the bromination reaction is (0.3-1): 1;
And/or, in the preparation method of the compound 2, the bromination reaction temperature is 0-60 ℃;
And/or, in the preparation method of the compound 2, the bromination reaction time is 1-8h.
21. The process according to claim 15, wherein in the process for producing compound 7, the catalyst is one or more of palladium acetate, tetrakis triphenylphosphine palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and tris (dibenzylideneacetone) dipalladium;
And/or, in the preparation method of the compound 7, in the coupling reaction, the mass ratio of the catalyst to the compound 6 is 0.009:1, 0.011:1, 0.015:1 or 0.048:1;
and/or, in the preparation method of the compound 7, the alkali in the coupling reaction is sodium carbonate;
And/or, in the preparation method of the compound 7, in the coupling reaction, the molar ratio of the base to the compound 6 is 2:1;
And/or, in the preparation method of the compound 7, in the coupling reaction, the volume-mass ratio of the water to the compound 6 is 1mL/g;
And/or, in the preparation method of the compound 7, in the coupling reaction, the molar ratio of the 4-formylphenylboronic acid to the compound 6 is 1:1;
and/or in the preparation method of the compound 7, in the coupling reaction, the organic solvent is ethanol, 1, 4-dioxane, tetrahydrofuran, N-dimethylformamide or ethylene glycol dimethyl ether;
and/or, in the preparation method of the compound 7, in the coupling reaction, the volume-mass ratio of the organic solvent to the compound 6 is 3mL/g;
And/or, in the preparation method of the compound 7, the coupling reaction time is 6 hours, 3 hours or 10 hours;
and/or, in the preparation method of the compound 7, the coupling reaction is performed by the following steps: at room temperature, the compound 6, the 4-formylphenyl boric acid, the alkali, the catalyst, the organic solvent and the water react under the protection of inert gas, wherein the inert gas is nitrogen;
And/or, in the preparation method of the compound 7, the coupling reaction further comprises the following purification steps: after the reaction was completed, the mixture was recrystallized from methanol/water.
22. The process according to claim 21, wherein in the process for producing compound 7, the catalyst in the coupling reaction is tetrakis triphenylphosphine palladium.
23. The method of claim 16, wherein,
In the preparation method of the compound 6, in the reductive amination reaction, the organic acid is formic acid or acetic acid;
And/or, in the preparation method of the compound 6, in the reductive amination reaction, the molar ratio of the organic acid to the borohydride is 5:1;
and/or, in the preparation method of the compound 6, in the reductive amination reaction, the borohydride is sodium borohydride;
And/or, in the preparation method of the compound 6, in the reductive amination reaction, the molar ratio of the borohydride to the compound 5 is 2:1;
And/or, in the preparation method of the compound 6, in the reductive amination reaction, the molar ratio of the acetaldehyde to the compound 5 is 10:1;
And/or, in the preparation method of the compound 6, the organic solvent is dichloromethane or methanol in the reductive amination reaction;
And/or, in the preparation method of the compound 6, in the reductive amination reaction, the volume-mass ratio of the organic solvent to the compound 5 is 10mL/g;
And/or, in the preparation method of the compound 6, the temperature of the reductive amination reaction is room temperature;
and/or, in the preparation method of the compound 6, the reductive amination reaction is carried out for 22 hours.
24. The method of claim 17, wherein,
In the preparation method of the compound 5, in the reductive amination reaction, the molar ratio of the tetrahydropyranone to the compound 4 is 1.5:1;
And/or, in the preparation method of the compound 5, in the reductive amination reaction, the borohydride is sodium borohydride;
and/or, in the preparation method of the compound 5, in the reductive amination reaction, the molar ratio of the borohydride to the compound 4 is 2:1;
and/or, in the preparation method of the compound 5, in the reductive amination reaction, the molar ratio of the organic acid to the borohydride is 3:1 or 4:1;
and/or, in the preparation method of the compound 5, in the reductive amination reaction, the volume-mass ratio of the organic solvent to the compound 4 is 20mL/g;
and/or, in the preparation method of the compound 5, the reductive amination reaction time is 2 hours or 3 hours.
25. The method of claim 18, wherein,
In the preparation method of the compound 4, in the reduction reaction, the catalyst is Raney nickel or Raney cobalt;
and/or, in the preparation method of the compound 4, in the reduction reaction, the mass ratio of the catalyst to the compound 3 is 0.09:1, 0.3:1 or 0.045:1;
and/or, in the preparation method of the compound 4, the organic solvent is methanol in the reduction reaction;
And/or, in the preparation method of the compound 4, in the reduction reaction, the volume-mass ratio of the organic solvent to the compound 3 is 10mL/g;
And/or, in the preparation method of the compound 4, the time of the reduction reaction is 8h.
