WO2024098531A1 - Intermediate and use and method of intermediate in preparation of pyrroloquinoline quinone - Google Patents

Intermediate and use and method of intermediate in preparation of pyrroloquinoline quinone Download PDF

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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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compound
formula
reaction
ethyl
dicarboxylic acid
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PCT/CN2022/142380
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French (fr)
Chinese (zh)
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蔡成法
王靖林
穆振强
刘桂贞
于瑞梅
廉琼琼
田翠翠
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山东原力泰医药科技有限公司
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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

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  • 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

An intermediate and a use and method of the intermediate in preparation of pyrroloquinoline quinone. The intermediate compound has a structure as shown in formula I or formula II. In the structure, R1 is C1-C3 straight-chain or branched-chain alkyl; R2 is nitro or amino; R3 is hydrogen or an amino protecting group; R4 is selected from hydrogen and C1-C3 straight-chain or branched-chain alkyl. The method has a simple route, mild reaction conditions and high yield, avoids the use of an oxidizing agent, ceric ammonium nitrate, and achieves the industrial large-scale production of pyrroloquinoline quinone.

Description

一种中间体及其在制备吡咯喹啉醌中的应用和方法An intermediate and its application and method in preparing pyrroloquinoline quinone
本发明要求于2022年11月11日提交中国专利局、申请号为202211415234.3、发明名称为“一种中间体及其在制备吡咯喹啉醌中的应用和方法”的中国专利申请的优先权，其全部内容通过引用结合在本发明中。The present invention claims the priority of the Chinese patent application filed with the Chinese Patent Office on November 11, 2022, with application number 202211415234.3 and invention name “An intermediate and its application and method in the preparation of pyrroloquinoline quinone”, the entire contents of which are incorporated by reference into the present invention.
技术领域Technical Field
本发明涉及有机化合物制备领域，具体涉及一种中间体及其在制备吡咯喹啉醌中的应用和方法。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.
背景技术Background technique
本发明背景技术中公开的信息旨在增加对本发明总体背景的理解，而该公开不应必然被视为承认或以任何形式暗示该信息已经成为本领域一般技术人员所公知的现有技术。The information disclosed in the background of the present invention is intended to increase the understanding of the overall background of the present invention, and the disclosure should not necessarily be regarded as an admission or any form of suggestion that the information has become the prior art known to ordinary technicians in the field.
吡咯喹啉醌，其化学名称为：4,5-二氧代-4,5-二氢-1H-吡咯并[2,3-f]喹啉-2,7,9-三羧酸，CAS号为72909-34-3。吡咯喹啉醌广泛存在于植物源性食物和动物源性食物中，比如水果、蔬菜、谷物等等。然而，吡咯喹啉醌在食物中的浓度仅为纳克至微克/公斤级的水平。因此，仅以膳食补充无法获取充足的PQQ，而且以生物生产和分离的方法获取吡咯喹啉醌既困难又昂贵。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. However, 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.
为此，很多学者开始研究吡咯喹啉醌的化学合成方法，Corey等人首次实现了吡咯喹啉醌的全合成(J.Am.Chem.Soc.1981,103,18,5599–5600)，其后，Martin等改进了Corey的路线(Helvetica chimica acta,1993,76(4):1667-1673)，后来，Kempf等通过组合Corey和Martin的路线实现了吡咯喹啉醌的克级规模的制备(WO2006/102642A1)，但需要浓硫酸纯化，且中间体的分离与纯化过程繁琐，在Kempf之前，Corey和Martin的方法只能实现50mg规模的吡咯喹啉醌制备，这些方法主要适用于实验室制备，难以工业化大规模生产。再后来，有研究以甲基卤苯为原料生产吡咯喹啉醌，该方法能够实现千克级别的吡咯喹啉醌的制备(WO2014/195896)，但是反应后段必须通过硝酸铈铵实现甲氧基-吡咯喹啉中间体到吡咯喹啉醌中间体的氧化。虽然该过程产物选择性较高，但是硝酸铈铵消耗量极大，一般是原料质量用量的8倍以上，硝酸铈铵价格高昂，导致生产成本高昂，且铈盐只能作为废物处理，排污压力大，而且该步骤的分离和纯化困难，导致该步骤的最优收率难以超过60％，且反应路线效率较低，生产耗时，获得千克级别的产品至少需要4-5周时间，使得吡咯喹啉醌的生产难以实现高效工业化。To this end, many scholars began to study the chemical synthesis methods of pyrroloquinoline quinone. Corey et al. first achieved the total synthesis of pyrroloquinoline quinone (J.Am.Chem.Soc.1981,103,18,5599–5600). Later, Martin et al. improved Corey's route (Helvetica chimica acta,1993,76(4):1667-1673). Later, Kempf et al. achieved the gram-scale preparation of pyrroloquinoline quinone by combining the routes of Corey and Martin (WO2006/102642A1). However, it required concentrated sulfuric acid purification, and the separation and purification process of the intermediates was cumbersome. Before Kempf, the methods of Corey and Martin could only achieve the preparation of 50 mg of pyrroloquinoline quinone. These methods were mainly suitable for laboratory preparation and difficult to industrial large-scale production. Later, there was a study on the production of pyrroloquinoline quinone using methyl halobenzene as raw material. This method can achieve the preparation of kilogram-level pyrroloquinoline quinone (WO2014/195896), but the oxidation of methoxy-pyrroloquinoline intermediate to pyrroloquinoline quinone intermediate must be achieved by ammonium cerium nitrate in the latter stage of the reaction. Although the product selectivity of this process is high, the consumption of ammonium cerium nitrate is extremely large, generally more than 8 times the mass of the raw material, and the price of ammonium cerium nitrate is high, resulting in high production costs, and cerium salts can only be treated as waste, with high sewage discharge pressure, and the separation and purification of this step is difficult, resulting in the optimal yield of this step being difficult to exceed 60%, and the reaction route efficiency is low, production is time-consuming, and it takes at least 4-5 weeks to obtain kilogram-level products, making it difficult to achieve efficient industrialization of the production of pyrroloquinoline quinone.
发明内容Summary of the invention
本发明提供了一种中间体化合物及其在制备吡咯喹啉醌中的应用和方法。以本发明的中间体制备吡咯喹啉醌能够大大简化反应路线，使反应路线控制在7步以内，并且反应条件温和，原料廉价易得，产品收率高，效率高，并且大大缩短了生产周期，在2-3周内即可获取公斤级别的产品，在1.5个月内能够实现百公斤级别吡咯喹啉醌的高效的工业化大规模生产。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.
具体地，本发明提供了下述技术方案：Specifically, the present invention provides the following technical solutions:
在本发明的第一方面，本发明提供了一种制备吡咯喹啉醌的中间体化合物，其具有式I或式II所示结构：In the first aspect of the present invention, the present invention provides an intermediate compound for preparing pyrroloquinoline quinone, which has a structure shown in Formula I or Formula II:
Figure PCTCN2022142380-appb-000001
Figure PCTCN2022142380-appb-000001
其中，R 1为C 1-C 3直链或支链烷基；R 2为硝基或氨基；R 3为氢或氨基保护基；R 4选自氢和C 1-C 3直链或支链烷基。 Wherein, 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; and R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
在本发明的一些实施方式中，R 1优选为甲基或乙基。 In some embodiments of the present invention, R 1 is preferably methyl or ethyl.
在本发明的一些实施方式中，R 3优选为氢或甲基羰基。 In some embodiments of the present invention, R3 is preferably hydrogen or methylcarbonyl.
在本发明的一些实施方式中，R 4优选为甲基、乙基或丙基。 In some embodiments of the present invention, R4 is preferably methyl, ethyl or propyl.
在本发明的实施方式中，式II化合物具有式I-1、式I-2、式II-1或式II-2所示的结构：In an embodiment of the present invention, the compound of formula II has a structure shown in formula I-1, formula I-2, formula II-1 or formula II-2:
Figure PCTCN2022142380-appb-000002
Figure PCTCN2022142380-appb-000002
其中，R 1为甲基或乙基，R 4为氢、甲基、乙基或丙基。 Wherein, R1 is methyl or ethyl, and R4 is hydrogen, methyl, ethyl or propyl.
具体地，作为示例，本发明所述中间体化合物选自以下结构：Specifically, as an example, the intermediate compound of the present invention is selected from the following structures:
N-(3,4-二甲氧基-5-硝基苯基)乙酰胺(化合物I-1-1)；N-(3,4-dimethoxy-5-nitrophenyl)acetamide (Compound I-1-1);
N-(3,4-二乙氧基-5-硝基苯基)乙酰胺(化合物I-1-2)；N-(3,4-diethoxy-5-nitrophenyl)acetamide (Compound I-1-2);
N-(3-氨基-4,5-二甲氧基苯基)乙酰胺(化合物I-2-1)；N-(3-amino-4,5-dimethoxyphenyl)acetamide (Compound I-2-1);
N-(3-氨基-4,5-二乙氧基苯基)乙酰胺(化合物I-2-2)；N-(3-amino-4,5-diethoxyphenyl)acetamide (Compound I-2-2);
5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸(化合物II-1-1，R 1为甲基，R 4为氢)； 5-Acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid (compound II-1-1, R 1 is methyl, R 4 is hydrogen);
5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二甲酯(化合物II-1-2，R 1为甲基，R 4为甲基)； 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-1-2, R 1 is methyl, R 4 is methyl);
5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二乙酯(化合物II-1-3，R 1为甲基，R 4为乙基)； 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid diethyl ester (compound II-1-3, R 1 is methyl, R 4 is ethyl);
5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二丙酯(化合物II-1-4，R 1为甲基，R 4为丙基)； 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-1-4, R 1 is methyl, R 4 is propyl);
5-乙酰氨基-7,8-二乙氧基喹啉-2,4-二羧酸(化合物II-1-5，R 1为乙基，R 4为氢)； 5-Acetylamino-7,8-diethoxyquinoline-2,4-dicarboxylic acid (compound II-1-5, R 1 is ethyl, R 4 is hydrogen);
5-乙酰氨基-7,8-二乙氧基喹啉-2,4-二甲酸二甲酯(化合物II-1-6，R 1为乙基，R 4为甲基)； 5-acetylamino-7,8-diethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-1-6, R 1 is ethyl, R 4 is methyl);
5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二甲酸二乙酯(化合物II-1-7，R 1为乙基，R 4为乙基)； 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid diethyl ester (compound II-1-7, R 1 is ethyl, R 4 is ethyl);
5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二羧酸二丙酯(化合物II-1-8，R 1为乙基，R 4为丙基)； 5-acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-1-8, R 1 is ethyl, R 4 is propyl);
5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸(化合物II-2-1，R 1为甲基，R 4为氢)； 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid (compound II-2-1, R 1 is methyl, R 4 is hydrogen);
5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸二甲酯(化合物II-2-2，R 1为甲基，R 4为甲基)； 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-2-2, R 1 is methyl, R 4 is methyl);
5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸二乙酯(化合物II-2-3，R 1为甲基，R 4为乙基)； 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid diethyl ester (compound II-2-3, R 1 is methyl, R 4 is ethyl);
5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸二丙酯(化合物II-2-4，R 1为甲基，R 4为丙基)； 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-2-4, R 1 is methyl, R 4 is propyl);
5-氨基-7,8-二乙氧基喹啉-2,4-二羧酸(化合物II-2-5，R 1为乙基，R 4为氢)； 5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid (compound II-2-5, R 1 is ethyl, R 4 is hydrogen);
5-氨基-7,8-二乙氧基喹啉-2,4-二甲酸二甲酯(化合物II-2-6，R 1为乙基，R 4为甲基)； 5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-2-6, R 1 is ethyl, R 4 is methyl);
5-氨基-7,8-二乙氧基喹啉-2,4-二甲酸二乙酯(化合物II-2-7，R 1为乙基，R 4为乙基)； 5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid diethyl ester (compound II-2-7, R 1 is ethyl, R 4 is ethyl);
5-氨基-7,8-二乙氧基喹啉-2,4-二甲酸二丙酯(化合物II-2-6，R 1为乙基，R 4为丙基)。 5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-2-6, R 1 is ethyl, R 4 is propyl).
