Synthesis method of dipyridamole

Abstract

The invention discloses a synthesis method of dipyridamole. The synthesis method of the dipyridamole comprises the following steps: by taking 2, 3-dioxosuccinic acid as an initial raw material, esterifying, condensing with acetylguanidine, chlorinating, carrying out nucleophilic substitution, hydrolyzing to remove acetyl, carrying out nucleophilic substitution with 2-chloro acetate, and finally hydrolyzing to obtain the dipyridamole. The synthesis method provided by the invention has the advantages of novel route, short synthesis route, no dangerous process, cheap and easily available raw materials, easy realization of industrialization of the process, and high purity of the obtained final product.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a method for synthesizing 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] There are several methods for the synthesis of dipyridamole:

[0004] Scheme 1: Take ethyl acetoacetate as the starting material, condense with thiourea, oxidize with nitric acid, nitrate, reduce the nitro group with hydrosulfite and condense with urea, chlorinate in the presence of Cl2, PCl3 and POCl3, react with piperidine nucleophilically, and finally react with ethanolamine nucleophilically to obtain the product. The reaction route is as follows:

[0005]

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

[0007] Scheme 2: Also using ethyl acetoacetate as the starting material, condensing with urea, oxidizing with nitric acid, nitrating, catalytic hydrogenation reduction of the nitro group, condensing with urea, chlorinating in the presence of Cl2, PCl3 and POCl3, reacting with piperidine nucleophilically, and finally reacting with ethanolamine nucleophilically 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, it is nitrated, catalytically hydrogenated, condensed with urea, chlorinated under the combined action of PCl3 and POCl3, and subjected to nucleophilic substitution and condensation. 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.

[0013] Scheme 4: Urea is used as the starting material, after carbonyl protection, condensation with 2,3-diaminosuccinic acid, chlorination, condensation, hydrolysis, and finally condensation with diethanolamine, hydrogenation reduction, the total yield is 48.74%, the reaction route is as follows:

[0014]

[0015] For example, Chinese patent CN201611006751.X, this solution has expensive reagents, uses heavy metals, and has harsh reaction conditions. Summary of the invention

[0016] The main purpose of the present invention is to provide a method for synthesizing dipyridamole to solve the problems existing in the prior art.

[0017] The invention provides a method for synthesizing dipyridamole, comprising: taking 2,3-dioxosuccinic acid as a starting material, subjecting the product to esterification, condensation with acetylguanidine, chlorination, nucleophilic substitution, hydrolysis to deacetylation, nucleophilic substitution with 2-chloroacetate, and finally hydrolysis to obtain dipyridamole.

[0018] Furthermore, 2,3-dioxosuccinic acid is used as a raw material, and ethyl 2,3-dioxosuccinate (Formula 1) is synthesized by acidification with thionyl chloride in ethanol and reflux reaction. The reaction route is as follows:

[0019]

[0020] Furthermore, in a polar solvent, ethyl 2,3-dioxosuccinate and acetylguanidine are condensed under alkaline conditions to synthesize 2,6-diacetamide-pyrimidine-[5,4-d]pyrimidone (Formula 2), and the reaction route is as follows:

[0021]

[0022] The polar solvent used includes one or more of methanol, ethanol, DMF, dioxane, and 1,2-dichloroethane. Preferably, the polar solvent used is methanol or ethanol.

[0023] The base used includes one or more of sodium methoxide, sodium ethoxide, potassium isopropoxide, and sodium isopropoxide. Preferably, the base used is sodium methoxide or sodium ethoxide.

[0024] Further, 2,6-diethylamide-pyrimido[5,4-d]pyrimidone is refluxed in a chlorination reagent to synthesize 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine (Formula 3), and the reaction route is as follows:

[0025]

[0026] The chlorinating agent used includes one or more of thionyl chloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride. Preferably, the chlorinating agent used is phosphorus oxychloride.

