DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202041009529 filed on Mar 05, 2020.
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of novel intermediates, which are key’s in the synthesis of Upadacitinib.

BACKGROUND OF THE INVENTION:
Upadacitinib, having a chemical name: (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- l-carboxamide and structure as below.

Upadacitinib is a JAK1-selective inhibitor in development for the treatment of adult patients with moderate to severe rheumatoid arthritis and it is developed by AbbVie. Upadacitinib, also known as ABT-494.

Upadacitinib is known in US 8426411 B2, it also discloses the synthetic preparation of Upadacitinib in a general route as mentioned in Scheme-II.

The present invention provides an improved process for preparing Upadacitinib by using novel intermediates.

OBJECT AND SUMMARY OF THE INVENTION.
The principle object of the present invention is to provide an improved process for the preparation of upadacitinib.

In one object, present invention provides an improved process for the preparation of novel intermediate of formula VI comprising the steps of:

a) reacting formula II with formula III to give formula IV;

b) condensing formula IV with formula V in presence of an inorganic base to give formula VI.

In another object, present invention provides novel intermediates of formula IV and VI, wherein the amine protecting group “Pg” is tosyl group and “R” is H.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Upadacitinib.

The present invention also provides a novel intermediates of formula IV and formula VI and process for the preparation of the same, which are key intermediates in the preparation of Upadacitinib.

In one embodiment, the present invention provides an improved process for the preparation of novel intermediate of formula VI comprising the steps of:

a) reacting formula II with formula III to give formula IV;

b) condensing formula IV with formula V in presence of an inorganic base to give formula VI.

Within the context of the reactions depicted and disclosed herein “Pg” is an amine protecting group and “X” is halogen include -F, -CI, -Br, and –I.
“R” is hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, heteroaryl, heterocycyl, alkoxy groups.
Amine protecting groups (“Pg”) are well known to those skilled in the art. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting can be found in prior art, such as J.F.W. McOmie (Ed.), Protective Groups in Organic Chemistry, Plenum Press, London (1973) and Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter G. M. Wuts, John Wiley & Sons, Inc., Hoboken, New Jersey (2014), which are incorporated herein by reference in their entirety. For example, suitable protecting groups include, but are not limited to, carbonyls (e.g., benzyloxy carbonyl; methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), tert-butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses),

tert-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), benzoyl (Bz), or 2-nitrophenylsulfenyl (Nps) groups. In some embodiments.
According to the present invention, formula II is reacted with formula III in presence of a catalyst and ligand in a suitable solvent to give formula IV. The suitable catalysts include, but not limited to palladium acetate, Pd(PPh3)4, Pd(dppf)Cl2, Pd(dba)2, Pd2(dba)3 and ligand include but not limited to xantophos, (S)-BINAP, (R)-(S)-Josiphos. The suitable solvent for the reaction selected from toluene, xylene, dimethyl formamide dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone and dimethyl acetamide; preferably toluene.
Next, the resulting formula IV is further condensed with formula V in presence of an inorganic base and solvent to give formula VI. An inorganic base includes but not limited to potassium carbonate, sodium carbonate, calcium carbonate, barium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, caesium carbonate, sodium bicarbonate; preferably potassium carbonate. The suitable solvent for the condensation includes, but not limited to dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone and dimethyl acetamide; preferably dimethyl formamide.
The above resulting formula VI is 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 an acid addition salt of formula VI.
As per the present invention, the use of inorganic base in the condensation of formula IV and formula V in the process of formula VI increases the rate of reaction conversion more than 99% which certainly results into higher yields and higher purity.
Yet another embodiment, the resulting formula VI may be further converted into upadacitinib by following procedures known in the literature.
In one more embodiment, the present invention provides novel intermediates of formula IV and formula VI, wherein the amine protecting group “Pg” is tosyl group, “R” is H.

In one more embodiment, the novel intermediates of formula IV and formula VI may be further converted into upadacitinib.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Examples:
Example 1- Preparation of formula II:
To the 300 ml (2.0 vol) of ammonia solution, 1.5 g (0.01 w/w) of tetra butyl ammonium bromide and 150.0 g (0.88 moles, 1.0 eq) of benzyl chloroformate was added at 15±5 °C. The contents were warmed to ambient temperature and allowed to stir for about 2 hours. After completion of the reaction, the reaction mass was cooled to 15±5 °C and charged 50.0 g of sodium bicarbonate (0.33 w/w) and continued stirring for additional one hour at the same temperature. The resulting formula II was isolated by filtration and dried at 35±5 °C for 4 hours.
Yield: 80.0 g (60% on theory).
Example 2- Preparation of formula IV:

A suspension of 10.0 g (0.028 moles, 1.0 eq) of formula III, 4.29 g of ( 0.028 moles, 1.0 eq) formula II and 11.75 g of (0.085 moles, 3.0 eq.) potassium carbonate in 100 ml of (10.0 vol) toluene was degassed with

argon for about 30 minutes and was added 0.10 g (0.01 w/w) of palladium acetate followed by 0.32 g (0.032 w/w) of xantphos. The argon purging was continued for additional 15 minutes and then raised the reaction mass temperature to 100±5 °C. The reaction mass was stirred for about 4 hours at the same temperature under argon atmosphere. After completion of reaction, the reaction mass was cooled to ambient temperature and the undissolved catalysts were separated by filtration. The filtrate was concentrated under vacuum and the crude product was isolated by filtration to get the pure product formula IV as light yellow solid.
Yield: 8.0 g (67% on theory).
Example 3-Preparation of Formula VI:

