CN115894362A - Intermediate and application and method thereof in preparation of pyrroloquinoline quinone - Google Patents
Intermediate and application and method thereof in preparation of pyrroloquinoline quinone Download PDFInfo
- Publication number
- CN115894362A CN115894362A CN202211415234.3A CN202211415234A CN115894362A CN 115894362 A CN115894362 A CN 115894362A CN 202211415234 A CN202211415234 A CN 202211415234A CN 115894362 A CN115894362 A CN 115894362A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- ethyl
- dicarboxylic acid
- 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.)
- Granted
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 120
- 238000002360 preparation method Methods 0.000 title claims abstract description 93
- 238000000034 method Methods 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 286
- 238000006243 chemical reaction Methods 0.000 claims abstract description 197
- 239000001257 hydrogen Substances 0.000 claims abstract description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 61
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 230000001590 oxidative effect Effects 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- -1 5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid Chemical compound 0.000 claims description 93
- 239000011343 solid material Substances 0.000 claims description 62
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 53
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 230000003301 hydrolyzing effect Effects 0.000 claims description 17
- 238000005119 centrifugation Methods 0.000 claims description 15
- SJLUBPYBSAERDO-UHFFFAOYSA-N 3,4-dimethoxy-5-nitroaniline Chemical group COC1=CC(N)=CC([N+]([O-])=O)=C1OC SJLUBPYBSAERDO-UHFFFAOYSA-N 0.000 claims description 14
- 238000006783 Fischer indole synthesis reaction Methods 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 230000000850 deacetylating effect Effects 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 238000010931 ester hydrolysis Methods 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 238000007336 electrophilic substitution reaction Methods 0.000 claims description 6
- FNENWZWNOPCZGK-UHFFFAOYSA-N ethyl 2-methyl-3-oxobutanoate Chemical compound CCOC(=O)C(C)C(C)=O FNENWZWNOPCZGK-UHFFFAOYSA-N 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 5
- 238000003381 deacetylation reaction Methods 0.000 claims description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract 1
- 229910002651 NO3 Inorganic materials 0.000 abstract 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000000543 intermediate Substances 0.000 description 32
- 238000001816 cooling Methods 0.000 description 28
- 238000001035 drying Methods 0.000 description 25
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 239000000463 material Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 210000003298 dental enamel Anatomy 0.000 description 21
- 239000011229 interlayer Substances 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000005406 washing Methods 0.000 description 17
- 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 description 16
- 239000007868 Raney catalyst Substances 0.000 description 13
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 13
- 229910000564 Raney nickel Inorganic materials 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-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
- 239000012267 brine Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- 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 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 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 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000006196 deacetylation Effects 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 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 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000007171 acid catalysis Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000013305 food Nutrition 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
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000000643 oven drying Methods 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 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
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 229940071870 hydroiodic acid Drugs 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 7h-pyrrolo[2,3-h]quinoline Chemical compound C1=CN=C2C(C=CN3)=C3C=CC2=C1 ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- YRAKJHSSPBAGSY-UHFFFAOYSA-N COC(C(C=CC(O)=O)=O)=O Chemical compound COC(C(C=CC(O)=O)=O)=O YRAKJHSSPBAGSY-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
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 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 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction 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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides an intermediate and application and a method thereof in preparation of pyrroloquinoline quinone, wherein the intermediate compound has a structure shown in a formula I or a formula II:
wherein R is 1 Is C 1 ‑C 3 A linear or branched alkyl group; r 2 Is nitro or amino; r 3 Is hydrogen or an amino protecting group; r 4 Selected from hydrogen and C 1 ‑C 3 Straight or branched chain alkyl. The method has simple route,The reaction condition is mild, the yield is high, the use of an oxidant ammonium ceric nitrate is avoided, and the industrialized scale production of pyrroloquinoline quinone is realized.
Description
Technical Field
The invention relates to the field of organic compound preparation, in particular to an intermediate and application and a method thereof in preparation of pyrroloquinoline quinone.
Background
The information disclosed in this background of the invention is intended to enhance an understanding of the general background of the invention and should not necessarily be taken as an acknowledgement or any form of suggestion that this information has become known as prior art to a person skilled in the art.
Pyrroloquinoline quinone, whose chemical name is: 4, 5-dioxo-4, 5-dihydro-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid, CAS number 72909-34-3. Pyrroloquinoline quinones are widely present in foods of plant origin and foods of animal origin, such as fruits, vegetables, grains and the like. However, the concentration of pyrroloquinoline quinone in food is only at levels on the order of nanograms to micrograms/kg. Therefore, sufficient PQQ is not available only with dietary supplementation, and pyrroloquinoline quinone is difficult and expensive to obtain in a biological production and isolation process.
For this reason, many researchers began studying the chemical synthesis of pyrroloquinoline quinone, corey et al first achieved total synthesis of pyrroloquinoline quinone (J.Am. Chem.Soc.1981,103,18, 5599-5600), and later, martin et al improved the Corey route (Helvetica chimica acta,1993,76 (4): 1667-1673), and later, kempf et al achieved gram scale production of pyrroloquinoline quinone by combining the Corey and Martin routes (WO 2006/102642A 1), but required concentrated sulfuric acid purification, and the isolation and purification process of intermediates was cumbersome, and the Corey and Martin methods achieved only 50mg scale production of pyrroloquinoline quinone before Kempf, which were mainly suitable for laboratory preparation and difficult to produce on a large scale industrially. Still later, there was a study on the production of pyrroloquinoline quinone starting from methyl halobenzene, which enables the preparation of pyrroloquinoline quinone on the kilogram scale (WO 2014/195896), but the oxidation of the methoxy-pyrroloquinoline intermediate to the pyrroloquinoline quinone intermediate must be achieved in the latter reaction stage by cerium ammonium nitrate. Although the selectivity of the product in the process is high, the consumption of ammonium cerium nitrate is extremely high, generally more than 8 times of the mass consumption of the raw materials, the ammonium cerium nitrate is high in price, the production cost is high, cerium salt can only be treated as waste, the pollution discharge pressure is high, the separation and purification in the step are difficult, the optimal yield in the step is difficult to exceed 60%, the reaction route efficiency is low, the production time is long, and at least 4-5 weeks are required for obtaining kilogram-level products, so that the production of pyrroloquinoline quinone is difficult to realize high-efficiency industrialization.
Disclosure of Invention
The invention provides an intermediate compound and application and a method thereof in preparation of pyrroloquinoline quinone. The intermediate disclosed by the invention can be used for preparing pyrroloquinoline quinone, so that the reaction route can be controlled within 7 steps, the reaction condition is mild, the raw materials are cheap and easy to obtain, the product yield is high, the efficiency is high, the production period is greatly shortened, kilogram-level products can be obtained within 2-3 weeks, and the efficient industrial large-scale production of hundred kilogram-level pyrroloquinoline quinone can be realized within 1.5 months.
Specifically, the invention provides the following technical scheme:
in a first aspect of the present invention, the present invention provides an intermediate compound for preparing pyrroloquinoline quinone, which has a structure represented by formula I or formula II:
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 2 Is nitro or amino; r 3 Is hydrogen or an amino protecting group; r is 4 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
In some embodiments of the invention, R 1 Preferably methyl or ethyl.
In some embodiments of the invention, R 3 Preferably hydrogen or methyl carbonyl.
In some embodiments of the invention, R 4 Preferably methyl, ethyl or propyl.
In an embodiment of the invention, the compound of formula II has the structure shown in formula I-1, formula I-2, formula II-1, or formula II-2:
wherein R is 1 Is methyl or ethyl, R 4 Is hydrogen, methyl, ethyl or propyl.
