DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202041036379 filed on Aug 24, 2020.
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Upadacitinib Intermediate.

BACKGROUND ART:
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 approved under brand name RINVOQ. RINVOQ is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

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 intermediate by using novel process.

OBJECT AND SUMMARY OF THE INVENTION.

The main object of the present invention is to provide a process for the preparation of Upadacitinib intermediate using novel process.

In one object, the present invention provides an improved process for the preparation of Formula-II comprising the steps of:

a) reacting Formula-B with Grignard reagent ethyl magnesium halide in presence of an Iron catalyst; and

wherein P1 is an amine protecting group; P2 is a hydroxy protecting group; R1 is an alkyl group.
b) isolating formula II.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Upadacitinib intermediate.
In one embodiment, the present invention provides an improved process for the preparation of Formula-II comprising the steps of:

a) reacting Formula-B with Grignard reagent ethyl magnesium halide in presence of an Iron catalyst; and

wherein P1 is an amine protecting group; P2 is a hydroxy protecting group; R1 is an alkyl group.
b) isolating formula II.

Within the context of the reactions depicted and disclosed herein “P1” is an amine protecting group. “P2” is hydroxy protecting group; “R” is an alkyl moiety.
Amine protecting groups (“P1”) 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, the protecting group is carboxybenzyl,

The hydroxy protecting groups (“P2” ) are well known to those skilled in the art. Examples of suitable hydroxy protecting groups are Examples of a hydroxy protecting group include lower alkyl, aralkyl (e.g. benzyl), acyl (e.g. acetyl, pivaloyl, benzoyl), alkoxyalkyl (e.g. methoxymethyl, methoxyethyl), lower alkylsulfonyl (e.g. methanesulfonyl), arylsulfonyl (e.g. benzenesulfonyl, toluenesulfonyl), alkoxycarbonyl (e.g. methoxycarbonyl) and the like. In some embodiments, the protecting group is pivaloyl, tosyl, mesyl and trifflic anhydride.

The term "lower alkyl" encompasses linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, most preferably 1 or 2 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl.

The term alkyl (“R1”) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, preferably ethyl.

In one embodiment, Formula B is reacted with Grignard reagent in presence of an Iron catalyst to give formula II. The reaction of Grignard reagent is carried out in presence of a solvent. The suitable solvent for the reaction is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, methyl tertiary butyl ether, diisopropyl ether and mixtures thereof.
The suitable Iron catalyst for the reaction is selected from Iron (III) acetyl acetonate, ferric chloride.
In another embodiment, the Grignard reagent ethyl magnesium halide is selected from ethyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium chloride and ethyl magnesium Iodide; preferably ethyl magnesium bromide.
According to the present invention, Formula B (wherein P1 is carboxybenzyl; P2 is pivolyl; R1 is ethyl) is reacted with Ethyl magnesium bromide in presence of an Iron (III) acetyl acetonate to give formula II.

The prior art processes employ Pd/C for in the preparation of Formula II, which is high in cost and also not user-friendly reaction. It also a tedious process to remove the traces of Pd in the final product. The present invention is user friendly and cost effective as it involves a use of an Iron catalyst in the preparation of Formula II. And it also provides 100 % reaction conversion resulting into good yield.
In another embodiment, the resulting compound of Formula II is hydrolysed to give an acid compound of formula C.

In one more embodiment, the compound of formula II can be further converted into Upadacitinib as per the processes known in US 8426411, WO 2017066775 & IN 201941012320.
Yet another embodiment, the compound of formula B can be prepared as per the processes known in the literature.
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:
A: Preparation of Protected glycine ester:

To a solution of 200 g (1.433 moles) of glycine ester in 300 mL of 5 N NaOH was charged 143.5 g (0.7486 moles) of ethyl acrylate at ~ 0-5 ° C. The mass for stirred for 12 hrs at 0-5 ° C. Upon completion of the reaction, the reaction mass was extracted with 1200 mL of dichloromethane. The layers were separated. Organic layer was washed with 200 mL of water. Separated organic layer, distilled off and purified by fractional distillation to get protected glycine ester.
Yield: 62%
B: Preparation of Protected glycine ester:
To a solution of 500 g (3.58 moles) of glycine ethyl ester in 750 mL of 5 N NaOH was charged 340 g (3.4 moles) of ethyl acrylate at ~ 0-5 ° C. The mass for stirred for 24 hrs at 20-30 ° C. Upon completion of the reaction, layers were separated. Aqueous layer was extracted with 1000 mL of toluene. The organic layers were combined, distilled off and purified by fractional distillation to get protected glycine ester.
Yield: 65%
Example 2:
A: Preparation of CBZ protected compound

