TITLE OF THE INVENTION

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

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 4-bromo-7H-pyrrolo [2.3-d] pyrimidine having the chemical structural Formula I.
BACKGROUND OF THE INVENTION

4-bromo-7H-pyrrolo [2,3-d] pyrimidine is a key intermediate used in the synthesis of APIs like Tofacitinib and Ruxolitinib. Ruxolitin.ib is used in the treatment of intermediate or high-risk myelofibrosis, resistant forms of polycythemia vera and graft-vs-host disease. Tofacitinib is used in the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease and ankylosing spondylitis.

The process for preparation of 4-bromo-7H-pyrrolo [2,3-d] pyrimidine is disclosed in US10738058B2 and CN109563098B.

The process disclosed in the prior art has drawbacks like low conversion, high cost of production and low yield.

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

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

In one embodiment, the present invention provides an improved for manufacturing of 4-bromo-7H-pyrrolo [2.3-d] pyrimidine compound of Formula I,
which comprises 4 steps:

a) coupling of 2- bromo- 1,1- dimethoxy ethane with ethyl 2-cyano acetate in presence of solvent, salt and base to obtain ethyl 2-cyano -4,4- dimethoxy butanoate compound of formula II;
b) condensation of ethyl 2- cyano- 4,4- dimethoxy butanoate with formamidinc acetate, in presence of base, acid and solvent to give 7H- Pyrrolo [2,3-d] pyrimidin-4-ol/PPC-l compound of formula III;
c) conversion of 7H-pyrrolo[2,3-d] pyrimidin-4-ol to 4-chiloro-7H-pyrrolo[2,3-d]pyrimidine compound of formula IV in presence of Phosphorous oxychloride and solvent;
d) conversion of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine to 4- bromo-7H-pyrrolo[2,3-d] pyrimidine formula I using HBr and 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 and process for the preparation of 4- bromo-7H-pyrrolo[2,3-d] pyrimidine compound of formula I which is outlined in below scheme.

Step i:

Coupling of 2- bromo- 1,1- dimethoxy ethane with ethyl 2- cyano-acetate in presence of solvent, salt and base to obtain ethyl 2- cyano-4,4- dimethoxy butanoate compound of formula II.
The base used in the reaction is selected from the group consisting of potassium carbonate, sodium carbonate or sodium bicarbonate; preferably potassium carbonate.

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

Solvent used in the reaction is selected from the group consisting of polar aprotic solvents like N, N dimethyl formamide, acetonitrile, dichloro methane, acetone or ethyl acetate; preferably N,N dimethyl formamide.

The reaction is carried out at temperature range of 90- 120 °C for 3-7 hours; preferably at a temperature in the range of 100- 105 °C for 3-4 hours.

Step ii:

Condensation of ethy!2- cyano- 4,4- dimethoxy butanoate compound of formula II with formamidine acetate in presence of base, acid and solvent to obtain 7H-Pyrrolo [2,3-d] pyrimidin-4-ol/PPC-l compound of formula III.
Solvent used in the step ii of the reaction is selected from the group consisting of polar protic solvents like water, methanol, ethanol, iso propyl alcohol or acetic acid; preferably methanol.

The reaction is carried for 4 hours and then reaction is carried out at a temperature range of 35- 55 °C for 2-6 hours; preferably at a temperature range of 40-45 °C for 2 hours. The pH is maintained at a range of 3.0-4.5 with aqueous ammonia.
Step iii

Conversion of 7H-pyrrolo[2,3-d] pyrimidin-4-ol compound of formula III to 4-chloro-7H-pyrrolo[2,3-d] pyrimidine compound of formula IV in presence of phosphorous oxychloride, base and solvent.
The base used in the reaction is selected from group consisting of N, N diisopropyl ethyl amine or triethyl amine.

Solvent used for step iii of the reaction is selected from the group consisting of organic solvents such as toluene, xylene, or n-hexane; preferably toluene.

The step iii of the reaction is carried out a temperature range of 50 -70 °C for 4-8 hours; preferably at a temperature range of 60-65 °C for 6 hours.

The pH of reaction mass is maintained at a range of 7- 7.9 with aqueous ammonia.

Solvent used for purification is selected from the group consisting of ethyl acetate, acetone or ethanol; preferably ethyl acetate.

step iv:

Conversion of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine compound of formula IV to 4- bromo-7H-pyrrolo[2,3-d] pyrimidine formula I in presence of Hydrobromic acid and solvent.
Solvent used in the step iv of the reaction is selected from the group consisting of acetic acid, methanol, ethanol or iso propyl alcohol; preferably acetic acid.

