A method for synthesizing a dipyridamole key intermediate

Abstract

The application discloses a synthesis method of a dipyridamole key intermediate. The synthesis method of the dipyridamole key intermediate comprises the following steps: condensing ethyl 2-nitroacetate with ethyl oxalate, then condensing with urea, reducing the nitro group, condensing with urea again, chlorinating, and finally condensing with piperidine, so as to obtain the dipyridamole key intermediate 2,6-di-chloro-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine. The method avoids traditional nitrification and nitric acid oxidation processes, and the whole process is free of dangerous process, the reaction condition is mild, and the product yield is high.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a synthesis method of a key intermediate of dipyridamole. BACKGROUND

[0002] Dipyridamole (7), chemically named 2,6-bis[diethanolamine]-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine, is a vasodilator drug developed by Bayer Company in Germany, and is mainly used as an antithrombotic drug in clinic. The anti-platelet aggregation effect of dipyridamole can be used for heart surgery or valve replacement, and can reduce the formation of thromboembolism. In combination with aspirin, dipyridamole can be used for preventing cerebral infarction, transient cerebral ischemia and preventing thrombosis to maintain the patency of coronary artery bypass surgery. In recent years, it has been found that dipyridamole also has a wide range of biological activities such as anti-virus, anti-inflammatory and anti-tumor.

[0003] The synthesis of dipyridamole is prepared by condensation of a key intermediate 2,6,-dichloro-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine and diethanolamine. The synthesis of 2,6,-dichloro-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine mainly has the following methods:

[0004] Scheme 1: taking ethyl acetoacetate as a starting material, condensation with thiourea, oxidation with nitric acid, nitration, reduction of nitro group with sodium hyposulfite and condensation with urea, chlorination in the presence of Cl2, PCl3 and POCl3, and nucleophilic substitution reaction with piperidine to prepare, the reaction route is as follows:

[0005]

[0006] As disclosed in “Synthetic Chemistry”, 2012, Vol. 20, No. 2, pages 257-259, “Process Improvement for the Synthesis of Dipyridamole”; the scheme has harsh reaction conditions and dangerous process.

[0007] Scheme 2: also taking ethyl acetoacetate as a starting material, condensation with urea, oxidation with nitric acid, nitration, catalytic hydrogenation reduction of nitro group, condensation with urea, chlorination in the presence of Cl2, PCl3 and POCl3, and nucleophilic substitution reaction with piperidine to prepare, the reaction route is as follows:

[0008]

[0009] As disclosed in a master's thesis of East China University of Technology, 2011, “Optimization of Dipyridamole Condensation Process”; the scheme also has a dangerous process and harsh reaction conditions.

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

[0011]

[0012] For example, Qingdao University of Science and Technology, 2021, optimization of dipyridamole condensation process. The starting material of this synthesis scheme is expensive, there are dangerous processes, and the reaction conditions are harsh. SUMMARY

[0013] The main purpose of the present application is to provide a synthesis method of a key intermediate of dipyridamole to solve the problems in the prior art.

[0014] The present application provides a synthesis method of 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, thereby obtaining the key intermediate of dipyridamole 2,6,-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine.

[0015] Further, ethyl 2-nitroacetate is condensed with ethyl oxalate under alkaline conditions to synthesize 2-nitro-3-oxo-succinic acid diethyl ester (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, dioxane, and preferably the solvent of the reaction is selected from 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, and preferably the base used is selected from sodium methoxide or sodium ethoxide.

[0019] Further, 2-nitro-3-oxo-succinic acid diethyl ester is condensed with urea under strong alkaline conditions to synthesize 5-nitro-pyrimidinone-4-ethyl carboxylate (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, and preferably the solvent of the reaction is selected from ethanol;

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

[0023] Further, the 5-nitro-pyrimidinone-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-pyrimidinone-4-carboxylic acid ethyl ester (Formula 3), as shown in the following reaction scheme:

[0024]

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

[0026] Further, the 5-amino-pyrimidinone-4-carboxylic acid ethyl ester is subjected to condensation with urea under alkaline conditions to synthesize 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (Formula 4), as shown in the following reaction scheme:

[0027]

[0028] The solvent used in the reaction includes one or more of the group consisting of DMF, NMR, DMSO, and preferably, the solvent used in the reaction is selected from DMF.

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

[0030] Further, the 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine is subjected to reflux reaction with a chlorinating agent to synthesize 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (Formula 5), as shown in the following reaction scheme:

[0031]

[0032] The chlorinating agent used includes one or more of the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride, and preferably, the chlorinating agent used is selected from phosphorus oxychloride.