To a solution of 30.0 g (0.071 moles, 1.0 eq.) of formula IV in 120 ml (, 4.0 vol.) of dimethyl formamide was added 58.83 g (0.43 moles, 6.0 eq) of potassium carbonate and the reaction mass was stirred at ambient temperature for about 4 hours. A solution of 42.76 g (0.11 moles, 1.5 eq) of formula V in 90.0 ml (3.0 vol.) of dimethyl formamide was added at ambient temperature and stirring was continued for additional 2 hours. After completion of the reaction, 450 ml (15 vol) of water was added and the reaction mass was extracted with ethyl acetate thrice (3 X 150 ml). The organic layer was washed with water twice (2 X 100 ml) and concentrated under vacuum to obtain crude product. The crude product was taken in 450 ml of methanol, stirred at 55±5 °C, cooled to room temperature and filtered to get the pure product formula VI as a light brown solid.
Yield: 42.0 g (85% on theory)
Example 4-Preparation of formula VII:

To a solution of 10.0 g (0.0144 moles, 1.0 eq) of formula VI and 9.68 g (0.122 moles, 8.5 eq.) pyridine in 50 ml (5.0 vol) of tetrahydrofuran was added 38.68 g (0.184 moles, 12.75 eq) of trifluoroacetic anhydride at room temperature. The reaction mass was stirred at room temperature for one hour, and at 55±5 °C for 10 hours. After completion of the reaction, the solvents were removed under vacuum and the crude was charged 50 ml of 2-Methyl tetrahydrofuran and 50 ml of 20% aqueous sodium hydroxide solution. The resulting biphasic mixture was heated to about 50 °C and stirred for about 12 hours. The reaction mixture was cooled to room temperature, layers were separated. The organic layers were concentrated under vacuum to afford the crude formula VII as an oil.
Yield: 4.0 g (71% on theory)
Example 5- Preparation of Formula VIII:

A solution of 1.4 g (0.0036 moles, 1.0 eq.) of formula VII in 15 ml (10.0 vol) ethanol in an Autoclave flask was charged 0.25 g (0.018 w/w) of 20% palladium hydroxide on carbon and stirred at 50 °C under 2.0 kg of hydrogen pressure for 15 hours. After completion of the reaction, the reaction mass was cooled to room temperature, filtered on Hyflo bed. To the filtrate, 0.5 ml of Con.HCl was added and concentrated under vacuum to get the crude product as solid. The solid was slurried in 15 ml of ethyl acetate and filtered to afford formula VIII as a solid.
Yield: 1.0 g.
Example 6- Preparation of Upadacitinib:

To a suspension of 0.68 g (0.0042 moles, 1.4 eq.) of carbonyldiimidazole in 6.0 ml of tetrahydrofuran was added 0.45 g (0.0045 moles, 1.5 eq.) of 2,2,2-Trifluoroethylamine slowly at 10 °C. After addition, the reaction mass turned clear and the solution was stirred for additional 60 minutes at the same temperature.
In another RBF, to a biphasic mixture of 1.0 g (0.003 moles, 1.0 eq) of formula VIII; 6 ml of tetrahydrofuran; 0.57 g (0.0033 moles, 1.1 eq) of potassium phosphate dibasic and 3 ml of water, was added 10% aqueous potassium hydroxide solution at room temperature and pH was adjusted to 9. The above prepared imidazolide solution was added and the resulting reaction mass was stirred at room temperature for about 60 minutes by maintaining the pH at 9 with the help of 10% aqueous potassium hydroxide solution. After completion of the reaction, the reaction mass was quenched with 6 ml of 20% aqueous citric acid, stirred for 60 minutes and the product was extracted into 20 ml of ethyl acetate. The organic layer was washed with 10% aqueous K2HPO4, followed by 20 ml of brine and concentrated under vacuum to get the crude Upadacitinib. The crude upadacitinib was isolated by filtration from ethyl acetate.
Yield: 0.30 g.
,CLAIMS:1. A process for the preparation of novel intermediate of formula VI by condensing formula IV with formula V in presence of an inorganic base to give formula VI.


2. The process as claimed in claim 1, wherein the inorganic base is potassium carbonate, sodium carbonate, calcium carbonate, barium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, caesium carbonate and sodium bicarbonate.

3. The process as claimed in claim 2, wherein the inorganic base is potassium carbonate.

4. The process as claimed in claim 1, wherein the formula IV is prepared by reacting formula II with formula III.

5. The process as claimed in claim 4, wherein the formula II is reacted with formula III in presence of a catalyst and ligand.

6. The process as claimed in claim 5, wherein the catalyst is palladium acetate, Pd(PPh3)4, Pd(dppf)Cl2, Pd(dba)2, Pd2(dba)3 and the ligand is xantophos, (S)-BINAP and (R)-(S)-Josiphos.

7. The process as claimed in claim 1 and 4, wherein the Pg” is tosyl group and “R” is H.

8. The process as claimed in claim 1, the formula VI may further converted into Upadacitinib.

9. The compounds of formula IV and VI.

10. The compounds as claimed in claim 9, may further converted into Upadacitinib.