DESC:FIELD OF THE INVENTION

The present invention relates to improved process for the preparation of Upadacitinib by involving the use of pure intermediates.

Particularly, the present invention relates to process for the preparation of substantially pure intermediates and use in the preparation of Upadacitinib thereof.

BACKGROUND OF THE INVENTION
Janus kinase inhibitors, also known as JAK inhibitors or Jakinibs, are a type of medication that functions by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signalling pathway.

As per references known in the art, (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is a JAK1 selective inhibitor being investigated to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, psoriatic arthritis, axial SpA and Giant Cell Arteritis.

Upadacitinib having its chemical name (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is represented by structural Formula I,
.

US patent number 8,426,411 B2 discloses a general process of preparing Upadacitinib. Scheme-1 mentioned below illustrates the method of the preparation of Upadacitinib as disclosed in US’411.
Scheme-1:

PCT application number 2019/016745 A1, discloses a process of preparing upadacitnib of formula I by reacting pent-2-ynoic acid or its derivative thereof with an optically active sultam compound to obtain pent-2-enamide and cyclizing the pent-2-enamide compound followed by hydrolysis to obtain (3R,4S)-1-benzyl-4-ethylpyrrolidine-3-carboxylic acid.

PCT application number 2020/043033 A1, discloses process of preparing upadacitinib and its key intermediate. The process disclosed in this patent is depicted below under scheme-2.
Scheme 2:

Upadacitinib process is also disclosed in patent applications such as WO 2019/016745, WO 2021/005484 and CN 111217819 A1.

Although there are several processes known in the prior published references, however, there is remains a need for an improved process for the preparation of pure intermediates and its salt thereof, in a cost effective way.

OBJECT OF THE INVENTION
The main object of the present invention is to develop an improved process for the preparation of Upadacitinib by involving the use of substantially pure intermediates.

Another object of the present invention is to prepare substantially pure intermediates of Upadacitinib and purification thereof;

SUMMARY OF THE INVENTION
In main aspect, the present invention provides an improved process for the preparation of Upadacitinib by involving the use of substantially pure intermediates.

In another aspect, the present invention provides an improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) converting (3R,4S)-N-Protected-4-ethylpyrrolidine-3-carboxylic acid compound of Formula II or its salt to (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid of Formula III or its salt in presence of suitable solvent,
;
wherein, R is represented as COR2, wherein; R2 is either or OR6, wherein R6 is selected from hydrogen, substituted/unsubstituted C1-C4 alkyl, aralkyl, and aryl;
b) reacting compound of Formula III or its salt with 2,2,2-trifluoroethyl amine in presence of suitable base and solvent to give compound of Formula IV or its salt,
; and
c) converting compound of Formula IV or its salt to Upadacitinib.

In one another aspect, the present invention provides an improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) amidating (3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-carboxylic acid compound of Formula IV or its salt to give (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide of Formula V or its salt;
;
b) converting compound of Formula V or its salt to (3R, 4S)-3-(2-halooacetyl)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide compound of Formula VII or its salts,
;
wherein, X is halogen;
c) crystallizing compound of Formula VII or its salt in suitable solvent to give substantially pure compound of Formula VII or its salt; and
d) converting the substantially pure compound of Formula VII or its salt to Upadacitinib of Formula I.

In one another aspect, the present invention provides an improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) amidating (3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-carboxylic acid compound of Formula IV or its salt to give (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide of Formula V or its salt;
;
b) converting compound of Formula V or its salt to compound of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally purified in a suitable solvent;
;
c) halogenating compound of Formula VI or its salt to give (3R, 4S)-3-(2-halooacetyl)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide compound of Formula VII or its salts,
;
wherein, X is halogen;
d) crystallizing compound of Formula VII or its salt in suitable solvent to give substantially pure compound of Formula VII or its salt; and
e) converting the substantially pure compound of Formula VII or its salt to Upadacitinib of Formula I.

