WO2024098531A1 - Intermédiaire, utilisation et procédé d'intermédiaire dans la préparation de pyrroloquinoléine quinone - Google Patents
Intermédiaire, utilisation et procédé d'intermédiaire dans la préparation de pyrroloquinoléine quinone Download PDFInfo
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- WO2024098531A1 WO2024098531A1 PCT/CN2022/142380 CN2022142380W WO2024098531A1 WO 2024098531 A1 WO2024098531 A1 WO 2024098531A1 CN 2022142380 W CN2022142380 W CN 2022142380W WO 2024098531 A1 WO2024098531 A1 WO 2024098531A1
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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 125
- 238000002360 preparation method Methods 0.000 title claims abstract description 91
- 238000000034 method Methods 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 280
- 238000006243 chemical reaction Methods 0.000 claims abstract description 124
- 239000001257 hydrogen Substances 0.000 claims abstract description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 58
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 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 N-(3,4-dimethoxy-5-nitrophenyl)acetamide Chemical compound 0.000 claims description 95
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 54
- 239000011343 solid material Substances 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 23
- 238000005119 centrifugation Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000002431 hydrogen Chemical group 0.000 claims description 20
- 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 17
- 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 14
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 14
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 14
- 230000001590 oxidative effect Effects 0.000 claims description 13
- 238000006783 Fischer indole synthesis reaction Methods 0.000 claims description 12
- 230000006196 deacetylation Effects 0.000 claims description 12
- 238000003381 deacetylation reaction Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 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
- 239000002253 acid Substances 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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 9
- 230000003301 hydrolyzing effect Effects 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 7
- FNENWZWNOPCZGK-UHFFFAOYSA-N ethyl 2-methyl-3-oxobutanoate Chemical compound CCOC(=O)C(C)C(C)=O FNENWZWNOPCZGK-UHFFFAOYSA-N 0.000 claims description 7
- 238000007336 electrophilic substitution reaction Methods 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000007254 oxidation reaction Methods 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
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000003647 oxidation 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
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 230000000850 deacetylating effect Effects 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 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 2
- 238000003756 stirring Methods 0.000 description 57
- 239000000543 intermediate Substances 0.000 description 37
- 239000000047 product Substances 0.000 description 27
- 239000000463 material Substances 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 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
- 238000002425 crystallisation Methods 0.000 description 18
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- 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
- 239000000203 mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- 239000005457 ice water Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 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 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
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
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- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 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
- 230000015572 biosynthetic process Effects 0.000 description 5
- 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 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
- 238000005481 NMR spectroscopy Methods 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
- 238000001035 drying Methods 0.000 description 4
- 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 4
- 229940098779 methanesulfonic acid Drugs 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
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 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
- 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
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 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
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- 238000005406 washing Methods 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
- 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
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- 125000003545 alkoxy group Chemical group 0.000 description 1
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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- 235000013311 vegetables Nutrition 0.000 description 1
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Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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
Definitions
- the invention relates to the field of organic compound preparation, and in particular to an intermediate and its application and method in the preparation of pyrroloquinoline quinone.
- 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 is 72909-34-3.
- Pyrroloquinoline quinone is widely present in plant-derived foods and animal-derived foods, such as fruits, vegetables, grains, etc.
- the concentration of pyrroloquinoline quinone in food is only at the level of nanograms to micrograms per kilogram. Therefore, it is impossible to obtain sufficient PQQ through dietary supplementation alone, and it is difficult and expensive to obtain pyrroloquinoline quinone through biological production and separation.
- the present invention provides an intermediate compound and its application and method in preparing pyrroloquinoline quinone.
- the preparation of pyrroloquinoline quinone using the intermediate of the present invention can greatly simplify the reaction route, so that the reaction route is controlled within 7 steps, and the reaction conditions are mild, the raw materials are cheap and easy to obtain, the product yield is high, the efficiency is high, and the production cycle is greatly shortened.
- Kilogram-level products can be obtained within 2-3 weeks, and efficient industrial large-scale production of 100-kilogram-level pyrroloquinoline quinone can be achieved within 1.5 months.
- the present invention provides the following technical solutions:
- the present invention provides an intermediate compound for preparing pyrroloquinoline quinone, which has a structure shown in Formula I or Formula II:
- R1 is a C1 - C3 straight chain or branched alkyl group
- R2 is a nitro group or an amino group
- R3 is hydrogen or an amino protecting group
- R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
- R 1 is preferably methyl or ethyl.
- R3 is preferably hydrogen or methylcarbonyl.
- R4 is preferably methyl, ethyl or propyl.
- the compound of formula II has a structure shown in formula I-1, formula I-2, formula II-1 or formula II-2:
- R1 is methyl or ethyl
- R4 is hydrogen, methyl, ethyl or propyl
- the intermediate compound of the present invention is selected from the following structures:
- the present invention provides a method for preparing the compound represented by the above formula I or formula II.
- the compound of formula I can be prepared by electrophilic substitution reaction of 3,4-dimethoxy-5-nitroaniline and acetic anhydride.
- 3,4-dimethoxy-5-nitroaniline can be prepared using 3,4-dimethoxy-5-nitrobenzoic acid or 3,4-dimethoxy-5-nitrobenzamide as raw materials.
- the compound of formula I has a structure shown in formula I-1 or formula I-2:
- R1 is methyl or ethyl.
- 3,4-dialkoxy-5-nitroaniline and acetic anhydride undergo electrophilic substitution reaction to prepare the compound of formula I-1, and the compound of formula I-1 can be reduced to obtain the compound of formula I-2.
- the reduction reaction can occur under conditions of Raney nickel catalytic high pressure hydrogenation.
- the compound of formula II may further have a structure shown in formula II-1 or formula II-2.
- the compound of formula II-1 may be prepared by reacting the compound of formula I-2 with the compound of formula V under the catalysis of Lewis acid in an oxygen atmosphere (aerobic); the compound of formula II-2 may be prepared by deacetylation and/or ester hydrolysis of the compound of formula II-1.
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- R1 is a C1 - C3 straight chain or branched alkyl group
- R2 is a nitro group or an amino group
- R3 is hydrogen or an amino protecting group
- R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
- the present invention provides a method for preparing pyrroloquinoline quinone, comprising: preparing a compound of formula III from a compound of formula II-2 by Fischer indole synthesis, hydrolyzing the compound of formula III to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare pyrroloquinoline quinone;
- R 1 and R 4 are as defined above;
- R1 is methyl or ethyl
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- the compound of formula II-2 can be prepared by deacetylation and/or ester hydrolysis of the compound of formula II-1;
- R 1 and R 4 are as defined above;
- R1 is methyl or ethyl
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- the present invention provides a method for preparing pyrroloquinoline quinone, which comprises: preparing a compound of formula II-2' by deacetylation and ester hydrolysis of a compound of formula II-1, preparing a compound of formula III' by Fischer indole synthesis, hydrolyzing the compound of formula III' to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare pyrroloquinoline quinone;
- R 1 and R 4 are as defined above;
- R1 is methyl or ethyl
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- the compound of formula II-1 is prepared by reacting the compound of formula I-2 with the compound of formula V under the catalysis of Lewis acid in an oxygen atmosphere (in the presence of oxygen);
- R 1 and R 4 are as defined above;
- R1 is methyl or ethyl
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- the present invention provides a method for preparing pyrroloquinoline quinone, which comprises: preparing a compound of formula II-1 from a compound of formula I-2 and a compound of formula V under the catalysis of Lewis acid in an oxygen atmosphere, preparing a compound of formula II-2' from the compound of formula II-1 after deacetylation and ester hydrolysis, preparing a compound of formula III' from the compound of formula II-2' by Fischer indole synthesis, hydrolyzing the compound of formula III' to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare pyrroloquinoline quinone;
- R 1 and R 4 are as defined above;
- R1 is methyl or ethyl
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- the compound of formula I-2 is prepared by reducing the compound of formula I-1.
- R 1 is as defined above;
- R 1 is methyl or ethyl.
- the reduction reaction occurs under Raney nickel catalytic high pressure hydrogenation conditions.
- the present invention provides a method for preparing pyrroloquinoline quinone, which comprises: reducing compound I-1 to prepare compound I-2, preparing compound II-1 with compound V under Lewis acid catalysis in an oxygen atmosphere, deacetylation and ester hydrolysis of compound II-1 to prepare compound II-2', preparing compound III' from compound II-2' by Fischer indole synthesis, hydrolyzing compound III' to prepare compound IV, and oxidizing compound IV to prepare pyrroloquinoline quinone;
- R 1 and R 4 are as defined above;
- R1 is methyl or ethyl
- R4 is selected from hydrogen, methyl, ethyl and propyl.
- the compound of formula I can be prepared by electrophilic substitution reaction of 3,4-dialkoxy-5-nitroaniline and acetic anhydride.
- 3,4-dialkoxy-5-nitroaniline can be prepared by using 3,4-dialkoxy-5-nitrobenzoic acid or 3,4-dialkoxy-5-nitrobenzamide as raw materials.
- the alkoxy group is mainly C 1 -C 3 alkoxy group.
- the compound of formula I has a structure shown in formula I-1 or formula I-2:
- R 1 is the same as defined above; preferably, R 1 is methyl or ethyl.
- 3,4-dialkoxy-5-nitroaniline and acetic anhydride undergo electrophilic substitution reaction to prepare compound I-1, and compound I-1 undergoes reduction reaction to prepare compound I-2.
- the reduction reaction can occur under conditions of Raney nickel catalytic high pressure hydrogenation.
- the advantages of the present invention are: the compound of the present invention is used as an intermediate to prepare pyrroloquinoline quinone, which can greatly simplify the reaction route, so that the reaction route is controlled within 7 steps, and the reaction conditions are mild, the raw materials are cheap and easily available, the product yield is high, and the efficiency is high. Kilogram-level products can be obtained within 2-3 weeks, and efficient industrial large-scale production of kilogram-level pyrroloquinoline quinone can be achieved.
- the prior art tends to synthesize the indole structure first and then synthesize the quinoline structure.
- the present invention uses the compound of formula I or the compound of formula II as an intermediate to first synthesize the quinoline structure when preparing pyrroloquinoline quinone, and then performs Fischer indole synthesis.
- the selectivity of indole synthesis is improved by quinoline occupancy, the generation of unnecessary by-products is avoided, the synthesis efficiency and yield are greatly improved, and the subsequent complicated purification work is reduced, so as to realize the high-efficiency large-scale production of pyrroloquinoline quinone at the level of hundreds of kilograms.
- Figure 1 Proton spectrum of an exemplary compound of Compound I-2.
- Figure 3 Proton spectrum of an exemplary compound of Compound II-1.
- Figure 4 Carbon spectrum of an exemplary compound of Compound II-1.
- Figure 5 Proton spectrum of an exemplary compound of Compound II-2.
- reagents or raw materials used in the present invention can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in a conventional manner in the art or in accordance with the product instructions. In addition, any method and material similar to or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.
- the present invention provides compounds as shown in Formula I or Formula II, and methods for preparing pyrroloquinoline quinone using these compounds as intermediates.
- R1 is a C1 - C3 straight chain or branched alkyl group
- R2 is a nitro group or an amino group
- R3 is a hydrogen or an amino protecting group
- R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
- R 1 is preferably methyl or ethyl.
- R3 is preferably hydrogen or methylcarbonyl.
- R4 is preferably hydrogen, methyl, ethyl or propyl.
- the method for preparing pyrroloquinoline quinone using the compound of formula II as an intermediate is carried out according to the following reaction scheme:
- R1 is methyl or ethyl
- R4 is hydrogen, methyl, ethyl or propyl
- the compound of formula II-2 can be prepared by deacetylation and/or ester hydrolysis of the compound of formula II-1.
- the method for preparing pyrroloquinoline quinone using the compound of formula II-1 as an intermediate is carried out according to the following reaction scheme:
- R 1 is methyl or ethyl
- R 4 is hydrogen, methyl, ethyl or propyl. If R 4 is hydrogen, then no ester hydrolysis is required after the first step of deacetylation.
- the method for preparing pyrroloquinoline quinone using the compound of formula I as an intermediate is carried out according to the following reaction scheme:
- R 1 is methyl or ethyl
- R 4 is hydrogen, methyl, ethyl or propyl. If R 4 is hydrogen, then no ester hydrolysis is required after deacetylation in step 2.
- the compound of formula I-2 can be prepared from the compound of formula I-1 by a reduction reaction, and the reduction reaction can occur under conditions such as Raney nickel catalysis and high pressure hydrogenation.
- the method for preparing pyrroloquinoline quinone using 3,4-dialkoxy-5-nitroaniline as an intermediate is carried out according to the following reaction scheme:
- R 1 is methyl or ethyl
- R 4 is hydrogen, methyl, ethyl or propyl. If R 4 is hydrogen, then no ester hydrolysis is required after deacetylation in step 4.
- 3,4-dialkoxy-5-nitroaniline compound is used as an intermediate to prepare pyrroloquinoline quinone by first synthesizing quinoline structure and then performing Fischer indole synthesis.
- the selectivity of indole synthesis is improved by quinoline occupancy, the generation of unnecessary substances is avoided, the synthesis efficiency and yield are greatly improved, and the subsequent complicated purification work is reduced.
- the last step in the above-mentioned various reactions is an oxidation reaction, which can be carried out in one step or according to the following reaction route:
- R 1 is methyl or ethyl.
- the preparation method of pyrroloquinoline quinone may include the following specific implementation steps:
- 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.
- the molar ratio of 3,4-dialkoxy-5-nitroaniline to acetic anhydride is 1:1-5.
- the temperature of step (1) during the reaction stage is controlled at 20-45°C.
- the compound of formula I-1 can be obtained by crystallization (such as cooling, etc.), centrifugation, drying, etc.; and, the solvent can be recovered from the mother liquor, and after the solvent is recovered, the residue can be further crystallized (such as cooling, etc.), centrifuged, dried, etc. to obtain the compound of formula I-1.
- the solvent in step (2) may be an alcohol, such as a simple alcohol, such as methanol, ethanol, etc.
- the reaction temperature of step (2) is 20-50°C, for example, it can be further 20-30°C or 40-50°C.
- the high pressure in step (2) is maintained at 0.5-2 MPa.
- the amount of the compound of formula I-1 used in step (2) is 10-24 times (mass ratio) the amount of Raney nickel used.
- the Raney nickel can be removed and the solvent recovered, and then the compound of formula I-2 can be obtained by crystallization (such as cooling, etc.), centrifugation, drying, etc.
- the molar ratio of compound of formula I-2 to compound of formula V is 1:1-3.
- the molar ratio of compound of formula I-2 to Lewis acid is 1:1-2.
- reaction solvent may be dichloromethane.
- the temperature of the reaction stage in step (3) is controlled at 10-35°C.
- the compound of formula II-1 can be obtained by recrystallization, centrifugation, drying and the like.
- step (4) comprises reacting the compound of formula II-1 to deacetylate under acidic conditions (such as adding methanesulfonic acid) at a temperature of 60-80°C, cooling the reaction temperature to below 20°C for crystallization and centrifugation after the reaction is completed; the solid material obtained by centrifugation or the reaction solution without centrifugation is put into an acid solution (such as hydrochloric acid or sulfuric acid), and the temperature is raised to 40-70°C for ester hydrolysis reaction. After the reaction is completed, centrifugation is performed at 40-50°C, the solid material is washed, and then centrifuged and dried to obtain the compound of formula II-2'.
- acidic conditions such as adding methanesulfonic acid
- compound II-2' is reacted with ethyl 2-methylacetoacetate, wherein the molar ratio of compound II-2 to ethyl 2-methylacetoacetate is 1:1-2.
- step (5) comprises mixing an anhydrous alcohol solvent with formula II-2 and stirring, cooling the system to below 10°C, then dropping concentrated hydrochloric acid or 50% sulfuric acid and stirring; cooling the system to 0°C or below (even -10°C or below), rapidly adding sodium nitrite, dropping it, stirring and reacting at -5°C-5°C, after the reaction is completed, dropping ethyl 2-methylacetoacetate at 0°C or below (even -5°C or below), adding sodium acetate at 0°C or below (even -5°C or below), and keeping the temperature at -5°C-5 for reaction, after the reaction is completed, heating the system to 20-25°C and stirring for reaction, centrifuging and washing with water to obtain a wet intermediate of the compound of formula III, mixing the wet intermediate with 50% sulfuric acid, heating the system to 35-45°C and stirring for reaction, after the reaction is completed, slowly adding the reaction solution to an ice-water mixture, precipitating solid material, centri
- Compound IV is oxidized to obtain PQQ, or compound IV is used to prepare intermediate G and then oxidized to obtain PQQ; for example, compound IV can be prepared by reacting with a protonic acid (for example, under HAC/HI acid conditions) to obtain intermediate G, and the protonic acid can be hydrobromic acid or hydroiodic acid, preferably hydroiodic acid; for example, the oxidation can be carried out using an oxidant, and the oxidant can be selected from one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone, preferably hydrogen peroxide.
- a protonic acid for example, under HAC/HI acid conditions
- the protonic acid can be hydrobromic acid or hydroiodic acid, preferably hydroiodic acid
- the oxidation can be carried out using an oxidant, and the oxidant can be selected from one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone, preferably hydrogen peroxide.
- the present invention provides the following preparation examples.
- the starting reactant 3,4-dimethoxy-5-nitroaniline can be prepared by using 3,4-dimethoxy-5-nitrobenzoic acid or 3,4-dimethoxy-5-nitrobenzamide as raw materials.
- 3,4-dimethoxy-5-nitroaniline can be prepared according to the method in U.S. Pat. No. 5,236,952, and the relevant contents of the patent are incorporated into the present invention by reference.
- the 3,4-dimethoxy-5-nitroaniline of the present invention can be prepared according to the following method:
- 3,4-diethoxy-5-nitrobenzoic acid is used as a raw material to replace 3,4-dimethoxy-5-nitrobenzoic acid to prepare 3,4-diethoxy-5-nitroaniline.
- the above-mentioned feeding reaction is carried out multiple times to accumulate 3,4-dimethoxy-5-nitroaniline material and 3,4-diethoxy-5-nitroaniline material for the preparation of the target product.
- the following examples illustrate the preparation process of the intermediates described in the present application and the specific process of preparing PQQ using the intermediates described in the present application under certain conditions.
- the following examples are examples of preparing products at the 100-gram level. In order to accumulate sufficient materials for each step of the reaction, the following examples will perform multiple feeding reactions in actual operations, and each feeding process is the same.
- the following preparation examples only illustrate a single feeding preparation process.
- N-(3,4-diethoxy-5-nitrophenyl)acetamide (Compound I-1-2) can be prepared according to the method described in Preparation Example 1-3, with a total molar yield of more than 90% and a purity of more than 99%.
- N-(3,4-dimethoxy-5-nitrophenyl)acetamide (compound I-1-1) with N-(3,4-diethoxy-5-nitrophenyl)acetamide (compound formula 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, with a total molar yield of more than 88% and a purity of not less than 99%.
- N-(3-amino-4,5-dimethoxyphenyl)acetamide (compound I-2-1) is replaced by N-(3-amino-4,5-diethoxyphenyl)acetamide (compound I-2-2), and 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid diethyl ester (compound II-1-7); 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-1-6) and 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-1-8) can be prepared according to the method described in Preparation Example 7-9, with a total molar yield of more than 80% and a purity of not less than 98%.
- the diethyl ester (compound II-1-3) is replaced by 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid diethyl ester (compound II-1-7), 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-1-6), and 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-1-8), respectively.
- 5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid (compound II-2-5) can be prepared with a total molar yield of more than 78% and a purity of not less than 98%.
- the molar yield is above 90%, and the HPLC purity is not less than 99%.
- the solid material was dried at 90°C to obtain 298.8kg of the wet product of the intermediate (compound G) of compound formula IV-1.
- 298.8kg of the wet product of the intermediate (compound G) of compound formula IV-1 and 900kg of 30% hydrogen peroxide solution were put into a 2000L enamel reactor, and stirring was started to stir the materials in the reactor evenly.
- Steam was introduced into the reactor interlayer and the temperature was raised to 35°C with stirring.
- the reaction was stirred at 30-35°C for 24 hours. After the reaction was completed, the temperature was lowered to 20°C, centrifuged, and the solid material was dried at 90°C to obtain 153.5 kg of compound PQQ.
- the molar yield was 93% and the HPLC purity was 99.8%.
- the solid material obtained 293.8kg of the wet product of the intermediate (compound G) of compound formula IV-1. 293.8kg of the wet product of the intermediate (compound G) of compound formula IV-1 and 900kg of 30% hydrogen peroxide solution were put into a 2000L enamel reactor, and stirring was started to stir the materials in the reactor evenly. Steam was introduced into the reactor interlayer and stirred to raise the temperature to 35°C, and the reaction was stirred at 30-35°C for 24 hours. After the reaction was completed, the temperature was lowered to 20°C, centrifuged, and the solid material was dried at 90°C to obtain 148.5 kg of compound PQQ. The molar yield was 90%, and the HPLC purity was 99.5%.
- the solid material obtained 272.2 kg of the wet product of the intermediate of compound IV-1 (compound G).
- 272.2 kg of the wet product of the intermediate of compound IV-1 (compound G) and 900 kg of 30% hydrogen peroxide solution were put into a 2000 L enamel reactor, and stirring was started to stir the materials in the reactor evenly.
- the reaction was stirred at 30-35°C for 24 hours.
- the temperature was lowered to 20°C, centrifuged, and the solid material was dried at 90°C to obtain 147.7 kg of compound PQQ.
- the molar yield was 89.5%, and the HPLC purity was 99.8%.
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Abstract
L'invention concerne un intermédiaire, une utilisation et un procédé de l'intermédiaire dans la préparation de pyrroloquinoléine quinone. Le composé intermédiaire a une structure telle que représentée dans la formule (I) ou la formule (II). Dans la structure, R1 est un alkyle en C1-C3 à chaîne droite ou ramifiée ; R2 est nitro ou amino ; R3 est hydrogène ou un groupe protecteur amino ; R4 est choisi parmi hydrogène et alkyle en C1-C3 à chaîne droite ou ramifiée. Le procédé a une voie simple, des conditions de réaction modérées et un rendement élevé, évite l'utilisation d'un agent oxydant, de nitrate d'ammonium cérique et permet la production industrielle à grande échelle de pyrroloquinoléine quinone.
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CN101193888A (zh) * | 2005-03-24 | 2008-06-04 | Clf医疗技术加速程序有限公司 | 吡咯喹啉醌(pqq)的合成方法 |
CN107089982A (zh) * | 2017-05-11 | 2017-08-25 | 山东康迈祺生物科技有限公司 | 4,5‑二取代‑1‑氢‑吡咯(2,3‑f)喹啉‑2,7,9‑三羧酸酯化合物及应用 |
CN110981873A (zh) * | 2019-12-31 | 2020-04-10 | 江西农业大学 | 一种五步法合成吡咯喹啉醌的制备方法 |
CN111087395A (zh) * | 2019-12-31 | 2020-05-01 | 江西农业大学 | 一种四步法合成吡咯喹啉醌的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101193888A (zh) * | 2005-03-24 | 2008-06-04 | Clf医疗技术加速程序有限公司 | 吡咯喹啉醌(pqq)的合成方法 |
CN107089982A (zh) * | 2017-05-11 | 2017-08-25 | 山东康迈祺生物科技有限公司 | 4,5‑二取代‑1‑氢‑吡咯(2,3‑f)喹啉‑2,7,9‑三羧酸酯化合物及应用 |
CN110981873A (zh) * | 2019-12-31 | 2020-04-10 | 江西农业大学 | 一种五步法合成吡咯喹啉醌的制备方法 |
CN111087395A (zh) * | 2019-12-31 | 2020-05-01 | 江西农业大学 | 一种四步法合成吡咯喹啉醌的制备方法 |
Non-Patent Citations (1)
Title |
---|
SLEATH, P. R. ET AL.: "Synthesis of 7,9-didecarboxymethoxatin (4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2-carboxylic acid) and comparison of its chemical properties with those of methoxatin and analogous o-quinones. Model studies directed toward the action of PQQ requiring bacterial oxidoreductases and mammalian p", J. AM. CHEM. SOC., vol. 107, no. 11, 31 December 1985 (1985-12-31), pages 3328 - 3338, XP002483159, DOI: 10.1021/ja00297a044 * |
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