Synthesis method of dipyridamole key intermediate

Abstract

The invention discloses a synthesis method of a dipyridamole key intermediate. The synthesis method of the dipyridamole key intermediate comprises the following steps: carrying out condensation on 2-nitroethyl acetate and ethyl oxalate, then carrying out condensation with urea, carrying out nitro reduction, then carrying out condensation with urea, carrying out chlorination, and finally carrying out condensation with piperidine so as to prepare the dipyridamole key intermediate 2, 6,-dichloro-4, 8-dipiperidyl-pyrimido [5, 4-d] pyrimidine. According to the method, traditional nitration and nitric acid oxidation processes are avoided, the whole process is free of danger, reaction conditions are mild, and the product yield is high.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for synthesizing a key intermediate of dipyridamole. Background Art

[0002] Dipyridamole (7), chemically named 2,6-bis[diethanolamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine, is a vasodilator developed by the German company Behring. It is mainly used as an antithrombotic drug in clinical practice. Its antiplatelet aggregation effect can be used in cardiac surgery or valve replacement surgery to reduce the formation of thromboembolism. It can be used in combination with aspirin to prevent cerebral infarction, transient cerebral ischemia, and prevent thrombosis to maintain the patency of coronary artery bypass grafting. In recent years' research, it has been found that it also has a variety of biological activities such as broad-spectrum antiviral, anti-inflammatory, and anti-tumor.

[0003] The synthesis of dipyridamole is prepared by condensing the key intermediate 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine with diethanolamine. The synthesis of 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine mainly includes the following methods:

[0004] Scheme 1: Using ethyl acetoacetate as the starting material, condensing with thiourea, oxidizing with nitric acid, nitrifying, reducing the nitro group with hydrosulfite and condensing with urea, chlorinating in the presence of Cl2, PCl3 and POCl3, and reacting with piperidine for nucleophilic substitution, the reaction route is as follows:

[0005]

[0006] For example, the synthesis process of dipyridamole was improved in the 2012 volume 20, issue 2, pages 257-259 of Synthetic Chemistry; this scheme has harsh reaction conditions and is a dangerous process.

[0007] Scheme 2: Also using ethyl acetoacetate as the starting material, condensing with urea, oxidizing with nitric acid, nitrifying, catalytic hydrogenation reduction of the nitro group, condensing with urea, chlorinating in the presence of Cl2, PCl3 and POCl3, and reacting with piperidine for nucleophilic substitution to obtain the product. The reaction route is as follows:

[0008]

[0009] For example, in the master's thesis of East China University of Science and Technology, 2011, the optimization of dipyridamole condensation process, this scheme also has dangerous processes and harsh reaction conditions.

[0010] Scheme 3: Using uracil-4-carboxylic acid as the starting material, after nitration, catalytic hydrogenation reduction, condensation with urea, chlorination under the joint action of PCl3 and POCl3, and nucleophilic substitution with piperidine, the reaction route is as follows:

[0011]

[0012] For example, Qingdao University of Science and Technology, 2021, Optimization of Dipyridamole Condensation Process. This synthesis scheme has expensive starting materials, dangerous processes, and harsh reaction conditions. Summary of the invention

[0013] The main purpose of the present invention is to provide a method for synthesizing a key intermediate of dipyridamole to solve the problems existing in the prior art.

[0014] The invention provides a method for synthesizing a key intermediate of dipyridamole, comprising: condensing ethyl 2-nitroacetate with ethyl oxalate, then condensing with urea, reducing the nitro group, condensing with urea, chlorinating, and finally condensing with piperidine, thereby preparing the key intermediate of dipyridamole 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine.

[0015] Further, ethyl 2-nitroacetate and ethyl oxalate are condensed under alkaline conditions to synthesize diethyl 2-nitro-3-oxo-succinate (Formula 1), and the reaction route is as follows:

[0016]

[0017] The solvent of the reaction includes one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, and dioxane. Preferably, the solvent of the reaction is methanol or ethanol;

[0018] The base used includes one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide. Preferably, the base used is sodium methoxide or sodium ethoxide.

[0019] Further, 2-nitro-3-oxo-succinic acid diethyl ester and urea are condensed under strong alkaline conditions to synthesize 5-nitro-pyrimidone-4-carboxylic acid ethyl ester (Formula 2), and the reaction route is as follows:

[0020]

[0021] The solvent of the reaction includes one or more of methanol, ethanol, water, and dioxane. Preferably, the solvent of the reaction is ethanol.

[0022] The base used includes one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide. Preferably, the base used is sodium methoxide or sodium ethoxide.