In another aspect, the present invention provides an improved process for the preparation of Upadacitinib, wherein said process comprising the steps of:
a) protecting 2-bromo-5H-pyrrolo[2,3-b]pyrazine of Formula VIII or its salt in suitable solvent to get N-protected compound of Formula IX,
;
wherein P1 is a suitable nitrogen protecting group;
b) converting compound of Formula IX to X or its salt in presence of suitable solvent,
;
wherein P1 and P2 independently represents suitable nitrogen protecting group;
c) crystallizing compound of Formula X or its salt in suitable solvent to give substantially pure compound of Formula X or its salt; and
d) converting the substantially pure compound of Formula X or its salt to Upadacitinib

DETAILED DESCRIPTION
Definitions:
The term “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, and organic bases such as dicyclohexyl amine, pyridine, trimethyl amine, diisopropyl amine, diisopropyl ethyl amine, and the like.

The term “suitable solvent” as used in present invention is selected from the group comprising of alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; formamides such as dimethyl formamide; acetamides such as dimethyl acetamide; pyrrolidines such as N-methyl pyrrolidine; morpholine; pyridine; sulfoxides such as dimethyl sulfoxide; carbonates; water; and mixtures thereof.

The term “substantially pure” as used in the context of the present invention refers to a purity of at least about 80%. In some embodiments, the purity of a compound of the present invention has a purity of at least about 85%, about 90%, about 95%, or about 99%. In a further embodiment, the purity of a compound of the present invention has a purity of at least about 99.5%, or about 99.8%. In an even further embodiment, the purity of a compound of the present invention has a purity of at least about 99.85%, about 99.90%, about 99.94%, about 99.95%, or about 99.99%.

In one embodiment, the present invention provides an improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) converting (3R,4S)-N-Protected-4-ethylpyrrolidine-3-carboxylic acid compound of Formula II or its salt to (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid of Formula III or its salt in presence of suitable solvent,
;
wherein, R is represented as COR2, wherein; R2 is either or OR6, wherein R6 is selected from hydrogen, substituted/unsubstituted C1-C4 alkyl, aralkyl, and aryl;
b) reacting compound of Formula III or its salt with 2,2,2-trifluoroethyl amine in presence of suitable base and solvent to give compound of Formula IV or its salt,
; and
c) converting compound of Formula IV or its salt to Upadacitinib of Formula I.

The starting material compound of formula II may be obtained by known processes known in literature.

R6 in compound of Formula II represents benzyl, o/m/p-methoxy benzyl, p-hydroxy benzyl, methyl, ethyl, propyl, iso-propyl, isobutyl, phenyl, anisole, hydrogen and the like.

The reaction of step a) involves converting compound of Formula II or its salt to compound of Formula III or its salt in presence of suitable solvent.

In an embodiment, compound of formula II in step a) is used in the form of its corresponding salt.

In a particular embodiment of step a), when compound of formula II is used as salt then the reaction mixture containing compound of formula II is first treated with an acid in presence of solvent to obtain compound of formula II as free base followed by deprotection in presence of solvent and deprotection agent to obtain compound of formula III.

In an embodiment, acid used in step a) is optionally selected from to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid; organic acids such as succinic acid, formic acids, acetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid. In a particular embodiment, acid used is orthophosphoric acid.

In an embodiment, deprotection agent is selected from Iron, noble metal catalyst such as Ruthenium (Ru), Rhodium (Rh), Palladium (Pd), Osmium (Os), Platinum (Pt), Silver (Ag) along with hydrogen source.

In an embodiment, the reaction mixture comprising compound of Formula III obtained after conversion is optionally distilled or taken forward for the next step.

The reaction of step b) involves reacting compound of Formula III or its salt with 2,2,2-trifluoroethyl amine in presence of suitable base to obtain compound of Formula IV or its salt thereof.

In an embodiment, wherein said base is selected from, but not limited to, lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide magnesium hydroxide and lithium tert-butoxide, phosphates such as potassium hydrogen phosphate, sodium phosphate, and mixture thereof. In a particular embodiment base used in step b) is potassium hydroxide, potassium hydrogen phosphate or its mixture.

It is observed that the use of base in combination with condensing agent drastically reduces the formation of side products.

In another embodiment, suitable coupling agent used for preparing compound of Formula IV is selected from the group consisting of carbonyldiimidazole (CDI), carbonyl-di(1,2,4-triazole), l-ethyl-3-(-3-dimethylamino propyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), 1,3-diisopropyl carbodiimide (DIC), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (WSC.HCl), and Hydroxybenzotriazole (HOBT). In a particular embodiment coupling agent used is CDI.

