CN115521316B - Preparation method of nucleoside compound or intermediate thereof and intermediate of nucleoside compound - Google Patents
Preparation method of nucleoside compound or intermediate thereof and intermediate of nucleoside compound Download PDFInfo
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- CN115521316B CN115521316B CN202211165527.0A CN202211165527A CN115521316B CN 115521316 B CN115521316 B CN 115521316B CN 202211165527 A CN202211165527 A CN 202211165527A CN 115521316 B CN115521316 B CN 115521316B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- -1 nucleoside compound Chemical class 0.000 title abstract description 123
- 239000002777 nucleoside Substances 0.000 title abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- 230000035484 reaction time Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 268
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 180
- 238000006243 chemical reaction Methods 0.000 claims description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000003054 catalyst Substances 0.000 claims description 48
- 238000006264 debenzylation reaction Methods 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 32
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 25
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 239000000872 buffer Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000337 buffer salt Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 3
- 239000008351 acetate buffer Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 description 49
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 42
- 125000004432 carbon atom Chemical group C* 0.000 description 36
- 125000000753 cycloalkyl group Chemical group 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000012074 organic phase Substances 0.000 description 32
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 31
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 28
- 125000003118 aryl group Chemical group 0.000 description 25
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 17
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 17
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 16
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 16
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 16
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 16
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 15
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 15
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 14
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 14
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical compound C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 description 14
- GPTJTTCOVDDHER-UHFFFAOYSA-N cyclononane Chemical compound C1CCCCCCCC1 GPTJTTCOVDDHER-UHFFFAOYSA-N 0.000 description 14
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 14
- 239000004914 cyclooctane Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 125000000623 heterocyclic group Chemical group 0.000 description 11
- 239000008213 purified water Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- YIHPGVCWGSURHO-VSBTWAGUSA-N [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methyl 2-methylpropanoate Chemical compound CC(C)C(OC[C@H]([C@H]([C@H]1O)O)O[C@]1(C1=CC=C2N1N=CN=C2N)C#N)=O YIHPGVCWGSURHO-VSBTWAGUSA-N 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 125000003944 tolyl group Chemical group 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- BRDWIEOJOWJCLU-LTGWCKQJSA-N GS-441524 Chemical compound C=1C=C2C(N)=NC=NN2C=1[C@]1(C#N)O[C@H](CO)[C@@H](O)[C@H]1O BRDWIEOJOWJCLU-LTGWCKQJSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004452 carbocyclyl group Chemical group 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 3
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960001997 adefovir Drugs 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical class C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JOHUAELJNSBTGS-UHFFFAOYSA-N cyclohexanecarbonyl cyclohexanecarboxylate Chemical compound C1CCCCC1C(=O)OC(=O)C1CCCCC1 JOHUAELJNSBTGS-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- 229910052754 neon Inorganic materials 0.000 description 2
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
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- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
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- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
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- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PJXBLWLWNWGFJO-TXLSGFARSA-N (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(phenylmethoxy)-5-(phenylmethoxymethyl)oxolane-2-carbonitrile Chemical compound NC1=NC=NN2C1=CC=C2[C@@]1(O[C@@H]([C@H]([C@H]1OCC1=CC=CC=C1)OCC1=CC=CC=C1)COCC1=CC=CC=C1)C#N PJXBLWLWNWGFJO-TXLSGFARSA-N 0.000 description 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 1
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 description 1
- FZQXMGLQANXZRP-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-3-(3-imidazol-1-ylpropyl)thiourea Chemical compound C1=C(OC)C(OC)=CC=C1NC(=S)NCCCN1C=NC=C1 FZQXMGLQANXZRP-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- KRTGJZMJJVEKRX-UHFFFAOYSA-N 2-phenylethan-1-yl Chemical group [CH2]CC1=CC=CC=C1 KRTGJZMJJVEKRX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical group [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000004305 biphenyl Chemical class 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 1
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical compound C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- RZZIKHSWRWWPAN-UHFFFAOYSA-N oxolane-2-carbonitrile Chemical compound N#CC1CCCO1 RZZIKHSWRWWPAN-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical class NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a nucleoside compound or an intermediate thereof and the intermediate of the nucleoside compound, belonging to the field of medicines. The preparation method has the advantages of high product yield, simple operation, short reaction time, low cost, industrialized production and the like. The intermediate of the nucleoside compound can be used for preparing the nucleoside compound.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of a nucleoside compound or an intermediate thereof and the intermediate of the nucleoside compound.
Background
Redox's (REMDESIVIR) derivatives of pyrrolotriazine as described above, which are inhibitors of RNA-dependent RNA polymerase (RdRp), can be used to combat viruses by inhibiting viral nucleic acid replication. Despite its good clinical efficacy, adefovir has limited utility and accessibility due to its relatively complex prodrug form, long synthetic procedures (j.med. Chem.2017,60, 1648-1661), high cost and the need for intravenous injection.
The Chinese patent application CN113735862A modifies the main metabolite GS-441524 of the adefovir according to the adefovir structure, and develops a series of novel carbon-nucleoside micromolecule medicaments, such as ATV006 and ATV014. The compound effectively improves the bioavailability of the Ruidexivir, optimizes the pharmacokinetic property and the patentability of the compound, and more importantly, the compound can effectively infect the current variant strains including delta and Omikovia strains in vitro and in vivo (Liu C., et al, science Translational Medicine, 2022).
However, for the synthesis of novel carbon-nucleoside micromolecule medicaments such as ATV006 and ATV014, the prior art still has the problems of low yield, complex operation, long preparation time and the like, for example, in Chinese patent application CN113735862A, the yield of ATV006 prepared from the compound GS-441524 is only 44.7%, and the yield of ATV014 prepared from the compound GS-441524 is only 41.8%; starting from compound 5, the preparation of ATV006 or ATV014 took 30.5 hours.
SARS-CoV-2 has been transmitting and has many mutations over the two years since discovery, and the form in which the virus will most likely coexist with humans has been present. In order to meet the requirements of subsequent clinical research and human anti-SARS-CoV-2, the research on large-scale preparation processes of ATV006, ATV014 and the like is of great significance. Therefore, the rapid development and optimization of a synthetic route for compounds such as ATV006 and ATV014, which are efficient, high in yield, low in cost and industrially applicable, is an important task for the synthesis and production of the above drugs.
Disclosure of Invention
In order to solve the problems, the invention provides the following technical scheme.
In a first aspect, the present invention provides a process for the preparation of a compound of formula B.
A process for the preparation of a compound of formula B comprising:
Reacting a compound shown in a formula A with a compound shown in a formula F in a solvent in the presence of a catalyst to obtain a compound shown in a formula B;
Wherein R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
In some embodiments, the catalyst is selected from at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, concentrated hydrochloric acid.
In some embodiments, the solvent comprises at least one of dichloromethane, 1, 2-dichloroethane.
In some embodiments, the molar ratio of the catalyst to the compound of formula a is from 0.1:1.0 to 2.0:1.0. In some embodiments, the molar ratio of the catalyst to the compound of formula a is from 0.5:1.0 to 2.0:1.0. In some embodiments, the molar ratio of catalyst to compound of formula a is 0.1:1.0, 0.5:1.0, 1.5:1.0, 2.0:1.0. In some preferred embodiments, the molar ratio of the catalyst to the compound of formula A is 1.0:1.0 to 2.0:1.0.
In some embodiments, the molar ratio of the compound of formula F to the compound of formula a is 3:1 to 5:1. In some embodiments, the molar ratio of the compound of formula F to the compound of formula A is 3:1, 3.5:1, 4.0:1, 4.5:1, or 5:1.
In some embodiments, the reaction temperature of the reaction is from-10 ℃ to 30 ℃. In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 25 ℃.