[0023] Further, 5-nitro-pyrimidone-4-carboxylic acid ethyl ester is subjected to catalytic hydrogenation under the action of a catalyst to reduce the nitro group to synthesize 5-amino-pyrimidone-4-carboxylic acid ethyl ester (Formula 3). The reaction route is as follows:

[0024]

[0025] The catalyst used includes one or more of insurance powder, sodium sulfide, iron powder, zinc powder, Pd / C-H2, and PtO2-H2. Preferably, the catalyst used is any one of insurance powder, iron powder or Pd / C-H2.

[0026] Furthermore, 5-amino-pyrimidone-4-carboxylic acid ethyl ester is condensed with urea under alkaline conditions to synthesize 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (Formula 4), and the reaction route is as follows:

[0027]

[0028] The solvent of the reaction includes one or more of DMF, NMR, and DMSO. Preferably, the solvent of the reaction is DMF;

[0029] The base used includes one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide. Preferably, the base used is potassium tert-butoxide.

[0030] Further, 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine is subjected to reflux reaction in the presence of a chlorinating agent to synthesize 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (Formula 5). The reaction route is as follows:

[0031]

[0032] The chlorination agent used includes one or more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride. Preferably, the chlorination agent used is phosphorus oxychloride.

[0033] Furthermore, 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine is condensed with piperidine to synthesize 2,6-dichloro-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine (Formula 6), and the reaction route is as follows:

[0034]

[0035] The solvent of the reaction includes one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, and dioxane. Preferably, the solvent of the reaction is acetone or tetrahydrofuran.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] The synthesis method of the key intermediate of dipyridamole of the present invention avoids the traditional nitration and acid oxidation processes, the whole process is non-hazardous, the reaction conditions are mild, the product yield is high, the raw materials used in the synthesis method are cheap and easy to obtain, the process is easy to realize industrialization, and the purity of the obtained final product can reach more than 99.5%. DETAILED DESCRIPTION

[0038] In view of the deficiencies in the prior art, the inventor of this case has proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution, its implementation process and principle will be further explained as follows.

[0039] One aspect of an embodiment of the present invention provides a method for synthesizing a key intermediate of dipyridamole, comprising: condensing ethyl 2-nitroacetate with ethyl oxalate, then condensing with urea, reducing the nitro group, then condensing with urea, chlorinating, and finally condensing with piperidine to obtain the key intermediate of dipyridamole 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine.

[0040] In some preferred embodiments, ethyl 2-nitroacetate and ethyl oxalate are condensed under alkaline conditions to synthesize diethyl 2-nitro-3-oxo-succinate (Formula 1), and the reaction scheme is as follows:

[0041]

[0042] The solvent of the reaction may include one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, dioxane, etc., but is not limited thereto; the base used may include one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc., but is not limited thereto.

[0043] In some more preferred embodiments, the solvent for the reaction is methanol or ethanol, and the base used is sodium methoxide or sodium ethoxide.

[0044] In some preferred embodiments, 2-nitro-3-oxo-succinic acid diethyl ester is condensed with urea under strong alkaline conditions to synthesize 5-nitro-pyrimidone-4-carboxylic acid ethyl ester (Formula 2), and the reaction scheme is as follows:

[0045]

[0046] The solvent of the reaction may include one or more of methanol, ethanol, water, dioxane, etc., but is not limited thereto; the base used may include one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., but is not limited thereto.

[0047] In some more preferred embodiments, the solvent for the reaction is ethanol, and the base used is sodium methoxide or sodium ethoxide.

[0048] In some preferred embodiments, 5-nitro-pyrimidone-4-carboxylic acid ethyl ester is subjected to catalytic hydrogenation in the presence of a catalyst to reduce the nitro group to synthesize 5-amino-pyrimidone-4-carboxylic acid ethyl ester (Formula 3). The reaction scheme is as follows:

[0049]

[0050] The catalyst used may include one or more of hydrosulfite, sodium sulfide, iron powder, zinc powder, Pd / C-H2, PtO2-H2, etc., but is not limited thereto.

[0051] In some more preferred embodiments, the catalyst used is any one of insurance powder, iron powder or Pd / C-H2.

[0052] In some preferred embodiments, 5-amino-pyrimidone-4-carboxylic acid ethyl ester is condensed with urea under alkaline conditions to synthesize 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (Formula 4), and the reaction scheme is as follows:

[0053]

[0054] The solvent of the reaction may include one or more of DMF, NMR, DMSO, etc., but is not limited thereto; the base used may include one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc., but is not limited thereto.

