Title Of The Invention

An Improved process for the preparation of 2,4-dichIoro-7H-pyrrolo [2,3-d] pyrimidine.

Field of the Invention

The present invention relates to an improved process for the preparation of

2.4- dichloro-7H-pyrrolo [2,3-d] pyrimidine having the chemical structural Formula I.
Background of the Invention

2.4- dichloro-7H-pyrrolo[2,3-d] pyrimidine is an intermediate in the synthesis of various drugs which inhibit the activity of Syk (Spleen associated tyrosine kinase) and JAK kinase (Janus kinase). These drugs are used to treat various conditions associated with cardiovascular disease, inflammatory disease, or autoimmune disease.

The process for synthesis of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine is disclosed in Chen et al’s Journal of Medicinal Chemistry (2010), 53(8), 3169-3182; US7705004B2, W02009026107.

The process for preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine described in these prior art references suffer from many shortcomings, such as low yield, usage of more solvents and chemicals for purification, less purity of
product. This will lead to high production cost.

In view of the above, there is a significant need to develop a cost effective, stable commercially viable, large scale and robust process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

Summary of the Invention

The present invention relates to the novel and cost-effective process for manufacturing of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine compound of Formula I with higher yield and purity.

In one embodiment, the present invention provides an improved process for the manufacturing of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine compound of Formula I.
which comprises:

i) coupling of chloro acetaldehyde dimethyl acetal or brom acetaldehyde dimethyl acetal with 6- amino uracil in presence of Hydrochloric acid, water, salt and base to obtain 1H- pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)- dione compound of formula II.
ii) reduction of 1H- pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)- dione compound of formula II in presence of phosphoryl chloride and solvent with or without solvent like toulene to give 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine compound of formula I.

iii) compound of formula I is purified by using organic solvent.

Detailed description of the invention

Accordingly, the present invention provides a novel and improved method for manufacturing 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine compound of formula I

The main embodiment of the current invention provides an improved process for the preparation of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine compound of formula I. which is outlined in below scheme.
Coupling of chloroacetaldehyde dimethyl acetal or bromoacetaldehyde dimethyl acetal with 6- aminouracil in presence of hydrochloric acid and water in the
combination of 1:1 ratio, base, and salt to obtain 1H- pyrrolo[2,3-d] pyrimidine-' 2,4(3H,7H)- dione compound of formula II.

The base used in the reaction is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide lithium hydroxide or sodium bicarbonate.

The salt used in the reaction is selected from the group consisting of potassium iodide or sodium iodide.

The reaction is carried out at room temperature for 16 hours. After that the reaction is carried out at a temperature range of 40-70°C for 2-6 hours. Preferably at a temperature in the range from 50-55 °C for a duration of 3-5 hours.

Solvent used in the reaction is selected from the group consisting of protic solvents like water, methanol, ethanol or iso propanol.
Reduction of 1H- pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)- dione compound formula II in presence of phosphoryl chloride and solvent toluene or without solvent to give 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine compound of formula I.
Solvents used in the step 2 of the reaction is selected from the group consisting of N,N’ dimethyl aniline orN,N’ diisopropyl ethyl amine.

The reaction temperature may range from 80- 130 °C. Preferably at a temperature in the range from 100-110 °C. The duration of reaction may range from 4-10 hours. Preferably for a duration of 6-8 hours. The pH is maintained at a range of 7-7.9.

Step iii.

Compound of formula I is further purified by using organic solvent.

Solvent used for purification is selected from the group consisting of Ethyl acetate, Methyl tert-butyl ether or Diethyl ether. Preferably, solvent used for purification is Ethyl acetate.

Experimental Portion

The details of the given invention are given below in the examples provided below, which are given to illustrate the invention only and therefore should not be constructed to limit the scope of the invention.

Example-1: Process for preparation of lH-pyrrolo[2,3-d] pyrimidine-2, 4(3H,7H)-dione

A solution of Chloroacetaldehyde dimethyl acetal (200 grams 1.605 mol), 6N Hydrochloric acid (400 mL) were stirred at 16 hours at room temperature. To this mixture, added 6-Amino Uracil (100 grams 0.786 mol), adjusted the pH to 10.0-11.0 with aqueous sodium carbonate, added Potassium Iodide (20 grams 0.16 mol), heated the reaction mass to 50-55°C for 3-4 hours. Cooled the reaction mass to room temperature, filtered the solid and washed with water (200 mL) to obtain lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (Yield: 98%).Example-2: Process for preparation of lH-pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)-dione

A solution of Chloroacetaldehyde dimethyl acetal (100 grams 0.8027 mol), 6N Hydrochloric acid (200 mL) were stirred at 16 hours at room temperature. To this mixture, added 6-Amino Uracil (50 grams 0.393 mol), adjusted the pH to 11.0-

12.0 with aqueous Potassium hydroxide, added Potassium Iodide (10 grams 0.16 mol), heated the reaction mass to 50-55°C for 3-4 hours. Cooled the reaction mass to room temperature, filtered the solid and washed with water (100 mL) to obtain lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (Yield: 95%).