在本发明的第二方面，本发明提供了制备上述式I或式II所示化合物的制备方法。In the second aspect of the present invention, the present invention provides a method for preparing the compound represented by the above formula I or formula II.
在本发明的实施方式中，式I化合物可由3,4-二甲氧基-5-硝基苯胺与乙酸酐发生亲电取代反应制备得到。3,4-二甲氧基-5-硝基苯胺可以3,4-二甲氧基-5-硝基苯甲酸或3,4-二甲氧基-5-硝基苯甲酰胺为原料制备得到。In an embodiment of the present invention, 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.
在本发明的实施方式中，式I化合物具有式I-1或式I-2所示的结构：In an embodiment of the present invention, the compound of formula I has a structure shown in formula I-1 or formula I-2:
Figure PCTCN2022142380-appb-000003
Figure PCTCN2022142380-appb-000003
其中，R 1为甲基或乙基。 Wherein, R1 is methyl or ethyl.
其中，3,4-二烷氧基-5-硝基苯胺与乙酸酐发生亲电取代反应制备式I-1化合物，还原式I-1化合物可制备得到式I-2化合物。在一种实施方式中，所述还原反应可在雷尼镍催化高压加氢的条件下发生。Wherein, 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. In one embodiment, the reduction reaction can occur under conditions of Raney nickel catalytic high pressure hydrogenation.
在本发明的实施方式中，式II化合物可以进一步具有式II-1或式II-2所示的结构，式II-1化合物可由式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围下(有氧)制备得到；式II-2化合物由式II-1化合物脱乙酰基和/或酯水解后制备得到In an embodiment of the present invention, 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.
Figure PCTCN2022142380-appb-000004
Figure PCTCN2022142380-appb-000004
其中，R 4选自氢、甲基、乙基和丙基。 Wherein, R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的第三方面，本发明上述第一方面中所述的任一种式I或式II所示化合物作为中间体在制备吡咯喹啉醌中的应用；In the third aspect of the present invention, use of any one of the compounds of formula I or formula II described in the first aspect of the present invention as an intermediate in the preparation of pyrroloquinoline quinone;
Figure PCTCN2022142380-appb-000005
Figure PCTCN2022142380-appb-000005
其中，R 1为C 1-C 3直链或支链烷基；R 2为硝基或氨基；R 3为氢或氨基保护基；R 4选自氢和C 1-C 3直链或支链烷基。 Wherein, 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; and R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
在本发明的第四方面，本发明提供了一种制备吡咯喹啉醌的方法，其包括：式II-2化合 物通过Fischer吲哚合成法制备式III化合物，式III化合物水解制备式IV化合物，式IV化合物氧化制备得到吡咯喹啉醌；In a fourth aspect of the present invention, 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;
Figure PCTCN2022142380-appb-000006
Figure PCTCN2022142380-appb-000006
其中，R 1、R 4同上文中所定义； Wherein, R 1 and R 4 are as defined above;
优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的一种实施方式中，式II-2化合物可以由式II-1化合物脱乙酰基和/或酯水解后制备得到；In one embodiment of the present invention, the compound of formula II-2 can be prepared by deacetylation and/or ester hydrolysis of the compound of formula II-1;
Figure PCTCN2022142380-appb-000007
Figure PCTCN2022142380-appb-000007
其中，R 1、R 4同上文中所定义； Wherein, R 1 and R 4 are as defined above;
优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的第五方面，本发明提供了一种制备吡咯喹啉醌的方法，其包括：式II-1化合物脱乙酰基、酯水解后制备得到式II-2’化合物，式II-2’化合物通过Fischer吲哚合成法制备得到式III’化合物，水解式III’化合物制备得到式IV化合物，氧化式IV化合物制备得到吡咯喹啉醌；In a fifth aspect of the present invention, 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;
Figure PCTCN2022142380-appb-000008
Figure PCTCN2022142380-appb-000008
其中，R 1、R 4同上文中所定义； Wherein, R 1 and R 4 are as defined above;
优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的一种实施方式中，式II-1化合物由式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围(有氧)下制备得到；In one embodiment of the present invention, 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);
Figure PCTCN2022142380-appb-000009
Figure PCTCN2022142380-appb-000009
其中，R 1、R 4同上文中所定义； Wherein, R 1 and R 4 are as defined above;
优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的第六方面，本发明提供了一种制备吡咯喹啉醌的方法，其包括：式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围下制备得到式II-1化合物，式II-1化合物脱乙酰、酯水解后制备式II-2’化合物，式II-2’化合物通过Fischer吲哚合成法制备式III’化合物，式III’化合物水解制备式IV化合物，式IV化合物氧化制备得到吡咯喹啉醌；In the sixth aspect of the present invention, 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;
Figure PCTCN2022142380-appb-000010
Figure PCTCN2022142380-appb-000010
其中，R 1、R 4同上文中所定义； Wherein, R 1 and R 4 are as defined above;
优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的一种实施方式中，式I-2化合物由式I-1化合物经还原反应制备得到，In one embodiment of the present invention, the compound of formula I-2 is prepared by reducing the compound of formula I-1.
Figure PCTCN2022142380-appb-000011
Figure PCTCN2022142380-appb-000011
其中，R 1同上文中所定义； Wherein, R 1 is as defined above;
优选地，R 1为甲基或乙基。 Preferably, R 1 is methyl or ethyl.
比如，在本发明的一种实施方式中，所述还原反应在雷尼镍催化高压加氢条件下发生。For example, in one embodiment of the present invention, the reduction reaction occurs under Raney nickel catalytic high pressure hydrogenation conditions.
在本发明的第七方面，本发明提供了一种制备吡咯喹啉醌的方法，其包括：还原I-1化合物制备得到式I-2化合物，式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围下制备得到式II-1化合物，式II-1化合物脱乙酰基、酯水解后制备得到式II-2’化合物，式II-2’化合物通过Fischer吲哚合成法制备式III’化合物，式III’化合物水解制备式IV化合物，式IV化合物氧化制备得到吡咯喹啉醌；In the seventh aspect of the present invention, 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;
Figure PCTCN2022142380-appb-000012
Figure PCTCN2022142380-appb-000012
其中，R 1、R 4同上文中所定义； Wherein, R 1 and R 4 are as defined above;
优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
在本发明的实施方式中，式I化合物可由3,4-二烷氧基-5-硝基苯胺与乙酸酐发生亲电取代反应制备得到。3,4-二烷氧基-5-硝基苯胺可以3,4-二烷氧基-5-硝基苯甲酸或3,4-二烷氧基-5-硝基苯甲酰胺为原料制备得到。所述烷氧基主要为C 1-C 3烷氧基。 In an embodiment of the present invention, 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.
在本发明的实施方式中，式I化合物具有式I-1或式I-2所示的结构：In an embodiment of the present invention, the compound of formula I has a structure shown in formula I-1 or formula I-2:
Figure PCTCN2022142380-appb-000013
Figure PCTCN2022142380-appb-000013
其中，R 1同上文中所定义；优选地，R 1为甲基或乙基。 Wherein, R 1 is the same as defined above; preferably, R 1 is methyl or ethyl.
其中，3,4-二烷氧基-5-硝基苯胺与乙酸酐发生亲电取代反应制备化合物式I-1，化合物式I-1经还原反应制备得到式I-2化合物。比如，在一种实施方式中，所述还原反应可以在雷尼镍催化高压加氢的条件下发生。Wherein, 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. For example, in one embodiment, the reduction reaction can occur under conditions of Raney nickel catalytic high pressure hydrogenation.
相较于现有技术，本发明的优势在于：本发明所述化合物作为中间体制备吡咯喹啉醌能够大大简化反应路线，使反应路线控制在7步以内，并且反应条件温和，原料廉价易得，产品收率高，效率高，在2-3周内即可获取公斤级别的产品，能够实现公斤级别吡咯喹啉醌的高效的工业化大规模生产。Compared with the prior art, 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.
此外，现有技术中往往倾向于先合成吲哚结构，然后再合成喹啉结构，发明人发现这样的操作方式在合成吲哚结构时，吲哚的合成是没有选择性的，这意味着该步的收率往往在50％-60％左右，因此容易产生不必要的杂质，影响终产物的收率且造成后续纯化繁琐，而如果以现有技术中的中间体先合成喹啉结构则又会导致反应路线过长，反应效率低下。本发明以式I化合物或式II化合物作为中间体在制备吡咯喹啉醌时首先通过合成喹啉结构，然后再进行Fischer吲哚合成，通过喹啉占位提高吲哚合成的选择性，避免了不必要副产物的产生，大大提升了合成效率和收率并且减少了后续的繁杂的纯化工作，实现了吡咯喹啉醌的百公斤级别的高效率的大规模生产。In addition, the prior art tends to synthesize the indole structure first and then synthesize the quinoline structure. The inventors found that when synthesizing the indole structure in such an operation mode, the synthesis of indole is non-selective, which means that the yield of this step is often around 50%-60%, so it is easy to produce unnecessary impurities, affecting the yield of the final product and causing the subsequent purification to be cumbersome. If the quinoline structure is first synthesized using the intermediate in the prior art, the reaction route will be too long and the reaction efficiency will be low. 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.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。以下，结合附图来详细说明本发明的实施方案，其中：The drawings constituting a part of the specification of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute an improper limitation of the present invention. The embodiments of the present invention are described in detail below in conjunction with the drawings, wherein:
图1：化合物I-2的示例化合物的氢谱。Figure 1: Proton spectrum of an exemplary compound of Compound I-2.
图2：化合物I-2的示例化合物的碳谱。Figure 2: Carbon spectrum of an exemplary compound of Compound I-2.
图3：化合物II-1的示例化合物的氢谱。Figure 3: Proton spectrum of an exemplary compound of Compound II-1.
图4：化合物II-1的示例化合物的碳谱。Figure 4: Carbon spectrum of an exemplary compound of Compound II-1.
图5：化合物II-2的示例化合物的氢谱。Figure 5: Proton spectrum of an exemplary compound of Compound II-2.
图6：化合物II-2的示例化合物的碳谱。Figure 6: Carbon spectrum of an exemplary compound of Compound II-2.
具体实施方式Detailed ways
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。本发明所使用的试剂或原料均可通过常规途径购买获得，如无特殊说明，本发明所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. The 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.
本发明提供了如式I或式II所示的化合物，及使用这些化合物作为中间体制备吡咯喹啉醌的方法。The present invention provides compounds as shown in Formula I or Formula II, and methods for preparing pyrroloquinoline quinone using these compounds as intermediates.
Figure PCTCN2022142380-appb-000014
Figure PCTCN2022142380-appb-000014
其中，R 1为C 1-C 3直链或支链烷基；R 2为硝基或氨基；R 3为氢或氨基保护基；R 4选自氢和C 1-C 3直链或支链烷基。 Wherein, 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; and R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
在本发明的一些实施方式中，R 1优选为甲基或乙基。 In some embodiments of the present invention, R 1 is preferably methyl or ethyl.
在本发明的一些实施方式中，R 3优选为氢或甲基羰基。 In some embodiments of the present invention, R3 is preferably hydrogen or methylcarbonyl.
在本发明的一些实施方式中，R 4优选为氢、甲基、乙基或丙基。 In some embodiments of the present invention, R4 is preferably hydrogen, methyl, ethyl or propyl.
在本发明的一些实施方式中，以式II化合物作为中间体制备吡咯喹啉醌的方法按照以下反应路线进行：In some embodiments of the present invention, the method for preparing pyrroloquinoline quinone using the compound of formula II as an intermediate is carried out according to the following reaction scheme:
Figure PCTCN2022142380-appb-000015
Figure PCTCN2022142380-appb-000015
其中，在一些优选的实施方式中，R 1为甲基或乙基，R 4为氢、甲基、乙基或丙基。 In some preferred embodiments, R1 is methyl or ethyl, and R4 is hydrogen, methyl, ethyl or propyl.
其中，式II-2化合物可以由式II-1化合物脱乙酰基和/或酯水解后制备得到。The compound of formula II-2 can be prepared by deacetylation and/or ester hydrolysis of the compound of formula II-1.
