A method for the synthesis of dipyridamole

Abstract

The application discloses a synthesis method of dipyridamole. The synthesis method of the dipyridamole comprises the following steps: taking 2,3-dioxosuccinic acid as a starting material, performing esterification, condensation with acetyl guanidine, chlorination, nucleophilic substitution, hydrolysis to remove acetyl, nucleophilic substitution with 2-chloroacetate, and finally hydrolysis to obtain dipyridamole. The synthesis method is novel in route, short in synthesis route, free of dangerous process, low in price of raw materials, easy to realize industrialization, and high in purity of the obtained final product.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a synthesis method 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 the German Bayer Company, and is mainly used as an antithrombotic drug in clinic. Its anti-platelet aggregation effect can be used for heart surgery or valve replacement, and can reduce the formation of thromboembolism. In combination with aspirin, it 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 it also has a wide range of antiviral, anti-inflammatory and antitumor biological activities.

[0003] There are mainly the following methods for synthesizing dipyridamole:

[0004] Scheme I: acetyl ethyl acetate is used as a starting material, is condensed with thiourea, is oxidized with nitric acid, is nitrated, the nitro group is reduced with safety powder and is condensed with urea, is chlorinated in the presence of Cl2, PCl3 and POCl3, is subjected to a nucleophilic substitution reaction with piperidine, and finally is subjected to a nucleophilic substitution reaction with ethanolamine to obtain dipyridamole, and the reaction route is as follows:

[0005] ;

[0006] As disclosed in Synthesis Chemistry, 2012, Vol. 20, No. 2, pages 257-259, the synthesis process of dipyridamole is improved; the scheme has a dangerous process and harsh reaction conditions.

[0007] Scheme II: acetyl ethyl acetate is also used as a starting material, is condensed with urea, is oxidized with nitric acid, is nitrated, the nitro group is reduced by catalytic hydrogenation, is condensed with urea, is chlorinated in the presence of Cl2, PCl3 and POCl3, is subjected to a nucleophilic substitution reaction with piperidine, and finally is subjected to a nucleophilic substitution reaction with ethanolamine to obtain dipyridamole, and the reaction route is as follows:

[0008] ;

[0009] As disclosed in a master's thesis of East China University of Technology, 2011, the condensation process of dipyridamole is optimized; the scheme also has a dangerous process and harsh reaction conditions.

[0010] Scheme III: uracil-4-carboxylic acid is used as a starting material, is subjected to nitration, catalytic hydrogenation reduction, condensation with urea, chlorination in the presence of PC13 and POCl3, nucleophilic substitution and condensation to obtain dipyridamole, and the reaction route is as follows:

[0011] ;

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

[0013] Scheme four: with urea as the starting material, carbonyl protection, condensation with 2,3-diamino succinic acid, chlorination, condensation, hydrolysis, and finally condensation with diethanolamine, hydrogenation reduction to obtain, the total yield is 48.74%, the reaction route is as follows:

[0014] ;

[0015] As Chinese patent CN201611006751.X, the reagent of this scheme is expensive, heavy metals are used, and the reaction conditions are harsh. SUMMARY

[0016] The main purpose of the present application is to provide a synthesis method of dipyridamole to solve the problems in the prior art.

[0017] The present application provides a synthesis method of dipyridamole, comprising: taking 2,3-dioxysuccinic acid as the starting material, esterification, condensation with acetyl guanidine, chlorination, nucleophilic substitution, hydrolysis of acetyl group, nucleophilic substitution with 2-chloroacetate, and finally hydrolysis to obtain dipyridamole.

[0018] Further, taking 2,3-dioxysuccinic acid as the raw material, acidifying with chlorosulfuric acid in ethanol, refluxing, synthesizing 2,3-dioxysuccinic acid ethyl ester (formula 1), the reaction route is as follows:

[0019] .

[0020] Further, in a polar solvent, 2,3-dioxysuccinic acid ethyl ester and acetyl guanidine are condensed under alkaline conditions to synthesize 2,6-diacetamide-pyrimidine-[5,4-d] pyrimidinone (formula 2), the reaction route is as follows:

[0021] ;

[0022] The polar solvent used includes one or more of methanol, ethanol, DMF, dioxane, 1,2-dichloroethane, preferably the polar solvent used is selected from methanol or ethanol;

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

[0024] Further, 2,6-diamide-pyrimido[5,4-d]pyrimidinone is reacted in a chlorinating agent under reflux to synthesize 2,6-diamide-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, and preferably the chlorinating agent used is phosphorus oxychloride.

[0027] Further, 2,6-diamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine is reacted with piperidine under nucleophilic substitution in an aprotic solvent at room temperature to synthesize 2,6-diamide-4,8-dipiperidinyl-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, and preferably the aprotic solvent used is acetone.

