CN115894362B - 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
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- CN115894362B CN115894362B CN202211415234.3A CN202211415234A CN115894362B CN 115894362 B CN115894362 B CN 115894362B CN 202211415234 A CN202211415234 A CN 202211415234A CN 115894362 B CN115894362 B CN 115894362B
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- 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 153
- 238000000034 method Methods 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims description 92
- 150000001875 compounds Chemical class 0.000 claims abstract description 300
- 238000006243 chemical reaction Methods 0.000 claims abstract description 195
- 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 42
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 230000001590 oxidative effect Effects 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- -1 N- (3, 4-dimethoxy-5-nitrophenyl) acetamide Chemical compound 0.000 claims description 97
- 239000011343 solid material Substances 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 49
- 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 group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 238000010931 ester hydrolysis 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
- 239000007868 Raney catalyst Substances 0.000 claims description 13
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 13
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 13
- 238000006783 Fischer indole synthesis reaction Methods 0.000 claims description 12
- 230000006196 deacetylation Effects 0.000 claims description 11
- 238000003381 deacetylation reaction Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 230000003301 hydrolyzing effect Effects 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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 238000005119 centrifugation Methods 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000006555 catalytic 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
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 230000003647 oxidation 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
- 230000000850 deacetylating effect Effects 0.000 claims description 3
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 3
- 230000009467 reduction 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
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 67
- 239000000543 intermediate Substances 0.000 description 37
- 239000000047 product Substances 0.000 description 34
- 239000000463 material Substances 0.000 description 32
- 238000001816 cooling Methods 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 238000001035 drying Methods 0.000 description 25
- 210000003298 dental enamel Anatomy 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000011229 interlayer Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 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 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
- 238000005406 washing Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution 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
- 235000019441 ethanol Nutrition 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- 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
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-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
- 239000012043 crude 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
- 238000001953 recrystallisation Methods 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
- 239000007858 starting material Substances 0.000 description 4
- 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 3
- 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
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000013305 food Nutrition 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
- 238000004321 preservation Methods 0.000 description 3
- 238000011085 pressure filtration Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 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
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 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
- XVZUXKIUSQRAFA-UHFFFAOYSA-N 4,5-dioxo-5-propoxypentanoic acid Chemical compound CCCOC(=O)C(=O)CCC(O)=O XVZUXKIUSQRAFA-UHFFFAOYSA-N 0.000 description 1
- IWALUEDCCVCEKL-UHFFFAOYSA-N 5-ethoxy-4,5-dioxopentanoic acid Chemical compound CCOC(=O)C(=O)CCC(O)=O IWALUEDCCVCEKL-UHFFFAOYSA-N 0.000 description 1
- UDPAQUGTQANQIB-UHFFFAOYSA-N 5-methoxy-4,5-dioxopentanoic acid Chemical compound COC(=O)C(=O)CCC(O)=O UDPAQUGTQANQIB-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-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
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 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 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
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 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
Classifications
-
- 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
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides an intermediate, and application and a method for preparing pyrroloquinoline quinone from the intermediate, 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 Linear or branched alkyl; r is R 2 Is nitro or amino; r is R 3 Is hydrogen or an amino protecting group; r is R 4 Selected from hydrogen and C 1 ‑C 3 Linear or branched alkyl. The method has the advantages of simple route, mild reaction conditions and high yield, avoids the use of an oxidant ceric ammonium nitrate, and realizes the industrial mass production of pyrroloquinoline quinone.
Description
Technical Field
The invention relates to the field of organic compound preparation, in particular to an intermediate, and application and a method for preparing pyrroloquinoline quinone.
Background
The information disclosed in the background of the invention is intended to enhance an understanding of the general background of the invention, and this disclosure should not necessarily be taken as an acknowledgement or any form of suggestion that this information has become known to a person of ordinary skill in the art.
Pyrroloquinoline quinone, its 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 quinone is widely present in plant-derived foods and animal-derived foods, such as fruits, vegetables, grains, and the like. However, pyrroloquinoline quinone is only present in foods at a level of nanograms to micrograms/kg. Thus, adequate PQQ cannot be obtained with dietary supplements alone, and pyrroloquinoline quinone is difficult and expensive to obtain with biological production and isolation methods.
For this reason, many scholars have started to study the chemical synthesis method of pyrroloquinoline quinone, corey et al have realized the total synthesis of pyrroloquinoline quinone for the first time (J.am.chem.Soc.1981, 103,18, 5599-5600), after which Martin et al have improved the Corey's route (Helvetica chimica acta,1993,76 (4): 1667-1673), and later Kempf et al have realized the gram-scale preparation of pyrroloquinoline quinone by combining the Corey and Martin routes (WO 2006/102642A 1), but concentrated sulfuric acid purification is required, and the separation and purification process of intermediates is cumbersome, and before Kempf, the method of Corey and Martin can only realize the preparation of pyrroloquinoline quinone at a scale of 50mg, which is mainly suitable for laboratory preparation, and difficult for industrial mass production. Still later, there was a study on the production of pyrroloquinoline quinone starting from methyl halobenzene, which enables the preparation of pyrroloquinoline quinone at kilogram level (WO 2014/195896), but the latter reaction stage necessitates the oxidation of methoxy-pyrroloquinoline intermediate to pyrroloquinoline quinone intermediate by ceric ammonium nitrate. Although the selectivity of the product is higher, the consumption of the ammonium cerium nitrate is extremely high, which is 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 of the step are difficult, the optimal yield of the step is difficult to exceed 60%, the efficiency of a reaction route is low, the production time is long, the kilogram-grade product is obtained for at least 4-5 weeks, and the efficient industrialization of the pyrroloquinoline quinone production is difficult to realize.
Disclosure of Invention
The invention provides an intermediate compound, and application and a method for preparing pyrroloquinoline quinone by using the intermediate compound. The preparation of pyrroloquinoline quinone by using the intermediate disclosed by the invention can greatly simplify a reaction route, control the reaction route within 7 steps, ensure that 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-grade products can be obtained within 2-3 weeks, and the efficient industrialized mass production of hundred kilogram-grade pyrroloquinoline quinone can be realized within 1.5 months.
