CN114805314A - Synthesis method of Ensaitevir - Google Patents
Synthesis method of Ensaitevir Download PDFInfo
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- CN114805314A CN114805314A CN202210418682.2A CN202210418682A CN114805314A CN 114805314 A CN114805314 A CN 114805314A CN 202210418682 A CN202210418682 A CN 202210418682A CN 114805314 A CN114805314 A CN 114805314A
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- Prior art keywords
- potassium
- synthesis method
- reaction
- ensaitevir
- sodium
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 22
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- WEDYTSQNYJKOPC-UHFFFAOYSA-N (1-methyl-1,2,4-triazol-3-yl)methanol Chemical compound CN1C=NC(CO)=N1 WEDYTSQNYJKOPC-UHFFFAOYSA-N 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- 238000002360 preparation method Methods 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- YRZNRFJEBAPCCO-UHFFFAOYSA-N Cn1cc2cc(N)c(Cl)cc2n1 Chemical compound Cn1cc2cc(N)c(Cl)cc2n1 YRZNRFJEBAPCCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 6
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 6
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 6
- 235000011009 potassium phosphates Nutrition 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- GAUXEYCSWSMMFZ-UHFFFAOYSA-N 1-(bromomethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CBr)C=C1F GAUXEYCSWSMMFZ-UHFFFAOYSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 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
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- UPTYCYWTFGTCCG-UHFFFAOYSA-N 5-(1-piperazinylsulfonyl)isoquinoline Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCNCC1 UPTYCYWTFGTCCG-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000980 entecavir Drugs 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000002386 leaching Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 208000003311 Cytochrome P-450 Enzyme Inhibitors Diseases 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940125675 paxlovid Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The invention discloses a synthesis method of Ensaitevir, and particularly relates to the technical field of compound synthesis. The synthesis method comprises the following steps: cyanuric chloride (SM) is used as a raw material to react to obtain an intermediate C-1; the intermediate C-1 reacts with (1-methyl-1H-1, 2, 4-triazole-3-yl) methanol to obtain an intermediate C-2; the intermediate C-2 reacts to obtain an intermediate C-3; and the intermediate C-3 reacts to obtain a product C-4, namely the Ensaitevir. The synthesis method disclosed by the invention simplifies the synthesis steps, reduces the price of raw materials, has higher yield and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a synthesis method of Ensaitevir.
Background
Ensatyvir, Ensittrelvir, is a small molecule drug developed by Japan salt-wild-corporation and North Hai Dai university in combination against a novel coronavirus. The 3CL proteinase inhibitor is mainly used for inhibiting the activity of new corona virus and various variant strains, thereby achieving the purpose of treating new corona. Different from the paris Paxlovid (PF-07321332), the encatevir can get rid of the dependence on a P450 enzyme inhibitor (such as ritonavir), realize single-drug therapy of Xinguan, and avoid the need of avoiding pharmacological reactions caused by the inhibition of the P450 enzyme of other medicines which need to be taken at the same time.
The structural formula is as follows:
at present, only an article in a BioRxiv database, namely Discovery of S-217622, a Non-equivalent Oral SARS-CoV-23 CL Protease Inhibitor Clinical diagnosis for Treating COVID-19, reports a synthetic method of Ensaitevir, and the synthetic route is as follows:
in the article, thiourea and bromoethane are used as raw materials to perform substitution reaction to produce an intermediate A-1. A-1 is subjected to ring closing and tertiary butyl protection to obtain an intermediate A-2. The intermediate A-3 is obtained by the substitution reaction of the A-2, the intermediate A-4 is obtained by deprotection, and the intermediate A-5 and the final product A-6 (namely Ensaitevir) are respectively obtained by the two steps of substitution reaction, and the total yield is about 5.1 percent. The route is long, the price of the reagent is high, the yield is low, and the production cost is high. The raw material smell is bad, and the trifluoroacetic acid used for deprotection has strong corrosion to equipment and is not beneficial to industrial production.
Disclosure of Invention
Aiming at the defects of the prior technical scheme, the invention aims to provide a synthesis method of Ensetvir micromolecule medicine, which simplifies the synthesis steps, has low raw material price and higher yield and is suitable for industrial production.