在本发明的一些实施方式中，以式II-1化合物作为中间体制备吡咯喹啉醌的方法按照以下反应路线进行：In some embodiments of the present invention, 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:
Figure PCTCN2022142380-appb-000016
Figure PCTCN2022142380-appb-000016
其中，在一些优选的实施方式中，R 1为甲基或乙基，R 4为氢、甲基、乙基或丙基。若R 4为氢，则在第1步脱乙酰基后无需酯水解。 Wherein, in some preferred embodiments, R 1 is methyl or ethyl, and 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.
在本发明的一些实施方式中，以式I化合物作为中间体制备吡咯喹啉醌的方法按照以下反应路线进行：In some embodiments of the present invention, the method for preparing pyrroloquinoline quinone using the compound of formula I as an intermediate is carried out according to the following reaction scheme:
Figure PCTCN2022142380-appb-000017
Figure PCTCN2022142380-appb-000017
其中，在一些优选的实施方式中，R 1为甲基或乙基，R 4为氢、甲基、乙基或丙基。若R 4为氢，则在第2步脱乙酰基后无需酯水解。 Wherein, in some preferred embodiments, R 1 is methyl or ethyl, and R 4 is hydrogen, methyl, ethyl or propyl. If R 4 is hydrogen, then no ester hydrolysis is required after deacetylation in step 2.
其中，式I-2化合物可由式I-1化合物经还原反应制备得到，该还原反应可在比如雷尼镍催化高压加氢的条件下发生。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.
在本发明的一些实施方式中，以3,4-二烷氧基-5-硝基苯胺为中间体制备吡咯喹啉醌的方 法按照以下反应路线进行：In some embodiments of the present invention, the method for preparing pyrroloquinoline quinone using 3,4-dialkoxy-5-nitroaniline as an intermediate is carried out according to the following reaction scheme:
Figure PCTCN2022142380-appb-000018
Figure PCTCN2022142380-appb-000018
其中，在一些优选的实施方式中，R 1为甲基或乙基，R 4为氢、甲基、乙基或丙基。若R 4为氢，则在第4步脱乙酰基后无需酯水解。 Wherein, in some preferred embodiments, R 1 is methyl or ethyl, and R 4 is hydrogen, methyl, ethyl or propyl. If R 4 is hydrogen, then no ester hydrolysis is required after deacetylation in step 4.
在本发明的反应路线中，以3,4-二烷氧基-5-硝基苯胺化合物作为中间体在制备吡咯喹啉醌时首先通过合成喹啉结构，然后再进行Fischer吲哚合成，通过喹啉占位提高吲哚合成的选择性，避免了不必要物质的产生，大大提升了合成效率和收率并且减少了后续的繁杂的纯化工作。In the reaction route of the present invention, 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.
在本发明的一些实施方式中，上述多种反应中的最后一步均为氧化反应，所述氧化反应可一步进行，也可按照以下反应路线进行：In some embodiments of the present invention, 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:
Figure PCTCN2022142380-appb-000019
Figure PCTCN2022142380-appb-000019
其中，在一些优选的实施方式中，R 1为甲基或乙基。 Wherein, in some preferred embodiments, R 1 is methyl or ethyl.
比如，在本发明的一种实施方式中，所述吡咯喹啉醌的制备方法可以包括以下具体实施步骤：For example, in one embodiment of the present invention, the preparation method of pyrroloquinoline quinone may include the following specific implementation steps:
(1)3,4-二烷氧基-5-硝基苯胺在溶剂里与乙酸酐发生亲电取代反应制得化合物式I-1；(1) 3,4-dialkoxy-5-nitroaniline reacts with acetic anhydride in a solvent to undergo an electrophilic substitution reaction to prepare a compound of formula I-1;
在本发明的一些实施方式中，所述3,4-二烷氧基-5-硝基苯胺可以为3,4-二甲氧基-5-硝基苯胺或3,4-二乙氧基-5-硝基苯胺；所述溶剂可选自乙酸乙酯、二氧六环和乙腈，优选为乙酸乙酯。In some embodiments of the present 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.
在本发明的一些实施方式中，3,4-二烷氧基-5-硝基苯胺与乙酸酐的摩尔比为1:1-5。In some embodiments of the present invention, the molar ratio of 3,4-dialkoxy-5-nitroaniline to acetic anhydride is 1:1-5.
在本发明的一些实施方式中，步骤(1)在反应阶段的温度控制在20-45℃。In some embodiments of the present invention, the temperature of step (1) during the reaction stage is controlled at 20-45°C.
进一步地，在反应结束后，可通过结晶(比如降温等)、离心、干燥等操作获取式I-1化合物；以及，可在母液中回收溶剂，回收溶剂后可对剩余物进一步结晶(比如降温等)、离心、 干燥等操作获取式I-1化合物。Furthermore, after the reaction is completed, 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.
(2)在雷尼镍催化高压加氢条件下还原化合物式I-1制备化合物式I-2；(2) reducing the compound of formula I-1 under Raney nickel catalytic high pressure hydrogenation conditions to prepare the compound of formula I-2;
在本发明的一些实施方式中，步骤(2)可选地溶剂为醇类，比如简单醇，如甲醇、乙醇等。In some embodiments of the present invention, the solvent in step (2) may be an alcohol, such as a simple alcohol, such as methanol, ethanol, etc.
在本发明的一些实施方式中，步骤(2)的反应温度在20-50℃，比如，可以进一步为20-30℃或者40-50℃。In some embodiments of the present invention, the reaction temperature of step (2) is 20-50°C, for example, it can be further 20-30°C or 40-50°C.
在本发明的一些实施方式中，步骤(2)中所述高压保持在0.5-2MPa。In some embodiments of the present invention, the high pressure in step (2) is maintained at 0.5-2 MPa.
在本发明的一些实施方式中，步骤(2)中化合物式I-1的用量为雷尼镍用量的10-24倍(质量比)。In some embodiments of the present invention, 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.
进一步地，在反应结束后，可在除去雷尼镍、回收溶剂后，通过结晶(比如降温等)、离心、干燥等操作获取式I-2化合物。Furthermore, after the reaction is completed, 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.
(3)化合物式I-2与化合物式V在Lewis酸催化作用下在氧气氛围下发生反应，制得化合物式II-1；(3) Compound I-2 reacts with compound V under the catalysis of Lewis acid in an oxygen atmosphere to obtain compound II-1;
在本发明的一些实施方式中，化合物式I-2与化合物式V的摩尔比为1:1-3。In some embodiments of the present invention, the molar ratio of compound of formula I-2 to compound of formula V is 1:1-3.
在本发明的一些实施方式中，化合物式I-2与Lewis酸的摩尔比为1:1-2。In some embodiments of the present invention, the molar ratio of compound of formula I-2 to Lewis acid is 1:1-2.
在本发明的一些实施方式中，反应溶剂可以为二氯甲烷。In some embodiments of the present invention, the reaction solvent may be dichloromethane.
在本发明的一些实施方式中，步骤(3)反应阶段的温度控制在10-35℃。In some embodiments of the present invention, the temperature of the reaction stage in step (3) is controlled at 10-35°C.
进一步地，在反应结束后，可通过重结晶、离心、干燥等操作获取式II-1化合物。Furthermore, after the reaction is completed, the compound of formula II-1 can be obtained by recrystallization, centrifugation, drying and the like.
(4)化合物式II-1在酸性条件下脱乙酰基并发生酯水解制得化合物式II-2’；(4) Compound II-1 is deacetylated under acidic conditions and undergoes ester hydrolysis to obtain compound II-2';
在本发明的一些实施方式中，步骤(4)包括式II-1在酸性条件下(比如加入甲磺酸)于60-80℃温度下反应脱乙酰基，反应结束后降温至20℃以下结晶、离心；将离心所得固体料或不经离心将反应液投入酸液(比如盐酸或硫酸)中，升温至40-70℃进行酯水解反应，反应结束后，于40-50℃离心、洗涤固体物料后离心、干燥，即得式II-2’化合物。In some embodiments of the present invention, 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'.
(5)化合物式II-2’通过Fischer吲哚合成法制得化合物式III’；(5) Compound II-2' is prepared by Fischer indole synthesis to obtain compound III';
在本发明的一些实施方式中，化合物式II-2’与2-甲基乙酰乙酸乙酯进行反应，其中，化合物式II-2与2-甲基乙酰乙酸乙酯的摩尔比为1:1-2。In some embodiments of the present invention, 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.
在本发明的一些实施方式中，步骤(5)包括将无水醇溶剂与式II-2混合搅拌，体系降温至10℃以下，然后滴加浓盐酸或50％硫酸，搅拌；体系降温至0℃及以下(甚至-10℃及以下)，快速流加亚硝酸钠，滴加完毕，-5℃-5℃搅拌反应，反应完毕后，于0℃及以下(甚至-5℃ 及以下)滴加2-甲基乙酰乙酸乙酯，投毕，于0℃及以下(甚至-5℃及以下)滴加乙酸钠，-5℃-5保温反应，反应完毕，体系升温至20-25℃搅拌反应，反应完毕离心、水洗获得式III化合物中间体湿品，将该湿品与50％硫酸混合，体系升温至35-45℃搅拌反应，反应完毕，反应液缓慢加入冰水混合液中，析出固体物料、离心、洗涤、干燥即得式III’化合物。In some embodiments of the present invention, 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, centrifuging, washing, and drying to obtain the compound of formula III'.
(6)化合物式III’发生酯水解反应制得化合物式IV。(6) Compound III' undergoes ester hydrolysis to obtain compound IV.
(7)化合物式IV经氧化制得PQQ，或者，化合物式IV制备得到中间体G后氧化得到PQQ；比如，化合物式IV可通过与质子酸(比如在HAC/HI酸条件下)反应制备得到中间体G，质子酸可以为氢溴酸或氢碘酸，优选为氢碘酸；比如，所述氧化可采用氧化剂，所述氧化剂可以选自双氧水、浓硫酸、浓硝酸和臭氧中的一种或多种，优选为双氧水。(7) 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.
具体地，结合上述反应路线，本发明给出以下制备示例。Specifically, in combination with the above reaction route, the present invention provides the following preparation examples.
其中，起始反应物3,4-二甲氧基-5-硝基苯胺可以3,4-二甲氧基-5-硝基苯甲酸或3,4-二甲氧基-5-硝基苯甲酰胺为原料制备得到。比如，3,4-二甲氧基-5-硝基苯胺可按照美国专利US5236952中的方法制备得到，专利中的相关内容通过引用合并入本发明。或者，作为示例，本发明所述的3,4-二甲氧基-5-硝基苯胺可按照下述方法制备得到：Wherein, 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. For example, 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. Alternatively, as an example, the 3,4-dimethoxy-5-nitroaniline of the present invention can be prepared according to the following method:
将甲苯908kg、亚硫酰氯180kg和3,4-二甲氧基-5-硝基苯甲酸227kg投入2000L反应釜中，开动搅拌，反应釜夹套通入蒸汽，升温至80℃，于70-80℃保温反应8h。反应完毕，减压蒸馏甲苯至85℃，剩余物稍冷却至50℃，用100kg丙酮稀释后，将剩余物缓慢反加至预先冷却至5℃以下的25％氨水1000kg中。反加完毕，析出固体料为3,4-二甲氧基-5-硝基苯甲酰胺。离心，得3,4-二甲氧基-5-硝基苯甲酰胺湿品452kg。Put 908kg of toluene, 180kg of thionyl chloride and 227kg of 3,4-dimethoxy-5-nitrobenzoic acid into a 2000L reactor, start stirring, pass steam into the reactor jacket, heat to 80℃, and keep the temperature at 70-80℃ for 8h. After the reaction is completed, distill toluene under reduced pressure to 85℃, cool the residue slightly to 50℃, dilute with 100kg of acetone, and slowly add the residue back to 1000kg of 25% ammonia water that has been pre-cooled to below 5℃. After the back addition is completed, the precipitated solid material is 3,4-dimethoxy-5-nitrobenzamide. Centrifuge to obtain 452kg of 3,4-dimethoxy-5-nitrobenzamide wet product.