[0027] Further, at room temperature, in an aprotic solvent, 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine and piperidine undergo a nucleophilic substitution reaction to synthesize 2,6-diethylamide-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine (Formula 4), and the reaction route is as follows:

[0028]

[0029] The aprotic solvent used includes one or more of tetrahydrofuran, dioxane, acetone, and acetonitrile. Preferably, the aprotic solvent used is acetone.

[0030] Further, 2,6-diethylamide-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in a polar solvent and refluxed and hydrolyzed in dilute hydrochloric acid to synthesize 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 5). The reaction route is as follows:

[0031]

[0032] The polar solvent used includes one or more of methanol, ethanol, tetrahydrofuran, dioxane, and DMF. Preferably, the polar solvent used is methanol or ethanol;

[0033] The mass concentration of the dilute hydrochloric acid is 30-50%.

[0034] Further, in a polar aprotic solvent, 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine and ethyl 2-chloroacetate undergo nucleophilic substitution reaction under alkaline conditions to synthesize 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 6), and the reaction route is as follows:

[0035]

[0036] The polar aprotic solvent used includes one or more of acetonitrile, tetrahydrofuran, dioxane, DMF, and 1,2-dichloroethane. Preferably, the polar aprotic solvent used is acetonitrile;

[0037] The base used includes one or more of sodium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, and NaH. Preferably, the base used is sodium methoxide or sodium ethoxide.

[0038] Further, 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in an alcohol solvent, and the ester is hydrolyzed with a base to synthesize dipyridamole (Formula 7). The reaction route is as follows:

[0039]

[0040] The alcohol solvent used includes one or more of methanol, ethanol, and isopropanol. Preferably, the alcohol solvent used is methanol;

[0041] The alkali used includes one or more of sodium hydroxide, sodium carbonate, and potassium carbonate. Preferably, the alkali used is sodium hydroxide.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] The synthesis method of dipyridamole of the present invention has a novel route, a short synthesis route, and no dangerous process. The raw materials used are cheap and easily available, the process is easy to realize industrialization, and the purity of the obtained final product can reach up to 99.8%. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0045] Figure 1 It is a liquid chromatography detection result diagram of dipyridamole of the present invention. DETAILED DESCRIPTION

[0046] 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.

[0047] One aspect of an embodiment of the present invention provides a method for synthesizing dipyridamole, comprising: using 2,3-dioxosuccinic acid as a starting material, esterifying, condensing with acetylguanidine, chlorinating, nucleophilic substitution, hydrolyzing to deacetyl, nucleophilic substitution with 2-chloroacetate, and finally hydrolyzing to obtain dipyridamole.

[0048] In some preferred embodiments, 2,3-dioxosuccinic acid is used as a raw material, and ethyl 2,3-dioxosuccinate (Formula 1) is synthesized by acidification with thionyl chloride and reflux reaction in ethanol. The reaction route is as follows:

[0049]

[0050] In some preferred embodiments, in a polar solvent, ethyl 2,3-dioxosuccinate and acetylguanidine are condensed under alkaline conditions to synthesize 2,6-diacetamide-pyrimidine-[5,4-d]pyrimidone (Formula 2), and the reaction scheme is as follows:

[0051]

[0052] The polar solvent used may include one or more of methanol, ethanol, DMF, dioxane, 1,2-dichloroethane, etc., but is not limited thereto; the base used may include one or more of sodium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, etc., but is not limited thereto.

[0053] In some more preferred embodiments, the polar solvent used is methanol or ethanol, and the base used is sodium methoxide or sodium ethoxide.

[0054] In some preferred embodiments, 2,6-diethylamide-pyrimido[5,4-d]pyrimidone is refluxed in a chlorination reagent to synthesize 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine (Formula 3), and the reaction route is as follows:

[0055]

[0056] The chlorinating agent used may include one or more of thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc., but is not limited thereto.

