CN115894483A - Intermediate and method for preparing pyrroloquinoline quinone - Google Patents
Intermediate and method for preparing pyrroloquinoline quinone Download PDFInfo
- Publication number
- CN115894483A CN115894483A CN202211415318.7A CN202211415318A CN115894483A CN 115894483 A CN115894483 A CN 115894483A CN 202211415318 A CN202211415318 A CN 202211415318A CN 115894483 A CN115894483 A CN 115894483A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- quinoline
- reaction
- pyrrolo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- MMXZSJMASHPLLR-UHFFFAOYSA-N pyrroloquinoline quinone Chemical compound C12=C(C(O)=O)C=C(C(O)=O)N=C2C(=O)C(=O)C2=C1NC(C(=O)O)=C2 MMXZSJMASHPLLR-UHFFFAOYSA-N 0.000 title claims abstract description 122
- 238000000034 method Methods 0.000 title claims abstract description 68
- 150000001875 compounds Chemical class 0.000 claims abstract description 248
- 238000006243 chemical reaction Methods 0.000 claims abstract description 195
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007858 starting material Substances 0.000 claims abstract description 15
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 15
- 230000001590 oxidative effect Effects 0.000 claims abstract description 14
- 238000006783 Fischer indole synthesis reaction Methods 0.000 claims abstract description 13
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 83
- -1 2-methyl ethyl Chemical group 0.000 claims description 67
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- MVOQKDHLANYMDU-UHFFFAOYSA-N O(C)C1=C2C=C(C(=O)O)NC2=C2C(C(=O)O)=CC(C(=O)O)=NC2=C1OC Chemical compound O(C)C1=C2C=C(C(=O)O)NC2=C2C(C(=O)O)=CC(C(=O)O)=NC2=C1OC MVOQKDHLANYMDU-UHFFFAOYSA-N 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- FNENWZWNOPCZGK-UHFFFAOYSA-N ethyl 2-methyl-3-oxobutanoate Chemical compound CCOC(=O)C(C)C(C)=O FNENWZWNOPCZGK-UHFFFAOYSA-N 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 238000006193 diazotization reaction Methods 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 abstract description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 239000011343 solid material Substances 0.000 description 46
- 238000000967 suction filtration Methods 0.000 description 38
- 239000000543 intermediate Substances 0.000 description 37
- 238000003756 stirring Methods 0.000 description 36
- 238000001816 cooling Methods 0.000 description 35
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 238000001035 drying Methods 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000463 material Substances 0.000 description 19
- 238000005406 washing Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- SJLUBPYBSAERDO-UHFFFAOYSA-N 3,4-dimethoxy-5-nitroaniline Chemical compound COC1=CC(N)=CC([N+]([O-])=O)=C1OC SJLUBPYBSAERDO-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- 239000011592 zinc chloride Substances 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- PBAWBCCUXJMEOI-UHFFFAOYSA-N 3,4-dimethoxy-5-nitrobenzamide Chemical compound COC1=CC(C(N)=O)=CC([N+]([O-])=O)=C1OC PBAWBCCUXJMEOI-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000006257 total synthesis reaction Methods 0.000 description 4
- GQNSKXYALDGGGN-UHFFFAOYSA-N 3,4-dimethoxy-5-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=CC([N+]([O-])=O)=C1OC GQNSKXYALDGGGN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 229940071870 hydroiodic acid Drugs 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- PVSHESSHBKMOKY-UHFFFAOYSA-N O(C)C1=C2C=C(C(=O)OCC)NC2=C2C(C(=O)OCC)=CC(C(=O)OCC)=NC2=C1OC Chemical compound O(C)C1=C2C=C(C(=O)OCC)NC2=C2C(C(=O)OCC)=CC(C(=O)OCC)=NC2=C1OC PVSHESSHBKMOKY-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- GCXJINGJZAOJHR-UHFFFAOYSA-N 2-methylacetoacetic acid Chemical compound CC(=O)C(C)C(O)=O GCXJINGJZAOJHR-UHFFFAOYSA-N 0.000 description 1
- IFYQITBEOBQUMC-UHFFFAOYSA-N 4,5-dioxo-1h-pyrrolo[2,3-f]quinoline-7,9-dicarboxylic acid Chemical compound O=C1C(=O)C2=NC(C(=O)O)=CC(C(O)=O)=C2C2=C1C=CN2 IFYQITBEOBQUMC-UHFFFAOYSA-N 0.000 description 1
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 1
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RUSDNXRPHQQECR-UHFFFAOYSA-N COC=1NC2=C3C(C=CC2=CC=1)=NC=C3 Chemical compound COC=1NC2=C3C(C=CC2=CC=1)=NC=C3 RUSDNXRPHQQECR-UHFFFAOYSA-N 0.000 description 1
- 150000000703 Cerium Chemical class 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- SBWGWYHMIZRBPQ-UHFFFAOYSA-N N-(5-amino-3-bromo-2-methoxyphenyl)acetamide Chemical compound O(C)C1=C(C=C(C=C1Br)N)NC(=O)C SBWGWYHMIZRBPQ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- AMBZDHXNCVCBRQ-ONEGZZNKSA-N dimethyl (e)-4-oxopent-2-enedioate Chemical compound COC(=O)\C=C\C(=O)C(=O)OC AMBZDHXNCVCBRQ-ONEGZZNKSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-M quinaldate Chemical compound C1=CC=CC2=NC(C(=O)[O-])=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-M 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/76—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The application provides an intermediate and a method for preparing pyrroloquinoline quinone, wherein the method comprises the following steps: preparing a compound of formula III by Fischer indole synthesis using a compound of formula II as a starting material, hydrolyzing the compound of formula III to prepare a compound of formula IV, oxidizing the compound of formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] pyrrole]Quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 Is C 1 ‑C 3 A linear or branched alkyl group; r is 3 Selected from hydrogen and C 1 ‑C 3 Straight or branched chain alkyl. The method has the advantages of simplicity, high yield, mild reaction conditionsThe method is simple to operate, the production period is obviously shortened, the method is easy to amplify, the production scale can reach the level of hectogram, and large-scale production can be realized.
Description
Technical Field
The application relates to the field of organic compound preparation, in particular to an intermediate and a method for preparing pyrroloquinoline quinone.
Background
The information disclosed in the background of the application is intended to enhance an understanding of the general background of the application and should not necessarily be taken as an acknowledgement or any form of suggestion that the information is already prior art to a person of ordinary skill in the art.
4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, also known as pyrroloquinoline quinone (PQQ), CAS number 72909-34-3, is a natural product. PQQ is widely found in various common foods such as fruits, vegetables, grains, and drinks, including foods of plant origin and foods of animal origin. However, the available concentrations of PQQ in food sources are very low, only at levels ranging from nanograms to micrograms per kilogram. Therefore, sufficient PQQ is not obtained by dietary supplementation alone, and chemical synthesis of PQQ becomes inevitable.
Corey et al, for the first time, have achieved total synthesis of PQQ, referred to as the Corey method, see Corey E J, tracutano A. Total synthesis of the quinoid alcohol dehydrogenase enzyme (1) of the heterologous bacteria [ J ]. Journal of the American Chemical Society,1981,103 (18): 5599-5600. According to Corey, PQQ can be prepared by total synthesis from commercial raw materials through a 10-step chemical process. Martin et al subsequently improved the route to the Corey method, reducing its total synthesis steps to 9 steps, called Martin method for short, see Martin P, steiner E, auer K, et al Zur Herstellung von PQQ in kg-Mengen [ J ]. Helvetica chimica acta,1993,76 (4): 1667-1673. In 2006, kempf et al synthesized PQQ on a large scale by a route combining the Corey method and the Martin method, abbreviated as Kempf method, see WO2006/102642A1. Both the Corey method and the Martin method have difficulty in the preparation of PQQ on a gram scale, wherein the Corey method can only obtain PQQ on a 50mg scale, the method is suitable for laboratory preparation and difficult to be applied industrially, although the synthesis steps of the Martin method are reduced compared with those of the Corey method, the overall process route is very similar, the synthesis scale is not obviously improved, and particularly, a complicated two-stage separation process is required in the last step of the synthesis. While the Kempf process enables gram-scale production of PQQ, it further requires purification of the final compound with sulfuric acid, and the multiple steps involve separation work of intermediates, a cumbersome process. In 2014, ANTHEM bioscience PVT company provided a PQQ synthesis method, see patent WO2014/195896, which is different in that PQQ is synthesized on a large scale by using methyl halobenzene as a raw material, but in the method and the existing route involving complete chemical synthesis of PQQ, a methoxy-pyrroloquinoline intermediate must be mildly oxidized to a pyrroloquinoline quinone intermediate through Cerium Ammonium Nitrate (CAN) in the later reaction stage. Although the process has high product selectivity, the consumption of ammonium cerium nitrate is extremely large (generally more than 8 times of the mass consumption of raw materials), and the final separation and purification are difficult, so that the optimal yield of the step is only about 60%. In addition, ammonium cerium nitrate is expensive, which results in high overall synthesis cost of PQQ, and cerium salt can only be treated as waste, resulting in high pollution discharge pressure. In addition, since the process is inefficient, it is difficult to efficiently and industrially produce PQQ.
