CN116354869A - Synthesis process of cyclohexene antiviral compound - Google Patents
Synthesis process of cyclohexene antiviral compound Download PDFInfo
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- CN116354869A CN116354869A CN202310140301.3A CN202310140301A CN116354869A CN 116354869 A CN116354869 A CN 116354869A CN 202310140301 A CN202310140301 A CN 202310140301A CN 116354869 A CN116354869 A CN 116354869A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 229
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 230000000840 anti-viral effect Effects 0.000 title abstract description 5
- -1 cyclohexene compound Chemical class 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 150000001540 azides Chemical class 0.000 claims abstract description 12
- 238000006722 reduction reaction Methods 0.000 claims abstract description 11
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 8
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- 239000003153 chemical reaction reagent Substances 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 39
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 38
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 38
- WHQOIXYNVRFCJC-QMMMGPOBSA-N (3s)-3-(2-methoxyethoxy)piperidine Chemical compound COCCO[C@H]1CCCNC1 WHQOIXYNVRFCJC-QMMMGPOBSA-N 0.000 claims description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 238000002425 crystallisation Methods 0.000 claims description 26
- 230000008025 crystallization Effects 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 230000003197 catalytic effect Effects 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000007127 saponification reaction Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 206010022000 influenza Diseases 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 2
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 46
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- 239000000203 mixture Substances 0.000 description 26
- 239000012065 filter cake Substances 0.000 description 25
- 238000001914 filtration Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000007605 air drying Methods 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- 238000004811 liquid chromatography Methods 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000001935 cyclohexenes Chemical class 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 6
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 6
- 241000712461 unidentified influenza virus Species 0.000 description 6
- 102000005348 Neuraminidase Human genes 0.000 description 5
- 108010006232 Neuraminidase Proteins 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- KMIKPBSZFDBYFM-QRPNPIFTSA-N (3S)-3-(2-methoxyethoxy)piperidine 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.COCCO[C@H]1CCCNC1 KMIKPBSZFDBYFM-QRPNPIFTSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 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 1
- 230000005540 biological transmission Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
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- AEDZKIACDBYJLQ-UHFFFAOYSA-N ethane-1,2-diol;hydrate Chemical compound O.OCCO AEDZKIACDBYJLQ-UHFFFAOYSA-N 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- 208000023504 respiratory system disease Diseases 0.000 description 1
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- 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 1
- 125000005629 sialic acid group Chemical group 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of cyclohexene antiviral compounds. Wherein, the cyclohexene compound has a structure of formula F, and the synthetic route comprises the following steps: (1) The compound with the structure of the formula A is subjected to azide reduction reaction to obtain a compound with the structure of the formula B; (2) The structural compound of the formula B is subjected to nucleophilic substitution reaction to obtain a structural compound of the formula C; (3) Tsuji-Trost reaction is carried out on the structural compound of the formula C to obtain a structural compound of the formula D; (4) And (3) hydrolyzing the structural compound of the formula D, and removing the Boc group of the tert-butoxycarbonyl group to obtain the structural compound of the formula F. The reaction route of the invention improves the reaction yield and the atom economy, reduces the cost, can realize the large-scale production and has huge commercial production value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of cyclohexene antiviral compounds.
Background
Influenza is a common respiratory disease caused by influenza virus, has strong infectivity and is easy to cause various complications, and the normal life of human beings is seriously affected.
Currently, the main means of influenza virus prevention and treatment is to use neuraminidase inhibitor drugs, which target Neuraminidase (NA) on the surface of influenza virus. Neuraminidase is a tetrameric glycoprotein in the form of a mushroom, and plays an important role in the process of replication of influenza virus out of host cells. When influenza virus enters host cells through haemagglutinin and replicates, hemagglutinin on the surface of mature viral cells is linked to the cell membrane of the host through sialic acid, and neuraminidase has enzymatic activity, which hydrolyzes sialic acid residues, ultimately causing the viral cells to leave the host. Therefore, neuraminidase is effectively inhibited, and the transmission of influenza virus in vivo can be prevented.
Chinese patent (CN 106496100A) discloses a cyclohexene compound, in particular discloses (3R, 4R, 5S) -4-acetamido-5-guanidino-3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-formic acid and a preparation method thereof, the cyclohexene compound has good inhibitory activity on various virus subtypes and drug resistance, has better in vivo pharmacokinetics and safety, but has the problems of lower yield and low atom utilization rate in the preparation process, so the development of a preparation method for synthesizing the cyclohexene compound with high efficiency and low cost is needed.
Disclosure of Invention
The technical problems solved by the invention are as follows: the cyclohexene antiviral compound synthesized in the prior art has the problems of low yield and low atom utilization rate. In view of the above problems, the present invention aims to provide a preparation process of cyclohexene compounds, in particular to a preparation process of 4-acetamido-5-guanidino-3- (-3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid.
Specifically, the invention provides the following technical scheme:
in one aspect, the invention provides a preparation method of cyclohexene compounds, wherein the cyclohexene compounds have a structure of formula F, and the synthetic route comprises the following steps:
(1) The compound with the structure of the formula A is subjected to azide reduction reaction to obtain a compound with the structure of the formula B;
(2) The structural compound of the formula B is subjected to nucleophilic substitution reaction to obtain a structural compound of the formula C;
(3) Tsuji-Trost reaction is carried out on the structural compound of the formula C to obtain a structural compound of the formula D;
(4) Hydrolyzing the structural compound of the formula D, and removing a Boc group of the t-butyloxycarbonyl group to obtain a structural compound of the formula F;
wherein R in the structural compound of formula A, the structural compound of formula B, the structural compound of formula C and the structural compound of formula D 1 Selected from alkyl groups containing 1 to 10 carbon atoms; r in the structural compound of the formula A, the structural compound of the formula B and the structural compound of the formula C 2 Selected from alkyl groups containing 1 to 10 carbon atoms; r in the structural compound of the formula A, the structural compound of the formula B, the structural compound of the formula C, the structural compound of the formula D and the structural compound of the formula F 3 Selected from alkyl groups containing 1 to 10 carbon atoms.
In some embodiments, R in the structural compound of formula A, the structural compound of formula B, the structural compound of formula C, and the structural compound of formula D 1 Selected from methyl, ethyl, propyl or isopropyl; r in the structural compound of the formula A, the structural compound of the formula B and the structural compound of the formula C 2 Selected from methyl, ethyl, propyl or isopropyl; r in the structural compound of the formula A, the structural compound of the formula B, the structural compound of the formula C, the structural compound of the formula D and the structural compound of the formula F 3 Selected from methyl, ethyl, propyl or isopropyl.
In some embodiments, the structural compound of formula a is a structural compound of formula (I), the structural compound of formula B is a structural compound of formula (II), the structural compound of formula C is a structural compound of formula (III), the structural compound of formula D is a structural compound of formula (IV), and the structural compound of formula F is a structural compound of formula (VI), the synthetic route comprising the steps of:
(1) The structural compound of the formula (I) is subjected to azide reduction reaction to obtain the structural compound of the formula (II);
(2) The structural compound of the formula (II) is subjected to nucleophilic substitution reaction to obtain the structural compound of the formula (III);
(3) Tsuji-Trost reaction is carried out on the structural compound shown in the formula (III) to obtain the structural compound shown in the formula (IV);
(4) Hydrolyzing the structural compound of the formula (IV) to remove a Boc group of the tert-butyloxycarbonyl group to obtain the structural compound of the formula (VI);
in some embodiments, in step (1), the catalytic reducing agent of the azide reduction reaction is selected from palladium-carbon, palladium-barium sulfate, platinum dioxide, raney nickel, lithium aluminum hydride, sodium borohydride, or triphenylphosphine.
In some embodiments, in step (1), the catalytic reducing agent of the azide reduction reaction is selected from raney nickel or triphenylphosphine.