Specifically, the invention provides the following technical scheme:
in a first aspect of the invention, the present invention provides an intermediate compound for preparing pyrroloquinoline quinone, having a structure represented by formula I or formula II:
wherein R is 1 Is C 1 -C 3 Linear or branched alkyl; r is R 2 Is nitro or amino; r is R 3 Is hydrogen or an amino protecting group; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched 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 a structure represented by 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, by way of 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-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (Compound II-1, R) 1 Is methyl, R 4 Hydrogen);
5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-2, R) 1 Is methyl, R 4 Methyl);
5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-1-3, R) 1 Is methyl, R 4 Ethyl);
5-acetamido-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 Hydrogen);
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-1-6, R) 1 Is ethyl, R 4 Methyl);
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-1-7, R) 1 Is ethyl, R 4 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 Hydrogen);
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-2, R 1 Is methyl, R 4 Methyl);
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-2-3, R) 1 Is methyl, R 4 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, R) 1 Is ethyl, R 4 Hydrogen);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester (Compound II-2-6, R) 1 Is ethyl, R 4 Methyl);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound II-2-7, R) 1 Is ethyl, R 4 Ethyl);
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester (Compound II-2-6, R) 1 Is ethyl, R 4 Propyl).
In a second aspect of the invention, the invention provides 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 by taking 3, 4-dimethoxy-5-nitrobenzoic acid or 3, 4-dimethoxy-5-nitroformamide as raw materials.
In an embodiment of the invention, the compound of formula I has a structure represented by formula I-1 or formula I-2:
wherein R is 1 Is methyl or ethyl.
Wherein, 3, 4-dialkoxy-5-nitroaniline and acetic anhydride undergo electrophilic substitution reaction to prepare a compound of formula I-1, and the compound of formula I-1 can be reduced to prepare a compound of formula I-2. In one embodiment, the reduction reaction may occur under conditions of raney nickel catalyzed high pressure hydrogenation.
In the embodiment of the invention, the compound of the formula II can further have a structure shown in the formula II-1 or the formula II-2, and the compound of the formula II-1 can be prepared from the compound of the formula I-2 and the compound of the formula V under the catalysis of Lewis acid and in an oxygen atmosphere (with oxygen); the compound of formula II-2 is prepared by deacetylation and/or ester hydrolysis of the compound of formula II-1
Wherein R is 4 Selected from hydrogen, methyl, ethyl and propyl.
In a third aspect of the invention, the use of any of the compounds of formula I or formula II as described in the first aspect of the invention as an intermediate in the preparation of pyrroloquinoline quinone;
wherein R is 1 Is C 1 -C 3 Linear or branched alkyl; r is R 2 Is nitro or amino; r is R 3 Is hydrogen or an amino protecting group; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched alkyl.
In a fourth aspect of the invention, there is provided a method of preparing pyrroloquinoline quinone comprising: preparing a compound of a formula III from a compound of a formula II-2 by a Fischer indole synthesis method, preparing a compound of a formula IV by hydrolyzing the compound of the formula III, and preparing pyrroloquinoline quinone by oxidizing the compound of the formula IV;
wherein R is 1 、R 4 As defined hereinabove;
preferably, R 1 Is methyl orEthyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In one embodiment of the invention, the compounds of formula II-2 may be prepared from the compounds of formula II-1 after deacetylation and/or ester hydrolysis;
wherein R is 1 、R 4 As defined hereinabove;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
In a fifth aspect of the invention, there is provided a method of preparing pyrroloquinoline quinone comprising: deacetylating the compound of the formula II-1, hydrolyzing the ester to obtain a compound of the formula II-2', preparing the compound of the formula II-2' into a compound of the formula III 'by a Fischer indole synthesis method, hydrolyzing the compound of the formula III' to obtain a compound of the formula IV, and oxidizing the compound of the formula IV to obtain pyrroloquinoline quinone;
Wherein R is 1 、R 4 As defined hereinabove;
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 the catalysis of a Lewis acid in an oxygen atmosphere (aerobic);
wherein R is 1 、R 4 As defined hereinabove;
preferably, R 1 Is methyl or ethyl, R 4 Selected from hydrogen,Methyl, ethyl and propyl.
In a sixth aspect of the invention, there is provided a method of preparing pyrroloquinoline quinone comprising: the method comprises the steps of preparing a compound of a formula I-2 and a compound of a formula V under the catalysis of Lewis acid in an oxygen atmosphere to obtain a compound of a formula II-1, performing deacetylation and ester hydrolysis on the compound of the formula II-1 to obtain a compound of a formula II-2', preparing a compound of a formula III ' from the compound of the formula II-2' through a Fischer indole synthesis method, 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 、R 4 As defined hereinabove;
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 hereinabove;
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 invention, there is provided a method of preparing pyrroloquinoline quinone comprising: reducing the compound I-1 to prepare a compound of a formula I-2, preparing the compound of the formula II-1 from the compound of the formula I-2 and the compound of the formula V under the catalysis of Lewis acid in an oxygen atmosphere, performing deacetylation and ester hydrolysis on the compound of the formula II-1 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 Fischer indole synthesis, 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 hereinabove;
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 formula I may be prepared by electrophilic substitution of 3, 4-dialkoxy-5-nitroaniline with acetic anhydride. The 3, 4-dialkoxy-5-nitroaniline can be prepared by taking 3, 4-dialkoxy-5-nitrobenzoic acid or 3, 4-dialkoxy-5-nitrobenzamide as raw materials. The alkoxy groups being predominantly C 1 -C 3 An alkoxy group.
In an embodiment of the invention, the compound of formula I has a structure represented by formula I-1 or formula I-2:
wherein R is 1 As defined hereinabove; preferably, R 1 Is methyl or ethyl.
Wherein, 3, 4-dialkoxy-5-nitroaniline and acetic anhydride undergo electrophilic substitution reaction to prepare a compound formula I-1, and the compound formula I-1 undergoes reduction reaction to prepare a compound 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 disclosed by the invention is used as an intermediate for preparing pyrroloquinoline quinone, so that a reaction route can be greatly simplified, the reaction route is controlled within 7 steps, the reaction condition is mild, raw materials are cheap and easy to obtain, the product yield is high, the efficiency is high, a kilogram-grade product can be obtained within 2-3 weeks, and the efficient industrialized mass production of the kilogram-grade pyrroloquinoline quinone can be realized.
In addition, the prior art tends to synthesize indole structure first and then quinoline structure, and the inventor finds that the operation mode is not selective in synthesizing indole structure, which means that the yield of the step is about 50% -60%, thus unnecessary impurities are easy to generate, the yield of the final product is influenced, the subsequent purification is complicated, and if quinoline structure is synthesized first by using intermediates in the prior art, the reaction route is too long, and the reaction efficiency is low. According to the invention, when the compound shown in the formula I or the compound shown in the formula II is used as an intermediate for preparing pyrroloquinoline quinone, a quinoline structure is synthesized firstly, then Fischer indole synthesis is carried out, 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 hundred-kilogram high-efficiency large-scale production of pyrroloquinoline quinone is realized.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
fig. 1: hydrogen spectrum of exemplary compounds of compound I-2.
