CN113801138A - Method for preparing lanimivir octanoate intermediate by one-pot method - Google Patents
Method for preparing lanimivir octanoate intermediate by one-pot method Download PDFInfo
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- CN113801138A CN113801138A CN202010532321.1A CN202010532321A CN113801138A CN 113801138 A CN113801138 A CN 113801138A CN 202010532321 A CN202010532321 A CN 202010532321A CN 113801138 A CN113801138 A CN 113801138A
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- compound
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- octanoate
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- 238000000034 method Methods 0.000 title claims abstract description 56
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 title claims abstract description 27
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 20
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 31
- 230000035484 reaction time Effects 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 150000007530 organic bases Chemical class 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 150000007529 inorganic bases Chemical class 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 5
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940126543 compound 14 Drugs 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 4
- -1 Benzyl Chemical group 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940061367 tamiflu Drugs 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- XYGKGASSKJWLTN-UHFFFAOYSA-N CCCCCCC.CCCCCCC Chemical compound CCCCCCC.CCCCCCC XYGKGASSKJWLTN-UHFFFAOYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical group ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 241000902900 cellular organisms Species 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- UKTIJASCFRNWCB-RMIBSVFLSA-N laninamivir octanoate hydrate Chemical compound CCCCCCCC(=O)OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O UKTIJASCFRNWCB-RMIBSVFLSA-N 0.000 description 1
- 229950005327 laninamivir octanoate hydrate Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QFNFDHNZVTWZED-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-pyrazol-1-ylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)N1C=CC=N1 QFNFDHNZVTWZED-UHFFFAOYSA-N 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention relates to the technical field of drug synthesis, in particular to a method for preparing a lanimivir octanoate intermediate by a one-pot method. The invention relates to a method for preparing a lanimivir octanoate intermediate by a one-pot method, which comprises the step of adding a compound shown as a formula (4) in an R1OH、NaH、(R1O)2Reacting in the presence of CO to obtain a compound shown as a formula (5), R1Is benzyl, substituted benzyl or allyl. The method creatively adopts a one-pot method to synthesize the lanimivir octanoate intermediate compound (5) from the compound (4), the reaction is mild and rapid, the next reaction can be carried out by simple post-treatment, the energy consumption is saved, the pollution is reduced, the operation is simple, the cost is low, and the method is suitable for industrial production. The invention adopts a one-pot method to prepare the lanimivir octanoate intermediate compound (5), and the yield is up to more than 87%.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for preparing a lanimivir octanoate intermediate by a one-pot method.
Background
Lanamivir octanoate (Laninavir) is a neuraminidase inhibitor developed by Biota Pharmaceuticals and Daiichi Sankyo, and can be used for treating influenza virus infection resistant to oseltamivir (Tamiflu). Approved in 2010 to be marketed in japan under the name Inavir.
The lanimivir octanoate has the following chemical structural formula:
the lanimivir octanoate has good effects on H1N1, H5N1, N9 and B type influenza viruses and Tamiflu-resistant viruses, and has not been marketed at home and registered by the manufacturer at present. In order to guide the research and development of the imitation drugs and improve the accessibility of the public drugs, the national food and drug administration drug evaluation center organization screens foreign marketed drugs which have expired, terminated and invalid internal compound patent rights and have no imitation applications, wherein the lanimivir octanoate is primarily screened and is included in the drug list which has expired, terminated and invalid first patent rights and has no imitation applications.
At present, the preparation method of the lanimivir octanoate is classified into the following three methods:
in the first method, patent CN101679339A discloses synthesis of lanimivir octanoate by using sialic acid as a starting material through 11 steps of reaction, wherein the synthetic route is as follows:
the route takes commercially supplied sialic acid as a starting material, and the lanimivir octanoate is synthesized through 11 steps of reaction, so that the unit reaction effect is good, and the overall yield is high.