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

[0031] ;

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

[0033] The dilute hydrochloric acid has a mass percentage concentration of 30-50%.

[0034] Further, 2,6-diamino-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is reacted with ethyl 2-chloroacetate under nucleophilic substitution in a polar aprotic solvent under basic conditions to synthesize 2,6-bis[diamido-diamine]-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, 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, NaH, preferably, the base used is sodium methoxide or sodium ethoxide.

[0038] Further, 2,6-bis[diacetyloxy-diethylamine]-4,8-dipiperidyl-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 route is as follows:

[0039] ;

[0040] The alcohol solvent used includes one or more of methanol, ethanol, isopropyl alcohol, preferably, the alcohol solvent used is methanol;

[0041] The base used includes one or more of sodium hydroxide, sodium carbonate, potassium carbonate, preferably, the base used is sodium hydroxide.

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

[0043] The synthesis method of dipyridamole has a novel route, a short synthesis route, no dangerous process, the raw materials used are cheap and easy to obtain, the process is easy to realize industrialization, and the purity of the final product obtained can be as high as 99.8%. BRIEF DESCRIPTION OF DRAWINGS

[0044] In order to more clearly illustrate the technical solutions in the embodiments or the prior art, the drawings needed in the embodiment or prior art description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments described in the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0045] Figure 1 is a liquid chromatogram detection result of dipyridamole of the present application. DETAILED DESCRIPTION

[0046] In view of the deficiencies in the prior art, the present inventors have long-term research and a large amount of practice, and have come up with the technical solutions of the present application. The technical solutions, their implementation processes and principles will be further explained as follows.

[0047] One aspect of the present application provides a method for synthesizing dipyridamole, comprising: using 2,3-dioxosuccinic acid as a starting material, esterification, condensation with acetyl guanidine, chlorination, nucleophilic substitution, hydrolysis to remove acetyl group, nucleophilic substitution with 2-chloroacetate, and finally hydrolysis to obtain dipyridamole.

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

[0049] .

[0050] In some preferred embodiments, ethyl 2,3-dioxosuccinate is condensed with acetyl guanidine in a polar solvent under basic conditions to synthesize 2,6-diacetamide-pyrimido[5,4-d]pyrimidinone (Formula 2), and the reaction route is as follows:

[0051] ;

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

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

[0055] ;

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

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

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

[0059] ;

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

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

[0062] In some preferred embodiments, 2,6-diamido-4,8-dipiperidinyl-pyrimido[5,4-d]pyrimidine is dissolved in a polar solvent, 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 used polar solvent can include one or more of methanol, ethanol, tetrahydrofuran, dioxane, DMF, etc., but is not limited thereto; the mass percentage concentration of the used dilute hydrochloric acid is 30-50%.

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

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

[0067] ;

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

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

[0071] ;

[0072] The alcohol solvent used can include one or more of methanol, ethanol, isopropyl alcohol, etc., but is not limited thereto; the base used can 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] By the above technical solution, the route is novel, the synthetic route is short, there is no dangerous process, the raw materials used are inexpensive and easy to obtain, the process is easy to realize industrialization, and the final product obtained has high purity.

[0075] 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.

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

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

[0078] .

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

[0080] Take 1000 milliliters of ethanol, add 202 grams of ethyl 2,3-dioxosuccinate, 222 grams of acetyl guanidine, and 204 grams of sodium ethoxide, heat the system to reflux for 24 hours, after the reaction is completed, cool the system to room temperature, recover most of the ethanol under reduced pressure, add 600 milliliters of ethyl acetate, stir for 20 minutes, slowly pour the system into ice water, separate the layers, wash the organic layer with water until it is neutral, dry the organic layer with anhydrous magnesium sulfate, filter, recover the solvent from the filtrate under reduced pressure, and recrystallize the residue with methanol to obtain 253 grams of light yellow solid (2,6-diacetamide-pyrimido[5,4-d]pyrimidinone) with a yield of 91%, and the main reaction route is as follows:

[0081] .

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

[0083] Take 2,6-diamide-pyrimido[5,4-d]pyrimidine ketone 139 grams, add phosphorus oxychloride 500 grams, the system is heated to reflux reaction, until all dissolved, continue to react for 4h, after the reaction is completed, the system is cooled to room temperature, recover unreacted phosphorus oxychloride under reduced pressure; ice bath cooling, dropwise add ammonia water to neutralize the reaction, until the pH to 8-9, filter, filter cake water wash to the center, dry the filter cake, the filter cake is recrystallized with methanol to get light yellow solid (2,6-diamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine) 141 grams, yield 90%, the main reaction route as follows:

[0084] .

