CN114014850A - Prudelamine intermediate, synthesis method thereof and method for synthesizing prasulamine from intermediate - Google Patents
Prudelamine intermediate, synthesis method thereof and method for synthesizing prasulamine from intermediate Download PDFInfo
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- CN114014850A CN114014850A CN202111550491.3A CN202111550491A CN114014850A CN 114014850 A CN114014850 A CN 114014850A CN 202111550491 A CN202111550491 A CN 202111550491A CN 114014850 A CN114014850 A CN 114014850A
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- China
- Prior art keywords
- bromopyridine
- prochloraz
- trifluoromethyl
- fluoro
- benzonitrile
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 238000001308 synthesis method Methods 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000005820 Prochloraz Substances 0.000 claims abstract description 34
- TVLSRXXIMLFWEO-UHFFFAOYSA-N prochloraz Chemical compound C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl TVLSRXXIMLFWEO-UHFFFAOYSA-N 0.000 claims abstract description 34
- LDPCQDCAPJOEAA-UHFFFAOYSA-N 2-[3-(5-bromopyridin-2-yl)propyl]-1,3-oxazole Chemical compound BrC1=CN=C(CCCC2=NC=CO2)C=C1 LDPCQDCAPJOEAA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- ATKULCGQSLCGEK-UHFFFAOYSA-N 2-(5-bromopyridin-2-yl)acetic acid Chemical compound OC(=O)CC1=CC=C(Br)C=N1 ATKULCGQSLCGEK-UHFFFAOYSA-N 0.000 claims abstract description 10
- MFNXWZGIFWJHMI-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)C(O)=O MFNXWZGIFWJHMI-UHFFFAOYSA-N 0.000 claims abstract description 10
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 claims abstract description 9
- OWIGNTFYLJUGDK-UHFFFAOYSA-N 4-amino-3-fluoro-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1F OWIGNTFYLJUGDK-UHFFFAOYSA-N 0.000 claims abstract description 9
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 8
- 150000001408 amides Chemical class 0.000 claims abstract description 5
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- -1 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile Chemical compound 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 claims description 2
- 229960003089 pramipexole Drugs 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 abstract description 4
- 238000005915 ammonolysis reaction Methods 0.000 abstract description 3
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000005755 formation reaction Methods 0.000 abstract description 2
- 230000000269 nucleophilic effect Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- KCBJGVDOSBKVKP-UHFFFAOYSA-N 4-[4,4-dimethyl-3-[6-[3-(1,3-oxazol-2-yl)propyl]pyridin-3-yl]-5-oxo-2-sulfanylideneimidazolidin-1-yl]-3-fluoro-2-(trifluoromethyl)benzonitrile Chemical compound O=C1C(C)(C)N(C=2C=NC(CCCC=3OC=CN=3)=CC=2)C(=S)N1C1=CC=C(C#N)C(C(F)(F)F)=C1F KCBJGVDOSBKVKP-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
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- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- 229940125286 pruxelutamide Drugs 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- XZQWPHKCEJPCDK-UHFFFAOYSA-N 2-(6-bromopyridin-2-yl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=N1 XZQWPHKCEJPCDK-UHFFFAOYSA-N 0.000 description 1
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 1
- LKBRUNFLJZACQA-UHFFFAOYSA-N 4-(5-nitropyridin-2-yl)butanoic acid Chemical compound OC(=O)CCCC1=CC=C([N+]([O-])=O)C=N1 LKBRUNFLJZACQA-UHFFFAOYSA-N 0.000 description 1
- CDZVQXNTALLHGF-UHFFFAOYSA-N 6-[3-(1,3-oxazol-2-yl)propyl]pyridin-3-amine Chemical compound N1=CC(N)=CC=C1CCCC1=NC=CO1 CDZVQXNTALLHGF-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000011960 computer-aided design Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 1
- NONOKGVFTBWRLD-UHFFFAOYSA-N isocyanatosulfanylimino(oxo)methane Chemical compound O=C=NSN=C=O NONOKGVFTBWRLD-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
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- 239000002547 new drug Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
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- 238000009522 phase III clinical trial Methods 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 239000012266 salt solution Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a prochloraz intermediate, a synthetic method thereof and a method for synthesizing prochloraz by using the intermediate, belonging to the technical field of drug synthesis. The preparation method comprises the steps of firstly, taking 5-bromopyridine-2-acetic acid as an initial raw material, and preparing a 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine serving as a prochloraz intermediate through an acylation reaction with Meldrum's acid, carbonyl reduction, nucleophilic ammonolysis decarboxylation and a cyclization reaction with vinylene carbonate; then 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile and N-tert-butoxycarbonyl-2-methylalanine are used as raw materials, and the prochloraz is synthesized through an amide condensation reaction, deprotection, Buchwald-Hartwig coupling reaction and intramolecular thiourea formation reaction. Compared with the prior art, the method has the advantages of few synthesis steps and simple operation, avoids using highly toxic cyanide, reduces the risk of environmental pollution, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a prochloraz intermediate, a synthesis method thereof and a method for synthesizing prochloraz by using the intermediate.