In the second method, patent CN103435582A discloses a zanamivir as a starting material, and the synthesis of lanimivir octanoate through 5-step reaction is as follows:
although the method has few steps, the zannanovir is used as the starting raw material, and the price of the raw material is too expensive, so that the requirement of the imitation drugs is difficult to meet;
in the third method, the mawei task group takes D-isoascorbic acid as a starting material, and synthesizes lanimivir octanoate through manual catalytic cyclization and a series of reactions such as oxidation, reduction, protection, deprotection and the like, wherein the synthetic route is as follows:
the synthetic route is novel, the unit reaction yield is moderate, but the market supply of starting materials and catalyst ligands is less, the price is high, the method is not suitable for large-scale production, and simultaneously, the chiral purity of the intermediate S-3 and the intermediate S-8 is not high, so that more subsequent isomer impurities are caused, and the quality of a final product is difficult to control.
In the three routes, the raw material price of the second route is too expensive, and the reagent of the third route is too expensive, so that the method is not suitable for industrial production, so that the research is focused on the process optimization of the patent CN101679339A, concentrated sulfuric acid needs to be added in the process of producing the compound 3 in the patent in the repeated process of CN101679339A, the reaction conditions are harsh, and the risk in industrial production is high; the reaction steps in the production process of the compounds 4-6 are complicated, column chromatography is needed, the industrial production requirements are difficult to meet, and further optimization is needed.
Disclosure of Invention
The invention aims to provide a method for preparing a lanimivir octanoate intermediate by a one-pot method.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for preparing a lanimivir octanoate intermediate by a one-pot method adopts a synthesis method comprising the following steps:
wherein R is1Is benzyl, substituted benzyl or allyl.
The substituted benzyl group mentioned above means: the benzene ring on the benzyl is mono-substituted or multi-substituted by chlorine, bromine, iodine, nitro, alkoxy, alkyl, aryl and other groups.
The method for preparing the lanimivir octanoate intermediate by the one-pot method comprises the following steps: mixing a compound represented by the formula (4) with an organic solvent R1OH is mixed and stirred, then NaH is added under the protection of nitrogen, stirring is carried out for 30-60 min, and then (R) is added1O)2And (3) stirring CO at the temperature of 0-80 ℃ for reaction for 30 min-24 h, and then separating to obtain the compound shown in the formula (5).
The crude compound of formula (5) is crystallized from toluene or methanol to obtain crystals of the compound of formula (5).
Preferably, the reaction temperature is 10-60 ℃.
Further preferably, the reaction temperature is 50-55 ℃.
Preferably, the reaction time is 30min to 5 h.
The organic solvent is any one or more of toluene, N-dimethylformamide, benzyl alcohol, N-heptane, methyl tert-butyl ether, tetrahydrofuran and 1, 4-dioxane.
The mass concentration of NaH is 60%.
Preferably, R1Is benzyl.
In the above process, the formula (4) is shownCompound, R1OH、NaH、(R1O)2The mass ratio of CO is 8-12: 15-30: 0.02-0.1: 12-36. Preferably, a compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 9.8: 20: 0.04: 24.22.
the compound represented by the above formula (4) is synthesized by the following route:
wherein R is1Is benzyl, substituted benzyl or allyl, X is Cl-、Br-、I-、MeSO4 -、TfO-。
Step 1, in the presence of a base, reacting a compound represented by the formula (1) with R1X reacts to produce a compound represented by the formula (2).
The base is not particularly limited, and may be neutralized with a carboxylic acid, and may be an organic base or an inorganic base.
Preferably, the organic base is such as triethylamine, diisopropylethylamine, N-dimethyl-4-aminopyridine or pyridine; inorganic bases such as cesium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
An inorganic base is preferred, and cesium carbonate or potassium carbonate is further preferred.
Step 2, reacting the compound represented by formula (2) with acetic anhydride in the presence of an organic base to produce a compound represented by formula (3). The organic base is not limited and may be neutralized with a carboxylic acid.
Preferably, the organic base is any one or more of triethylamine, diisopropylethylamine, N-dimethyl-4-aminopyridine and pyridine.