In some embodiments, in step (1), the molar ratio of the catalytic reducing agent to the compound of formula A is (1-3): 1.
In some embodiments, in the azide reduction reaction of step (1), water is added in addition to the catalytic reducing agent; wherein the molar ratio of water to the compound of formula A is (3-10): 1.
In some embodiments, in step (1), the reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile, N-dimethylformamide, dichloromethane, and toluene.
In some embodiments, in step (1), the reaction solvent is selected from acetonitrile or tetrahydrofuran;
In some embodiments, in step (1), the concentration of the structural compound of formula A in the reaction solvent is from 0.1 to 0.2g/mL.
In some embodiments, in step (1), the structural compound of formula a, the catalytic reducing agent and water are dispersed in a solvent and reacted at 20-30 ℃ for 1-3 hours; then heating to 35-80 ℃, preferably 35-60 ℃ and reacting for 3-7 h.
In some embodiments, in step (2), a first basic reagent and N, N-di-tert-butoxycarbonyl-1H-1-guanidinopyrazoles are added to the solution obtained in step (1), after the reaction is complete, the solution is concentrated and crystallization reagents are added to precipitate the compound of formula C.
In some embodiments, in step (2), the crystallization reagent is a mixed system of ethylene glycol dimethyl ether, ethanol, and n-hexane.
In some embodiments, in step (2), the volume ratio of ethylene glycol dimethyl ether to ethanol is 1:1.
In some embodiments, in step (2), the volume ratio of ethanol to n-hexane is 1:6.
In some embodiments, the reaction temperature of step (2) is from 20 to 30 ℃.
In some embodiments, the reaction time of step (2) is from 10 to 15 hours.
In some embodiments, in step (2), the amount of N, N-di-t-butoxycarbonyl-1H-1-guanidinopyrazoles is determined based on a molar ratio of (1-2): 1 to the amount of compound of formula A initially reacted in step (1).
In some embodiments, in step (2), the first basic reagent is selected from one or more of N-methylmorpholine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, N-diisopropylmethylamine, pyridine, triethylenediamine and aqueous ammonia.
In some embodiments, in step (2), the first basic reagent is N, N-diisopropylethylamine.
In some embodiments, in step (2), the amount of the first basic reagent is determined based on a molar ratio of (2-5): 1 to the amount of the compound of formula A initially reacted in step (1).
In some embodiments, in step (3), the compound of formula D is prepared by adding (S) -3- (2-methoxyethoxy) piperidine, a second basic reagent, a palladium catalyst, and a solvent to the compound of formula C.
In some embodiments, in step (3), the reaction temperature is 40 to 90 ℃.
In some embodiments, in step (3), the reaction temperature is 60 to 70 ℃.
In some embodiments, in step (3), the reaction time is from 3 to 7 hours.
In some embodiments, in step (3), the molar ratio of (S) -3- (2-methoxyethoxy) piperidine to the compound of formula C is (1-3): 1.
In some embodiments, in step (3), the second basic reagent is selected from one or more of N-methylmorpholine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, N-diisopropylmethylamine, pyridine, triethylenediamine and aqueous ammonia.
In some embodiments, in step (3), the second basic reagent is selected from N, N-diisopropylethylamine.
In some embodiments, in step (3), the molar ratio of the second basic reagent to the compound of formula C is (1-3): 1.
In some embodiments, in step (3), the palladium catalyst is selected from palladium acetate, diphenylphosphino ferrocene palladium dichloride, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, or palladium pivalate.
In some embodiments, in step (3), the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium.
In some embodiments, the molar ratio of palladium catalyst to structural compound of formula C in step (3) is (0.01 to 0.1): 1.
In some embodiments, in step (3), the solvent is selected from acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane, toluene, diethyl ether, or methyl tert-butyl ether.
In some embodiments, in step (3), the solvent is selected from acetonitrile.
In some embodiments, in step (3), the molar concentration of the structural compound of formula C in the solvent is from 0.1 to 0.2g/mL.
In some embodiments, step (4) comprises the following reaction steps:
wherein R in the structural compound of formula E 3 Selected from alkyl groups containing 1 to 10 carbon atoms; preferably methyl, ethyl, propyl or isopropyl;
wherein, the step (4) comprises the following steps:
(4a) Carrying out saponification reaction on a structural compound of a formula D to obtain a structural compound of a formula E;
(4b) And (3) removing the Boc protecting group of the tert-butyloxycarbonyl group from the structural compound of the formula E under the high-temperature condition to obtain the structural compound of the formula F.
In some embodiments, the structural compound of formula D is a structural compound of formula (IV), the structural compound of formula E is a structural compound of formula (V), the structural compound of formula F is a structural compound of formula (VI), and step (4) comprises the following reaction steps:
in some embodiments, in step (4 a), the reaction temperature is from 0 to 25 ℃.
In some embodiments, in step (4 a), the reaction temperature is 15 to 25 ℃.
In some embodiments, in step (4 a), the reaction time is from 10 to 15 hours.
In some embodiments, in step (4 a), the reaction solvent comprises ethylene glycol dimethyl ether.
In some embodiments, in step (4 a), the alkaline reagent used in the reaction is aqueous potassium hydroxide or sodium hydroxide.
In some embodiments, in step (4 a), the amount of potassium hydroxide or sodium hydroxide is determined based on a molar ratio of potassium hydroxide or sodium hydroxide to the amount of compound of formula (III) used in step (3) as initially described in the range of from 0.5 to 1.5:1.
In some embodiments, step (4 a) further comprises the step of adjusting the pH of the solution after the saponification reaction is completed to 4 to 5, concentrating, and adding a crystallization reagent to precipitate the compound of formula E.
In some embodiments, the crystallization reagent in step (4 a) is selected from one or more of ethylene glycol dimethyl ether, ethanol, N-hexane, ethyl acetate, methanol, ethanol, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane, toluene, diethyl ether, N-heptane, and acetone.
In some embodiments, the crystallization reagent in step (4 a) is a mixed system of ethyl acetate, water and n-heptane.
In some embodiments, the crystallization reagent in step (4 a) is ethyl acetate and water in a volume ratio of 130:11.5; the volume ratio of water to n-heptane was 11.5:130.
In some embodiments, in step (4 b), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100 ℃, and the t-butoxycarbonyl Boc protecting group is removed to give the compound of formula F.
In some embodiments, in step (4 b), the compound of formula E is dissolved in water, the temperature is adjusted to 60-80 ℃, and the t-butoxycarbonyl Boc protecting group is removed to give the compound of formula F.
In some embodiments, in step (4 b), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100 ℃, and the reaction is carried out for 3-7 hours, so as to remove the Boc protecting group of the tert-butoxycarbonyl group, thereby obtaining the compound of formula F.
In some embodiments, step (4 b) further comprises the steps of adding activated carbon after the reaction is completed, cooling, separating, and adding a crystallization reagent to the filtrate to precipitate the compound of formula F.
In some embodiments, in step (4 b), the crystallization reagent is a mixed system of isopropanol and methyl tert-butyl ether.
In some embodiments, in step (4 b), the volume ratio of isopropyl alcohol to methyl tert-butyl ether is 5.9:6.
In a second aspect, the invention provides a cyclohexene compound, which is prepared by the preparation method of the cyclohexene compound.
In a third aspect, the use of a cyclohexaene compound or a pharmaceutically acceptable salt, ester-based prodrug or stereoisomer thereof in the preparation of a medicament for the prophylaxis and treatment of influenza.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising the cyclohexaene compound or a pharmaceutically acceptable salt thereof, and an ester prodrug or stereoisomer thereof, and a pharmaceutically acceptable adjuvant or carrier.