Fig. 2: carbon spectrum of exemplary compound of compound I-2.
Fig. 3: hydrogen spectrum of exemplary compound of compound II-1.
Fig. 4: carbon spectrum of exemplary compound of compound II-1.
Fig. 5: hydrogen spectrum of exemplary compound of compound II-2.
Fig. 6: carbon spectrum of exemplary compound of compound II-2.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
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 materials used in the present invention may be purchased in conventional manners, and unless otherwise indicated, they may be used in conventional manners in the art or according to the product specifications. 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 methods and materials described herein are presented for illustrative purposes only.
The invention provides compounds of formula I or formula II, and methods of using these compounds as intermediates in the preparation of pyrroloquinoline quinone.
Wherein R is 1 Is C 1 -C 3 Linear or branched alkyl; r is R 2 Is nitro or amino; r is R 3 Is hydrogen or an amino protecting group; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched 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 hydrogen, methyl, ethyl or propyl.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using the 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 the formula II-2 can be prepared by deacetylation and/or ester hydrolysis of the compound of the formula II-1.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using the 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 step 1 deacetylation.
In some embodiments of the present invention, the process for preparing pyrroloquinoline quinone using the compound of formula I 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 step 2 deacetylation.
Wherein the compound of formula I-2 may be prepared from the compound of formula I-1 by a reduction reaction that may occur under conditions such as Raney nickel catalyzed high pressure hydrogenation.
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 step 4 deacetylation.
In the reaction route, 3, 4-dialkoxy-5-nitroaniline compound is used as an intermediate, when pyrroloquinoline quinone is prepared, a quinoline structure is firstly synthesized, then Fischer indole synthesis is carried out, the selectivity of indole synthesis is improved through quinoline occupation, the generation of unnecessary substances is avoided, the synthesis efficiency and yield are greatly improved, and the subsequent complicated purification work is reduced.
In some embodiments of the invention, the last of the above-described various reactions is an oxidation reaction, which may be carried out in one step or according to the following reaction scheme:
wherein, in some preferred embodiments, R 1 Is methyl or ethyl.
For example, in one 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 undergo electrophilic substitution reaction in a solvent to prepare a compound shown in 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 1:1-5.
In some embodiments of the invention, the temperature of step (1) in the reaction stage is controlled between 20 and 45 ℃.
Further, after the reaction is finished, the compound of the formula I-1 can be obtained through crystallization (such as temperature reduction and the like), centrifugation, drying and the like; and recovering solvent from the mother liquor, and crystallizing the residue (such as cooling, etc.), centrifuging, drying, etc. to obtain compound of formula I-1.
(2) Reducing the compound of formula I-1 under Raney nickel catalytic high-pressure hydrogenation conditions to prepare a compound of formula I-2;
in some embodiments of the invention, step (2) is optionally a solvent that is an alcohol, such as a simple alcohol, e.g., methanol, ethanol, or the like.
In some embodiments of the invention, the reaction temperature of step (2) is in the range of 20-50 ℃, e.g., may further be 20-30 ℃ or 40-50 ℃.
In some embodiments of the invention, the high pressure in step (2) is maintained at 0.5-2MPa.
In some embodiments of the invention, the amount of compound of formula I-1 in step (2) is 10-24 times (mass ratio) the amount of Raney nickel.
Further, after the reaction is completed, the compound of formula I-2 may be obtained by removing Raney nickel, recovering the solvent, crystallizing (e.g., cooling, etc.), centrifuging, drying, etc.
(3) The compound formula I-2 and the compound formula V react under the catalysis of Lewis acid in an oxygen atmosphere to prepare a compound formula II-1;
in some embodiments of the invention, the molar ratio of compound formula I-2 to compound formula V is 1:1-3.
In some embodiments of the invention, the molar ratio of compound formula I-2 to Lewis acid is 1:1-2.
In some embodiments of the invention, the reaction solvent may be methylene chloride.
In some embodiments of the invention, the temperature of the reaction stage of step (3) is controlled between 10 and 35 ℃.
Further, after the reaction is completed, the compound of formula II-1 may be obtained by recrystallization, centrifugation, drying, or the like.
(4) Deacetylating the compound of formula II-1 under acidic conditions and performing ester hydrolysis to obtain a compound of formula II-2';
in some embodiments of the present invention, step (4) comprises reacting the compound of formula II-1 under acidic conditions (e.g., adding methanesulfonic acid) at a temperature of 60-80deg.C, crystallizing by cooling to below 20deg.C after the reaction is completed, and centrifuging; and (3) adding 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 ℃ to perform 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 II-2' by a Fischer indole synthesis method;
in some embodiments of the invention, compound formula II-2' is reacted with ethyl 2-methylacetoacetate, wherein the molar ratio of compound formula II-2 to ethyl 2-methylacetoacetate is 1:1-2.
In some embodiments of the present invention, step (5) comprises mixing and stirring the anhydrous alcohol solvent with 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 ℃ or below (even-10 ℃ or below), rapidly feeding sodium nitrite, stirring at-5 ℃ to react after the dripping, dripping 2-methyl acetoacetate at 0 ℃ or below (even-5 ℃ or below), dripping sodium acetate at 0 ℃ or below (even-5 ℃ or below), keeping the temperature for reacting, heating the system to 20-25 ℃ to react, stirring, centrifuging and washing to obtain a compound intermediate wet product of the formula III after the reaction, mixing the wet product with 50% sulfuric acid, heating the system to 35-45 ℃ to stir, reacting, slowly adding the reaction solution into ice water mixed solution after the reaction is finished, separating out solid materials, centrifuging, washing and drying to obtain the compound III'.
(6) And (3) carrying out ester hydrolysis reaction on the compound shown in the formula III' to obtain the compound shown in the formula IV.
(7) Oxidizing the compound formula IV to obtain PQQ, or oxidizing the compound formula IV to obtain an intermediate G to obtain PQQ; for example, compound formula IV may be prepared as intermediate G by reaction with a protic acid (e.g., under HAC/HI acid conditions), which may be hydrobromic or hydroiodic acid, preferably hydroiodic acid; for example, the oxidizing agent may be used as the oxidizing agent, and the oxidizing agent may be one or more selected from hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone, preferably hydrogen peroxide.