The reaction temperature of the step 2 is-30 ℃ to 100 ℃. Preferably 0 to 35 ℃.
The reaction time of the step 2 is 30 min-24 h. Preferably 10-15 h.
Step 3, the compound represented by the formula (3) is catalyzed by trimethylsilyl trifluoromethanesulfonate to produce a compound represented by the formula (4).
And 3, the reaction temperature is 0-70 ℃. Preferably from 30 ℃ to 60 ℃.
The reaction time of the step 3 is 1.0-24 h. Preferably 1.0 to 3.0 hours.
And 3, dropwise adding triethylamine to the post-treatment in the step to quench the reaction.
A preparation method of lanimivir octanoate (a compound shown in a formula I) adopts a synthesis method comprising the following steps:
step 5 is a reaction of the compound represented by formula (5) with dimethyl sulfate or methyl iodide in the presence of a base to give a compound represented by formula (6).
The reaction temperature in step 5 is 0 to 70 ℃ and preferably 0 to 30 ℃.
The reaction time of the step 5 is 30 min-24 h, preferably 1.0-15 h.
Step 6 is to react the compound represented by formula (6) with trimethylsilyl azide under catalysis of titanium isopropoxide to produce a compound represented by formula (7).
The reaction temperature in the step 6 is 0-120 ℃, and preferably 0-40 ℃.
The reaction time of the step 6 is 3.0-48 h, preferably 3.0-24 h.
Step 7 is a reaction of the compound represented by formula (7) with triphenylphosphine to give a compound represented by formula (8).
The reaction temperature in the step 7 is-10 to 80 ℃, and preferably 0 to 60 ℃.
The reaction time of the step 7 is 10 minutes to 48 hours, preferably 10 minutes to 5 hours.
Step 8 is a reaction of the compound represented by formula (8) with a base to give a compound represented by formula (9).
As the base, an inorganic base is preferable, and lithium hydroxide, sodium hydroxide, and potassium hydroxide are more preferable.
The reaction temperature in the step 8 is preferably-10 to 100 ℃, and more preferably 0 to 50 ℃.
The reaction time in step 8 is preferably 10 minutes to 48 hours, and more preferably 0.5 hour to 6 hours.
Step 9 is a reaction of the compound represented by formula (9) with the compound represented by formula (10) to give the compound represented by formula (11).
The step 9 reaction solvent is preferably purified water.
The reaction temperature in the step 9 is 0-100 ℃, and preferably 5-50 ℃.
The reaction time of the step 9 is 24-72 h, and preferably 24-60 h.
Step 10 is a reaction of the compound represented by formula (11) in the presence of trifluoroacetic acid to give the compound represented by formula (12).
The reaction temperature in the step 10 is-20 to 100 ℃, and preferably 0 to 45 ℃.
The reaction time of the step 10 is 0.5 to 24 hours, and preferably 0.5 to 8 hours.
Step 11 is to react a compound represented by formula (12) with compound 13 or compound 14 in the presence of an acid, followed by reaction with water to produce a compound represented by formula (i) or a pharmacologically acceptable salt thereof.
The acid in step 11 is preferably an inorganic acid, and more preferably hydrochloric acid.
The reaction temperature in the step 11 is preferably-10 to 70 ℃, and preferably 0 to 50 ℃.
The step 11 reaction time is preferably 10 minutes to 24 hours, and more preferably 10 minutes to 5 hours.
Compound 13 and compound 14 can be prepared by prior art methods of preparation; it can also be prepared by the following route:
the invention has the beneficial effects that:
when CN101679339A is adopted to prepare the compound 3, concentrated sulfuric acid needs to be added, which is not suitable for industrial production, researchers find that TMSOTf can be used for better reaction, the aftertreatment is easy, and industrial pollution cannot be generated.
The method creatively adopts a one-pot method to synthesize the lanimivir octanoate intermediate compound (5) from the compound (4), the reaction is mild and rapid, the product does not need column chromatography, the next reaction can be carried out by simple post-treatment, the energy consumption is saved, the pollution is reduced, the operation is simple, the cost is low, and the method is suitable for industrial production.