In order to achieve the purpose, the invention provides a synthesis method of Ensaitevir, which comprises the following steps:
cyanuric chloride (SM) is used as a raw material to carry out hydrolysis reaction to obtain an intermediate C-1; the intermediate C-1 reacts with (1-methyl-1H-1, 2, 4-triazole-3-yl) methanol to obtain an intermediate C-2; the intermediate C-2 reacts to obtain an intermediate C-3; the intermediate C-3 reacts to obtain a product C-4, namely Ensaitevir, and the reaction equation is shown as the following formula (1):
the hydrolysis reaction of SM to C-1 in the synthesis method is carried out in an alkaline or acidic environment; the alkali is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid; preferably one of sodium hydroxide or sulfuric acid.
The reaction of C-1 to C-2 is carried out under the condition of containing a reaction reagent, and the reaction reagent is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.
Preferably, the reactive agent is diisopropyl azodicarboxylate.
The reaction of the intermediate C-2 to C-3 in the synthesis method is that the intermediate C-2 reacts with 2,4, 5-trifluorobenzyl bromide under the action of alkali; the alkali is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine; preferably potassium carbonate or sodium methoxide.
The intermediate C-3 is reacted again to obtain a product C-4, wherein the intermediate C-3 is reacted with 6-chloro-2-methyl-2H-indazole-5-amine under the action of alkali; the alkali is selected from one or more of potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium bis-trimethylsilyl amido, sodium bis-trimethylsilyl amido and potassium bis-trimethylsilyl amido; lithium bistrimethylsilyl amide or potassium carbonate is preferred.
The synthesis method of Ensaitevir specifically comprises the following steps:
(1) preparation of intermediate C-1: adding cyanuric chloride into water or alcohol for heating reaction to obtain an intermediate C-1 after the reaction is finished, wherein the reaction equation is shown as the following formula (2):
(2) preparation of intermediate C-2:
adding the intermediate C-1, triphenylphosphine and (1-methyl-1H-1, 2, 4-triazole-3-yl) methanol obtained in the step (1) into a solvent 1, adding a reaction reagent, and adding a crystallization solvent after the reaction is finished to obtain an intermediate C-2, wherein the reaction equation is shown as the following formula (3):
(3) preparation of intermediate C-3:
adding the intermediate C-2 obtained in the step (2), 2,4, 5-trifluorobenzyl bromide and alkali into a solvent 2, reacting under a heating condition, and adding a crystallization solvent after the reaction is finished to obtain an intermediate C-3, wherein the reaction equation is shown as the following formula (4):
(4) preparation of Ensaitevir (intermediate C-4): adding the intermediate C-3 and 6-chloro-2-methyl-2H-indazole-5-amine obtained in the step (3) into a solvent 3, adding a base, and obtaining Ensaitevir C-4 after the reaction is finished, wherein the reaction equation is shown as the following formula (5):
the heating reaction in the step (1) is carried out under an alkaline or acidic condition, wherein the alkali is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; preferably sodium hydroxide; the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid; preferably sulfuric acid.
The reaction reagent in the step (2) is diethyl azodicarboxylate or diisopropyl azodicarboxylate.
Preferably, the reactive agent in step (2) is diisopropyl azodicarboxylate.
The solvent 1 in the step (2) is one or more of tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, N, N-dimethylformamide, dichloromethane and toluene.
And (3) the crystallization solvent is one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, n-heptane, petroleum ether, acetonitrile, dichloromethane and toluene.
Preferably, the crystallization solvent in step (2) and step (3) is one or more of ethyl acetate, methyl tert-butyl ether and toluene.
The alkali in the step (3) is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine.
Preferably, the base in step (3) is potassium carbonate or/and sodium methoxide.
The alkali in the step (4) comprises one or more of potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide.
Preferably, the base in the step (4) is lithium bistrimethylsilyl amine or/and potassium carbonate.
In conclusion, the invention has the following beneficial effects:
firstly, cyanuric chloride (SM) which is cheap and easy to obtain is used as a raw material, so that the complicated step of synthesizing triazine ring in the original research route is avoided;
secondly, the reaction of the intermediate C-1 and (1-methyl-1H-1, 2, 4-triazole-3-yl) methanol selectively reacts with nitrogen on 6 position, so as to avoid the complicated steps of protecting the nitrogen on 2 position or 4 position by using tert-butyl and then removing the protecting group in the original research route.
Thirdly, the operation is simple, the corrosion to equipment is low, the product yield is high, and the method is suitable for industrial production.