In some embodiments, the reaction time of the reaction is from 3 hours to 10 hours. In some embodiments, the reaction time of the reaction is from 4 hours to 8 hours. In some embodiments, the reaction time of the reaction is from 5 hours to 7 hours.
In some embodiments, the C 1-C10 alkyl group comprises a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group, a C 6 alkyl group, a C 7 alkyl group, a C 8 alkyl group, a C 9 alkyl group, or a C 10 alkyl group.
In some embodiments, the C 3-C12 cycloalkyl group comprises C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, or C 12 cycloalkyl.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl. In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane. In some embodiments, the aryl group comprises phenyl or tolyl.
In a second aspect, the present invention provides a process for preparing a compound of formula C.
A process for the preparation of a compound of formula C comprising:
Reacting a compound shown in a formula B with alkali in a solvent to obtain a compound shown in a formula C; wherein the compound shown in the formula B is prepared by a preparation method of the compound shown in the formula B in the first aspect.
In some embodiments, the base comprises at least one of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, tripotassium phosphate; sodium carbonate is preferred.
In some embodiments, the solvent comprises at least one of tetrahydrofuran, methanol, ethanol, isopropanol, preferably methanol or ethanol.
In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 30 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is 15 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 25 ℃.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl.
In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane. In some embodiments, the aryl group comprises phenyl or tolyl.
In a third aspect, the present invention provides a process for preparing a compound of formula D.
A process for the preparation of a compound of formula D comprising:
Reacting a compound shown in a formula A with a compound shown in a formula F or a compound shown in a formula G in a solvent in the presence of a catalyst and a compound shown in a formula H to obtain a compound shown in a formula D;
Wherein R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
r 2 is at least one selected from chlorine and bromine atoms.
In some embodiments, the catalyst is selected from at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, concentrated hydrochloric acid.
In some embodiments, the solvent comprises at least one of dichloromethane, 1, 2-dichloroethane.
In some embodiments, the molar ratio of catalyst to compound of formula a is from 0.1:1.0 to 2.0:1.0, preferably from 1.0:1.0 to 2.0:1.0.
In some embodiments, the ratio of the dosed volume of the compound of formula H to the dosed molar amount of the compound of formula A is 1ml:1mmol to 2ml:1mmol.
In some embodiments, the molar ratio of the compound of formula F or the compound of formula G to the compound of formula a is 3:1 to 5:1.
In some embodiments, the reaction temperature of the reaction is from-10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 20 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 15 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 10 ℃. In some embodiments, the reaction temperature of the reaction is 0 ℃,1 ℃,2 ℃,3 ℃,4 ℃,5 ℃,6 ℃, 7 ℃,8 ℃, 9 ℃, or 10 ℃.
In some embodiments, the reaction time of the reaction is from 2 hours to 8 hours. In some embodiments, the reaction time of the reaction is from 3 hours to 8 hours. In some embodiments, the reaction time of the reaction is from 3 hours to 5 hours.
In some embodiments, the C 1-C10 alkyl group comprises a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group, a C 6 alkyl group, a C 7 alkyl group, a C 8 alkyl group, a C 9 alkyl group, or a C 10 alkyl group.
In some embodiments, the C 3-C12 cycloalkyl group comprises C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, or C 12 cycloalkyl.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl.
In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, the aryl group comprises phenyl or tolyl.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane. In a fourth aspect, the present invention provides a process for preparing a compound of formula C.
In a fourth aspect, the present invention provides a process for preparing a compound of formula C.
A process for the preparation of a compound of formula C comprising:
reacting a compound shown in a formula D with alkali in a solvent to obtain a compound shown in a formula C; wherein the compound shown in the formula D is prepared by a preparation method of the compound shown in the formula D in the third aspect.
In some embodiments, the base comprises at least one of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, tripotassium phosphate; sodium carbonate is preferred.
In some embodiments, the solvent comprises at least one of tetrahydrofuran, methanol, ethanol, isopropanol, preferably methanol or ethanol.
In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 30 ℃. In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is 15 ℃ to 25 ℃. In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 25 ℃.
In some embodiments, the C 1-C10 alkyl group comprises a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group, a C 6 alkyl group, a C 7 alkyl group, a C 8 alkyl group, a C 9 alkyl group, or a C 10 alkyl group.
In some embodiments, the C 3-C12 cycloalkyl group comprises C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, or C 12 cycloalkyl.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl.
In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, the aryl group comprises phenyl or tolyl.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane. In a fifth aspect, the present invention provides a process for preparing a compound of formula C.
In a fifth aspect, the present invention provides a process for preparing another compound of formula C.
A process for preparing a compound of formula C comprising
In an inert gas atmosphere, the compound shown in the formula A reacts in a solvent in the presence of an oxidant and a buffer to obtain the compound shown in the formula C.
In some embodiments, the oxidizing agent comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or ozone.
In some embodiments, the solvent comprises at least one of dichloromethane, 1, 2-dichloroethane, toluene.
In some embodiments, the reaction temperature of the reaction is from 40 ℃ to 100 ℃. In some embodiments, the reaction temperature of the reaction is from 50 ℃ to 90 ℃. In some embodiments, the reaction temperature of the reaction is from 60 ℃ to 85 ℃. In some embodiments, the reaction temperature of the reaction is from 70 ℃ to 85 ℃. In some embodiments, the reaction temperature of the reaction is from 75 ℃ to 85 ℃. In some embodiments, the reaction temperature of the reaction is from 80 ℃ to 90 ℃.
In some embodiments, the buffer comprises at least one of phosphate buffer, acetate buffer.
In some embodiments, the pH of the buffer is between 6 and 7.
In some embodiments, the buffer salt concentration in the buffer is 0.1mol/L to 0.3mol/L.
In some embodiments, the buffer salt comprises at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate, or the buffer salt comprises at least one of sodium acetate and ammonium acetate.
In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula A is 2ml:1mmol to 8ml:1mmol. In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula A is 2.5ml:1mmol to 8ml:1mmol. In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula A is 2.8ml:1mmol to 8ml:1mmol. In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula A is 2.8ml:1mmol to 6ml:1mmol. In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula A is 2.8ml:1mmol to 5ml:1mmol. In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula A is 2.8ml:1mmol to 4ml:1mmol. In some embodiments, the ratio of the dosed volume of buffer to the dosed molar amount of the compound of formula a is 2ml:1mmol, 2.5ml:1mmol 2.8ml:1mmol, 3ml:1mmol, 4ml:1mmol, 5ml:1mmol, 6ml:1mmol, 7ml:1mmol, or 8ml:1mmol.
In some embodiments, the molar ratio of the oxidant to the compound of formula a is 4:1 to 6:1. In some embodiments, the molar ratio of the oxidant to the compound of formula a is 5:1 to 6:1. In some embodiments, the molar ratio of oxidant to compound of formula a is 4:1, 5:1, or 6:1.
In some embodiments, the inert gas comprises at least one of nitrogen, helium, neon, or argon.
In a sixth aspect, the present invention provides a method for preparing a compound of formula D.
A process for the preparation of a compound of formula D comprising:
reacting a compound shown in a formula C with a compound shown in a formula H in a solvent in the presence of a catalyst and a condensing agent to obtain a compound shown in a formula D; wherein R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
In some embodiments, the catalyst comprises at least one of 4-dimethylaminopyridine or 4-pyrrolidinylpyridine.
In some embodiments, the condensing agent comprises at least one of DCC (dicyclohexylcarbodiimide), DIC (N, N-diisopropylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate); DCC (dicyclohexylcarbodiimide), DIC (N, N-diisopropylcarbodiimide) are preferred.
In some embodiments, the solvent comprises at least one of acetonitrile, dichloromethane, chloroform, or1, 2-dichloroethane.