The yield of the lanimivir octanoate intermediate compound (5) prepared by the one-pot method is up to more than 87%, and the yield of the lanimivir octanoate prepared by the intermediate is more than 85%. The method adopting CN101679339A has more impurities and needs column chromatography, and the yield of the two-step method is only 76.9%.
Drawings
FIG. 1 is a hydrogen spectrum of compound (2);
FIG. 2 is a hydrogen spectrum of compound (3);
FIG. 3 is a hydrogen spectrum of compound (4);
FIG. 4 is a hydrogen spectrum of compound (5);
FIG. 5 is a hydrogen spectrum of compound (6);
FIG. 6 is a hydrogen spectrum of compound (12);
fig. 7 is a hydrogen spectrum of compound (13).
Detailed Description
The invention relates to a method for preparing a lanimivir octanoate intermediate by a one-pot method, which adopts a synthesis method comprising the following steps:
wherein R is1Is benzyl, substituted benzyl or allyl.
The substituted benzyl group mentioned above means: the benzene ring on the benzyl is mono-substituted or multi-substituted by chlorine, bromine, iodine, nitro, alkoxy, alkyl, aryl and other groups.
The method for preparing the lanimivir octanoate intermediate by the one-pot method comprises the following steps: mixing a compound represented by the formula (4) with an organic solvent R1OH is mixed and stirred, then NaH is added under the protection of nitrogen, stirring is carried out for 30-60 min, and then (R) is added1O)2And (3) stirring CO at the temperature of 0-80 ℃ for reaction for 30 min-24 h, and then separating to obtain the compound shown in the formula (5).
The crude compound of formula (5) is crystallized from toluene or methanol to obtain crystals of the compound of formula (5).
Preferably, the reaction temperature is 10-60 ℃.
Further preferably, the reaction temperature is 50-55 ℃.
Preferably, the reaction time is 30min to 5 h.
The organic solvent is any one or more of toluene, N-dimethylformamide, benzyl alcohol, N-heptane, methyl tert-butyl ether, tetrahydrofuran and 1, 4-dioxane.
The mass concentration of NaH is 60%.
Preferably, R1Is benzyl.
In the above process, the compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 8-12: 15-30: 0.02-0.1: 12-36. Preferably, a compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 9.8: 20: 0.04: 24.22.
the compound represented by the above formula (4) is synthesized by the following route:
wherein R is1Is benzyl, substituted benzyl or allyl, X is Cl-、Br-、I-、MeSO4 -、TfO-。
Step 1, in the presence of a base, reacting a compound represented by the formula (1) with R1X reacts to produce a compound represented by the formula (2).
The base is not particularly limited, and may be neutralized with a carboxylic acid, and may be an organic base or an inorganic base.
Preferably, the organic base is such as triethylamine, diisopropylethylamine, N-dimethyl-4-aminopyridine or pyridine; inorganic bases such as cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
An inorganic base is preferred, and cesium carbonate or potassium carbonate is further preferred.
Step 2, reacting the compound represented by formula (2) with acetic anhydride in the presence of an organic base to produce a compound represented by formula (3). The organic base is not limited and may be neutralized with a carboxylic acid.
Preferably, the organic base is any one or more of triethylamine, diisopropylethylamine, N-dimethyl-4-aminopyridine and pyridine.
The reaction temperature of the step 2 is-30 ℃ to 100 ℃. Preferably 0 to 35 ℃.
The reaction time of the step 2 is 30 min-24 h. Preferably 10-15 h.
Step 3, the compound represented by the formula (3) is catalyzed by trimethylsilyl trifluoromethanesulfonate to produce a compound represented by the formula (4).
And 3, the reaction temperature is 0-70 ℃. Preferably from 30 ℃ to 60 ℃.
The reaction time of the step 3 is 1.0-24 h. Preferably 1.0 to 3.0 hours.
And 3, dropwise adding triethylamine to the post-treatment in the step to quench the reaction.