Specifically, as an example, the intermediate compounds of the present invention are selected from the following structures:
n- (3, 4-dimethoxy-5-nitrophenyl) acetamide (compound I-1-1);
n- (3, 4-diethoxy-5-nitrophenyl) acetamide (Compound I-1-2);
n- (3-amino-4, 5-dimethoxyphenyl) acetamide (compound I-2-1);
n- (3-amino-4, 5-diethoxyphenyl) acetamide (Compound I-2-2);
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-1, R) 1 Is methyl, R 4 Is hydrogen);
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-2, R 1 Is methyl, R 4 Is methyl);
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-1-3, R 1 Is methyl, R 4 Is ethyl);
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-1-4, R 1 Is methyl, R 4 Is propyl);
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid (Compound II-1-5, R 1 Is ethyl, R 4 Is hydrogen);
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-6, R 1 Is ethyl, R 4 Is methyl);
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-1-7, R 1 Is ethyl, R 4 Is ethyl);
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-1-8, R 1 Is ethyl, R 4 Is propyl);
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-2-1, R 1 Is methyl, R 4 Is hydrogen);
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-2, R 1 Is methyl, R 4 Is methyl);
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-2-3 1 Is methyl, R 4 Is ethyl);
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-2-4, R 1 Is methyl, R 4 Is propyl);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid (Compound II-2-5 1 Is ethyl, R 4 Is hydrogen);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-2-6 1 Is ethyl, R 4 Is methyl);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-2-7, R 1 Is ethyl, R 4 Is ethyl);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-2-6, R 1 Is ethyl, R 4 Is propyl).
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I or formula II as described above.
In an embodiment of the invention, the compound of formula I may be prepared by electrophilic substitution of 3, 4-dimethoxy-5-nitroaniline with acetic anhydride. The 3, 4-dimethoxy-5-nitroaniline can be prepared from 3, 4-dimethoxy-5-nitrobenzoic acid or 3, 4-dimethoxy-5-nitrobenzamide.
In an embodiment of the invention, the compound of formula I has the structure shown in formula I-1 or formula I-2:
wherein R is 1 Is methyl or ethyl.
Wherein, 3, 4-dialkoxy-5-nitroaniline and acetic anhydride carry out electrophilic substitution reaction to prepare the compound shown in the formula I-1, and the compound shown in the formula I-2 can be prepared by reducing the compound shown in the formula I-1. In one embodiment, the reduction reaction may occur under conditions of raney nickel catalyzed high pressure hydrogenation.
In embodiments of the invention, the compound of formula II may further have a structure represented by formula II-1 or formula II-2, and the compound of formula II-1 may be prepared by reacting the compound of formula I-2 with the compound of formula V under Lewis acid catalysis in an oxygen atmosphere (with oxygen); the compound of formula II-2 is prepared by deacetylating and/or ester hydrolyzing the compound of formula II-1
Wherein R is 4 Selected from hydrogen, methyl, ethyl and propyl.
In a third aspect of the present invention, the use of any one of the compounds of formula I or formula II as described in the first aspect of the present invention as an intermediate in the preparation of pyrroloquinoline quinone;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 2 Is nitro or amino; r is 3 Is hydrogen or an amino protecting group; r 4 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
In a fourth aspect of the present invention, the present invention provides a method for preparing pyrroloquinoline quinone, comprising: preparing a compound shown in a formula III from the compound shown in the formula II-2 by a Fischer indole synthesis method, hydrolyzing the compound shown in the formula III to prepare a compound shown in a formula IV, and oxidizing the compound shown in the formula IV to prepare pyrroloquinoline quinone;
wherein R is 1 、R 4 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the present invention, the compound of formula II-2 can be prepared by deacetylating and/or hydrolyzing the ester of the compound of formula II-1;
wherein R is 1 、R 4 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In a fifth aspect of the present invention, the present invention provides a method for preparing pyrroloquinoline quinone, comprising: deacetylating the compound of the formula II-1, hydrolyzing ester to prepare a compound of a formula II-2', preparing a compound of a formula III' from the compound of the formula II-2 'by a Fischer indole synthesis method, hydrolyzing the compound of the formula III' to prepare a compound of a formula IV, and oxidizing the compound of the formula IV to prepare pyrroloquinoline quinone;
wherein R is 1 、R 4 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the invention, the compound of formula II-1 is prepared from a compound of formula I-2 and a compound of formula V under Lewis acid catalysis in an oxygen atmosphere (with oxygen);
wherein R is 1 、R 4 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In a sixth aspect of the present invention, the present invention provides a method for preparing pyrroloquinoline quinone, comprising: preparing a compound shown in a formula I-2 and a compound shown in a formula V under the catalysis of Lewis acid in an oxygen atmosphere to obtain a compound shown in a formula II-1, deacetylating the compound shown in the formula II-1, hydrolyzing ester to prepare a compound shown in a formula II-2', preparing a compound shown in a formula III' from the compound shown in the formula II-2 'by a Fischer indole synthesis method, hydrolyzing the compound shown in the formula III' to prepare a compound shown in a formula IV, and oxidizing the compound shown in the formula IV to prepare pyrroloquinoline quinone;
wherein R is 1 、R 4 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the invention, the compound of formula I-2 is prepared from the compound of formula I-1 by reduction,
wherein R is 1 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl.
For example, in one embodiment of the invention, the reduction reaction occurs under raney nickel catalyzed high pressure hydrogenation conditions.
In a seventh aspect of the present invention, the present invention provides a method for preparing pyrroloquinoline quinone, comprising: reducing the compound I-1 to prepare a compound I-2, preparing the compound I-2 and the compound V in the presence of Lewis acid catalysis in an oxygen atmosphere to obtain a compound II-1, deacetylating and hydrolyzing the compound II-1 to obtain a compound II-2', preparing a compound III' from the compound II-2 'by a Fischer indole synthesis method, hydrolyzing the compound III' to prepare a compound IV, and oxidizing the compound IV to obtain pyrroloquinoline quinone;
wherein R is 1 、R 4 As defined hereinbefore;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In an embodiment of the invention, the compounds of the formula I can be prepared by electrophilic substitution of 3, 4-dialkoxy-5-nitroaniline with acetic anhydride. The 3, 4-dialkoxy-5-nitroaniline may be prepared from 3, 4-dialkoxy-5-nitrobenzoic acid or 3, 4-dialkoxy-5-nitrobenzamide as a starting material. The alkoxy is mainly C 1 -C 3 An alkoxy group.
In an embodiment of the invention, the compound of formula I has the structure shown in formula I-1 or formula I-2:
wherein R is 1 As defined hereinbefore; preferably, R 1 Is methyl or ethyl.
Wherein, 3, 4-dialkoxy-5-nitroaniline and acetic anhydride have electrophilic substitution reaction to prepare a compound shown in formula I-1, and the compound shown in formula I-1 is subjected to reduction reaction to prepare a compound shown in formula I-2. For example, in one embodiment, the reduction reaction may occur under conditions of raney nickel catalyzed high pressure hydrogenation.
Compared with the prior art, the invention has the advantages that: the compound provided by the invention can be used as an intermediate for preparing pyrroloquinoline quinone, so that the reaction route can be controlled within 7 steps, the reaction condition is mild, the raw materials are cheap and easy to obtain, the product yield is high, the efficiency is high, kilogram-level products can be obtained within 2-3 weeks, and the high-efficiency industrial large-scale production of kilogram-level pyrroloquinoline quinone can be realized.
In addition, the prior art tends to synthesize an indole structure first and then synthesize a quinoline structure, and the inventors find that in the operation mode, when the indole structure is synthesized, the indole is not selectively synthesized, which means that the yield of the step is about 50% -60%, so that unnecessary impurities are easily generated, the yield of a final product is influenced, and subsequent purification is complicated, and if the quinoline structure is synthesized by using an intermediate in the prior art first, the reaction route is too long, and the reaction efficiency is low. According to the invention, the compound of the formula I or the compound of the formula II is used as an intermediate, a quinoline structure is synthesized firstly, and then Fischer indole synthesis is carried out, so that the selectivity of indole synthesis is improved through quinoline occupation, the generation of unnecessary byproducts is avoided, the synthesis efficiency and yield are greatly improved, the subsequent complicated purification work is reduced, and the high-efficiency large-scale production of pyrroloquinoline quinone at the level of hundreds of kilograms is realized.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1: hydrogen spectra of exemplary compounds of Compound I-2.
FIG. 2: carbon spectra of exemplary compounds of Compound I-2.
FIG. 3: hydrogen spectra of exemplary compounds of Compound II-1.
FIG. 4: carbon spectra of exemplary compounds of Compound II-1.
FIG. 5: hydrogen spectra of exemplary compounds of Compound II-2.
FIG. 6: carbon spectra of exemplary compounds of compound II-2.