Disclosure of Invention
Intermediates and methods for preparing pyrroloquinoline quinone are provided. The intermediate is used for preparing pyrroloquinoline quinone, the reaction route is simple, the reaction yield is high, the purity is good, the reaction condition is mild, the reaction raw materials are cheap and easy to obtain, the reaction cost can be greatly reduced, the reaction route can be controlled within 6 steps, the reaction route is greatly simplified, the reaction efficiency is improved, the production period is obviously shortened, the method is easy to amplify, the production scale can reach the hundred gram level, and the large-scale production can be realized.
Specifically, the present application provides the following technical solutions:
in a first aspect of the present application, there is provided a compound of formula I and formula II, having the structural formula:
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 2 Is nitro or amino; r 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
Further, the compounds described herein have the structure shown below:
wherein R is 1 、R 2 And R 3 As defined hereinabove.
In some embodiments of the present application, R 1 Preferably methyl or ethyl.
In some embodiments of the present application, R 3 Preferably hydrogen, methyl, ethyl or propyl.
In a second aspect of the present application, there is provided the use of a compound of formula I, a compound of formula II or a compound of formula X as an intermediate in the preparation of 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (also known as pyrroloquinoline quinone, PQQ or methoxatin);
wherein R is 1 、R 2 And R 3 As defined hereinbefore.
As an example, the compounds that can be used as intermediates in the preparation of pyrroloquinoline quinone according to the above first aspect are selected from the following structures:
3, 4-dimethoxy-5-nitroaniline;
3, 4-diethoxy-5-nitroaniline;
(Z) -ethyl 2- (2- (3, 4-dimethoxy-5-nitrophenyl) hydrazino) propionate (Compound I-1, R) 1 Is methyl, R 2 Is nitro);
(Z) -ethyl 2- (2- (3, 4-diethoxy-5-nitrophenyl) hydrazino) propionate (Compound I-1-2, R) 1 Is ethyl, R 2 Is nitro);
(Z) -ethyl 2- (2- (3-amino-4, 5-dimethoxyphenyl) hydrazino) propionate (Compound I-2-1, R) 1 Is methyl, R 2 Is amino);
(Z) -ethyl 2- (2- (3-amino-4, 5-diethoxyphenyl) hydrazino) propionate (Compound I-2, R) 1 Is methyl, R 2 Is an amino group);
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-1, R) 1 Is methyl, R 3 Is hydrogen);
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-2, R) 1 Is methyl, R 3 Is methyl);
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-1-3, R 1 Is methyl, R 3 Is ethyl);
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-1-4, R) 1 Is methyl, R 3 Is propyl);
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid (Compound II-2-1, R) 1 Is ethyl, R 3 Is hydrogen);
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-2, R 1 Is ethyl, R 3 Is methyl);
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-2-3, R 1 Is ethyl, R 3 Is ethyl)；
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-2-4, R) 1 Is ethyl, R 3 Is propyl).
Particularly, when the compound is used for preparing pyrroloquinoline quinone, the reaction yield is high, the purity is good, the reaction is simple, the condition is mild, the reaction route can be realized only by 6 steps, the reaction method is greatly simplified, the reaction efficiency is improved, the reaction raw materials are cheap and easy to obtain, the reaction cost is greatly reduced, and the preparation of pyrroloquinoline quinone by the intermediate compound is easy to amplify and can be used for large-scale production.
In a third aspect of the present application, there is provided a method of making 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, the method comprising: preparing a compound of formula III from a compound of formula II by a Fischer indole synthesis method, hydrolyzing the compound of formula III to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 、R 3 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 3 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the present application, the compound of formula II may be prepared by reacting a compound of formula I-2 with a compound of formula V under Lewis acid catalysis,
wherein R is 1 、R 3 As defined hereinabove.
Preferably, R 1 Is methyl or ethyl, R 3 Selected from hydrogen, methyl, ethyl and propyl.
In a fourth aspect of the present application, there is provided a method of preparing 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, the method comprising: preparing a compound shown in formula II by a compound shown in formula I-2 and a compound shown in formula V under the catalysis of Lewis acid, preparing a compound shown in formula III by a Fischer indole synthesis method by using the compound shown in formula II, hydrolyzing the compound shown in formula III to prepare a compound shown in formula IV, and oxidizing the compound shown in formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 、R 3 As defined above.
Preferably, R 1 Is methyl or ethyl, R 3 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the present application, the compound of formula I-2 may be prepared by reducing a compound of formula I-1.
In a fifth aspect of the present application, there is provided a method of making a 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, said method comprising: reducing a compound of formula I-1 to prepare a compound of formula I-2, then reacting the compound of formula I-2 with a compound of formula V under the catalysis of a Lewis acid to prepare a compound of formula II, then preparing a compound of formula III from the compound of formula II by a Fischer indole synthesis method, then hydrolyzing the compound of formula III to prepare a compound of formula IV, and finally oxidizing the compound of formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 、R 3 As defined above.
Preferably, R 1 Is methyl or ethyl, R 3 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the present application, the compounds of formula I-1 may be prepared by diazotization of a 3, 4-dialkoxy-5-nitroaniline, such as a compound of formula X, followed by condensation with ethyl 2-methylacetoacetate, wherein R is 1 As defined hereinbefore.
In a sixth aspect of the present application, there is provided a method of making 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, the method comprising: 3, 4-dialkoxy-5-nitroaniline (compound of formula X) is diazotized and condensed with 2-methyl ethyl acetoacetate to prepare a compound of formula I-1, the compound of formula I-1 is reduced to prepare a compound of formula I-2, then the compound of formula I-2 and a compound of formula V are catalyzed by Lewis acid to prepare a compound of formula II, then the compound of formula II is prepared into a compound of formula III by a Fischer indole synthesis method, then the compound of formula III is hydrolyzed to prepare a compound of formula IV, and finally the compound of formula IV is oxidized to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 、R 3 As defined above.
Preferably, R 1 Is methyl or ethyl, R 3 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the present application, the 3, 4-dialkoxy-5-nitroaniline (compound of formula X) can be prepared starting from 3, 4-dialkoxy-5-nitrobenzoic acid or 3, 4-dialkoxy-5-nitrobenzamide, where R is 1 As defined hereinabove.
In one embodiment of the present application, the last oxidation step in the above preparation process, i.e., the step of oxidizing the compound of formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, may be a direct oxidation or comprise: the compound of formula IV is reacted with protonic acid to produce 2- (ethoxycarbonyl) -4, 5-dihydroxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid, which is then oxidized with an oxidizing agent to produce 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid.
In embodiments herein, the protic acid may be hydrobromic acid, hydroiodic acid, or hydrochloric acid. The oxidant can be hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid or ozone.
Compared with the prior art, the method has the advantages that: when the intermediate is used for preparing pyrroloquinoline quinone, the reaction route is simple, the reaction yield is high (the single step yield is over 75 percent, the total yield is obviously improved), the purity is good, the reaction condition is mild, the reaction raw materials are cheap and easy to obtain, the reaction cost can be greatly reduced, the reaction route can be controlled within 6 steps, the reaction route is greatly simplified, the reaction efficiency is improved, the reaction period is shortened, the method is easy to amplify, the production scale can reach the hundred gram level, and the large-scale production can be realized.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application. Embodiments of the present application are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a hydrogen spectrum of an exemplary compound of formula I-1.