The preparation method of the lanimivir octanoate (compound shown in the formula I) adopts the following synthesis method:
step 5 is a reaction of the compound represented by formula (5) with dimethyl sulfate or methyl iodide in the presence of a base to give a compound represented by formula (6).
The reaction temperature in step 5 is 0 to 70 ℃ and preferably 0 to 30 ℃.
The reaction time of the step 5 is 30 min-24 h, preferably 1.0-15 h.
Step 6 is to react the compound represented by formula (6) with trimethylsilyl azide under catalysis of titanium isopropoxide to produce a compound represented by formula (7).
The reaction temperature in the step 6 is 0-120 ℃, and preferably 0-40 ℃.
The reaction time of the step 6 is 3.0-48 h, preferably 3.0-24 h.
Step 7 is a reaction of the compound represented by formula (7) with triphenylphosphine to give a compound represented by formula (8).
The reaction temperature in the step 7 is-10 to 80 ℃, and preferably 0 to 60 ℃.
The reaction time of the step 7 is 10 minutes to 48 hours, preferably 10 minutes to 5 hours.
Step 8 is a reaction of the compound represented by formula (8) with a base to give a compound represented by formula (9).
As the base, an inorganic base is preferable, and lithium hydroxide, sodium hydroxide, and potassium hydroxide are more preferable.
The reaction temperature in the step 8 is preferably-10 to 100 ℃, and more preferably 0 to 50 ℃.
The reaction time in step 8 is preferably 10 minutes to 48 hours, and more preferably 0.5 hour to 6 hours.
Step 9 is a reaction of the compound represented by formula (9) with the compound represented by formula (10) to give the compound represented by formula (11).
The step 9 reaction solvent is preferably purified water.
The reaction temperature in the step 9 is 0-100 ℃, and preferably 5-50 ℃.
The reaction time of the step 9 is 24-72 h, and preferably 24-60 h.
Step 10 is a reaction of the compound represented by formula (11) in the presence of trifluoroacetic acid to give the compound represented by formula (12).
The reaction temperature in the step 10 is-20 to 100 ℃, and preferably 0 to 45 ℃.
The reaction time of the step 10 is 0.5 to 24 hours, and preferably 0.5 to 8 hours.
Step 11 is to react a compound represented by formula (12) with compound 13 or compound 14 in the presence of an acid, followed by reaction with water to produce a compound represented by formula (i) or a pharmacologically acceptable salt thereof.
The acid in step 11 is preferably an inorganic acid, and more preferably hydrochloric acid.
The reaction temperature in the step 11 is preferably-10 to 70 ℃, and preferably 0 to 50 ℃.
The step 11 reaction time is preferably 10 minutes to 24 hours, and more preferably 10 minutes to 5 hours.
Compound 13 and compound 14 can be prepared by prior art methods of preparation; it can also be prepared by the following route:
example 1
The preparation of compound (2) comprises the following steps:
at normal temperature, 30.93g of N-acetylneuraminic acid (compound 1) and Cs are sequentially added into a 500ml reaction bottle2CO316.30g, 125ml of DMF and 26.70g of BrBn, reacting for 24h by magnetic stirring, filtering after the reaction is finished, concentrating the mother liquor to be dry, adding 300ml of isopropanol, heating to 70 ℃, carrying out heat filtration to remove insoluble substances, stirring the filtrate for 3-4h at normal temperature, filtering, leaching the filter cake with isopropanol, drying the filter cake under reduced pressure and constant weight to obtain 18.50g of white powder of the compound (2), wherein the yield is 46.25%. The hydrogen spectrum of compound (2) is shown in FIG. 1.
In other examples, compound (2) may be prepared by adding 300ml of isopropanol, heating to 80 ℃ or 75 ℃, and then filtering off insoluble substances.