Detailed Description
The invention will be further illustrated with reference to the following 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 invention. Experimental procedures without specific conditions noted in the following examples, generally 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 invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with 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 invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The invention provides compounds shown as a formula I or a formula II, and a method for preparing pyrroloquinoline quinone by using the compounds as intermediates.
Wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 2 Is nitro or amino; r 3 Is hydrogen or an amino protecting group; r 4 Selected from hydrogen and C 1 -C 3 Straight or branched chainAn alkyl group.
In some embodiments of the invention, R 1 Preferably methyl or ethyl.
In some embodiments of the invention, R 3 Preferably hydrogen or methyl carbonyl.
In some embodiments of the invention, R 4 Preferably hydrogen, methyl, ethyl or propyl.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using a compound of formula II as an intermediate proceeds according to the following reaction scheme:
wherein, in some preferred embodiments, R 1 Is methyl or ethyl, R 4 Is hydrogen, methyl, ethyl or propyl.
Wherein, the compound of formula II-2 can be prepared by deacetylating and/or ester hydrolyzing the compound of formula II-1.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using a compound of formula II-1 as an intermediate proceeds according to the following reaction scheme:
wherein, in some preferred embodiments, R 1 Is methyl or ethyl, R 4 Is hydrogen, methyl, ethyl or propyl. If R is 4 Hydrogen, no ester hydrolysis is required after the deacetylation in step 1.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using a compound of formula I as an intermediate proceeds according to the following reaction scheme:
among them, some are preferredIn the embodiment, R 1 Is methyl or ethyl, R 4 Is hydrogen, methyl, ethyl or propyl. If R is 4 Hydrogen, no ester hydrolysis is required after step 2 deacetylation.
Wherein, the compound of formula I-2 can be prepared from the compound of formula I-1 by reduction reaction, and the reduction reaction can be carried out under the condition of high-pressure hydrogenation catalyzed by Raney nickel.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using 3, 4-dialkoxy-5-nitroaniline as an intermediate proceeds according to the following reaction scheme:
wherein, in some preferred embodiments, R 1 Is methyl or ethyl, R 4 Is hydrogen, methyl, ethyl or propyl. If R is 4 Hydrogen, no ester hydrolysis is required after the 4 th deacetylation step.
In the reaction route of the invention, when the 3, 4-dialkoxy-5-nitroaniline compound is used as an intermediate for preparing pyrroloquinoline quinine, a quinoline structure is firstly synthesized, and then Fischer indole synthesis is carried out, so that indole synthesis selectivity is improved through quinoline occupation, unnecessary substances are avoided, synthesis efficiency and yield are greatly improved, and subsequent complicated purification work is reduced.
In some embodiments of the present invention, the last step of the above-mentioned reactions is an oxidation reaction, and the oxidation reaction can be performed in one step or according to the following reaction scheme:
wherein, in some preferred embodiments, R 1 Is methyl or ethyl.
For example, in an embodiment of the present invention, the preparation method of pyrroloquinoline quinone may include the following specific implementation steps:
(1) 3, 4-dialkoxy-5-nitroaniline and acetic anhydride are subjected to electrophilic substitution reaction in a solvent to prepare a compound shown as a formula I-1;
in some embodiments of the invention, the 3, 4-dialkoxy-5-nitroaniline may be 3, 4-dimethoxy-5-nitroaniline or 3, 4-diethoxy-5-nitroaniline; the solvent may be selected from ethyl acetate, dioxane and acetonitrile, preferably ethyl acetate.
In some embodiments of the invention, the molar ratio of 3, 4-dialkoxy-5-nitroaniline to acetic anhydride is 1 to 5.
In some embodiments of the invention, the temperature of step (1) in the reaction stage is controlled at 20-45 ℃.
Further, after the reaction is finished, the compound of formula I-1 can be obtained by crystallization (such as cooling and the like), centrifugation, drying and the like; and recovering the solvent from the mother liquor, and further crystallizing (such as cooling) the remainder after recovering the solvent, centrifuging, drying and the like to obtain the compound of the formula I-1.
(2) Reducing the compound shown in the formula I-1 under the condition of Raney nickel catalytic high-pressure hydrogenation to prepare a compound shown in the formula I-2;
in some embodiments of the present invention, the solvent in step (2) is optionally an alcohol, such as a simple alcohol, e.g., methanol, ethanol, etc.
In some embodiments of the present invention, the reaction temperature of step (2) is 20 to 50 ℃, for example, may be further 20 to 30 ℃ or 40 to 50 ℃.
In some embodiments of the invention, the high pressure in step (2) is maintained at 0.5 to 2MPa.
In some embodiments of the present invention, the compound of formula I-1 is used in step (2) in an amount 10 to 24 times (by mass) the amount of Raney nickel.
Further, after the reaction is completed, the compound of formula I-2 can be obtained by removing Raney nickel, recovering the solvent, crystallizing (e.g., cooling, etc.), centrifuging, drying, etc.
(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-1;
in some embodiments of the invention, the molar ratio of compound of formula I-2 to compound of formula V is 1-3.
In some embodiments of the invention, the compound of formula I-2 is present in a 1-2 molar ratio to Lewis acid.
In some embodiments of the invention, the reaction solvent may be dichloromethane.
In some embodiments of the invention, the temperature of the reaction stage of step (3) is controlled at 10-35 ℃.
Further, after the reaction is finished, the compound of formula II-1 can be obtained by operations of recrystallization, centrifugation, drying and the like.
(4) Deacetylating the compound II-1 under an acidic condition and carrying out ester hydrolysis to obtain a compound II-2';
in some embodiments of the present invention, step (4) comprises reacting formula II-1 under acidic conditions (such as adding methanesulfonic acid) at a temperature of 60-80 ℃ for deacetylation, cooling to below 20 ℃ after the reaction is completed, crystallizing, and centrifuging; and (3) putting the solid material obtained by centrifugation or the reaction solution into acid solution (such as hydrochloric acid or sulfuric acid) without centrifugation, heating to 40-70 ℃ for ester hydrolysis reaction, centrifuging at 40-50 ℃ after the reaction is finished, washing the solid material, centrifuging, and drying to obtain the compound shown in the formula II-2'.
(5) Preparing a compound shown in a formula III 'from the compound shown in a formula II-2' by a Fischer indole synthesis method;
in some embodiments of the invention, the compound of formula II-2' is reacted with ethyl 2-methylacetoacetate, wherein the molar ratio of the compound of formula II-2 to ethyl 2-methylacetoacetate is 1-2.
In some embodiments of the invention, the step (5) comprises mixing and stirring the absolute alcohol solvent and the formula II-2, cooling the system to below 10 ℃, then dropwise adding concentrated hydrochloric acid or 50% sulfuric acid, and stirring; cooling the system to 0 ℃ and below (even minus 10 ℃ and below), quickly adding sodium nitrite in a flowing manner, stirring and reacting at minus 5 ℃ to 5 ℃, after the reaction is finished, dropwise adding 2-methyl ethyl acetoacetate at 0 ℃ and below (even minus 5 ℃ and below), after the reaction is finished, dropwise adding sodium acetate at 0 ℃ and below (even minus 5 ℃ and below), keeping the temperature for reaction at minus 5 ℃ to 5 ℃, after the reaction is finished, heating the system to 20 ℃ to 25 ℃, stirring and reacting, after the reaction is finished, centrifuging, washing to obtain a compound intermediate wet product of the formula III, mixing the wet product with 50% sulfuric acid, heating the system to 35 ℃ to 45 ℃, stirring and reacting, after the reaction is finished, slowly adding a reaction solution into a mixed solution, separating out a solid material, centrifuging, washing and drying to obtain the compound of the formula III'.
(6) The compound III' is subjected to ester hydrolysis reaction to obtain a compound IV.
(7) Oxidizing the compound shown in the formula IV to obtain PQQ, or oxidizing the intermediate G obtained in the preparation of the compound shown in the formula IV to obtain PQQ; for example, compound of formula IV can be prepared to give intermediate G by reaction with a protic acid (e.g., under HAC/HI acid conditions), which can be hydrobromic or hydroiodic acid, preferably hydroiodic acid; 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.
Specifically, in combination with the above reaction scheme, the present invention gives the following preparation examples.