向另一3000L反应釜中投入10％次氯酸钠950kg和10％碳酸钠1060kg，开动搅拌，反应釜夹套通5℃冷凝水，冷却至20℃以下。停止搅拌，向反应釜中投入3,4-二甲氧基-5-硝基苯甲酰胺湿品452kg，开动搅拌，于15-20℃搅拌反应3h。反应完毕，停止冷却，反应釜夹套内通入蒸汽，于1h内升温至70℃，于70-75℃搅拌反应3h。反应完毕，冷却至5℃以下，搅拌结晶3h，离心得3,4-二甲氧基-5-硝基苯胺湿品380kg，于烘箱内90℃烘干得3,4-二甲氧基-5-硝基苯胺干品172.8kg。摩尔收率：87.3％，HPLC纯度99％。Add 950kg of 10% sodium hypochlorite and 1060kg of 10% sodium carbonate to another 3000L reactor, start stirring, pass 5℃ condensed water through the reactor jacket, and cool to below 20℃. Stop stirring, add 452kg of 3,4-dimethoxy-5-nitrobenzamide wet product to the reactor, start stirring, and stir and react at 15-20℃ for 3h. After the reaction is completed, stop cooling, pass steam into the reactor jacket, heat to 70℃ within 1h, and stir and react at 70-75℃ for 3h. After the reaction is completed, cool to below 5℃, stir and crystallize for 3h, centrifuge to obtain 380kg of 3,4-dimethoxy-5-nitroaniline wet product, and dry it in an oven at 90℃ to obtain 172.8kg of 3,4-dimethoxy-5-nitroaniline dry product. Molar yield: 87.3%, HPLC purity 99%.
根据上述方法，以3,4-二乙氧基-5-硝基苯甲酸为原料替换3,4-二甲氧基-5-硝基苯甲酸，可制备得到3,4-二乙氧基-5-硝基苯胺。According to the above 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.
进行多次上述投料反应以积累3,4-二甲氧基-5-硝基苯胺物料和3,4-二乙氧基-5-硝基苯胺物料用于目标产物的制备。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.
下述实施例中示意了本申请所述中间体的制备过程以及在一些条件下的以本申请所述中间体制备PQQ的具体过程，下述实施例是制备百克级别产品时的示例，为了积累足够的物料进行每一步反应，下述示例在实际操作中会进行多次投料反应，每次投料过程均相同，以下各制备例仅示意一次投料制备过程。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.
实施例1式I化合物的制备Example 1 Preparation of Compounds of Formula I
Figure PCTCN2022142380-appb-000020
Figure PCTCN2022142380-appb-000020
制备例1：N-(3,4-二甲氧基-5-硝基苯基)乙酰胺(化合物I-1-1)的制备Preparation Example 1: Preparation of N-(3,4-dimethoxy-5-nitrophenyl)acetamide (Compound I-1-1)
将3,4-二甲氧基-5-硝基苯胺198kg和乙酸乙酯792kg投入1500L搪瓷反应釜中，开动搅拌使物料混合均匀。于20-30℃用滴加罐向反应釜中缓慢滴加乙酸酐122.4kg，滴加完毕，搅拌1h。反应釜夹套通入蒸汽，将温度升至回流，搅拌反应2h。反应完毕，冷却至20℃，用10％碳酸钠调pH值至7-8。搅拌结晶30min，离心，收集固体料于90℃烘干得化合物I-1-1干品228kg。母液回收乙酸乙酯，剩余物降温至15-20℃，离心得化合物I-1-1粗品湿品，于90℃烘干得化合物I-1-1粗品3.8kg。总摩尔收率：96.58％，HPLC纯度：99.3％。198kg of 3,4-dimethoxy-5-nitroaniline and 792kg of ethyl acetate were put into a 1500L enamel reactor, and stirring was started to mix the materials evenly. 122.4kg of acetic anhydride was slowly added to the reactor at 20-30°C using a dropping tank. After the addition was completed, stirring was performed for 1h. Steam was introduced into the jacket of the reactor, the temperature was raised to reflux, and the reaction was stirred for 2h. After the reaction was completed, the reaction was cooled to 20°C, and the pH value was adjusted to 7-8 with 10% sodium carbonate. Stirring crystallization for 30min, centrifugation was performed, and the solid material was collected and dried at 90°C to obtain 228kg of compound I-1-1 dry product. Ethyl acetate was recovered from the mother liquor, and the residue was cooled to 15-20°C, centrifuged to obtain a crude wet product of compound I-1-1, and dried at 90°C to obtain 3.8kg of crude compound I-1-1. Total molar yield: 96.58%, HPLC purity: 99.3%.
制备例2：N-(3,4-二甲氧基-5-硝基苯基)乙酰胺(化合物I-1-1)的制备Preparation Example 2: Preparation of N-(3,4-dimethoxy-5-nitrophenyl)acetamide (Compound I-1-1)
将3,4-二甲氧基-5-硝基苯胺198kg和乙腈792kg投入1500L搪瓷反应釜中，开动搅拌使物料混合均匀。于35-45℃用滴加罐向反应釜中缓慢滴加乙酸酐122.4kg，滴加完毕，搅拌1h。反应釜夹套通入蒸汽，将温度升至回流，搅拌反应2h。反应完毕，冷却至15-20℃，用10％碳酸钠调pH值至7-8。搅拌结晶30min，离心，收集固体料于90℃烘干得化合物I-1-1干品216kg。母液回收乙酸乙酯，剩余物降温至15-20℃，离心得化合物I-1-1粗品湿品，于90℃烘干得化合物I-1-1粗品8.3kg。总摩尔收率：93.4％，HPLC纯度：99.09％。198kg of 3,4-dimethoxy-5-nitroaniline and 792kg of acetonitrile were put into a 1500L enamel reactor, and stirring was started to mix the materials evenly. 122.4kg of acetic anhydride was slowly added to the reactor at 35-45°C using a dropping tank. After the addition was completed, stirring was performed for 1h. Steam was introduced into the jacket of the reactor, the temperature was raised to reflux, and the reaction was stirred for 2h. After the reaction was completed, the reaction was cooled to 15-20°C, and the pH value was adjusted to 7-8 with 10% sodium carbonate. Stirring crystallization for 30min, centrifugation, and solid material was collected and dried at 90°C to obtain 216kg of compound I-1-1 dry product. Ethyl acetate was recovered from the mother liquor, and the residue was cooled to 15-20°C, centrifuged to obtain a crude wet product of compound I-1-1, and dried at 90°C to obtain 8.3kg of crude compound I-1-1. Total molar yield: 93.4%, HPLC purity: 99.09%.
制备例3：N-(3,4-二甲氧基-5-硝基苯基)乙酰胺(化合物I-1-1)的制备Preparation Example 3: Preparation of N-(3,4-dimethoxy-5-nitrophenyl)acetamide (Compound I-1-1)
将3,4-二甲氧基-5-硝基苯胺198kg和二氧六环792kg投入1500L搪瓷反应釜中，开动搅拌使物料混合均匀。于20-30℃用滴加罐向反应釜中滴加乙酸酐122.4kg，滴加完毕，搅拌1h。反应釜夹套通入蒸汽，将温度升至回流，搅拌反应2h。反应完毕，冷却至20℃，用10％碳酸钠调 pH值至7-8。搅拌结晶30min，离心，收集固体料于90℃烘干得化合物I-1-1干品213.6kg。母液回收乙酸乙酯，剩余物降温至20℃，离心得化合物I-1-1粗品湿品，于90℃烘干得化合物I-1-1粗品6.9kg。总摩尔收率：91.8％，HPLC纯度：98.9％。198kg of 3,4-dimethoxy-5-nitroaniline and 792kg of dioxane were put into a 1500L enamel reactor, and stirring was started to mix the materials evenly. 122.4kg of acetic anhydride was added to the reactor at 20-30℃ using a dropping tank. After the addition was completed, stirring was performed for 1h. Steam was introduced into the jacket of the reactor, the temperature was raised to reflux, and the reaction was stirred for 2h. After the reaction was completed, the reaction was cooled to 20℃, and the pH value was adjusted to 7-8 with 10% sodium carbonate. Stirring crystallization for 30min, centrifugation was performed, and the solid material was collected and dried at 90℃ to obtain 213.6kg of compound I-1-1 dry product. Ethyl acetate was recovered from the mother liquor, and the residue was cooled to 20℃ and centrifuged to obtain a crude wet product of compound I-1-1, which was dried at 90℃ to obtain 6.9kg of crude compound I-1-1. Total molar yield: 91.8%, HPLC purity: 98.9%.
将原料3,4-二甲氧基-5-硝基苯胺替换为3,4-二乙氧基-5-硝基苯胺，可根据制备例1-3中所述的方法制备得到N-(3,4-二乙氧基-5-硝基苯基)乙酰胺(化合物I-1-2)，总摩尔收率在90％以上，纯度在99％以上。By replacing the raw material 3,4-dimethoxy-5-nitroaniline with 3,4-diethoxy-5-nitroaniline, 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%.
制备例4：N-(3-氨基-4,5-二甲氧基苯基)乙酰胺(化合物I-2-1)制备Preparation Example 4: Preparation of N-(3-amino-4,5-dimethoxyphenyl)acetamide (Compound I-2-1)
将240kg化合物I-1-1(制备例1)、乙醇960kg和雷尼镍19.2kg投入2000L高压加氢反应釜。投料完毕，氮气置换空气三次，氢气置换氮气三次。开动搅拌，向反应釜中充入氢气保持氢压在0.5MPa。当压力减少时，及时补充氢气，如此操作一直到氢气压力不再减少为止。继续搅拌反应2h，反应期间温度保持在20-30℃。反应完毕，将反应液压滤，除去雷尼镍。滤液先常压后减压回收乙醇，剩余物冷却至20℃，搅拌结晶2h。结晶完毕，离心，固体料80℃烘干得化合物I-2-1，产量201.6kg，其氢谱和碳谱分别如图1和图2所示。摩尔收率：96％，HPLC纯度：99％。240kg of compound I-1-1 (Preparation Example 1), 960kg of ethanol and 19.2kg of Raney nickel were put into a 2000L high-pressure hydrogenation reactor. After the feeding was completed, nitrogen replaced the air three times, and hydrogen replaced the nitrogen three times. Start stirring, fill the reactor with hydrogen to keep the hydrogen pressure at 0.5MPa. When the pressure decreases, replenish hydrogen in time, and do this until the hydrogen pressure no longer decreases. Continue stirring the reaction for 2h, and keep the temperature at 20-30°C during the reaction. After the reaction is completed, filter the reaction liquid to remove Raney nickel. The filtrate is first compressed and then reduced pressure to recover ethanol, the residue is cooled to 20°C, and stirred for crystallization for 2h. After crystallization is completed, centrifuge, and the solid material is dried at 80°C to obtain compound I-2-1, with a yield of 201.6kg, and its hydrogen spectrum and carbon spectrum are shown in Figures 1 and 2, respectively. Molar yield: 96%, HPLC purity: 99%.
制备例5：N-(3-氨基-4,5-二甲氧基苯基)乙酰胺(化合物I-2-1)制备Preparation Example 5: Preparation of N-(3-amino-4,5-dimethoxyphenyl)acetamide (Compound I-2-1)
将240kg化合物式I-1-1(制备例1)、甲醇960kg和雷尼镍24kg投入2000L高压加氢反应釜。投料完毕，氮气置换空气三次，氢气置换氮气三次。开动搅拌，向反应釜中充入氢气保持氢压在0.5MPa。当压力减少时，及时补充氢气，如此操作一直到氢气压力不再减少为止。继续搅拌反应2h，反应期间温度保持在20-30℃。反应完毕，将反应液压滤，除去雷尼镍。滤液先常压后减压回收甲醇，剩余物冷却至20℃，搅拌结晶2h。结晶完毕，离心，固体料80℃烘干得化合物I-2-1，产量189.6kg，其核磁数据与制备例4制备得到的化合物基本一致。摩尔收率：90.3％，HPLC纯度：99％。240kg of compound formula I-1-1 (Preparation Example 1), 960kg of methanol and 24kg of Raney nickel were put into a 2000L high-pressure hydrogenation reactor. After the feeding was completed, nitrogen replaced the air three times, and hydrogen replaced the nitrogen three times. Start stirring, fill the reactor with hydrogen to keep the hydrogen pressure at 0.5MPa. When the pressure decreases, replenish hydrogen in time, and do this until the hydrogen pressure no longer decreases. Continue stirring and reacting for 2h, and the temperature is maintained at 20-30°C during the reaction. After the reaction is completed, the reaction liquid is filtered to remove Raney nickel. The filtrate is first compressed and then reduced to recover methanol, and the residue is cooled to 20°C and stirred for crystallization for 2h. After crystallization is completed, centrifuge, and the solid material is dried at 80°C to obtain compound I-2-1, with a yield of 189.6kg, and its nuclear magnetic resonance data is basically consistent with the compound prepared in Preparation Example 4. Molar yield: 90.3%, HPLC purity: 99%.