To a solution of 40 g (0.1968 moles) of protected glycine ester and 27.84 g (0.2751 moles) of triethyl amine in 320 mL of toluene was charged 40.17 g (0.2355 moles) of benzyl chloroformate at 0-5 ° C. The resultant reaction mixture was heated to 25-30 ° C and stirred for 6 hrs at 25-30 ° C. Upon completion of the reaction, the reaction mixture was quenched with 200 mL of 1 N HCl, followed by 200 mL of water wash. The organic layers were distilled off completely and swapped with toluene (80 ml) to get CBZ protected compound.
Yield: 98%
B: Preparation of CBZ protected compound:
To a solution of 500 g (2.46 moles) of protected glycine ester in 1000 mL of toluene was added 500 mL of aq. sodium bicarbonate (310 g (3.68 moles) of sodium bicarbonate in water). The reaction mixture was cooled and was added 400 g (2.35 moles) of benzyl chloroformate at 15-25 ° C. The resultant reaction mixture was heated to 20-30 ° C, and stirred for 6 hrs at 20-30 ° C. Upon completion of the reaction, layers were separated. The aqueous layer was extracted with 1000 mL of toluene. The organic layers were combined and washed with 1000 mL of 1 N aqueous HCl, followed by water wash. The organic layers were distilled off completely to get CBZ protected compound.
Yield: 94%
Example 3:
A: Preparation of alcohol compound:

To a solution of 60 g (0.1778 moles) of CBZ protected compound in 480 mL of toluene was charged 14.51 g (0.2133 moles) of sodium ethoxide. The resulting reaction mixture was stirred for 1 hour at 30-35° C. Upon completion of the reaction, the reaction mass was cooled to 5-10° C. The pH of the reaction mass adjusted to 4-5 with 210 mL of 1 N HCl. The layers were separated and washed organic layer with 300 mL of 10 % NaCl solution. The organic layer was distilled off completely and dried to get crude alcohol compound.
Yield: 96 %.
B: Preparation of alcohol compound:
To a solution of 500 g (1.48 moles) of CBZ protected compound in 4000 mL of toluene was charged 120.9 g (1.77 moles) of sodium ethoxide. The resulting reaction mixture was stirred for 4 hours at 20-30° C. Upon completion of the reaction, the reaction mass was cooled to 5-15° C. The pH of the reaction mass adjusted to 4 - 5 with 2000 mL of 1 N HCl. The layers were separated and washed organic layer with 2000 mL of 10 % NaCl solution. The organic layer was concentrated up to 6-6.5 Volumes and the resulting alcohol compound was used further without isolation.
Example 4:

General Procedure: To a solution of 1.0 eq of alcohol compound in 8 vol of dichloromethane, 1.1-1.2 eq of trifluoro methane sulfonic anhydride solution/ Methane sulfonic anhydride/ para Toluene sulfonyl chloride/ Pivaloyl chloride was added followed by 1.5 -2.0 eq of N, N Diisopropyl ethyl amine was added. The resultant reaction mass was stirred under ambient temperature. Upon the completion of the reaction, the reaction mass was quenched with 0.5 M HCl solution (15 vol), followed by washing with water (2X5 volumes). The organic layers were distilled off completely under vacuum to get the crude Protected alcohol of formula B.
Yield: 89%.
A: preparation of Pivaloyl compound:
To a solution of 4 g (0.01373 moles) of alcohol compound in 32 mL of dichloromethane, 2.66 g (0.02058 moles) of DIPEA was charged followed by 1.81 g (0.015 moles) of pivaloyl chloride at 0-5 ° C. The resultant reaction mixture was stirred for one hour at 24-30° C. Upon completion of reaction the reaction the reaction mass was washed with 20 mL of water, followed by 20 ml of 5 % sodium bicarbonate solution. The organic layer was distilled off completely and dried to yield pivaloyl protected compound of formula B.
Yield: 97 %

B: Preparation of Pivaloyl compound:
To a cooled solution of 432g (~1.48 moles) of alcohol compound in ~2500 mL of toluene was added 287.9 g (2.227 moles) of DIPEA followed by 195.6g (1.62 moles) of pivaloyl chloride at 0-5 ° C. The resulting reaction mixture was stirred for one hour at 0-5° C. Upon completion of reaction, the reaction mass was quenched with 2000 mL of water. Layers were separated and organic layer was washed with 10 % sodium bicarbonate solution followed by 10% sodium chloride solution. The organic layer was concentrated up to 4-4.5 volume and the resulting pivaloyl compound formula B directly used for the next reaction without isolation.
C: Triflet Compound:
To a solution of 7 g (0.02403 moles) of alcohol compound in 84 mL of diisopropyl ether was added 9.48 g (0.03364 moles) of trifflic anhydride followed by 4.67 g (0.0361 moles) of DIPEA at 0-5 ° C. The resultant reaction mixture was stirred for one hour at 24-30° C. Upon completion of the reaction, the reaction the reaction mass was washed with 105 mL of 0.5 M HCl and followed by washing with 20 mL of water. The organic layers were distilled off completely and dried to get Triflet protected compound of Formula B.
Example 5:
A: Preparation of Formula II from Formula B:
To a solution of 3 g (0.008 moles) of pivaloyl protected alcohol of formula B in 24 ml of THF; 0.5 ml of NMP and 141 mg (0.0004 moles) of Iron (III) acetyl acetonate was purged under nitrogen. The reaction mass was cooled to -15 to -10°C. To the reaction mixture was added 14.4 ml (0.0144 moles, 1.0 M solution) of ethyl magnesium bromide at -15 to -10°C. The dark coloured reaction mass was stirred for 30-60 min. Upon completion of the reaction, the reaction mass was quenched with 15 ml of 10 % ammonium chloride solution. Organic layer was separated and re-extracted with 10 ml of ethyl acetate. The obtained organic layers were washed with 10 ml of water. The organic layers were combined and washed with water and distilled off completely to get formula II.
Yield: 100 %.