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, the 3, 4-dimethoxy-5-nitroaniline of the invention can be prepared by the following method:
putting 908kg of toluene, 180kg of thionyl chloride and 227kg of 3, 4-dimethoxy-5-nitrobenzoic acid into a 2000L reaction kettle, starting stirring, introducing steam into a jacket of the reaction kettle, heating to 80 ℃, and carrying out heat preservation reaction for 8 hours at 70-80 ℃. After the reaction, toluene was distilled under reduced pressure to 85 ℃ and the residue was slightly cooled to 50 ℃ and diluted with 100kg of acetone, the residue was slowly added back to 1000kg of 25% ammonia water previously cooled to 5 ℃ or lower. After the reaction, solid material of 3, 4-dimethoxy-5-nitrobenzamide is separated out. Centrifuging to obtain 452kg of wet 3, 4-dimethoxy-5-nitrobenzamide.
950kg of 10 percent sodium hypochlorite and 1060kg of 10 percent sodium carbonate are put into another 3000L reaction kettle, stirring is started, 5 ℃ condensed water is introduced into a jacket of the reaction kettle, and the reaction kettle is cooled to be below 20 ℃. Stopping stirring, adding 452kg of 3, 4-dimethoxy-5-nitrobenzamide wet product into the reaction kettle, starting stirring, and stirring for reaction at 15-20 ℃ for 3h. After the reaction is finished, stopping cooling, introducing steam into a jacket of the reaction kettle, heating to 70 ℃ within 1h, and stirring and reacting at 70-75 ℃ for 3h. After the reaction is finished, cooling to below 5 ℃, stirring and crystallizing for 3 hours, centrifuging to obtain 380kg of wet product of 3, 4-dimethoxy-5-nitroaniline, and drying in an oven at 90 ℃ to obtain 172.8kg of dry product of 3, 4-dimethoxy-5-nitroaniline. Molar yield: 87.3% and 99% purity by HPLC.
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 1 preparation of Compounds of formula I
Preparation example 1: preparation of N- (3, 4-dimethoxy-5-nitrophenyl) acetamide (Compound I-1-1)
198kg of 3, 4-dimethoxy-5-nitroaniline and 792kg of ethyl acetate are put into a 1500L enamel reaction kettle, and stirring is started to uniformly mix the materials. And (3) slowly dropwise adding 122.4kg of acetic anhydride into the reaction kettle at the temperature of between 20 and 30 ℃ by using a dropwise adding tank, and stirring for 1 hour after the dropwise adding is finished. Steam is introduced into the jacket of the reaction kettle, the temperature is increased to reflux, and the reaction is stirred for 2 hours. After the reaction is finished, cooling to 20 ℃, and adjusting the pH value to 7-8 by using 10% sodium carbonate. Stirring and crystallizing for 30min, centrifuging, collecting solid material, and oven drying at 90 deg.C to obtain 228kg of compound I-1-1 dry product. Recovering ethyl acetate from the mother liquor, cooling the remainder to 15-20 ℃, centrifuging to obtain a wet product of the crude product of the compound I-1-1, and drying at 90 ℃ to obtain 3.8kg of the crude product of the compound I-1-1. Total molar yield: 96.58%, HPLC purity: 99.3 percent.
Preparation example 2: preparation of N- (3, 4-dimethoxy-5-nitrophenyl) acetamide (Compound I-1-1)
198kg of 3, 4-dimethoxy-5-nitroaniline and 792kg of acetonitrile are put into a 1500L enamel reaction kettle, and stirring is started to uniformly mix the materials. And (3) slowly dropwise adding 122.4kg of acetic anhydride into the reaction kettle at the temperature of between 35 and 45 ℃ by using a dropwise adding tank, and stirring for 1 hour after the dropwise adding is finished. Steam is introduced into a jacket of the reaction kettle, the temperature is raised to reflux, and the reaction is stirred for 2 hours. After the reaction is finished, cooling to 15-20 ℃, and adjusting the pH value to 7-8 by using 10% sodium carbonate. Stirring and crystallizing for 30min, centrifuging, collecting solid material, and drying at 90 deg.C to obtain 216kg of compound I-1-1 dry product. Recovering ethyl acetate from the mother liquor, cooling the remainder to 15-20 ℃, centrifuging to obtain a wet product of the crude product of the compound I-1-1, and drying at 90 ℃ to obtain 8.3kg of the crude product of the compound I-1-1. Total molar yield: 93.4%, HPLC purity: 99.09 percent.
Preparation example 3: preparation of N- (3, 4-dimethoxy-5-nitrophenyl) acetamide (Compound I-1-1)
198kg of 3, 4-dimethoxy-5-nitroaniline and 792kg of dioxane are put into a 1500L enamel reaction kettle, and stirring is started to uniformly mix the materials. Dropping 122.4kg of acetic anhydride into the reaction kettle by using a dropping pot at the temperature of 20-30 ℃, and stirring for 1h after dropping. Steam is introduced into the jacket of the reaction kettle, the temperature is increased to reflux, and the reaction is stirred for 2 hours. After the reaction, the mixture is cooled to 20 ℃, and the pH value is adjusted to 7-8 by 10% sodium carbonate. Stirring for crystallization for 30min, centrifuging, collecting solid material, and oven drying at 90 deg.C to obtain 213.6kg of dried product of compound I-1-1. Recovering ethyl acetate from the mother liquor, cooling the remainder to 20 ℃, centrifuging to obtain a wet crude product of the compound I-1-1, and drying at 90 ℃ to obtain 6.9kg of a crude product of the compound I-1-1. Total molar yield: 91.8%, HPLC purity: 98.9 percent.
N- (3, 4-diethoxy-5-nitrophenyl) acetamide (compound I-1-2) can be prepared according to the method described in preparation examples 1-3, replacing the starting material 3, 4-dimethoxy-5-nitroaniline with 3, 4-diethoxy-5-nitroaniline, with a total molar yield of 90% or more and a purity of 99% or more.
Preparation example 4: preparation of N- (3-amino-4, 5-dimethoxyphenyl) acetamide (Compound I-2-1)
240kg of compound I-1-1 (preparation example 1), 960kg of ethanol and 19.2kg of Raney nickel were charged into a 2000L high-pressure hydrogenation reactor. After the feeding is finished, the nitrogen replaces the air for three times, and the hydrogen replaces the nitrogen for three times. Starting stirring, and filling hydrogen into the reaction kettle to keep the hydrogen pressure at 0.5MPa. When the pressure is reduced, the hydrogen is replenished in time, and the operation is carried out until the hydrogen pressure is not reduced. The reaction was continued for 2h with stirring, during which time the temperature was kept at 20-30 ℃. And after the reaction is finished, carrying out filter pressing on the reaction solution to remove the Raney nickel. Recovering ethanol from the filtrate under normal pressure and reduced pressure, cooling the residue to 20 deg.C, stirring, and crystallizing for 2 hr. After the crystallization is finished, centrifuging, and drying the solid material at 80 ℃ to obtain the compound I-2-1 with the yield of 201.6kg, wherein the hydrogen spectrum and the carbon spectrum are respectively shown in figure 1 and figure 2. The molar yield is as follows: 96%, HPLC purity: 99 percent.
Preparation example 5: preparation of N- (3-amino-4, 5-dimethoxyphenyl) acetamide (Compound I-2-1)
240kg of the compound of formula I-1-1 (preparation example 1), 960kg of methanol and 24kg of Raney nickel were charged in a 2000L high-pressure hydrogenation reactor. After the feeding is finished, the nitrogen replaces the air for three times, and the hydrogen replaces the nitrogen for three times. Starting stirring, and filling hydrogen into the reaction kettle to keep the hydrogen pressure at 0.5MPa. When the pressure is reduced, the hydrogen is replenished in time, and the operation is carried out until the hydrogen pressure is not reduced. The reaction was continued for 2h with stirring, during which time the temperature was kept at 20-30 ℃. And after the reaction is finished, carrying out filter pressing on the reaction solution to remove the Raney nickel. Recovering methanol from the filtrate under normal pressure and reduced pressure, cooling the residue to 20 deg.C, stirring, and crystallizing for 2 hr. After the crystallization, the mixture was centrifuged, and the solid material was dried at 80 ℃ to obtain Compound I-2-1 in a yield of 189.6kg, whose nuclear magnetic data was substantially identical to that of the compound prepared in preparation example 4. Molar yield: 90.3%, HPLC purity: 99 percent.
