DESC:DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of amorphous Upadacitinib and also process for the preparation of Upadacitinib Oxalate salt and Upadacitinib di-p-toluoyl-L-tartarate salt.

Instrumentation Details:
Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns of said polymorphs of the present invention were measured on BRUKER D8 Discover powder diffractometer. The copper anode is used as radiation source with Lynx eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.03° step size and 0.4 seconds step time.

In one embodiment, Upadacitinib may be prepared by the processes known in the art such as US 8426411 and WO2017066775.

In one embodiment, the present invention provides an improved process for the preparation of amorphous upadacitinib comprising the steps of:
a) reacting upadacitinib with an organic acid;
b) optionally purifying the acid addition salt obtained in step a); and
c) converting the acid addition salt into an amorphous form of Upadacitinib.

Within the context of the present invention, upadacitinb is reacted with an organic acid. The reaction of upadacitinib with an organic acid is carried out in presence of an organic solvent. The suitable organic acid for the rection includes, but not limited to oxalic acid, di-p-toluoyl tartaric acid, acetic acid, lactic acid, salicylic acid, citric acid, succinic acid, maleic acid, fumaric acid, benzoic acid, methane sulfonic acid, tartaric acid, mandelic acid, ethane sulphonic acid. The suitable solvent for the reaction includes but not limited to ester solvents such as ethyl acetate, methyl acetate, butyl acetate, tert-butyl acetate, isopropyl acetate, n-butyl acetate, ketonic solvents such as acetone, methyl ethyl ketone, diethyl ketone; alcoholic solvents such as methanol, ethanol, propanol, iso propanol, butanol, or mixtures thereof.

In one embodiment, the reaction of Upadacitinib with an organic acid is carried out by stirring the mixture for 0.5-10 hrs, preferably 1-4 hrs; more preferably 2-3 hrs to isolate Upadacitinib organic acid addition salt.

The upadacitinib acid addition salt resulting from the above embodiment is optionally purified with suitable solvents or mixtures thereof by the processes known in general such as crystallization, solvent evaporation, solvent extraction or solvent-anti solvent method. The suitable solvent for the purification includes but not limited to ester solvents such as ethyl acetate, methyl acetate, butyl acetate, tert-butyl acetate, isopropyl acetate, n-butyl acetate, ketonic solvents such as acetone, methyl ethyl ketone, diethyl ketone; alcoholic solvents such as methanol, ethanol, propanol, iso propanol, butanol, or mixtures thereof.

Next, to the resulting acid addition salt is added a suitable solvent and a base; and the solid was further isolated as amorphous Upadacitinib. The suitable solvent includes polar solvents includes water, alcohols solvents such as methanol, ethanol, propanol, iso propanol, butanol or mixtures thereof. The pH of the resulting suspension is adjusted to 8-9.5; preferably 8.5-9 with base and stirred the reaction for 30 mins to 90 mins, preferably 60 mins at room temperature. The suitable base for the reaction includes, but not limited sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and lithium hydroxide.

In one more embodiment, the resulting Upadacitinib of the above embodiment may in a foamy residue; oily reside or in a solid form and it is further treated with suitable solvent or mixtures thereof to isolate an amorphous form of Upadacitinib. Suitable solvent for the reaction includes but not limited to alcoholic solvents such as methanol, ethanol, propanol, iso propanol, butanol, water and mixtures thereof, preferably mixture of ethanol and water.

In another embodiment, the above resulting Upadacitinib solution pH is adjusted to 7.5-11, preferably 8-11, more preferably 8-10 with suitable buffer or base to isolate amorphous Upadacitinib. The suitable buffer includes but not limited to potassium phosphate, sodium phosphate. The suitable base includes, but not limited to sodium bicarbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide. The isolation of amorphous Upadacitinib may be carried out by methods well known in the art, for example, by filtering the reaction mixture or solvent evaporation to yield a solid.

As per the process of the present invention, the resulting amorphous Upadacitinib is with the enhanced purity and yield.

In another embodiment, the present invention provides a process for the preparation of upadacitinib oxalate salt comprising the steps of:
a) reacting upadacitinib with oxalic acid; and
b) isolating upadacitinib oxalate salt.

Within the context of the present invention, Upadacitinb is reacted with an oxalic acid to isolate upadacitinib oxalate. The reaction of upadacitinib with oxalic acid is carried out in presence of an organic solvent. The suitable solvent for the reaction includes but not limited to ester solvents such as ethyl acetate, methyl acetate, butyl acetate, tert-butyl acetate, isopropyl acetate, n-butyl acetate, ketonic solvents such as acetone, methyl ethyl ketone, diethyl ketone; alcoholic solvents such as methanol, ethanol, propanol, iso propanol, butanol or mixtures thereof.
In one embodiment, the reaction of Upadacitinib with oxalic acid is carried out by stirring the mixture for 0.5-10 hrs, preferably 1-4 hrs; more preferably 2-3 hrs to isolate Upadacitinib oxalate salt.

