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RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Patent Application No. 201941030360 filed on July 26, 2019; the disclosures of which are incorporated herein by reference.

Field of the Invention
The invention relates to an improved process for purification of Dipyridamole. More particularly, the invention relates to a process for preparing purified Dipyridamole, having total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w.

Background of the Invention
Dipyridamole exhibits anti-thrombotic properties and marketed for anti-platelet therapy. Dipyridamole is chemically known as 2,2',2'',2'''-[(4,8-Dipiperidinopyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol represented by the Formula I.

Dipyridamole was first disclosed in the patent US 3031450. This patent discloses a process for the preparation of Dipyridamole involving the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine without a solvent at temperature of 190 to 195°C. The resulting reaction mass is viscous and difficult for work-up in large scale. This viscous mass was triturated with small amount of acetone for precipitation and then the precipitated material was recrystallized for four times in ethyl acetate for better purity.

The Patent DE 1812918 involves the preparation of Dipyridamole by the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at 150 to 200°C. The workup was done by extraction procedures that are not easy to handle in large scale. Further use of chloroform at the final purification process is not advisable in view of regulatory perspective.
The Patent DD115670 involves the purification of Dipyridamole by refluxing with butyl acetate for 2 hours in the presence of silica gel or silica gel column chromatography.

The Patent IN 271796 involves the preparation of Dipyridamole by the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine in a solvent selected from the group consisting of 1-methyl-2-pyrrolidinone, sulfonlane and polyethylene glycol at 190 to 195°C. The work-up process involves purification process in ketone solvent and a purification process in a mixture isopropyl alcohol and water.

The Patent US8946414 discloses the preparation of Dipyridamole to reduce the impurities in the final API by the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at temperatures below 130°C that takes 45 to 48 hours. The purity of Dipyridamole of about 99.9% by HPLC is achieved by the purification process involving the steps of dissolving a solution of dipyridamole in diethanolamine at 80°C; adding ethanol, toluene and water to the solution; and then precipitating the solid by cooling the solution.

The impurity B of Dipyridamole listed in the Pharmacopeia is chemically known as 2,2’,2”,2’”,2””[[8-Piperidin-1-yl]pyrimido[5,4-d]pyrimidine-2,4,6-triyl]trinitrilo]hexaethanol represented by the below mentioned formula:

This is formed as a side product during the preparation of Dipyridamole. This impurity formation is controlled by performing the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at temperatures below 130°C for 48 hours or by complex purification process after completion of the reaction.

The impurity E and C are represented by the formula as mentioned below:

The US Pharmacopeia and European Pharmacopeia discloses the Dipyridamole having a chemical purity ranging from 98.0% to 102.0%. Dipyridamole injection and tablets contains not less than 90% and not more than 110% of Labeled amount of Dipyridamole. Dipyridamole API for pharmaceutical finished products should have a chemical purity ranging from 98.0% to 102.0%; impurity B not more than 0.5%; impurity C not more than 0.1%; impurity E not more than 0.2% and total impurities not more than 1.0 % for marketing in US and Europe.

Besides, the availability of different methods for achieving the purity in Dipyridamole API during the preparation Dipyridamole in state of the art, there is a need for an improved process for the purification of Dipyridamole that is economically significant and industrially viable.

Objects of the Invention

The primary object of the present invention is to provide an improved process for the purification of Dipyridamole having high chemical purity.

Another object of the invention is to provide an improved process for preparing purified Dipyridamole, having total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w.

Summary of the Invention

Accordingly, there is provided a process for purification of Dipyridamole wherein, purified Dipyridamole, has total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w

An aspect of the present invention provides an improved process for purifying Dipyridamole, wherein the said purified Dipyridamole is having total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w, comprising the steps of:
(i) suspending crude dipyridamole in a mixture of organic solvent, organic acid and water;
(ii) optionally heating the obtained suspension in step (i);
(iii) isolating the solid from the suspension obtained in step (ii) or step (i);
(iv) dissolving the solid obtained in step (iii) in a mixture of isopropyl alcohol and water;
(v) optionally heating the solution obtained in step (iv);
(vi) cooling the solution obtained in step (v) or step (iv) to 30°C;
(vii) isolating the solid resulted in step (vi);
(viii) dissolving the solid obtained in step (vii) in a mixture of ester solvent and water;
(ix) optionally heating the solution obtained in step (viii);
(x) cooling the solution obtained in step (viii) or step (ix) to 30°C;
(xi) maintaining the solution obtained in step (x) at 30°C till the crystallization or precipitation; and
(xii) isolating the solid resulted in step (xi).