In some embodiments, the reaction temperature of the reaction is from-5 ℃ to 40 ℃, preferably from 0 ℃ to 10 ℃.
In some embodiments, the C 1-C10 alkyl group comprises a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group, a C 6 alkyl group, a C 7 alkyl group, a C 8 alkyl group, a C 9 alkyl group, or a C 10 alkyl group.
In some embodiments, the C 3-C12 cycloalkyl group comprises C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, or C 12 cycloalkyl.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl.
In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, the aryl group comprises phenyl or tolyl.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane. In a sixth aspect, the present invention provides a process for preparing a compound of formula E.
In a seventh aspect, the present invention provides a process for preparing a compound of formula E.
In some embodiments of the invention, a method for preparing a compound of formula E comprises:
The compound shown in the formula A reacts with the compound shown in the formula F in a solvent in the presence of a catalyst and the compound shown in the formula H to obtain a compound E,
R 1 is selected from isopropyl or cyclohexyl, and the compound shown in the formula H is isobutyric acid or cyclohexyl formic acid.
In some embodiments, the catalyst comprises at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, concentrated hydrochloric acid.
In some embodiments, the solvent in the reaction comprises at least one of dichloromethane, 1, 2-dichloroethane.
In some embodiments, the molar ratio of catalyst to compound of formula a in the reaction is from 2.5:1.0 to 3.5:1.0. In some embodiments, the molar ratio of catalyst to compound of formula a in the reaction is 3.2:1.0 to 3.5:1.0.
In some embodiments, the feed molar ratio of the compound of formula F to the compound of formula a in the reaction is from 9:1 to 15:1.
In some embodiments, the ratio of the charged volume of the compound of formula H to the charged molar amount of the compound of formula A in the reaction is 1ml:1mmol to 2ml:1mmol.
In some embodiments, the reaction temperature in the reaction is from-10 ℃ to 30 ℃. In some embodiments, the reaction temperature in the reaction is from-10 ℃ to 25 ℃. In some embodiments, the reaction temperature in the reaction is from-5 ℃ to 20 ℃. In some embodiments, the reaction temperature in the reaction is from-5 ℃ to 10 ℃. In some embodiments, the reaction temperature in the reaction is from-5 ℃ to 5 ℃.
In an eighth aspect, the present invention provides a process for preparing another compound of formula E.
A process for the preparation of a compound of formula E comprising:
In inert gas atmosphere, the compound shown in the formula D is subjected to debenzylation reaction 1 in methylene dichloride in the presence of Lewis acid to obtain a compound E,
R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
In some embodiments of the invention, a method for preparing a compound of formula E comprises:
The method comprises the steps that a compound shown in a formula D and a compound shown in a formula F or a compound shown in a formula G are subjected to debenzylation reaction 2 in a solvent in the presence of a catalyst and a compound shown in a formula H to obtain a compound shown in a formula E; wherein R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; r 2 is selected from chlorine atom or bromine atom.
In some embodiments of the invention, a method for preparing a compound of formula E comprises:
In an inert gas atmosphere, carrying out debenzylation reaction 3 on a compound shown in a formula D in a solvent in the presence of an oxidant and a buffer solution to obtain a compound shown in a formula E; wherein R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
In some embodiments, the lewis acid comprises at least one of boron trichloride or boron tribromide.
In some embodiments, the catalyst comprises at least one of concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid, concentrated hydrochloric acid.
In some embodiments, the oxidizing agent comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), ozone.
In some embodiments, the buffer comprises at least one of phosphate buffer, acetate buffer.
In some embodiments, the pH of the buffer is between 6 and 7.
In some embodiments, the solvent in the debenzylation reaction 1 comprises at least one of dichloromethane, 1, 2-dichloroethane.
In some embodiments, the solvent in the debenzylation reaction 2 comprises at least one of dichloromethane, 1, 2-dichloroethane.
In some embodiments, the solvent in the debenzylation reaction 3 comprises at least one of dichloromethane, 1, 2-dichloroethane, toluene.
In some embodiments, the molar ratio of lewis acid to compound of formula D in debenzylation reaction 1 is 2.2:1.0 to 2.6:1.0.
In some embodiments, the molar ratio of catalyst to compound of formula D in the debenzylation reaction 2 is 1.2:1.0 to 2.4:1.0. In some embodiments, the molar ratio of catalyst to compound of formula D in the debenzylation reaction 2 is 1.5:1.0 to 2.4:1.0. In some embodiments, the molar ratio of catalyst to compound of formula D in the debenzylation reaction 2 is from 2.0:1.0 to 2.4:1.0.
In some embodiments, the debenzylation reaction 2 has a ratio of the charged volume of the compound of formula H to the charged molar amount of formula D of 1ml:1mmol to 2ml:1mmol. In some embodiments, the debenzylation reaction 2 has a ratio of the charged volume of the compound of formula H to the charged molar amount of formula D of from 1.2ml:1mmol to 2ml:1mmol.
In some embodiments, the feed molar ratio of the compound of formula F or the compound of formula G to the compound of formula D in the debenzylation reaction 2 is from 5:1 to 8:1. In some embodiments, the debenzylation reaction 2 has a feed molar ratio of the compound of formula F or the compound of formula G to the compound of formula D of 5:1, 6:1, 7:1 or 8:1.
In some embodiments, the molar ratio of oxidant to compound of formula D in debenzylation reaction 3 is from 8:1 to 12:1. In some embodiments, the molar ratio of oxidant to compound of formula D in debenzylation reaction 3 is 8:1, 9:1, 10:1, 11:1, or 12:1. In some embodiments, the molar ratio of the oxidant to the compound of formula D in the debenzylation reaction 3 is from 10:1 to 12:1.
In some embodiments, the concentration of buffer salt in the buffer in the debenzylation reaction 3 is from 0.1mol/L to 0.3mol/L.
In some embodiments, the buffer salt comprises at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate.
In some embodiments, the ratio of the volume of buffer charged to the molar amount of compound indicated as D in debenzylation reaction 3 is from 3ml:1mmol to 8ml:1mmol. In some embodiments, the ratio of the volume of buffer charged to the molar amount of compound indicated as D in debenzylation reaction 3 is 3.5ml:1mmol to 8ml:1mmol. In some embodiments, the ratio of the volume of buffer charged to the molar amount of compound indicated as D in debenzylation reaction 3 is 3.8ml:1mmol to 8ml:1mmol. In some embodiments, the ratio of the volume of buffer charged to the molar amount of compound indicated as D in debenzylation reaction 3 is 3.8ml:1mmol to 5ml:1mmol. In some embodiments, the ratio of the charged volume of buffer to the charged molar amount of compound shown in D in debenzylation reaction 3 is 3ml:1mmol, 3.5ml:1mmol, 3.8ml:1mmol, 4ml:1mmol, 4.2ml:1mmol, 5ml:1mmol, 6ml:1mmol, 7ml:1mmol, or 8ml:1mmol.
In some embodiments, the reaction temperature of the debenzylation reaction 1 is from-78 ℃ to-40 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 1 is from-78 ℃ to-45 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 1 is from-60 ℃ to-45 ℃.
In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-10 ℃ to 30 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-10 ℃ to 25 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-5 ℃ to 20 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-5 ℃ to 10 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 2 is from-5 ℃ to 5 ℃.
In some embodiments, the reaction temperature of the debenzylation reaction 3 is from 40 ℃ to 100 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is 50 ℃ to 90 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is from 60 ℃ to 90 ℃. In some embodiments, the reaction temperature of the debenzylation reaction 3 is from 70 ℃ to 85 ℃. In some embodiments, the reaction temperature of debenzylation reaction 3 is from 80 ℃ to 90 ℃.