The resulting upadacitinib oxalate salt is optionally purified and isolated. The isolation may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid. The solid may be further processed by drying to obtain upadacitinib oxalate salt.

In another object, the present invention provides a process for the preparation of upadacitinib di-p-toluoyl tartarate salt comprising the steps of:
a) reacting upadacitinib with di-p-toluoyl -L-tartaric acid; and
b) isolating upadacitinib di-p-toluoyl-L-tartarate salt.

Within the context of the present invention, upadacitinb is reacted with an di-p-toluoyl -L-tartaric acid to isolate upadacitinib di-p-toluoyl-L-tartarate salt. The reaction of upadacitinib with di-p-toluoyl -L-tartaric acid is carried out in presence of an organic solvent. The suitable solvent for the reaction includes but not limited to ester solvents such as ethyl acetate, methyl acetate, butyl acetate, tert-butyl acetate, isopropyl acetate, n-butyl acetate, ketonic solvents such as acetone, methyl ethyl ketone, diethyl ketone; alcoholic solvents such as methanol, ethanol, propanol, iso propanol, butanol or mixtures thereof.

In one embodiment, the reaction of Upadacitinib with di-p-toluoyl-L-tartaric acid is carried out by stirring the mixture for 0.5-10 hrs, preferably 1-4 hrs; more preferably 2-3 hrs to isolate Upadacitinib di-p-toluoyl-L-tartarate salt.

The resulting upadacitinib di-p-toluoyl-L-tartarate salt is optionally purified and isolated. The isolation may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid. The solid may be further processed by drying to obtain upadacitinib di-p-toluoyl-L-tartarate salt.

In one more embodiment, the present invention provides, Upadacitinib oxalate salt and Upadacitinib di-p-toluoyl-L-tartarate salt.
The salts obtained in the present invention can be further converted into a different polymorph of upadacitinib as per the processes known in the art.

The examples mentioned below explain various aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Examples:
Example 1: Preparation of amorphous upadacitinib.
To a solution of 10 g of upadacitinib in 60 ml of ethyl acetate was added a solution of 2.4 g anhydrous oxalic acid in 60 mL of ethyl acetate at room temperature and stir the reaction for 10 mins. The resulting suspension was stirred for additional two hours, filtered, and dried under vacuum to afford upadacitinib oxalate salt (~12 g). The upadacitinib oxalate salt was dissolved in 50 ml of water and adjusted the pH to 8.5-9.0 with 50 ml of 10% aqueous sodium hydroxide solution. The resulting suspension was stirred for about one hour at room temperature, filtered and dried at room temperature to 50 °C to afford amorphous Upadacitinib compound as white to light brown gray color solid.
Yield: 8.0 g.

Example 2: Preparation of amorphous upadacitinib:
To a solution of 1.0 g of upadacitinib in ethyl acetate was added (6 ml solution/suspension of 1.17 gm of Di-p-toluoyl -L-tartaric acid in 6 ml of ethyl acetate) at room temperature and stir the reaction for 10 mins. The resulting suspension was stirred for additional two hours, filtered, and dried under vacuum to afford upadacitinib Di-p-toluoyl -L-tartaric acid salt (~1.9 g). The upadacitinib Di-p-toluoyl -L-tartarate salt was suspended in 5.0 ml of water and adjusted the pH to 8.5-9.0 with sodium carbonate solution (~ 0.5 gm in 5.0 mol water). The resulting suspension was stirred for about one hour at room temperature, filtered, washed with 2 ml of water and dried at room temperature to 50 °C to afford amorphous Upadacitinib compound as white to light brown gray color solid.
Yield: 0.75 g.

Example 3: Preparation of amorphous upadacitinib
To a solution of 1.5 g of upadacitinib in 9 ml ethyl acetate was added a solution/suspension of 1.75 gm Di-p-Toluoyl -L-tartaric acid in 9 ml of ethyl acetate at room temperature and the reaction was stirred for 5-10 minutes. The resulting suspension was stirred for additional two hours, filtered, and dried under vacuum to afford upadacitinib Di-p-toluoyl -L-tartaric acid salt (~2.85 g).
The upadacitinib Di-p-toluoyl -L-tartarate salt (~2.85 gm) was suspended in 15.0 ml water and 15.0 ml of ethyl acetate at 25 -30 °C and reaction was cooled to 15- 20 °C and stirred for 10-15 minutes at 15- 20 °C. The pH of the reaction mass was adjusted to 8.5-11 by using 10 % aq. sodium hydroxide solution (~ 15 to 30 ml). The reaction mass was warmed to room temperature and stirred for ~half an hour. The reaction mass was allowed to settle for half an hour and then after ethyl acetate layer was separated. The aqueous layer was further extracted with 15.0 ml of ethyl acetate. Both the ethyl acetate layers were combined and charcolized using 100 mg activated carbon. The charcolized ethyl acetate layer was further distilled under reduced pressure to get foamy /oily residue (1.15 gm).
To the crude residue (1.15 gm) was charged 2.3 ml of ethanol and stirred for 15-30 minutes at 25- 30 °C to get a clear solution. Then after, at 25- 30 °C the clear solution was added through dropping funnel in 50 ml of water with stirring. Further pH of the reaction mass was adjusted between 8-10 using potassium phosphate (~50 -100 mg). After pH adjustment, the obtained slurry was further stirred for 2-3 hrs and product was filtered and washed with water (1.15 ml) and dried under vacuum at 25- 30 °C for 24 to 28 hrs to get 0.9 gm of amorphous Upadacitinib.