Specifically, in connection 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 by taking 3, 4-dimethoxy-5-nitrobenzoic acid or 3, 4-dimethoxy-5-nitroformamide as raw materials. For example, 3, 4-dimethoxy-5-nitroaniline may be prepared according to the method of U.S. Pat. No. 5, 5236952, the disclosure of which is incorporated herein by reference. Alternatively, as an example, the 3, 4-dimethoxy-5-nitroaniline according to the present invention may be prepared as follows:
908kg of toluene, 180kg of thionyl chloride and 227kg of 3, 4-dimethoxy-5-nitrobenzoic acid are put into a 2000L reaction kettle, stirring is started, steam is introduced into a jacket of the reaction kettle, the temperature is raised to 80 ℃, and the reaction is carried out at 70-80 ℃ for 8 hours. After the reaction, toluene was distilled under reduced pressure to 85℃and the residue was cooled slightly to 50℃and diluted with 100kg of acetone, the residue was slowly reacted to 1000kg of 25% aqueous ammonia previously cooled to 5℃or below. After the reverse addition is finished, the solid material is 3, 4-dimethoxy-5-nitrobenzamide. Centrifuging to obtain 452kg of wet 3, 4-dimethoxy-5-nitrobenzamide.
Adding 950kg of 10% sodium hypochlorite and 1060kg of 10% sodium carbonate into another 3000L reaction kettle, starting stirring, introducing 5 ℃ condensed water into the jacket of the reaction kettle, and cooling to below 20 ℃. Stopping stirring, adding 452kg of 3, 4-dimethoxy-5-nitrobenzamide wet product into the reaction kettle, starting stirring, and stirring and reacting for 3h at 15-20 ℃. Stopping cooling after the reaction is finished, introducing steam into the jacket of the reaction kettle, heating to 70 ℃ within 1h, and stirring and reacting for 3h at 70-75 ℃. After the reaction is finished, cooling to below 5 ℃, stirring and crystallizing for 3 hours, centrifuging to obtain 380kg of 3, 4-dimethoxy-5-nitroaniline wet product, and drying in an oven at 90 ℃ to obtain 172.8kg of 3, 4-dimethoxy-5-nitroaniline dry product. Molar yield: 87.3% and 99% HPLC purity.
According to the method, 3, 4-diethoxy-5-nitroaniline can be prepared by taking 3, 4-diethoxy-5-nitrobenzoic acid as a raw material to replace 3, 4-dimethoxy-5-nitrobenzoic acid.
The above-mentioned feeding reaction is carried out for a plurality of times to accumulate 3, 4-dimethoxy-5-nitroaniline material and 3, 4-diethoxy-5-nitroaniline material for the preparation of the target product.
The preparation of the intermediates of the present application and, under certain conditions, the preparation of PQQ with the intermediates of the present application are illustrated in the following examples, which are examples of preparation of hundred gram grade products, which in practice are performed with multiple dosing reactions, each time the same, in order to accumulate sufficient material for each step of reaction.
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 reactor, and stirring is started to uniformly mix the materials. 122.4kg of acetic anhydride is slowly dripped into the reaction kettle by a dripping tank at 20-30 ℃ and stirred for 1h after the dripping is finished. Steam was introduced into the reactor jacket, the temperature was raised to reflux, and the reaction was stirred for 2 hours. After the reaction, 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 drying at 90deg.C to obtain 228kg of compound I-1-1 dry product. Recovering ethyl acetate from the mother liquor, cooling the remainder to 15-20deg.C, centrifuging to obtain crude product wet product of compound I-1-1, and oven drying at 90deg.C to obtain 3.8kg crude product of compound I-1-1. Total molar yield: 96.58%, HPLC purity: 99.3%.
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 reactor, and stirring is started to uniformly mix the materials. 122.4kg of acetic anhydride is slowly dripped into the reaction kettle by a dripping tank at the temperature of 35-45 ℃ and stirred for 1h after the dripping is finished. Steam was introduced into the reactor jacket, the temperature was raised to reflux, and the reaction was stirred for 2 hours. After the reaction, 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 90deg.C to obtain 216kg of compound I-1-1 dry product. Recovering ethyl acetate from the mother liquor, cooling the remainder to 15-20deg.C, centrifuging to obtain crude product wet product of compound I-1-1, and oven drying at 90deg.C to obtain 8.3kg crude product of compound I-1-1. Total molar yield: 93.4%, HPLC purity: 99.09%.
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 reactor, and stirring is started to uniformly mix the materials. 122.4kg of acetic anhydride is dripped into the reaction kettle by a dripping tank at 20-30 ℃ and stirred for 1h after the dripping is finished. Steam was introduced into the reactor jacket, the temperature was raised to reflux, and the reaction was stirred for 2 hours. After the reaction, 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 drying at 90deg.C to obtain 213.6kg of compound I-1-1 dry product. Recovering ethyl acetate from the mother liquor, cooling the remainder to 20deg.C, centrifuging to obtain crude compound I-1-1 wet product, and oven drying at 90deg.C to obtain 6.9kg of crude compound I-1-1. Total molar yield: 91.8%, HPLC purity: 98.9%.
The raw material 3, 4-dimethoxy-5-nitroaniline is replaced by 3, 4-diethoxy-5-nitroaniline, and N- (3, 4-diethoxy-5-nitrophenyl) acetamide (compound I-1-2) can be prepared according to the method described in preparation examples 1-3, wherein the total molar yield is above 90%, and the purity is above 99%.
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 material is fed, the nitrogen replaces air three times, and the hydrogen replaces nitrogen three times. Stirring is started, and hydrogen is filled into the reaction kettle to keep the hydrogen pressure at 0.5MPa. When the pressure is reduced, hydrogen is replenished in time, and the operation is performed until the hydrogen pressure is no longer reduced. The reaction was continued with stirring for 2h, during which the temperature was maintained at 20-30 ℃. And after the reaction is finished, the reaction liquid is subjected to pressure filtration to remove Raney nickel. The filtrate is recovered under normal pressure and then reduced pressure, the residue is cooled to 20 ℃, and stirred and crystallized for 2 hours. After crystallization, the solid material is centrifuged and dried at 80 ℃ to obtain the compound I-2-1 with the yield of 201.6kg, and the hydrogen spectrum and the carbon spectrum are respectively shown in the figure 1 and the figure 2. Molar yield: 96%, HPLC purity: 99%.
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 into a 2000L high-pressure hydrogenation reactor. After the material is fed, the nitrogen replaces air three times, and the hydrogen replaces nitrogen three times. Stirring is started, and hydrogen is filled into the reaction kettle to keep the hydrogen pressure at 0.5MPa. When the pressure is reduced, hydrogen is replenished in time, and the operation is performed until the hydrogen pressure is no longer reduced. The reaction was continued with stirring for 2h, during which the temperature was maintained at 20-30 ℃. And after the reaction is finished, the reaction liquid is subjected to pressure filtration to remove Raney nickel. The filtrate is recovered under normal pressure and then reduced pressure, the residue is cooled to 20 ℃, and stirred and crystallized for 2 hours. After crystallization, the solid material is centrifuged and dried at 80 ℃ to obtain the compound I-2-1 with the yield of 189.6kg, and the nuclear magnetic data of the compound is basically consistent with that of the compound prepared in preparation example 4. Molar yield: 90.3%, HPLC purity: 99%.