FIG. 2 is a carbon spectrum of an exemplary compound of formula I-1.
FIG. 3 is a hydrogen spectrum of an exemplary compound of formula I-2.
FIG. 4 is a carbon spectrum of an exemplary compound of formula I-2.
Detailed Description
The present application is further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present application. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present application can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present application can be used in the conventional manner in the art or in the product specification. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred embodiments and materials described herein are intended to be exemplary only.
The present application provides compounds of formula I and formula II and methods for their preparation, as well as methods for preparing 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid using compounds of formula I, compounds of formula II, and/or compounds of formula X as intermediates.
In some embodiments of the present application, the process for preparing pyrroloquinoline quinone using formula II as an intermediate can be performed according to the following reaction scheme:
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
In a more preferred embodiment of the present application, R 1 Is methyl or ethyl, R 3 Is methyl, ethyl or propyl.
In the reaction route of the application, when the compound of the formula II is used as an intermediate for Fischer indole synthesis, quinoline in the structure can play a role in occupying space so as to improve the selectivity of the indole synthesis, avoid the generation of unnecessary side reaction substances, greatly improve the synthesis efficiency and yield and reduce the subsequent complicated purification work.
In some embodiments of the present application, the method for preparing pyrroloquinoline quinone using formula I as an intermediate (formula I-2) can be performed according to the following reaction scheme:
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 2 Is amino, R 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
In a more preferred embodiment of the present application, R 1 Is methyl or ethyl, R 3 Is methyl, ethyl or propyl.
Wherein, further, the reaction route can be:
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
In a more preferred embodiment of the present application, R 1 Is methyl or ethyl, R 3 Is methyl, ethyl or propyl.
In the reaction route, when the compound of formula I is used as an intermediate for preparing pyrroloquinoline quinone, a quinoline structure is firstly synthesized, and then Fischer indole synthesis is carried out, so that the indole synthesis selectivity is improved through quinoline occupation, unnecessary side reaction substances are avoided, the synthesis efficiency and yield are greatly improved, and the subsequent complicated purification work is reduced.
In some embodiments herein, the process for preparing pyrroloquinoline quinone from a 3,4-dialkoxy-5-nitroaniline compound (compound of formula X) can be carried out according to the following reaction scheme:
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
In a more preferred embodiment of the present application, R 1 Is methyl or ethylRadical, R 3 Is methyl, ethyl or propyl.
In the reaction route of the application, a 3, 4-dialkoxy-5-nitroaniline compound (a compound shown in a formula X) is used as an intermediate, a quinoline structure is synthesized firstly when pyrroloquinoline quinone is prepared, then Fischer indole synthesis is carried out, indole synthesis selectivity is improved through quinoline occupation, unnecessary side reaction substances are avoided, synthesis efficiency and yield are greatly improved, and subsequent complicated purification work is reduced.
In some embodiments of the present application, the last step of the above-mentioned reactions is an oxidation reaction, which may be performed in one step or according to the following reaction scheme:
for example, in a more specific embodiment, the method for preparing pyrroloquinoline quinone comprises:
(1) Diazotizing a compound 3, 4-dialkoxy-5-nitroaniline (a compound shown in a formula X) and a sodium nitrite solution under an acidic condition, and then condensing the diazotized compound and 2-methyl ethyl acetoacetate under an alkaline condition to form a compound shown in a formula I-1;
in some embodiments of the present application, the molar ratio of the compound of formula X to ethyl 2-methylacetoacetate is 1 to 5.
In some embodiments herein, the reaction stage temperature of step (1) is controlled at-10 ℃ to 0 ℃.
For example, in some embodiments of the present application, step (1) comprises: absolute ethyl alcohol is used as a solvent to be stirred and mixed with the compound of the formula X, the temperature of a reaction system is reduced to minus 10 ℃ to 0 ℃, acid (such as concentrated hydrochloric acid or concentrated sulfuric acid) is added, the temperature of the reaction system is kept at minus 10 ℃ to 0 ℃, sodium nitrite is added, stirring is carried out at minus 10 ℃ to 0 ℃, 2-methyl ethyl acetoacetate is added, sodium acetate is added, and heat preservation stirring reaction is carried out at minus 10 ℃ to 0 ℃.
(2) The compound of the formula I-1 is subjected to a reduction reaction under the action of a reducing agent to prepare a compound of the formula I-2;
in some embodiments of the present application, the compound of formula I-1 is reduced with a reducing agent such as iron powder in an acetic acid solution at a temperature controlled between 60 ℃ and 80 ℃.
(3) Reacting the compound shown in the formula I-2 with a compound shown in the formula V under the catalysis of Lewis acid in an oxygen atmosphere to obtain a compound shown in the formula II;
in some embodiments of the present application, the molar ratio of compound of formula I-2 to compound of formula V is 1 to 5.
For example, in some embodiments of the present application, step (3) comprises: after the compound of formula I-2 and a solvent (e.g., dichloromethane) are stirred uniformly, the compound of formula V and a Lewis acid (e.g., zinc chloride) are added thereto and the reaction is stirred at room temperature.
(4) Preparing a compound shown in the formula III from the compound shown in the formula II by a Fischer indole synthesis method;
in some embodiments herein, the reaction temperature is controlled at 30-55 ℃.
For example, in some embodiments of the present application, step (4) includes: and (3) stirring the excessive sulfuric acid and the compound II uniformly, heating the reaction system to 30-55 ℃, and stirring for reaction.
(5) Carrying out ester hydrolysis reaction on the compound of the formula III to obtain a compound of a formula IV;
in some embodiments herein, the ester hydrolysis reaction occurs in an alkaline environment, with the temperature controlled at 80-90 ℃.
(6) Oxidizing the compound of formula IV to obtain PQQ, or preparing an intermediate F from the compound of formula IV and oxidizing to obtain PQQ;
for example, intermediate E can be prepared by reacting with a protonic acid, which can be hydrobromic acid, hydrochloric acid or hydroiodic acid, preferably hydroiodic acid, to give intermediate F; for example, the oxidation may be performed by using an oxidant, and the oxidant may be one or more selected from hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid, and ozone, and is preferably hydrogen peroxide.
It should be confirmed that the most important part of the present application is the design of intermediates and experimental routes to obtain the target product PQQ with intermediates. The operation of adjusting or changing the reaction environment and reaction parameters based on the intermediates disclosed in the present application and the routes designed based on the intermediates is the basic operation skill of those skilled in the art, and does not substantially constitute an improvement of the technical solution described in the present application, and all of them should be included in the protection scope of the present application.
Specifically, in combination with the above reaction scheme, the following preparation examples are given herein.
Unless otherwise stated, the room temperature in the experiments of the present application means 20-25 ℃.
Wherein, the initial reactant 3, 4-dimethoxy-5-nitroaniline can be prepared from 3, 4-dimethoxy-5-nitrobenzoic acid or 3, 4-dimethoxy-5-nitrobenzamide as raw materials. For example, 3,4-dimethoxy-5-nitroaniline can be prepared according to the method of U.S. Pat. No. 5,36952, the contents of which are incorporated herein by reference. Alternatively, as an example, 3, 4-dimethoxy-5-nitroaniline can be prepared as follows:
putting 908g of toluene, 180g of thionyl chloride and 227g of 3, 4-dimethoxy-5-nitrobenzoic acid into a 2000mL reaction bottle, heating to 80 ℃, and keeping the temperature at 70-80 ℃ for reaction for 8 hours. After the reaction was completed, toluene was distilled under reduced pressure to 85 ℃ and the residue was slightly cooled to 50 ℃ and diluted with 100g of acetone, and the residue was slowly added back to 1000g of 25% aqueous ammonia previously cooled to 5 ℃ or lower. After the reaction, solid material of 3, 4-dimethoxy-5-nitrobenzamide is separated out. Suction filtration is carried out, thus obtaining 490g of wet product of 3, 4-dimethoxy-5-nitrobenzamide.