In one another embodiment, the intermediates of compound of Formula II to IV may be used/isolated in the form of their pharmaceutically acceptable salts wherein said salts are as defined above.

In another embodiment, the suitable solvent used for preparing compounds of Formula III and IV are selected from, but not limited to, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, acetonitrile, propionitrile, water, or mixtures thereof. Preferably the solvent is selected from, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, methanol, ethanol, isopropyl alcohol, butanol, t-butanol, or mixture thereof.

In another embodiment, condensation of compound of Formula III or its salt with 2,2,2-trifluoroethyl amine is carried out a temperature in the range of 0oC to reflux temperature of the solvent. Preferably, the reaction is carried out at a temperature in the range of 10oC to 45oC.

In an embodiment, the reaction mixture comprising compound of Formula IV obtained is optionally distilled or taken forward for the next step.

The reaction of step c) involves converting compound of Formula IV or its salt to Upadacitinib of Formula I.

In one another embodiment, the present invention provides an improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) amidating (3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-carboxylic acid compound of Formula IV or its salt to give (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide of Formula V or its salt;
;
b) converting compound of Formula V or its salt to (3R, 4S)-3-(2-halooacetyl)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide compound of Formula VII or its salts,
;
wherein, X is halogen;
c) crystallizing compound of Formula VII or its salt in suitable solvent to give substantially pure compound of Formula VII or its salt; and
d) converting the substantially pure compound of Formula VII or its salt to Upadacitinib of Formula I.

The reaction of step a) involves amidating (3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-carboxylic acid compound of Formula IV or its salt with N,O-Dimethylhydroxylamine HCl in presence of base, coupling agent and a solvent to give (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide of Formula V or its salt;

In another embodiment, base used is selected from, but not limited to, trimethyl amine, diisopropyl amine, diisopropyl ethyl amine, pyridine, dimethyl amino pyridine, aniline, ethylamine, n-butylamine, n-octylamine, n-dodecylamine, hexamethylenediamine, cyclohexylamine, benzylamine; dimethylamine, diethylamine, di-n-propylamine, dicyclohexylamine, pyrrolidine, piperidine, piperazine, morpholine, tri-n-butylamine, N-methyl pyrrolidine, N-methylmorpholine, 1,4-diazabicyclo[;2.2.2];-octane, toluidine, naphthylamine, N-methylaniline, diphenylamine and N,N-diethylaniline, picoline, indoline, quinolone, and the like. In a particular embodiment base used is dimethyl amino pyridine.

In another embodiment, the suitable solvent used for preparing compounds of Formula V or its salt and for conversion of compound of Formula V or its salt to VII or its salt is selected from, but not limited to, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, acetonitrile, propionitrile, xylene, toluene, anisole, water, or mixtures thereof. Preferably the solvent is selected from, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, or mixture thereof.

In another embodiment, suitable coupling agent used is selected from the group consisting of carbonyldiimidazole (CDI), carbonyl-di(1,2,4-triazole), l-ethyl-3-(-3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), dicyclohexylcarbodiimide (DCC), 1,3-diisopropyl carbodiimide (DIC), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (WSC.HCl), and Hydroxybenzotriazole (HOBT). In an particular embodiment coupling agent used is EDC.HCl.

In another embodiment, the process of amidation of compound of Formula IV or its salt is carried out at a temperature in the range of 0oC to reflux temperature of the solvent. Preferably, the reaction is carried out at a temperature in the range of 10oC to 45oC.

In one another embodiment, the present invention provides an improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) amidating (3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-carboxylic acid compound of Formula IV or its salt to give (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide of Formula V or its salt;
;
b) converting compound of Formula V or its salt to compound of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally purified in a suitable solvent;
;
c) halogenating compound of Formula VI or its salt to give (3R, 4S)-3-(2-halooacetyl)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide compound of Formula VII or its salts,
;
wherein, X is halogen;
d) crystallizing compound of Formula VII or its salt in suitable solvent to give substantially pure compound of Formula VII or its salt; and
e) converting the substantially pure compound of Formula VII or its salt to Upadacitinib of Formula I.