Example 2
The preparation of compound (3) comprises the following steps:
at normal temperature, in a 250ml reaction bottle, adding about 70ml of pyridine and 18.50g of compound (2) in sequence, controlling the temperature within the range of 20-25 ℃ after adding, dropwise adding 37.50g of acetic anhydride, then adding about 0.2g of 4-Dimethylaminopyridine (DMAP), maintaining the temperature at 20-25 ℃, stirring for reacting overnight, pouring the reaction solution into a mixed solution of 350ml of purified water and 1850ml of ethyl acetate, standing for layering after adding, sequentially extracting and washing an organic layer with 200ml of 25.0% HCl aqueous solution and 200ml of 2 saturated sodium bicarbonate aqueous solution, drying the organic layer with anhydrous sodium sulfate, filtering, leaching, and concentrating under reduced pressure until dried to obtain 30.02g of colorless oily matter with the yield of 106.4%. Purification was performed by column chromatography (n-heptane to n-heptane/ethyl acetate 1/2), and the objective component (developing solvent: ethyl acetate) was collected and concentrated under reduced pressure to dryness to obtain 14.50g of the compound (3) as a white powder. The hydrogen spectrum of compound (3) is shown in FIG. 2.
Example 3
The preparation of compound (4) comprises the following steps:
normal temperature, N2Under protection, 13.20g of the compound (3) and 265ml of ethyl acetate are sequentially added into a 1000ml reaction bottle, stirred, dissolved and clarified, the temperature is controlled to be 15-25 ℃, 14.46g of TMSOTf is dropwise added, the temperature is controlled to be 50-55 ℃, stirred and reacted for 2 hours, then the temperature is controlled to be 0-5 ℃, 11.0g of triethylamine is dropwise added, then 100ml of ice water is added, stirred for 10 minutes, kept stand and layered, an organic layer is extracted and washed twice by 100ml and 50ml of purified water, and the organic layer is dried by anhydrous sodium sulfate, filtered, leached and concentrated under reduced pressure to be dry to obtain colorless oily matter. Column chromatography purification (n-heptane-n-heptane/ethyl acetate 1/1-ethyl acetate) was performed to collect the objective component, and the product was concentrated under reduced pressure to dryness to obtain 9.14g of compound (4) as a colorless oil. The hydrogen spectrum of compound (4) is shown in FIG. 3.
Example 4
The preparation of compound (5) comprises the following steps:
at normal temperature, 9.80g of the compound (4), 40ml of toluene and benzyl alcohol (R) are added into a reaction flask in sequence1Benzyl) 20.0ml, stirring at room temperature under nitrogen protection, adding 60% NaH 0.04g, stirring for 30min, adding dibenzyl carbonate (R)1Benzyl) 24.22g is taken, stirred and reacted for 1h at 50 ℃, 0.032mol of glacial acetic acid is added to quench the reaction, the reaction is carried out on a column by a wet method, dichloromethane washes small polar impurities, dichloromethane/methanol is 40/1, the target component is washed, and the mixture is concentrated under reduced pressure to obtain the compound (5) white solid, 6.85g, yield is 87.96%. The yield is far higher than the yield (76.9%) of the compound (5) obtained by the two-step method in CN 101679339A. The hydrogen spectrum of compound (5) is shown in FIG. 4.
In the preparation example of the other compound (5), dibenzyl carbonate was added and the reaction was stirred at 55 ℃ for 2 hours. In other embodiments, the stirring reaction temperature may also be 10 ℃, 52 ℃, 60 ℃ or 80 ℃. The stirring reaction time can be adjusted within 30 min-24 h. The yield of the compound (5) was substantially the same as in example 4 by changing the above reaction temperature or time.
In other preparation examples of the compound (5), the toluene solvent may be replaced with any one or more of N, N-dimethylformamide, benzyl alcohol, N-heptane, methyl t-butyl ether, tetrahydrofuran, and 1, 4-dioxane.
In another production example of the compound (5), the compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 8: 30: 0.02: 36.
in another production example of the compound (5), the compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 12: 15: 0.1: 12.
in other embodiments, R1 can also be benzyl substituted with chloro, bromo, iodo, nitro, alkoxy, alkyl, or aryl; even R1 can be allyl.