Background
Proxalutamide (GT-0918), a new generation of AR (estrogen receptor) antagonist developed by Suzhou development pharmaceutical industry, is a novel compound based on the core structure of Enzalutamide (MDV3100), a new drug against prostate cancer, and obtained by computer-aided design and repeated optimization based on the crystal structure of a target protein, and the chemical structure of the drug has multiple changes compared with that of Enzalutamide (MDV3100), thereby improving the molecular solubility and kinetic properties. Since the outbreak of new crown, the pharmaceutical industry was developed to use procluiamine for the potential treatment of covi-19, and the results showed that the conversion of patients with new crown from mild to severe could be significantly reduced, the U.S. FDA approved procluine to develop a phase III clinical trial for treating mild-moderate male patients with new crown in 4 months in 2021, and the national public health and social welfare department (MSPBS) of paraguay granted procluine Emergency Use Authority (EUA) in 7 months in 2021 for the treatment of patients with new crown hospitalization; from the existing clinical data, the effect of treating new coronary patients by the prochloraz is excellent and the safety is good.
The chemical name of prochloraz is 4- [4, 4-dimethyl-3- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] -5-carbonyl-2-thio-1 imidazolidinyl ] -3-fluoro-2- (trifluoromethyl) benzonitrile, CAS number 1398046-21-3, and the chemical structure is as follows:
the synthesis method of the prochloraz disclosed at present is only the patents CN102482230 and CN103608333 in Suzhou development pharmaceutical industry, and the synthesis route is as follows:
taking 2-chloro-5-nitropyridine as a starting material, sequentially reacting with dimethyl malonate, methyl acrylate and alkaline hydrolysis decarboxylation to obtain 5-nitropyridine-2-butyric acid, carrying out methyl esterification, ammonolysis, cyclization and hydrogenation reduction to obtain 3-amino-6- [3- (2-oxazolyl) propyl ] pyridine, carrying out Strecker reaction with acetone and trimethylsilyl cyanide to obtain an isopropanamine intermediate, and finally carrying out condensation cyclization with a thioisocyanate intermediate to obtain the prochloraz. The steps of the route are too long, the process operation is more complicated, the highly toxic trimethylcyanosilane is used in the route, the risk of environmental pollution is greater, and the cost of the production route is higher, so that a synthetic route which has simple process, higher yield and low cost and is suitable for industrial production needs to be developed.
Disclosure of Invention
The invention aims to provide a prochloraz intermediate which is simple in process operation, low in cost and suitable for industrial production, a synthetic method thereof and a method for synthesizing prochloraz by using the intermediate.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a prochloraz intermediate is named as 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, and the structural formula is as follows:
the synthesis method of the prochloraz intermediate comprises the following steps:
1) 5-bromopyridine-2-acetic acid (compound 2) and Meldrum's acid are subjected to acylation reaction under the action of a condensing agent dicyclohexylcarbodiimide and alkali, and then carbonyl reduction reaction is carried out at low temperature by using sodium borohydride/acetic acid to obtain an intermediate 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (compound 3).
2) The intermediate 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (compound 3) and concentrated ammonia water react in an autoclave to obtain 4- (5-bromopyridine-2-substituted) butyramide (compound 4).
3)4- (5-bromopyridine-2-substituted) butanamide (Compound 4) is reacted with vinylene carbonate in methanesulfonic acid to give 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine (Compound 1).