In another embodiment, the halogenation of compound of Formula V, or VI is performed in presence of a halogen source and an alcoholic solvent. Preferably, the halogenation is performed in presence of bromine source wherein said brominating agent is selected from N-bromosuccinimide or elemental bromine.

In one another embodiment, the intermediates of compound of Formula IV to VII may be used/isolated in the form of their pharmaceutically acceptable salts wherein said salts are as defined above.

In another embodiment, the conversion of compound of V or its salt to compound of Formula VI or its salt is carried out in presence of Grignard reagent selected from one of methyl magnesium chloride, methyl magnesium bromide, and methyl magnesium iodide; and wherein said Grignard reaction is carried out at a temperature of -10oC to 50oC, preferably at 0oC to 35oC.

In another embodiment, the suitable solvent used for crystallizing compound of Formula VII or its salt is selected from, but not limited to, tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, methyl ethyl ether, 1,4-dioxane, methyl-tetrahydrofuran, ethyl acetate, butyl acetate, n-propyl acetate, and mixture thereof.

In another embodiment, the present invention provides a process for the preparation of Upadacitinib, wherein said process comprising the steps of:
a) protecting 2-bromo-5H-pyrrolo[2,3-b]pyrazine of Formula VIII or its salt in suitable solvent to get N-protected compound of Formula IX,
;
wherein P1 is a suitable nitrogen protecting group;
b) converting compound of Formula IX to X or its salt in presence of suitable solvent,
;
wherein P1 and P2 independently represents suitable nitrogen protecting group;
c) crystallizing compound of Formula X or its salt in suitable solvent to give substantially pure compound of Formula X or its salt; and
d) converting the substantially pure compound of Formula X or its salt to Upadacitinib.

In another embodiment, compound of Formula X or its salt is crystallized in a suitable solvent such as diisopropyl ether, methyl t-butyl ether, methyl ethyl ether, 1,4-dioxane, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or mixture thereof.

In another embodiment, the suitable protecting groups P1 and P2 are independently represents acetyl, Di-tert-butyl dicarbonate, Fmoc (9ß-fluorenylmethoxycarbonyl), benzyloxycarbonyl, benzyl, and the like.

In preferred embodiment, P1 in compound of Formula IX represents acetyl and acetylation of compound of Formula VIII is carried out in presence of suitable acetylating agent such as acetic anhydride, or acetic acid, at a temperature in the range of 0oC to reflux temperature of the solvent.

In one another embodiment, the intermediates of compound of Formula VIII and X, may be used/isolated in the form of their pharmaceutically acceptable salts wherein said salts are selected from, but not limited to, hydrochloride salt, hydrobromide salt, sulphate salt, phosphate salt, succinate salt, formate salt, acetate salt, propionate salt, butyrate salt, lactate salt, citrate salt, tartarate salt, maleate salt, adipic acid salt, aspartate salt, fumarate salt, benzoate salt, p-chlorobenzoate salt, dibenzoyl tartarate salt, and oxalate salt.

In another embodiment, the suitable solvent used for preparing compound of Formula X or its salt from compound of Formula VIII or its salt is selected from, but not limited to, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, acetonitrile, propionitrile, water, xylene, toluene, anisole, or mixtures thereof. Preferably the solvent is selected from, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, toluene, or mixture thereof.

In another embodiment, the present invention provides a process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) reacting compound of Formula VII or its salt with compound of Formula X or its salt in presence of suitable solvent to give compound of Formula XI or its salt,
;
wherein X represent halogen, and P1 and P2 independently represents suitable nitrogen protecting group;
b) crystallizing compound of Formula XI or its salt in suitable solvent to give substantially pure compound of Formula XI or its salt;
c) in-situ converting substantially pure compound of Formula XI or its salt to compound of Formula XII or its salt in presence of suitable reagent without isolation of intermediates;
;
wherein P1 is as defined above;
d) converting compound of Formula XII or its salt to Upadacitinib of Formula I; and
e) optionally purifying Upadacitinib of Formula I.

In another embodiment, the suitable protecting groups P1 and P2 are independently represents acetyl, di-tert-butyl dicarbonate, Fmoc (9ß-fluorenylmethoxycarbonyl), benzyloxycarbonyl, benzyl, and the like.