Example 5
The preparation of compound (6) comprises the following steps:
N2under protection, sequentially adding 6.85g of compound (5), 28ml of THF and 7ml of DMF into a 250ml reaction bottle, stirring until the compound is dissolved and clarified after the addition is finished, controlling the temperature to be within the range of 0-5 ℃, adding 0.91g of 60% NaH in batches, maintaining the temperature to be 0-5 ℃, stirring for 30min after the addition is finished, adding 2.88g of dimethyl sulfate, maintaining the temperature, stirring for reaction overnight, then adding 100ml of toluene and 1.06g of glacial acetic acid for quenching reaction, and using 40ml of 25.0% NaHCO to react a reaction solution3The aqueous solution was extracted 2 times, the aqueous layer was extracted 2 times with 70ml of 2 toluene, all toluene layers were combined and dried over anhydrous sodium sulfate, filtered, rinsed, concentrated to near dryness, and purified by column chromatography (dichloromethane → dichloromethane/methanol 20/1) to give compound (6) as a colorless oil 8.0 g. The hydrogen spectrum of compound (6) is shown in FIG. 5.
Example 6
The preparation of compound (7) comprises the following steps:
N2under protection, 7.10g of the compound (6), 21ml of toluene and 7ml of tertiary butanol are sequentially added into a 100ml reaction bottle at room temperature, stirring is carried out until the mixture is dissolved and clarified, and TMSN is added34.10g and 1.55g of titanium isopropoxide, maintaining the temperature of 20-25 ℃, stirring for reaction for 24 hours, then filtering, draining the filtrate, rinsing with 10ml of methanol, and carrying out oil pump to dry the filter cake to obtain 5.76g of compound (7) as an off-white solid, wherein the yield is as follows: 72.6 percent.
Example 7
The preparation of compound (8) comprises the following steps:
and (3) at normal temperature, sequentially adding 5.00g of the compound (7) and 20ml of tetrahydrofuran into a 100ml reaction bottle, stirring until the mixture is dissolved, adding 3.24g of triphenylphosphine, heating to 40-50 ℃ after the addition is finished, stirring for reaction for 10min, performing TLC (DCM/ME ═ 10/1), allowing the raw materials to disappear, and cooling to room temperature to obtain a reaction solution of the compound (8).
Example 8
The preparation of compound (9) comprises the following steps:
to the reaction solution of the compound (8) in example 7, 12.5g of purified water and 5.40g of a 25% aqueous solution of NaOH were added, the reaction was performed with stirring at a temperature of 40 to 45 ℃ for 2 hours, TLC (DCM/ME ═ 10/1) was used, the starting material was cooled to room temperature, the mixture was allowed to stand for liquid separation, 6ml of thf was added to the aqueous layer for washing, about 4ml of concentrated hydrochloric acid was added dropwise to the aqueous layer, the PH was adjusted to 2 to 3, and the PH was adjusted to 9 to 10 with a 25% aqueous solution of NaOH to obtain a reaction solution of a compound (9).
Example 9
The preparation of compound (11) comprises the following steps:
to the reaction mixture of the compound (9) of example 8 was added 30ml of methanol and 3.82g of N, N' -bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine (compound 10) at room temperature, and the mixture was stirred and reacted at 20 to 25 ℃ for 48 hours to adjust the pH to 8.5 to 8.8, the reaction mixture was concentrated to dryness, 100ml of ethyl acetate was added and the mixture was concentrated under reduced pressure to remove methanol, the concentrate was washed with 50ml of 3 ethyl acetate 3 times, the aqueous layer was adjusted to 2 to 3 with about 1.3g of concentrated hydrochloric acid, the aqueous layer was extracted with 50ml of 3 ethyl acetate, and the organic layers were combined and concentrated to dryness to obtain 5.20g of a white solid (compound 11) with a yield of 85.1%.