26. The method of claim 19, wherein,
In the preparation method of the compound 3, in the methyl esterification reaction, the organic solvent is methanol;
And/or, in the preparation method of the compound 3, in the methyl esterification reaction, the volume-mass ratio of the organic solvent to the compound 2 is 1.6mL/g;
And/or, in the preparation method of the compound 3, in the methyl esterification reaction, the molar ratio of the thionyl chloride to the compound 2 is 1.5:1;
and/or, in the preparation method of the compound 3, the temperature of the methyl esterification reaction is room temperature;
And/or, in the preparation method of the compound 3, the methyl esterification reaction time is 7h.
27. The method of claim 20, wherein,
In the preparation method of the compound 2, in the bromination reaction, the acid is concentrated sulfuric acid;
and/or, in the preparation method of the compound 2, in the bromination reaction, the volume-mass ratio of the acid to the compound 1 is 4mL/g;
and/or, in the preparation method of the compound 2, in the bromination reaction, the mol ratio of the bromination reagent to the compound 1 is 0.6:1;
And/or, in the preparation method of the compound 2, the bromination reaction temperature is room temperature;
and/or, in the preparation method of the compound 2, the bromination reaction time is 6h.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110172947.0A CN114907299B (en) | 2021-02-08 | 2021-02-08 | Salt form of key intermediate of tazistat, preparation method and intermediate thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110172947.0A CN114907299B (en) | 2021-02-08 | 2021-02-08 | Salt form of key intermediate of tazistat, preparation method and intermediate thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114907299A CN114907299A (en) | 2022-08-16 |
CN114907299B true CN114907299B (en) | 2024-06-25 |
Family
ID=82761881
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110172947.0A Active CN114907299B (en) | 2021-02-08 | 2021-02-08 | Salt form of key intermediate of tazistat, preparation method and intermediate thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114907299B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016140501A1 (en) * | 2015-03-04 | 2016-09-09 | Kainos Medicine, Inc. | Pyridine n-oxide for enhancer of zeste homolog 2 inhibitors |
CN107311921A (en) * | 2011-04-13 | 2017-11-03 | Epizyme股份有限公司 | Aryl or heteroaryl-substituted compound |
-
2021
- 2021-02-08 CN CN202110172947.0A patent/CN114907299B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107311921A (en) * | 2011-04-13 | 2017-11-03 | Epizyme股份有限公司 | Aryl or heteroaryl-substituted compound |
WO2016140501A1 (en) * | 2015-03-04 | 2016-09-09 | Kainos Medicine, Inc. | Pyridine n-oxide for enhancer of zeste homolog 2 inhibitors |
Non-Patent Citations (1)
Title |
---|
Amination of Functionally Substituted Benzaldehydes in the Presence of Sodium Tetrahydroborate: New Preparation Method for Benzylamines;Zh. V. Ignatovich, et al.;《Russian Journal of Organic Chemistry》;第43卷(第10期);第1573-1574页 * |
Also Published As
Publication number | Publication date |
---|---|
CN114907299A (en) | 2022-08-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108440330B (en) | Preparation method of doxycycline hydrochloride | |
EP3988545A1 (en) | Methods for preparing cdk4/6 inhibitor and salt and intermediate thereof | |
CN111704573B (en) | Preparation method of rabeprazole chloride and intermediate thereof | |
CN113121416A (en) | Preparation method of lefenacin | |
CN109867673B (en) | Method for synthesizing palbociclib | |
CN111892599B (en) | Synthesis method of 2,5-diazabicyclo [2.2.2] octane-2-tert-butyl carboxylate | |
CN114907299B (en) | Salt form of key intermediate of tazistat, preparation method and intermediate thereof | |
CN114907300B (en) | Preparation method of tazistat key intermediate and intermediate thereof | |
CN105693603A (en) | Improved indacaterol maleate preparation technology | |
CN114315755B (en) | Synthesis method of key intermediate of Tubulysin and analogues thereof | |
CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
CN111377822B (en) | Preparation method of vilanaflo | |
CN114702451B (en) | Preparation method of clonazepam and intermediate thereof | |
CN110903254A (en) | Synthetic method of heterocyclic intermediate applied to JAK inhibitor drugs | |
CN113200997B (en) | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof | |
CN115181093B (en) | Preparation method of Sunvozertinib intermediate | |
US4011231A (en) | 2-Phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-4H-pyrido[3,2-d]-1,3-dioxin maleate and its use as an intermediate | |
CN114805302B (en) | Preparation method of 4- [ (4-chlorophenyl) -2-pyridylmethoxy ] -1-piperidine carboxylic ester | |
CN113563305B (en) | Preparation method of 2- (4-phenoxyphenyl) -6- (N-substituted oxycarbonyl piperidine-4-) nicotinamide | |
CN109810052A (en) | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun | |
KR20140071474A (en) | Methods for the preparation of 5-[2-[7-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]ethynyl]-2-pyridinamine | |
CN111100112B (en) | Benzothiophene derivative and process for producing the same | |
CN107602439B (en) | Synthetic method for preparing marine alkaloid Baculiferin-L intermediate | |
CN114409552A (en) | Preparation method of levalbuterol hydrochloride | |
CN114805220A (en) | Preparation method of quinazolinone compound |
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 | ||
GR01 | Patent grant |