B: Preparation of Formula II from Formula B:
To a toluene solution of 555.62 g (1.48 moles) of pivaloyl protected compound of formula B were added 2000 mL of THF; 80 mL of NMP and 10 g (0.003 moles) of Iron (III) acetone acetyl acetonate. The resulting reaction mass was purged with nitrogen gas. The reaction mass was cooled to -30 to -40°C and was added 2225 mL (2.22 moles, 1.0 M solution) of ethyl magnesium bromide. The reaction mass was stirred for 30-60 min. After completion of the reaction, the reaction mass was quenched with 1M aqueous HCl solution. The organic layer was separated and re-extracted with 1000 mL of toluene. The obtained organic layers were washed with 1000 mL 10% sodium chloride solution. The organic layers were distilled off completely and strip off with THF to get ethyl compound formula II. The crude ethyl compound of formula II was directly used for next reaction without isolation.
Example 6: Preparation of Formula II from Triflet protected alcohol:
To a solution of 3 g (0.0071 moles) of triflet protected alcohol of formula B in 24 ml of THF; 0.5 mL of NMP and 125 mg (0.000355 moles) of Iron (III) acetyl acetonate was purged under nitrogen. The reaction mass was cooled to -15 to -10°C. To the reaction mixture was added 13 mL (0.0128 moles, 1.0 M solution) of ethyl magnesium bromide at -15 to -10 °C. The dark coloured reaction mass was stirred for 30-60 min. Upon completion of the reaction, the reaction mass was quenched with 15 ml of 10 % ammonium chloride solution. The organic layer was separated and re-extracted with 10 ml of ethyl acetate. The organic layers were washed with 10 mL of water. The combined organic layers were washed with water and distilled off and dried to get Formula II.
Yield: 100 %
Example 7:
A: Preparation of Acid compound of Formula C from Formula II:

To a solution of 2.5 g (0.00825 moles) of Formula II in 2.5 mL of THF was added 0.525 g of (0.525 g in 17.5 ml of water, 0.0131 moles in 7.0 vol water) sodium hydroxide solution. The resulting reaction mixture was heated to 52-58 °C and stirred for 8 hours. Distilled off THF under reduced pressure. The aqueous layer was washed with 12.5 mL toluene at 52-58 °C. The pH of the aqueous layer was adjusted 4.0 - 5.0 with 1.5 mL of 3 N HCl at 10-20 °C. Filtered the resultant solid and washed with 12.5 mL water and dried under vacuum to get acid compound of formula C.
B: Preparation of Acid compound of Formula C from Formula II:
To the 449 g (1.48 moles) of compound formula II was added 500 mL of THF; and aq. sodium hydroxide solution (100 g NaOH in 3500 ml water, 2.5 moles in 7.0 vol water) and 2.38g TBAB (0.0074 moles). The resulting reaction mixture was heated to 50-55 °C and stirred for 8 hours. After completion of reaction, the reaction mixture was cooled and was added 1000 ml of dichloromethane; 25 g of activated carbon and stirred the reaction mass for 30 mins. The reaction mass was filtered through hyflo followed by a washing with DCM. Layers were separated, the separated aqueous layer was cooled to 5-15 °C and adjusted the reaction mass pH to 4-5 with aqueous HCl. The reaction mixture was stirred for 60 mins, filtered and the resulting solid was washed with water. The obtained crude was dried under vacuum to get crude acid compound of formula C. The crude acid compound was further purified in ethyl acetate to get acid compound of formula C.
Yield: 61%
,CLAIMS:1. A process for the preparation of Formula II comprising the steps of:
a. reacting Formula-B with Grignard reagent ethyl magnesium bromide in presence of an Iron catalyst; and

wherein P1 is an amine protecting group; P2 is a hydroxy protecting group; R1 is an alkyl group.
b. isolating formula II.

2. The process as claimed in claim 1, wherein the amine protecting group is carboxybenzyl group.

3. The process as claimed in claim 1, wherein the hydroxy protecting group is pivaloyl group.

4. The process as claimed in claim 1, wherein the Iron catalyst is Iron (III) acetyl acetonate or ferric chloride.

5. The process as claimed in claim 1, wherein the Formula II is further converted into Upadacitinib.