The step iv of reaction is carried out a temperature range of 70- 90 °C for 3-6 hours; preferably at a temperature range of 80-85 °C for 4 hours.

Water is used for the purification of compound of Formula I. 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.

Procedure 1: Process for the preparation of Ethyl 2-cyano-4,4-dimethoxybutanoate

To a solution of Potassium carbonate (490 grams, 3.55 mol) and N, N’ Dimethyl formamide (l.SLit), added 2-Bromo-l,l-dimethoxy ethane (500 grams, 2,96 mol), Ethyl-2-cyano acetate (836.5 grams, 7.40 mol) and Potassium Iodide (80 grams, 0.16 mol) at room temperature. This mixture is heated to 100-105 °C, stirred for 3-4 hours. The reaction mixture is cooled to room temperature and added chilled water (6 Lit), extracted with Ethyl acetate (4 Lit). Evaporated the organic layer completely under reduced pressure. The obtained crude is subjected to HVD (5 Ton at vapor, temperature of 90-115 °C) to obtain Ethyl 2-cyano-4,4-dimethoxybutanoate (Yield:
66%).

Example 1: Process for the preparation of 7H-pyrrolo[2,3-d] pyrimidin-4-oI

A solution of Sodium methoxide (537 grams, 9.94 mol) and Methanol (1.75 Lit) were cooled to 10-15 °C, added Formamidine Acetate (362 grams, 3.47 mol) and Ethyl 2-cyano-4,4-dimethoxybutanoate (500 grams, 2.48 mol). Reaction mixture is refluxed for 4 hours, distilled off the reaction mass completely under reduced pressure. Water (2 Lit) was added to the resultant crude, cooled to 5 °C, adjusted the pH to 1.0-2.0 with Concentrated Hydrochloric acid (1.15 Lit). Heated the reaction mass to 40-45 °C, for 2 hours. Cooled the mass to 5 °C, adjusted the pH to 3.0-4.5 with aqueous ammonia (202 mL), and stirred for 2 hours. Filtered the solid, washed the solid with water (250 mL) to get 7H-pyrrolo[2,3-d] pyrimidin-4-ol (Yield: 67%).

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

A mixture of 7H-pyrrolo[2,3-d] pyrimidin-4-ol (300 grams, 2.20 mol) and Toluene (750 mL) were cooled to 5°C, added Phosphoryl chloride (688 grams, 4.44 mol). Heated to 40-45 °C, added N, N’ Di-isopropyl ethyl amine (358.6 grams, 2.72 mol), heated to 60-65 °C, stirred for 5 hours. Cooled the reaction mass to 5 °C, quenched with water (1.2 Lit), adjusted the pH of the reaction mass to 7.0-7.9 with aqueous ammonia (1.51 Lit), filtered the solid and washed with water (600 mL) and dried the solid. This solid was purified in Ethyl acetate, added activated carbon to get the white solid of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (Yield: 70%).

Example 3: Process for the preparation of 4-Bromo-7H-pyrrolo[2,3-d) pyrimidine

To a solution of Acetic acid (450 mL) and 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (150 grams), added 600 mL of Hydro bromic acid (in Acetic acid, 30-33%) was added at room temperature, heated to 80-85 °C, stirred for 4 hours. Cooled the mass to room temperature, stirred for 15 minutes and filtered the solid and washed with water (300 mL) to obtain 4-Bromo-7H-pyrrolo[2,3-d] pyrimidine (Yield: 78%).
THE PRESENT INVENTION HAS THE FOLLOWING ADVANTAGES:

1. Inclusion of polar aprotic solvent N, N’ dimethylformamide improved the product formation, lowered the impurities, and increased conversion. The conversion in the step I of the current invention is more (>90%) as compared to the conversion reported in the prior art (75- 82 %).

2. The present invention discloses the novel, cost effective and simplified method for preparation of 4-Bromo-7H-pyrrolo[2,3-d] pyrimidine using HBr and acetic acid.

3. Both the reagents used in step iv of the reaction can be recovered and reused which reduces the quantity of reagents required and cost of production.

4. The current invention involves purification of final product 4-Bromo-7H-pyrrolo[2,3-d] pyrimidine compound having structural Formula I using water as solvent which makes this process eco-friendly and cost effective.

5. The current invention reduces the cost of production of intermediates which in turn reduces the cost of production of active pharmaceutical ingredients and formulation.