The beneficial effects of the invention are that
In the synthesis process of the invention, (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-ethyl formate is taken as a raw material. In the first step, after azide in the raw material is reduced into amino, the amino is directly reacted with a guanidine substrate, so that fragment splicing is completed, the amino can be used as an amino protecting group, and another side chain (piperidine) is connected by using Tsuji-Trost reaction to obtain a compound of the formula IV, so that the reaction steps of amino protection-deprotection are avoided, the reaction yield and the atom economy are improved, the cost is reduced, the amplified production is realized, and the commercial production value is great.
Drawings
FIG. 1 is a schematic diagram of a compound of formula (III) of example 1 1 H-NMR chart.
FIG. 2 is a mass spectrum of a compound of formula (III) of example 1.
FIG. 3 is a schematic diagram of a compound of formula (VI) of example 1 1 H-NMR chart.
FIG. 4 is a schematic illustration of a compound of formula (VI) of example 1 1 C-NMR chart.
FIG. 5 is a synthetic route diagram of cyclohexene compounds of the present invention.
Detailed Description
As described above, the invention aims to provide a preparation process of cyclohexene compounds, in particular to a preparation process of (3R, 4R, 5S) -4-acetamido-5-guanidino-3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid. The preparation process improves the reaction yield and the atom economy, reduces the cost and has huge commercial production value.
In a first aspect, the synthetic route for the cyclohexene compound of the invention, 4-acetamido-5-guanidino-3- (-3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid, is shown below:
wherein R in the structural compound of formula A, the structural compound of formula B, the structural compound of formula C and the structural compound of formula D 1 Selected from alkyl groups containing 1 to 10 carbon atoms; r is R 1 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.
R in the structural compound of the formula A, the structural compound of the formula B and the structural compound of the formula C 2 Selected from alkyl groups containing 1 to 10 carbon atoms; r is R 2 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.
R in the structural compound of the formula A, the structural compound of the formula B, the structural compound of the formula C, the structural compound of the formula D and the structural compound of the formula F 3 Selected from alkyl groups containing 1 to 10 carbon atoms; r is R 3 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl.
R in the compound of formula (A), the compound of formula (B), the compound of formula (C), the compound of formula (D), the compound of formula (E) and the compound of formula (F) 1 Selected from ethyl; r is R 2 Selected from ethyl; r is R 3 Selected from ethyl groups.
In some embodiments, the invention provides a preparation method of cyclohexene compound, wherein the cyclohexene compound has a structural formula (IV), and the synthetic route comprises the following steps:
(1) The structural compound of the formula (I) is subjected to azide reduction reaction to obtain the structural compound of the formula (II);
(2) The structural compound of the formula (II) is subjected to nucleophilic substitution reaction to obtain the structural compound of the formula (III);
(3) Tsuji-Trost reaction is carried out on the structural compound shown in the formula (III) to obtain the structural compound shown in the formula (IV);
(4) Hydrolyzing the structural compound of the formula (IV) to remove a Boc protecting group of the tert-butyloxycarbonyl group to obtain the structural compound of the formula (VI);
wherein R in the structural compound of formula (I), the structural compound of formula (II), the structural compound of formula (III) and the structural compound of formula (IV) 1 Selected from alkyl groups containing 1 to 10 carbon atoms, R 1 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl; preferably methyl, ethyl, propyl or isopropyl; r in the structural compound of formula (I), the structural compound of formula (II) and the structural compound of formula (III) 2 Selected from alkyl groups containing 1 to 10 carbon atoms, R 2 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl; preferably methyl, ethyl, propyl or isopropyl; r in the structural compound of formula (I), structural compound of formula (II), structural compound of formula (III), structural compound of formula (IV) and structural compound of formula (VI) 3 Selected from alkyl groups containing 1 to 10 carbon atoms, R 3 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl; methyl, ethyl, propyl or isopropyl are preferred.
Preferably, step (4) comprises the following reaction steps:
wherein R in the structural compound of formula (V) 3 Selected from alkyl groups containing 1 to 10 carbon atoms; r is R 3 Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl; preferably methyl group, Ethyl, propyl or isopropyl;
wherein, the step (4) comprises the following steps:
(i) The structural compound of the formula (IV) is subjected to saponification reaction to obtain the structural compound of the formula E;
(ii) And (3) removing the Boc protecting group of the tert-butyloxycarbonyl group from the structural compound of the formula (V) under the high-temperature condition to obtain the structural compound of the formula (VI).
Preferably, in step (i), the reaction temperature is from 0 to 25 ℃.
Preferably, in step (i), the reaction temperature is 15 to 25 ℃.
Preferably, the step (i) further comprises a step of adjusting the pH of the solution after the completion of the saponification reaction to 4 to 5, concentrating, and adding a crystallization reagent to precipitate the compound of formula E.
Preferably, the crystallization reagent in the step (i) is one or more selected from ethylene glycol dimethyl ether, ethanol, N-hexane, ethyl acetate, methanol, ethanol, methyl tertiary butyl ether, acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane, toluene, diethyl ether, N-heptane and acetone.
Preferably, the crystallization reagent in the step (i) is a mixed system of ethyl acetate, water and n-heptane.
Preferably, the crystallization reagent in the step (i) is ethyl acetate and water in a volume ratio of 130:11.5; the volume ratio of water to n-heptane was 11.5:130.
Preferably, in step (ii), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100 ℃, preferably 60-80 ℃, and the Boc protecting group of the t-butoxycarbonyl group is removed to obtain the compound of formula F.
Preferably, step (ii) further comprises the steps of adding activated carbon after the reaction is completed, cooling, separating, and adding a crystallization reagent to the filtrate to precipitate the compound of formula F.
Preferably, in step (ii), the crystallization reagent is a mixed system of isopropanol and methyl tert-butyl ether.
Preferably, in step (ii), the volume ratio of isopropanol to methyl tert-butyl ether is 5.9:6.
Preferably, the present invention provides a synthetic route for (3R, 4R, 5S) -4-acetamido-5-guanidino-3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid as follows:
the preparation method of cyclohexene comprises the following steps:
(1) Taking (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (formula I) as a starting material, adding triphenylphosphine, water and a solvent, and carrying out reduction reaction at the temperature of 20-80 ℃ to reduce azido into amino to obtain a solution containing (3R, 4R, 5S) -4-acetamido-5-amino-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (formula II);
(2) Cooling the solution obtained in the step (1) to 20-30 ℃, then adding N, N' -di-Boc-1H-1-guanidyl pyrazole and a first alkaline reagent, concentrating the solution under reduced pressure after the reaction is finished, adding a solvent for crystallization (ethylene glycol dimethyl ether, ethanol and N-hexane), and filtering to obtain ethyl (3R, 4R, 5S) -4-acetamido-5- ((Z) -2, 3-di (tert-butoxycarbonyl) guanidyl) -3-acetoxy-1-cyclohexene-1-carboxylate (formula III);
(3) Dissolving the compound of the formula (III) obtained in the step (2) in an organic solvent, then adding (S) -3- (2-methoxyethoxy) piperidine, a second alkaline reagent and a palladium catalyst, reacting at the temperature of 40-90 ℃, concentrating under reduced pressure after the reaction is finished, adding methyl tertiary butyl ether and sodium bisulfate aqueous solution, stirring at room temperature, filtering, standing for liquid separation, and separating an organic layer (containing the compound of the formula IV) for later use;
(4) Concentrating the organic layer solution obtained in the step (3) under reduced pressure, adding ethylene glycol dimethyl ether and water, cooling to 0-25 ℃, slowly dropwise adding an inorganic alkali solution for saponification reaction, adding dichloromethane after the reaction is finished, adjusting the pH value to be acidic by using acid, standing, separating liquid, extracting a water layer by using dichloromethane, merging the organic layers, concentrating under reduced pressure, adding a reagent for crystallization (ethyl acetate, water and n-heptane), stirring and filtering to obtain (3R, 4R, 5S) -4-acetamido-5- ((E) -2, 3-di (tert-butoxycarbonyl) guanidino) -3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid pentahydrate (formula V);
(5) Dissolving the compound of the formula V obtained in the step (4) in a solvent, regulating the temperature to 50-100 ℃, removing a Boc protecting group, adding active carbon after the reaction is finished, cooling, separating and filtering, adding a crystallization reagent (isopropanol and methyl tertiary butyl ether) and a small amount of seed crystal into the filtrate, and filtering to obtain the (3R, 4R, 5S) -4-acetamido-5-guanidino-3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid.