[0057] In some more preferred embodiments, the chlorinating agent used is phosphorus oxychloride.

[0058] In some preferred embodiments, at room temperature, in an aprotic solvent, 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine and piperidine undergo a nucleophilic substitution reaction to synthesize 2,6-diethylamide-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine (Formula 4), and the reaction route is as follows:

[0059]

[0060] The aprotic solvent used includes one or more of tetrahydrofuran, dioxane, acetone, acetonitrile, etc., but is not limited thereto.

[0061] In some more preferred embodiments, the aprotic solvent used is acetone.

[0062] In some preferred embodiments, 2,6-diethylamide-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in a polar solvent and refluxed and hydrolyzed in dilute hydrochloric acid to synthesize 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 5), ​​and the reaction route is as follows:

[0063]

[0064] The polar solvent used may include one or more of methanol, ethanol, tetrahydrofuran, dioxane, DMF, etc., but is not limited thereto; the mass concentration of the dilute hydrochloric acid is 30-50%.

[0065] In some more preferred embodiments, the polar solvent used is methanol or ethanol.

[0066] In some preferred embodiments, in a polar aprotic solvent, 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine and ethyl 2-chloroacetate are reacted under alkaline conditions by nucleophilic substitution to synthesize 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 6), and the reaction route is as follows:

[0067]

[0068] The polar aprotic solvent used may include one or more of acetonitrile, tetrahydrofuran, dioxane, DMF, 1,2-dichloroethane, etc., but is not limited thereto; the base used may include one or more of sodium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, NaH, etc., but is not limited thereto.

[0069] In some more preferred embodiments, the polar aprotic solvent used is acetonitrile, and the base used is sodium methoxide or sodium ethoxide.

[0070] In some preferred embodiments, 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in an alcohol solvent, and the ester is hydrolyzed with a base to synthesize dipyridamole (Formula 7), and the reaction scheme is as follows:

[0071]

[0072] The alcohol solvent used may include one or more of methanol, ethanol, isopropanol, etc., but is not limited thereto; the alkali used may include one or more of sodium hydroxide, sodium carbonate, potassium carbonate, etc., but is not limited thereto.

[0073] In some more preferred embodiments, the alcohol solvent used is methanol, and the base used is sodium hydroxide.

[0074] Through the above technical scheme, the route is novel, the synthesis route is short, there is no dangerous process, the raw materials used are cheap and easy to obtain, the process is easy to industrialize, and the final product obtained has high purity.

[0075] 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.

[0076] Example 1 Synthesis of ethyl 2,3-dioxosuccinate (1)

[0077] Take 600 ml of ethanol, add 100 g of thionyl chloride dropwise under ice bath, continue stirring for 10 minutes after the addition is complete, add 146 g of 2,3-dioxobutanedioic acid, stir and react for 30 minutes under ice bath, heat the system to reflux reaction for 5 hours, after the reaction is completed, cool the system to room temperature, recover methanol under reduced pressure, add 300 ml of ethyl acetate to the system, stir for 20 minutes, slowly pour the system into ice water, separate the liquids, wash the organic layer with 10% sodium bicarbonate by mass percentage, wash the organic layer with water until neutral, dry the organic layer with anhydrous sodium sulfate, filter, recover the solvent by decompression of the filtrate, and distill the residue under reduced pressure to obtain 194 g of colorless liquid (ethyl 2,3-dioxobutanedioate) with a yield of 94%. The main reaction route is as follows:

[0078]

[0079] Example 2 Synthesis of 2,6-diethylamide-pyrimido[5,4-d]pyrimidone (2)