In some embodiments, the C 1-C10 alkyl group comprises a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group, a C 6 alkyl group, a C 7 alkyl group, a C 8 alkyl group, a C 9 alkyl group, or a C 10 alkyl group.
In some embodiments, the C 3-C12 cycloalkyl group comprises C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, or C 12 cycloalkyl.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl.
In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, the aryl group comprises phenyl or tolyl.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane. In some embodiments, the halogen atom is selected from a fluorine atom, a chlorine atom, or a bromine atom.
In some embodiments, the inert gas comprises at least one of nitrogen, helium, neon, or argon.
Ninth aspect the present invention provides a compound.
A compound selected from the following structures:
Wherein R 1 is selected from substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C12 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
In some embodiments, the C 1-C10 alkyl group comprises a C 1 alkyl group, a C 2 alkyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group, a C 6 alkyl group, a C 7 alkyl group, a C 8 alkyl group, a C 9 alkyl group, or a C 10 alkyl group.
In some embodiments, the C 3-C12 cycloalkyl group comprises C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl, C 9 cycloalkyl, C 10 cycloalkyl, C 11 cycloalkyl, or C 12 cycloalkyl.
In some embodiments, the C 1-C10 alkyl group includes methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, or n-octyl.
In some embodiments, the C 3-C12 cycloalkyl group comprises cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane.
In some embodiments, the aryl group comprises phenyl or tolyl.
In some embodiments, R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, i-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-octyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or cyclodecane. In some embodiments, R 1 is methyl, 2-propyl, or cyclohexane.
In some embodiments, the compound is selected from the following structures:
Advantageous effects
Compared with the prior art, one embodiment of the invention has at least one of the following beneficial effects:
(1) The method for synthesizing the ATV006, ATV014 and other compounds by the compound formula A has few synthesis steps, high total yield, mild reaction conditions, no need of ultralow temperature reaction, convenient operation and suitability for industrial production.
(2) In the preparation method of the compound shown in the formula B, compared with other catalysts, the catalyst provided by the invention is more beneficial to improving the yield and purity of the product, and particularly, concentrated sulfuric acid is preferred as the catalyst.
(3) In the preparation method of the compound shown in the formula D, compared with other catalysts, the catalyst provided by the invention is more beneficial to improving the yield of the compound shown in the formula D, and has unexpected technical effects.
(4) In the preparation method of the compound shown in the formula D, compared with other condensing agents, the condensing agent provided by the invention is more beneficial to improving the yield of the compound shown in the formula D, and has unexpected technical effects.
(5) In the preparation method of the compound shown in the formula E from the compound shown in the formula A, isobutyric acid or cyclohexylformic acid (the compound shown in the formula H) is adopted, so that the reaction route is shortened, and the operation is simplified. In addition, compared with other acids, isobutyric acid or cyclohexyl formic acid (the compound shown in the formula H) is favorable for directly generating the compound shown in the formula E, preventing the generation of mixed anhydride and different esters and facilitating the subsequent separation and purification.
Description of the terms
Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:
In the present invention, the expressions "compound I" and "compound represented by formula I" mean the same compound.
In the present invention, the expression "5.0 eq" means "5.0 equivalent".
The "H" is a hydrogen atom and the "D" is a deuterium atom. The "halogen atom" means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), an iodine atom (I), an astatine atom (At) or a mother-of-pearl atom (Ts).
"Room temperature" in the present invention refers to an ambient temperature, which is from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to a temperature from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" refers to 10 ℃, 15 ℃,20 ℃, 25 ℃,30 ℃, 35 ℃,40 ℃, and the like.
The "Bn" group represents benzyl.
The term "M" means mol/L.
"Alkyl" is a hydrocarbon containing a normal, secondary, tertiary, or cyclic carbon atom. For example, the alkyl group can have 1 to 10 carbon atoms (i.e., C 1-C10 alkyl or C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl or C 10 alkyl), 1 to 8 carbon atoms (i.e., C 1-C8 alkyl), or 1 to 6 carbon atoms (i.e., C 1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), 1-propyl (i-Pr, i-propyl, -CH 2CH2CH3), 2-propyl (i-Pr, i-propyl), -CH (CH 3)2), 1-butyl (n-Bu, n-butyl, -CH 2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH (CH 3)CH2CH3), a catalyst for the preparation of a pharmaceutical composition, 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH 3)3), 1-pentyl (n-pentyl, -CH 2CH2CH2CH2CH3), 2-pentyl (-CH (CH 3)CH2CH2CH3), 3-pentyl (-CH (CH 2CH3)2)), a catalyst for the preparation of a pharmaceutical composition, 2-methyl-2-butyl (-C (CH 3)2CH2CH3), 3-methyl-2-butyl (-CH (CH 3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH 2CH(CH3)CH2CH3), 1-hexyl (-CH 2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH 3)CH2CH2CH2CH3), 3-hexyl (-CH (CH 2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH 3)2CH2CH2CH3)), a catalyst, 3-methyl-2-pentyl (-CH (CH 3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (CH 3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C (CH 3)(CH2CH3)2), 2-methyl-3-pentyl (-CH (CH 2CH3)CH(CH3)2)), a catalyst for the preparation of a pharmaceutical composition, 2, 3-dimethyl-2-butyl (-C (CH 3)2CH(CH3)2), 3-dimethyl-2-butyl (-CH (CH 3)C(CH3)3) and n-octyl (- (CH 2)7CH3)).
"Alkenyl" is a hydrocarbon containing a normal carbon atom, a secondary carbon atom, a tertiary carbon atom, or a cyclic carbon atom with at least one unsaturated site, i.e., a carbon-carbon sp 2 double bond. For example, alkenyl groups may have 2 to 10 carbon atoms (C 2-C10 alkenyl), 2 to 12 carbon atoms (C 2-C12 alkenyl), or 2 to 6 carbon atoms (C 2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-ch=ch 2), allyl (-CH 2CH＝CH2), cyclopentenyl (-C 5H7), and 5-hexenyl (-CH 2CH2CH2CH2CH＝CH2).
"Alkynyl" is a hydrocarbon containing a normal carbon atom, a secondary carbon atom, a tertiary carbon atom, or a cyclic carbon atom with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. For example, an alkynyl group may have 2 to 10 carbon atoms (C 2-C10 alkynyl), 2 to 12 carbon atoms (C 2-C12 alkynyl), or 2 to 6 carbon atoms (C 2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-c=ch), propargyl (-CH 2 c=ch), and the like.
"Aryl" means an aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms (e.g., 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms), 6 to 14 carbon atoms, or 6 to 10 carbon atoms (e.g., 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms). Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
"Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp 3 carbon atom) is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Arylalkyl groups can include from 7 to 20 carbon atoms, for example, the alkyl moiety is from 1 to 6 carbon atoms and the aryl moiety is from 6 to 14 carbon atoms.
The terms "substituted" such as "substituted C 1-C10 alkyl", "substituted C 6-C20 aryl", "substituted arylalkyl", "substituted C 1-C20 heterocycle" and "substituted carbocyclyl" in relation to alkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl and the like, mean C 1-C10 alkyl, C 6-C20 aryl, arylalkyl, C 1-C20 heterocycle, carbocyclyl, respectively, wherein one or more hydrogen atoms are each independently replaced by a non-hydrogen substituent. Unless otherwise indicated, when the term "substituted" is used in conjunction with a group having two or more moieties capable of substitution, such as arylalkyl, a substituent may be attached to the aryl moiety, the alkyl moiety, or both.
The term "prodrug" as used herein refers to any compound that when administered to a biological system produces a drug, i.e., an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. Prodrugs are thus covalently modified analogues or potential forms of the therapeutically active compound.