The crystallization reagent of the invention is a solvent which can precipitate a product by adding the crystallization reagent into a reaction system.
Compared with the comparison document (patent application number: 201610814412.8), the technical scheme of the invention has different synthetic routes and reaction conditions of each step, and the advantages and meanings of the synthetic route selected by the invention are briefly described. The final product (VI) in the invention and the comparison document are both obtained through the synthesis of the intermediate in the formula (IV), the biggest difference is that the routes for synthesizing the compound in the formula (IV) are different, the azido in the initial raw material (formula I) is reduced to amino, then the amino reacts with the guanidine substrate segment, finally the other side chain (the N atom connected with the piperidine ring) is connected to obtain the compound in the formula (IV), and the initial raw material (formula I) is connected to the other side chain (the N atom connected with the piperidine ring) in the first step of the comparison document, the azido is reduced to amino, and finally the amino reacts with the guanidine substrate segment to obtain the compound in the formula (IV).
The synthetic route of the present invention has three advantages compared with the synthetic route of comparative document 1:
on one hand, the yield of the product obtained by the synthetic route is higher; the catalyst used in the first step of the comparison document for the attachment of the starting material to the other side chain was Pd (PPh 3 ) 4 The azide in the starting material oxidizes triphenylphosphine contained in the catalyst, and the catalyst is deactivated while byproducts are generated, so that the yield of the product obtained by the synthetic route of the reference document is lower. Second, the comparison file is closedThe catalyst used in the first step of the route is high in dosage, so that the production investment cost is high. The method is simple to operate, mild in condition, suitable for industrial large-scale production and high in commercial production value; the reference is not suitable for industrial scale-up production.
The various reagents/instruments used in the examples and comparative examples of the present invention are conventional commercial products unless otherwise specified.
Wherein, the manufacturer of the initial raw material (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester is Hai Ruidean Biotechnology Co., ltd. The manufacturer of the (S) -3- (2-methoxyethoxy) piperidine is Lewei medicine (Tianjin) limited company. The manufacturer of the N, N' -di-BOC-1H-1-guanidylpyrazole disclosed by the invention is Suzhou Kabushiki Kaisha. The instrument model of the nuclear magnetic resonance hydrogen spectrometer used in the invention is QUANTUM-Iplus AS400, and the manufacturer is the Sharpness oxford Spectroscopy Co.
In order to better understand the technical scheme of the present invention, the following describes the technical scheme of the present invention in detail with reference to specific embodiments.
Example 1
(1) 50g (0.161 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula I) are dissolved in 500.0mL of tetrahydrofuran at room temperature, stirred, 55g (0.210 mol) of triphenylphosphine and 8.7g (0.483 mol) of water are added, stirred for 2h at 20-30℃and then heated to 55℃and stirred for 5h.
(2) The reaction solution obtained in the above step was cooled to 25℃and 60g (0.193 mol) of N, N' -di-BOC-1H-1-guanidinopyrazoles, 62.5g (0.483 mol) of N, N-diisopropylethylamine were added thereto and stirred for 12 hours. Concentrating under reduced pressure, adding 100.0mL of ethylene glycol dimethyl ether and 100.0mL of ethanol, slowly dropwise adding 600.0mL of n-hexane, and stirring for 12h. Filtering, leaching the filter cake with 100.0mL of n-hexane, and drying the filter cake in a forced air drying oven at 40 ℃ for 10 hours to obtain 55.2g of white solid with the yield of 65.1%. The purity of the liquid chromatography was 98.33%.
FIG. 1 shows a compound of formula (III) 1 HNMRSpectrogram of the graph: 1 HNMR(400MHz,CDCl 3 )δ/ppm＝11.3854(s,1H),8.6285(m,1H),6.6722(m,1H),6.6596(m,1H),5.6425(m,1H),4.5109(m,1H),4.2318(m,3H),2.8949(m,1H),2.4024(m,1H),2.0997(s,3H),1.8949(s,3H),1.5079(s,9H),1.5027(s,9H),1.3027(m,3H)。
FIG. 2 is a MS spectrum of the structure of formula (III): MS (ESI) M/z [ M+H ] +:527.27.
(3) 50.0g (0.095 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5- ((Z) -2, 3-di (t-butoxycarbonyl) guanidino) -3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula III) are dissolved in 500.0mL of acetonitrile at room temperature and stirred, 15.1g (0.095 mol) of (S) -3- (2-methoxyethoxy) piperidine, 13.5g (0.104 mol) of N, N-diisopropylethylamine, 1.1g (0.95 mmol) of tetrakis (triphenylphosphine) palladium are added and replaced with nitrogen. Heating to 60 ℃, stirring for 4 hours, concentrating under reduced pressure at 45 ℃, adding 500.0mL of methyl tertiary butyl ether into the concentrate, stirring and dissolving, adding 100.0g of 10% sodium bisulfate aqueous solution, stirring for 0.5 hours at room temperature, filtering, standing and separating liquid, concentrating an organic layer under reduced pressure, adding 380.0mL of ethylene glycol dimethyl ether into the concentrate, stirring and dissolving, and dissolving for later use.
(4) 125.0mL of water is added into the solution in the step (3), the solution is cooled to below 15 ℃ under stirring, 116.0mL of 1mol/L KOH aqueous solution is slowly added dropwise, and the solution is stirred for 12h. 1000.0mL of dichloromethane was added, the mixture was cooled to 10 ℃, 2mol/L of aqueous HCl was added dropwise to adjust the pH to 5, about 78mL of the mixture was allowed to stand and separated, the aqueous layer was extracted with 500.0mL of dichloromethane, the organic layers were combined, concentrated under reduced pressure, 130.0mL of ethyl acetate and 11.5mL of water were added, and the mixture was stirred at room temperature, 130.0mL of n-heptane was added dropwise, and stirring was continued for 8 hours. The mixture was filtered and the filter cake was rinsed with 146.0mL of n-heptane. The filter cake was dried in a forced air drying oven at 45℃for 8 hours to give 42.5g of a white solid with a yield of 65.0% and a liquid chromatography purity of 99.61%.
(5) The (3R, 4R, 5S) -4-acetamido-5- ((E) -2, 3-di (t-butoxycarbonyl) guanidino) -3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid pentahydrate (structural compound of formula V) obtained in step (4) was dissolved in 120.0mL of water at room temperature, and heated to 70℃and stirred for 5h. 1.0g of active carbon is added, cooled to 25 ℃ and stirred for 0.5h. After filtration, 236.0mL of isopropanol is added into the filtrate, the temperature is raised to 35 ℃ and the mixture is stirred, 240.0mL of methyl tertiary butyl ether and a small amount of seed crystal are slowly added, the mixture is continuously stirred for 8 hours and then is filtered, and the filter cake is leached by 100.0mL of methyl tertiary butyl ether to obtain 20.8g of white solid, the yield is 90.0%, and the liquid phase purity is 99.93%.