The synthetic route is as follows:
further, the molar ratio of the 5-bromopyridine-2-acetic acid, the Meldrum's acid, the dicyclohexylcarbodiimide and the base in the step 1) is 1 (1.0-1.5): (1.0-1.5): 1.0-2.0), preferably 1 (1.0-1.1): 1.0-1.2): 1.2-1.5, and the base is one of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine; the molar ratio of the 5-bromopyridine-2-acetic acid to the sodium borohydride is 1.0 (2.0-15) to 1.0-5.0, preferably 1.0 (8-12) to 1.5-3.0. The acylation reaction temperature is-10-10 ℃, the acylation reaction time is 18-48h, the temperature is preferably-5-5 ℃, and the time is preferably 20-30 h; the temperature of the carbonyl reduction reaction is-10-10 ℃, the time of the carbonyl reduction reaction is 20-48h, the temperature is preferably-5-5 ℃, and the time is preferably 20-30 h.
Further, in the step 2), the weight ratio of 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone to concentrated ammonia water (volume concentration is 25% -28%) is 1 (5-15), preferably 1 (8-12); reacting for 16-36h at 80-120 ℃; the temperature is preferably 90-110 ℃ and the reaction time is preferably 20-30 h.
Further, the molar ratio of 4- (5-bromopyridine-2-substituted) butyramide to vinylene carbonate in the step 3) is 1 (1.0-3.0), preferably 1: (1.2-2.0); the weight ratio of the 4- (5-bromopyridine-2-substituted) butyramide to the methanesulfonic acid is 1 (2.0-5.0), preferably 1 (3.0-4.0); reacting at 80-150 deg.C for 2-12h, preferably at 90-120 deg.C, and preferably for 4-10 h.
The method for synthesizing the prochloraz by the prochloraz intermediate comprises the following steps:
a. 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile (compound 5) and N-tert-butoxycarbonyl-2-methylalanine (compound 6) are subjected to amide condensation reaction under the action of Carbonyldiimidazole (CDI) and organic base to obtain 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile (compound 7);
b. deprotecting 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile (compound 7) in a solution of hydrogen chloride in isopropanol (6N) to give 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride (compound 8);
c. 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride (Compound 8) and 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine (Compound 1) are subjected to Buchwald-Hartwig coupling reaction under palladium acetate, an organophosphine ligand and an inorganic base to give 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile (Compound 9);
d. 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile (compound 9) is reacted with N, N' -Thiocarbonyldiimidazole (TCDI) to prepare pramine.
The synthetic route is as follows:
further, the molar ratio of the 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile, the N-t-butyloxycarbonyl-2-methylalanine, the Carbonyldiimidazole (CDI) and the organic base in the step a is 1.0 (1.0-2.0): 1.0-2.0 (1.0-2.0), preferably 1.0 (1.0-1.3): 1.0-1.2): 1.0-1.3, and the organic base is one of triethylamine, diisopropylethylamine, pyridine, and 1, 8-diazabicycloundec-7-ene (DBU), preferably 1, 8-diazabicycloundec-7-ene (DBU).
Further, the molar ratio of 4- (N-tert-butoxycarbonyl-2-aminoisobutyramido) -3-fluoro-2- (trifluoromethyl) benzonitrile to the isopropanol solution of hydrogen chloride in the step b is 1.0 (5.0-20), preferably 1.0 (5.0-1.0).
Further, the organic phosphine ligand in the step c is one of P (o-tolyl)3, P (t-Bu)3, Binap, XantPhos, BrettPhos, XPhos and the like, and is preferably P (t-Bu) 3; the inorganic base is one of potassium carbonate, cesium carbonate, sodium tert-butoxide and the like, preferably potassium carbonate; the molar ratio of 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride, 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, palladium acetate, organophosphine ligand and inorganic base is 1.0 (0.8-1.2): 0.01-0.04): 0.01-0.3): 1.0-5.0, preferably 1.0 (0.9-1.1): 0.015-0.035 ]: 0.05-0.2): 1.5-3.5.
Further, the molar ratio of 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile to N, N' -thiocarbonyldiimidazole in the step d is 1.0 (1.0-1.5), preferably 1.0 (1.0-1.2); the organic solvent is one of dichloromethane, tetrahydrofuran, N-dimethylformamide, toluene and acetonitrile, preferably acetonitrile; 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile in an organic solvent at a concentration of 0.05 to 0.20mol/L, preferably 0.07 to 0.15 mol/L.