"Heterocycle" or "heterocyclyl" as used herein includes, by way of example and not limitation, those heterocycles described in the following: paquette, leo A.: PRINCIPLES OF MODERN HETEROCYCLIC CHEMISTRY (w.a. benjamin, new York, 1968), in particular chapters 1, 3, 4, 6, 7 and 9: THE CHEMISTRY of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, new York,1950 to now), in particular volumes 13, 14, 16, 19 and 28 and j.am.chem.soc. (1960) 82:5566. in a particular embodiment of the invention, "heterocycle" includes "carbocycle" as defined herein in which one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyl groups include, for example, heterocycles substituted with any substituent disclosed herein including carbonyl.
Examples of heterocycles include by way of example and not by way of limitation, pyridyl, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothienyl, thioxotetrahydrothienyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuryl, thianaphtyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azacinyl (azacyclooctanyl), triazinyl, 6H-1,2, 5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chroenyl, xanthenyl, phenoflavinyl 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4 aH-carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochroman, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazole, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinyl and bis-tetrahydrofuranyl.
"Heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included on the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all those aromatic rings listed in the definition of "heterocyclyl" including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazolyl, and the like.
The term "treating" as used herein, unless indicated otherwise, means reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition for which the term is applicable or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to a therapeutic action, as "treatment" is defined immediately above.
The compounds described by formula I may have chiral centers, for example chiral carbons. The compounds of formula I thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, the chiral centers similar to those described are provided as chiral isomers or as racemic mixtures. Mixtures of racemic and diastereoisomers, as well as isolated or synthetic individual optical isomers substantially free of their enantiomeric or diastereoisomeric partners, are within the scope of the present invention. The racemic mixtures are separated into their individual, essentially optically pure isomers by well-known techniques, such as separating the diastereoisomeric salts with an optically active auxiliary (e.g. an acid or base), which are then converted back into the optically active substance. In most cases, the desired optical isomer is synthesized by a stereospecific reaction starting from the appropriate stereoisomer of the desired starting material.
Whenever a compound described herein is substituted with more than one of the same designated groups (e.g., "R" or "R 1"), it is understood that these groups may be the same or different, i.e., each group is independently selected.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
In order to better understand the technical solution of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
Example 1 Synthesis of Compound B01{ ((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis benzyloxy-5-cyanotetrahydrofuran-2-) methylacetate }:
(2 r,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (compound represented by formula a) (5.6 g,10mmol,1.0 eq.) was mixed with dichloromethane (28 mL), acetic anhydride (3 eq.) was cooled to 0 ℃, sulfuric acid (1.0 eq.) was added dropwise with dichloromethane (11 mL), after the addition, the reaction solution was cooled to 0 ℃ for 6 hours at 25 ℃, purified water (11 mL) was added and stirred for 15 minutes, triethylamine was added to adjust the reaction solution ph=7, the separated liquid was collected, the organic phase was washed twice with saturated common salt (11 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the ethyl acetate (V/V) =100:0 to 70:30) was separated by a column to obtain compound B (4.2 g, 78%) in a yield of 78%. Taking a proper amount of the obtained compound B01 to detect mass spectrum and hydrogen spectrum, and obtaining the result ：MS(ESI):554.3[M-H]-;1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.38(s,1H),7.41–7.23(m,11H),7.03(d,J＝4.8Hz,1H),4.97(d,J＝4.9Hz,1H),4.92(d,J＝11.7Hz,1H),4.82(d,J＝11.7Hz,1H),4.63–4.51(m,2H),4.50(dt,J＝5.5,2.7Hz,1H),4.30(dd,J＝12.3,3.3Hz,1H),4.19(dd,J＝12.3,5.1Hz,1H),4.12(dd,J＝6.1,4.9Hz,1H),2.41(s,3H),1.98(s,3H).
Example 2 Synthesis of Compound B01{ ((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis benzyloxy-5-cyanotetrahydrofuran-2-) methylacetate }:
(2 r,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (compound represented by formula a) (5.6 g,10mmol,1.0 eq.) was mixed with dichloromethane (28 mL), acetic anhydride (5 eq.) was cooled to 0 ℃, sulfuric acid (1.5 eq.) was added dropwise with dichloromethane (11 mL), after the addition, the reaction solution was cooled to 0 ℃ for 10 hours at 25 ℃, purified water (11 mL) was added and stirred for 15 minutes, triethylamine was added to adjust the reaction solution ph=8, the separated liquid was collected, the organic phase was washed twice with saturated common salt (11 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the ethyl acetate (V/V) =100:0 to 70:30) was separated by a column to obtain compound B (4.6 g,84% yield). Taking a proper amount of the obtained compound B01 to detect mass spectrum and hydrogen spectrum, and obtaining the result ：MS(ESI):554.3[M-H]-;1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.38(s,1H),7.41–7.23(m,11H),7.03(d,J＝4.8Hz,1H),4.97(d,J＝4.9Hz,1H),4.92(d,J＝11.7Hz,1H),4.82(d,J＝11.7Hz,1H),4.63–4.51(m,2H),4.50(dt,J＝5.5,2.7Hz,1H),4.30(dd,J＝12.3,3.3Hz,1H),4.19(dd,J＝12.3,5.1Hz,1H),4.12(dd,J＝6.1,4.9Hz,1H),2.41(s,3H),1.98(s,3H).
Example 3: synthesis of Compound C { (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bis (benzyloxy) -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile }
Compound B01 (2.2 g,4 mmol) was mixed with methanol (10 mL), saturated aqueous sodium carbonate (5 mL), stirred at 25℃for 1 hour, methylene chloride (10 mL) was added, saturated brine (5 mL) was stirred, the solution was separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound C (1.82 g,98% yield).
EXAMPLE 4 Synthesis of Compound D01{ ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-dibenzyloxy-5-cyanotetrahydrofuran-2-) methylacetate } -
(2 R,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (16.8 g,30mmol,1.0 eq.) was mixed, acetic anhydride (3 eq.) was cooled to 0 ℃, a mixed solution of sulfuric acid (1.0 eq.) and glacial acetic acid (34 mL) was added dropwise, the reaction solution was cooled to 0 ℃, dichloromethane (85 mL) was added, purified water (34 mL) was stirred for 15 minutes, triethylamine was added to adjust the reaction solution ph=7, the organic phase was collected, washed twice with saturated brine (34 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the column separation (dichloromethane: ethyl acetate (V/V): 100:0 to 60:40) was purified to give compound D01 (13.0 g,85% yield). Taking a proper amount of the obtained compound D01 to detect mass spectrum and hydrogen spectrum, and obtaining the result ：512.2[M-H]-;1H NMR(400MHz,DMSO-d6)δ8.06–7.79(m,3H),7.54–7.17(m,10H),6.92(d,J＝4.6Hz,1H),6.78(d,1H),4.96(d,J＝5.0Hz,1H),4.88(d,J＝11.7Hz,1H),4.78(d,J＝11.7Hz,1H),4.64–4.50(m,2H),4.44(td,J＝5.6,3.3Hz,1H),4.29(dd,J＝12.3,3.4Hz,1H),4.17(dd,J＝12.3,5.3Hz,1H),4.09(t,J＝5.5Hz,1H),1.97(s,3H).