Example 4: Preparation of amorphous Upadacitinib :
To a solution of 1.0 g of upadacitinib in 6.0 ml of ethyl acetate was added a solution of 0.240 g anhydrous oxalic acid in 6 mL of ethyl acetate at room temperature and stirred for 10-15 minutes. The resulting suspension was stirred for additional two hours, filtered, and dried under vacuum to afford upadacitinib oxalate salt (~1.2 g).
The upadacitinib oxalate salt (~1.2 gm) was suspended in 12 ml of water and 12 ml of ethyl acetate at 25 -30 °C and the reaction was cooled to 15- 20 °C and stirred for 10-15 minutes. At the same temperature the pH of the reaction mass was adjusted to 8.5-11 by using 10 % aq. sodium hydroxide solution (~ 12 to 24 ml). The reaction mass was warmed to room temperature and stirred for ~half an hour. The reaction mass was allowed to settle for half an hour and then after, the ethyl acetate layer was separated. The aqueous layer was further extracted with 12 ml of ethyl acetate. Both ethyl acetate layers were combined and charcolized using 50 mg of activated carbon. The charcolized ethyl acetate layer was further distilled under reduced pressure to get foamy /oily residue (800 mg).
To the crude residue (800 mg) was charged 1.6 ml of ethanol and stirred for 15-30 minutes at 25- 30 °C to get a clear solution. Then after, at 25- 30 °C, the clear solution was added through dropping funnel in 40 ml of water with stirring. Further, the pH of the reaction mass was adjusted between 8-10 using potassium phosphate (~30 -75 mg). After the pH adjustment the obtained slurry was further stirred for 2-3 hrs and product was filtered and washed with water (0.800 ml). Product was dried under vacuum at 25- 30 °C for 24 to 28 hrs to get 700 mg of amorphous Upadacitinib.

,CLAIMS:We Claim:
1. A process for the preparation of amorphous upadacitinib comprising the steps of:
a) reacting upadacitinib with an organic acid;
b) optionally purifying the acid addition salt obtained in step a); and
c) converting the acid addition salt into an amorphous form of Upadacitinib.

2. The process as claimed in claim 1, where in the reaction of Upadacitinib with organic acid is carried out in presence of a suitable solvent or mixtures thereof.

3. The process as claimed in claim 2, where in the suitable solvent is ester solvent or alcoholic solvent or mixtures thereof.

4. The process as claimed in claim 3, wherein the ester solvent is selected from ethyl acetate, methyl acetate, butyl acetate, tert-butyl acetate, isopropyl acetate, n-butyl acetate, ketonic solvents such as acetone, methyl ethyl ketone, diethyl ketone; alcoholic solvent is selected from methanol, ethanol, propanol, iso propanol and butanol.

5. The process as claimed in claim 1, wherein the conversion of Upadacitinib acid addition salt into amorphous form is carried out by treating Upadacitinib acid addition salt with a base and solvent.

6. The process as claimed in claim 5, wherein the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and lithium hydroxide.

7. The process as claimed in claim 5, wherein the solvent is selected from alcohols solvents such as methanol, ethanol, propanol, iso propanol, butanol or mixtures thereof.

8. The process as claimed in claim 1, wherein the organic acid is oxalic acid, di-p-toluoyl tartaric acid, acetic acid, lactic acid, salicylic acid, citric acid, succinic acid, maleic acid, fumaric acid, benzoic acid, methane sulfonic acid, tartaric acid, mandelic acid and ethane sulphonic acid

9. A process for the preparation of upadacitinib oxalate salt comprising the steps of:
a) reacting upadacitinib with oxalic acid; and
b) isolating upadacitinib oxalate salt.
10. A process for the preparation of upadacitinib di-p-toluoyl tartarate salt comprising the steps of:
a) reacting upadacitinib with di-p-toluoyl -L-tartaric acid; and
b) isolating upadacitinib di-p-toluoyl-L-tartarate salt.