[0080] Take 1000 ml of ethanol, add 202 g of ethyl 2,3-dioxobutanedioate, 222 g of acetylguanidine, and 204 g of sodium ethoxide. The system is heated and refluxed for 24 hours. After the reaction is completed, the system is cooled to room temperature, most of the ethanol is recovered under reduced pressure, 600 ml of ethyl acetate is added, stirred for 20 minutes, and the system is slowly poured into ice water, separated, the organic layer is washed with water until neutral, the organic layer is dried over anhydrous magnesium sulfate, filtered, and the filtrate is decompressed to recover the solvent. The residue is recrystallized with methanol to obtain 253 g of a light yellow solid (2,6-diethylamide-pyrimido[5,4-d]pyrimidone) with a yield of 91%. The main reaction route is as follows:

[0081]

[0082] Example 3 Synthesis of 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine (3)

[0083] Take 139 grams of 2,6-diethylamide-pyrimido[5,4-d]pyrimidinone, add 500 grams of phosphorus oxychloride, heat the system and reflux to react until all dissolved, continue the reaction for 4 hours, after the reaction is completed, cool the system to room temperature, and recover the unreacted phosphorus oxychloride under reduced pressure; the residue is cooled in an ice bath, and ammonia water is added dropwise to react until the pH reaches 8-9, filter, wash the filter cake with water to the center, dry the filter cake, and recrystallize the filter cake with methanol to obtain 141 grams of light yellow solid (2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine) with a yield of 90%. The main reaction route is as follows:

[0084]

[0085] Example 4 Synthesis of 2,6-diethylamide-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (4)

[0086] Take 200 ml of acetone, add 31.4 g of 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine, stir to completely dissolve, cool to 0-5°C in an ice bath, add 20.4 g of piperidine dropwise, react at this temperature for 1 h, after the reaction is completed, recover most of the acetone under reduced pressure, add 200 ml of ice water to the system, stir for 30 minutes, filter, wash the filter cake with water, dry the filter cake, and recrystallize the solid with isopropanol to obtain 39 g of yellow solid (2,6-diethylamide-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine) with a yield of 95%. The main reaction route is as follows:

[0087]

[0088] Example 5 Synthesis of 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (5)

[0089] Take 41.2 g of 2,6-diethylamide-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine, dissolve it in 120 ml of methanol, add 120 ml of 40% dilute hydrochloric acid by mass percentage, heat and reflux for 7 hours, after the reaction, slowly cool the system to room temperature, cool the system in an ice bath, slowly drop a saturated solution of sodium carbonate under stirring, the pH of the system reaches 9-10, filter, wash the filter cake with water until it is neutral, dry the filter cake, and recrystallize the solid with isopropanol to obtain 29 g of a yellow solid (2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine) with a yield of 89%. The main reaction route is as follows:

[0090]

[0091] Example 6 Synthesis of 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (6)

[0092] Take 32.8 g of 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine, dissolve it in 200 ml of acetonitrile, add 32.4 g of sodium methoxide, stir for 30 minutes, add 60 g of ethyl 2-chloroacetate dropwise, heat the system to reflux for reaction, react for 8 hours, after the reaction is completed, cool the reaction system to room temperature, slowly pour the reaction solution into 300 ml of ice water, stir for 20 minutes, filter, wash the filter cake with water until neutral, dry the filter cake, and recrystallize the solid with methanol to obtain 62.4 g of yellow solid powder (2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine) with a yield of 94%. The main reaction route is as follows:

[0093]

[0094] Example 7 Synthesis of Dipyridamole (7)

[0095] Take 67.2 g of 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine, dissolve it in 150 ml of methanol, add sodium hydroxide solution (18 g of sodium hydroxide, 50 ml of water), heat the system to reflux for 2 h, after the reaction is completed, cool the system to room temperature, add 150 ml of ice water to the system, continue stirring for 30 minutes, filter, wash the filter cake with water until neutral, dry the filter cake, and recrystallize the solid with ethyl acetate to obtain 48.4 g of yellow solid powder (dipyridamole), with a yield of 96%. The main reaction route is as follows:

[0096]

[0097] Liquid chromatography detection, such as Figure 1 As shown in the table below, the content of dipyridamole in the finished product is 99.8%.