制备例6：N-(3-氨基-4,5-二甲氧基苯基)乙酰胺(化合物I-2-1)制备Preparation Example 6: Preparation of N-(3-amino-4,5-dimethoxyphenyl)acetamide (Compound I-2-1)
将240kg化合物I-1-1(制备例1)、乙醇960kg和雷尼镍12kg投入2000L高压加氢反应釜。投料完毕，氮气置换空气三次，氢气置换氮气三次。开动搅拌，向反应釜中充入氢气保持氢压在0.5MPa。当压力减少时，及时补充氢气，如此操作一直到氢气压力不再减少为止。继续搅拌反应2h，反应期间温度保持在40-50℃。反应完毕，将反应液压滤，除去雷尼镍。滤液先常压后减压回收乙醇，剩余物冷却至20℃，搅拌结晶2h。结晶完毕，离心，固体料80℃烘干得化合 物I-2-1，产量178.5kg，其核磁数据与制备例4制备得到的化合物基本一致。摩尔收率：85％，HPLC纯度：99％。240kg of compound I-1-1 (Preparation Example 1), 960kg of ethanol and 12kg of Raney nickel were put into a 2000L high-pressure hydrogenation reactor. After the feeding was completed, nitrogen replaced the air three times, and hydrogen replaced the nitrogen three times. Start stirring, fill the reactor with hydrogen to keep the hydrogen pressure at 0.5MPa. When the pressure decreases, replenish hydrogen in time, and do this until the hydrogen pressure no longer decreases. Continue stirring and reacting for 2h, and the temperature during the reaction is maintained at 40-50℃. After the reaction is completed, the reaction liquid is filtered to remove Raney nickel. The filtrate is first compressed and then reduced pressure to recover ethanol, the residue is cooled to 20℃, and stirred for crystallization for 2h. After crystallization is completed, centrifuge, and the solid material is dried at 80℃ to obtain compound I-2-1, with a yield of 178.5kg, and its nuclear magnetic resonance data is basically consistent with the compound prepared in Preparation Example 4. Molar yield: 85%, HPLC purity: 99%.
将原料N-(3,4-二甲氧基-5-硝基苯基)乙酰胺(化合物I-1-1)替换为N-(3,4-二乙氧基-5-硝基苯基)乙酰胺(化合物式I-1-2)，可根据制备例4-6中所述的方法制备得到N-(3-氨基-4,5-二乙氧基苯基)乙酰胺(化合物I-2-2)，总摩尔收率在88％以上，纯度不低于99％。By replacing the raw material 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%.
实施例2式II化合物的制备Example 2 Preparation of Compound of Formula II
制备例7：5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二乙酯(化合物式II-1-3)的制备Preparation Example 7: Preparation of 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid diethyl ester (Compound Formula II-1-3)
将210kg化合物I-2-1(制备例4)和二氯甲烷1260kg投入3000L搪瓷反应釜中，开动搅拌，再向反应釜中投入2-氧代戊烯二酸乙酯501.5kg和氯化锌200kg。投料完毕，于20-25℃搅拌反应24h。反应完毕，反应釜通蒸汽条件下，先常压后减压蒸馏二氯甲烷至60℃。蒸馏完毕，向反应釜中投入70％乙醇1200kg，投毕，升温至70℃搅拌1h，使物料充分均匀分散开。完毕，降温至15℃冷却结晶3h，析出浅黄色固体。离心，固体料于90℃烘干得化合物II-1-3，产量362.7kg，摩尔收率：93％，HPLC纯度99％。210kg of compound I-2-1 (Preparation Example 4) and 1260kg of dichloromethane were put into a 3000L enamel reactor, stirring was started, and 501.5kg of ethyl 2-oxopentaconedioate and 200kg of zinc chloride were put into the reactor. After the feeding was completed, the reaction was stirred at 20-25°C for 24h. After the reaction was completed, dichloromethane was distilled to 60°C under normal pressure and then reduced pressure under steam conditions in the reactor. After the distillation was completed, 1200kg of 70% ethanol was added to the reactor, and after the addition, the temperature was raised to 70°C and stirred for 1h to fully and evenly disperse the materials. After completion, the temperature was lowered to 15°C and cooled to crystallize for 3h to precipitate a light yellow solid. Centrifugation, the solid material was dried at 90°C to obtain compound II-1-3, with a yield of 362.7kg, a molar yield of 93%, and a HPLC purity of 99%.
制备例8：5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二甲酯(化合物II-1-2)的制备Preparation Example 8: Preparation of 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (Compound II-1-2)
将210kg化合物I-2-1(制备例4)和二氯甲烷1260kg投入3000L搪瓷反应釜中，开动搅拌，再向反应釜中投入2-氧代戊烯二酸甲酯477.7kg和氯化锌200kg。投料完毕，于10-20℃搅拌反应24h。反应完毕，反应釜通蒸汽条件下，先常压后减压蒸馏二氯甲烷至70℃。蒸馏完毕，向反应釜中投入70％乙醇1200kg，投毕，升温至70℃搅拌1h，使物料充分均匀分散开。完毕，降温至15℃冷却结晶3h，析出浅黄色固体。离心，固体料于90℃烘干得化合物II-1-2，产量304.1kg，摩尔收率：91.05％，HPLC纯度98.2％。210kg of compound I-2-1 (Preparation Example 4) and 1260kg of dichloromethane were put into a 3000L enamel reactor, stirring was started, and 477.7kg of methyl 2-oxopentaconedioate and 200kg of zinc chloride were put into the reactor. After the feeding was completed, the reaction was stirred at 10-20°C for 24h. After the reaction was completed, dichloromethane was distilled to 70°C under normal pressure and then under reduced pressure under steam in the reactor. After the distillation was completed, 1200kg of 70% ethanol was added to the reactor, and after the addition, the temperature was raised to 70°C and stirred for 1h to fully and evenly disperse the materials. After completion, the temperature was lowered to 15°C and cooled to crystallize for 3h to precipitate a light yellow solid. Centrifugation, the solid material was dried at 90°C to obtain compound II-1-2, with a yield of 304.1kg, a molar yield of 91.05%, and an HPLC purity of 98.2%.
制备例9：5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二丙酯(化合物II-1-4)的制备Preparation Example 9: Preparation of 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (Compound II-1-4)
将210kg化合物I-2-1(制备例4)和二氯甲烷1260kg投入3000L搪瓷反应釜中，开动搅拌，再向反应釜中投入2-氧代戊烯二酸丙酯525kg和氯化锌200kg。投料完毕，于25-35℃搅拌反应24h。反应完毕，反应釜通蒸汽条件下，先常压后减压蒸馏二氯甲烷至60℃。蒸馏完毕，向反应釜中投入70％乙醇1200kg，投毕，升温至70℃搅拌1h，使物料充分均匀分散开。完毕，降温至15℃冷却结晶3h，析出浅黄色固体。离心，固体料于90℃烘干得化合物II-1-4，产量344.8kg，其氢谱和碳谱分别如图3和图4所示。摩尔收率：82.5％，HPLC纯度98.8％。210kg of compound I-2-1 (Preparation Example 4) and 1260kg of dichloromethane were put into a 3000L enamel reactor, stirring was started, and 525kg of 2-oxopentaconedioic acid propyl ester and 200kg of zinc chloride were put into the reactor. After the feeding was completed, the reaction was stirred at 25-35°C for 24h. After the reaction was completed, dichloromethane was distilled to 60°C at normal pressure and then under reduced pressure under steam conditions in the reactor. After the distillation was completed, 1200kg of 70% ethanol was added to the reactor, and after the addition, the temperature was raised to 70°C and stirred for 1h to fully and evenly disperse the materials. After completion, the temperature was lowered to 15°C and cooled to crystallize for 3h to precipitate a light yellow solid. Centrifugation, the solid material was dried at 90°C to obtain compound II-1-4, with a yield of 344.8kg, and its hydrogen spectrum and carbon spectrum are shown in Figures 3 and 4, respectively. Molar yield: 82.5%, HPLC purity 98.8%.
将原料N-(3-氨基-4,5-二甲氧基苯基)乙酰胺(化合物I-2-1)替换为N-(3-氨基-4,5-二乙氧基苯基)乙酰胺(化合物I-2-2)，根据制备例7-9中所述的方法可分别制备得到5-乙酰胺基-7,8- 二乙氧基喹啉-2,4-二甲酸二乙酯(化合物II-1-7)；5-乙酰氨基-7,8-二乙氧基喹啉-2,4-二甲酸二甲酯(化合物II-1-6)和5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二羧酸二丙酯(化合物II-1-8)，总摩尔收率在80％以上，纯度不低于98％。The raw material 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%.
制备例10：5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸(化合物II-2-1)的制备Preparation Example 10: Preparation of 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid (Compound II-2-1)
将甲磺酸192kg、无水乙醇840kg和化合物II-1-4(制备例9)418kg投入2000L搪瓷反应釜中。投毕，开动搅拌至固体料完全溶解，反应釜夹层通入蒸汽，搅拌下升温至75-80℃搅拌反应10h。反应完毕，降温至20℃，搅拌结晶3h。结晶完毕，离心。将离心完毕所得固体料湿品投入10％盐酸2150kg中，反应釜夹层通入蒸汽升温至60-70℃，于60-70℃搅拌反应12h。反应完毕，降温至40℃，离心，固体料先用纯化水淋洗再水洗一次，离心，所得固体料于90℃烘干得化合物II-2-1，产量259.8kg，其氢谱和碳谱分别如图5和图6所示。摩尔收率：89％，HPLC纯度：98.5％。192kg of methanesulfonic acid, 840kg of anhydrous ethanol and 418kg of compound II-1-4 (Preparation Example 9) were put into a 2000L enamel reactor. After the addition, stirring was started until the solid material was completely dissolved, steam was passed into the reactor interlayer, and the temperature was raised to 75-80°C under stirring for 10h. After the reaction was completed, the temperature was lowered to 20°C, and the crystallization was stirred for 3h. After the crystallization was completed, centrifugation was performed. The wet solid product obtained after centrifugation was put into 2150kg of 10% hydrochloric acid, steam was passed into the reactor interlayer and the temperature was raised to 60-70°C, and the reaction was stirred at 60-70°C for 12h. After the reaction was completed, the temperature was lowered to 40°C, centrifuged, the solid material was first rinsed with purified water and then washed with water once, centrifuged, and the obtained solid material was dried at 90°C to obtain compound II-2-1, with a yield of 259.8kg, and its hydrogen spectrum and carbon spectrum are shown in Figures 5 and 6 respectively. Molar yield: 89%, HPLC purity: 98.5%.