Into another 3000mL reaction flask were charged 950g of 10% sodium hypochlorite and 1060g of 10% sodium carbonate, and the mixture was cooled to 20 ℃ or lower. 490g of a wet 3, 4-dimethoxy-5-nitrobenzamide was put into a reaction flask, and the reaction was stirred at 15 to 20 ℃ for 3 hours. After the reaction is finished, the temperature is raised to 70 ℃ within 1h, and the reaction is stirred at 70-75 ℃ for 3h. After the reaction is finished, cooling to below 5 ℃, stirring and crystallizing for 3 hours, obtaining 390g of wet product of 3, 4-dimethoxy-5-nitroaniline by suction filtration, and drying in an oven at 90 ℃ to obtain 168.3g of dry product of 3, 4-dimethoxy-5-nitroaniline. The molar yield is as follows: 85% and 99% HPLC purity.
3, 4-diethoxy-5-nitroaniline was prepared according to the above method using 3, 4-diethoxy-5-nitrobenzoic acid as a starting material in place of 3, 4-dimethoxy-5-nitrobenzoic acid.
The above-described charge reactions were carried out multiple times to accumulate the 3, 4-dimethoxy-5-nitroaniline feed and the 3, 4-diethoxy-5-nitroaniline feed for the preparation of the target product.
The following examples illustrate the preparation of the intermediates described herein and the specific preparation of PQQ using the intermediates described herein under certain conditions, and are illustrative of the preparation of hectogram grades, and in order to build up enough material for each step of the reaction, the following examples are actually carried out in multiple charges, each charge being the same, and the following preparations are illustrative of only one charge preparation.
Example 1Preparation of Compounds of formula I
Preparation example 1: preparation of ethyl (Z) -2- (2- (3, 4-dimethoxy-5-nitrophenyl) hydrazine) propionate (Compound I-1-1)
500g of absolute ethyl alcohol and 198g of 3, 4-dimethoxy-5 nitroaniline are added into a reaction bottle and stirred and mixed evenly. And (3) cooling the temperature of the reaction system to-10 ℃, dripping 365g of concentrated hydrochloric acid into the reaction bottle, cooling the reaction system to-10 ℃ after dripping, and quickly dripping 233g of 40% sodium nitrite. After the dropwise addition, the mixture was stirred at-5 ℃ for 1 hour. After the reaction, 200g of 2-methyl ethyl acetoacetate was added into the reaction flask at-5 ℃ and, after the addition, 1366.7g of 30% sodium acetate was added dropwise at-5 ℃. After the dropwise addition, the mixture is kept at the temperature of between 5 ℃ below zero and 0 ℃ and stirred for reaction for 4 hours. After the reaction is finished, heating the reaction system to room temperature, and stirring for reaction for 16h. After the reaction is finished, performing suction filtration, washing the solid material once, drying and drying to obtain a compound I-1-1, wherein the yield is 280g, and the yield is as follows: 89.9%, HPLC purity 97%, the hydrogen spectrum and carbon spectrum of compound of formula I-1-1 are shown in FIGS. 1 and 2, respectively.
Preparation example 2: preparation of ethyl (Z) -2- (2- (3, 4-dimethoxy-5-nitrophenyl) hydrazine) propionate (Compound I-1-1)
500g of absolute ethyl alcohol and 198g of 3, 4-dimethoxy-5 nitroaniline are added into a reaction bottle and stirred and mixed evenly. Cooling the temperature of a reaction system to-10 ℃, dropping 365g of concentrated hydrochloric acid into the reaction bottle, cooling the reaction system to-10 ℃ after dropping, and quickly dropping 233g of 40% sodium nitrite, wherein the dropping temperature is controlled to-5-0 ℃. After the dropwise addition, stirring for 1h at the temperature of-5-0 ℃. After the reaction, 200g of 2-methyl ethyl acetoacetate is added into the reaction bottle at 0 ℃, and after the addition is finished, 1366.7g of 30% sodium acetate is dropwise added at-5-0 ℃. After the dropwise addition, the mixture is kept at the temperature of between 5 ℃ below zero and 0 ℃ and stirred for reaction for 4 hours. After the reaction is finished, heating the reaction system to 20-25 ℃, and stirring for reaction for 16h. After the reaction is finished, performing suction filtration, washing the solid material with water once, drying and drying to obtain the compound I-1-1 with the yield of 268g, wherein the nuclear magnetic data of the compound is basically consistent with that of the compound prepared in the preparation example 1. Yield: 86.2% and HPLC purity 98%.
Preparation example 3: preparation of ethyl (Z) -2- (2- (3, 4-dimethoxy-5-nitrophenyl) hydrazine) propionate (Compound I-1-1)
500g of absolute ethyl alcohol and 198g of 3, 4-dimethoxy-5 nitroaniline are added into a reaction bottle and stirred and mixed evenly. Cooling the temperature of the reaction system to-10 ℃, dropping 900g of 40% sulfuric acid into the reaction bottle, cooling the reaction system to-10 ℃ after dropping, and quickly dropping 233g of 40% sodium nitrite, wherein the dropping temperature is controlled at-10 ℃. After the dropwise addition, the mixture is stirred for 1 hour at the temperature of between 5 ℃ below zero and 0 ℃. After the reaction, 200g of 2-methylacetoacetate was added into the reaction flask at-5 to 0 ℃ and, after the addition, 2263g of 30% sodium bicarbonate was added dropwise at-5 to 0 ℃. After the dropwise addition, the mixture is kept at the temperature of between 5 ℃ below zero and 0 ℃ and stirred for reaction for 4 hours. After the reaction is finished, heating the reaction system to room temperature, and stirring for reaction for 16h. After the reaction is finished, performing suction filtration, washing the solid material with water once, drying and drying to obtain the compound I-1-1 with the yield of 251.9g, wherein the nuclear magnetic data of the compound is basically consistent with that of the compound prepared in the preparation example 1. Yield: 81% and 97.2% HPLC purity.
The starting material 3, 4-dimethoxy-5-nitroaniline was replaced with 3, 4-diethoxy-5-nitroaniline, and ethyl (Z) -2- (2- (3, 4-diethoxy-5-nitrophenyl) hydrazino) propionate (compound of formula I-1-2) was prepared according to the method described in preparation examples 1-3 with a molar yield of 85% or more and an HPLC purity of 95% or more.
Preparation example 4: preparation of ethyl (Z) -2- (2- (3-amino-4, 5-dimethoxyphenyl) hydrazino) propionate (Compound I-2-1)
168g of iron powder and 1000g of 10% acetic acid are put into a reaction flask, stirred uniformly, heated to 80 ℃ and stirred for reaction for 1 hour. 311g of Compound I-1-1 (preparation 1) was slowly added with cooling. After being mixed evenly, the temperature is increased to 75 to 80 ℃, the mixture is stirred and reacted for 6 hours, and the reaction is finished. Cooling the reaction liquid to room temperature, adjusting the pH value to 8-9 with saturated sodium carbonate solution, and filtering. And repeatedly washing the solid with hot alcohol for 2 times, collecting ethanol filtrate, performing rotary drying on ethanol under reduced pressure to separate out a large amount of crystals, cooling to 20 ℃, performing suction filtration, collecting the solid, and drying to obtain 267g of granular crystals, namely the compound I-2-1. Molar yield: 95%, HPLC purity: 98.9%, the hydrogen spectrum and the carbon spectrum of the compound of formula I-2-1 are shown in FIGS. 3 and 4, respectively.
Preparation example 5: preparation of ethyl (Z) -2- (2- (3-amino-4, 5-dimethoxyphenyl) hydrazino) propionate (Compound of formula I-2-1)
168g of iron powder and 1000g of 10% acetic acid are put into a reaction flask, stirred uniformly, heated to 80 ℃ and stirred for reaction for 1 hour. Slightly cooled, 311g of Compound I-1-1 (preparation example 1) was slowly charged into the reaction flask at 50-65 ℃. After being mixed evenly, the temperature is raised to 60 to 70 ℃, the mixture is stirred and reacted for 6 hours, and the reaction is finished. Cooling the reaction liquid to 20-25 deg.C, adjusting pH to 8-9 with saturated sodium carbonate solution, and vacuum filtering. And (3) repeatedly washing the solid with hot ethanol for 2 times, collecting ethanol filtrate, carrying out reduced pressure spin-drying on the ethanol, separating out a large amount of crystals, cooling to 20 ℃, carrying out suction filtration, collecting the solid, and drying to obtain 250g of granular crystals, namely the compound I-2-1, wherein the nuclear magnetic data of the compound is basically consistent with that of the compound prepared in the preparation example 4. Molar yield: 89%, HPLC purity: 98 percent.