The invention has the following beneficial effects: the preparation method comprises the steps of firstly, taking 5-bromopyridine-2-acetic acid as an initial raw material, and preparing a 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine serving as a prochloraz intermediate through an acylation reaction with Meldrum's acid, carbonyl reduction, nucleophilic ammonolysis decarboxylation and a cyclization reaction with vinylene carbonate; then 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile and N-tert-butoxycarbonyl-2-methylalanine are used as raw materials, and the prochloraz is synthesized through an amide condensation reaction, deprotection, Buchwald-Hartwig coupling reaction and intramolecular thiourea formation reaction. Compared with the prior art, the method has the advantages of few synthesis steps and simple operation, avoids using virulent cyanides, reduces the risk of environmental pollution, provides a preparation method of a new intermediate 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine for synthesizing the prochloraz, synthesizes the prochloraz by using the intermediate through a new route, and promotes the industrial production process of the bulk drugs.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
EXAMPLE 1 Synthesis of 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, an intermediate of Prokluyama (Compound 1)
5-bromopyridine-2-acetic acid (215g, 1.0mol), Meldrum's acid (151.2g, 1.05mol) and 4-dimethylaminopyridine (DMAP, 183.25g,1.5mol) were dissolved in 2.0L of dichloromethane, the temperature was reduced to 0 ℃ and dicyclohexylcarbodiimide (DCC, 226.8g, 1.1mol) was slowly added in portions over 1 hour, and after the addition, the reaction was continued with stirring at 0 ℃ for 24 hours. After completion of the reaction, the precipitate was removed by filtration, and the filtrate was washed with a 5% aqueous solution of potassium hydrogensulfate (1.0L. times.2) and a saturated saline solution (500ml) in this order, and dried with anhydrous sulfuric acid for 16 hours; filtering, adding glacial acetic acid (600g, 10.0mol) into the filtrate, cooling to 0 ℃, slowly adding sodium borohydride (94.5g, 2.5mol) in batches, and continuing to stir at 0 ℃ for reaction for 24 hours after the addition is finished. After completion of the reaction, the reaction solution was poured into 2L of purified water, liquid-separated, the organic layer was concentrated under reduced pressure, the residue was dissolved in 1.5L of ethyl acetate, washed with a 5% aqueous solution of sodium carbonate (500ml), a 5% aqueous solution of potassium hydrogensulfate (500ml) and a saturated brine (500ml) in this order, dried over anhydrous sodium sulfate for 16 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was recrystallized from isopropanol/n-heptane (V/V, 2/1), and dried under vacuum to give 246.1 g of 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione as a pale yellow solid in a yield of 75%.
In a 5L autoclave, 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (230g,0.7mol) is added into 2.3L of strong ammonia water (25% -28%), heated to 100 ℃, stirred and reacted for 24 hours; cooling to 5-10 ℃, stirring for crystallization for 2 hours, filtering, drying to obtain 160.5 g of white solid 4- (5-bromopyridine-2-substituted) butyramide with the yield of 94.3%.
4- (5-bromopyridine-2-substituted) butanamide (158g, 0.65mol) was added to 500ml of methanesulfonic acid under nitrogen protection, followed by vinylene carbonate (86g, 1.0mol), and the mixture was slowly heated to 120 ℃ and stirred for reaction for 6 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure, cooled to room temperature, and the residue was poured into 1L of purified water, the pH of the aqueous solution was adjusted to 10 with 10% NaOH under ice-cooling, and the mixture was further stirred for 1 hour, and filtered to obtain a crude yellow solid, which was recrystallized from isopropyl ether to obtain 130.5 g of pale yellow solid, 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, with a yield of 75.2%.
EXAMPLE 2 Synthesis of 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, an intermediate of Prokluyama (Compound 1)
6-bromopyridine-2-acetic acid (215g, 1.0mol), Meldrum's acid (144.1g, 1.0mol) and 4-dimethylaminopyridine (DMAP, 122.2g,1.0mol) were dissolved in 2.0L of dichloromethane, the temperature was reduced to 0 ℃ and dicyclohexylcarbodiimide (DCC, 206.3g, 1.0mol) was slowly added in portions over 1 hour, and after the addition, the reaction was continued with stirring at 10 ℃ for 18 hours. After completion of the reaction, the precipitate was removed by filtration, and the filtrate was washed with a 5% aqueous solution of potassium hydrogensulfate (1.0L. times.2) and a saturated saline solution (500ml) in this order, and dried with anhydrous sulfuric acid for 16 hours; filtering, adding glacial acetic acid (120g, 2.0mol) into the filtrate, cooling to 0 ℃, slowly adding sodium borohydride (37.8g, 1.0mol) in batches, and continuing to stir at 10 ℃ for reaction for 48 hours after the addition is finished. After completion of the reaction, the reaction solution was poured into 2L of purified water, liquid-separated, the organic layer was concentrated under reduced pressure, the residue was dissolved in 1.5L of ethyl acetate, washed with a 5% aqueous solution of sodium carbonate (500ml), a 5% aqueous solution of potassium hydrogensulfate (500ml) and a saturated brine (500ml), dried over anhydrous sodium sulfate for 16 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was recrystallized from isopropanol/n-heptane (V/V, 2/1), and dried under vacuum to give 229.7g of pale yellow solid 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione in a yield of 70%.