制备例11：5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸(化合物II-2-1)的制备Preparation Example 11: Preparation of 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid (Compound II-2-1)
将甲磺酸192kg、无水乙醇840kg和化合物II-1-2(制备例8)362kg投入2000L搪瓷反应釜中。投毕，开动搅拌至固体料完全溶解，反应釜夹层通入蒸汽，搅拌下升温至60-70℃搅拌反应12h。反应完毕，降温至20℃，搅拌结晶3h。结晶完毕，离心。将离心完毕所得固体料湿品投入10％盐酸2150kg中，反应釜夹层通入蒸汽升温至40-50℃，于40-50℃搅拌反应16h。反应完毕，离心，固体料先用纯化水淋洗再水洗一次，离心，所得固体料于90℃烘干得化合物II-2-1，产量238.3kg，其核磁数据与制备例10制备得到的产物基本一致。摩尔收率：81.6％HPLC纯度：99.03％。192kg of methanesulfonic acid, 840kg of anhydrous ethanol and 362kg of compound II-1-2 (Preparation Example 8) were put into a 2000L enamel reactor. After the addition, stirring was started until the solid material was completely dissolved, steam was passed into the reactor interlayer, and the temperature was raised to 60-70°C and stirred for reaction for 12h. After the reaction was completed, the temperature was lowered to 20°C and stirred for crystallization for 3h. After the crystallization was completed, centrifugation was performed. The wet solid product obtained after centrifugation was put into 2150kg of 10% hydrochloric acid, steam was passed into the reactor interlayer and the temperature was raised to 40-50°C, and the reaction was stirred at 40-50°C for 16h. After the reaction was completed, centrifugation was performed, the solid material was first rinsed with purified water and then washed with water once, centrifuged, and the obtained solid material was dried at 90°C to obtain compound II-2-1, with a yield of 238.3kg, and its nuclear magnetic resonance data was basically consistent with the product prepared in Preparation Example 10. Molar yield: 81.6% HPLC purity: 99.03%.
制备例12：5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸(化合物II-2-1)的制备Preparation Example 12: Preparation of 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid (Compound II-2-1)
将甲磺酸192kg、无水乙醇840kg和化合物II-1-3(制备例7)390kg投入2000L搪瓷反应釜中。投毕，开动搅拌至固体料完全溶解，反应釜夹层通入蒸汽，搅拌下升温至75-80℃搅拌反应10h。反应完毕，降温至20℃，搅拌结晶3h。结晶完毕，离心。将离心完毕所得固体料湿品投入10％硫酸2886kg中，反应釜夹层通入蒸汽升温至60-70℃，于60-70℃搅拌反应12h。反应完毕，降温至40℃，离心，固体料先用纯化水淋洗再水洗一次，离心，所得固体料于90℃烘干得化合物II-2-1，产量229.5kg，其核磁数据与制备例10制备得到的产物基本一致。摩尔收率：78.6％，HPLC纯度：98.4％。192kg of methanesulfonic acid, 840kg of anhydrous ethanol and 390kg of compound II-1-3 (Preparation Example 7) were put into a 2000L enamel reactor. After the addition, stirring was started until the solid material was completely dissolved, steam was introduced into the reactor interlayer, and the temperature was raised to 75-80°C and stirred for 10h. After the reaction was completed, the temperature was lowered to 20°C and stirred for crystallization for 3h. After the crystallization was completed, centrifugation was performed. The wet solid product obtained after centrifugation was put into 2886kg of 10% sulfuric acid, steam was introduced into the reactor interlayer and the temperature was raised to 60-70°C, and the reaction was stirred at 60-70°C for 12h. After the reaction was completed, the temperature was lowered to 40°C and centrifuged. The solid material was first rinsed with purified water and then washed with water once, centrifuged, and the obtained solid material was dried at 90°C to obtain compound II-2-1, with a yield of 229.5kg, and its nuclear magnetic resonance data was basically consistent with the product prepared in Preparation Example 10. Molar yield: 78.6%, HPLC purity: 98.4%.
将原料5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二丙酯(化合物II-1-4)、5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二甲酯(化合物II-1-2)、5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸 二乙酯(化合物II-1-3)分别替换为5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二甲酸二乙酯(化合物II-1-7)、5-乙酰氨基-7,8-二乙氧基喹啉-2,4-二甲酸二甲酯(化合物II-1-6)、5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二羧酸二丙酯(化合物II-1-8)，按照制备例10-12中所述的方法可制备得到5-氨基-7,8-二乙氧基喹啉-2,4-二羧酸(化合物II-2-5)，总摩尔收率在78％以上，纯度不低于98％。The raw materials 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dipropyl ester (compound II-1-4), 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dimethyl ester (compound II-1-2), 5-acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid 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. According to the method described in Preparation Examples 10-12, 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%.
实施例3式III化合物的制备Example 3 Preparation of Compound of Formula III
制备例13：2-(乙氧羰基)-4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-7,9-二羧酸(化合物III-1)的制备Preparation Example 13: Preparation of 2-(ethoxycarbonyl)-4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-7,9-dicarboxylic acid (Compound III-1)
将无水乙醇500kg和化合物II-2-1(制备例10)292kg投入3000L搪瓷反应釜中，开动搅拌，使釜内物料充分搅拌均匀。反应釜夹层通入冷盐水，将反应体系降温至10℃。降温完毕，用滴加罐向反应釜中滴加浓盐酸325kg。滴加完毕，搅拌30min。完毕，将反应体系降温至-10℃，用滴加罐向反应釜中快速流加40％亚硝酸钠233kg。流加完毕，于-5℃-0℃搅拌反应3h，物料为亮黄色稠液。反应完毕，于-5℃，向反应釜中加入2-甲基乙酰乙酸乙酯200kg。投毕，于-5℃用滴加罐向反应釜中滴加30％乙酸钠1038kg。滴加完毕，于-5℃-0保温搅拌反应4h。反应完毕，反应釜夹层撤掉冷盐水，将反应体系缓慢升温至20-25℃，并于20-25℃搅拌反应16h。反应完毕，离心，固体料水洗一次。得化合物式III-1中间体湿品872kg。500kg of anhydrous ethanol and 292kg of compound II-2-1 (Preparation Example 10) were added to a 3000L enamel reactor, and stirring was started to fully stir the materials in the reactor. Cold brine was introduced into the reactor interlayer to cool the reaction system to 10°C. After cooling, 325kg of concentrated hydrochloric acid was added to the reactor using a dropping tank. After the addition was completed, stir for 30min. After completion, the reaction system was cooled to -10°C, and 233kg of 40% sodium nitrite was quickly added to the reactor using a dropping tank. After the addition was completed, the reaction was stirred at -5°C-0°C for 3h, and the material was a bright yellow viscous liquid. After the reaction was completed, 200kg of ethyl 2-methylacetoacetate was added to the reactor at -5°C. After the addition was completed, 1038kg of 30% sodium acetate was added to the reactor using a dropping tank at -5°C. After the addition was completed, the reaction was stirred at -5°C-0 for 4h. After the reaction was completed, the cold brine was removed from the reactor interlayer, the reaction system was slowly heated to 20-25°C, and stirred at 20-25°C for 16 hours. After the reaction was completed, the solid material was centrifuged and washed with water once to obtain 872 kg of the intermediate of compound III-1.
将1000kg 50％硫酸和化合物III-1中间体湿品872kg投入2000L反应釜中，搅拌均匀，反应釜夹层投入蒸汽，将反应体系升温至40℃搅拌反应16h。反应完毕，将反应液缓慢反加至3000kg冰水混合液中，析出固体料，离心，固体料水洗至中性，离心，固体料于80℃干燥烘干得化合物III-1，产量333.7kg，摩尔收率：86％，HPLC纯度99％1000kg 50% sulfuric acid and 872kg wet intermediate of compound III-1 were put into a 2000L reactor, stirred evenly, steam was added to the reactor interlayer, and the reaction system was heated to 40°C and stirred for 16 hours. After the reaction was completed, the reaction solution was slowly added back to 3000kg ice-water mixture, solid material was precipitated, centrifuged, washed with water until neutral, centrifuged, and dried at 80°C to obtain compound III-1, with a yield of 333.7kg, a molar yield of 86%, and a HPLC purity of 99%
制备例14：2-(乙氧羰基)-4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-7,9-二羧酸(化合物III-1)的制备Preparation Example 14: Preparation of 2-(ethoxycarbonyl)-4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-7,9-dicarboxylic acid (Compound III-1)
将无水乙醇500kg和化合物II-2-1(制备例10)292kg投入3000L搪瓷反应釜中，开动搅拌，使釜内物料充分搅拌均匀。反应釜夹层通入冷盐水，将反应体系降温至10℃。降温完毕，用滴加罐向反应釜中滴加浓盐酸325kg。滴加完毕，搅拌30min。完毕，将反应体系降温至0℃，用滴加罐向反应釜中快速流加40％亚硝酸钠233kg。流加完毕，于0℃-5℃搅拌反应3h，物料为亮黄色稠液。反应完毕，于0℃，向反应釜中加入2-甲基乙酰乙酸乙酯200kg。投毕，于0℃用滴加罐向反应釜中滴加30％乙酸钠1038kg。滴加完毕，于0-5℃保温搅拌反应4h。反应完毕，反应釜夹层撤掉冷盐水，将反应体系缓慢升温至20-25℃，并于20-25℃搅拌反应16h。反应完 毕，离心，固体料水洗一次。得化合物III-1中间体湿品863kg。Put 500kg of anhydrous ethanol and 292kg of compound II-2-1 (Preparation Example 10) into a 3000L enamel reactor, start stirring, and stir the materials in the reactor to fully stir. Cold brine is passed into the reactor interlayer to cool the reaction system to 10°C. After cooling, 325kg of concentrated hydrochloric acid is added to the reactor with a dropping tank. After the addition is complete, stir for 30min. After completion, cool the reaction system to 0°C, and quickly add 233kg of 40% sodium nitrite to the reactor with a dropping tank. After the addition is complete, stir and react at 0°C-5°C for 3h, and the material is a bright yellow viscous liquid. After the reaction is complete, add 200kg of ethyl 2-methylacetoacetate to the reactor at 0°C. After the addition is complete, add 1038kg of 30% sodium acetate to the reactor with a dropping tank at 0°C. After the addition is complete, keep warm and stir at 0-5°C for 4h. After the reaction was completed, the cold brine was removed from the reactor interlayer, the reaction system was slowly heated to 20-25°C, and stirred at 20-25°C for 16 hours. After the reaction was completed, the solid material was centrifuged and washed with water once to obtain 863 kg of the wet intermediate of compound III-1.
将1000kg 50％硫酸和化合物III-1中间体湿品863kg投入3000L反应釜中，搅拌均匀，反应釜夹层投入蒸汽，将反应体系升温至40℃搅拌反应16h。反应完毕，将反应液缓慢反加至3000kg冰水混合液中，析出固体料，离心，固体料水洗至中性，离心，固体料于80℃干燥烘干得化合物III-1，产量322kg，摩尔收率：83％，HPLC纯度99％。1000kg 50% sulfuric acid and 863kg wet intermediate of compound III-1 were put into a 3000L reactor, stirred evenly, steam was added into the reactor interlayer, and the reaction system was heated to 40°C and stirred for 16 hours. After the reaction was completed, the reaction solution was slowly added back into 3000kg ice-water mixture, solid material was precipitated, centrifuged, washed with water until neutral, centrifuged, and dried at 80°C to obtain compound III-1, with a yield of 322kg, a molar yield of 83%, and a HPLC purity of 99%.
制备例15：2-(乙氧羰基)-4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-7,9-二羧酸(化合物III-1)的制备Preparation Example 15: Preparation of 2-(ethoxycarbonyl)-4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-7,9-dicarboxylic acid (Compound III-1)
将无水甲醇500kg和化合物II-2-1(制备例10)292kg投入3000L搪瓷反应釜中，开动搅拌，使釜内物料充分搅拌均匀。反应釜夹层通入冷盐水，将反应体系降温至10℃。降温完毕，用滴加罐向反应釜中滴加50％硫酸641kg。滴加完毕，搅拌30min。完毕，将反应体系降温至-10℃，用滴加罐向反应釜中快速流加40％亚硝酸钠233kg。流加完毕，于-5℃-0℃搅拌反应3h，物料为亮黄色稠液。反应完毕，于-5℃，向反应釜中加入2-甲基乙酰乙酸乙酯200kg。投毕，于-5℃用滴加罐向反应釜中滴加30％乙酸钠1038kg。滴加完毕，于-5℃-0保温搅拌反应4h。反应完毕，反应釜夹层撤掉冷盐水，将反应体系缓慢升温至20-25℃，并于20-25℃搅拌反应16h。反应完毕，离心，固体料水洗一次。得化合物III-1中间体湿品820kg。500kg of anhydrous methanol and 292kg of compound II-2-1 (Preparation Example 10) were added to a 3000L enamel reactor, and stirring was started to fully stir the materials in the reactor. Cold brine was introduced into the reactor interlayer to cool the reaction system to 10°C. After cooling, 641kg of 50% sulfuric acid was added to the reactor using a dropping tank. After the addition was completed, stir for 30min. After completion, the reaction system was cooled to -10°C, and 233kg of 40% sodium nitrite was quickly added to the reactor using a dropping tank. After the addition was completed, the reaction was stirred at -5°C-0°C for 3h, and the material was a bright yellow viscous liquid. After the reaction was completed, 200kg of ethyl 2-methylacetoacetate was added to the reactor at -5°C. After the addition was completed, 1038kg of 30% sodium acetate was added to the reactor using a dropping tank at -5°C. After the addition was completed, the reaction was stirred and kept warm at -5°C-0 for 4h. After the reaction was completed, the cold brine was removed from the reactor interlayer, the reaction system was slowly heated to 20-25°C, and stirred at 20-25°C for 16 hours. After the reaction was completed, the mixture was centrifuged and the solid material was washed with water once to obtain 820 kg of the wet intermediate of compound III-1.