Preparation example 6: preparation of ethyl (Z) -2- (2- (3-amino-4, 5-dimethoxyphenyl) hydrazino) propionate (Compound I-2-1)
168g of iron powder, 500g of ethanol and 500g of 20% acetic acid are put into a reaction bottle, stirred uniformly, heated to 80 ℃ and stirred for reaction for 1 hour. 311g of Compound I-1-1 (preparation 1) was slowly added with cooling. After being mixed evenly, the temperature is increased to 75 to 80 ℃, the mixture is stirred and reacted for 6 hours, and the reaction is finished. Cooling the reaction liquid to room temperature, adjusting the pH value to 8-9 by using a saturated sodium carbonate solution, and performing suction filtration. And repeatedly washing the solid with hot alcohol for 2 times, collecting ethanol filtrate, performing rotary drying on ethanol under reduced pressure to separate out a large amount of crystals, cooling to 20 ℃, performing suction filtration, collecting the solid, and drying to obtain 258.5g of granular crystals, namely the compound I-2-1, wherein the nuclear magnetic data of the granular crystals are basically consistent with that of the compound prepared in preparation example 4. Molar yield: 92%, HPLC purity: 99 percent.
The starting material ethyl (Z) -2- (2- (3, 4-dimethoxy-5-nitrophenyl) hydrazine) propionate (compound formula I-1-1) was replaced with ethyl (Z) -2- (2- (3, 4-diethoxy-5-nitrophenyl) hydrazino) propionate (compound I-1-2), and ethyl (Z) -2- (2- (3-amino-4, 5-diethoxyphenyl) hydrazino) propionate (compound I-2-2) was prepared according to the method described in preparation examples 4-6, with a molar yield of 90% or more and a purity of 98% or more.
Example 2Preparation of the Compound of formula II
Preparation example 7: preparation of (Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-2)
562g of Compound I-2-1 (preparation example 4) and 3000g of methylene chloride were put into a reaction flask, and after stirring them well, 980g of (E) -4-oxopent-2-enedioic acid dimethyl ester and 544g of zinc chloride were added, and the mixture was stirred at room temperature for 24 hours. After the reaction is finished, the solvent is evaporated to dryness under normal pressure and reduced pressure. Adding 2000g of 70% ethanol into the residues, heating to 70 ℃, stirring for 30min, cooling to 15 ℃ after stirring, and separating out light yellow solid. Suction filtration and drying are carried out, thus obtaining 703g of compound II-1-2. Molar yield: 81.2% and 99.1% HPLC purity.
Preparation example 8: preparation of (Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-1-3)
562g of Compound I-2-1 (preparation example 4) and 3000g of methylene chloride were put into a reaction flask, and after stirring them well, 980g of diethyl (E) -4-oxopent-2-enoate and 544g of zinc chloride were added, and the mixture was reacted at 20 to 25 ℃ for 24 hours with stirring. After the reaction is finished, the solvent is evaporated to dryness under normal pressure and then under reduced pressure. Adding 2000g of 70% ethanol into the residues, heating to 70 ℃, stirring for 30min, cooling to 15 ℃ after stirring, and separating out light yellow solid. And performing suction filtration and drying to obtain 733g of compound II-1-3. Molar yield: 79.5% and HPLC purity 99.1%
Preparation example 9: preparation of (Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-1-4)
562g of Compound I-2-1 (preparation example 4) and 3000g of acetonitrile were charged into a reaction flask, and after stirring the mixture uniformly, 980g of dipropyl (E) -4-oxopent-2-enedioate and 544g of zinc chloride were added, and the mixture was stirred at room temperature for 24 hours. After the reaction is finished, the solvent is evaporated to dryness under normal pressure and then under reduced pressure. Adding 2000g of 50% ethanol into the residue, heating to 70 ℃, stirring for 30min, cooling to 15 ℃ after stirring, and separating out light yellow solid. Suction filtration and drying are carried out, thus obtaining 743.3g of compound II-1-4. The molar yield is as follows: 76% and HPLC purity 99.1%
The starting material ethyl (Z) -2- (2- (3-amino-4, 5-dimethoxyphenyl) hydrazino) propionate (compound I-2-1) in preparation 7-9 was replaced with ethyl (Z) -2- (2- (3-amino-4, 5-diethoxyphenyl) hydrazino) propionate (compound I-2-2), and dimethyl (Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylate (compound II-2-2), (Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylate (compound II-2-3) and (Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylate (compound II-dipropyl) were each prepared according to the procedures described in preparation 7-9 in a yield of 99% or more by mole.
Example 3Preparation of the Compound of formula III
Preparation example 10: preparation of ethyl 4, 5-dimethoxy-7, 9-bis (methoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (Compound III-1-2)
2200g of sulfuric acid and 433g of compound II-1-2 (preparation example 7) were put into a reaction flask, stirred uniformly, and the reaction system was heated to 40 ℃ and stirred for reaction for 16 hours. And after the reaction is finished, adding the reaction liquid back to 8800g of ice-water mixed liquid, separating out a solid material, performing suction filtration, washing the solid material to be neutral, performing suction filtration, and drying the solid material to obtain 382.7g of the compound III-1-2. Molar yield: 92% and 99% HPLC purity.
Preparation example 11: preparation of ethyl 4, 5-dimethoxy-7, 9-bis (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (Compound III-1-3)
2200g of sulfuric acid and 461g of the compound II-1-3 (preparation example 8) were put into a reaction flask, stirred uniformly, and the reaction system was heated to 45 to 55 ℃ and stirred to react for 16 hours. And after the reaction is finished, adding the reaction liquid back to 8800g of ice-water mixed liquid, separating out a solid material, performing suction filtration, washing the solid material to be neutral, performing suction filtration, and drying the solid material to obtain 390.7g of compound III-1-3. The molar yield is as follows: 88% and 99% HPLC purity.
Preparation example 12: preparation of ethyl 4, 5-dimethoxy-7, 9-bis [ (propyloxy) carbonyl ] -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (Compound III-1-4)
2200g of sulfuric acid and 489g of the compound II-1-4 (preparation example 9) were put into a reaction flask, stirred uniformly, and the reaction system was heated to 30 to 40 ℃ and stirred for reaction for 16 hours. After the reaction is finished, adding the reaction liquid back to 8800g of ice-water mixed liquid, separating out a solid material, carrying out suction filtration, washing the solid material to be neutral, carrying out suction filtration, and drying the solid material to obtain 424.8g of the compound shown in the formula III-1-4. Molar yield: 90% and 98.6% purity by HPLC.
The starting materials dimethyl (Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylate (Compound II-1-2), (Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylate (Compound II-1-3) and dipropyl (Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylate (Compound II-1-4) in preparation examples 10-12 were replaced with dimethyl (Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylate (Compound II-2-2), respectively (Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-2-3) and (Z) -7, 8-diethoxy-5- (2-, (2-) ( 1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid dipropyl ester (compound II-2-4) was prepared according to the methods described in preparation examples 7-9 to give ethyl 4, 5-diethoxy-7, 9-bis (methoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound III-2-2), ethyl 4, 5-diethoxy-7, 9-bis (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound III-2-3) and ethyl 4, 5-diethoxy-7, 9-bis [ (propyloxy) carbonyl ] -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound III-2-4), respectively, in molar yields of 85% or more and HPLC purities of 98% or more.