Another aspect of the present invention provides a process for purifying dipyridamole comprising the steps of:
(i) suspending crude dipyridamole in a mixture of dichloromethane, acetic acid and water;
(ii) optionally heating the obtained suspension in step (i);
(iii) isolating the solid from the suspension obtained in step (ii) or step (i) by filtration;
(iv) dissolving the solid obtained in step (iii) in a mixture of ethyl acetate and water;
(v) optionally heating the solution obtained in step (iv);
(vi) cooling the solution obtained in step (v) or step (iv) to 30°C;
(vii) maintaining the solution obtained in step (vi) at 30°C till the crystallization or precipitation; and
(viii) isolating the solid resulted in step (vii) by filtration.

Yet another aspect of the present invention provides a process for purifying dipyridamole comprising the steps of:
(i) suspending dipyridamole in a mixture of dichloromethane, acetic acid and water;
(ii) optionally heating the obtained suspension in step (i); and
(iii) isolating the solid from the suspension obtained in step (ii) or step (i).

In the present invention, the starting material crude Dipyridamole is prepared according to the literature available in the prior art.

Detailed Description of the Invention
Detailed embodiments of the present invention are disclosed herein below. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. The scope of the invention is not limited to the disclosed embodiments and terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention.

The invention provides a process for purification of Dipyridamole wherein, purified Dipyridamole, has total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w.

The crude Dipyridamole used in the present invention may have impurity B more than 0.4% or the reaction mass resulted from the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine by known methods in the state of art.

One embodiment of the present invention provides an improved process for purifying dipyridamole, wherein the said purified Dipyridamole is having total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w comprising the steps of:
(i) suspending crude dipyridamole in a mixture of organic solvent, organic acid and water;
(ii) optionally heating the obtained suspension in step (i);
(iii) isolating the solid from the suspension obtained in step (ii) or step (i);
(iv) dissolving the solid obtained in step (iii) in a mixture of isopropyl alcohol and water;
(v) optionally heating the solution obtained in step (iv);
(vi) cooling the solution obtained in step (v) or step (iv) to 30°C;
(vii) isolating the solid resulted in step (vi);
(viii) dissolving the solid obtained in step (vii) in a mixture of ester solvent and water;
(ix) optionally heating the solution obtained in step (viii);
(x) cooling the solution obtained in step (viii) or step (ix) to 30°C;
(xi) maintaining the solution obtained in step (x) at 30°C till the crystallization or precipitation; and
(xii) isolating the solid resulted in step (xi).

In preferred embodiment of the invention the organic solvent used in step (i) is Dichloromethane.

In the same embodiment, the organic acid used in step (i) is acetic acid.

In the same embodiment, the ester solvent used in the purification process in step (viii) is ethyl acetate.

In further embodiment, the isolation of the purified solid is performed by filtration.

Surprisingly, the present purification process completely removes the impurity B and impurity C from Dipyridamole and also reduced the other individual as well as unspecified impurities. Present purification process does not involve the complex purification procedures as in the prior art.

In Another embodiment, the present invention provides an improved process for purifying dipyridamole comprising the steps of:
(i) suspending crude dipyridamole in a mixture of dichloromethane, acetic acid and water;
(ii) optionally heating the obtained suspension in step (i);
(iii) isolating the solid from the suspension obtained in step (ii) or step (i) by filtration;
(iv) dissolving the solid obtained in step (iii) in a mixture of ethyl acetate and water;
(v) optionally heating the solution obtained in step (iv);
(vi) cooling the solution obtained in step (v) or step (iv) to 30°C;
(vii) maintaining the solution obtained in step (vi) at 30°C till the crystallization or precipitation; and
(viii) isolating the solid resulted in step (vii) by filtration.