In a 5L autoclave, 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (229.7g,0.7mol) was added into 1.15L of concentrated ammonia (25% -28%), heated to 120 ℃ and stirred for reaction for 16 hours; cooling to 5-10 ℃, stirring for crystallization for 2 hours, filtering, drying to obtain 152.7 g of white solid 4- (5-bromopyridine-2-substituted) butyramide with the yield of 89.7 percent.
4- (5-bromopyridine-2-substituted) butanamide (150g, 0.62mol) was added to 300g of methanesulfonic acid under nitrogen, followed by vinylene carbonate (53.3g, 1.0mol), and the reaction was stirred slowly to 150 ℃ for 2 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure, cooled to room temperature, and the residue was poured into 1L of purified water, the pH of the aqueous solution was adjusted to 10 with 10% NaOH under ice-cooling, and the mixture was further stirred for 1 hour, and filtered to obtain a crude yellow solid, which was recrystallized from isopropyl ether to obtain 121.5 g of 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine as a pale yellow solid with a yield of 70.0%.
EXAMPLE 3 Synthesis of 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, an intermediate of Prokluyama (Compound 1)
5-bromopyridine-2-acetic acid (215g, 1.0mol), Meldrum's acid (216.2g, 1.5mol) and 4-dimethylaminopyridine (DMAP, 244.4g,2.0mol) were dissolved in 2.0L of dichloromethane, the temperature was reduced to 0 ℃ and dicyclohexylcarbodiimide (DCC, 309.5g, 1.5mol) was slowly added in portions over 1 hour, and after the addition, the reaction was continued with stirring at-10 ℃ for 48 hours. After completion of the reaction, the precipitate was removed by filtration, and the filtrate was washed with a 5% aqueous solution of potassium hydrogensulfate (1.0L. times.2) and a saturated saline solution (500ml) in this order, and dried with anhydrous sulfuric acid for 16 hours; filtering, adding glacial acetic acid (900g, 15.0mol) into the filtrate, cooling to 0 ℃, slowly adding sodium borohydride (189g, 5.0mol) in batches, and continuing to stir at-10 ℃ for reaction for 20 hours after the addition is finished. After completion of the reaction, the reaction solution was poured into 2L of purified water, liquid-separated, the organic layer was concentrated under reduced pressure, the residue was dissolved in 1.5L of ethyl acetate, washed with a 5% aqueous solution of sodium carbonate (500ml), a 5% aqueous solution of potassium hydrogensulfate (500ml) and a saturated brine (500ml), dried over anhydrous sodium sulfate for 16 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was recrystallized from isopropanol/n-heptane (V/V, 2/1), and dried under vacuum to give 234.6 g of 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione as a pale yellow solid in a yield of 71.5%.
In a 5L autoclave, 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (230g,0.7mol) is added into 3.45L of strong ammonia water (25% -28%), heated to 80 ℃ and stirred for reaction for 36 hours; cooling to 5-10 ℃, stirring for crystallization for 2 hours, filtering, drying to obtain 156.7 g of white solid 4- (5-bromopyridine-2-substituted) butyramide with the yield of 92.1%.
Under nitrogen, 4- (5-bromopyridine-2-substituted) butanamide (150g, 0.62mol) was added to 750g of methanesulfonic acid, followed by vinylene carbonate (160g, 1.86mol), and the mixture was slowly heated to 80 ℃ and stirred for reaction for 12 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure, cooled to room temperature, and the residue was poured into 1L of purified water, the pH of the aqueous solution was adjusted to 10 with 10% NaOH under ice-cooling, and the mixture was further stirred for 1 hour, and filtered to obtain a crude yellow solid, which was recrystallized from isopropyl ether to obtain 118.9 g of 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine as a pale yellow solid with a yield of 68.5%.