将1000kg 50％硫酸和化合物III-1中间体湿品820kg投入2000L反应釜中，搅拌均匀，反应釜夹层投入蒸汽，将反应体系升温至40℃搅拌反应16h。反应完毕，将反应液缓慢反加至3000kg冰水混合液中，析出固体料，离心，固体料水洗至中性，离心，固体料于80℃干燥烘干得化合物III-1，产量291kg，摩尔收率：75％，HPLC纯度99％。1000kg 50% sulfuric acid and 820kg wet intermediate of compound III-1 were put into a 2000L reactor, stirred evenly, steam was added into the reactor interlayer, and the reaction system was heated to 40°C and stirred for 16h. After the reaction was completed, the reaction solution was slowly added back into 3000kg ice-water mixture, solid material was precipitated, centrifuged, washed with water until neutral, centrifuged, and dried at 80°C to obtain compound III-1, with a yield of 291kg, a molar yield of 75%, and a HPLC purity of 99%.
将原料5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸(化合物II-2-1)替换为5-氨基-7,8-二乙氧基喹啉-2,4-二羧酸(化合物II-2-5)，按照制备例13-15中所述的方法可制备得到4,5-二乙氧基-2-(乙氧基羰基)-1H-吡咯并[2,3-f]喹啉-7,9-二羧酸(化合物III-2)，摩尔收率不低于75％，HPLC纯度不低于99％。The raw material 5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid (compound II-2-1) is replaced by 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) can be 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%.
实施例4式IV化合物的制备Example 4 Preparation of Compound of Formula IV
制备例16：4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-2,7,9-三羧酸(化合物IV-1)的制备Preparation Example 16: Preparation of 4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (Compound IV-1)
将氢氧化钠160kg和纯化水1680kg投入3000L搪瓷反应釜中，搅拌至固体料完全溶解，再投入化合物III-1(制备例13)388kg，投毕，将反应釜夹层中通入蒸汽升温至80℃搅拌反应3h。反应完毕，冷却至30℃，酸调至pH至2-3，离心，固体料水洗一次，离心，固体料90℃烘干得式IV-1化合物335g。摩尔收率93％，HPLC纯度98.5％。160 kg of sodium hydroxide and 1680 kg of purified water were added to a 3000 L enamel reactor, stirred until the solid material was completely dissolved, and then 388 kg of compound III-1 (Preparation Example 13) was added. After the addition, steam was introduced into the reactor interlayer and the temperature was raised to 80°C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to 30°C, the acid was adjusted to pH 2-3, and the mixture was centrifuged. The solid material was washed with water once, centrifuged, and the solid material was dried at 90°C to obtain 335 g of compound IV-1. The molar yield was 93%, and the HPLC purity was 98.5%.
制备例17：4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-2,7,9-三羧酸(化合物式IV-1)的制备Preparation Example 17: Preparation of 4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (Compound Formula IV-1)
将氢氧化钾224kg和纯化水1680kg投入3000L搪瓷反应釜中，搅拌至固体料完全溶解，再投入化合物式III-1(制备例13)388kg，投毕，将反应釜夹层中通入蒸汽升温至80℃搅拌反应3h。反应完毕，冷却至30℃，酸调至pH至2-3，离心，固体料水洗一次，离心，固体料90℃烘干得化合物IV-1，产量316.8g。摩尔收率88％，HPLC纯度99.5％。224 kg of potassium hydroxide and 1680 kg of purified water were added to a 3000 L enamel reactor, stirred until the solid material was completely dissolved, and then 388 kg of compound III-1 (Preparation Example 13) was added. After the addition, steam was introduced into the reactor interlayer and the temperature was raised to 80°C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to 30°C, the acid was adjusted to pH 2-3, and the mixture was centrifuged. The solid material was washed with water once, centrifuged, and the solid material was dried at 90°C to obtain compound IV-1 with a yield of 316.8 g. The molar yield was 88%, and the HPLC purity was 99.5%.
制备例18：4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-2,7,9-三羧酸(化合物式IV-1)的制备Preparation Example 18: Preparation of 4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (Compound Formula IV-1)
将氢氧化钠160kg和纯化水1680kg投入3000L搪瓷反应釜中，搅拌至固体料完全溶解，再投入化合物III-1(制备例13)388kg，投毕，将反应釜夹层中通入蒸汽升温至50-60℃搅拌反应6h。反应完毕，冷却至30℃，酸调至pH至2-3，离心，固体料水洗一次，离心，固体料90℃烘干得化合物IV-1，产量324g。摩尔收率90％，HPLC纯度99％。160 kg of sodium hydroxide and 1680 kg of purified water were added to a 3000 L enamel reactor, stirred until the solid material was completely dissolved, and then 388 kg of compound III-1 (Preparation Example 13) was added. After the addition, steam was introduced into the reactor interlayer to raise the temperature to 50-60°C and stirred for 6 hours. After the reaction was completed, the mixture was cooled to 30°C, the acid was adjusted to pH 2-3, and the mixture was centrifuged. The solid material was washed with water once, centrifuged, and the solid material was dried at 90°C to obtain compound IV-1 with a yield of 324 g. The molar yield was 90%, and the HPLC purity was 99%.
将原料2-(乙氧羰基)-4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-7,9-二羧酸(化合物式III-1)替换为4,5-二乙氧基-2-(乙氧基羰基)-1H-吡咯并[2,3-f]喹啉-7,9-二羧酸(化合物式III-2)，根据制备例16-18所述的方法可制备得到4,5-二乙氧基-1H-吡咯[2,3-f]喹啉-2,7,9-三羧酸(化合物The raw material 2-(ethoxycarbonyl)-4,5-dimethoxy-1H-pyrrolo[2,3-f]quinoline-7,9-dicarboxylic acid (compound formula III-1) is replaced with 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 formula III-2) can be prepared according to the method described in Preparation Examples 16-18.
IV-2)，摩尔收率在90％以上，HPLC纯度不低于99％。IV-2), the molar yield is above 90%, and the HPLC purity is not less than 99%.
实施例5吡咯喹啉醌(PQQ)的制备Example 5 Preparation of pyrroloquinoline quinone (PQQ)
制备例19：Preparation Example 19:
将化合物IV-1(制备例16)180kg和900kg醋酸投入2000L搪瓷反应釜中。开动搅拌，于30-40℃用滴加罐向反应釜中缓慢滴加40％HI 540kg溶液。滴加完毕，升温至70-80℃保温搅拌反应10h。反应完毕，反应釜夹套中通入冷盐水，将物料降温至20℃，将物料缓慢反加至2000kg冰水中，析出固体料，离心，纯化水洗涤固体料至pH至4-5，离心，固体料用甲醇重结晶，固体料90℃烘干得化合物IV-1中间体(化合物G)湿品298.8kg。将化合物式IV-1中间体(化合物G)湿品298.8kg和900kg 30％过氧化氢溶液投入2000L搪瓷反应釜中，开动搅拌，使釜内物料搅拌均匀。反应釜夹层通入蒸汽搅拌升温至35℃，于30-35℃搅拌反应24h。反应完毕，降温至20℃，离心，固体料于90℃烘干得化合物PQQ 153.5kg。摩尔收率93％，HPLC纯度99.8％。180kg of compound IV-1 (Preparation Example 16) and 900kg of acetic acid were put into a 2000L enamel reactor. Stirring was started, and 540kg of 40% HI solution was slowly added to the reactor at 30-40°C using a dropping tank. After the addition was completed, the temperature was raised to 70-80°C and stirred for 10 hours. After the reaction was completed, cold brine was passed into the jacket of the reactor, the material was cooled to 20°C, and the material was slowly added back to 2000kg of ice water to precipitate solid material, centrifuged, and the solid material was washed with purified water until the pH reached 4-5, centrifuged, and the solid material was recrystallized with methanol. 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%.
制备例20：Preparation Example 20:
将化合物IV-1(制备例16)180kg和900kg醋酸投入2000L搪瓷反应釜中。开动搅拌，于20-30℃用滴加罐向反应釜中缓慢滴加40％HI 540kg溶液。滴加完毕，升温至60-70℃保温搅拌反应12h。反应完毕，反应釜夹套中通入冷盐水，将物料降温至20℃，将物料缓慢反加至2000kg冰水中，析出固体料，离心，纯化水洗涤固体料至pH至4-5，离心，固体料用甲醇重结晶，固 体料得化合物式IV-1中间体(化合物G)湿品293.8kg。将化合物式IV-1中间体(化合物G)湿品293.8kg和900kg 30％过氧化氢溶液投入2000L搪瓷反应釜中，开动搅拌，使釜内物料搅拌均匀。反应釜夹层通入蒸汽搅拌升温至35℃，于30-35℃搅拌反应24h。反应完毕，降温至20℃，离心，固体料于90℃烘干得化合物PQQ 148.5kg。摩尔收率90％，HPLC纯度99.5％。180kg of compound IV-1 (Preparation Example 16) and 900kg of acetic acid were put into a 2000L enamel reactor. Stirring was started, 40% HI 540kg solution was slowly added to the reactor at 20-30℃ using a dropping tank. After the addition was completed, the temperature was raised to 60-70℃ and stirred for 12h. After the reaction was completed, cold brine was passed into the jacket of the reactor, the material was cooled to 20℃, and the material was slowly added back to 2000kg of ice water to precipitate solid material, centrifuged, and the solid material was washed with purified water until the pH reached 4-5, centrifuged, and the solid material was recrystallized with methanol. 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%.
制备例21：Preparation Example 21:
将化合物IV-1(制备例16)180kg和900kg醋酸投入2000L搪瓷反应釜中。开动搅拌，于30-40℃用滴加罐向反应釜中缓慢滴加30％HI 720kg溶液。滴加完毕，升温至70-80℃保温搅拌反应10h。反应完毕，反应釜夹套中通入冷盐水，将物料降温至20℃，将物料缓慢反加至2000kg冰水中，析出固体料，离心，纯化水洗涤固体料至pH至4-5，离心，固体料用甲醇重结晶，固体料得化合物IV-1中间体(化合物G)湿品272.2kg。将化合物IV-1中间体(化合物G)湿品272.2kg和900kg 30％过氧化氢溶液投入2000L搪瓷反应釜中，开动搅拌，使釜内物料搅拌均匀。反应釜夹层通入蒸汽搅拌升温至35℃，于30-35℃搅拌反应24h。反应完毕，降温至20℃，离心，固体料于90℃烘干得化合物PQQ 147.7kg。摩尔收率89.5％，HPLC纯度99.8％。180 kg of compound IV-1 (Preparation Example 16) and 900 kg of acetic acid were put into a 2000 L enamel reactor. Stirring was started, and 720 kg of 30% HI solution was slowly added to the reactor at 30-40 ° C using a dropping tank. After the addition was completed, the temperature was raised to 70-80 ° C and stirred for 10 hours. After the reaction was completed, cold brine was passed into the jacket of the reactor, the material was cooled to 20 ° C, and the material was slowly added back to 2000 kg of ice water to precipitate solid material, centrifuged, and the solid material was washed with purified water until the pH reached 4-5, centrifuged, and the solid material was recrystallized with methanol. 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. 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 147.7 kg of compound PQQ. The molar yield was 89.5%, and the HPLC purity was 99.8%.