In another embodiment, the condensation of compound of Formula VII to X is carried out in presence of suitable base, wherein said base is selected from, but not limited to, lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide magnesium hydroxide and lithium tert-butoxide, phosphates such as potassium hydrogen phosphate, sodium phosphate, and mixture thereof. Further, said condensation is carried out in presence of suitable solvent selected from the group comprising of alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; formamides such as dimethyl formamide; acetamides such as dimethyl acetamide; pyrrolidines such as N-methyl pyrrolidine; morpholine; pyridine; sulfoxides such as dimethyl sulfoxide; carbonates; water; and mixtures thereof. Preferably, the solvent is aprotic polar solvent such as dimethyl acetamide, dimethyl formamide, and N-methyl pyrrolidine.

In another embodiment, compound of Formula XI or its salt is crystallized in a solvent selected from, but not limited to, diisopropyl ether, methyl t-butyl ether, methyl ethyl ether, 1,4-dioxane, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate; acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone and mixture thereof.

In another embodiment, in-situ deprotection and cyclization of compound of Formula XI or its salt is carried out in presence of trifluoroacetic acid or trifluoro acetic anhydride at a temperature in the range of 20oC-120oC, preferably at a temperature of 40-100oC.

In a preferred embodiment, the in-situ reaction is performed in a suitable solvent selected from methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, anisole, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, toluene, acetonitrile, prioionitrile, butanenitrile, water, or mixture thereof.

In another embodiment, the present invention provides process for the purification of Upadacitinib comprising the steps of:
a) preparing a solution of Upadacitinib in a suitable solvent;
b) adding the solution of step a) to chilled water; and
c) isolating the crystals of step b) to get pure Upadacitinib.

In one another embodiment, the Upadacitinib and its pharmaceutically acceptable salt prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%.

EXAMPLES
Example 1: Synthesis of compound of Formula IX (P1 is acetyl)
Charged tetrahydrofuran (170ml), 2-bromo-5H-pyrrolo[2,3-b]pyrazine (17.0 g), triethylamine (30 ml) and acetic anhydride (14 g) in a three-neck 500ml RBF. Stirred 4-5 hrs at room temperature. After completion of reaction, distilled out the organic layer and degassed at 40-45ºC. Added 140 ml saturated sodium bicarbonate solution in the distilled mass, stirred, filtered and washed with 35ml DM water. Dried the material to get 19.0g of the desired compound.
Example 2: Synthesis of compound of Formula X (P1 is acetyl and P2 is Boc)
Charged 5-acetyl-2-bromo-5H-pyrrolo[2,3-b]pyrazine (19.0 g), 190 ml toluene, tert-butyl carbamate (18.5 g,), potassium carbonate (21.5 g,), palladium acetate (0.53g,) and 9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene (Xantphos) (2.73 g) in a three-neck RBF and stirred overnight under reflux. Cooled to room temperature and added water and ethyl acetate. Separated the layers Distilled out the organic layer and degassed at 40-45ºC. Charged 190.0 ml of MTBE (methyl tert. butyl ether) and stirred at 40-45ºC for 1-2 hrs. Filtered the undesired solid so formed and distilled out the mother liquor. Charged 40.0 ml of methanol to the distilled mass and stirred for 1-2 hrs at 20-25ºC. Filtered the solid and washed the solid so obtained with 10.0ml methanol. Dried in hot air oven at 40-45ºC for 10-12hr to get 15.0g of desired compound.
Example 3: Synthesis of Compound of Formula III
Charged DCHA salt of (3R,4S)-1-[(benzyloxy)carbonyl]-4-ethylpyrrolidine-3-carboxylic acid (85.0 g), 10% orthophosphoric acid solution to methyl tert butyl ether (MTBE). Stirred and distilled the solvents. Charged free base of (3R,4S)-1-[(benzyloxy)carbonyl]-4-ethylpyrrolidine-3-carboxylic acid (50.0 g) so obtained in methanol (500.0ml) and added Pd/C (3.0 g) in a autoclave. Flushed with nitrogen two times and filled the hydrogen gas up to 5 Kg pressure. Raised the temperature up to 50-55ºC. Stirred the reaction mass for 4-5 hours. After completion of reaction cooled the reaction mass and released the hydrogen pressure. Filtered through Celite bed and distilled out the filtrate under vacuum at 50-55ºC to get 15.0g of desired compound.