FIG. 3 shows a compound of formula (VI) 1 An H-NMR chart of the sample, 1 H-NMR(400MHz,D 2 O)δ＝6.38(t,1H),4.02(dd,J1＝10.3,J2＝8.9Hz,1H),3.67～3.52(m,4H),3.51～3.41(m,3H),3.27(m,3H),2.81(dd,J1＝10.8,J2＝3.8Hz,1H),2.72～2.59(m,2H),2.35～2.16(m,3H),1.92(m,4H),1.64(m,1H),1.43～1.31(m,1H),1.18～1.13(m,1H)。
FIG. 4 shows a compound of formula (VI) 1 C-NMR-chart of the sample, 13 C-NMR(100MHz,D2O)δ＝174.30,174.11,156.79,136.02,132.15,75.17,71.31,67.00,64.17,58.02,52.46,52.15,49.75,49.67,30.71,29.49,22.62,22.14。
example 2
(1) 50g (0.161 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula I) are dissolved in 500.0mL of tetrahydrofuran at room temperature, stirred, 50.7g (0.193 mol) of triphenylphosphine and 8.7g (0.483 mol) of water are added, stirred for 2h at 20-30℃and then heated to 55℃and stirred for 5h.
(2) The reaction solution obtained in the above step was cooled to 25℃and 60g (0.193 mol) of N, N' -di-BOC-1H-1-guanidinopyrazoles, 41.7g (0.322 mol) of N, N-diisopropylethylamine were added thereto and stirred for 12 hours. Concentrating under reduced pressure, adding 100.0mL of ethylene glycol dimethyl ether and 100.0mL of ethanol, slowly dropwise adding 600.0mL of n-hexane, and stirring for 12h. Filtering, leaching the filter cake with 100.0mL of n-hexane, and drying the filter cake in a forced air drying oven at 40 ℃ for 10 hours to obtain 50.9g of white solid with the yield of 60.0% and the liquid chromatography purity of 97.33%.
(3) 50.0g (0.095 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5- ((Z) -2, 3-di (t-butoxycarbonyl) guanidino) -3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula III) are dissolved in 500.0mL of acetonitrile at room temperature and stirred, 15.1g (0.095 mol) of (S) -3- (2-methoxyethoxy) piperidine, 13.5g (0.104 mol) of N, N-diisopropylethylamine, 1.1g (0.95 mmol) of tetrakis (triphenylphosphine) palladium are added and replaced with nitrogen. Heating to 60 ℃, stirring for 4 hours, concentrating under reduced pressure at 45 ℃, adding 500.0mL of methyl tertiary butyl ether into the concentrate, stirring and dissolving, adding 100.0g of 10% sodium bisulfate aqueous solution, stirring for 0.5 hours at room temperature, filtering, standing and separating liquid, concentrating an organic layer under reduced pressure, adding 380.0mL of ethylene glycol dimethyl ether into the concentrate, stirring and dissolving, and dissolving for later use.
(4) 125.0mL of water was added to the solution in step (3), cooled to 15℃with stirring, 116.0mL of a 1mol/L KOH aqueous solution was slowly added dropwise, and the mixture was stirred for 12 hours. 1000.0mL of methylene chloride was added, cooled to 10℃and 2 mol.L of water was added dropwise -1 The pH was adjusted to 5, about 78.0mL, the mixture was allowed to stand, the aqueous layer was extracted with 500.0mL of methylene chloride, the organic layers were combined, concentrated under reduced pressure, 130.0mL of ethyl acetate and 11.5mL of water were added, and the mixture was stirred at room temperature, 130.0mL of n-heptane was added dropwise, and stirring was continued for 8h. The mixture was filtered and the filter cake was rinsed with 146.0mL of n-heptane. The filter cake was dried in a forced air drying oven at 45℃for 8 hours to give 39.2g of a white solid with a yield of 60.0% and a liquid chromatography purity of 99.03%.
(5) The (3R, 4R, 5S) -4-acetamido-5- ((E) -2, 3-di (t-butoxycarbonyl) guanidino) -3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid pentahydrate (structural compound of formula V) obtained in step (4) was dissolved in 105.0mL of water at room temperature, and heated to 70℃and stirred for 5h. 1.0g of active carbon is added, cooled to 25 ℃ and stirred for 0.5h. After filtration, 206.5mL of isopropanol was added to the filtrate, the temperature was raised to 35℃and stirred, 210mL of methyl tert-butyl ether and a small amount of seed crystal were slowly added, stirring was continued for 8 hours, filtration was performed, and the filter cake was rinsed with 87.0mL of methyl tert-butyl ether to obtain 17.2g of a white solid, a yield of 85.0%, and a liquid phase purity of 99.87%.
Example 3
(1) 100g (0.322 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula I) are dissolved in 500.0mL of tetrahydrofuran at room temperature and stirred, 110g (0.420 mol) of triphenylphosphine and 17.4g (0.966 mol) of water are added, and after stirring at 20-30℃for 2h, the temperature is raised to 55℃and stirred for 5h.
(2) The reaction solution obtained in the above step was cooled to 25℃and 120g (0.386 mol) of N, N' -di-BOC-1H-1-guanidinopyrazoles, 125.0g (0.966 mol) of N, N-diisopropylethylamine were added thereto and stirred for 12 hours. Concentrating under reduced pressure, adding 200.0mL of ethylene glycol dimethyl ether and 200.0mL of ethanol, slowly dropwise adding 1200.0mL of n-hexane, and stirring for 12h. Filtering, leaching the filter cake with 200.0mL of n-hexane, and drying the filter cake at 40 ℃ for 10 hours in a forced air drying oven to obtain 122.2g of white solid with a yield of 72.0% and a liquid chromatography purity of 98.87%.
(3) 100.0g (0.19 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5- ((Z) -2, 3-di (t-butoxycarbonyl) guanidino) -3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula III) are dissolved in 500.0mL of acetonitrile at room temperature and stirred, 30.2g (0.19 mol) of (S) -3- (2-methoxyethoxy) piperidine, 27.0g (0.209 mol) of N, N-diisopropylethylamine, 2.2g (1.9 mmol) of tetrakis (triphenylphosphine) palladium are added and replaced with nitrogen. Heating to 60 ℃, stirring for 4 hours, concentrating under reduced pressure at 45 ℃, adding 1000.0mL of methyl tertiary butyl ether into the concentrate, stirring and dissolving, adding 200.0g of 10% sodium bisulfate aqueous solution, stirring for 0.5 hours at room temperature, filtering, standing and separating liquid, concentrating an organic layer under reduced pressure, adding 760.0mL of ethylene glycol dimethyl ether into the concentrate, stirring and dissolving, and dissolving for later use.
(4) 250.0mL of water was added to the solution in step (3), cooled to 15℃and 232.0mL of 1mol/L KOH aqueous solution was slowly added dropwise thereto and stirred for 12 hours. 2000.0mL of dichloromethane was added, the mixture was cooled to 10℃under stirring, a 2mol/L aqueous HCl solution was added dropwise to adjust the pH to 5, about 160.0mL, the mixture was allowed to stand and separated, the aqueous layer was extracted with 1000.0mL of dichloromethane, the organic layers were combined, concentrated under reduced pressure, 260.0mL of ethyl acetate and 23.0mL of water were added, the mixture was stirred at room temperature, 260.0mL of n-heptane was added dropwise, and stirring was continued for 8 hours. The mixture was filtered and the filter cake was rinsed with 292.0mL of n-heptane. The filter cake was dried in a forced air drying oven at 45℃for 8 hours to give 101.9g of a white solid, yield 78.0% and liquid chromatography purity 99.73%.
(5) The (3R, 4R, 5S) -4-acetamido-5- ((E) -2, 3-di (t-butoxycarbonyl) guanidino) -3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid pentahydrate (structural compound of formula V) obtained in step (4) was dissolved in 300.0mL of water at room temperature, and heated to 70℃and stirred for 5h. 2.5g of active carbon is added, cooled to 25 ℃ and stirred for 0.5h. After filtration, 590.0mL of isopropanol was added to the filtrate, the temperature was raised to 35℃and stirred, 600.0mL of methyl tert-butyl ether and a small amount of seed crystal were slowly added, stirring was continued for 8 hours, filtration was performed, and the filter cake was rinsed with 250.0mL of methyl tert-butyl ether to obtain 53.2g of a white solid, a yield of 92.0% and a liquid phase purity of 99.95%.