Preparation example 6: preparation of N- (3-amino-4, 5-dimethoxyphenyl) acetamide (Compound I-2-1)
240kg of compound I-1-1 (preparation example 1), 960kg of ethanol and 12kg of Raney nickel were charged in a 2000L high-pressure hydrogenation reactor. After the feeding is finished, the nitrogen replaces the air for three times, and the hydrogen replaces the nitrogen for three times. Starting stirring, and filling hydrogen into the reaction kettle to keep the hydrogen pressure at 0.5MPa. When the pressure is reduced, the hydrogen is replenished in time, and the operation is carried out until the hydrogen pressure is not reduced. The reaction was continued with stirring for 2h, during which the temperature was kept at 40-50 ℃. And after the reaction is finished, carrying out filter pressing on the reaction liquid to remove the Raney nickel. Recovering ethanol from the filtrate under normal pressure and reduced pressure, cooling the residue to 20 deg.C, stirring, and crystallizing for 2 hr. After the crystallization, the mixture is centrifuged, and the solid material is dried at 80 ℃ to obtain the compound I-2-1 with the yield of 178.5kg, wherein the nuclear magnetic data of the compound is basically consistent with that of the compound prepared in the preparation example 4. Molar yield: 85%, HPLC purity: 99 percent.
N- (3-amino-4, 5-diethoxyphenyl) acetamide (compound I-2-2) can be obtained by replacing the starting material N- (3, 4-dimethoxy-5-nitrophenyl) acetamide (compound I-1-1) with N- (3, 4-diethoxy-5-nitrophenyl) acetamide (compound I-1-2), according to the method described in preparation examples 4-6, in a total molar yield of 88% or more and a purity of not less than 99%.
EXAMPLE 2 preparation of the Compound of formula II
Preparation example 7: preparation of diethyl 5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylate (compound of formula II-1-3)
210kg of Compound I-2-1 (preparation example 4) and 1260kg of methylene chloride were placed in a 3000L enamel reactor, stirred, and 501.5kg of ethyl 2-oxopentendioate and 200kg of zinc chloride were placed in the reactor. After the feeding is finished, stirring and reacting for 24 hours at the temperature of 20-25 ℃. After the reaction is finished, under the condition that steam is introduced into the reaction kettle, the dichloromethane is distilled to 60 ℃ under normal pressure and reduced pressure. After distillation, 1200kg of 70% ethanol is added into the reaction kettle, and after the addition is finished, the temperature is raised to 70 ℃ and stirring is carried out for 1h, so that the materials are fully and uniformly dispersed. After that, the temperature is reduced to 15 ℃, and the mixture is cooled and crystallized for 3 hours, and light yellow solid is separated out. Centrifuging, drying the solid material at 90 ℃ to obtain a compound II-1-3 with the yield of 362.7kg and the molar yield: 93% and 99% purity by HPLC.
Preparation example 8: preparation of 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-2)
210kg of Compound I-2-1 (preparation example 4) and 1260kg of methylene chloride were charged into a 3000L enamel reactor, and stirred, and 477.7kg of methyl 2-oxopentendioate and 200kg of zinc chloride were further charged into the reactor. After the feeding is finished, stirring and reacting for 24 hours at the temperature of 10-20 ℃. After the reaction is finished, under the condition that steam is introduced into the reaction kettle, the dichloromethane is distilled to 70 ℃ under normal pressure and reduced pressure. After distillation, 1200kg of 70% ethanol is added into the reaction kettle, and after the addition is finished, the temperature is raised to 70 ℃ and stirring is carried out for 1h, so that the materials are fully and uniformly dispersed. After that, the temperature is reduced to 15 ℃, and the mixture is cooled and crystallized for 3 hours, and light yellow solid is separated out. Centrifuging, drying the solid material at 90 ℃ to obtain a compound II-1-2 with the yield of 304.1kg and the molar yield: 91.05% and 98.2% purity by HPLC.
Preparation example 9: preparation of 5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-1-4)
210kg of Compound I-2-1 (preparation example 4) and 1260kg of methylene chloride were placed in a 3000L enamel reactor, stirred, and 525kg of propyl 2-oxopentendioate and 200kg of zinc chloride were placed in the reactor. After the feeding is finished, stirring and reacting for 24 hours at the temperature of 25-35 ℃. After the reaction is finished, under the condition that steam is introduced into the reaction kettle, the dichloromethane is distilled to 60 ℃ under normal pressure and reduced pressure. After distillation, 1200kg of 70% ethanol is added into the reaction kettle, and after the addition is finished, the temperature is raised to 70 ℃ and stirring is carried out for 1h, so that the materials are fully and uniformly dispersed. After that, the temperature is reduced to 15 ℃, and the mixture is cooled and crystallized for 3 hours, and light yellow solid is separated out. Centrifuging, and oven drying the solid material at 90 deg.C to obtain compound II-1-4 with yield of 344.8kg, and its hydrogen spectrum and carbon spectrum are shown in FIG. 3 and FIG. 4 respectively. Molar yield: 82.5% and 98.8% purity by HPLC.
By substituting the starting material N- (3-amino-4, 5-dimethoxyphenyl) acetamide (Compound I-2-1) with N- (3-amino-4, 5-diethoxyphenyl) acetamide (Compound I-2-2), diethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (Compound II-1-7), respectively, was prepared according to the procedures described in preparation examples 7-9; the total molar yield of the 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (compound II-1-6) and the 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (compound II-1-8) is more than 80 percent, and the purity is not less than 98 percent.
Preparation example 10: preparation of 5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-2-1)
192kg of methanesulfonic acid, 840kg of absolute ethanol and 418kg of compound II-1-4 (preparation example 9) were placed in a 2000L enamel reactor. After the feeding is finished, starting stirring until the solid materials are completely dissolved, introducing steam into the interlayer of the reaction kettle, heating to 75-80 ℃ under stirring, and stirring for reaction for 10 hours. After the reaction is finished, cooling to 20 ℃, and stirring for crystallization for 3 hours. And (5) centrifuging after crystallization is finished. And putting the wet solid material obtained after centrifugation into 2150kg of 10% hydrochloric acid, introducing steam into the interlayer of the reaction kettle, heating to 60-70 ℃, and stirring and reacting at 60-70 ℃ for 12 hours. After the reaction is finished, the temperature is reduced to 40 ℃, the centrifugation is carried out, the solid material is firstly rinsed by purified water and then washed by water once, the centrifugation is carried out, the obtained solid material is dried at 90 ℃ to obtain the compound II-2-1, the yield is 259.8kg, and the hydrogen spectrum and the carbon spectrum are respectively shown in figure 5 and figure 6. The molar yield is as follows: 89%, HPLC purity: 98.5 percent.
Preparation example 11: preparation of 5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-2-1)
192kg of methanesulfonic acid, 840kg of absolute ethanol and 362kg of the compound II-1-2 (preparation example 8) were placed in a 2000L enamel reactor. After the feeding is finished, starting stirring until the solid material is completely dissolved, introducing steam into the interlayer of the reaction kettle, heating to 60-70 ℃ while stirring, and stirring for reaction for 12 hours. After the reaction is finished, cooling to 20 ℃, and stirring for crystallization for 3 hours. And (5) centrifuging after crystallization is finished. And putting the wet solid material obtained after centrifugation into 2150kg of 10% hydrochloric acid, introducing steam into the interlayer of the reaction kettle, heating to 40-50 ℃, and stirring and reacting at 40-50 ℃ for 16 hours. And after the reaction is finished, centrifuging, washing the solid material with purified water, washing with water once again, centrifuging, drying the obtained solid material at 90 ℃ to obtain the compound II-2-1 with the yield of 238.3kg, wherein the nuclear magnetic data of the compound II-2-1 is basically consistent with that of the product prepared in the preparation example 10. Molar yield: 81.6% HPLC purity: 99.03 percent.