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 into a 2000L high-pressure hydrogenation reactor. After the material is fed, the nitrogen replaces air three times, and the hydrogen replaces nitrogen three times. Stirring is started, and hydrogen is filled into the reaction kettle to keep the hydrogen pressure at 0.5MPa. When the pressure is reduced, hydrogen is replenished in time, and the operation is performed until the hydrogen pressure is no longer reduced. The reaction was continued with stirring for 2h, during which the temperature was maintained at 40-50 ℃. And after the reaction is finished, the reaction liquid is subjected to pressure filtration to remove Raney nickel. The filtrate is recovered under normal pressure and then reduced pressure, the residue is cooled to 20 ℃, and stirred and crystallized for 2 hours. After crystallization, the solid material is centrifuged and dried at 80 ℃ to obtain the compound I-2-1 with the yield of 178.5kg, and the nuclear magnetic data of the compound is basically consistent with that of the compound prepared in preparation example 4. Molar yield: 85%, HPLC purity: 99%.
The raw material N- (3, 4-dimethoxy-5-nitrophenyl) acetamide (compound I-1-1) is replaced by N- (3, 4-diethoxy-5-nitrophenyl) acetamide (compound I-1-2), N- (3-amino-4, 5-diethoxyphenyl) acetamide (compound I-2-2) can be prepared according to the method described in preparation example 4-6, and the total molar yield is more than 88%, and the purity is not lower than 99%.
EXAMPLE 2 preparation of Compounds of formula II
Preparation example 7: preparation of 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid diethyl ester (Compound formula II-1-3)
210kg of compound I-2-1 (preparation 4) and 1260kg of methylene chloride were introduced into a 3000L enamel reactor, stirring was started, and 501.5kg of ethyl 2-oxoglutarate and 200kg of zinc chloride were introduced into the reactor. After the material is fed, stirring and reacting for 24 hours at 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 then reduced pressure. After distillation, 1200kg of 70% ethanol is added into the reaction kettle, and after the addition, the temperature is raised to 70 ℃ and the mixture is stirred for 1h, so that the materials are fully and uniformly dispersed. After the completion, the temperature is reduced to 15 ℃ for cooling and crystallizing for 3 hours, and pale yellow solid is separated out. Centrifuging, and drying the solid material at 90 ℃ to obtain a compound II-1-3, wherein the yield is 362.7kg, and the molar yield is: 93% HPLC purity.
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 4) and 1260kg of methylene chloride were placed in a 3000L enamel reactor, stirring was started, and 477.7kg of methyl 2-oxoglutarate and 200kg of zinc chloride were placed in the reactor. After the material is fed, 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 then reduced pressure. After distillation, 1200kg of 70% ethanol is added into the reaction kettle, and after the addition, the temperature is raised to 70 ℃ and the mixture is stirred for 1h, so that the materials are fully and uniformly dispersed. After the completion, the temperature is reduced to 15 ℃ for cooling and crystallizing for 3 hours, and pale yellow solid is separated out. Centrifuging, and drying the solid material at 90 ℃ to obtain a compound II-1-2, wherein the yield is 304.1kg, and the molar yield is: 91.05% and HPLC purity 98.2%.
Preparation example 9: preparation of dipropyl 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylate (Compound II-1-4)
210kg of compound I-2-1 (preparation 4) and 1260kg of methylene chloride were introduced into a 3000L enamel reactor, stirring was started, and 525kg of propyl 2-oxoglutarate and 200kg of zinc chloride were introduced into the reactor. After the material is added, stirring and reacting for 24 hours at 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 then reduced pressure. After distillation, 1200kg of 70% ethanol is added into the reaction kettle, and after the addition, the temperature is raised to 70 ℃ and the mixture is stirred for 1h, so that the materials are fully and uniformly dispersed. After the completion, the temperature is reduced to 15 ℃ for cooling and crystallizing for 3 hours, and pale yellow solid is separated out. Centrifuging, and drying the solid material at 90deg.C to obtain compound II-1-4, wherein the yield is 344.8kg, and the hydrogen spectrum and carbon spectrum are shown in FIG. 3 and FIG. 4 respectively. Molar yield: 82.5% and HPLC purity 98.8%.
The starting material N- (3-amino-4, 5-dimethoxyphenyl) acetamide (compound I-2-1) was replaced with N- (3-amino-4, 5-diethoxyphenyl) acetamide (compound I-2-2), and diethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-7) was prepared according to the method described in preparation examples 7-9, respectively; dimethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-6) and dipropyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-8) have a total molar yield of 80% or more and a purity of not less than 98%.
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 the compound II-1-4 (preparation 9) were charged into a 2000L enamel reactor. After the addition, stirring is started until the solid materials are completely dissolved, steam is introduced into the interlayer of the reaction kettle, the temperature is raised to 75-80 ℃ under stirring, and the reaction is stirred for 10 hours. After the reaction is finished, the temperature is reduced to 20 ℃, and the mixture is stirred and crystallized for 3 hours. And (5) after crystallization, centrifuging. Putting the solid wet product obtained after centrifugation into 2150kg of 10% hydrochloric acid, introducing steam into the interlayer of the reaction kettle, heating to 60-70 ℃, and stirring at 60-70 ℃ for reaction for 12h. After the reaction, the temperature is reduced to 40 ℃, the solid material is centrifuged, the solid material is rinsed with purified water and then washed once, 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 of the compound II-2-1 are respectively shown in fig. 5 and 6. Molar yield: 89%, HPLC purity: 98.5%.
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 compound II-1-2 (preparation 8) were introduced into a 2000L enamel reactor. After the addition, stirring is started until the solid materials are completely dissolved, steam is introduced into the interlayer of the reaction kettle, the temperature is raised to 60-70 ℃ under stirring, and the reaction is stirred for 12 hours. After the reaction is finished, the temperature is reduced to 20 ℃, and the mixture is stirred and crystallized for 3 hours. And (5) after crystallization, centrifuging. Putting the solid wet product obtained after centrifugation into 2150kg of 10% hydrochloric acid, introducing steam into the interlayer of the reaction kettle, heating to 40-50 ℃, and stirring at 40-50 ℃ for reaction for 16h. After the reaction, the solid material is centrifuged, the solid material is rinsed with purified water and then washed once, the obtained solid material is dried at 90 ℃ to obtain the compound II-2-1, the yield is 238.3kg, and the nuclear magnetic data of the compound II-2-1 is basically consistent with the product prepared in preparation example 10. Molar yield: 81.6% hplc purity: 99.03%.