Example 4
(1) 50g (0.161 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula I) are dissolved in 500.0mL of tetrahydrofuran at room temperature, stirred, 126.8g (0.483 mol) of triphenylphosphine and 29.0g (1.611 mol) of water are added, stirred for 2h at 20-30℃and then heated to 60℃and stirred for 3h.
(2) The reaction solution obtained in the above step was cooled to 25℃and 100.0g (0.322 mol) of N, N' -di-BOC-1H-1-guanidinopyrazoles, 104.1g (0.806 mol) of N, N-diisopropylethylamine were added thereto and stirred for 10 hours. Concentrating under reduced pressure, adding 100.0mL of ethylene glycol dimethyl ether and 100.0mL of ethanol, slowly dropwise adding 600.0mL of n-hexane, and stirring for 10h. Filtering, leaching the filter cake with 100.0mL of n-hexane, and drying the filter cake in a forced air drying oven at 40 ℃ for 10 hours to obtain 55.2g of white solid with the yield of 65.1% and the liquid chromatography purity of 97.33%.
(3) 50.0g (0.095 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5- ((Z) -2, 3-di (t-butoxycarbonyl) guanidino) -3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula III) are dissolved in 500.0mL of acetonitrile at room temperature and stirred, 45.4g (0.285 mol) of (S) -3- (2-methoxyethoxy) piperidine, 24.6g (0.190 mol) of N, N-diisopropylethylamine, 11.0g (9.5 mmol) of tetrakis (triphenylphosphine) palladium are added and replaced with nitrogen. Heating to 60 ℃, stirring for 3 hours, concentrating under reduced pressure at 45 ℃, adding 500.0mL of methyl tertiary butyl ether into the concentrate, stirring and dissolving, adding 100.0g of 10% sodium bisulfate aqueous solution, stirring for 0.5 hours at room temperature, filtering, standing and separating liquid, concentrating an organic layer under reduced pressure, adding 380.0mL of ethylene glycol dimethyl ether into the concentrate, stirring and dissolving, and dissolving for later use.
(4) 125.0mL of water is added into the solution in the step (3), the solution is cooled to below 15 ℃ under stirring, 116.0mL of 1mol/L KOH aqueous solution is slowly added dropwise, and the solution is stirred for 12h. 1000.0mL of dichloromethane was added, the mixture was cooled to 10 ℃, 2mol/L of aqueous HCl was added dropwise to adjust the pH to 5, about 78mL of the mixture was allowed to stand and separated, the aqueous layer was extracted with 500.0mL of dichloromethane, the organic layers were combined, concentrated under reduced pressure, 130.0mL of ethyl acetate and 11.5mL of water were added, and the mixture was stirred at room temperature, 130.0mL of n-heptane was added dropwise, and stirring was continued for 8 hours. The mixture was filtered and the filter cake was rinsed with 146.0mL of n-heptane. The filter cake was dried in a forced air drying oven at 45℃for 8 hours to give 40.5g of a white solid with a yield of 62.0% and a liquid chromatography purity of 98.61%.
(5) The (3R, 4R, 5S) -4-acetamido-5- ((E) -2, 3-di (t-butoxycarbonyl) guanidino) -3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid pentahydrate (structural compound of formula V) obtained in step (4) was dissolved in 120.0mL of water at room temperature, and heated to 70℃and stirred for 5h. 1.0g of active carbon is added, cooled to 25 ℃ and stirred for 0.5h. After filtration, 236.0mL of isopropanol is added into the filtrate, the temperature is raised to 35 ℃ and the mixture is stirred, 240.0mL of methyl tertiary butyl ether and a small amount of seed crystal are slowly added, the mixture is continuously stirred for 8 hours and then is filtered, and the filter cake is leached by 100.0mL of methyl tertiary butyl ether to obtain 20.8g of white solid, the yield is 90.0%, and the liquid phase purity is 99.0%.
Example 5
(1) 50g (0.161 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula I) are dissolved in 500.0mL of tetrahydrofuran at room temperature, stirred, 126.8g (0.483 mol) of triphenylphosphine and 17.4g (0.966 mol) of water are added, stirred for 2h at 20-30℃and then heated to 35℃and stirred for 7h.
(2) The reaction solution obtained in the above step was cooled to 25℃and 100.0g (0.322 mol) of N, N' -di-BOC-1H-1-guanidinopyrazoles, 104.1g (0.806 mol) of N, N-diisopropylethylamine were added thereto and stirred for 15 hours. Concentrating under reduced pressure, adding 100.0mL of ethylene glycol dimethyl ether and 100.0mL of ethanol, slowly dropwise adding 600.0mL of n-hexane, and stirring for 10h. Filtering, leaching the filter cake with 100.0mL of n-hexane, and drying the filter cake in a forced air drying oven at 40 ℃ for 10 hours to obtain 54.2g of white solid with the yield of 63.9% and the liquid chromatography purity of 97.33%.
(3) 50.0g (0.095 mol) of ethyl (3R, 4R, 5S) -4-acetamido-5- ((Z) -2, 3-di (t-butoxycarbonyl) guanidino) -3-acetoxy-1-cyclohexene-1-carboxylate (structural compound of formula III) are dissolved in 500.0mL of acetonitrile at room temperature and stirred, 45.4g (0.285 mol) of (S) -3- (2-methoxyethoxy) piperidine, 36.8g (0.285 mol) of N, N-diisopropylethylamine, 5.5g (4.75 mmol) of tetrakis (triphenylphosphine) palladium are added and replaced with nitrogen. Heating to 60 ℃, stirring for 3 hours, concentrating under reduced pressure at 45 ℃, adding 500.0mL of methyl tertiary butyl ether into the concentrate, stirring and dissolving, adding 100.0g of 10% sodium bisulfate aqueous solution, stirring for 0.5 hours at room temperature, filtering, standing and separating liquid, concentrating an organic layer under reduced pressure, adding 380.0mL of ethylene glycol dimethyl ether into the concentrate, stirring and dissolving, and dissolving for later use.
(4) 125.0mL of water is added into the solution in the step (3), the solution is cooled to below 15 ℃ under stirring, 116.0mL of 1mol/L KOH aqueous solution is slowly added dropwise, and the solution is stirred for 12h. 1000.0mL of dichloromethane was added, the mixture was cooled to 10 ℃, 2mol/L of aqueous HCl was added dropwise to adjust the pH to 5, about 78mL of the mixture was allowed to stand and separated, the aqueous layer was extracted with 500.0mL of dichloromethane, the organic layers were combined, concentrated under reduced pressure, 130.0mL of ethyl acetate and 11.5mL of water were added, and the mixture was stirred at room temperature, 130.0mL of n-heptane was added dropwise, and stirring was continued for 8 hours. The mixture was filtered and the filter cake was rinsed with 146.0mL of n-heptane. The filter cake was dried in a forced air drying oven at 45℃for 8 hours to give 38.5g of a white solid with a yield of 59.0% and a liquid chromatography purity of 97.61%.
(5) The (3R, 4R, 5S) -4-acetamido-5- ((E) -2, 3-di (t-butoxycarbonyl) guanidino) -3- ((S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid pentahydrate (structural compound of formula V) obtained in step (4) was dissolved in 114.0mL of water at room temperature, and the temperature was raised to 70℃and stirred for 5h. 1.0g of active carbon is added, cooled to 25 ℃ and stirred for 0.5h. 224.2mL of isopropanol is added into the filtrate after filtration, the temperature is raised to 35 ℃ and the mixture is stirred, 240.0mL of methyl tertiary butyl ether and a small amount of seed crystal are slowly added, the mixture is continuously stirred for 8 hours and then filtered, and the filter cake is leached by 95.0mL of methyl tertiary butyl ether to obtain 18.8g of white solid, the yield is 81.0%, and the liquid phase purity is 98.0%.