Preparation example 12: preparation of 5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-2-1)
192kg of methanesulfonic acid, 840kg of absolute ethanol and 390kg of compound II-1-3 (preparation example 7) were placed in a 2000L enamel reactor. After the feeding is finished, starting stirring until the solid material is completely dissolved, introducing steam into the interlayer of the reaction kettle, heating to 75-80 ℃ while stirring, and stirring for reaction for 10 hours. After the reaction is finished, cooling to 20 ℃, and stirring for crystallization for 3 hours. And (5) centrifuging after crystallization is finished. And putting the wet solid material obtained after centrifugation into 2886kg of 10% sulfuric acid, introducing steam into an interlayer of the reaction kettle, heating to 60-70 ℃, and stirring and reacting at 60-70 ℃ for 12 hours. After the reaction is finished, the temperature is reduced to 40 ℃, the reaction product is centrifuged, the solid material is rinsed by purified water and then washed by water once, the reaction product is centrifuged, the obtained solid material is dried at 90 ℃ to obtain the compound II-2-1, the yield is 229.5kg, and the nuclear magnetic data of the compound II-2-1 is basically consistent with that of the product prepared in the preparation example 10. Molar yield: 78.6%, HPLC purity: 98.4 percent.
The starting materials, dipropyl 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylate (compound II-1-4), dimethyl 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylate (compound II-1-2), diethyl 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylate (compound II-1-3) were replaced with diethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-7), dimethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-6), dipropyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-8), respectively, and 5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid (compound II-2-5) was prepared according to the method described in preparation examples 10-12, in a total molar yield of 78% or more and a purity of 98% or higher.
EXAMPLE 3 preparation of the Compound of formula III
Preparation example 13: preparation of 2- (ethoxycarbonyl) -4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (Compound III-1)
500kg of absolute ethyl alcohol and 292kg of compound II-2-1 (preparation example 10) are put into a 3000L enamel reaction kettle, and stirring is started to fully and uniformly stir the materials in the kettle. And (3) introducing cold saline water into the interlayer of the reaction kettle, and cooling the reaction system to 10 ℃. After the temperature reduction is finished, 325kg of concentrated hydrochloric acid is dripped into the reaction kettle by using a dripping tank. After the dropwise addition, stirring was carried out for 30min. After the reaction, the temperature of the reaction system is reduced to-10 ℃, and 233kg of 40% sodium nitrite is rapidly fed into the reaction kettle by a dropping tank. After the feeding is finished, stirring and reacting for 3 hours at the temperature of minus 5-0 ℃, and the material is bright yellow thick liquid. After the reaction, 200kg of ethyl 2-methylacetoacetate was added into the reaction kettle at-5 ℃. After the completion of the addition, 30% sodium acetate 1038kg was added dropwise to the reaction vessel at-5 ℃ from a dropping pot. After the dropwise addition, stirring and reacting for 4 hours at the temperature of-5-0. After the reaction is finished, removing the cold brine from the interlayer of the reaction kettle, slowly heating the reaction system to 20-25 ℃, and stirring and reacting for 16 hours at 20-25 ℃. After the reaction, centrifuging and washing the solid material once. 872kg of intermediate wet product of the compound shown in the formula III-1 is obtained.
1000kg of 50% sulfuric acid and 872kg of intermediate product of compound III-1 are put into a 2000L reaction kettle and stirred uniformly, steam is put into the interlayer of the reaction kettle, and the reaction system is heated to 40 ℃ and stirred for reaction for 16 hours. After the reaction is finished, slowly adding the reaction solution back to 3000kg of ice-water mixed solution, separating out a solid material, centrifuging, washing the solid material to be neutral, centrifuging, drying and drying the solid material at the temperature of 80 ℃ to obtain a compound III-1, wherein the yield is 333.7kg, and the molar yield is as follows: 86% and HPLC purity 99%
Preparation example 14: preparation of 2- (ethoxycarbonyl) -4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (Compound III-1)
500kg of absolute ethyl alcohol and 292kg of compound II-2-1 (preparation example 10) are put into a 3000L enamel reaction kettle, and stirring is started to fully and uniformly stir the materials in the kettle. And (3) introducing cold saline water into the interlayer of the reaction kettle, and cooling the reaction system to 10 ℃. And after the temperature reduction is finished, 325kg of concentrated hydrochloric acid is dripped into the reaction kettle by using a dripping tank. After the dropwise addition, stirring was carried out for 30min. After the reaction, the temperature of the reaction system is reduced to 0 ℃, and 233kg of 40% sodium nitrite is rapidly fed into the reaction kettle by using a dropping tank. After the feeding is finished, stirring and reacting for 3 hours at the temperature of 0-5 ℃, and the material is bright yellow thick liquid. After the reaction, 200kg of ethyl 2-methylacetoacetate was added into the reaction kettle at 0 ℃. After the completion of the addition, 30% sodium acetate 1038kg was added dropwise to the reaction vessel at 0 ℃ from a dropping pot. After the dropwise addition, the mixture is kept at the temperature of 0-5 ℃ and stirred for reaction for 4 hours. After the reaction is finished, removing the cold brine from the interlayer of the reaction kettle, slowly heating the reaction system to 20-25 ℃, and stirring and reacting for 16 hours at 20-25 ℃. After the reaction, centrifuging and washing the solid material once. 863kg of wet intermediate product of the compound III-1 is obtained.
1000kg of 50% sulfuric acid and 863kg of intermediate wet product of the compound III-1 are put into a 3000L reaction kettle and stirred evenly, steam is put into an interlayer of the reaction kettle, and the reaction system is heated to 40 ℃ and stirred for reaction for 16 hours. After the reaction is finished, slowly adding the reaction solution back to 3000kg of ice-water mixed solution, separating out a solid material, centrifuging, washing the solid material to be neutral, centrifuging, drying and drying the solid material at the temperature of 80 ℃ to obtain a compound III-1, wherein the yield is 322kg, and the molar yield is as follows: 83% and 99% HPLC purity.
Preparation example 15: preparation of 2- (ethoxycarbonyl) -4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (Compound III-1)
500kg of anhydrous methanol and 292kg of compound II-2-1 (preparation example 10) are put into a 3000L enamel reaction kettle, and stirring is started to fully and uniformly stir the materials in the kettle. And (3) introducing cold saline water into the interlayer of the reaction kettle, and cooling the reaction system to 10 ℃. After the temperature reduction is finished, 641kg of 50% sulfuric acid is dripped into the reaction kettle by using a dripping tank. After the dropwise addition, stirring was carried out for 30min. After the reaction, the temperature of the reaction system is reduced to-10 ℃, and 233kg of 40% sodium nitrite is rapidly fed into the reaction kettle by a dropping tank. After the feeding is finished, stirring and reacting for 3 hours at the temperature of minus 5-0 ℃, and the material is bright yellow thick liquid. After the reaction, 200kg of ethyl 2-methylacetoacetate was added into the reaction kettle at-5 ℃. After the addition, 1038kg of 30% sodium acetate was added dropwise to the reaction vessel at-5 ℃ using a dropping pot. After the dropwise addition, stirring and reacting for 4 hours at the temperature of-5-0. After the reaction is finished, removing the cold brine from the interlayer of the reaction kettle, slowly heating the reaction system to 20-25 ℃, and stirring and reacting for 16 hours at 20-25 ℃. After the reaction, centrifuging and washing the solid material once. 820kg of wet intermediate product of the compound III-1 is obtained.
1000kg of 50% sulfuric acid and 820kg of intermediate product of the compound III-1 are put into a 2000L reaction kettle and evenly stirred, steam is put into the interlayer of the reaction kettle, and the reaction system is heated to 40 ℃ and stirred for reaction for 16 hours. After the reaction is finished, slowly adding the reaction solution back to 3000kg of ice-water mixed solution, separating out a solid material, centrifuging, washing the solid material to be neutral, centrifuging, drying and drying the solid material at the temperature of 80 ℃ to obtain a compound III-1, wherein the yield is 291kg, and the molar yield is as follows: 75% and 99% HPLC purity.
By replacing the starting 5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (compound II-2-1) with 5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid (compound II-2-5), 4, 5-diethoxy-2- (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound III-2) was prepared according to the method described in preparation examples 13-15 in a molar yield of not less than 75% and an HPLC purity of not less than 99%.