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 7) were introduced into a 2000L enamel reactor. After the addition, stirring is started until the solid materials are completely dissolved, steam is introduced into the interlayer of the reaction kettle, the temperature is raised to 75-80 ℃ under stirring, and the reaction is stirred for 10 hours. After the reaction is finished, the temperature is reduced to 20 ℃, and the mixture is stirred and crystallized for 3 hours. And (5) after crystallization, centrifuging. Putting the solid wet product obtained after centrifugation into 2886kg of 10% sulfuric acid, introducing steam into the interlayer of the reaction kettle, heating to 60-70 ℃, and stirring at 60-70 ℃ for reaction for 12h. After the reaction, cooling to 40 ℃, centrifuging, eluting the solid material with purified water and washing once, centrifuging, drying the obtained solid material at 90 ℃ to obtain a compound II-2-1, wherein 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 preparation example 10. Molar yield: 78.6%, HPLC purity: 98.4%.
The starting materials, i.e., 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), and 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), and dipropyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate (compound II-1-8) were replaced with each other, and the total molar yields of 5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid (compound II-2-5) were not lower than 78% by the method described in preparation examples 10-12.
EXAMPLE 3 preparation of Compounds 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 introducing cold brine into the interlayer of the reaction kettle, and cooling the reaction system to 10 ℃. After cooling, 325kg of concentrated hydrochloric acid is dripped into the reaction kettle by a dripping tank. After the completion of the dropwise addition, stirring for 30min. After the completion of the reaction, the temperature of the reaction system was lowered to-10℃and 233kg of 40% sodium nitrite was rapidly fed into the reaction vessel using a dropping tank. After the addition, stirring and reacting for 3 hours at the temperature of between 5 ℃ below zero and 0 ℃ below zero, wherein the material is bright yellow thick liquid. After the completion of the reaction, 200kg of ethyl 2-methylacetoacetate was added to the reaction vessel 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 dripping is finished, the mixture is stirred and reacts for 4 hours at the temperature of-5 ℃ to 0 ℃. After the reaction is finished, the cold brine is removed from the interlayer of the reaction kettle, the reaction system is slowly heated to 20-25 ℃, and the reaction is stirred for 16 hours at 20-25 ℃. After the reaction, the mixture is centrifuged, and the solid material is washed once with water. 872kg of intermediate wet product of the compound formula III-1 is obtained.
1000kg of 50% sulfuric acid and 872kg of a compound III-1 intermediate wet product are put into a 2000L reaction kettle, uniformly stirred, steam is put into an interlayer of the reaction kettle, and the reaction system is heated to 40 ℃ and stirred for 16h for reaction. After the reaction is finished, slowly adding the reaction solution into 3000kg ice water mixed solution, separating out solid materials, centrifuging, washing the solid materials to be neutral, centrifuging, drying and drying the solid materials at 80 ℃ to obtain a compound III-1, wherein the yield is 333.7kg, and the molar yield is: 86%, 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 introducing cold brine into the interlayer of the reaction kettle, and cooling the reaction system to 10 ℃. After cooling, 325kg of concentrated hydrochloric acid is dripped into the reaction kettle by a dripping tank. After the completion of the dropwise addition, stirring for 30min. After the completion of the reaction, the temperature of the reaction system was lowered to 0℃and 233kg of 40% sodium nitrite was rapidly fed into the reaction vessel using a dropping tank. After the addition, stirring and reacting for 3 hours at the temperature of 0-5 ℃ and obtaining bright yellow thick liquid. After the completion of the reaction, 200kg of ethyl 2-methylacetoacetate was added to the reaction vessel at 0 ℃. After the addition, 1038kg of 30% sodium acetate was added dropwise to the reaction vessel at 0℃using a dropping pot. After the dripping is finished, the mixture is stirred and reacts for 4 hours at the temperature of 0-5 ℃. After the reaction is finished, the cold brine is removed from the interlayer of the reaction kettle, the reaction system is slowly heated to 20-25 ℃, and the reaction is stirred for 16 hours at 20-25 ℃. After the reaction, the mixture is centrifuged, and the solid material is washed once with water. 863kg of wet compound III-1 intermediate is obtained.
1000kg of 50% sulfuric acid and 863kg of compound III-1 intermediate wet product are put into a 3000L reaction kettle, uniformly stirred, steam is put into an interlayer of the reaction kettle, and the reaction system is heated to 40 ℃ and stirred for 16h for reaction. After the reaction is finished, slowly adding the reaction solution into 3000kg of ice water mixed solution, separating out solid materials, centrifuging, washing the solid materials to be neutral, centrifuging, drying and drying the solid materials at 80 ℃ to obtain a compound III-1, wherein the yield is 322kg, and the molar yield is: 83%, HPLC purity 99%.
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 absolute methanol and 292kg of compound II-2-1 (preparation example 10) are put into a 3000L enamel reactor, and stirring is started to fully and uniformly stir the materials in the reactor. And introducing cold brine into the interlayer of the reaction kettle, and cooling the reaction system to 10 ℃. After the completion of the cooling, 641kg of 50% sulfuric acid was added dropwise to the reaction vessel with a dropping tank. After the completion of the dropwise addition, stirring for 30min. After the completion of the reaction, the temperature of the reaction system was lowered to-10℃and 233kg of 40% sodium nitrite was rapidly fed into the reaction vessel using a dropping tank. After the addition, stirring and reacting for 3 hours at the temperature of between 5 ℃ below zero and 0 ℃ below zero, wherein the material is bright yellow thick liquid. After the completion of the reaction, 200kg of ethyl 2-methylacetoacetate was added to the reaction vessel 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 dripping is finished, the mixture is stirred and reacts for 4 hours at the temperature of-5 ℃ to 0 ℃. After the reaction is finished, the cold brine is removed from the interlayer of the reaction kettle, the reaction system is slowly heated to 20-25 ℃, and the reaction is stirred for 16 hours at 20-25 ℃. After the reaction, the mixture is centrifuged, and the solid material is washed once with water. 820kg of wet product of the intermediate of the compound III-1 is obtained.
1000kg of 50% sulfuric acid and 820kg of wet product of the compound III-1 intermediate are put into a 2000L reaction kettle, uniformly stirred, steam is put into an interlayer of the reaction kettle, and the reaction system is heated to 40 ℃ and stirred for 16h for reaction. After the reaction is finished, slowly adding the reaction solution into 3000kg ice water mixed solution, separating out solid materials, centrifuging, washing the solid materials to be neutral, centrifuging, drying and drying the solid materials at 80 ℃ to obtain the compound III-1, wherein the yield is 291kg, and the molar yield is: 75% HPLC purity.