Example 4 Synthesis of Prokluylamine
Carbonyldiimidazole (CDI, 89.2g, 0.55mol) is slowly added into a 1.8L tetrahydrofuran solution of 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile (102.1g, 0.5mol) and N-tert-butoxycarbonyl-2-methylalanine (122g, 0.6mol), heated to 60 ℃,1, 8-diazabicycloundecen-7-ene (DBU, 91.3g, 0.6mol) is added dropwise, and the reaction solution is continuously stirred and reacted for 4 hours under heat preservation; after concentration under reduced pressure, 1.5L of methylene chloride and a 20% aqueous solution of citric acid were added to the residue, followed by liquid separation, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, vacuum-filtered, and the filtrate was concentrated under reduced pressure to obtain 180.6 g of 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile as a white solid in a yield of 92.8%.
4- (N-tert-Butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile (167.4g, 0.43mol) was added to a 6N isopropanol solution of hydrogen chloride (500mL), and the reaction was stirred at room temperature for 24 hours; insoluble matter was filtered off, and the filtrate was poured into 2L of isopropyl ether, stirred at 5 ℃ for 2 hours, and filtered by suction to give 124.1% of 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride as a white solid in a yield of 88.6%.
5- (2-Aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride (114g, 0.35mol), 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine (93.5g, 0.35mol) and potassium carbonate (120.9g, 0.875mol) were suspended in 2.0L of tetrahydrofuran, stirred for 15 minutes, palladium acetate (1.96g, 8.75mmol) and tri-tert-butylphosphine (P (t-Bu)3, 7.08g, 35mmol) were added, and the reaction was heated under reflux under nitrogen for 36 hours; after completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was poured into a mixture of 1.0L of saturated brine and 2.0L of ethyl acetate to separate an organic layer, which was dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol and water to give 133.2 g of 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyramido ] -3-fluoro-2- (trifluoromethyl) benzonitrile as a pale yellow solid, in 80.05% yield.
Experiments prove that the organic phosphine ligand P (t-Bu)3 can be replaced by one of P (o-tolyl)3, Binap, XantPhos, BrettPhos and XPhos; the inorganic base potassium carbonate can be replaced by one of cesium carbonate, sodium carbonate and sodium tert-butoxide; the molar ratio of 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride, 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, palladium acetate, organophosphine ligand and inorganic base may be 1.0 (0.8-1.2): 0.01-0.04): 0.01-0.3): 1.0-5.0.
4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile (95.1g, 0.2mol) was dissolved in 500ml of acetonitrile, N' -thiocarbonyldiimidazole (TCDI, 39.2g, 0.22mol) was added, and the reaction was refluxed for 20 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, 1.0L of dichloromethane was added to dissolve the solution, the solution was washed with saturated aqueous sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from isopropanol and water to give 79.6 g of a pale yellow solid product, pramipexole, in a yield of 76.9%.
Example 5 Synthesis of Prokluylamine
Carbonyl diimidazole (CDI, 81.1g, 0.5mol) is slowly added into a 1.8L tetrahydrofuran solution of 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile (102.1g, 0.5mol) and N-tert-butoxycarbonyl-2-methylalanine (101.7g, 0.5mol), the mixture is heated to 60 ℃,1, 8-diazabicycloundecen-7-ene (DBU, 76.1g, 0.5mol) is added dropwise, and the reaction solution is kept at the temperature and stirred for reaction for 4 hours; after concentration under reduced pressure, 1.5L of methylene chloride and a 20% aqueous solution of citric acid were added to the residue, followed by liquid separation, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered under suction, and concentrated under reduced pressure to give 175.5 g of 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile as a white solid in a yield of 90.2%.
4- (N-tert-Butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile (167.4g, 0.43mol) was added to a 6N isopropanol solution of hydrogen chloride (360mL), and the reaction was stirred at room temperature for 24 hours; insoluble matter was filtered off, and the filtrate was poured into 2L of isopropyl ether, stirred at 5 ℃ for 2 hours, and filtered by suction to give 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride as a white solid at 121.5% yield of 86.7%.
(2-Aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride (114g, 0.35mol), 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine (74.8g, 0.28mol) and potassium carbonate (48.4g, 0.35mol) were suspended in 2.0L of tetrahydrofuran, stirred for 15 minutes, added palladium acetate (0.78g, 3.5mmol) and tri-tert-butylphosphine (P (t-Bu)3, 0.71g, 3.5mmol), and heated at reflux under nitrogen for 36 hours; after completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was poured into a mixture of 1.0L of saturated brine and 2.0L of ethyl acetate to separate an organic layer, which was dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol and water to give 100.5 g of 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyramido ] -3-fluoro-2- (trifluoromethyl) benzonitrile as a pale yellow solid in a yield of 60.7%.