EXAMPLE 4 preparation of the Compound of formula IV
Preparation example 16: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (Compound IV-1)
Putting 160kg of sodium hydroxide and 1680kg of purified water into a 3000L enamel reaction kettle, stirring until the solid materials are completely dissolved, then putting 388kg of compound III-1 (preparation example 13), introducing steam into the interlayer of the reaction kettle, heating to 80 ℃, stirring and reacting for 3 hours. After the reaction is finished, cooling to 30 ℃, adjusting the pH value to 2-3 with acid, centrifuging, washing the solid material with water once, centrifuging, and drying the solid material at 90 ℃ to obtain 335g of the compound shown in the formula IV-1. The molar yield was 93% and the HPLC purity 98.5%.
Preparation example 17: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound of formula IV-1)
Putting 224kg of potassium hydroxide and 1680kg of purified water into a 3000L enamel reaction kettle, stirring until solid materials are completely dissolved, then putting 388kg of the compound shown in the formula III-1 (preparation example 13), introducing steam into the interlayer of the reaction kettle, heating to 80 ℃, stirring and reacting for 3 hours. After the reaction is finished, cooling to 30 ℃, adjusting the pH value to 2-3 with acid, centrifuging, washing the solid material with water once, centrifuging, and drying the solid material at 90 ℃ to obtain a compound IV-1 with the yield of 316.8g. The molar yield was 88% and the HPLC purity was 99.5%.
Preparation example 18: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound of formula IV-1)
Putting 160kg of sodium hydroxide and 1680kg of purified water into a 3000L enamel reaction kettle, stirring until the solid materials are completely dissolved, then putting 388kg of compound III-1 (preparation example 13), introducing steam into the interlayer of the reaction kettle, heating to 50-60 ℃, stirring and reacting for 6 hours. After the reaction is finished, cooling to 30 ℃, adjusting the pH value to 2-3 with acid, centrifuging, washing the solid material with water once, centrifuging, and drying the solid material at 90 ℃ to obtain the compound IV-1 with the yield of 324g. Molar yield 90% and HPLC purity 99%.
By replacing the starting material 2- (ethoxycarbonyl) -4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound formula III-1) with 4, 5-diethoxy-2- (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound formula III-2), 4, 5-diethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-2) can be prepared according to the procedures described in preparation examples 16-18 in a molar yield of 90% or more and an HPLC purity of 99% or more.
EXAMPLE 5 preparation of pyrroloquinoline quinone (PQQ)
Preparation example 19:
180kg of Compound IV-1 (preparation example 16) and 900kg of acetic acid were placed in a 2000L enamel reactor. Starting stirring, 40% HI 540kg of solution was slowly added dropwise into the reaction kettle at 30-40 ℃ by using a dropping pot. After the dropwise addition, the temperature is raised to 70-80 ℃, and the reaction is carried out for 10 hours with stirring and heat preservation. And after the reaction is finished, introducing cold brine into a jacket of the reaction kettle, cooling the material to 20 ℃, slowly adding the material to 2000kg of ice water in a reverse mode, separating out a solid material, centrifuging, washing the solid material with purified water until the pH value is 4-5, centrifuging, recrystallizing the solid material with methanol, and drying the solid material at 90 ℃ to obtain 298.8kg of an intermediate (compound G) of the compound IV-1. 298.8kg of wet intermediate (compound G) of the compound IV-1 and 900kg of 30% hydrogen peroxide solution are put into a 2000L enamel reaction kettle, and stirring is started to ensure that the materials in the kettle are uniformly stirred. Introducing steam into the interlayer of the reaction kettle, stirring, heating to 35 ℃, and stirring and reacting at 30-35 ℃ for 24 hours. After the reaction is finished, the temperature is reduced to 20 ℃, the centrifugation is carried out, and the solid material is dried at 90 ℃ to obtain a compound PQQ 153.5kg. The molar yield was 93% and the HPLC purity was 99.8%.
Preparation example 20:
180kg of Compound IV-1 (preparation example 16) and 900kg of acetic acid were placed in a 2000L enamel reactor. Starting stirring, 40% HI 540kg of solution was slowly added dropwise into the reaction kettle at 20-30 ℃ by using a dropping pot. After the dropwise addition, the temperature is raised to 60-70 ℃, and the reaction is carried out for 12 hours with stirring and heat preservation. And (3) after the reaction is finished, introducing cold brine into a jacket of the reaction kettle, cooling the material to 20 ℃, slowly adding the material to 2000kg of ice water in a reverse mode, separating out a solid material, centrifuging, washing the solid material with purified water until the pH value is 4-5, centrifuging, recrystallizing the solid material with methanol, and obtaining 293.8kg of wet product of the intermediate (compound G) of the compound IV-1 from the solid material. 293.8kg of wet intermediate (compound G) of the compound IV-1 and 900kg of 30% hydrogen peroxide solution are put into a 2000L enamel reaction kettle, and stirring is started to uniformly stir the materials in the kettle. Introducing steam into the interlayer of the reaction kettle, stirring, heating to 35 ℃, and stirring and reacting at 30-35 ℃ for 24 hours. After the reaction, the temperature is reduced to 20 ℃, the centrifugation is carried out, and the solid material is dried at 90 ℃ to obtain 148.5kg of compound PQQ. The molar yield was 90% and the HPLC purity was 99.5%.
Preparation example 21:
180kg of Compound IV-1 (preparation 16) and 900kg of acetic acid were placed in a 2000L enamel reactor. Starting stirring, slowly dropping 30% HI 720kg solution into the reaction kettle at 30-40 deg.C with a dropping tank. After the dropwise addition, the temperature is raised to 70-80 ℃, and the reaction is carried out for 10 hours with stirring and heat preservation. And after the reaction is finished, introducing cold brine into a jacket of the reaction kettle, cooling the material to 20 ℃, slowly adding the material to 2000kg of ice water in a reverse mode, separating out a solid material, centrifuging, washing the solid material with purified water until the pH value is 4-5, centrifuging, recrystallizing the solid material with methanol, and obtaining 272.2kg of a wet product of the intermediate (compound G) of the compound IV-1 from the solid material. 272.2kg of wet intermediate (compound G) of compound IV-1 and 900kg of 30% hydrogen peroxide solution were put into a 2000L enamel reactor, and stirred to stir the materials in the reactor uniformly. Introducing steam into the interlayer of the reaction kettle, stirring, heating to 35 ℃, and stirring and reacting at 30-35 ℃ for 24 hours. After the reaction, the temperature is reduced to 20 ℃, the centrifugation is carried out, and the solid material is dried at 90 ℃ to obtain 147.7kg of the compound PQQ. The molar yield was 89.5% and the HPLC purity was 99.8%.
PQQ was prepared according to the method described in preparation examples 19-21 by replacing the starting 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-1) with 4, 5-diethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-2), with a molar yield of not less than 90% and an HPLC purity of not less than 99.5%.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An intermediate compound for preparing pyrroloquinoline quinone, which has a structure shown in formula I or formula II:
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 2 Is nitro or amino; r is 3 Is hydrogen or an amino protecting group; r is 4 Selected from hydrogen and C 1 -C 3 Straight or branched chain alkyl.
2. The intermediate compound of claim 1, wherein the compound has the structure shown below:
wherein R is 1 Is methyl or ethyl, R 4 Is methyl, ethyl or propyl.
3. Intermediate compound according to claim 1 or 2, characterized in that it is selected from the following structures:
n- (3, 4-dimethoxy-5-nitrophenyl) acetamide;
n- (3, 4-diethoxy-5-nitrophenyl) acetamide;
n- (3-amino-4, 5-dimethoxyphenyl) acetamide;
n- (3-amino-4, 5-diethoxyphenyl) acetamide;
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid;
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester;
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester;
5-acetylamino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester;
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid;
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester;
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid diethyl ester;
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester;
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid;
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester;
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester;
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester;
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid;
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester;
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid diethyl ester;
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester.
4. Use of an intermediate compound as claimed in any one of claims 1 to 3 in the preparation of pyrroloquinoline quinone.