The starting 5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid (compound II-2-1) was replaced with 5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid (compound II-2-5), and 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, with a molar yield of not less than 75% and an HPLC purity of not less than 99%.
EXAMPLE 4 preparation of Compounds 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)
160kg of sodium hydroxide and 1680kg of purified water are put into a 3000L enamel reaction kettle, stirred until solid materials are completely dissolved, 388kg of compound III-1 (preparation example 13) is put into the enamel reaction kettle, and after the adding, steam is introduced into an interlayer of the reaction kettle, the temperature is raised to 80 ℃ and the mixture is stirred for 3 hours for reaction. After the reaction is finished, cooling to 30 ℃, adjusting the pH to 2-3 by acid, centrifuging, washing the solid material once by water, 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 was 98.5%.
Preparation example 17: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (Compound formula IV-1)
224kg of potassium hydroxide and 1680kg of purified water are put into a 3000L enamel reaction kettle, stirred until solid materials are completely dissolved, 388kg of compound formula III-1 (preparation example 13) is put into the enamel reaction kettle, and after the adding, steam is introduced into an interlayer of the reaction kettle, the temperature is raised to 80 ℃ and the mixture is stirred for 3 hours for reaction. After the reaction, cooling to 30 ℃, adjusting the pH to 2-3 with acid, centrifuging, washing the solid material once with water, centrifuging, and drying the solid material at 90 ℃ to obtain the compound IV-1, wherein the yield is 316.8g. Molar yield 88%, HPLC purity 99.5%.
Preparation example 18: preparation of 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (Compound formula IV-1)
160kg of sodium hydroxide and 1680kg of purified water are put into a 3000L enamel reaction kettle, stirred until solid materials are completely dissolved, 388kg of compound III-1 (preparation example 13) is put into the enamel reaction kettle, and after the adding, steam is introduced into an interlayer of the reaction kettle, the temperature is raised to 50-60 ℃ and the mixture is stirred for 6 hours for reaction. After the reaction is finished, cooling to 30 ℃, adjusting the pH to 2-3 by acid, centrifuging, washing the solid material once by water, centrifuging, and drying the solid material at 90 ℃ to obtain the compound IV-1, wherein the yield is 324g. Molar yield 90%, HPLC purity 99%.
The starting material 2- (ethoxycarbonyl) -4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound formula III-1) is replaced by 4, 5-diethoxy-2- (ethoxycarbonyl) -1H-pyrrolo [2,3-f ] quinoline-7, 9-dicarboxylic acid (compound formula III-2), and 4, 5-diethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-2) can be prepared according to the method described in preparation examples 16-18, wherein the molar yield is more than 90%, and the HPLC purity is not less than 99%.
EXAMPLE 5 preparation of pyrroloquinoline quinone (PQQ)
Preparation example 19:
180kg of the compound IV-1 (preparation 16) and 900kg of acetic acid were charged into a 2000L enamel reactor. Stirring was started and 40% HI 540kg of solution was slowly added dropwise to the reaction vessel at 30-40℃using a dropping pot. After the dripping is finished, the temperature is raised to 70-80 ℃, and the mixture is stirred for reaction for 10 hours under heat preservation. After the reaction is finished, cold brine is introduced into a jacket of the reaction kettle, the materials are cooled to 20 ℃, the materials are slowly and reversely added into 2000kg ice water, solid materials are separated out, the solid materials are centrifugated, purified water washes the solid materials until the pH value is 4-5, the solid materials are centrifugated, methanol is used for recrystallisation, and 298.8kg of wet product of compound IV-1 intermediate (compound G) is obtained after the solid materials are dried at 90 ℃. 298.8kg of intermediate (compound G) of the compound formula IV-1 and 900kg of 30% hydrogen peroxide solution are put into a 2000L enamel reaction kettle, and stirring is started to uniformly stir materials in the kettle. Introducing steam into the interlayer of the reaction kettle, stirring and heating to 35 ℃, and stirring and reacting for 24 hours at 30-35 ℃. After the reaction, cooling to 20 ℃, centrifuging, and drying the solid material at 90 ℃ to obtain 153.5kg of compound PQQ. The molar yield was 93% and the HPLC purity was 99.8%.
Preparation example 20:
180kg of the compound IV-1 (preparation 16) and 900kg of acetic acid were charged into a 2000L enamel reactor. Stirring was started and 40% HI 540kg of solution was slowly added dropwise to the reaction vessel at 20-30deg.C using a dropping pot. After the dripping is finished, the temperature is raised to 60-70 ℃, and the reaction is carried out for 12 hours with heat preservation and stirring. After the reaction is finished, cold brine is introduced into a jacket of the reaction kettle, the temperature of the materials is reduced to 20 ℃, the materials are slowly and reversely added into 2000kg ice water, solid materials are separated out, the solid materials are centrifugated, purified water washes the solid materials until the pH value is 4-5, the solid materials are centrifugated, methanol is used for recrystallisation, and 293.8kg of wet product of compound IV-1 intermediate (compound G) is obtained. 293.8kg of intermediate (compound G) of the compound formula IV-1 and 900kg of 30% hydrogen peroxide solution are put into a 2000L enamel reaction kettle, and stirring is started to uniformly stir materials in the kettle. Introducing steam into the interlayer of the reaction kettle, stirring and heating to 35 ℃, and stirring and reacting for 24 hours at 30-35 ℃. After the reaction, cooling to 20 ℃, centrifuging, and drying the solid material at 90 ℃ to obtain 148.5kg of compound PQQ. Molar yield 90%, HPLC purity 99.5%.
Preparation example 21:
180kg of the compound IV-1 (preparation 16) and 900kg of acetic acid were charged into a 2000L enamel reactor. Stirring was started and 30% HI 720kg of solution was slowly added dropwise to the reaction vessel at 30-40℃using a dropping pot. After the dripping is finished, the temperature is raised to 70-80 ℃, and the mixture is stirred for reaction for 10 hours under heat preservation. After the reaction is finished, cold brine is introduced into a jacket of the reaction kettle, the materials are cooled to 20 ℃, the materials are slowly and reversely added into 2000kg ice water, solid materials are separated out, the solid materials are centrifugated, purified water washes the solid materials until the pH value is 4-5, the solid materials are centrifugated, methanol is used for recrystallisation, and 272.2kg of wet product of the compound IV-1 intermediate (compound G) is obtained from the solid materials. 272.2kg of compound IV-1 intermediate (compound G) wet product and 900kg of 30% hydrogen peroxide solution are put into a 2000L enamel reaction kettle, and stirring is started to uniformly stir materials in the kettle. Introducing steam into the interlayer of the reaction kettle, stirring and heating to 35 ℃, and stirring and reacting for 24 hours at 30-35 ℃. After the reaction is finished, the temperature is reduced to 20 ℃, the mixture is centrifuged, and the solid material is dried at 90 ℃ to obtain the compound PQQ 147.7kg. The molar yield was 89.5% and the HPLC purity was 99.8%.