[0098] Signal: VWD1A, Wavelength = 288nm

[0099] name Retention time [min1 Peak width[min] Peak area high Peak area% 3.198 0.35 0.86 0.11 0.003 4.308 0.36 1.31 0.13 0.004 4.577 0.34 2.54 0.25 0.008 4.916 0.32 1.26 0.15 0.004 9.793 0.67 4.27 0.27 0.014 11.102 1.85 30471.68 1569.38 99.811 11.957 1.59 27.90 1.40 0.091 19.495 1.88 19.58 0.59 0.064 sum 30529.41

[0100] 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.

[0101] 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 dipyridamole, characterized in that: include: Using 2,3-dioxosuccinic acid as the starting material, dipyridamole is prepared through esterification, condensation with acetylguanidine, chlorination, nucleophilic substitution, hydrolysis, deacetylation, nucleophilic substitution with 2-chloroacetate, and finally hydrolysis.

2. The method for synthesizing dipyridamole according to claim 1, characterized in that: include: Using 2,3-dioxosuccinic acid as a raw material, ethyl 2,3-dioxosuccinate (Formula 1) is synthesized by acidification with thionyl chloride in ethanol and reflux reaction. The reaction route is as follows:

3. The method for synthesizing dipyridamole according to claim 2, characterized in that: include: In a polar solvent, ethyl 2,3-dioxosuccinate and acetylguanidine are condensed under alkaline conditions to synthesize 2,6-diacetamide-pyrimidine-[5,4-d]pyrimidone (Formula 2). The reaction route is as follows: The polar solvent used includes one or more of methanol, ethanol, DMF, dioxane, and 1,2-dichloroethane; the base used includes one or more of sodium methoxide, sodium ethoxide, potassium isopropoxide, and sodium isopropoxide.

4. The method for synthesizing dipyridamole according to claim 3, characterized in that: include: 2,6-diethylamide-pyrimido[5,4-d]pyrimidone is refluxed in a chlorination reagent to synthesize 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine (Formula 3). The reaction route is as follows: The chlorinating agent used includes one or more of thionyl chloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride.

5. The method for synthesizing dipyridamole according to claim 4, characterized in that: include: At room temperature, in an aprotic solvent, 2,6-diethylamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine reacts with piperidine through a nucleophilic substitution reaction to synthesize 2,6-diethylamide-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine (Formula 4). The reaction route is as follows: The aprotic solvent used includes one or more of tetrahydrofuran, dioxane, acetone, and acetonitrile.

6. The method for synthesizing dipyridamole according to claim 5, characterized in that: include: 2,6-diethylamide-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in a polar solvent and refluxed and hydrolyzed in dilute hydrochloric acid to synthesize 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 5). The reaction route is as follows: The polar solvent used includes one or more of methanol, ethanol, tetrahydrofuran, dioxane, and DMF, and the mass concentration of the dilute hydrochloric acid is 30-50%.

7. The method for synthesizing dipyridamole according to claim 6, characterized in that: include: In a polar aprotic solvent, 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine and ethyl 2-chloroacetate react under alkaline conditions through nucleophilic substitution to synthesize 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine (Formula 6). The reaction route is as follows: The polar aprotic solvent used includes one or more of acetonitrile, tetrahydrofuran, dioxane, DMF, and 1,2-dichloroethane; the base used includes one or more of sodium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, and NaH.

8. The method for synthesizing dipyridamole according to claim 7, characterized in that: include: 2,6-bis[diacetoxy-diethylamine]-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in an alcohol solvent, and the ester is hydrolyzed with a base to synthesize dipyridamole (Formula 7). The reaction route is as follows: The alcohol solvent used includes one or more of methanol, ethanol, and isopropanol, and the base used includes one or more of sodium hydroxide, sodium carbonate, and potassium carbonate.

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