Comparative example 1
The applicant prepared cyclohexene compounds of the structural formula X according to the preparation procedure of (3 r,4r, 5S) -4-acetamido-5-guanidino-3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid trifluoroacetate described in chinese patent (patent application No. 201610814412.8) and example 11, as follows:
(1) Preparation of ethyl (3R, 4S, 5S) -4-acetamido-5-azido-3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylate
According to the above equation, 20mmol of ethyl (3 r,4r, 5S) -4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylate and lmmo1 of tetrakis triphenylphosphine palladium were placed in a dry two-port flask, after displacing the air in the system twice with nitrogen, 40mL of redistilled DMF (dimethylformamide) was added with a syringe and stirred evenly, 40mmo1 of DIPEA (N, N-diisopropylethylamine) was added and stirred and cooled to 0 ℃, a solution of DMF (40 mL) of (3S) -3- (2-methoxyethoxy) piperidine trifluoroacetate was slowly added dropwise, stirring was continued for 20 minutes at 0 ℃ after the addition was completed, and the reaction was carried out for 1 hour in an oil bath at 70 ℃, thin layer chromatography TLC (DCM: meoh=10:1, i.e. dichloromethane: methanol=10:1) showed complete reaction, water was slowly added dropwise to 0 ℃, EA (ethyl acetate) was extracted evenly after stirring evenly, and DMF was obtained as brown viscous product by oil pumping. Column purification (MeOH: dcm=1:50) afforded 3.8g of a yellow-white powder solid in 46.4% yield.
(2) Preparation of ethyl (3R, 4R, 5S) -4-acetamido-5-amino-3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexen-1-carboxylate
According to the above reaction scheme, (3R, 4S, 5S) -4-acetamido-5-azido-3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexane-1-carboxylic acid ethyl ester was placed in a single port flask, after adding catalytic amount of Raney nickel, 40mL absolute ethanol and stirring well, the system air was replaced with hydrogen and stirred at room temperature for 2 hours, TLC (DCM: meOH=10:1) showed completion of the reaction, the Raney nickel was filtered off with celite and the solvent was evaporated off, column purification (DCM: meOH=5:1) afforded 2.85g as a white foamy solid with a yield of 75.0%.
(3) Preparation of ethyl (3R, 4R, 5S) -4-acetamido-5- (2, 3-di (t-butoxycarbonyl) guanidino) -3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexanecene-1-carboxylate
According to the above equation, 0.5 mmol 1 of (3R, 4R, 5S) -4-acetamido-5-amino-3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexane-1-carboxylate is placed in a single-necked flask, after adding 10mL acetonitrile and stirring uniformly at room temperature, 1.5mmol DIPEA and 0.5 mmol 1N, N' -di-BOC-1H-1-guanidinopyrazoles are added, stirring continuously at room temperature for 3H, TLC (PE: EA=1:1) shows that the reaction is complete, 20mL water is added, EA extraction, dried over anhydrous sodium sulfate and evaporated to dryness, column purification (PE: EA=3:1) gives 0.23g as a white solid with a yield of 70.0%.
(4) Preparation of (3R, 4R, 5S) -4-acetamido-5- (2, 3-di (t-butoxycarbonyl) guanidino) -3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid
0.368mmol of ethyl (3R, 4R, 5S) -4-acetamido-5- (2, 3-di (t-butoxycarbonyl) guanidino) -3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylate is placed in a single vial, 5.5mL of 1, 4-dioxane and 0.55mL of water, 0.55mL of 1N KOH aqueous solution are added and stirred at room temperature overnight. TLC (PE: ea=1:1) showed the reaction was complete, the solvent was evaporated, pumped down with oil pump and dissolved in 5mL of methanol, ph=5 was adjusted with acid resin, filtered and evaporated to dryness column purified, DCM: meoh=10:1 eluted to give 1.65g of white solid with a yield of 75.0%.
(5) Preparation of (3R, 4R, 5S) -4-acetamido-5-guanidino-3- ((3S) -3- (2-methoxyethoxy) piperidine) -1-cyclohexene-1-carboxylic acid trifluoroacetate salt (Compound of formula X)
0.8g of (3R, 4R, 5S) -4-acetamido-5- (2, 3-di (t-butoxycarbonyl) guanidino) -3- (3S) -3- (2-methoxy) ethoxy) piperidine) -1-cyclohexane-1-carboxylic acid was placed in a single vial, 50% TFA in DCM was added, stirring at room temperature for 1h, TLC (DCM: meOH=10:1) showed completion of the reaction, the solvent was evaporated off, the oil pump was pumping off the excess TFA, ether was added to slurry, and thin layer chromatography was filtered (DCM: meoh=10: 1) The reaction was shown to be complete, the solvent was evaporated, the oil pump was pumping excess TFA, ether was added to slurry, and filtration gave 0.66g of a white solid product with a yield of 80.0%.
The foregoing is directed to embodiments of the present invention and is not intended to limit the scope of the invention, but rather to cover all modifications and variations within the scope of the present invention.
Claims (21)
1. The preparation method of the cyclohexene compound is characterized in that the cyclohexene compound has a structure shown in a formula F, and the synthetic route comprises the following steps:
(1) The compound with the structure of the formula A is subjected to azide reduction reaction to obtain a compound with the structure of the formula B;
(2) The structural compound of the formula B is subjected to nucleophilic substitution reaction to obtain a structural compound of the formula C;
(3) Tsuji-Trost reaction is carried out on the structural compound of the formula C to obtain a structural compound of the formula D;
(4) Hydrolyzing the structural compound of the formula D, and removing a Boc group of the t-butyloxycarbonyl group to obtain a structural compound of the formula F;
wherein R in the structural compound of formula A, the structural compound of formula B, the structural compound of formula C and the structural compound of formula D 1 Selected from alkyl groups containing 1 to 10 carbon atoms;
r in the structural compound of the formula A, the structural compound of the formula B and the structural compound of the formula C 2 Selected from alkyl groups containing 1 to 10 carbon atoms;
r in the structural compound of the formula A, the structural compound of the formula B, the structural compound of the formula C, the structural compound of the formula D and the structural compound of the formula F 3 Is selected from the group consisting ofAlkyl groups of 1 to 10 carbon atoms.
2. The method for producing cyclohexene compound according to claim 1, wherein R in the structural compound of formula A, the structural compound of formula B, the structural compound of formula C and the structural compound of formula D 1 Selected from methyl, ethyl, propyl or isopropyl;
r in the structural compound of the formula A, the structural compound of the formula B and the structural compound of the formula C 2 Selected from methyl, ethyl, propyl or isopropyl;
r in the structural compound of the formula A, the structural compound of the formula B, the structural compound of the formula C, the structural compound of the formula D and the structural compound of the formula F 3 Selected from methyl, ethyl, propyl or isopropyl.
3. The method for producing cyclohexene compound according to claim 1 or 2, wherein in the step (1), the catalyst reducing agent for the azide reduction reaction is selected from palladium-carbon, palladium-barium sulfate, platinum dioxide, raney nickel, lithium aluminum hydride, sodium borohydride or triphenylphosphine;
preferably, the catalytic reducing agent is selected from raney nickel or triphenylphosphine;
more preferably, the molar ratio of the catalytic reducing agent to the compound of formula A is (1-3): 1.
4. The process for producing cyclohexene compound according to claim 3, wherein in the azide reduction reaction in the step (1), water is added in addition to the catalytic reducing agent; wherein the molar ratio of water to the compound of formula A is (3-10): 1.