Detailed Description
Hereinafter, the present invention will be described with reference to specific embodiments. However, the present invention is not limited to the above description, and various changes, modifications, and improvements can be made without departing from the scope of the present invention according to the knowledge of the skilled person.
EXAMPLE 1 Synthesis of intermediate C-1
The method specifically comprises the following steps:
184g of cyanuric chloride are added to 1000g of water, heated to 40 ℃ and a 25% aqueous sodium hydroxide solution is added with stirring until the pH of the solution remains between 12 and 13, and stirring is continued for 2 hours. After the reaction is finished, hydrochloric acid is dropwise added to adjust the pH value to 6-7, the solution is cooled to 5-10 ℃, the stirring is continued for 0.5 hour, the filtration, the water leaching and the drying are carried out to obtain 130.9g of intermediate C-1 which is a white solid, the HPLC purity is 99.3 percent, and the yield is 88.7 percent.
EXAMPLE 2 Synthesis of intermediate C-1
The method specifically comprises the following steps:
184g of cyanuric chloride are added to 1000g of water, heated to 50 ℃ and 25% dilute sulfuric acid is added with stirring until the pH of the solution remains at 1, and stirring is continued for 1 hour. After the reaction is finished, sodium bicarbonate aqueous solution is added dropwise to adjust the pH value to 6-7, the solution is cooled to 5-10 ℃, the stirring is continued for 0.5 hour, the filtration, the water leaching and the drying are carried out to obtain 119.6g of intermediate C-1 which is white solid, the HPLC purity is 96.5 percent, and the yield is 81.1 percent.
EXAMPLE 3 Synthesis of intermediate C-1
The method specifically comprises the following steps:
184g of cyanuric chloride are added to 1000g of water, heated to 25 ℃ and a 25% aqueous solution of lithium hydroxide is added with stirring until the pH of the solution remains between 12 and 13, and stirring is continued for 15 hours. After the reaction is finished, hydrochloric acid is dropwise added to adjust the pH value to 6-7, the solution is cooled to 5-10 ℃, the stirring is continued for 0.5 hour, the filtering, the water leaching and the drying are carried out, and 115.5g of the intermediate C-1 is obtained as a white solid, the HPLC purity is 97.7 percent, and the yield is 78.3 percent.
1-H NMR(400MHz,DMSO-d6)δ11.95(2H,br).
EXAMPLE 4 Synthesis of intermediate C-2
The method specifically comprises the following steps:
intermediate C-1(29.6g, 0.2mol) obtained in example 1, triphenylphosphine (62.8g, 0.24mol) and (1-methyl-1H-1, 2, 4-triazol-3-yl) methanol (22.6g, 0.2mol) were added to 500mL tetrahydrofuran, the mixture was purged with nitrogen, cooled in an ice-water bath, and diisopropyl azodicarboxylate (48.4g, 0.24mol) was slowly added dropwise with stirring. After the dropwise addition, the temperature is raised to room temperature, the stirring is continued for 3 hours, TLC shows that the raw materials are completely reacted, the reaction solution is concentrated to dryness, 600mL of ethyl acetate is added, 200mL of water is used for washing an organic phase, anhydrous sodium sulfate is used for drying the organic phase, the filtration is carried out, a solid is obtained by concentration, 200mL of ethyl acetate is added, the stirring is carried out for 1 hour, the filtration is carried out, a small amount of ethyl acetate is used for leaching, and the solid is dried to obtain 35.6g of intermediate C-2, the HPLC purity is 94.3%, and the yield is 73.3%.
EXAMPLE 5 Synthesis of intermediate C-2
The method specifically comprises the following steps:
intermediate C-1(14.8g, 0.1mol) obtained in example 1, triphenylphosphine (31.4g, 0.12mol) and (1-methyl-1H-1, 2, 4-triazol-3-yl) methanol (11.3g, 0.1mol) were added to 250mL diethyl ether, the mixture was purged with nitrogen, cooled in an ice-water bath, and diethyl azodicarboxylate (20.9g, 0.12mol) was slowly added dropwise with stirring. After the dropwise addition, the temperature is raised to room temperature, stirring is continued for 3 hours, TLC shows that the raw materials are completely reacted, the reaction solution is concentrated to dryness, 300mL of ethyl acetate is added, 100mL of water is used for washing an organic phase, the organic phase is dried by anhydrous sodium sulfate, filtering is carried out, a solid is obtained by concentration, 100mL of methyl tert-butyl ether is added, stirring is carried out for 1 hour, filtering is carried out, a small amount of ethyl acetate is used for leaching, and the solid is dried to obtain 14.9g of intermediate C-2, the HPLC purity is 92.7%, and the yield is 61.3%.