Example 5: synthesis of Compound D01{ { ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-dibenzyloxy-5-cyanotetrahydrofuran-2-) methylacetate } -
(2 R,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (16.8 g,30mmol,1.0 eq.) was mixed, acetic anhydride (5 eq.) was cooled to 0 ℃, a mixed solution of sulfuric acid (1.2 eq.) and glacial acetic acid (34 mL) was added dropwise, the reaction solution was cooled to 0 ℃, dichloromethane (85 mL) was added, purified water (34 mL) was stirred for 15 minutes, triethylamine was added to adjust the reaction solution ph=8, the organic phase was collected, washed twice with saturated brine (34 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the column separation (dichloromethane: ethyl acetate (V/V): 100:0 to 60:40) was purified to give compound D01 (14.1 g,92% yield). Taking a proper amount of the obtained compound D01 to detect mass spectrum and hydrogen spectrum, and obtaining the result ：512.2[M-H]-;1H NMR(400MHz,DMSO-d6)δ8.06–7.79(m,3H),7.54–7.17(m,10H),6.92(d,J＝4.6Hz,1H),6.78(d,1H),4.96(d,J＝5.0Hz,1H),4.88(d,J＝11.7Hz,1H),4.78(d,J＝11.7Hz,1H),4.64–4.50(m,2H),4.44(td,J＝5.6,3.3Hz,1H),4.29(dd,J＝12.3,3.4Hz,1H),4.17(dd,J＝12.3,5.3Hz,1H),4.09(t,J＝5.5Hz,1H),1.97(s,3H).
EXAMPLE 6 Synthesis of Compound C { (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bis (benzyloxy) -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile)
Compound D01 (5.1 g,10 mmol) was mixed with methanol (15 mL), saturated aqueous sodium carbonate (10 mL), stirred at 25℃for 1 hour, methylene chloride (20 mL) was added, saturated brine (10 mL) was stirred for 10 minutes, the liquid was separated, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound C (4.5 g,97% yield).
EXAMPLE 7 Synthesis of Compound C { (2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bis (benzyloxy) -5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile)
(2R, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (the compound of formula A) (5.6 g,10mmol,1.0 eq.) was mixed with 1, 2-dichloromethane (28 mL), 0.1M phosphate buffer (pH=7.0) (28 mL) was added, and 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) (11.4 g,50mmol,5 eq.) was further added under nitrogen atmosphere, and heated at 80℃under reflux for 8 hours. The reaction solution was cooled to 0 ℃, saturated sodium bicarbonate solution was added, ph=6-7 was adjusted, dichloromethane (28 mL) was extracted twice, the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by column separation (dichloromethane: ethyl acetate (V/V) =100:0 to 50:50) to give compound C (3.2 g,68% yield).
Example 8: compound D02 (((2 r,3r,4r,5 r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methylcyclohexylformate) was synthesized:
An acetonitrile solution (60 mL) containing compound C (11.8 g,25mmol,1.0 eq), DMAP (4-dimethylaminopyridine) (0.5 eq.), cyclohexylformic acid H01 (1.2 eq.), DIC (N, N-diisopropylcarbodiimide) (1.25 eq.) was mixed, stirred for 24 hours at 5±5 ℃, the reaction was ended, concentrated, and purified by column separation (dichloromethane: EA (V/V) =100:0 to 50:50), to give compound D02 (13 g,90% yield). Taking a proper amount of the obtained compound D02 to detect mass spectrum and hydrogen spectrum, and obtaining the result ：MS(ESI):582.4[M+H]+;1H NMR(400MHz,DMSO-d6)δ8.05–7.84(m,3H),7.42–7.24(m,10H),6.92(d,J＝4.6Hz,1H),6.76(d,J＝4.5Hz,1H),4.96(d,J＝4.9Hz,1H),4.90(d,J＝11.7Hz,1H),4.81(d,J＝11.7Hz,1H),4.59(d,J＝11.9Hz,1H),4.50(d,J＝11.9Hz,1H),4.45(dt,J＝6.4,3.9Hz,1H),4.28(dd,J＝12.4,3.3Hz,1H),4.17(dd,J＝12.4,4.4Hz,1H),4.08(dd,J＝6.4,4.9Hz,1H),2.18(ddd,J＝14.2,9.5,3.4Hz,1H),1.74–1.50(m,5H),1.26–1.15(m,5H).
Example 9: compound D03 (((2 r,3r,4r,5 r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methyl isobutyrate) was synthesized:
An acetonitrile solution (60 mL) containing compound C (11.8 g,25mmol,1.0 eq.), DMAP (4-dimethylaminopyridine) (0.5 eq.), isobutyric acid H02 (1.2 eq.), DIC (N, N-diisopropylcarbodiimide) (1.25 eq.) was mixed, stirred for 24 hours at 5±5 ℃, the reaction was terminated, concentrated, and purified by column separation (dichloromethane: EA (V/V) =100:0 to 50:50) to give compound D03 (11.8 g,87% yield). Taking a proper amount of the obtained compound D03 to detect mass spectrum and hydrogen spectrum, and obtaining the result ：MS(ESI):540.2[M-H]-;1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.36–7.19(m,10H),6.96(d,J＝4.6Hz,1H),6.65(d,J＝4.6Hz,1H),5.89(s,2H),4.99–4.90(m,2H),4.83(d,J＝12.1Hz,1H),4.63(ddd,J＝6.8,5.0,3.6Hz,1H),4.54(d,J＝11.9Hz,1H),4.43–4.26(m,3H),3.93(dd,J＝6.8,5.1Hz,1H),2.52(dt,J＝14.0,7.0Hz,1H),1.17(d,J＝6.5Hz,3H),1.12(d,J＝6.5Hz,3H).
Example 10: preparation of Compound E01 (method one)
Compound D02 (10 mmol,5.8g,1.0 eq.) was mixed with dichloromethane (30 mL) under nitrogen atmosphere, cooled to-78 ℃, 1M boron trichloride in dichloromethane (22 mL,2.2 eq.) was added, the reaction was terminated at-50 ℃, methanol (12 mL) was added, then methanol (12 mL) solution of triethylamine (4.6 eq.) was added to quench the reaction, warmed to room temperature, concentrated under reduced pressure, n-hexane (12 mL) was added to wash 3 times, dichloromethane (12 mL) was further added, water (30 mL) was stirred, left to stand, split, an organic phase layer was collected, an aqueous phase layer was extracted twice with dichloromethane (12 mL), an organic phase layer was combined, washed with pure water (12 mL), dried over sodium sulfate, filtered, filtrate was concentrated, and column separation (dichloromethane: methanol (V/V) =40:1) was purified to give compound E01 (2.9 g,72% yield).
Example 11: preparation of Compound E01 (method two)
Compound D02 (10 mmol,5.8g,1.0 eq.), acetic anhydride (5 eq.), a mixed solution of sulfuric acid (2 eq.) and glacial acetic acid (12 mL) was mixed, cooled to 0 ℃, reacted at 25 ℃ until the consumption of the raw material was complete, concentrated under reduced pressure, the concentrated solution was cooled to 0 ℃, dichloromethane (30 mL) was added, purified water (18 mL) was stirred for 15min, triethylamine was further added to adjust the pH of the reaction solution to 7, the separated solution was extracted twice with dichloromethane (30 mL), the organic phase was collected, washed twice with saturated brine (18 mL/time), the organic phase was dried over sodium sulfate, filtered, concentrated, and column separated (dichloromethane: methanol (V/V) =40:1) was purified to give compound E01 (3.7 g,92% yield).
Example 12: preparation of Compound E01 (method three)
Compound D02 (10 mmol,5.8g,1.0 eq.) and 1,2 dichloroethane (42 mL) were mixed under nitrogen, 0.1M phosphate buffer (ph=7.0) (42 mL) was added, and finally 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) (10 eq.) was added and heated to reflux at 80 ℃ for 6 hours. The reaction solution was cooled to 0 ℃, saturated sodium bicarbonate solution was added, ph=6 was adjusted, dichloromethane (30 mL) was extracted twice, the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by column separation (dichloromethane: methanol (V/V) =40:1) to give compound E01 (2.5 g,62% yield).