[0033] Further, the 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine is subjected to condensation with piperidine to synthesize 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 6), as shown in the following reaction scheme:

[0034]

[0035] The solvent used in the reaction includes one or more of the group consisting of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, and dioxane, and preferably, the solvent used in the reaction is selected from acetone or tetrahydrofuran.

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

[0037] The synthesis method of the dipyridamole key intermediate avoids the traditional nitration and acid oxidation process, the whole process is free of dangerous process, the reaction condition is 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 99.5% or above. DETAILED DESCRIPTION

[0038] In view of the deficiencies in the prior art, the present application has been proposed after long-term research and a large number of practices. The technical solution, the implementation process and principles will be further explained as follows.

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

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

[0041]

[0042] The solvent of the reaction can include one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, dioxane, etc., but is not limited thereto; and the base used can 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 of the reaction is selected from methanol or ethanol, and the base used is selected from 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-pyrimidinone-4-carboxylic acid ethyl ester (Formula 2), and the reaction route is as follows:

[0045]

[0046] The solvent of the reaction can include one or more of methanol, ethanol, water, dioxane, etc., but is not limited thereto; and the base used can 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 used in the reaction is selected from ethanol, and the base used is selected from sodium methoxide or sodium ethoxide.

[0048] In some preferred embodiments, the 5-nitro-pyrimidinone-4-ethyl formate is subjected to catalytic hydrogenation in the presence of a catalyst to reduce the nitro group and synthesize 5-amino-pyrimidinone-4-ethyl formate (Formula 3), as shown in the following reaction scheme:

[0049]

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

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

[0052] In some preferred embodiments, the 5-amino-pyrimidinone-4-ethyl formate is subjected to condensation with urea under alkaline conditions to synthesize 2,4,6,8-tetrahydroxy pyrimido[5,4-d]pyrimidine (Formula 4), as shown in the following reaction scheme:

[0053]

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

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

[0056] In some preferred embodiments, the 2,4,6,8-tetrahydroxy pyrimido[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), as shown in the following reaction scheme:

[0057]

[0058] The chlorinating agent used can include one or more of, but not limited to, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.

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

[0060] In some preferred embodiments, 2, 6-dichloro-4, 8-dipiperidinyl-pyrimido [5, 4-d] pyrimidine (Formula 6) is synthesized by condensation of 2, 4, 6, 8-tetrachloropyrimido [5, 4-d] pyrimidine with piperidine, and the reaction route is as follows:

[0061]

[0062] The solvent of the reaction can 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 of the reaction is acetone or tetrahydrofuran.

[0064] By the above technical solution, the traditional nitration and acid oxidation process is avoided, the entire process is free of dangerous process, the reaction condition is 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 final product obtained has high purity.

[0065] The technical solution of the present application will be further described in detail below in combination with several preferred embodiments, but the present application is not limited only to the following embodiments.

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

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

[0068]

[0069] Example 2 Synthesis of ethyl 5-nitro-pyrimidinone-4-carboxylate (2)

[0070] Take 2-nitro-3-oxo-butyric acid diethyl ester 233 grams, 800 milliliters of ethanol, urea 66 grams, sodium ethoxide 170 grams, heated to reflux for 24 hours, after the reaction is completed, the reaction solution is slowly poured into ice water, stirring for 30 minutes, filtration, filter cake water washing to neutral, filter cake drying, the filter cake is recrystallized with isopropyl alcohol to obtain a light yellow solid (5-nitro-pyrimidinone-4-carboxylic acid ethyl ester) 199.23 grams, yield 87%, the main reaction route is as follows:

[0071]

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

[0073] Take 5-nitro-pyrimidinone-4-carboxylic acid ethyl ester 229 grams, add 600 milliliters of ethanol, add Pd / C 15 grams, replace the air in the kettle with nitrogen three times, replace nitrogen with hydrogen, maintain 2 atmospheres in the kettle, heat to 80°C, continuous reaction for 8 hours, after the reaction is completed, cut off the hydrogen source, the system is slowly cooled to room temperature, the reaction solution is filtered to remove Pd / C, most of the solvent is recovered by reducing pressure, the residue is stirred with 400 milliliters of ice water, filtered, and the filter cake is dried to obtain a yellow solid powder (5-amino-pyrimidinone-4-carboxylic acid ethyl ester) 195 grams, yield 98%, the main reaction route is as follows:

[0074]

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

[0076] Take 5-amino-pyrimidinone-4-carboxylic acid ethyl ester 199 grams, dissolve in 800 milliliters of DMF, add urea 72 grams, add potassium tert-butoxide 246.4 grams, heat the system to 140°C for 24 hours, after the reaction is completed, the system is cooled to room temperature, half of the solvent is recovered by reducing pressure, the residue is slowly poured into 400 milliliters of ice water, stirred for 30 minutes, filtered, the filter cake is washed with water until neutral, the filter cake is dried, and the dried solid is recrystallized with methanol to obtain a light yellow solid powder (2,4,6,8-tetrahydroxy-pyrimido[5,4-d]pyrimidine) 178.36 grams, yield 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 2,4,6,8-tetrahydroxy pyrimido [5,4-d] pyrimidine 196 grams, add 600 grams of phosphorus oxychloride, heat to reflux reaction, until the solid is completely dissolved, stirring reaction 6h, after the reaction is completed, the system is cooled to room temperature, the unreacted phosphorus oxychloride is recovered under reduced pressure, the residue is cooled to below 5℃ in ice bath, slowly add ammonia water to the system until the pH of the system is 8-9, filter, filter cake is washed to neutral with water, dry the filter cake, dry the solid with methanol to recrystallize to get yellow solid powder (2,4,6,8-tetrachloropyrimido [5,4-d] pyrimidine) 237.63 grams, yield 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 2,4,6,8-tetrachloropyrimido [5,4-d] pyrimidine 26.7 grams, dissolve in 120 milliliters of acetone, cool to 0-5℃ in ice bath, add piperidine 18.7 grams, react at this temperature for 40 minutes, after the reaction is completed, recover half of the acetone under reduced pressure, add 100 milliliters of ice water to the system, stir for 30 minutes, filter, wash the filter cake with water three times, dry the filter cake, recrystallize the solid with isopropyl alcohol to get yellow solid (2,6,-dichloro-4,8-dipiperidinyl-pyrimido [5,4-d] pyrimidine) 33.67 grams, yield 92%, the main reaction route is as follows:

[0083]

[0084] In addition, the present inventors have also carried out tests with other raw materials, process operations, process conditions described in the specification with reference to the foregoing examples, and all obtained relatively ideal results.

[0085] Although the present application has been described with reference to the illustrative embodiments, workers skilled in the art will recognize that various other changes, omissions and / or additions can be made thereto without departing from the spirit and scope of the application. In addition, many modifications can be made to adapt a particular situation or material to the teachings of the application without departing from its scope. Therefore, the present disclosure is not intended to be limited to the disclosed embodiments for carrying out the present application, but is intended to cover all embodiments falling within the scope of the claims. Furthermore, unless specifically stated otherwise, any use of the terms first, second, etc. do not indicate any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.

Claims

1. A process for the synthesis of a key intermediate of dipyridamole, characterized by, Comprising the following steps: S1: Synthesis of 2-nitro-3-oxo-butanedioic acid diethyl ester (Formula 1) by condensation of ethyl 2-nitroacetate with diethyl oxalate under basic condition with sodium ethoxide as base in ethanol as reaction solvent, reaction route as follows: ； S2: Synthesis of 5-nitro-pyrimidinone-4-carboxylic acid ethyl ester (Formula 2) by condensation of 2-nitro-3-oxo-butanedioic acid diethyl ester with urea under strong basic condition with sodium ethoxide as base in ethanol as reaction solvent, reaction route as follows: ； S3: Synthesis of 5-amino-pyrimidinone-4-carboxylic acid ethyl ester (Formula 3) by catalytic hydrogenation of 5-nitro-pyrimidinone-4-carboxylic acid ethyl ester under the action of Pd / C-H2 in ethanol as reaction solvent, reaction route as follows: ； S4: Synthesis of 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (Formula 4) by condensation of 5-amino-pyrimidinone-4-carboxylic acid ethyl ester with urea under basic condition with potassium tert-butoxide as base in DMF as reaction solvent, reaction route as follows: ； S5: Synthesis of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (Formula 5) by refluxing reaction of 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine with chlorinating reagent of phosphorus oxychloride, reaction route as follows: ； S6: Synthesis of 2,6-dichloro-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 6) by condensation of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine with piperidine, reaction route as follows: 。 2. The process for synthesis of dipyridamole key intermediate as claimed in claim 1, wherein: In step S6, The solvent of the reaction is selected from one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, dioxane. ​

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