1-H NMR(400MHz,DMSO-d6)δ3.88(3H,s),5.09(2H,s),6.71(1H,s),10.66(1H, br).
EXAMPLE 6 Synthesis of intermediate C-3
The method specifically comprises the following steps:
intermediate C-2(24.3g, 0.1mol) obtained in example 4, 2,4, 5-trifluorobenzyl bromide (23.6g, 1.05mol) and potassium carbonate (20.7g, 0.15mol) were added to 250mL of toluene, warmed to room temperature of 85 ℃ and stirred for 3 hours, TLC indicated that the starting material was reacted. The reaction solution was diluted with 100mL of toluene, the organic phase was washed with 150mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid, 50mL of ethyl acetate was added, stirred for 1 hour, filtered, and the solid was dried to give 36.7g of intermediate C-3, HPLC purity 95.1%, yield 94.8%.
EXAMPLE 7 Synthesis of intermediate C-3
The method specifically comprises the following steps:
intermediate C-2(2.4g, 10mmol) obtained in example 4, 2,4, 5-trifluorobenzyl bromide (2.4g, 10.5mmol) and sodium methoxide (4.9g, 15mmol) were added to 50mL of toluene, warmed to room temperature of 100 deg.C, stirred for 1 hour and TLC indicated that the starting material was reacted. The reaction solution was diluted with 50mL of toluene, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid, 15mL of toluene was added, stirred for 1 hour, filtered, and the solid was dried to give 3.4g of intermediate C-3, HPLC purity 93.3%, yield 88.3%.
1-H NMR(400MHz,CDCl3)δ3.87(3H,s),5.13(2H,s),5.22(2H,s),6.67(1H,s), 6.91-6.97(1H,m),7.12-7.19(1H,m).
Example 8 Synthesis of Ensaitevir
The method specifically comprises the following steps:
intermediate C-3(3.8g, 0.01mol) obtained in example 7 and 6-chloro-2-methyl-2H-indazol-5-amine (2.0g, 0.011mol) were added to 50mL of anhydrous tetrahydrofuran, purged with nitrogen, and cooled to 0 ℃. Slowly adding 1mol/L lithium bis (trimethylsilyl) amide (15mL, 0.015mol) dropwise under stirring, after finishing adding dropwise for about 1 hour, continuing stirring for 1 hour at 0 ℃, raising the temperature to room temperature and stirring for 1 hour. The reaction solution was quenched by adding to 60mL of saturated ammonium chloride solution, extracted twice with 30mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (methanol: dichloromethane ═ 5% to 15%) to give 4.7g of encyclopedivir (C-4) as a solid with HPLC purity of 98.9% and yield of 88.1%.
Example 9 Synthesis of Ensaitevir
The method specifically comprises the following steps:
intermediate C-3(3.8g, 0.01mol) obtained in example 7 and 6-chloro-2-methyl-2H-indazol-5-amine (2.0g, 0.011mol) were added to 50mL of anhydrous tetrahydrofuran, purged with nitrogen, and cooled to 0 ℃. While stirring, 1mol/L potassium carbonate (15mL, 0.015mol) was slowly added dropwise over about 1 hour, and stirring was continued at 0 ℃ for 1 hour, and then the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was quenched by adding to 60mL of saturated ammonium chloride solution, extracted twice with 30mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (methanol: dichloromethane ═ 5% to 15%) to give 1.9g of entecavir (C-4) as a pale brown solid with HPLC purity of 98.7% and yield of 34.8%.
Example 10 Synthesis of Ensaitevir
The method specifically comprises the following steps:
intermediate C-3(3.8g, 0.01mol) obtained in example 7 and 6-chloro-2-methyl-2H-indazol-5-amine (2.0g, 0.011mol) were added to 50mL of anhydrous tetrahydrofuran, purged with nitrogen, and cooled to 0 ℃. Slowly adding 1mol/L bis (trimethylsilyl) amino potassium (15mL, 0.015mol) dropwise under stirring, after finishing adding dropwise for about 1 hour, continuing stirring for 1 hour at 0 ℃, raising the temperature to room temperature and stirring for 1 hour. The reaction solution was quenched by adding to 60mL of saturated ammonium chloride solution, extracted twice with 30mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (methanol: dichloromethane ═ 5% to 15%) to give 3.0g of encyclopedia vir (C-4) as a solid with HPLC purity of 96.7% and yield of 55.8%.