Example 4Preparation of the Compound of formula IV
Preparation example 13: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (Compound IV-1)
160g of sodium hydroxide and 1680g of purified water were put into a reaction flask, stirred until the solid was completely dissolved, and 433g of compound III-1-2 (preparation example 10) was put into the reaction flask, and after the completion of the addition, the temperature was raised to 90 ℃ and the reaction was stirred for 8 hours. After the reaction is finished, cooling to 30 ℃, adjusting the pH value to 2-3 with acid, carrying out suction filtration, washing the solid material once with water, carrying out suction filtration, and drying the solid material at 90 ℃ to obtain a compound IV-1 with the yield of 335g. The molar yield was 93% and the HPLC purity 98.5%.
Preparation example 14: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (Compound IV-1)
160g of sodium hydroxide and 1680g of purified water were put into a reaction flask, stirred until the solid was completely dissolved, 461g of compound III-1-3 (preparation example 11) was put into the flask, and after the completion of the addition, the temperature was raised to 80 to 90 ℃ and the reaction was stirred for 8 hours. After the reaction is finished, cooling to 30 ℃, adjusting the pH value to 2-3 with acid, carrying out suction filtration, washing the solid material with water once, carrying out suction filtration, and drying the solid material at 90 ℃ to obtain a compound IV-1 with the yield of 320g. The molar yield was 88.9% and the HPLC purity 98.7%.
Preparation example 15: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (Compound IV-1)
224g of potassium hydroxide and 1680g of purified water were put into a reaction flask, stirred until the solid was completely dissolved, and then compound of formula III-1-4 489g (preparation example 12) was put into the flask, and after the completion of the addition, the temperature was raised to 80-90 ℃ and the reaction was stirred for 8 hours. After the reaction is finished, cooling to 30 ℃, adjusting the pH value to 2-3 with acid, carrying out suction filtration, washing the solid material with water once, carrying out suction filtration, and drying the solid material at 90 ℃ to obtain a compound IV-1 with the yield of 327.6g. The molar yield was 91% and the HPLC purity was 99.05%.
The starting materials ethyl 4, 5-dimethoxy-7, 9-bis (methoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound formula III-1-2), ethyl 4, 5-dimethoxy-7, 9-bis (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound formula III-1-3) and ethyl 4, 5-dimethoxy-7, 9-bis [ (propyloxy) carbonyl ] -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound formula III-1-4) were replaced with ethyl 4, 5-diethoxy-7, 9-bis (methoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound III-2-2), ethyl 4, 5-diethoxy-7, 9-bis (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound III-2-2), and ethyl 4, 5-diethoxy-7, 9-bis (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-2-carboxylate (compound III-2-2) and ethyl 4, 5-diethoxy-carbonyl ] -4, 3-f ] quinoline-2-carboxylate (compound formula III-1-3-4, 3-f) were each, 4,5-diethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-2) was prepared respectively according to the procedures in preparation examples 13 to 15 ) The molar yield is more than 88%, and the HPLC purity is more than 98%.
Example 54, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2, 3-f)]Preparation of quinoline-2, 7, 9-tricarboxylic acid (PQQ) preparation 16:
360g of Compound IV-1 (preparation example 13) and 1800g of acetic acid were charged into a reaction flask. After the materials are stirred uniformly, 40 percent HI 1080g solution is slowly dripped into the reaction bottle at the temperature of 20-30 ℃, and after the dripping is finished, the temperature is increased to 60-70 ℃, and the reaction is kept for stirring and reacting for 12 hours. After the reaction is finished, cooling the material to 20 ℃, slowly adding the cooled material to 3000g of ice water in a reverse mode, separating out a solid material, performing suction filtration, washing the solid material with purified water until the pH value is 4-5, performing suction filtration, recrystallizing the solid material with methanol, and obtaining 587.6g of an intermediate compound VI wet product from the solid material. 587.6g of wet intermediate compound VI and 1800g of 30% hydrogen peroxide solution are put into a reaction flask and stirred, so that the materials in the reaction flask are uniformly stirred. Heating to 35 ℃, and stirring and reacting for 24 hours at the temperature of 30-35 ℃. After the reaction is finished, the temperature is reduced to 20 ℃, the filtration is carried out, and the solid material is dried at 90 ℃ to obtain the PQQ 297g. The molar yield was 90% and the HPLC purity was 99.5%.
Preparation example 17:
360g of Compound IV-1 (preparation example 13) and 1800g of acetic acid were charged into a reaction flask. After the materials are stirred uniformly, 40 percent HI 1080g solution is slowly dripped into the reaction bottle at the temperature of 30-40 ℃, and after the dripping is finished, the temperature is increased to 70-80 ℃, and the reaction is kept for stirring and reacting for 12 hours. After the reaction is finished, cooling the material to 20 ℃, slowly adding the cooled material to 3000g of ice water in a reverse mode, separating out a solid material, performing suction filtration, washing the solid material with purified water until the pH value is 4-5, performing suction filtration, recrystallizing the solid material with methanol, and obtaining 544.4g of an intermediate compound VI wet product from the solid material. 544.4g of intermediate compound VI wet product and 1800g of 30% hydrogen peroxide solution are put into a reaction bottle and stirred, so that the materials in the reaction bottle are uniformly stirred. Heating to 35 ℃, and stirring and reacting for 24 hours at the temperature of 30-35 ℃. After the reaction, the temperature is reduced to 20 ℃, the filtration is carried out, and the solid material is dried at 90 ℃ to obtain 292.7g of PQQ. The molar yield was 88.7% and the HPLC purity was 99.5%.
Preparation example 18:
360g of Compound IV-1 (preparation example 13) and 1800g of acetic acid were charged into a reaction flask. Stirring the materials uniformly, slowly adding 30% HI 1080g solution dropwise into the reaction bottle at 20-30 deg.C, heating to 60-70 deg.C, keeping the temperature, stirring, and reacting for 12h. And after the reaction is finished, cooling the material to 20 ℃, slowly adding the cooled material into 3000g of ice water in a reverse manner, separating out a solid material, performing suction filtration, washing the solid material with purified water until the pH value is 4-5, performing suction filtration, recrystallizing the solid material with methanol, and obtaining 568g of an intermediate compound VI wet product from the solid material. 568g of intermediate compound VI wet product and 1800g of 30% hydrogen peroxide solution are put into a reaction flask and stirred, so that the materials in the reaction flask are uniformly stirred. Heating to 35 ℃, and stirring and reacting for 24 hours at the temperature of 30-35 ℃. After the reaction is finished, the temperature is reduced to 20 ℃, the filtration is carried out, and the solid material is dried at 90 ℃ to obtain 290g of PQQ. The molar yield was 87.9% and the HPLC purity was 99.5%.
PQQ was prepared according to the method described in preparation examples 16 to 18, replacing the starting material 2- (ethoxycarbonyl) -4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound IV-1) with 4, 5-diethoxy-2- (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound IV-2), in a molar yield of 86% or more and in an HPLC purity of 99% or more.
Comparative example
In this comparative example, PQQ was prepared using N- (5-amino-3-bromo-2-methoxyphenyl) acetamide as an intermediate, and in the reaction, the quinoline ring and then the indole ring were synthesized according to the following reaction scheme:
wherein, in the reaction of the 3 rd step, the compound C is closed to form an indole ring at the same time of closing to form a quinoline ring, so that the side reaction exists in the stepThe yield and the yield are seriously influenced, the molar yield of the step is only 52 percent, the HPLC purity is only about 98 percent, and the molar yield can be kept above 75 percent when quinoline rings are synthesized in the above examples of the application, and the HPLC purity is above 99 percent; at the same time, the bromine atom on the benzene ring of the starting material needs to be changed into-Br to-OCH by Ullmann reaction in the 6 th step 3 The reaction route becomes longer, resulting in further decrease in final yield and purity, and the total yield of the reaction route is less than 20%. The existing intermediate for preparing PQQ usually has the problem, so the intermediate in the prior art can select to close an indole ring first and then close a quinoline ring.
Specifically, the specific operation process is as follows:
(1) 1200g of 30% hydrochloric acid and 500g of absolute ethyl alcohol and 147.5g of the compound are put into a clean and dry reaction bottle, and the reaction solution is cooled to-5 ℃ and stirred for reaction for 1h. When the internal temperature reached-5 ℃, 197g of 40% sodium acetate was added dropwise under rapid stirring, and the rate of addition was controlled so that the internal temperature was not higher than 5 ℃. After dripping, stirring for 120-180 min at 0-5 ℃, and detecting the disappearance of the compound A.