Yet another embodiment of the present invention provides a process for purifying dipyridamole comprising the steps of:
(i) suspending dipyridamole in a mixture of dichloromethane, acetic acid and water;
(ii) optionally heating the obtained suspension in step (i); and
(iii) isolating the solid from the suspension obtained in step (ii) or step (i).

Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

Examples
Example-1:
Step-A: Preparation of Dipyridamole: A mixture of 2,6-dichloro-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine (50 gm) and diethanolamine (375 ml) was heated to 145-150 °C and stirred for 8 hours at the same temperature. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mass was heated to 145-150 °C and stirred for 1 hour at the same temperature. The reaction was cooled to 50°C. Isopropyl alcohol (100 ml) was added to the cooled reaction mass; stirred for 30 minutes; and cooled to 30-35 °C. Water (750 ml) was slowly added to the reaction mass for 2 hours at 30-35 °C and stirred for 2 hours. The resultant solid was filtered. Wet weight: 100 gm

Step-B: To the wet solid (100 gm) obtained in step A, dichloromethane (350 ml), acetic acid (7.2 g) and water (450 ml) was charged and heated to 35-40 °C and stirred for 1 hour at the same temperature. The contents were cooled to 10-15 °C and stirred for 1 hours at the same temperature. The contents were then filtered, washed with dichloromethane (50 ml); a mixture of isopropyl alcohol (25 ml) and water (75 ml) and dried. Yield: 50 gm

Step-C: To the mixture of Ethyl acetate (200ml) and water (50ml), the solid (25.0g) obtained in step B was added and heated to 70-75°C and maintained for 30 minutes at the same temperature. The contents were then cooled to 30°C and stirred for 30 minutes at the same temperature. The resultant solid was filtered, washed with a mixture ethyl acetate (40 ml) and water (10 ml) and dried at 50-55 °C under vacuum. Yield: 23 gm

Example-2:
Step-A: Preparation of Dipyridamole: A mixture of 2,6-dichloro-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine (50 gm) and diethanolamine (375 ml) was heated to 145-150 °C and stirred for 8 hours at the same temperature. The progress of the reaction was monitored by UPLC. After completion of the reaction, the reaction mass then heated to 145-150 °C and stirred for 1 hour at the same temperature. The reaction was cooled to 45-50°C. Isopropyl alcohol (100 ml) was added to the cooled reaction mass; stirred for 30 minutes; and cooled to 30-35 °C. Water (750 ml) was slowly added to the reaction mass for 2 hours at 30-35 °C °C and stirred for 2 hours. The resultant solid was filtered. Yield: 110 gm

Step-B: To the wet solid (110 gm) as obtained in step-A, dichloromethane (350 ml), acetic acid (7.2 g) and water (450 ml) was added and heated to 35-40 °C and stirred for 1 hour at the same temperature. The contents were cooled to 10-15 °C and stirred for 1 hours at the same temperature. The cooled contents were then filtered, washed with dichloromethane (50 ml); a mixture of isopropyl alcohol (25 ml) and water (75 ml). Yield: 54 gm

Step-C: A mixture of wet solid obtained in Step-B (54 gm) and isopropyl alcohol (200 ml) was heated to 60-65°C and maintained at the same temperature for 30 minutes. The contents were cooled to 30-35 °C. To the cooled mass, water (500 ml) was slowly added at 30-35 °C and stirred for 1 hour at the same temperature. The contents were then cooled to 5-10°C and stirred for 1 hour at the same temperature. The resultant solid was filtered, washed with a mixture of isopropyl alcohol (17 ml) and water (33 ml) and dried at 50-55 °C for 5 hours under vacuum. Yield: 51 gm