1-H NMR(400 MHz,pyridine-d5)δ3.89(3H,s),4.13(3H,s),5.06(2H,s),5.28 (2H,s),7.47(1H,m),7.53-7.67(2H,m),7.75(1H,s),8.43(1H,s),9.34(1H,s)。
Claims (10)
1. A synthesis method of Ensaitevir is characterized in that: the synthesis method comprises the following steps:
cyanuric chloride is used as a raw material to react to obtain an intermediate C-1; the intermediate C-1 reacts with (1-methyl-1H-1, 2, 4-triazole-3-yl) methanol to obtain an intermediate C-2; the intermediate C-2 reacts to obtain an intermediate C-3; the intermediate C-3 reacts to obtain a product C-4, namely Ensaitevir, and the reaction equation is shown as the following formula (1):
2. the synthesis method of Ensetvir according to claim 1, wherein: the method specifically comprises the following steps:
(1) preparation of intermediate C-1: adding cyanuric chloride into water or alcohol for heating reaction to obtain an intermediate C-1 after the reaction is finished, wherein the reaction equation is shown as the following formula (2):
(2) preparation of intermediate C-2: adding the intermediate C-1, triphenylphosphine and (1-methyl-1H-1, 2, 4-triazole-3-yl) methanol obtained in the step (1) into a solvent 1, adding a reaction reagent, adding a crystallization solvent after the reaction is finished to obtain an intermediate C-2, wherein the reaction equation is shown as the following formula (3):
(3) preparation of intermediate C-3: adding the intermediate C-2 obtained in the step (2), 2,4, 5-trifluorobenzyl bromide and alkali into a solvent 2, reacting under a heating condition, and adding a crystallization solvent after the reaction is finished to obtain an intermediate C-3, wherein the reaction equation is shown as the following formula (4):
(4) preparation of Ensaitevir, C-4: adding the intermediate C-3 and 6-chloro-2-methyl-2H-indazole-5-amine obtained in the step (3) into a solvent 3, adding a base, and obtaining Ensaitevir C-4 after the reaction is finished, wherein the reaction equation is shown as the following formula (5):
3. the synthesis method of Ensaitevir according to claim 2, wherein the heating reaction in step (1) is carried out under alkaline or acidic conditions.
4. The synthesis method of Ensaitevir as claimed in claim 3, wherein the alkali is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
5. The synthesis method of encyclovir according to claim 3, wherein the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid.
6. The synthesis method of Ensaitevir as claimed in claim 2, wherein the reaction reagent in step (2) is diethyl azodicarboxylate or diisopropyl azodicarboxylate.
7. The synthesis method of Ensaitevir as claimed in claim 2, wherein the solvent 1 in step (2) is one or more of tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, N, N-dimethylformamide, dichloromethane or toluene.
8. The synthesis method of Ensaitevir as claimed in claim 2, wherein the crystallization solvent in step (2) and step (3) is one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, n-heptane, acetonitrile, dichloromethane or toluene.
9. The synthesis method of Encetavir according to claim 2, characterized in that the base in step (3) is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine.
10. The synthesis method of entecavir according to claim 2, wherein the base in step (4) comprises one or more of potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide.
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| CN115819407A (en) * | 2022-12-13 | 2023-03-21 | 浙江乐普药业股份有限公司 | Ensittrelvir analogue, preparation method thereof and new crown resistant application |
| CN116514786A (en) * | 2023-06-26 | 2023-08-01 | 北京科翔中升医药科技有限公司 | Preparation method of deuterated indazole triazine compound |
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| WO2023193818A1 (en) * | 2022-04-08 | 2023-10-12 | 湖北九康通生物医药有限公司 | Method for synthesizing polysubstituted triazine compound |
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| CN115819407A (en) * | 2022-12-13 | 2023-03-21 | 浙江乐普药业股份有限公司 | Ensittrelvir analogue, preparation method thereof and new crown resistant application |
| CN116514786A (en) * | 2023-06-26 | 2023-08-01 | 北京科翔中升医药科技有限公司 | Preparation method of deuterated indazole triazine compound |
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