After cooling to-15 ℃ with a cold trap, 144g of ethyl 2-methylacetoacetate was added. After the addition, the reaction solution was cooled to-10 to-15 ℃. 462g of 30% sodium acetate was initially fed and the flow acceleration was controlled so that the internal temperature was not higher than-5 ℃. After the dropwise addition, slowly raising the temperature to 20-25 ℃ under rapid stirring, and stirring for reaction for 12 hours. After the reaction is finished, cooling the reaction solution to below 0 ℃, carrying out suction filtration, washing the solid material twice, centrifuging, and drying the solid material to obtain 150g of compound B. The molar yield was 80% and the HPLC purity 98.6%.
(2) A reflux condenser was attached to the washed and dried reaction flask. After the completion of the mounting, 1300g of ethanol, 200g of methanesulfonic acid and 372g of compound B were put into a reaction flask. After the addition, the temperature is raised to 80-85 ℃ for reflux reaction for 6h (liquid phase detection shows that the substrate reaction is complete). After the reaction is finished, the reaction kettle is cooled to 20 ℃,1000 g of 10% sodium carbonate is added, and after the addition is finished, the temperature is increased and the reflux is carried out for 1h. Detecting the pH =7-8 (based on the pH), cooling, crystallizing, filtering, temporarily storing solid materials, recovering ethanol from ethanol filtrate, cooling and crystallizing residues, filtering, combining solid materials, washing residual salt with water, and drying to obtain 247.5g of a compound C. The molar yield was 75%, and the HPLC purity was 99.3%.
(3) 165g of Compound C and 1500g of methylene chloride were put into a reaction flask, and after stirring the mixture uniformly, 490g of dipropyl (E) -4-oxopent-2-enedioate and 25g of zinc chloride were added, and the mixture was stirred at room temperature for 24 hours. After the reaction is finished, the solvent is evaporated to dryness under normal pressure and reduced pressure. Adding 1000g of 70% ethanol into the residue, heating to 70 deg.C, stirring for 30min, cooling to below 15 deg.C, and precipitating to obtain pale yellow solid. Suction filtration and drying are carried out, thus obtaining 145g of compound D. The molar yield was 52% and the HPLC purity 98%.
(4) 2000g of methanesulfonic acid and 538g of compound D were put into a reaction flask which had been washed and dried. After the addition, the temperature is raised to 70 ℃, and the reaction is stirred for 24 hours (the liquid phase detection shows that the substrate reaction is complete). After the reaction is finished, adding the reaction liquid into 15000 ice water, controlling the temperature to be not higher than 40 ℃, stirring for 1h, separating out crystals, adjusting the pH to 6-7 by using 10% sodium carbonate while stirring, performing suction filtration, washing 1000g of solid materials with water, and cooling the reaction liquid to 20 ℃ for crystallization for 1h. Filtering, drying the solid material (the water content is less than 0.5%) to obtain 468.9g of compound E. The molar yield was 90% and the HPLC purity 98.8%.
(5) A reflux condenser was attached to the washed and dried reaction flask. After completion of the installation, 1800g of 30% methanol/sodium methoxide, 1500g of pyridine, 48g of CuI and 260.5g of Compound E were placed in a reaction flask. After the charging, the temperature is raised and the reflux is carried out for 8 hours. After the reaction was complete, methanol and pyridine were distilled off under reduced pressure to a maximum internal temperature of 110 ℃. 2000g of water is added into the residue, the temperature is raised to 80-85 ℃, and the reaction is carried out for 2h under the condition that the temperature reaches 90-95 ℃. After the reaction is finished, cooling the reaction liquid to 30 ℃, performing suction filtration, adjusting the pH value of the filtrate to 2-3 by using dilute sulfuric acid, separating out a large amount of crystals, performing suction filtration, adding water into solid materials, boiling 1000-2000g of residual acid and copper sulfate once, performing cooling suction filtration, and drying to obtain 153g of a compound F, wherein the molar yield is 85%, and the HPLC purity is 98.5%.
(6) A reflux condenser was attached to the washed and dried reaction flask. After completion of the mounting, 3600g of 30% methanol/sodium methoxide, 3000g of pyridine, 96g of CuI and 521g of compound F were put into a reaction flask. After the charging, the temperature is raised and the reflux is carried out for 8 hours. After the reaction is complete, methanol and pyridine are distilled off under reduced pressure to a maximum internal temperature of 90 ℃. 4000g of water is added into the residue, the temperature is raised to 80-85 ℃, and the reaction is carried out for 2h under the condition that the temperature reaches 90-95 ℃. After the reaction is finished, cooling the reaction solution to 30 ℃, adjusting the pH value of the filtrate to 2-3 by using dilute sulfuric acid, separating out a large amount of crystals, cooling, filtering, and drying to obtain 325.8G of a compound G, wherein the molar yield is 90.5%, and the HPLC purity is as follows: 99.2 percent.
(7) 360G of Compound G and 1800G of acetic acid were put into a reaction flask. After the materials are stirred uniformly, 30 percent HI 1080g solution is slowly dripped into the reaction bottle at the temperature of 20-30 ℃, and after the dripping is finished, the temperature is increased to 60-70 ℃, and the reaction is kept for stirring and reacting for 12 hours. After the reaction is finished, cooling the material to below 20 ℃, slowly adding the cooled material in 3000g of ice water in a reverse mode, separating out a solid material, performing suction filtration, washing the solid material with purified water until the pH value is 4-5, performing suction filtration, recrystallizing the solid material with methanol, and obtaining 568g of a compound PQQ intermediate wet product from the solid material. 568G of intermediate wet product of the compound G and 1800G of 30% hydrogen peroxide solution are put into a reaction bottle and stirred, so that the materials in the reaction bottle are uniformly stirred. Heating to 35 ℃, and stirring and reacting for 24 hours at the temperature of 30-35 ℃. After the reaction is finished, the temperature is reduced to below 20 ℃, the centrifugation is carried out, and the solid material is dried at 90 ℃ to obtain 290g of compound PQQ. The molar yield was 87.9% and the HPLC purity was 99.5%.
Although the present application has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described in the foregoing embodiments, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A method of preparing 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, the method comprising: preparing a compound of formula III by Fischer indole synthesis using a compound of formula II as a starting material, hydrolyzing the compound of formula III to prepare a compound of formula IV, oxidizing the compound of formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r is 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
2. A method of preparing 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, said method comprising: preparing a compound shown in formula II by taking a compound shown in formula I-2 as a starting material and a compound shown in formula V under the catalysis of Lewis acid, preparing a compound shown in formula III by using the compound shown in formula II through a Fischer indole synthesis method, then hydrolyzing the compound shown in formula III to prepare a compound shown in formula IV, and oxidizing the compound shown in formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
3. A method of preparing 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, said method comprising: using a compound of formula I-1 as a starting material, reducing the compound of formula I-1 to prepare a compound of formula I-2, then using the compound of formula I-2 and a compound of formula V to prepare a compound of formula II under the catalysis of Lewis acid, then using the compound of formula II to prepare a compound of formula III through a Fischer indole synthesis method, then hydrolyzing the compound of formula III to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r is 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
4. A method of preparing 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, said method comprising: the compound of formula X is used as a starting material, the compound of formula X is subjected to diazotization and then condensed with 2-methyl ethyl acetoacetate to prepare a compound of formula I-1, the compound of formula I-1 is reduced to prepare a compound of formula I-2, the compound of formula I-2 and the compound of formula V are subjected to Lewis acid catalysis to prepare a compound of formula II, the compound of formula II is subjected to Fischer indole synthesis to prepare a compound of formula III, the compound of formula III is hydrolyzed to prepare a compound of formula IV, and the compound of formula IV is oxidized to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
5. The method of any one of claims 1 to 4, wherein oxidizing 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid to produce 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid comprises: 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid is reacted with a protonic acid to prepare 2- (ethoxycarbonyl) -4, 5-dihydroxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid, and then the 2- (ethoxycarbonyl) -4, 5-dihydroxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid is oxidized to prepare 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid.