4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile (95.1g, 0.2mol) was dissolved in 400ml of acetonitrile, N' -thiocarbonyldiimidazole (TCDI, 35.6g, 0.2mol) was added, and the reaction was refluxed for 20 hours under nitrogen atmosphere. The reaction solution is decompressed and concentrated, 1.0L of dichloromethane is added for dissolution, the mixture is washed by saturated sodium bicarbonate aqueous solution and saturated brine in turn, anhydrous sodium sulfate is dried and filtered, the filtrate is decompressed and concentrated, the obtained residue is recrystallized by isopropanol and water to obtain 68.7 g of the prochloraz which is a light yellow solid product, and the yield is 66.4%.
Example 6 Synthesis of Prokluylamine
Carbonyldiimidazole (CDI, 162.2g, 1.0mol) is slowly added into a 1.8L tetrahydrofuran solution of 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile (102.1g, 0.5mol) and N-tert-butoxycarbonyl-2-methylalanine (203.3g, 1.0mol), heated to 60 ℃,1, 8-diazabicycloundecen-7-ene (DBU, 152.2g, 1.0mol) is added dropwise, and the reaction solution is kept at the temperature and stirred for reaction for 4 hours; after concentration under reduced pressure, 1.5L of methylene chloride and a 20% aqueous solution of citric acid were added to the residue, followed by liquid separation, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, vacuum-filtered, and the filtrate was concentrated under reduced pressure to obtain 170.5 g of 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile as a white solid in a yield of 87.6%.
4- (N-tert-Butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile (167.4g, 0.43mol) was added to a 6N isopropanol solution of hydrogen chloride (1400mL), and the reaction was stirred at room temperature for 24 hours; insoluble matter was filtered off, and the filtrate was poured into 14L isopropyl ether, stirred at 5 ℃ for 2 hours, and filtered by suction to give 122.5% white solid 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride in 87.5% yield.
6- (2-Aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride (114g, 0.35mol), 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine (112.2g, 0.42mol) and potassium carbonate (241.8g, 1.75mol) were suspended in 2.0L of tetrahydrofuran, stirred for 15 minutes, added palladium acetate (3.14g, 14mmol) and tri-tert-butylphosphine (P (t-Bu)3, 21.2g, 105mmol), and heated at reflux under nitrogen for 36 hours; after completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was poured into a mixture of 1.0L of saturated brine and 2.0L of ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol and water to give 113.5 g of 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyramido ] -3-fluoro-2- (trifluoromethyl) benzonitrile as a pale yellow solid, with a yield of 68.2%.
4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile (95.1g, 0.2mol) was dissolved in 4.0L of acetonitrile, N' -thiocarbonyldiimidazole (TCDI, 53.5g, 0.3mol) was added, and the reaction was refluxed for 20 hours under nitrogen atmosphere. The reaction solution is decompressed and concentrated, 1.0L of dichloromethane is added for dissolution, the mixture is washed by saturated sodium bicarbonate aqueous solution and saturated salt solution in sequence, anhydrous sodium sulfate is dried and filtered, the filtrate is decompressed and concentrated, the obtained residue is recrystallized by isopropanol and water to obtain 70.5 g of pale yellow solid product, namely the prochloraz, with the yield of 68.1%.
The present invention is not limited to the above embodiments, and any structural changes made under the teaching of the present invention shall fall within the scope of the present invention, which is similar or similar to the technical solutions of the present invention.
The techniques, shapes, and configurations not described in detail in the present invention are all known techniques.
Claims (9)
1. A prochloraz intermediate, which is characterized by being named 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine and having a structural formula as follows:
the synthesis method comprises the following steps:
1) carrying out acylation reaction on 5-bromopyridine-2-acetic acid and Meldrum's acid under the action of a condensing agent dicyclohexylcarbodiimide and alkali, and then carrying out carbonyl reduction reaction at low temperature by using sodium borohydride/acetic acid to obtain an intermediate 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone;
2) reacting the intermediate 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone with concentrated ammonia water in a high-pressure kettle to obtain 4- (5-bromopyridine-2-substituted) butyramide;
3)4- (5-bromopyridine-2-substituted) butanamide is reacted with vinylene carbonate in methanesulfonic acid to give 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine.