The starting material 4, 5-dimethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-1) was replaced with 4, 5-diethoxy-1H-pyrrolo [2,3-f ] quinoline-2, 7, 9-tricarboxylic acid (compound IV-2), and PQQ was prepared according to the method described in preparation examples 19-21, with a molar yield of not less than 90% and an HPLC purity of not less than 99.5%.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (22)
1. An intermediate compound for preparing pyrroloquinoline quinone, which has a structure shown in a formula I or a formula II:
wherein R is 1 Is C 1 -C 3 Linear or branched alkyl; r is R 2 Is nitro or amino; r is R 3 Is hydrogen or methyl carbonyl; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched alkyl.
2. An intermediate compound according to 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 said compound 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-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid;
5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dimethyl ester;
diethyl 5-acetamido-7, 8-dimethoxyquinoline-2, 4-dicarboxylate;
2, 4-dicarboxylic acid dipropyl 5-acetamido-7, 8-dimethoxyquinoline;
5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid;
dimethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate;
diethyl 5-acetamido-7, 8-diethoxyquinoline-2, 4-dicarboxylate;
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;
diethyl 5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylate;
5-amino-7, 8-dimethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester;
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid;
dimethyl 5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid;
diethyl 5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylate;
5-amino-7, 8-diethoxyquinoline-2, 4-dicarboxylic acid dipropyl ester.
4. Use of an intermediate compound according to any one of claims 1 to 3 for the preparation of pyrroloquinoline quinone.
5. A method of preparing pyrroloquinoline quinone, comprising: preparing a compound of a 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 Linear or branched alkyl; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched alkyl.
6. The method for preparing pyrroloquinoline quinone according to claim 5, wherein R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
7. A method of preparing pyrroloquinoline quinone, comprising: deacetylating the compound of the formula II-1, hydrolyzing the ester to obtain a compound of the formula II-2', preparing the compound of the formula II-2' into a compound of the formula III 'by a Fischer indole synthesis method, hydrolyzing the compound of the formula III' to obtain a compound of the formula IV, and oxidizing the compound of the formula IV to obtain pyrroloquinoline quinone;
；
wherein R is 1 Is C 1 -C 3 Linear or branched alkyl; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched alkyl.
8. The method for preparing pyrroloquinoline quinone according to claim 7, wherein R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
9. A method of preparing pyrroloquinoline quinone, comprising: the method comprises the steps of preparing a compound of a formula I-2 and a compound of a formula V under the catalysis of Lewis acid in an oxygen atmosphere to obtain a compound of a formula II-1, performing deacetylation and ester hydrolysis on the compound of the formula II-1 to obtain a compound of a formula II-2', preparing the compound of the formula II-2' into a compound of a formula III 'through a Fischer indole synthesis method, 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 Linear or branched alkyl; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched alkyl.
10. The method for preparing pyrroloquinoline quinone according to claim 9, wherein R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
11. A method of preparing pyrroloquinoline quinone, comprising: reducing the compound I-1 to prepare a compound of a formula I-2, preparing the compound of the formula I-2 and the compound of a formula V under the catalysis of Lewis acid in an oxygen atmosphere to obtain a compound of a formula II-1, performing deacetylation and ester hydrolysis on the compound of the formula II-1 to prepare a compound of a formula II-2', preparing the compound of the formula II-2' into a compound of a formula III 'through 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 Is C 1 -C 3 Linear or branched alkyl; r is R 4 Selected from hydrogen and C 1 -C 3 Linear or branched alkyl.
12. The method for preparing pyrroloquinoline quinone according to claim 11, wherein R 1 Is methyl or ethyl, R 4 Selected from hydrogen, methyl, ethyl and propyl.
13. The process for the preparation of pyrroloquinoline quinone according to claim 11, wherein the compound of formula I-1 is prepared by electrophilic substitution of 3, 4-dialkoxy-5-nitroaniline with acetic anhydride in a solvent;
the alkoxy group is C 1 -C 3 An alkoxy group.
14. The method of preparing pyrroloquinoline quinone according to claim 13, wherein the 3, 4-dialkoxy-5-nitroaniline is 3, 4-dimethoxy-5-nitroaniline or 3, 4-diethoxy-5-nitroaniline.
15. The method of preparing pyrroloquinoline quinone according to claim 13, wherein the solvent is selected from ethyl acetate, dioxane and acetonitrile.
16. The method for preparing pyrroloquinoline quinone according to claim 13, wherein the reaction temperature is controlled at 20-45 ℃.
17. The process for preparing pyrroloquinoline quinone according to claim 11, wherein the reaction for preparing the compound of formula I-2 by reduction of the compound of formula I-1 is carried out under raney nickel catalysed high pressure hydrogenation conditions at a temperature of 20-50 ℃ and a pressure of 0.5-2 MPa.
18. The method for preparing pyrroloquinoline quinone according to claim 11, wherein the compound of formula I-2 and the compound of formula V are prepared under the catalytic action of Lewis acid under the oxygen atmosphere, wherein the reaction temperature is controlled at 10-35 ℃.
19. The method for preparing pyrroloquinoline quinone according to claim 11, wherein the compound of formula II-1 is prepared by deacetylation and ester hydrolysis, wherein the method comprises the steps of reacting the compound of formula II-1 under acidic condition at 60-80 ℃, crystallizing after the reaction, centrifuging, adding the solid material obtained by centrifugation or the reaction solution obtained by centrifugation into acid liquor, and heating to 40-70 ℃ for ester hydrolysis.
20. The method of preparing pyrroloquinoline quinone according to claim 11, wherein the compound of formula II-2' is reacted with ethyl 2-methylacetoacetate for Fischer indole synthesis.
21. The method of preparing pyrroloquinoline quinone according to claim 11, wherein oxidizing the compound of formula IV to prepare PQQ comprises direct oxidation or post oxidation of the compound of formula IV to prepare intermediate G to obtain PQQ;
the intermediate G is。
22. The method of preparing pyrroloquinoline quinone according to claim 11, wherein the oxidation employs an oxidizing agent;
The oxidant is selected from one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone.
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| 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 |
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| 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 |
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| 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 |
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