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

[0086] Take acetone 200 milliliters, add 2,6-diamide-4,8-dichloro-pyrimido[5,4-d]pyrimidine 31.4 grams, stirring completely dissolved, ice bath cooling to 0-5℃, dropwise add piperidine 20.4 grams, at this temperature for 1h, after the reaction is completed, most of the acetone is recovered under reduced pressure, add 200 milliliters of ice water to the system, stirring for 30 minutes, filter, filter cake water wash, dry the filter cake, the solid is recrystallized with isopropyl alcohol to get yellow solid (2,6-diamide-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine) 39 grams, yield 95%, the main reaction route as follows:

[0087] .

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

[0089] Take 2,6-diamide-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine 41.2 grams, dissolved in 120 milliliters of methanol, add 40% mass concentration of dilute hydrochloric acid 120 milliliters, heated to reflux reaction for 7h, after the reaction is completed, the system is slowly cooled to room temperature, ice bath cooling, slowly dropwise add saturated solution of sodium carbonate, the system pH to 9-10, filter, filter cake water wash to neutral, dry the filter cake, the solid is recrystallized with isopropyl alcohol to get yellow solid (2,6-diamino-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine) 29 grams, yield 89%, the main reaction route as follows:

[0090] .

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

[0092] Take 2,6-diamino-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine 32.8 grams, dissolved in 200 milliliters of acetonitrile, add sodium methoxide 32.4 grams, stirring for 30 minutes, drop 2-chloroethyl acetate 60 grams, the system to warm to reflux reaction, reaction 8h, after the reaction, the reaction system to room temperature, slowly pour the reaction liquid into 300 milliliters of ice water, stirring for 20 minutes, filter, filter cake water wash to neutral, filter cake drying, solid recrystallized with methanol to get yellow solid powder (2,6-bis[diacetyloxy-diethylamine]-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine) 62.4 grams, yield 94%, the main reaction route as follows:

[0093] .

[0094] Example 7 Synthesis of dipyridamole (7)

[0095] Take 2,6-bis[diacetyloxy-diethylamine]-4,8-dipiperidyl-pyrimido[5,4-d]pyrimidine 67.2 grams, dissolved in 150 milliliters of methanol, add sodium hydroxide solution (sodium hydroxide 18 grams, water 50 milliliters), the system to warm to reflux reaction 2h, after the reaction, the system to room temperature, add 150 milliliters of ice water to the system, continue to stir for 30 minutes, filter, filter cake water wash to neutral, filter cake drying, solid recrystallized with ethyl acetate yellow solid powder (dipyridamole) 48.4 grams, yield 96%, the main reaction route as follows:

[0096] ;

[0097] By liquid chromatography, as shown in Table 1 below, the dipyridamole content of finished product reached 99.8%. Figure 1

[0098] Table 1 Liquid chromatography detection results of dipyridamole

[0099]

[0100] In addition, the present inventors also refer to the foregoing examples, with other raw materials, process operations, process conditions described in this specification, and all obtained more ideal results.

[0101] ​While the application has been described with reference to the illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and / or additions can be made without departing from the spirit and scope of the application. Further, many modifications can be made to adapt a particular situation or material to the teachings of the application without departing from its scope. Therefore, it is intended that the application not be limited to the disclosed embodiments, but will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated otherwise, any use of the terms first, second, etc., does not denote any ordinal, or importance, but merely distinguishes one element from another.

Claims

1. A method for synthesizing dipyridamole, characterized in that, Includes the following steps: S1: Starting with 2,3-dioxosuccinic acid, compound 1 was synthesized in ethanol via acidification with thionyl chloride and reflux reaction. The reaction route is as follows: ； S2: Compound of Formula 1 is condensed with acetylguanidine under strongly basic conditions with ethanol as the reaction solvent and sodium ethoxide as the base to synthesize compound of Formula 2. The reaction route is as follows: ； S3: Compound of Formula 2 is refluxed in phosphorus oxychloride as the chlorinating agent to synthesize compound of Formula 3. The reaction route is as follows: ； S4: At room temperature, in an aprotic solvent, compound 3 reacts with piperidine via a nucleophilic substitution reaction to synthesize compound 4. The reaction route is as follows: ； The aprotic solvent is selected from one or more of tetrahydrofuran, dioxane, acetone, and acetonitrile. S5: Compound S4 is dissolved in methanol and hydrolyzed under reflux in 30-50% dilute hydrochloric acid to synthesize compound S5. The reaction route is as follows: ； S6: Compound S5 was synthesized from 2-chloroethyl acetate via nucleophilic substitution under basic conditions with acetonitrile as a polar aprotic solvent and sodium methoxide as a base. The reaction route is as follows: ； S7: Compound S6 is dissolved in methanol, and the ester is hydrolyzed with sodium hydroxide to synthesize compound S7, dipyridamole. The reaction route is as follows: 。

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