Example-3:Process for preparation of lH-pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)-dione

A solution of bromoacetaldehyde dimethyl acetal (100 grams 0.591 mol), 6N Hydrochloric acid (200 mL) were stirred at 16 hours at room temperature. To this mixture, added 6-Amino Uracil (50 grams 0.393 mol), adjusted the pH to 11.0-

12.0 with aqueous sodium carbonate, added Potassium Iodide (10 grams 0,16 mol), heated the reaction mass to 50-55°C for 3-4 hours. Cooled the reaction mass to room temperature, filtered the solid and washed with water (100 mL) to obtain lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (Yield: 97.2%).

Example-4: Process for preparation of lH-pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)-dione

A solution of bromoacetaldehyde dimethyl acetal (100 grams 0.591 mol), 6N Hydrochloric acid (200 mL) were stirred at 16 hours at room temperature. To this mixture, added 6-Amino Uracil (50 grams 0.393 mol), adjusted the pH to 11.0-

12.0 with aqueous Potassium hydroxide, added Potassium Iodide (10 grams 0.16 mol), heated the reaction mass to 50-55°C for 3-4 hours. Cooled the reaction mass to room temperature, filtered the solid and washed with water (100 mL) to obtain lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (Yield: 98.6%).
Example-5: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To the compound lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione(20grams 0.132 mol, obtained from Example-1 to 4) added Phosphoryl chloride (67.2 grams 0.438mol) at 5°C. Heated to 40-45°C, added N,N’ dimethyl aniline (19.12 grams 0.157 mol), heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 raL), extracted with Methyl tert-butyl ether (2 XI00 mL), treated the organic layer with activated carbon, filtered through celite and distilled off the organic layer to get 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 61%).

Example-6: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To the compound lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione(20 grams 0.132 mol, obtained from Example-1 to 4) added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N,N’ dimethyl aniline (19.12 grams 0.157 mol),heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), adjusted the pH of the reaction mass to 7.0-8.5 with aqueous ammonia (110 mL), filtered the solid and washed with water (40 mL) and dried the solid. This solid was purified in Methyl tert-butyl ether, added activated carbon to get2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 58%).

Example-7: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To the compound lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (20 grams 0.132 mol, obtained from Example-1 to 4) added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N,N’ dimethyl aniline (19.12 grams 0.157 mol),heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), adjusted the pH of the reaction mass to 7.0-8.5 with aqueous ammonia (110 mL), filtered the solid and washed with water (40
mL) and dried the solid. This solid was purified in Ethyl acetate, added activated carbon to get2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 53%).

Example-8; Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To the compound 1 H-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (20 grams 0.132 mol, obtained from Example-1 to 4) added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N, N’ diisopropyl ethyl amine (14.84 grams 0.15 mol), heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), extracted with Methyl tert-butyl ether (2 XI00 mL), treated the organic layer with activated carbon, filtered through celite and distilled off the organic layer to get 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 52%).

Example-9: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To the compound lH-pyrrolo[2,3-d] pyrimidine-2,4(3H,7H)-dione (20 grams 0.132 mol, obtained from Example-1 to 4) added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N,N’ diisopropyl ethyl amine (14.84 grams 0.15 mol),heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), adjusted the pH of the reaction mass to 7.0-8.5 with aqueous ammonia (110 mL), filtered the solid and washed with water (40 mL) and dried the solid. This solid was purified in Methyl tert-butyl ether, added activated carbon to get2,4-dich!oro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 48%).

Example-10: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To the compound lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (20 grams 0.132 mol, obtained from Example-1 to 4) added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N, N’ diisopropyl ethyl amine
(14.84 grams 0.15 mol), heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), adjusted the pH of the reaction mass to 7.0-8.5 with aqueous ammonia (110 mL), filtered the solid and washed with water (40 mL) and dried the solid. This solid was purified in Ethyl acetate, added activated carbon to get2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 44%).

Example-11: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To solution of lH-pyrrolo(2,3-d] pyrimidine -2,4(3H,7H)-dione (20 grams 0.132 mol, obtained from Example-1 to 4) and Toluene (50 mL), added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N,N’ dimethyl aniline (19.12 grams 0.157 mol), heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), adjusted the pH of the reaction mass to 7.0-8.5 with aqueous ammonia (110 mL), filtered the solid and washed with water (40 mL) and dried the solid. This solid was purified in Methyl tert-butyl ether, added activated carbon to get 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 49 %).

Example-12: Process for the preparation of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine.

To solution of lH-pyrrolo[2,3-d] pyrimidine -2,4(3H,7H)-dione (20 grams 0.132 mol, obtained from Example-1 to 4) and Toluene (50 mL), added Phosphoryl chloride (67.2 grams 0.438 mol) at 5°C. Heated to 40-45°C, added N, N’ diisopropyl ethyl amine (14.84 grams 0.15 mol), heated to 100-110°C, stirred for 6-8 hours. Cooled the reaction mass to 5°C, quenched with water (80 mL), adjusted the pH of the reaction mass to 7.0-8.5 with aqueous ammonia (110 mL), filtered the solid and washed with water (40 mL) and dried the solid. This solid was purified in Methyl tert-butyl ether, added activated carbon to get 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (Yield: 40 %).
THE PRESENT INVENTION HAS THE FOLLOWING ADVANTAGES:

1. In the prior art purification of product is a lengthy process which involves usage of many reagents. The present invention involves extraction of product with solvents like ethyl acetate and followed by carbon treatment which gives product of 99% purity.

2. The present invention results in higher yield 61% as compared with yield reported in the prior art 43% and 31%.