5. The process for producing cyclohexene compound according to any one of claims 1 to 4, wherein in the step (1), the reaction solvent is one or more selected from the group consisting of tetrahydrofuran, acetonitrile, N-dimethylformamide, methylene chloride and toluene;
preferably, the reaction solvent is selected from acetonitrile or tetrahydrofuran;
more preferably, the concentration of the compound of formula A in the reaction solvent is from 0.1 to 0.2g/mL.
6. The process for producing cyclohexene compound according to any one of claims 1 to 5, wherein in step (1), the compound of the formula A, the catalytic reducing agent and water are dispersed in a solvent and reacted at 20 to 30℃for 1 to 3 hours; then heating to 35-80 ℃, preferably 35-60 ℃ and reacting for 3-7 h.
7. The process for producing cyclohexene compound according to any one of claims 1 to 6, wherein in the step (2), the first basic reagent and N, N-di-t-butoxycarbonyl-1H-1-guanidinopyrazoles are added to the solution obtained in the step (1), and after the reaction, the solution is concentrated and the crystallization reagent is added to precipitate the compound of the formula C;
preferably, in the step (2), the crystallization reagent is a mixed system of ethylene glycol dimethyl ether, ethanol and n-hexane;
Preferably, the reaction temperature of the step (2) is 20-30 ℃;
and/or the reaction time of the step (2) is 10-15 h.
8. The process for producing a cyclohexene compound according to claim 7, wherein in the step (2), the amount of N, N-di-t-butoxycarbonyl-1H-1-guanidinopyrazoles is determined based on the molar ratio of (1 to 2): 1, which is the molar ratio of the amount of the compound of the formula A to the amount of the compound of the formula A in the step (1).
9. The method for producing cyclohexene compound according to claim 7 or 8, wherein in the step (2), the first basic reagent is one or more selected from the group consisting of N-methylmorpholine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, N-diisopropylmethylamine, pyridine, triethylenediamine and aqueous ammonia;
preferably, the first basic agent is N, N-diisopropylethylamine;
more preferably, the amount of the first alkaline agent is determined based on the molar ratio of the first alkaline agent to the amount of the compound of formula A in the initial reaction in step (1) of (2 to 5): 1.
10. The method for producing a cyclohexene compound according to any one of claims 1 to 9, wherein, in the step (3), the compound of the formula D is produced after the completion of the reaction by adding (S) -3- (2-methoxyethoxy) piperidine, a second basic agent, a palladium catalyst and a solvent to the compound of the formula C;
Preferably, in the step (3), the reaction temperature is 40-90 ℃;
more preferably, the reaction temperature is 60 to 70 ℃;
and/or the reaction time is 3-7 h.
11. The process for producing cyclohexene compound according to claim 10, wherein in the step (3), the molar ratio of (S) -3- (2-methoxyethoxy) piperidine to the compound of the formula C is (1-3): 1.
12. The process for producing cyclohexene compound according to claim 10 or 11, wherein in the step (3), the second basic reagent is one or more selected from the group consisting of N-methylmorpholine, triethylamine, 4-dimethylaminopyridine, N-diisopropylethylamine, N-diisopropylmethylamine, pyridine, triethylenediamine and aqueous ammonia;
preferably, the second alkaline agent is selected from N, N-diisopropylethylamine;
more preferably, the molar ratio of the second basic agent to the compound of formula C is (1-3): 1.
13. The method for producing cyclohexene-based compound according to any one of claims 9 to 12, wherein in the step (3), the palladium catalyst is selected from palladium acetate, diphenylphosphino ferrocene palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, palladium trifluoroacetate or palladium pivalate;
Preferably, the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium;
more preferably, the molar ratio of the palladium catalyst to the compound of formula C in step (3) is (0.01 to 0.1): 1.
14. The process for producing cyclohexene compound according to any one of claims 9 to 12, wherein in the step (3), the solvent is selected from acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane, toluene, diethyl ether and methyl tert-butyl ether;
preferably, the solvent is selected from acetonitrile;
more preferably, the molar concentration of the compound of formula C in the solvent is from 0.1 to 0.2g/mL.
15. The method for producing a cyclohexene compound according to any one of claims 1 to 14, wherein the step (4) comprises the following reaction steps:
wherein R in the structural compound of formula E 3 Selected from alkyl groups containing 1 to 10 carbon atoms, preferably methyl, ethyl, propyl or isopropyl;
wherein, the step (4) comprises the following steps:
(4a) Carrying out saponification reaction on a structural compound of a formula D to obtain a structural compound of a formula E;
(4b) Removing the Boc protecting group of the tert-butyloxycarbonyl group from the compound of the formula E to obtain the compound of the formula F.
16. The method for producing cyclohexene compound according to claim 15, wherein in the step (4 a), the reaction temperature is 0 to 25 ℃;
More preferably, the reaction temperature is 10 to 25 ℃.
17. The process for producing cyclohexene compound according to claim 15 or 16, wherein step (4 a) further comprises the step of adjusting the pH of the solution after completion of the saponification reaction to 4 to 5, concentrating, and adding a crystallization reagent to precipitate the compound of the formula E;
preferably, the crystallization reagent in the step (4 a) is one or more selected from ethylene glycol dimethyl ether, ethanol, N-hexane, ethyl acetate, methanol, ethanol, methyl tertiary butyl ether, acetonitrile, tetrahydrofuran, N-dimethylformamide, dichloromethane, toluene, diethyl ether, N-heptane and acetone;
preferably, the crystallization reagent in the step (4 a) is a mixed system of ethyl acetate, water and n-heptane.
18. The process for producing cyclohexene compound according to any one of claims 15 to 17, wherein in the step (4 b), the compound of the formula E is dissolved in water, the temperature is adjusted to 50 to 100 ℃, preferably 60 to 80 ℃, and the Boc protecting group is removed to obtain the compound of the formula F;
and/or, the step (4 b) further comprises the steps of adding active carbon after the reaction is finished, cooling, separating, and adding a crystallization reagent into the filtrate to precipitate the structural compound of the formula F;
Preferably, in step (4 b), the crystallization reagent is a mixed system of isopropanol and methyl tert-butyl ether.
19. Cyclohexene compound, characterized in that it is prepared by the preparation method of cyclohexene compound according to any one of claims 1 to 18.
20. Use of a cyclohexaene compound of claim 19 or a pharmaceutically acceptable salt, ester-based prodrug or stereoisomer thereof in the preparation of a medicament for the prophylaxis and treatment of influenza.
21. A pharmaceutical composition comprising a cyclohexaene compound of claim 19 or a pharmaceutically acceptable salt thereof, and an ester-based prodrug or stereoisomer thereof, and a pharmaceutically acceptable adjuvant or carrier.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001028981A1 (en) * | 1999-10-19 | 2001-04-26 | Abbott Laboratories | 1-cyclohexene-1-carboxylic acid and 1-cyclohexene-1-carboxylates as neuraminidase inhibitors |
| CN106496100A (en) * | 2016-09-09 | 2017-03-15 | 广州市恒诺康医药科技有限公司 | Cyclohexene compound and application thereof |
| CN107325040A (en) * | 2016-04-28 | 2017-11-07 | 广州市恒诺康医药科技有限公司 | Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001028981A1 (en) * | 1999-10-19 | 2001-04-26 | Abbott Laboratories | 1-cyclohexene-1-carboxylic acid and 1-cyclohexene-1-carboxylates as neuraminidase inhibitors |
| CN107325040A (en) * | 2016-04-28 | 2017-11-07 | 广州市恒诺康医药科技有限公司 | Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof |
| CN106496100A (en) * | 2016-09-09 | 2017-03-15 | 广州市恒诺康医药科技有限公司 | Cyclohexene compound and application thereof |
| WO2018045950A1 (en) * | 2016-09-09 | 2018-03-15 | 广州市恒诺康医药科技有限公司 | Cyclohexene compounds and use thereof |
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