Step-D: A mixture of wet solid obtained in step-C (50 gm), ethyl acetate (400 ml) and water (100 ml) was stirred for 30 minutes at 30-35°C. The stirred mass was heated to 70-75 °C and maintained for 30 minutes at the same temperature. Then the reaction mass was cooled to 30-35 °C and stirred for 30 minutes at the same temperature. The resultant solid was filtered, washed with a mixture ethyl acetate (40 ml) and water (10 ml) and dried at 50-55 °C under vacuum. Yield: 47.5 gm

Dipyridamole resulted in the examples-1 and 2 and USP Standard were analyzed in UPLC and the results were tabulated.
Table-1
Dipyridamole Purity comparison
S.No. Dipyridamole Impurities USP Limit Example-1 Example-2 USP standard

1 Impurity-A as specified in USP NMT 0.50 0.03 0.03 0.01
2 Impurity-B as specified in USP NMT 0.50 0.11 0.06 0.01
3 Impurity-C as specified in USP NMT 0.10 ND ND 0.04
4 Impurity-D as specified in USP NMT 0.20 0.01 ND 0.05
5 Impurity-E as specified in USP NMT 0.20 ND ND 0.08
6 Impurity-F as specified in USP NMT 0.10 0.02 ND ND
7 Any Unspecified impurity NMT 0.10 0.02 0.02 0.03
8 Total impurities NMT 1.0 0.23 0.11 0.31

The Dipyridamole purity comparison results given in above Table 1, indicate that the present invention of process of purification of Dipyridamole limits all the specified as well as unspecified impurities and total impurities below the stated USP limit.
,CLAIMS:1. An improved process for purification of dipyridamole, comprising the steps of:
(i) suspending crude dipyridamole in a mixture of organic solvent, organic acid and water;
(ii) optionally heating the obtained suspension in step (i);
(iii) isolating the solid from the suspension obtained in step (ii) or step (i);
(iv) dissolving the solid obtained in step (iii) in a mixture of isopropyl alcohol and water;
(v) optionally heating the solution obtained in step (iv);
(vi) cooling the solution obtained in step (v) or step (iv) to 30°C;
(vii) isolating the solid resulted in step (vi);
(viii) dissolving the solid obtained in step (vii) in a mixture of ester solvent and water;
(ix) optionally heating the solution obtained in step (viii);
(x) cooling the solution obtained in step (viii) or step (ix) to 30°C;
(xi) maintaining the solution obtained in step (x) at 30°C till the crystallization or precipitation; and
(xii) isolating the solid resulted in step (xi).

2. The process as claimed in claim 1, wherein the organic solvent in step (i) is Dichloromethane.

3. The process as claimed in claim 1, wherein the organic acid in step (i) is acetic acid.

4. The process as claimed in claim 1, wherein the ester solvent in step (viii) is ethyl acetate.

5. The process as claimed in claim 1, wherein the isolation of solid in step (iii), step (vii) and step (xii) is performed by filtration.

6. The process as claimed in claim-1, wherein said purified Dipyridamole obtained from the process has total impurities not more than 0.50% w/w and any individual impurity not more than 0.1 % w/w,

7. The process as claimed in claim 1, wherein said Dipyridamole is substantially free of impurities A, B, C, D, E and F wherein each impurity is less than about 0.1% w/w.

8. An improved process for purification of dipyridamole comprising the steps of:
(i) suspending crude dipyridamole in a mixture of dichloromethane, acetic acid and water;
(ii) optionally heating the obtained suspension in step (i);
(iii) isolating the solid from the suspension obtained in step (ii) or step (i) by filtration;
(iv) dissolving the solid obtained in step (iii) in a mixture of ethyl acetate and water;
(v) optionally heating the solution obtained in step (iv);
(vi) cooling the solution obtained in step (v) or step (iv) to 30°C;
(vii) maintaining the solution obtained in step (vi) at 30°C till the crystallization or precipitation; and
(viii) isolating the solid resulted in step (vii) by filtration.

9. A process for purifying dipyridamole comprising the steps of:
(i) suspending dipyridamole in a mixture of dichloromethane, acetic acid and water;
(ii) optionally heating the obtained suspension in step (i); and
(iii) isolating the solid from the suspension obtained in step (ii) or step (i).