Example 13: preparation of Compound E01 (method four)
Compound a (10 mmol,5.8g,1.0 eq.) and cyclohexylformic anhydride (5 eq.) were mixed, cooled to 0 ℃, and a mixed solution of sulfuric acid (1.2 eq.) and cyclohexylformic acid (12 mL) was added dropwise, and reacted at 25 ℃ until the consumption of raw materials was complete, mainly to give compound D02; the addition of cyclohexylformic anhydride (8 eq.) was continued, cooled to 0deg.C, sulfuric acid (2.0 eq.) was added dropwise, the reaction was continued at 25deg.C until D02 was consumed completely, concentrated under reduced pressure, the concentrate was cooled to 0deg.C, dichloromethane (30 mL) was added, purified water (18 mL) was stirred for 15min, triethylamine was further added to adjust the pH of the reaction solution to 7, the solution was separated, the aqueous phase was extracted twice with dichloromethane (30 mL), the organic phase was collected, washed twice with saturated brine (18 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and column separated (dichloromethane: methanol (V/V) =40:1) was purified to give compound E01 (3.0 g,76% yield).
Example 14: preparation of Compound E02 (method one)
Compound D03 (10 mmol,5.4g,1.0 eq.) was mixed with dichloromethane (27 mL) under nitrogen atmosphere, cooled to-78 ℃, 1M boron trichloride in dichloromethane (22 mL,2.2 eq.) was added, the reaction was terminated at-50 ℃, methanol (11 mL) was added, further methanol (11 mL) was added to quench the reaction, the temperature was raised to room temperature, concentration under reduced pressure, washing 3 times with n-hexane (11 mL) was added, further dichloromethane (11 mL) was added, purified water (30 mL) was stirred, left to stand, the liquid was separated, the organic phase layer was collected, the aqueous phase layer was extracted twice with dichloromethane (11 mL), the organic phase layer was combined, washed with pure water (11 mL), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the column separation (dichloromethane: methanol (V/V) =40:1) was purified to give compound E02 (2.3 g,65% yield).
Example 15: preparation of Compound E02 (method two)
Compound D03 (10 mmol,5.4g,1.0 eq.), acetic anhydride (5 eq.), a mixed solution of sulfuric acid (2 eq.) and glacial acetic acid (11 mL) were mixed, cooled to 0 ℃, reacted at 25 ℃ until the consumption of the raw material was complete, concentrated under reduced pressure, the concentrated solution was cooled to 0 ℃, dichloromethane (11 mL) was added, purified water (30 mL) was stirred for 15min, triethylamine was further added to adjust the pH of the reaction solution to 7, the separated solution was extracted twice with dichloromethane (27 mL), the organic phase was collected, the organic phase was washed twice with saturated brine (16 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the column separation (dichloromethane: methanol (V/V) =40:1) was purified to give compound E02 (3.2 g,88% yield).
Example 16: preparation of Compound E02 (method three)
Compound D03 (10 mmol,5.4g,1.0 eq.) and 1,2 dichloroethane (38 mL) were mixed under nitrogen, 0.1M phosphate buffer (ph=7.0) (38 mL) was added, and finally 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ) (10 eq.) was added and heated to reflux at 80 ℃ for 6 hours. The reaction solution was cooled to 0 ℃, saturated sodium bicarbonate solution was added, ph=6 was adjusted, dichloromethane (27 mL) was extracted twice, the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by column separation (dichloromethane: methanol (V/V) =40:1) to give compound E02 (1.8 g,50% yield).
Example 17: preparation of Compound E02 (method four)
Compound a (10 mmol,5.6g,1.0 eq.) and isobutyric anhydride (5 eq.) are mixed, cooled to 0 ℃, sulfuric acid (1.2 eq.) and isobutyric acid (11 mL) mixed solution are added dropwise, and reacted at 25 ℃ until the consumption of raw materials is complete, mainly compound D03 is obtained; continuously adding isobutyric anhydride (8 eq.), cooling to 0 ℃, dropwise adding sulfuric acid (2.0 eq.), reacting at 25 ℃ until D03 is consumed completely, concentrating under reduced pressure, cooling the concentrated solution to 0 ℃, adding dichloromethane (28 mL), stirring purified water (17 mL) for 15min, adding triethylamine to adjust the pH=7 of the reaction solution, separating liquid, extracting aqueous phase by dichloromethane (28 mL) twice, collecting organic phase, washing the organic phase twice (17 mL/time) with saturated salt, drying the organic phase by sodium sulfate, filtering, concentrating the filtrate, and purifying by column separation (dichloromethane: methanol (V/V) =40:1) to obtain a compound E02 (2.6 g,73% yield).
Comparative example 1: synthesis of Compound B01{ ((2R, 3R,4R, 5R) -5- (4-acetamidopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-dibenzyloxy-5-cyanotetrahydrofuran-2-) methyl acetate }:
A mixed solution of (2 r,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (compound represented by formula a) (5.6 g,10mmol,1.0 eq.) and methylene chloride (28 mL), acetic anhydride (3 eq.) was cooled to 0 ℃, trifluoroacetic acid (1.0 eq.) and methylene chloride (11 mL.) were added dropwise, the reaction solution was cooled to 0 ℃ after the addition of the dropwise, purified water (11 mL) was added and stirred for 15 minutes, triethylamine was added to adjust the reaction solution ph=7, the liquid was separated, the organic phase was collected twice (11 mL/time), the organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated, and the ethyl acetate (V/V) =100:0 to 70:30) was separated by a column to obtain compound B (0.4 g,7% yield).
Comparative example 2 Synthesis of Compound D01{ ((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-) -3, 4-dibenzyloxy-5-cyanotetrahydrofuran-2-) methylacetate } } - (reaction without glacial acetic acid)
(2 R,3r,4r,5 r) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- [ (benzyloxy) methyl ] tetrahydrofuran-2-carbonitrile (16.8 g,30mmol,1.0 eq.) was mixed, acetic anhydride (3 eq.) was cooled to 0 ℃, a mixed solution of sulfuric acid (1.0 eq.) was added dropwise, the reaction solution was allowed to react for 3 hours at 25 ℃, the reaction solution was cooled to 0 ℃, dichloromethane (85 mL) was added, purified water (34 mL) was stirred for 15 minutes, triethylamine was added to adjust the reaction solution ph=7, the organic phase was collected, washed twice with saturated brine (34 mL/time), the organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated, and the column separation (dichloromethane: ethyl acetate (V/V) =100:0 to 60:40) was purified to give compound D01 (6.5 g,42% yield).
Example 18: synthesis of Compound D02 (((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methylcyclohexylformate) (investigation of condensing agent):
An acetonitrile solution (60 mL) containing compound C (11.8 g,25mmol,1.0 eq), DMAP (4-dimethylaminopyridine) (0.5 eq.), cyclohexylformic acid H01 (1.2 eq.), a condensing agent shown in table 1 (1.25 eq.) was mixed, stirred at 5±5 ℃ for 24 hours, and after completion of the reaction, concentrated, and purified by column separation (dichloromethane: EA (V/V) =100:0 to 50:50), to obtain compound D02, the results of which are shown in table 1.
Table 1: investigation of condensing Agents in the Synthesis of Compound D02
Example 19: synthesis of Compound D02 (((2R, 3R,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazine-7-) -3, 4-bis (benzyloxy) -5-cyanotetrahydrofuran-2-) methylcyclohexylformate) (examination of the catalyst):
Acetonitrile solution (85 mL) containing compound C (11.8 g,25mmol,1.0 eq), catalyst (0.5 eq.) shown in table 2, cyclohexylformic acid H01 (1.2 eq.) and DIC (N, N-diisopropylcarbodiimide) (1.25 eq.) was mixed, stirred at 5±5 ℃ for 24 hours, the reaction was completed, concentrated, and purified by column separation (dichloromethane: EA (V/V) =100:0 to 50:50), to obtain compound D02, the results of which are shown in table 2.