[0055] In some more preferred embodiments, the solvent for the reaction is DMF, and the base used is potassium tert-butoxide.

[0056] In some preferred embodiments, 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine is subjected to a reflux reaction in the presence of a chlorinating agent to synthesize 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (Formula 5), ​​and the reaction scheme is as follows:

[0057]

[0058] The chlorination agent used may include one or more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc., but is not limited thereto.

[0059] In some more preferred embodiments, the chlorination agent used is phosphorus oxychloride.

[0060] In some preferred embodiments, 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine is condensed with piperidine to synthesize 2,6-dichloro-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine (Formula 6), and the reaction scheme is as follows:

[0061]

[0062] The solvent of the reaction may include one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, dioxane, etc., but is not limited thereto.

[0063] In some more preferred embodiments, the solvent for the reaction is acetone or tetrahydrofuran.

[0064] By using the above technical solution, the traditional nitration and acid oxidation processes are avoided, the entire process is a non-hazardous process, the reaction conditions are mild, the product yield is high, and the raw materials used in the synthesis method are cheap and easy to obtain, the process is easy to industrialize, and the final product obtained has high purity.

[0065] The technical solution of the present invention is further described in detail below in conjunction with several preferred embodiments, but the present invention is not limited to the following embodiments.

[0066] Example 1 Synthesis of diethyl 2-nitro-3-oxo-succinate (1)

[0067] Take 133 g of ethyl 2-nitroacetate, dissolve it in 350 ml of ethanol, cool the system to below 10°C in an ice bath, add 74.8 g of sodium ethoxide in batches, stir for 20 minutes, add 153.3 g of ethyl oxalate dropwise to the system, continue stirring for 20 minutes, heat the system to reflux reaction for 4 hours, after the reaction is completed, cool the system to room temperature, recover most of the solvent under reduced pressure, add 300 ml of dichloromethane to the system, stir for 20 minutes, slowly pour the reaction solution into 300 ml of ice water, separate the liquids, wash the filtrate with water until neutral, dry the organic layer over anhydrous magnesium sulfate, filter, recover dichloromethane, and recrystallize the residue with petroleum ether to obtain 233.68 g of white solid (2-nitro-3-oxo-succinic acid diethyl ester) with a yield of 96%. The main reaction route is as follows:

[0068]

[0069] Example 2 Synthesis of 5-nitro-pyrimidone-4-carboxylic acid ethyl ester (2)

[0070] Take 233 g of 2-nitro-3-oxo-succinic acid diethyl ester, 800 ml of ethanol, 66 g of urea, and 170 g of sodium ethoxide, heat and reflux for 24 h. After the reaction is completed, the reaction solution is slowly poured into ice water, stirred for 30 minutes, filtered, and the filter cake is washed with water until neutral. The filter cake is dried and recrystallized from isopropanol to obtain 199.23 g of a light yellow solid (5-nitro-pyrimidone-4-carboxylic acid ethyl ester) with a yield of 87%. The main reaction route is as follows:

[0071]

[0072] Example 3 Synthesis of 5-amino-pyrimidone-4-carboxylic acid ethyl ester (3)

[0073] Take 229 g of 5-nitro-pyrimidone-4-carboxylic acid ethyl ester, add 600 ml of ethanol, add 15 g of Pd / C, introduce nitrogen to replace the air in the kettle three times, introduce hydrogen to expel nitrogen, maintain 2 atmospheres in the kettle, heat to an external temperature of 80°C, and react for 8 hours. After the reaction is completed, cut off the hydrogen source, and slowly cool the system to room temperature. The reaction solution is filtered to remove Pd / C, and the reaction solution is decompressed to recover most of the solvent. The residue is stirred with 400 ml of ice water, filtered, and the filter cake is dried to obtain 195 g of a yellow solid powder (5-amino-pyrimidone-4-carboxylic acid ethyl ester) with a yield of 98%. The main reaction route is as follows:

[0074]

[0075] Example 4 Synthesis of 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (4)

[0076] Take 199 g of 5-amino-pyrimidone-4-carboxylic acid ethyl ester, dissolve it in 800 ml of DMF, add 72 g of urea, add 246.4 g of potassium tert-butoxide, heat the system to 140°C and react for 24 hours. After the reaction is completed, cool the system to room temperature, recover half of the solvent under reduced pressure, slowly pour the residue into 400 ml of ice water, stir for 30 minutes, filter, wash the filter cake with water until neutral, dry the filter cake, and recrystallize the dried solid with methanol to obtain 178.36 g of light yellow solid powder (2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine) with a yield of 91%. The main reaction route is as follows:

[0077]

[0078] Example 5 Synthesis of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (5)

[0079] Take 196 grams of 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine, add 600 grams of phosphorus oxychloride, heat to reflux reaction until the solid is completely dissolved, stir and react for 6 hours. After the reaction is completed, the system is cooled to room temperature, and the unreacted phosphorus oxychloride is recovered under reduced pressure. The residue is cooled to below 5°C in an ice bath, and ammonia water is slowly added to the system until the pH of the system reaches 8-9, filtered, and the filter cake is washed with water until neutral, and the filter cake is dried. The dried solid is recrystallized with methanol to obtain 237.63 grams of yellow solid powder (2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine) with a yield of 89%. The main reaction route is as follows:

[0080]

[0081] Example 6 Synthesis of 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (6)

[0082] Take 26.7 g of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine, dissolve it in 120 ml of acetone, cool it to 0-5°C in an ice bath, add 18.7 g of piperidine dropwise, react at this temperature for 40 minutes, and when the reaction is finished, recover half of the acetone under reduced pressure, add 100 ml of ice water to the system, stir for 30 minutes, filter, wash the filter cake three times with water, dry the filter cake, and recrystallize the solid with isopropanol to obtain 33.67 g of yellow solid (2,6,-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine) with a yield of 92%. The main reaction route is as follows:

[0083]

[0084] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0085] Although the present invention has been described with reference to illustrative embodiments, it will be appreciated by those skilled in the art that various other changes, omissions and / or additions may be made without departing from the spirit and scope of the present invention and that the elements of the embodiments may be replaced by substantial equivalents. In addition, many modifications may be made without departing from the scope of the present invention to adapt specific circumstances or materials to the teachings of the present invention. Therefore, it is not intended herein to limit the present invention to the disclosed specific embodiments for performing the present invention, but it is intended that the present invention will include all embodiments within the scope of the appended claims. In addition, unless specifically stated, any use of the terms first, second, etc. does not indicate any order or importance, but rather uses the terms first, second, etc. to distinguish one element from another.

Claims

1. A method for synthesizing a key intermediate of dipyridamole, characterized in that: include: The key intermediate of dipyridamole, 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine, is prepared by condensing ethyl 2-nitroacetate with ethyl oxalate, then condensing with urea, reducing the nitro group, condensing with urea, chlorinating, and finally condensing with piperidine.

2. The method for synthesizing a key intermediate of dipyridamole according to claim 1, wherein include: Ethyl 2-nitroacetate and ethyl oxalate are condensed under alkaline conditions to synthesize diethyl 2-nitro-3-oxo-succinate (Formula 1). The reaction scheme is as follows: The solvent of the reaction includes one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, and dioxane, and the base used includes one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

3. The method for synthesizing the key intermediate of dipyridamole according to claim 2, wherein: include: 2-nitro-3-oxo-succinic acid diethyl ester and urea are condensed under strong alkaline conditions to synthesize 5-nitro-pyrimidone-4-carboxylic acid ethyl ester (Formula 2). The reaction route is as follows: The solvent of the reaction includes one or more of methanol, ethanol, water, and dioxane, and the base used includes one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.

4. The method for synthesizing the key intermediate of dipyridamole according to claim 3, wherein: include: 5-nitro-pyrimidone-4-carboxylic acid ethyl ester is subjected to catalytic hydrogenation under the action of a catalyst to reduce the nitro group and synthesize 5-amino-pyrimidone-4-carboxylic acid ethyl ester (Formula 3). The reaction route is as follows: The catalyst used includes one or more of hydrosulfite, sodium sulfide, iron powder, zinc powder, Pd / C-H2, and PtO2-H2.

5. The method for synthesizing the key intermediate of dipyridamole according to claim 4, characterized in that: include: 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (Formula 4) is synthesized by condensing 5-amino-pyrimidone-4-carboxylic acid ethyl ester with urea under alkaline conditions. The reaction route is as follows: The solvent of the reaction includes one or more of DMF, NMR, and DMSO, and the base used includes one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

6. The method for synthesizing the key intermediate of dipyridamole according to claim 5, characterized in that: include: 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine is subjected to reflux reaction in the presence of a chlorinating agent to synthesize 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (Formula 5). The reaction route is as follows: The chlorination agent used includes one or more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride.

7. The method for synthesizing the key intermediate of dipyridamole according to claim 6, characterized in that: include: 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine is condensed with piperidine to synthesize 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 6). The reaction route is as follows: The solvent of the reaction includes one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran and dioxane.

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