6. The method of any one of claims 1 to 4, wherein R is 1 Is methyl or ethyl, R 3 Is methyl, ethyl or propyl;
preferably, the compound of formula X is diazotized with sodium nitrite solution under acidic condition, and then condensed with ethyl 2-methylacetoacetate under alkaline condition to form the compound of formula I-1; preferably, the molar ratio of the compound of formula X to ethyl 2-methylacetoacetate is 1-5; preferably, the temperature of the reaction stage in the step is controlled to be-10-0 ℃;
preferably, the compound of the formula I-1 is subjected to a reduction reaction under the action of a reducing agent to prepare the compound of the formula I-2, and the reaction temperature in the step is preferably 60-80 ℃;
preferably, in preparing the compound of formula II, the molar ratio of the compound of formula I-2 to the compound of formula V is 1-5;
preferably, in the preparation of the compound of the formula III, the reaction temperature is controlled to be 30-55 ℃;
preferably, the hydrolysis of the compound of formula III to produce the compound of formula IV occurs in an alkaline environment, preferably with the temperature controlled at 80-90 ℃;
preferably, the compound of formula IV is oxidized with an oxidizing agent selected from one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone.
7. A compound for use in the preparation of 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, the structure of which is as shown in formula I or formula II:
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 2 Is nitro or amino, R 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
8. The compound of claim 7, wherein the compound has the structure shown below:
wherein R is 1 Is methyl or ethyl, R 3 Is hydrogen, methyl, ethyl or propyl;
preferably, the compound is selected from the following structures:
(Z) -ethyl 2- (2- (3, 4-dimethoxy-5-nitrophenyl) hydrazino) propionate;
(Z) -ethyl 2- (2- (3, 4-diethoxy-5-nitrophenyl) hydrazino) propionate;
(Z) -ethyl 2- (2- (3-amino-4, 5-dimethoxyphenyl) hydrazino) propionate;
(Z) -ethyl 2- (2- (3-amino-4, 5-diethoxyphenyl) hydrazino) propionate;
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid;
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester;
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester;
(Z) -5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) -7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester;
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid;
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid dimethyl ester;
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid diethyl ester;
(Z) -7, 8-diethoxy-5- (2- (1-ethoxy-1-oxoprop-2-ylidene) hydrazino) quinoline-2, 4-dicarboxylic acid dipropyl ester.
9. Use of a compound as claimed in claim 7 or 8 and/or a compound of formula X as an intermediate in the preparation of 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid;
wherein R is 1 Is C 1 -C 3 Straight or branched alkyl, R 2 Is nitro or amino; r 3 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
10. Use according to claim 9, wherein R is 1 Is methyl or ethyl, R 2 Is nitro or amino, R 3 Is hydrogen, methyl, ethyl or propyl.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211415318.7A CN115894483A (en) | 2022-11-11 | 2022-11-11 | Intermediate and method for preparing pyrroloquinoline quinone |
| PCT/CN2022/142378 WO2024098530A1 (en) | 2022-11-11 | 2022-12-27 | Intermediate and method for preparing pyrroloquinoline quinone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211415318.7A CN115894483A (en) | 2022-11-11 | 2022-11-11 | Intermediate and method for preparing pyrroloquinoline quinone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115894483A true CN115894483A (en) | 2023-04-04 |
Family
ID=86494987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211415318.7A Withdrawn CN115894483A (en) | 2022-11-11 | 2022-11-11 | Intermediate and method for preparing pyrroloquinoline quinone |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115894483A (en) |
| WO (1) | WO2024098530A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070072894A1 (en) * | 2005-03-24 | 2007-03-29 | Kempf J V | Synthesis of pyrroloquinoline quinone (PQQ) |
| CN101193888A (en) * | 2005-03-24 | 2008-06-04 | Clf医疗技术加速程序有限公司 | Synthesis of pyrroloquinoline quinone (PQQ) |
| CN107089982A (en) * | 2017-05-11 | 2017-08-25 | 山东康迈祺生物科技有限公司 | 4,5 two 1 hydrogen pyrroles of substitution (2,3 f) quinoline 2,7,9 tricarboxylic ester compounds and applications |
| CN111087395A (en) * | 2019-12-31 | 2020-05-01 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by four-step method |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9115128B2 (en) * | 2013-06-06 | 2015-08-25 | Anthem Biosciences Pvt. Ltd. | Compounds of 3-(5-substituted Oxy-2, 4-dinitrophenyl)-2-oxo-propionic acid ester, synthesis and applications thereof |
| CN104557921B (en) * | 2014-12-24 | 2018-04-27 | 常熟理工学院 | The synthetic method of pyrroloquinoline quinone |
| CN110981873A (en) * | 2019-12-31 | 2020-04-10 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by five-step method |
-
2022
- 2022-11-11 CN CN202211415318.7A patent/CN115894483A/en not_active Withdrawn
- 2022-12-27 WO PCT/CN2022/142378 patent/WO2024098530A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070072894A1 (en) * | 2005-03-24 | 2007-03-29 | Kempf J V | Synthesis of pyrroloquinoline quinone (PQQ) |
| CN101193888A (en) * | 2005-03-24 | 2008-06-04 | Clf医疗技术加速程序有限公司 | Synthesis of pyrroloquinoline quinone (PQQ) |
| CN107089982A (en) * | 2017-05-11 | 2017-08-25 | 山东康迈祺生物科技有限公司 | 4,5 two 1 hydrogen pyrroles of substitution (2,3 f) quinoline 2,7,9 tricarboxylic ester compounds and applications |
| US20200071319A1 (en) * | 2017-05-11 | 2020-03-05 | Jinglin WANG | 4,5-disubstituted-1h-pyrrolo(2,3-f)quinolin-2,7,9-tricarboxylate compound and use thereof |
| CN111087395A (en) * | 2019-12-31 | 2020-05-01 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by four-step method |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024098530A1 (en) | 2024-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104628572B (en) | The synthetic method of 2 (2,4-dinitrophenoxy of 5 fluorine 2,4) acetic acid esters | |
| CN115894483A (en) | Intermediate and method for preparing pyrroloquinoline quinone | |
| CN114605328A (en) | Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine | |
| EP0727418B1 (en) | Process for producing 1-amino-1,2,3-triazole | |
| CN114685313B (en) | Preparation method of trifloxystrobin | |
| US20080306256A1 (en) | Salts in the Preparation of Cephalosporin Antibiodies | |
| IE65777B1 (en) | Process for the prodution of ebselen in highly pure form | |
| HU188778B (en) | Process for preparing n-naphthoyl-glycine derivatives | |
| Chauvette et al. | Chemistry of cephalosporin antibiotics. XXVII. 3-Methylenecephams | |
| CN115894362B (en) | Intermediate and application and method thereof in preparation of pyrroloquinoline quinone | |
| CN111285789A (en) | Method for preparing florfenicol intermediate and compound obtained by method | |
| EP0036636A1 (en) | A method and intermediates for preparing 3,3'-azo-bis-(6-hydroxy benzoic acid) | |
| CN109942397B (en) | Preparation method of royal jelly acid | |
| US5324860A (en) | Process for 3,5-di-tert-butylsalicylaldehyde | |
| CA2374686A1 (en) | A process for the preparation of .beta.-lactam derivatives | |
| JPH03135983A (en) | Preparation of 1,1-dioxo-7-substituted cephem | |
| CN112759556B (en) | Synthetic method for preparing 5-mercapto-1, 2, 3-triazole sodium salt by one-pot method | |
| EP0337434B1 (en) | Process for preparing diphenol monoesters substituted with aryl groups | |
| CN112592289B (en) | Preparation method of gabapentin intermediate | |
| EP0323846B1 (en) | Process of preparing thiamphenicol | |
| US5945556A (en) | Process for preparing N-carboxymethylene-4-chloro-anthranilic acid and its dialkyl esters | |
| CN112341351B (en) | Preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide | |
| CN106188201B (en) | Technique is simple, synthesis testosterone method suitable for reducing reductant concentration | |
| US4166183A (en) | Tricyclic cyclitolamines | |
| SU1518335A1 (en) | Method of producing acenapthenequinone and/or naphthalic anhydride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20230404 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40087678 Country of ref document: HK |