Table 2: investigation of condensing Agents in the Synthesis of Compound D02
| Catalyst | Yield of Compound D02 |
| DMAP (4-dimethylaminopyridine) | 90％ |
| Pyridine compound | 53％ |
| 4-Pyrrolidinylpyridine | 78％ |
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (13)
1. A process for preparing a compound of formula D comprising
Reacting a compound shown in a formula C with a compound shown in a formula H in a solvent in the presence of a catalyst and a condensing agent to obtain a compound shown in a formula D; wherein R 1 is selected from cyclohexane, methyl or 2-propyl;
The catalyst is 4-dimethylaminopyridine; the condensing agent is DIC (N, N-diisopropylcarbodiimide);
The solvent is acetonitrile;
the reaction temperature of the reaction is 0-10 ℃.
2. The production method according to claim 1, further comprising a production method of a compound represented by formula C:
in an inert gas atmosphere, the compound shown in the formula A reacts in a solvent in the presence of an oxidant and a buffer to obtain the compound shown in the formula C.
3. The method of preparing a compound of formula C according to claim 2, wherein the oxidizing agent comprises at least one of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or ozone; and/or
The solvent in the preparation method of the compound shown in the formula C comprises at least one of dichloromethane, 1, 2-dichloroethane and toluene; and/or
The reaction temperature of the reaction in the preparation method of the compound shown in the formula C is 40-100 ℃; and/or
The buffer solution in the preparation method of the compound shown in the formula C comprises at least one of phosphate buffer solution and acetate buffer solution; and/or
In the preparation method of the compound shown in the formula C, the pH of the buffer solution is 6-7; and/or
In the preparation method of the compound shown in the formula C, the concentration of buffer salt in the buffer solution is 0.1 mol/L-0.3 mol/L; and/or
The buffer salt in the preparation method of the compound shown in the formula C comprises at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate or at least one of sodium acetate and ammonium acetate; and/or
In the preparation method of the compound shown in the formula C, the ratio of the feeding volume of the buffer solution to the feeding molar quantity of the compound shown in the formula A is 2ml:1 mmol-8 ml:1mmol; and/or
In the preparation method of the compound shown in the formula C, the feeding molar ratio of the oxidant to the compound shown in the formula A is 4:1-6:1.
4. The production method according to claim 1, further comprising a production method of a compound represented by formula C:
reacting a compound shown in a formula B with alkali in a solvent to obtain a compound shown in a formula C;
the alkali in the preparation method of the formula C comprises at least one of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate and tripotassium phosphate;
The solvent in the preparation method of the formula C comprises at least one of tetrahydrofuran, methanol, ethanol and isopropanol;
the reaction temperature of the reaction in the preparation method of the formula C is 0-30 ℃;
The preparation method of the formula B comprises the following steps:
Reacting a compound shown in a formula A with a compound shown in a formula F in a solvent in the presence of a catalyst to obtain a compound shown in a formula B;
wherein R 1 is selected from cyclohexane, methyl or 2-propyl;
the catalyst in the preparation method of the formula B is at least one selected from concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid and concentrated hydrochloric acid;
The solvent in the preparation method of the formula B comprises at least one of dichloromethane and 1, 2-dichloroethane.
5. A process for producing according to claim 4,
In the preparation method of the formula B, the feeding molar ratio of the catalyst to the compound shown in the formula A is 0.1:1.0-2.0:1.0; and/or
In the preparation method of the formula B, the feeding mole ratio of the compound shown in the formula F to the compound shown in the formula A is 3:1-5:1; and/or
The reaction temperature of the reaction in the preparation method of the formula B is-10 ℃ to 30 ℃; and/or
The reaction time of the reaction in the preparation method of the formula B is 3-10 hours.
6. The process according to claim 4, wherein the molar ratio of the catalyst to the compound of formula A in the process of formula B is 1.0:1.0 to 2.0:1.0.
7. A process for the preparation of a compound of formula E comprising:
The compound shown in the formula A reacts with the compound shown in the formula F in a solvent in the presence of a catalyst and the compound shown in the formula H to obtain a compound E,
R 1 is selected from isopropyl or cyclohexyl, and the compound shown in the formula H is isobutyric acid or cyclohexyl formic acid;
the catalyst comprises concentrated sulfuric acid;
The solvent in the reaction comprises at least one of dichloromethane and 1, 2-dichloroethane;
The molar ratio of the catalyst to the compound shown in the formula A in the reaction is 2.5:1.0-3.5:1.0;
the feeding mole ratio of the compound shown in the formula F to the compound shown in the formula A in the reaction is 9:1-15:1;
the ratio of the volume of the compound shown in the formula H to the molar quantity of the compound shown in the formula A in the reaction is 1ml:1 mmol-2 ml:1mmol;
the reaction temperature in the reaction is-10 ℃ to 30 ℃.
8. A process for the preparation of a compound of formula E comprising:
The method comprises the steps that a compound shown in a formula D and a compound shown in a formula F or a compound shown in a formula G are subjected to debenzylation reaction 2 in a solvent in the presence of a catalyst and a compound shown in a formula H to obtain a compound shown in a formula E; wherein R 1 is selected from cyclohexane, methyl or 2-propyl;
the catalyst is concentrated sulfuric acid.
9. A process for producing according to claim 8,
The solvent in the debenzylation reaction 2 comprises at least one of dichloromethane and 1, 2-dichloroethane; and/or
The feeding mole ratio of the catalyst to the compound shown in the formula D in the debenzylation reaction 2 is 1.2:1.0-2.4:1.0; and/or
The ratio of the feeding volume of the compound shown in the formula H to the feeding molar quantity of the compound shown in the formula D in the debenzylation reaction 2 is 1ml:1 mmol-2 ml:1mmol; and/or
The feeding mole ratio of the compound shown in the formula F or the compound shown in the formula G to the compound shown in the formula D in the debenzylation reaction 2 is 5:1-8:1;
The reaction temperature of the debenzylation reaction 2 is-10 ℃ to 30 ℃.
10. The production method according to any one of claims 8 to 9, wherein the production method of the compound represented by formula E further comprises a production method of a compound represented by formula D:
Reacting a compound shown in a formula A with a compound shown in a formula F or a compound shown in a formula G in a solvent in the presence of a catalyst and a compound shown in a formula H to obtain a compound shown in a formula D;
wherein R 1 is selected from cyclohexane, methyl or 2-propyl;
r 2 is at least one of chlorine and bromine atoms;
the catalyst in the preparation method of the compound shown in the formula D is at least one selected from concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrobromic acid, perchloric acid and concentrated hydrochloric acid;
The solvent in the preparation method of the compound shown in the formula D comprises at least one of dichloromethane and 1, 2-dichloroethane.
11. A process for producing according to claim 10,
In the preparation method of the compound shown in the formula D, the feeding mole ratio of the catalyst to the compound shown in the formula A is 0.1:1.0-2.0:1.0; and/or
In the preparation method of the compound shown in the formula D, the ratio of the feeding volume of the compound shown in the formula H to the feeding molar quantity of the compound shown in the formula A is 1 ml/1 mmol-2 ml/1 mmol; and/or
In the preparation method of the compound shown in the formula D, the feeding molar ratio of the compound shown in the formula F or the compound shown in the formula G to the compound shown in the formula A is 3:1-5:1; and/or
The reaction temperature of the reaction in the preparation method of the compound shown in the formula D is-10-25 ℃; and/or
The reaction time of the reaction in the preparation method of the compound shown in the formula D is 2-8 hours.
12. The preparation method of the compound shown in the formula D, wherein the feeding molar ratio of the catalyst to the compound shown in the formula A is 1.0:1.0-2.0:1.0.
13. A compound selected from the following structures:
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