将原料4,5-二甲氧基-1H-吡咯并[2,3-f]喹啉-2,7,9-三羧酸(化合物IV-1)替换为4,5-二乙氧基-1H-吡咯[2,3-f]喹啉-2,7,9-三羧酸(化合物IV-2)，根据制备例19-21中所述的方法制备PQQ，摩尔收率不低于90％，HPLC纯度不低于99.5％。The raw 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%.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

  1. 一种制备吡咯喹啉醌的中间体化合物，其具有式I或式II所示结构：An intermediate compound for preparing pyrroloquinoline quinone, which has a structure shown in Formula I or Formula II:
    Figure PCTCN2022142380-appb-100001
    Figure PCTCN2022142380-appb-100001
    其中，R 1为C 1-C 3直链或支链烷基；R 2为硝基或氨基；R 3为氢或氨基保护基；R 4选自氢和C 1-C 3直链或支链烷基。 Wherein, 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; and R4 is selected from hydrogen and a C1 - C3 straight chain or branched alkyl group.
  2. 根据权利要求1所述的中间体化合物，其特征在于，所述化合物具有如下所示的结构：The intermediate compound according to claim 1, characterized in that the compound has the structure shown below:
    Figure PCTCN2022142380-appb-100002
    Figure PCTCN2022142380-appb-100002
    其中，R 1为甲基或乙基，R 4为甲基、乙基或丙基。 Wherein, R1 is methyl or ethyl, and R4 is methyl, ethyl or propyl.
  3. 根据权利要求1或2所述的中间体化合物，其特征在于，所述化合物选自以下结构：The intermediate compound according to claim 1 or 2, characterized in that the compound is selected from the following structures:
    N-(3,4-二甲氧基-5-硝基苯基)乙酰胺；N-(3,4-dimethoxy-5-nitrophenyl)acetamide;
    N-(3,4-二乙氧基-5-硝基苯基)乙酰胺；N-(3,4-diethoxy-5-nitrophenyl)acetamide;
    N-(3-氨基-4,5-二甲氧基苯基)乙酰胺；N-(3-amino-4,5-dimethoxyphenyl)acetamide;
    N-(3-氨基-4,5-二乙氧基苯基)乙酰胺；N-(3-amino-4,5-diethoxyphenyl)acetamide;
    5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸；5-Acetylamino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid;
    5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二甲酯；5-Acetamido-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dimethyl ester;
    5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二乙酯；5-Acetamido-7,8-dimethoxyquinoline-2,4-dicarboxylic acid diethyl ester;
    5-乙酰氨基-7,8-二甲氧基喹啉-2,4-二羧酸二丙酯；5-Acetamido-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dipropyl ester;
    5-乙酰氨基-7,8-二乙氧基喹啉-2,4-二羧酸；5-Acetylamino-7,8-diethoxyquinoline-2,4-dicarboxylic acid;
    5-乙酰氨基-7,8-二乙氧基喹啉-2,4-二甲酸二甲酯；5-Acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dimethyl ester;
    5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二甲酸二乙酯；5-Acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid diethyl ester;
    5-乙酰胺基-7,8-二乙氧基喹啉-2,4-二羧酸二丙酯；5-Acetamido-7,8-diethoxyquinoline-2,4-dicarboxylic acid dipropyl ester;
    5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸；5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid;
    5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸二甲酯；5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dimethyl ester;
    5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸二乙酯；5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid diethyl ester;
    5-氨基-7,8-二甲氧基喹啉-2,4-二羧酸二丙酯；5-amino-7,8-dimethoxyquinoline-2,4-dicarboxylic acid dipropyl ester;
    5-氨基-7,8-二乙氧基喹啉-2,4-二羧酸；5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid;
    5-氨基-7,8-二乙氧基喹啉-2,4-二甲酸二甲酯；5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid dimethyl ester;
    5-氨基-7,8-二乙氧基喹啉-2,4-二甲酸二乙酯；5-amino-7,8-diethoxyquinoline-2,4-dicarboxylic acid diethyl ester;
    5-氨基-7,8-二乙氧基喹啉-2,4-二甲酸二丙酯。Dipropyl 5-amino-7,8-diethoxyquinoline-2,4-dicarboxylate.
  4. 权利要求1至3中任一项所述的中间体化合物在制备吡咯喹啉醌中的应用。Use of the intermediate compound according to any one of claims 1 to 3 in the preparation of pyrroloquinoline quinone.
  5. 一种制备吡咯喹啉醌的方法，其包括：式II-2化合物通过Fischer吲哚合成法制备得到式III化合物，水解式III化合物制备得到式IV化合物，氧化式IV化合物制备得到吡咯喹啉醌；A method for preparing pyrroloquinoline quinone, comprising: preparing a compound of formula III by a Fischer indole synthesis method from a compound of formula II-2, hydrolyzing the compound of formula III to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare pyrroloquinoline quinone;
    Figure PCTCN2022142380-appb-100003
    Figure PCTCN2022142380-appb-100003
    其中，R 1为C 1-C 3直链或支链烷基；R 4选自氢和C 1-C 3直链或支链烷基； wherein R 1 is a C 1 -C 3 straight chain or branched chain alkyl; R 4 is selected from hydrogen and a C 1 -C 3 straight chain or branched chain alkyl;
    优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
  6. 一种制备吡咯喹啉醌的方法，其包括：式II-1化合物脱乙酰基、酯水解后制备得到式II-2’化合物，式II-2’化合物通过Fischer吲哚合成法制备得到式III’化合物，水解式III’化合物制备得到式IV化合物，氧化式IV化合物制备得到吡咯喹啉醌；A method for preparing pyrroloquinoline quinone, comprising: deacetylation and ester hydrolysis of a compound of formula II-1 to obtain a compound of formula II-2', preparing a compound of formula III' by the Fischer indole synthesis method, hydrolyzing the compound of formula III' to obtain a compound of formula IV, and oxidizing the compound of formula IV to obtain pyrroloquinoline quinone;
    Figure PCTCN2022142380-appb-100004
    Figure PCTCN2022142380-appb-100004
    其中，R 1为C 1-C 3直链或支链烷基；R 4选自氢和C 1-C 3直链或支链烷基； wherein R 1 is a C 1 -C 3 straight chain or branched chain alkyl; R 4 is selected from hydrogen and a C 1 -C 3 straight chain or branched chain alkyl;
    优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
  7. 一种制备吡咯喹啉醌的方法，其包括：式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围下制备得到式II-1化合物，式II-1化合物脱乙酰基、酯水解后制备得到式II-2’化合物，式II-2’化合物通过Fischer吲哚合成法制备得到式III’化合物，水解式III’化合物制备得到式IV化合物，氧化式IV化合物制备得到吡咯喹啉醌；A method for preparing pyrroloquinoline quinone, comprising: 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;
    Figure PCTCN2022142380-appb-100005
    Figure PCTCN2022142380-appb-100005
    其中，R 1为C 1-C 3直链或支链烷基；R 4选自氢和C 1-C 3直链或支链烷基； wherein R 1 is a C 1 -C 3 straight chain or branched alkyl group; R 4 is selected from hydrogen and a C 1 -C 3 straight chain or branched alkyl group;
    优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
  8. 一种制备吡咯喹啉醌的方法，其包括：还原I-1化合物制备得到式I-2化合物，式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围下制备得到式II-1化合物，式II-1化合物脱乙酰基、酯水解后制备得到式II-2’化合物，式II-2’化合物通过Fischer吲哚合成法制备得到式III’化合物，水解式III’化合物制备得到式IV化合物，氧化式IV化合物制备得到吡咯喹啉醌；A method for preparing pyrroloquinoline quinone, comprising: reducing a compound I-1 to prepare a compound of formula I-2, preparing a compound of formula II-1 with a compound of formula V under the catalysis of Lewis acid in an oxygen atmosphere, deacetylating the compound of formula II-1 and performing ester hydrolysis to prepare a compound of formula II-2', preparing a compound of formula III' by a Fischer indole synthesis method, hydrolyzing the compound of formula III' to prepare a compound of formula IV, and oxidizing the compound of formula IV to prepare pyrroloquinoline quinone;
    Figure PCTCN2022142380-appb-100006
    Figure PCTCN2022142380-appb-100006
    其中，R 1为C 1-C 3直链或支链烷基；R 4选自氢和C 1-C 3直链或支链烷基； wherein R 1 is a C 1 -C 3 straight chain or branched chain alkyl; R 4 is selected from hydrogen and a C 1 -C 3 straight chain or branched chain alkyl;
    优选地，R 1为甲基或乙基，R 4选自氢、甲基、乙基和丙基。 Preferably, R1 is methyl or ethyl, and R4 is selected from hydrogen, methyl, ethyl and propyl.
  9. 根据权利要求8所述的方法，其特征在于，式I-1化合物可通过3,4-二烷氧基-5-硝基苯胺在溶剂里与乙酸酐发生亲电取代反应制备；The method according to claim 8, characterized in that the compound of formula I-1 can be prepared by an electrophilic substitution reaction of 3,4-dialkoxy-5-nitroaniline with acetic anhydride in a solvent;
    优选地，所述3,4-二烷氧基-5-硝基苯胺为3,4-二甲氧基-5-硝基苯胺或3,4-二乙氧基-5-硝基苯胺；Preferably, the 3,4-dialkoxy-5-nitroaniline is 3,4-dimethoxy-5-nitroaniline or 3,4-diethoxy-5-nitroaniline;
    优选地，所述溶剂选自选自乙酸乙酯、二氧六环和乙腈；Preferably, the solvent is selected from ethyl acetate, dioxane and acetonitrile;
    优选地，反应温度控制在20-45℃。Preferably, the reaction temperature is controlled at 20-45°C.
  10. 根据权利要求8所述的方法，其特征在于，还原式I-1化合物制备得到式I-2化合物的反应在雷尼镍催化高压加氢条件下进行，反应温度为20-50℃，压力为0.5-2MPa；The method according to claim 8, characterized in that the reaction of reducing the compound of formula I-1 to prepare the compound of formula I-2 is carried out under Raney nickel catalytic high-pressure hydrogenation conditions, the reaction temperature is 20-50° C., and the pressure is 0.5-2MPa;
    优选地，式I-2化合物与式V化合物在Lewis酸催化作用下在氧气氛围下制备式II-1化合物，其中，反应温度控制在10-35℃；Preferably, the compound of formula I-2 and the compound of formula V are reacted with Lewis acid catalysis in an oxygen atmosphere to prepare the compound of formula II-1, wherein the reaction temperature is controlled at 10-35°C;
    优选地，式II-1化合物经脱乙酰基、酯水解后制备式II-2’化合物，包括式II-1在酸性条件下于60-80℃温度下反应脱乙酰基，反应结束后降温结晶、离心，将离心所得固体料或不经离心经反应液投入酸液中，升温至40-70℃进行酯水解反应；Preferably, the compound of formula II-1 is subjected to deacetylation and ester hydrolysis to prepare the compound of formula II-2', comprising reacting the compound of formula II-1 to deacetylate at 60-80°C under acidic conditions, cooling and crystallizing after the reaction, centrifuging, and putting the solid material obtained by centrifugation or the reaction liquid without centrifugation into an acid solution, and heating to 40-70°C for ester hydrolysis reaction;
    优选地，化合物式II-2’与2-甲基乙酰乙酸乙酯反应进行Fischer吲哚合成；Preferably, the compound of formula II-2' is reacted with ethyl 2-methylacetoacetate to carry out Fischer indole synthesis;
    优选地，氧化化合物式IV制备PQQ包括直接氧化或者化合物式IV制备得到中间体G后氧化得到PQQ；Preferably, oxidizing the compound of formula IV to prepare PQQ comprises direct oxidation or preparing the intermediate G from the compound of formula IV and then oxidizing it to obtain PQQ;
    优选地，所述氧化剂选自双氧水、浓硫酸、浓硝酸和臭氧中的一种或多种。Preferably, the oxidant is selected from one or more of hydrogen peroxide, concentrated sulfuric acid, concentrated nitric acid and ozone.
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