Alternately, Charged dibenzylamine salt of (3R,4S)-1-[(benzyloxy)carbonyl]-4-ethylpyrrolidine-3-carboxylic acid (85.0 g), 10% orthophosphoric acid solution to methyl tert butyl ether (MTBE). Stirred and distilled the solvents. Charged free base of (3R,4S)-1-[(benzyloxy)carbonyl]-4-ethylpyrrolidine-3-carboxylic acid (50.0 g) so obtained in methanol (500.0ml) and added Pd/C (3.0 g) in a autoclave. Flushed with nitrogen two times and filled the hydrogen gas up to 5 Kg pressure. Raised the temperature up to 50-55ºC. Stirred the reaction mass for 4-5 hours. After completion of reaction cooled the reaction mass and released the hydrogen pressure. Filtered through Celite bed and distilled out the filtrate under vacuum at 50-55ºC to get 15.0g of desired compound.
Example 4: Synthesis of Compound of Formula IV
Charged (3R,4S)-4-ethylpyrrolidine-3-carboxylate (15.0g), tetrahydrofuran (150.0ml), DM water (75.0ml), KOH (5.9g), and K2HPO4 (20.58g) in 250 ml four neck round bottom flask. Prepared a solution of 50.0 ml tetrahydrofuran and 1,1'-Carbonyldiimidazole (34.0 g) and 2,2,2-trifluoroethyl amine (21.0 g) in another 50ml four neck round bottom flask at 20-25ºC. Charged this later solution at 20-25ºC to former mixture. Stirred the reaction mixture so obtained at 4-5 hours at 20-25ºC. After completion of reaction, the reaction was quenched with 20% citric acid solution (50.0ml). Stirred the reaction mass for 1 hour. Compound was extracted with 50.0 ml ethyl acetate at 20-25ºC. Separated the organic layer at 20-25ºC. Washed the organic layer with 50.0 ml brine solution at 20-25ºC. Separated the organic layer at 20-25ºC. Distilled out the organic layer under vacuum at 50-55ºC to get 28.0g of desired compound.
Example 5: Synthesis of Compound of Formula V
Charged dichloromethane (280.0 ml), tetrahydrofuran (84ml), (3R,4S)-4-ethyl-1-[(trifluoro methyl)carbamoyl]pyrrolidine-3-carboxylic acid (28.0 g), EDC.HCl (25.0g), DMAP (39.0 g) and N,O-Dimethylhydroxylamine HCl (17.0 g) sequentially in a 500ml four neck RBF at 20-25ºC. Stirred the reaction mass for 2-3 hours at 20-25ºC. Charged 160.0 ml of DM water followed by stirring for 15 minute at 20-25ºC. Separated the layers and distilled out the organic layer at 40-45ºC to get 32.0 g of desired compound.
Example 6: Synthesis of compound of Formula VI
Charged tetrahydrofuran (160.0 ml) and (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide (32.0 g) in a 1000ml four neck RBF at 20-25ºC under nitrogen atmosphere. Cooled at 0-5ºC and slowly added methyl magnesium bromide in THF (1.5M) (0.5 Litre) at 0-5ºC. Stirred the reaction mass for 1 hour at 20-25ºC under nitrogen atmosphere. Charged saturated ammonium chloride solution (320ml), and ethyl acetate (160.0ml) at 20-25ºC. Stirred the reaction mass for 10-15minute at 20-25ºC. Separated the layers and distilled out the organic layer. Charged 100.0 ml of diisopropyl ether to the distilled mass and heated to 40-45ºC for 20 minute. Cooled the reaction mass to 20-25ºC and stirred for 14 hrs at 20-25ºC. Filtered and washed with 15.0 ml diisopropyl ether. Suck dried properly to get 23.2 g of desired compound.
Example 7: Synthesis of Compound of Formula VII (X is Br)