5. A method of preparing pyrroloquinoline quinone, comprising: preparing a compound shown in the formula II-2 by a Fischer indole synthesis method to obtain a compound shown in the formula III, hydrolyzing the compound shown in the formula III to obtain a compound shown in the formula IV, and oxidizing the compound shown in the formula IV to obtain pyrroloquinoline quinone;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 4 Selected from hydrogen and C 1 -C 3 A linear or branched alkyl group;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
6. A method of preparing pyrroloquinoline quinone, comprising: deacetylating the compound of the formula II-1, hydrolyzing ester to obtain a compound of a formula II-2', preparing the compound of the formula II-2' by a Fischer indole synthesis method to obtain a compound of a formula III ', hydrolyzing the compound of the formula III' to obtain a compound of a formula IV, and oxidizing the compound of the formula IV to obtain pyrroloquinoline quinone;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r is 4 Selected from hydrogen and C 1 -C 3 A linear or branched alkyl group;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
7. A method of preparing pyrroloquinoline quinone, comprising: preparing a compound shown in a formula I-2 and a compound shown in a formula V under the catalysis of Lewis acid in an oxygen atmosphere to obtain a compound shown in a formula II-1, deacetylating the compound shown in the formula II-1, hydrolyzing ester to obtain a compound shown in a formula II-2', preparing the compound shown in the formula II-2' through a Fischer indole synthesis method to obtain a compound shown in a formula III ', hydrolyzing the compound shown in the formula III' to obtain a compound shown in a formula IV, and oxidizing the compound shown in the formula IV to obtain pyrroloquinoline quinone;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 4 Selected from hydrogen and C 1 -C 3 A linear or branched alkyl group;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
8. A method of preparing pyrroloquinoline quinone, comprising: reducing the compound I-1 to prepare a compound I-2, preparing the compound I-2 and the compound V in the presence of Lewis acid as catalysts in an oxygen atmosphere to obtain a compound II-1, deacetylating the compound II-1, and hydrolyzing esters to obtain a compound II-2', preparing the compound II-2' in a Fischer indole synthesis method to obtain a compound III ', hydrolyzing the compound III' in the formula III to obtain a compound IV, and oxidizing the compound IV to obtain pyrroloquinoline quinone;
wherein R is 1 Is C 1 -C 3 A linear or branched alkyl group; r 4 Selected from hydrogen and C 1 -C 3 A linear or branched alkyl group;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
9. The process of claim 8, wherein the compound of formula I-1 is prepared by electrophilic substitution of 3, 4-dialkoxy-5-nitroaniline with acetic anhydride in a solvent;
preferably, the 3, 4-dialkoxy-5-nitroaniline is 3, 4-dimethoxy-5-nitroaniline or 3, 4-diethoxy-5-nitroaniline;
preferably, the solvent is selected from the group consisting of ethyl acetate, dioxane and acetonitrile;
preferably, the reaction temperature is controlled at 20-45 ℃.
10. The method according to claim 8, wherein the reaction for preparing the compound of formula I-2 by reducing the compound of formula I-1 is carried out under raney nickel-catalyzed high-pressure hydrogenation conditions at a temperature of 20 to 50 ℃ and a pressure of 0.5 to 2MPa;
preferably, the compound of formula I-2 and the compound of formula V are used for preparing the compound of formula II-1 under the catalysis of Lewis acid and in an oxygen atmosphere, wherein the reaction temperature is controlled to be 10-35 ℃;
preferably, the compound of formula II-1 is deacetylated and ester hydrolyzed to prepare the compound of formula II-2', the deacetylation reaction of formula II-1 is carried out under acidic condition at 60-80 ℃, after the reaction is finished, the temperature is reduced, crystallization and centrifugation are carried out, the solid material obtained by centrifugation or the reaction solution without centrifugation is put into acid solution, and the temperature is increased to 40-70 ℃ for ester hydrolysis reaction;
preferably, the compound of formula II-2' is reacted with ethyl 2-methylacetoacetate to perform Fischer indole synthesis;
preferably, oxidation of compound formula IV to produce PQQ comprises direct oxidation or oxidation of compound formula IV to produce intermediate G to produce PQQ;
preferably, the oxidant is selected from one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211415234.3A CN115894362B (en) | 2022-11-11 | 2022-11-11 | Intermediate and application and method thereof in preparation of pyrroloquinoline quinone |
| PCT/CN2022/142380 WO2024098531A1 (en) | 2022-11-11 | 2022-12-27 | Intermediate and use and method of intermediate in preparation of pyrroloquinoline quinone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211415234.3A CN115894362B (en) | 2022-11-11 | 2022-11-11 | Intermediate and application and method thereof in preparation of pyrroloquinoline quinone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115894362A true CN115894362A (en) | 2023-04-04 |
| CN115894362B CN115894362B (en) | 2023-11-07 |
Family
ID=86481865
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211415234.3A Active CN115894362B (en) | 2022-11-11 | 2022-11-11 | Intermediate and application and method thereof in preparation of pyrroloquinoline quinone |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115894362B (en) |
| WO (1) | WO2024098531A1 (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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) |
| WO2012170378A1 (en) * | 2011-06-06 | 2012-12-13 | Us Cosmeceu Techs, Llc | Skin treatments containing pyrroloquinoline quinine (pqq) esters and methods of preparation and use thereof |
| 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 |
| CN110981873A (en) * | 2019-12-31 | 2020-04-10 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by five-step method |
| CN111087395A (en) * | 2019-12-31 | 2020-05-01 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by four-step method |
| CN114890999A (en) * | 2022-05-27 | 2022-08-12 | 江苏海洋大学 | Preparation method of PQQ |
-
2022
- 2022-11-11 CN CN202211415234.3A patent/CN115894362B/en active Active
- 2022-12-27 WO PCT/CN2022/142380 patent/WO2024098531A1/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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) |
| WO2012170378A1 (en) * | 2011-06-06 | 2012-12-13 | Us Cosmeceu Techs, Llc | Skin treatments containing pyrroloquinoline quinine (pqq) esters and methods of preparation and use thereof |
| 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 |
| CN110981873A (en) * | 2019-12-31 | 2020-04-10 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by five-step method |
| CN111087395A (en) * | 2019-12-31 | 2020-05-01 | 江西农业大学 | Preparation method for synthesizing pyrroloquinoline quinone by four-step method |
| CN114890999A (en) * | 2022-05-27 | 2022-08-12 | 江苏海洋大学 | Preparation method of PQQ |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024098531A1 (en) | 2024-05-16 |
| CN115894362B (en) | 2023-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112521299B (en) | Preparation method of pregabalin intermediate | |
| CN112608296B (en) | Synthesis method of Brazilane natural product Brazilane | |
| CN101462974B (en) | Process for synthesizing 5-aminovaleric acid hydrochloride | |
| CN114539048B (en) | Carlong anhydride intermediate and preparation method of Carlong anhydride | |
| CN115894362B (en) | Intermediate and application and method thereof in preparation of pyrroloquinoline quinone | |
| US5831095A (en) | Synthesis of 5-aminocarbonyl-5H-dibenzo a,d!cyclohepten-5,10-imine | |
| US6160113A (en) | Process and compositions for nitration of n-nitric acid at elevated temperatures to form HNIW and recovery of gamma HNIW with high yields and purities and crystallizations to recover epsilon HNIW crystals | |
| KR970009318B1 (en) | Process for the preparation of stilbenedicarboxylic derivatives | |
| CN102617335A (en) | Process for synthesizing p-tert-butylbenzoic acid | |
| CN106542958B (en) | Preparation method of o-iodoaniline | |
| WO2024098530A1 (en) | Intermediate and method for preparing pyrroloquinoline quinone | |
| CN109942397B (en) | Preparation method of royal jelly acid | |
| CN115536494B (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol | |
| JPS6210510B2 (en) | ||
| CN109956891B (en) | Technical method for preparing 1, 1-dimethyl urea | |
| CN115368234B (en) | Synthetic method of cable Ma Lutai side chain and intermediate thereof | |
| CN114456194B (en) | Intermediate of Ai Duosha class tosylate and preparation method thereof | |
| CN115784916B (en) | Method for preparing 2- (S) -amino-4-arylbutyric acid compound | |
| CN115124440B (en) | Preparation method of prothioconazole intermediate | |
| CN112592289B (en) | Preparation method of gabapentin intermediate | |
| KR930000919B1 (en) | Method for the preparation of phenol | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| CN115873002A (en) | Synthesis method of Reidesciclovir intermediate | |
| CN118146181A (en) | 4-Bromophenic anhydride and its synthesis process | |
| WO2004018408A1 (en) | Synthesis and purification of nateglinide |
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 | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40088271 Country of ref document: HK |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |