A five-step method for synthesizing pyrroloquinoline quinone

Abstract

The invention discloses a five-step method for synthesizing pyrroloquinoline quinone, which uses 4-methyl-5-nitro-2-fluoroaniline (2) as a raw material, undergoes two ring-closing reactions, obtains a key intermediate 5-fluoro-1H-pyrrole [2,3-f] quinoline-2,7,9-tricarboxylic acid trialkyl ester (6), and then undergoes hydrolysis reaction, substitution reaction and oxidation reaction to obtain pyrroloquinoline quinone (PQQ, 1). The invention has the advantages of being green and environmentally friendly, easy to obtain raw materials, low cost, simple method, and suitable for industrial production. The preparation method solves the problems of high preparation cost and difficulty in industrial production in the prior art.

Description

Technical Field

[0001] The invention relates to the field of organic synthetic chemistry, and in particular to a preparation method for synthesizing pyrroloquinoline quinone by a five-step method. Background Art

[0002] Pyrroloquinoline quinone (PQQ) is a new coenzyme of oxidoreductase discovered in the late 1970s. It is the second coenzyme of flavin nucleotides (FMN, FAD) and nicotinamide nucleotides (NAD + , NADP + ) is the third enzyme discovered after the oxidoreductase. As a redox enzyme cofactor, PQQ exists in almost all biological tissues and is a new type of water-soluble vitamin. Studies have shown that PQQ has some important functions: stimulating microbial growth, promoting the synthesis of nerve growth factor, and being an essential factor for animal growth and development. Therefore, it is of great theoretical and practical significance to study the synthesis and production of pyrroloquinoline quinone, which is pollution-free, has readily available raw materials, and is low in cost. Summary of the invention

[0003] The purpose of the present invention is to provide a method for preparing pyrroloquinoline quinone which is green, pollution-free, environmentally friendly, has readily available raw materials, a wide range of sources, low cost, a simple method, and is suitable for industrial production. The preparation method solves the problems of high preparation cost, great environmental pollution and difficulty in industrial production in the prior art.

[0004] The object of the present invention is achieved in that:

[0005] A five-step method for synthesizing pyrroloquinoline quinone, characterized by:

[0006] A. Preparation of 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (5): 4-methyl-5-nitro-2-fluoroaniline (2) is used as a raw material, and 4-oxo-2-eneglutaric acid dialkyl ester, a first acidic catalyst and a first solvent are used to generate 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (3), and then oxalic acid dialkyl ester, a second basic catalyst and a second solvent are used to generate 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (4). or, using 4-methyl-5-nitro-2-fluoroaniline (2) as a raw material, generating 3-(4-amino-2-nitro-5-fluoro)phenyl-2-oxopropionic acid alkyl ester (4) in the presence of dialkyl oxalate, a second alkaline catalyst and a second solvent, and then generating 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (5) in the presence of dialkyl 4-oxo-2-eneglutaric acid ester, a first acidic catalyst and a first solvent;

[0007] B. Preparation of 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6): using 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (5) prepared in step A as a raw material, generating 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6) under the action of a first reagent / catalyst and a third solvent;

[0008] C. Preparation of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7): using the 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6) prepared in step B as a raw material, generating a carboxylate under the action of a third alkaline catalyst and methanol, and then acidifying with a second reagent to obtain 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7);

[0009] D. Preparation of pyrroloquinoline quinone (PQQ, 1): Using 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7) prepared in step C as a raw material, pyrroloquinoline quinone (PQQ, 1) is obtained in the presence of an oxidizing agent, ammonium cerium nitrate, and a fourth solvent.

[0010] In step A, the hydrocarbon group is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl or benzyl; the first acidic catalyst is dilute hydrochloric acid, dilute sulfuric acid, hypochlorous acid, chloric acid, perchloric acid, dilute phosphoric acid, phosphorous acid, hypophosphorous acid, formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, capric acid, palmitic acid, stearic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, acrylic acid, phthalic acid, benzoic acid, benzoic acid substituted on the benzene ring, benzene Acetic acid, phenylacetic acid substituted on the benzene ring, α-naphthoic acid, β-naphthoic acid, α-naphthoacetic acid, β-naphthoacetic acid, α-naphthoic acid substituted on the naphthalene ring, β-naphthoic acid substituted on the naphthalene ring, α-naphthoic acid substituted on the naphthalene ring, β-naphthoic acid substituted on the naphthalene ring, cinnamic acid, hydroxyacetic acid, 2-hydroxypropionic acid, malic acid, tartaric acid, citric acid, glyoxylic acid, 2-oxopropionic acid, glycine, 2-aminopropionic acid, 2-furancarboxylic acid, 3-furancarboxylic acid, 2-pyridinecarboxylic acid, 3-pyridinecarboxylic acid, 4-pyridinecarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or benzenesulfonic acid substituted on the benzene ring; the first solvent is n-hexane, petroleum ether, cyclohexane, octane, benzene, toluene, xylene, trimethylbenzene, ethylbenzene, n-propylbenzene, isopropylbenzene, dichloromethane, Chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, sec-butyl ether, tert-butyl ether, n-pentyl ether, isopentyl ether, sec-pentyl ether, neopentyl ether, n-hexyl ether, isohexyl ether, sec-hexyl ether, neohexyl ether, cyclopropyl ether, cyclobutyl ether, cyclopentyl ether, cyclohexyl ether, anisole, diphenyl ether, α-naphthyl ether, β-naphthyl methyl ether, ethylene oxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, n-butyl formate, isobutyl formate, sec-butyl formate, tert-butyl formate, n-pentyl formate, isopentyl formate, sec-pentyl formate, neopentyl formate, n-hexyl formate Esters, isohexyl formate, secondary hexyl formate, neohexyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, n-pentyl acetate, isopentyl acetate, sec-pentyl acetate, neopentyl acetate, n-hexyl acetate, isohexyl acetate, sec-hexyl acetate, neohexyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isopentyl propionate, sec-pentyl propionate, neopentyl propionate, n-hexyl propionate, isohexyl propionate, sec-hexyl propionate, neohexyl propionate, methyl isopropionate, ethyl isopropionate, n-propyl isopropionate, isopropyl isopropionate,n-Butyl isopropionate, isobutyl isopropionate, sec-butyl isopropionate, tert-butyl isopropionate, n-pentyl isopropionate, isopentyl isopropionate, sec-pentyl isopropionate, neopentyl isopropionate, n-hexyl isopropionate, isohexyl isopropionate, sec-hexyl isopropionate, neohexyl isopropionate, methyl butyrate, ethyl butyrate, n-propyl butyrate, isopropyl butyrate, n-butyl butyrate, isobutyl butyrate Ester, sec-butyl butyrate, tert-butyl butyrate, n-pentyl butyrate, isopentyl butyrate, sec-pentyl butyrate, neopentyl butyrate, n-hexyl butyrate, isohexyl butyrate, sec-hexyl butyrate, neohexyl butyrate, methyl isobutyrate, ethyl isobutyrate, n-propyl isobutyrate, isopropyl isobutyrate, n-butyl isobutyrate, isobutyl isobutyrate, sec-butyl isobutyrate, tert-butyl isobutyrate Butyl ester, amyl isobutyrate, isoamyl isobutyrate, sec-amyl isobutyrate, neopentyl isobutyrate, n-hexyl isobutyrate, isohexyl isobutyrate, sec-hexyl isobutyrate, neohexyl isobutyrate, methyl valerate, ethyl valerate, n-propyl valerate, isopropyl valerate, n-butyl valerate, isobutyl valerate, sec-butyl valerate, tert-butyl valerate, n-pentyl valerate, n-pentyl isopentyl ester, sec-pentyl pentyl ester, neopentyl pentyl ester, n-hexyl pentyl ester, isohexyl pentyl ester, sec-hexyl pentyl ester, neohexyl pentyl ester, methyl isovalerate, ethyl isovalerate, n-propyl isovalerate, isopropyl isovalerate, n-butyl isovalerate, isobutyl isovalerate, sec-butyl isovalerate, tert-butyl isovalerate, n-pentyl isovalerate, isopentyl pentyl ester, sec-pentyl isovalerate, isovalerate Neopentyl valerate, n-hexyl isovalerate, isohexyl isovalerate, sec-hexyl isovalerate, neohexyl isovalerate, methyl hexanoate, ethyl hexanoate, n-propyl hexanoate, isopropyl hexanoate, n-butyl hexanoate, isobutyl hexanoate, sec-butyl hexanoate, tert-butyl hexanoate, n-pentyl hexanoate, isopentyl hexanoate, sec-pentyl hexanoate, neopentyl hexanoate, n-hexyl hexanoate , isohexyl hexanoate, sec-hexyl hexanoate, neohexyl hexanoate, methyl isohexanoate, ethyl isohexanoate, n-propyl isohexanoate, isopropyl isohexanoate, n-butyl isohexanoate, isobutyl isohexanoate, sec-butyl isohexanoate, tert-butyl isohexanoate, n-pentyl isohexanoate, isopentyl isohexanoate, sec-pentyl isohexanoate, neopentyl isohexanoate, n-hexyl isohexanoate, isohexyl isohexanoate, sec-hexyl isohexanoate ester or neohexyl isohexanoate; the second alkaline catalyst is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium hydride, calcium hydride, dimethylamine lithium or n-butyl lithium; the second solvent is n-hexane, petroleum ether, cyclohexane, octane, benzene, carbon tetrachloride, ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, sec-butyl ether, tert-butyl ether, n-pentyl ether, isopentyl ether, sec-pentyl ether, neopentyl ether, n-hexyl ether, isohexyl ether, sec-hexyl ether, neohexyl ether, cyclopropyl ether, cyclobutyl ether, cyclopentyl ether, cyclohexyl ether, anisole, diphenyl ether, α-naphthyl methyl ether, β-naphthyl methyl ether, ethylene oxide, tetrahydrofuran,One of 2-methyltetrahydrofuran and 1,4-dioxane.

[0011] In step A, the hydrocarbon group is preferably ethyl; the first acidic catalyst is preferably dilute hydrochloric acid; the first solvent is preferably 1,2-dichloroethane; and the second alkaline catalyst is preferably potassium carbonate.

[0012] In step B, the hydrocarbon group is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl or benzyl; the first reagent / catalyst is one of hydrogen / palladium carbon, hydrogen / Raney nickel, hydrogen / platinum carbon, hydrochloric acid / iron, hydrochloric acid / tin, hydrochloric acid / zinc, acetic acid / iron, acetic acid / tin or acetic acid / zinc; the third solvent is water, n-hexane , benzene, toluene, xylene, trimethylbenzene, ethylbenzene, n-propylbenzene, isopropylbenzene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, sec-pentanol, neopentyl alcohol, n-hexanol, isohexanol, sec-hexanol, neohexanol, heptanol, octanol, nonanol, decanol, 1,2-ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol or glycerol.

[0013] In step B, the hydrocarbon group is preferably ethyl; the first reagent / catalyst is preferably hydrogen / palladium on carbon; and the third solvent is preferably methanol.

[0014] In step C, the alkaline catalyst is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium hydride, calcium hydride, dimethylamine lithium or n-butyl lithium; the second reagent is dilute hydrochloric acid, dilute sulfuric acid, hypochlorous acid, chloric acid, perchloric acid, dilute phosphoric acid, phosphorous acid, hypophosphorous acid, formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, capric acid, palmitic acid, stearic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid , acrylic acid, phthalic acid, benzoic acid, benzoic acid substituted on the benzene ring, phenylacetic acid, phenylacetic acid substituted on the benzene ring, α-naphthoic acid, β-naphthoic acid, α-naphthoic acid, β-naphthoic acid, α-naphthoic acid substituted on the naphthalene ring, β-naphthoic acid substituted on the naphthalene ring, α-naphthoic acid substituted on the naphthalene ring, β-naphthoic acid substituted on the naphthalene ring, α-naphthoic acid substituted on the naphthalene ring, β-naphthoic acid substituted on the naphthalene ring, cinnamic acid, hydroxyacetic acid, 2-hydroxypropionic acid, malic acid, tartaric acid, citric acid, glyoxylic acid, 2-carbonylpropionic acid, glycine, 2-aminopropionic acid, 2-furancarboxylic acid, 3-furancarboxylic acid, 2-pyridinecarboxylic acid, 3-pyridinecarboxylic acid, 4-pyridinecarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or one of the benzenesulfonic acids substituted on the benzene ring.

[0015] In step C, the third alkaline catalyst is preferably potassium carbonate; and the second reagent is preferably dilute hydrochloric acid.

[0016] In step D, the fourth solvent is n-hexane, petroleum ether, cyclohexane, octane, benzene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, sec-butyl ether, tert-butyl ether, n-pentyl ether, isopentyl ether, sec-pentyl ether, neopentyl ether, n-hexyl ether, isohexyl ether, sec-hexyl ether, neohexyl ether, cyclopropyl ether, cyclobutyl ether, cyclopentyl ether, cyclohexyl ether, anisole, diphenyl ether, α-naphthyl methyl ether, β-naphthyl methyl ether, ethylene oxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, n-butyl formate, isobutyl formate, methyl formate sec-butyl formate, tert-butyl formate, n-pentyl formate, isopentyl formate, sec-pentyl formate, neopentyl formate, n-hexyl formate, isohexyl formate, sec-hexyl formate, neohexyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, n-pentyl acetate, isopentyl acetate, sec-pentyl acetate, neopentyl acetate, n-hexyl acetate, isohexyl acetate, sec-hexyl acetate, neohexyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isopentyl propionate, sec-pentyl propionate, neopentyl propionate, n-hexyl propionate, isohexyl propionate, sec-hexyl propionate, neohexyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isopentyl propionate, sec-pentyl propionate, neopentyl propionate, n-hexyl propionate, isohexyl propionate, n- sec-hexyl propionate, neohexyl propionate, methyl isopropionate, ethyl isopropionate, n-propyl isopropionate, isopropyl isopropionate, n-butyl isopropionate, isobutyl isopropionate, sec-butyl isopropionate, tert-butyl isopropionate, n-pentyl isopropionate, isopentyl isopropionate, sec-pentyl isopropionate, neopentyl isopropionate, n-hexyl isopropionate, isohexyl isopropionate, sec-hexyl isopropionate, neohexyl isopropionate, n-butyl Methyl butyrate, ethyl butyrate, n-propyl butyrate, isopropyl butyrate, n-butyl butyrate, isobutyl butyrate, sec-butyl butyrate, tert-butyl butyrate, n-pentyl butyrate, isopentyl butyrate, sec-pentyl butyrate, neopentyl butyrate, n-hexyl butyrate, isohexyl butyrate, sec-hexyl butyrate, neohexyl butyrate, methyl isobutyrate, ethyl isobutyrate, n-propyl butyrate Esters, isopropyl isobutyrate, n-butyl isobutyrate, isobutyl isobutyrate, sec-butyl isobutyrate, tert-butyl isobutyrate, n-amyl isobutyrate, isoamyl isobutyrate, sec-amyl isobutyrate, neopentyl isobutyrate, n-hexyl isobutyrate, isohexyl isobutyrate, sec-hexyl isobutyrate, neohexyl isobutyrate, methyl valerate, ethyl valerate, n-propyl valerate, isopropyl valerate, n-butyl valerate , isobutyl valerate, sec-butyl valerate, tert-butyl valerate, n-pentyl valerate, isopentyl valerate, sec-pentyl valerate, neopentyl valerate, n-hexyl valerate, isohexyl valerate, sec-hexyl valerate, neohexyl valerate, methyl isovalerate, ethyl isovalerate, n-propyl isovalerate, isopropyl isovalerate, n-butyl isovalerate, isobutyl isovalerate, sec-butyl isovalerate,Tert-butyl isovalerate, n-pentyl isovalerate, isopentyl isovalerate, sec-pentyl isovalerate, neopentyl isovalerate, n-hexyl isovalerate, isohexyl isovalerate, sec-hexyl isovalerate, neohexyl isovalerate, methyl hexanoate, ethyl hexanoate, n-propyl hexanoate, isopropyl hexanoate, n-butyl hexanoate, isobutyl hexanoate, sec-butyl hexanoate, tert-butyl hexanoate, n-pentyl hexanoate, isopentyl hexanoate, sec-pentyl hexanoate, neopentyl hexanoate ester, n-hexyl hexanoate, isohexyl hexanoate, secondary hexyl hexanoate, neohexyl hexanoate, methyl isohexanoate, ethyl isohexanoate, n-propyl isohexanoate, isopropyl isohexanoate, n-butyl isohexanoate, isobutyl isohexanoate, secondary butyl isohexanoate, tert-butyl isohexanoate, n-pentyl isohexanoate, isohexyl isohexanoate, secondary pentyl isohexanoate, neopentyl isohexanoate, n-hexyl isohexanoate, isohexyl isohexanoate, secondary hexyl isohexanoate or neohexyl isohexanoate.

[0017] In step D, the fourth solvent is preferably acetonitrile.

[0018] The present invention uses 4-methyl-5-nitro-2-fluoroaniline (2) as a raw material, undergoes two ring-closing reactions to obtain a key intermediate 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6), and then undergoes hydrolysis reaction, substitution reaction and oxidation reaction to obtain pyrroloquinoline quinone (PQQ, 1).

[0019] The invention has the advantages of being green and environmentally friendly, having readily available raw materials, low cost, simple method, and being suitable for industrial production. The preparation method solves the problems of high preparation cost and difficulty in industrial production in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The synthetic route of the present invention is shown in FIG. DETAILED DESCRIPTION

[0021] The present invention is further described below in conjunction with the embodiments and with reference to the accompanying drawings. The following is only a preferred embodiment of the present invention. It should be noted that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

[0022] Example 1

[0023] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), 1,2-dichloroethane (1.00 L), 4-oxo-2-eneglutaric acid diethyl ester (200.19 g, 1.00 mol) and concentrated hydrochloric acid (8 mL, 0.1 mol) were placed in a three-necked flask, heated to reflux for 5 h, and after the reaction was cooled, the liquid was separated, dried, and the solvent was recovered under reduced pressure to obtain a crude product of 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid diethyl ester (3). Compound 3, diethyl oxalate (146.14 g, 1.00 mol), sodium carbonate (212.00 g, 2.00 mol) and tetrahydrofuran (1.00 L) were placed in a three-necked flask, heated to reflux for 5 h. h, after the reaction was cooled, filtered, and the solvent was recovered under reduced pressure to obtain a crude product of 6-(2-ethoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid diethyl ester (5); Compound 5, 5% palladium carbon (2 g) and methanol (1.00 L) were placed in a high-pressure reactor, filled with hydrogen, maintained at a pressure of 5 atmospheres, heated to 50 ° C, reacted for 8 h, filtered, and obtained a methanol solution of 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid triethyl ester (6); The methanol solution of compound 6 and sodium hydroxide (40 g, 1.00 mol) were placed in a three-necked flask and stirred at 25 ° C for 24 h, the solvent was dried under reduced pressure, and then diluted hydrochloric acid was added dropwise to acidify to pH 5.0, extracted with 1,2-dichloroethane, washed with water, dried, and filtered to obtain a 1,2-dichloroethane solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the 1,2-dichloroethane solution of compound 7 and ammonium cerium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was decompressed to recover the solvent to obtain pyrroloquinoline quinone (61.63 g, total yield 18.66%).

[0024] Example 2

[0025] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), dichloromethane (1.00 L), 4-oxo-2-eneglutaric acid dimethyl ester (172.14 g, 1.00 mol) and 5 M dilute sulfuric acid (20 mL, 0.1 mol) were placed in a three-necked flask, heated to reflux for 5 h, and after the reaction was cooled, the liquid was separated, dried, and the solvent was recovered under reduced pressure to obtain a crude product of 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dimethyl ester (3); compound 3, dimethyl oxalate (118.09 g, 1.00 mol), potassium carbonate (276.00 g, 2.00 mol) and 2-methyltetrahydrofuran (1.00 L) were placed in a three-necked flask, heated to reflux for 5 h. h, after the reaction was cooled, filtered, and the solvent was recovered under reduced pressure to obtain crude 6-(2-methoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dimethyl ester (5); Compound 5, Raney nickel (5 g) and methanol (1.00 L) were placed in a high-pressure reactor, filled with hydrogen, maintained at a pressure of 5 atmospheres, heated to 50 ° C, reacted for 10 h, filtered, and crude 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (6) methanol solution was obtained; the methanol solution of compound 6 and potassium hydroxide (56 g, 1.00 mol) were placed in a three-necked flask and stirred at 25 ° C for 24 h, the solvent was dried under reduced pressure, and then diluted hydrochloric acid was added dropwise to acidify to pH 5.0, extracted with dichloromethane, washed with water, dried, and filtered to obtain a dichloromethane solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the dichloromethane solution of compound 7 and ammonium cerium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was decompressed to recover the solvent to obtain pyrroloquinoline quinone (59.38 g, total yield 17.98%).

[0026] Example 3

[0027] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), benzene (1.00 L), 4-oxo-2-eneglutaric acid dibenzyl ester (324.33 g, 1.00 mol) and methanesulfonic acid (9.61 g, 0.1 mol) are placed in a three-necked flask, heated to reflux for 5 h, and after the reaction is cooled, washed with water, separated and dried to obtain a benzene solution of 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dibenzyl ester (3); the benzene solution of compound 3, dibenzyl oxalate (270.28 g, 1.00 mol) and sodium hydroxide (40.00 g, 1.00 mol) are placed in a three-necked flask, heated to reflux for 5 h. h, after the reaction was cooled, the solvent was recovered under reduced pressure to obtain crude product 6-(2-benzyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dibenzyl ester (5); Compound 5, 20% platinum carbon (5 g) and ethanol (1.00 L) were placed in a high-pressure reactor, filled with hydrogen, maintained at a pressure of 5 atmospheres, heated to 50 ° C, reacted for 12 h, and the solvent was recovered under reduced pressure to obtain crude product 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid tribenzyl ester (6); Compound 6, sodium carbonate (212.00 g, 2.00 mol) and methanol (1.00 L) were placed in a three-necked flask and stirred at 25 ° C for 24 h, vacuum-dry the solvent, then dropwise add dilute hydrochloric acid to acidify to pH 5.0, extract with benzene, wash with water, dry, and filter to obtain a benzene solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the benzene solution of compound 7 and cerium ammonium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was decompressed to recover the solvent to obtain pyrroloquinoline quinone (58.00 g, total yield 17.56%).

[0028] Example 4

[0029] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), ethyl acetate (1.00 L), 4-oxo-2-eneglutaric acid diethyl ester (200.19 g, 1.00 mol) and p-toluenesulfonic acid (17.22 g, 0.1 mol) were placed in a three-necked flask, heated to reflux for 4 h, and after the reaction was cooled, the liquid was separated, dried, and the solvent was recovered under reduced pressure to obtain a crude product of 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid diethyl ester (3); compound 3, diethyl oxalate (146.14 g, 1.00 mol), potassium hydroxide (56.00 g, 1.00 mol) and anisole (1.00 L) were placed in a three-necked flask, heated to reflux for 4 h. h, after the reaction was cooled, washed with water, dried, and the solvent was recovered under reduced pressure to obtain a crude product of 6-(2-ethoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid diethyl ester (5); Compound 5, 10% palladium carbon (5 g) and methanol (1.00 L) were placed in a high-pressure reactor, filled with hydrogen, maintained at a pressure of 5 atmospheres, heated to 50 ° C, reacted for 12 h, filtered, and obtained a methanol solution of 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid triethyl ester (6); The methanol solution of compound 6 and potassium carbonate (276.00 g, 2.00 mol) were placed in a three-necked flask and stirred at 25 ° C for 24 h, vacuum-dried the solvent, then added dilute hydrochloric acid dropwise to acidify to pH 5.0, extracted with ethyl acetate, washed with water, dried, and filtered to obtain an ethyl acetate solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the ethyl acetate solution of compound 7 and cerium ammonium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was vacuum-reduced to recover the solvent to obtain pyrroloquinoline quinone (60.30 g, total yield 18.26%).

[0030] Example 5

[0031] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), diethyl oxalate (146.14 g, 1.00 mol), lithium diisopropylamide (107.12 g, 1.00 mol) and tetrahydrofuran (1.00 L) were placed in a three-necked flask, stirred at room temperature for 5 h, filtered, washed with water, dried, and the solvent was recovered under reduced pressure to obtain crude 3-(4-amino-2-nitro-5-fluoro)phenyl-2-oxopropionic acid ethyl ester (4); compound 4, 1,2-dichloroethane (1.00 L), 4-oxo-2-eneglutaric acid diethyl ester (200.19 g, 1.00 mol) and concentrated hydrochloric acid (8 mL, 0.1 mol) were placed in a three-necked flask, heated to reflux for 5 h, and then heated to reflux for 5 h. h, after the reaction was cooled, the liquid was separated, dried, and the solvent was recovered under reduced pressure to obtain crude 6-(2-ethoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid diethyl ester (5); Compound 5, iron powder (168.00 g, 3.00 mol) and acetic acid (1.00 L) were placed in a three-necked flask, heated to 50 °C, reacted for 8 h, and the solvent was recovered under reduced pressure to obtain crude 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid triethyl ester (6); Compound 6, sodium hydroxide (40 g, 1.00 mol) and methanol (1.00 L) were placed in a three-necked flask, stirred at 25 °C for 24 h, the solvent was dried under reduced pressure, and then diluted hydrochloric acid was added dropwise to acidify to pH 5.0, extracted with 1,2-dichloroethane, washed with water, dried, and filtered to obtain a 1,2-dichloroethane solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the 1,2-dichloroethane solution of compound 7 and ammonium cerium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was decompressed to recover the solvent to obtain pyrroloquinoline quinone (62.79 g, total yield 19.01%).

[0032] Example 6

[0033] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), dimethyl oxalate (118.09 g, 1.00 mol), sodium carbonate (212.00 g, 2.00 mol) and 2-methyltetrahydrofuran (1.00 L) were placed in a three-necked flask, heated to reflux for 5 h, and after the reaction was cooled, filtered, the solvent was recovered under reduced pressure to obtain crude 3-(4-amino-2-nitro-5-fluoro)phenyl-2-oxopropionic acid methyl ester (4); compound 4, dichloromethane (1.00 L), 4-oxo-2-eneglutaric acid dimethyl ester (172.14 g, 1.00 mol) and 5 M dilute sulfuric acid (20 mL, 0.1 mol) were placed in a three-necked flask, heated to reflux for 5 h. h, after the reaction was cooled, the liquid was separated, dried, and the solvent was recovered under reduced pressure to obtain crude 6-(2-methoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dimethyl ester (5); Compound 5, zinc powder (195 g, 3.00 mol) and acetic acid (1.00 L) were placed in a three-necked flask, heated to 50 °C, reacted for 10 h, and the solvent was recovered under reduced pressure to obtain crude 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (6); Compound 6, sodium hydroxide (40 g, 1.00 mol) and methanol (1.00 L) were placed in a three-necked flask, stirred at 25 °C for 24 h, vacuum-dried the solvent, then added dilute hydrochloric acid dropwise to acidify to pH 5.0, extracted with 2-methyltetrahydrofuran, washed with water, dried, and filtered to obtain a 2-methyltetrahydrofuran solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the 2-methyltetrahydrofuran solution of compound 7 and cerium ammonium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was vacuum-reduced to recover the solvent to obtain pyrroloquinoline quinone (59.58 g, total yield 18.04%).

[0034] Example 7

[0035] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), dimethyl oxalate (118.09 g, 1.00 mol), potassium carbonate (276.00 g, 2.00 mol) and acetonitrile (1.00 L) were placed in a three-necked flask, heated to reflux for 5 h, and after the reaction was cooled, filtered to obtain an acetonitrile solution of 3-(4-amino-2-nitro-5-fluoro)phenyl-2-oxopropionic acid methyl ester (4); the acetonitrile solution of compound 4, dimethyl 4-oxo-2-eneglutarate (172.14 g, 1.00 mol) and methanesulfonic acid (9.61 g, 0.1 mol) were placed in a three-necked flask, heated to reflux for 5 h. h, after the reaction was cooled, the liquid was separated, dried, and the solvent was recovered under reduced pressure to obtain crude 6-(2-methoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dimethyl ester (5); Compound 5, tin powder (356.13 g, 3 mol) and acetic acid (1.00 L) were placed in a three-necked flask, heated to 50 °C, reacted for 12 h, and the solvent was recovered under reduced pressure to obtain crude 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (6); Compound 6, potassium hydroxide (56 g, 1.00 mol) and methanol (1.00 L) were placed in a three-necked flask, stirred at 25 °C for 24 h, vacuum-dried the solvent, then added dilute hydrochloric acid to acidify to pH 5.0, extracted with benzene, washed with water, dried, and filtered to obtain a benzene solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the benzene solution of compound 7 and cerium ammonium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was decompressed to recover the solvent to obtain pyrroloquinoline quinone (56.45 g, total yield 17.09%).

[0036] Example 8

[0037] Preparation method of pyrroloquinoline quinone: 4-methyl-5-nitro-2-fluoroaniline (2) (170.14 g, 1.00 mol), diethyl oxalate (146.14 g, 1.00 mol), lithium diisopropylamide (107.12 g, 1.00 mol) and n-hexane (1.00 L) were placed in a three-necked flask, heated under reflux for 4 h, and after the reaction was cooled, washed with water, separated, dried, and filtered to obtain a n-hexane solution of ethyl 3-(4-amino-2-nitro-5-fluoro)phenyl-2-oxopropanoate (4); the n-hexane solution of compound 4, diethyl 4-oxo-2-eneglutarate (200.19 g, 1.00 mol) and p-toluenesulfonic acid (17.22 g, 0.1 mol) were placed in a three-necked flask, heated under reflux for 4 h. h, after the reaction was cooled, washed with water, separated, dried, and the solvent was recovered under reduced pressure to obtain crude 6-(2-ethoxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid diethyl ester (5); Compound 5, 10% palladium carbon (5 g) and methanol (1.00 L) were placed in a high-pressure reactor, filled with hydrogen, maintained at a pressure of 5 atmospheres, heated to 50 ° C, reacted for 12 h, filtered, and obtained a methanol solution of crude 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid triethyl ester (6); The methanol solution of compound 6 and potassium hydroxide (56 g, 1.00 mol) were placed in a three-necked flask and stirred at 25 ° C for 24 h, vacuum-dried the solvent, then added dilute hydrochloric acid dropwise to acidify to pH 5.0, extracted with n-hexane, washed with water, dried, and filtered to obtain a n-hexane solution of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); the n-hexane solution of compound 7 and cerium ammonium nitrate (548.22 g, 1.00 mol) were placed in a three-necked flask, stirred at 25 °C for 24 h, filtered, and the mother liquor was vacuum-reduced to recover the solvent to obtain pyrroloquinoline quinone (59.38 g, total yield 17.98%).

Claims

1. A five-step method for synthesizing pyrroloquinoline quinone, characterized in that: A. Preparation of 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (5): 4-methyl-5-nitro-2-fluoroaniline (2) is used as a raw material, 4-oxo-2-eneglutaric acid dialkyl ester, a first acidic catalyst and a first solvent are used to generate 6-methyl-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (3), and then oxalic acid dialkyl ester, a second basic catalyst and a second solvent are used to generate 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (4). or, using 4-methyl-5-nitro-2-fluoroaniline (2) as a raw material, generating 3-(4-amino-2-nitro-5-fluoro)phenyl-2-oxopropionic acid alkyl ester (4) in the presence of dialkyl oxalate, a second alkaline catalyst and a second solvent, and then generating 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (5) in the presence of dialkyl 4-oxo-2-eneglutaric acid ester, a first acidic catalyst and a first solvent; B. Preparation of 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6): using 6-(2-alkyloxycarbonyl-2-oxoethyl)-5-nitro-8-fluoroquinoline-2,4-dicarboxylic acid dialkyl ester (5) prepared in step A as a raw material, generating 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6) under the action of a first reagent / catalyst and a third solvent; C. Preparation of 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7): using the 5-fluoro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trialkyl ester (6) prepared in step B as a raw material, generating a carboxylate under the action of a third alkaline catalyst and methanol, and then acidifying with a second reagent to obtain 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7); D. Preparation of pyrroloquinoline quinone (PQQ, 1): Using 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (7) prepared in step C as a raw material, pyrroloquinoline quinone (PQQ, 1) is obtained under the action of an oxidant, cerium ammonium nitrate and a fourth solvent.

2. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 1, characterized in that: In step A, the hydrocarbon group is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl or benzyl; the first acidic catalyst is one of dilute hydrochloric acid, dilute sulfuric acid, hypochlorous acid, chloric acid, perchloric acid, dilute phosphoric acid, phosphorous acid, hypophosphorous acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or benzenesulfonic acid substituted on the benzene ring; the first solvent is n-hexane, petroleum ether, cyclohexane, octane, benzene, toluene, xylene, trimethylbenzene, ethylbenzene, n-propylbenzene, isopropylbenzene, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, sec-butyl ether, Tert-butyl ether, n-pentyl ether, isopentyl ether, sec-pentyl ether, neopentyl ether, n-hexyl ether, isohexyl ether, sec-hexyl ether, neohexyl ether, cyclopropyl ether, cyclobutyl ether, cyclopentyl ether, cyclohexyl ether, anisole, diphenyl ether, α-naphthyl methyl ether, β-naphthyl methyl ether, ethylene oxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, butyronitrile, valeronitrile, hexanenitrile, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, n-butyl formate, isobutyl formate, sec-butyl formate, tert-butyl formate, n-pentyl formate, isopentyl formate, sec-pentyl formate, neopentyl formate, n-hexyl formate, isohexyl formate, sec-hexyl formate, neohexyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, Isobutyl acetate, sec-butyl acetate, tert-butyl acetate, n-pentyl acetate, isoamyl acetate, sec-pentyl acetate, neopentyl acetate, n-hexyl acetate, isohexyl acetate, sec-hexyl acetate, neohexyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isoamyl propionate, sec-pentyl propionate, neopentyl propionate, n-hexyl propionate, isohexyl propionate, sec-hexyl propionate, neohexyl propionate, methyl isopropionate, ethyl isopropionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isoamyl propionate, sec-pentyl propionate Ester, neopentyl isopropionate, n-hexyl isopropionate, isohexyl isopropionate, sec-hexyl isopropionate, neohexyl isopropionate, methyl butyrate, ethyl butyrate, n-propyl butyrate, isopropyl butyrate, n-butyl butyrate, isobutyl butyrate, sec-butyl butyrate, tert-butyl butyrate, n-pentyl butyrate, isohexyl butyrate, sec-pentyl butyrate, neopentyl butyrate, n-hexyl butyrate , isohexyl isobutyrate, sec-hexyl isobutyrate, neohexyl isobutyrate, methyl isobutyrate, ethyl isobutyrate, n-propyl isobutyrate, isopropyl isobutyrate, n-butyl isobutyrate, isobutyl isobutyrate, sec-butyl isobutyrate, tert-butyl isobutyrate, n-pentyl isobutyrate, isopentyl isobutyrate, sec-pentyl isobutyrate, neopentyl isobutyrate, n-hexyl isobutyrate, isohexyl isobutyrate, sec-hexyl isobutyrate,Neohexyl isobutyrate, methyl valerate, ethyl valerate, n-propyl valerate, isopropyl valerate, n-butyl valerate, isobutyl valerate, sec-butyl valerate, tert-butyl valerate, n-pentyl valerate, isopentyl valerate, sec-pentyl valerate, neopentyl valerate, n-hexyl valerate, isohexyl valerate, sec-hexyl valerate, neohexyl valerate, methyl isovalerate, ethyl isovalerate, n-propyl isovalerate, isopropyl valerate, n-butyl valerate, isobutyl valerate, sec-butyl valerate, tert-butyl valerate, n-pentyl valerate, isopentyl valerate, sec-pentyl valerate, neohexyl valerate, methyl isovalerate, ethyl isovalerate, n-propyl isovalerate, isopropyl valerate, n-butyl valerate, isovalerate, sec-butyl valerate, tert-butyl valerate, n-pentyl valerate Esters, isopentyl isovalerate, secondary amyl isovalerate, neopentyl isovalerate, n-hexyl isovalerate, isohexyl isovalerate, secondary hexyl isovalerate, neohexyl isovalerate, methyl hexanoate, ethyl hexanoate, n-propyl hexanoate, isopropyl hexanoate, n-butyl hexanoate, isobutyl hexanoate, secondary butyl hexanoate, tert-butyl hexanoate, n-pentyl hexanoate, isopentyl hexanoate, secondary amyl hexanoate, neopentyl hexanoate, n-hexyl hexanoate, isohexyl hexanoate, secondary hexyl hexanoate, neohexyl hexanoate, methyl isocaproate, ethyl isocaproate, tert-butyl hexanoate, n-pentyl hexanoate, isopentyl hexanoate, secondary amyl hexanoate, neohexyl hexanoate, n-hexyl hexanoate, isohexyl hexanoate, secondary hexyl hexanoate, neohexyl hexanoate, methyl isocaproate, ethyl isocaproate, isohexanoate One of n-propyl ester, isopropyl isohexanoate, n-butyl isohexanoate, isobutyl isohexanoate, sec-butyl isohexanoate, tert-butyl isohexanoate, n-pentyl isohexanoate, isopentyl isohexanoate, sec-pentyl isohexanoate, neopentyl isohexanoate, n-hexyl isohexanoate, isohexyl isohexanoate, sec-hexyl isohexanoate or neohexyl isohexanoate; the second alkaline catalyst is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium hydride, calcium hydride, lithium dimethylamine or n-butyl lithium The second solvent is one of n-hexane, petroleum ether, cyclohexane, octane, benzene, carbon tetrachloride, ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, sec-butyl ether, tert-butyl ether, n-pentyl ether, isopentyl ether, sec-pentyl ether, neopentyl ether, n-hexyl ether, isohexyl ether, sec-hexyl ether, neohexyl ether, cyclopropyl ether, cyclobutyl ether, cyclopentyl ether, cyclohexyl ether, anisole, diphenyl ether, α-naphthyl methyl ether, β-naphthyl methyl ether, ethylene oxide, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane.

3. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 2, characterized in that: In step A, the hydrocarbon group is preferably ethyl; the first acidic catalyst is preferably dilute hydrochloric acid; the first solvent is preferably 1,2-dichloroethane; and the second alkaline catalyst is preferably potassium carbonate.

4. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 1, characterized in that: In step B, the hydrocarbon group is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl or benzyl; the first reagent / catalyst is one of hydrogen / palladium carbon, hydrogen / Raney nickel, hydrogen / platinum, hydrochloric acid / iron, hydrochloric acid / tin, hydrochloric acid / zinc, acetic acid / iron, acetic acid / tin or acetic acid / zinc; the third solvent is water, n-hexane , benzene, toluene, xylene, trimethylbenzene, ethylbenzene, n-propylbenzene, isopropylbenzene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, sec-pentanol, neopentyl alcohol, n-hexanol, isohexanol, sec-hexanol, neohexanol, heptanol, octanol, nonanol, decanol, 1,2-ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol or glycerol.

5. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 4, characterized in that: In step B, the hydrocarbon group is preferably ethyl; the first reagent / catalyst is preferably hydrogen / palladium on carbon; and the third solvent is preferably methanol.

6. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 1, characterized in that: In step C, the third alkaline catalyst is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium hydride, calcium hydride, lithium dimethylamine or n-butyl lithium; the second reagent is one of dilute hydrochloric acid, dilute sulfuric acid, hypochlorous acid, chloric acid, perchloric acid, dilute phosphoric acid, phosphorous acid, hypophosphorous acid, and formic acid.

7. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 6, characterized in that: In step C, the third alkaline catalyst is preferably potassium carbonate; and the second reagent is preferably dilute hydrochloric acid.

8. The method for preparing pyrroloquinoline quinone by a five-step method according to claim 1, characterized in that: In step D, the fourth solvent is n-hexane, petroleum ether, cyclohexane, octane, benzene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, sec-butyl ether, tert-butyl ether, n-pentyl ether, isopentyl ether, sec-pentyl ether, neopentyl ether, n-hexyl ether, isohexyl ether, sec-hexyl ether, neohexyl ether, cyclopropyl ether, cyclobutyl ether, cyclopentyl ether, cyclohexyl ether, anisole, diphenyl ether, α-naphthyl methyl ether, β-naphthyl methyl ether, ethylene oxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, n-butyl formate, isobutyl formate, methyl formate sec-butyl formate, tert-butyl formate, n-pentyl formate, isopentyl formate, sec-pentyl formate, neopentyl formate, n-hexyl formate, isohexyl formate, sec-hexyl formate, neohexyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, n-pentyl acetate, isopentyl acetate, sec-pentyl acetate, neopentyl acetate, n-hexyl acetate, isohexyl acetate, sec-hexyl acetate, neohexyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isopentyl propionate, sec-pentyl propionate, neopentyl propionate, n-hexyl propionate, isohexyl propionate, sec-hexyl propionate, neohexyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, sec-butyl propionate, tert-butyl propionate, n-pentyl propionate, isopentyl propionate, sec-pentyl propionate, neopentyl propionate, n-hexyl propionate, isohexyl propionate, n- sec-hexyl propionate, neohexyl propionate, methyl isopropionate, ethyl isopropionate, n-propyl isopropionate, isopropyl isopropionate, n-butyl isopropionate, isobutyl isopropionate, sec-butyl isopropionate, tert-butyl isopropionate, n-pentyl isopropionate, isopentyl isopropionate, sec-pentyl isopropionate, neopentyl isopropionate, n-hexyl isopropionate, isohexyl isopropionate, sec-hexyl isopropionate, neohexyl isopropionate, n-butyl Methyl butyrate, ethyl butyrate, n-propyl butyrate, isopropyl butyrate, n-butyl butyrate, isobutyl butyrate, sec-butyl butyrate, tert-butyl butyrate, n-pentyl butyrate, isopentyl butyrate, sec-pentyl butyrate, neopentyl butyrate, n-hexyl butyrate, isohexyl butyrate, sec-hexyl butyrate, neohexyl butyrate, methyl isobutyrate, ethyl isobutyrate, n-propyl butyrate Esters, isopropyl isobutyrate, n-butyl isobutyrate, isobutyl isobutyrate, sec-butyl isobutyrate, tert-butyl isobutyrate, n-amyl isobutyrate, isoamyl isobutyrate, sec-amyl isobutyrate, neopentyl isobutyrate, n-hexyl isobutyrate, isohexyl isobutyrate, sec-hexyl isobutyrate, neohexyl isobutyrate, methyl valerate, ethyl valerate, n-propyl valerate, isopropyl valerate, n-butyl valerate , isobutyl valerate, sec-butyl valerate, tert-butyl valerate, n-pentyl valerate, isopentyl valerate, sec-pentyl valerate, neopentyl valerate, n-hexyl valerate, isohexyl valerate, sec-hexyl valerate, neohexyl valerate, methyl isovalerate, ethyl isovalerate, n-propyl isovalerate, isopropyl isovalerate, n-butyl isovalerate, isobutyl isovalerate, sec-butyl isovalerate,Tert-butyl isovalerate, n-pentyl isovalerate, isopentyl isovalerate, sec-pentyl isovalerate, neopentyl isovalerate, n-hexyl isovalerate, isohexyl isovalerate, sec-hexyl isovalerate, neohexyl isovalerate, methyl hexanoate, ethyl hexanoate, n-propyl hexanoate, isopropyl hexanoate, n-butyl hexanoate, isobutyl hexanoate, sec-butyl hexanoate, tert-butyl hexanoate, n-pentyl hexanoate, isopentyl hexanoate, sec-pentyl hexanoate, neopentyl hexanoate ester, n-hexyl hexanoate, isohexyl hexanoate, secondary hexyl hexanoate, neohexyl hexanoate, methyl isohexanoate, ethyl isohexanoate, n-propyl isohexanoate, isopropyl isohexanoate, n-butyl isohexanoate, isobutyl isohexanoate, secondary butyl isohexanoate, tert-butyl isohexanoate, n-pentyl isohexanoate, isohexyl isohexanoate, secondary pentyl isohexanoate, neopentyl isohexanoate, n-hexyl isohexanoate, isohexyl isohexanoate, secondary hexyl isohexanoate or neohexyl isohexanoate.

9. The five-step method for synthesizing pyrroloquinoline quinone according to claim 8, characterized in that: In step D, the fourth solvent is preferably acetonitrile.

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