Charged (3R,4S)-3-acetyl-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (23.0 g), methanol (230.0ml) and bromine (24.7 g) at 15-25ºC. Allowed the temperature to come at 20-25ºC. Stirred for 4-5 hours at said temperature. Cooled the reaction mass to 0-5ºC. Charged saturated sodium metabisulphite solution (50.0 ml) at 0-5ºC followed by addition of (23ml) ethyl acetate. Stirred and separated the layer at 20-25ºC. Distilled the organic layer at 40-45ºC and degassed. Charged 180.0 ml of 2% ethylacetate in diisopropyl ether in the above distilled mass and heated to 55-60ºC. Stirred for 5-10 minutes at 55-60ºC. Cooled to 20-25ºC and stirred it for 10-12 hrs at 20-25ºC. Further cooled to 0-5ºC and stirred it for 2 hrs. Filtered the solid and washed with pre-chilled 20.0 ml 2% ethylacetate in diisopropyl ether. Dried the material so obtained to get 18.0 g of desired compound.
Example 8: Synthesis of Compound of Formula XI ((P1 is acetyl and P2 is Boc)
Charged compound of Formula X (P1 is acetyl and P2 is Boc) (15.0 g), dimethyl acetamide (50.0 ml), KI (3.0) and potassium carbonate (25.0g) at 20-25ºC. Stirred for 60-120 minute at 20-25ºC. Charged solution of compound of Formula VII (X is Br) (17.0 g) in dimethyl acetamide (50.0 ml) at 20-25ºC to the above solution and stirred for 5-6 hrs at 20-25ºC. After completion of reaction added acetic acid (15.0ml) to the reaction mass. The reaction mass so obtained is added to DM water (150.0 ml) and filtered. Charged 300.0 ml of MTBE to the above filtered solid in the RBF under stirring. Separated the layers and washed the organic layer with DM water (150.0ml) two times. Separated the layers and washed the organic layer with 150.0 ml of brine solution. Distilled the organic layer with 40-45ºC. Added 75.0 ml of ethyl acetate to the above distilled mass. Heated it to 65-70ºC under stirring. Added diisopropyl ether (90.0 ml) to the mass at 65-70ºC. Allowed to temperature of the reaction mass to reduce to 20-25ºC and stirred for 20 hrs at 20-25ºC. Filtered the solids so obtained and washed the solids with 30.0 ml Diisopropyl ether. Dried the solids to get 23.2 g of desired compound.
Example 9: Synthesis of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Upadacitinib) of Formula I
Charged acetonitrile (75.0ml) to compound of Formula XI ((P1 is acetyl and P2 is Boc) (15.0 g) followed by addition of Trifluoro acetic anhydride (22.5 g) in 250 ml RBF at 20-25ºC. Stirred for 15-20 hours at 60-100ºC. After completion of reaction, distilled out the solvents from the reaction mass. Charged 150 ml of ethyl acetate and 75.0 ml DM water to the mass so obtained. Stirred and separated the layers. Distilled the organic layer at 40-45ºC to get a distilled crude mass.
Charged 1,4-dioxan (75.0ml), DM water (8.0ml) and sodium hydroxide (6.0 g) at 20-25ºC to the distilled crude mass. Heated to 50-60ºC for 3-4 hours. Cooled to 20-25ºC and extracted the compound with 75.0 ml ethyl acetate at 20-25ºC. Separated the organic layer at 20-25ºC. Added 10% phosphoric acid solution to the organic layer. Separated the layers. Again added saturated sodium carbonate solution to the aqueous layer so obtained followed by addition of 150 ml of ethyl acetate to the aqueous layer. Stirred and separate the layers. Distilled out the organic layer under vacuum at 50-55ºC. Charged 180.0 ml of DM water to the 250.0 ml four neck RBF and cooled to 0-5ºC. Meanwhile prepared a solution of above distilled mass and 22.0 ml ethanol. Charge this solution to above chilled water. Stirred it for 1-2 hrs at 0-5ºC. Filtered and dried. Charged filtered material in RBF and added 45.0 ml DM water. Stirred it for 1 hrs at 20-25ºC. Filter and washed with 45.0 ml of DM water. Dried under vacuum at 20-25ºC to get 7.0 g of desired compound.