2. The prochloraz intermediate as set forth in claim 1, wherein in step 1) of the synthesis method, the molar ratio of 5-bromopyridine-2-acetic acid, Meldrum's acid, dicyclohexylcarbodiimide to base is 1 (1.0-1.5) to 1.0-1.5 (1.0-2.0), the base is one of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, the molar ratio of 5-bromopyridine-2-acetic acid, acetic acid to sodium borohydride is 1.0 (2.0-15) to 1.0-5.0, the acylation reaction temperature is-10-10 ℃, the acylation reaction time is 18-48h, the carbonyl reduction reaction temperature is-10-10 ℃, and the carbonyl reduction reaction time is 20-48 h.
3. The prochloraz intermediate as claimed in claim 1, wherein in step 2) of the synthesis method, the volume concentration of concentrated ammonia water is 25% -28%, the weight ratio of 5- (2- (5-bromopyridine-2-substituted) ethyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone to concentrated ammonia water is 1 (5-15), the reaction temperature is 80-120 ℃, and the reaction time is 16-36 h.
4. The prochloraz intermediate as claimed in claim 1, wherein in step 3) of the synthesis method, the molar ratio of 4- (5-bromopyridine-2-substituted) butyramide to vinylene carbonate is 1 (1.0-3.0), the weight ratio of 4- (5-bromopyridine-2-substituted) butyramide to methanesulfonic acid is 1 (2.0-5.0), the reaction temperature is 80-150 ℃, and the reaction time is 2-12 h.
5. A process for the synthesis of prochloraz from the prochloraz intermediate of any one of claims 1 to 4, comprising the steps of:
a. 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile and N-tert-butoxycarbonyl-2-methylalanine are subjected to amide condensation reaction under the action of an amide condensation agent carbonyldiimidazole and organic base to prepare 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile;
b. deprotecting 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile in a 6N hydrogen chloride in isopropanol to give 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride;
c. 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride and 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine are subjected to Buchwald-Hartwig coupling reaction under the conditions of palladium acetate, an organic phosphine ligand and an inorganic base to obtain 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile;
d. 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] amino isobutyryl amino ] -3-fluoro-2- (trifluoromethyl) benzonitrile is reacted with N, N' -thiocarbonyl diimidazole in an organic solvent to prepare the pramipexole.
6. The method for synthesizing prochloraz from prochloraz intermediate of claim 5, wherein the molar ratio of 4-amino-3-fluoro-2- (trifluoromethyl) benzonitrile, N-t-butoxycarbonyl-2-methylalanine, carbonyldiimidazole and organic base in step a is 1.0 (1.0-2.0): 1.0-2.0: (1.0-2.0), and the organic base is one of triethylamine, diisopropylethylamine, pyridine and 1, 8-diazabicycloundecen-7-ene.
7. The method for synthesizing prochloraz of claim 5, wherein the molar ratio of 4- (N-tert-butoxycarbonyl-2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile to the isopropanol solution of hydrogen chloride in step b is 1.0 (5.0-20).
8. The method for synthesizing prochloraz by using the prochloraz intermediate as claimed in claim 5, wherein the organic phosphine ligand in step c is one of P (o-tolyl)3, P (t-Bu)3, Binap, XantPhos, BrettPhos and XPhos, and the inorganic base is one of potassium carbonate, cesium carbonate, sodium carbonate and sodium tert-butoxide; the molar ratio of 4- (2-aminoisobutyrylamino) -3-fluoro-2- (trifluoromethyl) benzonitrile hydrochloride, 2- [3- (2-oxazolyl) propyl ] -5-bromopyridine, palladium acetate, organophosphine ligand and inorganic base is 1.0 (0.8-1.2): 0.01-0.04): 0.01-0.3): 1.0-5.0.
9. The method for synthesizing prochloraz as claimed in claim 5, the molar ratio of 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyrylamino ] -3-fluoro-2- (trifluoromethyl) benzonitrile to N, N' -thiocarbonyldiimidazole in step d is 1.0: (1.0-1.5), the organic solvent is one of dichloromethane, tetrahydrofuran, N-dimethylformamide, toluene and acetonitrile, and the concentration of 4- [2- [6- [3- (2-oxazolyl) propyl ] -3-pyridyl ] aminoisobutyramido ] -3-fluoro-2- (trifluoromethyl) benzonitrile in the organic solvent is 0.05-0.20 mol/L.
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