Example 10
The preparation of compound (12) comprises the following steps:
the compound (11) obtained in example 9 was added to 50ml of dichloromethane, 5g of trifluoroacetic acid was added to the mixture and reacted at room temperature for 3 hours, the mixture was concentrated to dryness under reduced pressure, 25ml of purified water was added, and the mixture was adjusted to pH 6 to 8 with 10% aqueous sodium hydroxide solution. Adding 50ml of methanol, stirring at normal temperature for crystallization, filtering, leaching filter cakes with methanol, and drying at 40 ℃ under reduced pressure to obtain 2.74g of compound (12) white powder with the yield of 70.62%. The hydrogen spectrum of compound (12) is shown in FIG. 7.
Example 11
Normal temperature, N2Under protection, 2.00g of the compound (12), 10ml of methanol and 3.54g of the compound 13 are sequentially added into a 100ml reaction flask, finally 10.5ml of a methanol solution of HCl (1N hydrogen chloride) is added, the mixture is clarified, the temperature is maintained at 20-25 ℃, the mixture is stirred for reaction for 1 hour, reduced pressure concentration and near drying are carried out, 20ml of purified water is added, 20ml of ethyl acetate is used for extraction and washing for three times, the pH value of a water layer is adjusted to be 7 by saturated sodium carbonate, the mixture is stirred for 1 hour, then, the pH value is adjusted to be 8.5-9.0 by saturated sodium carbonate, the mixture is stirred for 3 hours, the pH value is adjusted to be 5-6 by 6N hydrochloric acid, the mixture is stirred for 30 minutes, filtered, filter cake is rinsed by purified water, the filter cake is 35 ℃, and the mixture is dried under reduced pressure to a constant weight, and 2.34g of the compound (I) white powder is obtained, the yield is 85.6%, and the HPLC is 99.84%.
Compound 13 in this example can be replaced with Compound 14, with the other conditions remaining unchanged.
Comparative example 1
This comparative example differs from example 4 only in that dibenzyl carbonate is replaced with carbonyldiimidazole. The product has more impurities, column chromatography is needed, and the yield of the finally obtained compound (5) is only 20%.
Comparative example 2
This comparative example differs from example 4 only in that dibenzyl carbonate was replaced with benzyl chloroformate. The yield of the compound (5) finally obtained is only 25% due to the fact that column chromatography is required because of a large amount of impurities.
Various other modifications and changes may be made by those skilled in the art based on the above-described technical solutions and concepts, and all such modifications and changes should fall within the scope of the claims of the present invention.
Claims (10)
2. The method of claim 1, comprising the steps of: mixing a compound represented by the formula (4) with an organic solvent R1OH is mixed and stirred, then NaH is added under the protection of nitrogen, stirring is carried out for 30-60 min, and then (R) is added1O)2And (3) stirring CO at the temperature of 0-80 ℃ for reaction for 30 min-24 h, and then separating to obtain the compound shown in the formula (5).
3. The method according to claim 2, wherein the reaction temperature is 10 to 60 ℃.
4. The method according to claim 3, wherein the reaction temperature is 50 to 55 ℃.
5. The method according to claim 2, wherein the reaction time is 30min to 5 h.
6. The method according to claim 2, wherein the organic solvent is any one or more of toluene, N-dimethylformamide, benzyl alcohol, N-heptane, methyl tert-butyl ether, tetrahydrofuran and 1, 4-dioxane.
7. The method according to claim 1, wherein the NaH is present at a concentration of 60% by mass.
8. The method of any one of claims 1-7, wherein R is1Is benzyl.
9. The method according to claim 1, wherein the compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 8-12: 15-30: 0.02-0.1: 12-36.
10. The method according to claim 9, wherein the compound represented by the formula (4), R1OH、NaH、(R1O)2The mass ratio of CO is 9.8: 20: 0.04: 24.22.
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CN105037309A (en) * | 2011-12-16 | 2015-11-11 | 第一三共株式会社 | Method for producing neuraminic acid derivative |
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MX2021002569A (en) * | 2018-09-06 | 2021-06-08 | Cidara Therapeutics Inc | Compositions and methods for the treatment of viral infections. |
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