CLAIMS:

We Claim:

1. An improved process for the preparation of Upadacitinib of Formula I,

wherein said process comprising the steps of:
a) converting (3R,4S)-N-Protected-4-ethylpyrrolidine-3-carboxylic acid compound of Formula II or its salt to (3R,4S)-4-ethylpyrrolidine-3-carboxylic acid of Formula III or its salt in presence of suitable solvent,
;
wherein, R is represented as COR2, wherein; R2 is either or OR6, wherein R6 is selected from hydrogen, substituted/unsubstituted C1-C4 alkyl, aralkyl, and aryl;
b) reacting compound of Formula III or its salt with 2,2,2-trifluoroethyl amine in presence of suitable base and solvent to give compound of Formula IV or its salt,
; and
c) converting compound of Formula IV or its salt to Upadacitinib.

2. The process as claimed in claim 1, wherein said process further comprising the steps of:
a) amidating (3R,4S)-4-ethyl-1-((2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-3-carboxylic acid compound of Formula IV or its salt to give (3R,4S)-4-ethyl-N3-methoxy-N3-methyl-N1-(2,2,2-trifluoroethyl)pyrrolidine-1,3-dicarboxamide of Formula V or its salt;
;
b) converting compound of Formula V or its salt to compound of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally purified in a suitable solvent;
;
c) halogenating compound of Formula VI or its salt to give (3R, 4S)-3-(2-halooacetyl)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide compound of Formula VII or its salts,
;
wherein, X is halogen;
d) crystallizing compound of Formula VII or its salt in suitable solvent to give substantially pure compound of Formula VII or its salt; and
e) converting the substantially pure compound of Formula VII or its salt to Upadacitinib of Formula I.

3. The process as claimed in claim 1, wherein said base used in step b) is selected from lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate magnesium carbonate, sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate, magnesium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide magnesium hydroxide, lithium tert-butoxide, potassium hydrogen phosphate, sodium phosphate, and mixture thereof.

4. The process as claimed in claim 1, wherein formation of compound of formula IV in step b) is carried out in presence of suitable coupling agent selected from carbonyldiimidazole (CDI), carbonyl-di(1,2,4-triazole), l-ethyl-3-(-3-dimethylamino propyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), 1,3-diisopropyl carbodiimide (DIC), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (WSC.HCl), and Hydroxybenzotriazole (HOBT).

5. The process as claimed in claim 2, wherein said suitable solvent used in step d) is selected from tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, methyl ethyl ether, 1,4-dioxane, methyl-tetrahydrofuran, ethyl acetate, butyl acetate, n-propyl acetate, and mixture thereof.

6. A process for the preparation of Upadacitinib, wherein said process comprising the steps of:
a) protecting 2-bromo-5H-pyrrolo[2,3-b]pyrazine of Formula VIII or its salt in suitable solvent to get N-protected compound of Formula IX,
;
wherein P1 is a suitable nitrogen protecting group;
b) converting compound of Formula IX to X or its salt in presence of suitable solvent,
;
wherein P1 and P2 independently represents suitable nitrogen protecting group;
c) crystallizing compound of Formula X or its salt in suitable solvent to give substantially pure compound of Formula X or its salt; and
d) converting the substantially pure compound of Formula X or its salt to Upadacitinib.
7. The process as claimed in claim 6, wherein said suitable nitrogen protecting group P1 and P2 are independently selected from acetyl, Di-tert-butyl dicarbonate, Fmoc (9ß-fluorenylmethoxycarbonyl), benzyloxycarbonyl, and benzyl.

8. The process as claimed in claim 6, wherein said process further comprising the steps of:
a) reacting compound of Formula VII or its salt with compound of Formula X or its salt in presence of suitable solvent to give compound of Formula XI or its salt,
;
wherein X represent halogen, and P1 and P2 are as defined in claim 7;
b) crystallizing compound of Formula XI or its salt in suitable solvent to give substantially pure compound of Formula XI or its salt;
c) in-situ converting substantially pure compound of Formula XI or its salt to compound of Formula XII or its salt in presence of suitable reagent without isolation of intermediates;
;
wherein P1 is as defined in claim 7; and
d) converting compound of Formula XII or its salt to Upadacitinib.

9. The process as claimed in claim 8, wherein said suitable solvent used in step b) is selected from diisopropyl ether, methyl t-butyl ether, methyl ethyl ether, 1,4-dioxane, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate; acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone and mixture thereof.

10. The process as claimed in claim 8, wherein said suitable reagent used in step c) is selected from trifluoroacetic acid and trifluoro acetic anhydride.