Process for the preparation of upadacitinib active substance and intermediates

Abstract

The object of the invention is the preparation of upadacitinib drug substance of the formula (I) by a new process, which is novel, environmentally friendly, has an advantageous pollution profile, and also can be realized on an industrial scale, using novel intermediates not yet known from the literature.

Description

[0001] PROCESS FOR THE PREPARATION OF UPADACITINIB ACTIVE SUBSTANCE AND INTERMEDIATES

[0002] The object of the present invention is the preparation of upadacitinib drug substance by a novel, environmentally friendly process, which has advantageous contaminant profile and can be realized on an industrial scale, using novel intermediates not yet known from the literature.

[0003] STATE OF THE ART

[0004] The formula of the active substance upadacitinib or ABT-494, chemically known as (3S,4R)-3- ethyl-4- { 1 ,5,7, 10-tetraazatricyclo[7.3.0.02,6]dodeca-2(6),3 ,7,9, 11 -pentaen-12-yl} -N-(2,2,2- trifhioroethyl)pyrrolidine-l -carboxamide, developed by Abbott Laboratories (AbbVie), is as follows Upadacitinib

[0005] Upadacitinib is one of the JAK1 selective inhibitors marketed under the name RINVOQ. RINVOQ is indicated for the treatment of moderate-to-severe active rheumatoid arthritis and psoriatic arthritis in adult patients who have had an inadequate response or are intolerant to one or more diseasemodifying anti-rheumatic drugs. RINVOQ can be used as monotherapy or in combination with methotrexate. It is also indicated for the treatment of psoriatic arthritis (arthritis with concomitant psoriasis), axial spondyloarthritis, atopic dermatitis andulcerative colitis.

[0006] The active ingredient and the process for the preparation thereof were first described in international patent application WO2011068881 from Abbott Laboratories (AbbVie).

[0007] In the synthesis Y described in international patent application WO2011068881, after the preparation of the two key intermediates, the tert-butylcarbamate intermediate of formula (II) is N- alkylated with a-bromoketone of formula (III) in the common branch of the synthesis, the Boc protecting group is removed from the resulting adduct, and the secondary amine is then subjected to a ring-closure reaction with Lawesson's reagent. The Cbz-protecting group is removed from the tricyclic compound containing the tosyl group, and the 7V-tosyl-protected pyrrolidine compound is V-carbamoylated with the imidazolide (Vila) prepared from CDI and 2,2,2-trifluoroethylamine. Finally, the tosyl protecting group is removed from the sulphamate thus prepared under alkaline conditions to give the base upadacitinib of formula (I). The steps of the process described in international patent application WO2011068881 are summarized in Figure 1.

[0008] 1. Figure

[0009] In international patent application WO2017066775, the originator makes a number of significant changes to the route of synthesis.

[0010] Instead of the previously preferred terc-butylcarbamate key intermediate of formula (II), the more crystallizable and thus well purifiable ethylcarbamate derivative, compound of formula (VIII), is used, the TV-alkylation of which is achieved with a-bromo ketone of formula (III) using t-BuOLi. The cyclization of a-keto carbamate (IX) is carried out with trifluoroacetic anhydride and pyridine, then followed by the removal of the tosyl protecting group by alkaline treatment to give the compound of formula (X). The Cbz protecting group of the latter is removed by catalytic reduction to give the compound of formula (XI), which is isolated as dihydrochloride of formula (XI). The pyrrolidinyl ring is selectively N-carbamoylated with imidazolide (Vila), already discussed above. The Z-(+)-tartaric acid salt of upadacitinib is also prepared from the resulting upadacitinib base.

[0011] The synthesis described in international patent application WO2017066775 is described in Figure 2.

[0012]

[0013] Figure 2.

[0014] Although the compound of formula (XI), which is the hydrochloric acid salt of the base obtained from the compound of formula (X) in Figure 2 by catalytic reduction of the protecting group, is a well purifiable entity, due to its production it is heavily contaminated with palladium, the removal or the reduction of which below the regulatory levels causes serious problems not only at this point but also in the contamination profile of the final product.

[0015] In the final step, the carbamoylation of the dihydrochloride salt of compound of formula (XI) with compound of formula (Vila) also slightly carbamoylates the 3H-imidazo-[l,2-a]pyrrolo[2,3- e]pyrazine ring at position 3, generating a characteristic dicarbamoyl impurity, which is difficult to remove.

[0016] One of the aims of the procedure of the present invention is to eliminate the above disadvantages.

[0017] The procedure described in Figure 2 is discussed in the article Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib (Organic Process Research&Development 2022, 26, 949-962), where the possibilities of coupling of the intermediates of formulae (VIII) and (III), the optimal realization of ring closure and achieving the most favorable impurity profile are investigated.

[0018] In Mankind's international patent application W02021005484, the key intermediate of formula (XII) is reacted with a new derivative of a-bromo ketone of formula (III), namely a compound containing the 2,2,2-trifluoroethylamine group of formula (XIII). The compound thus obtained, designated formula (XIV), is subjected to a ring-closing reaction with Lawesson's reagent and then converted into upadacitinib of formula (I) by removal of the protecting group. The synthesis described in international patent application WO2021005484 is shown in Figure 3.

[0019] (XII) (XIII) (XIV) (XV) (I)

[0020] Upadacitinib

[0021] Figure 3.

[0022] The disadvantage of the process is that the preparation of starting compounds of formulae (XII) and (XIII) can only be achieved by an extremely lengthy synthesis, as no commercially available intermediates are available due to the deviation from the originator process. In contrast, our process according to the invention starts from the well known compound of formula (IX), which is itself a commercially available intermediate, and can be prepared in one step from readily available starting materials (VIII and III).

[0023] In the final step of the process, during the removal of the protecting acetyl-group at position 3 of the 3 / / -imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring, the cleavage of the 2,2,2-trifluoroethyl- carbamoyl group of the final product can be more easily achieved than in the solution according to the present invention. In our process, the risk of cleavage of the 2,2,2-trifluoroethyl-carbamoyl group is eliminated due to the milder reaction conditions used in the removal of the tosyl protecting group, which has a significantly better leaving-group property. In Mankind's process, the cleavage of the carbamoyl group of the final product also results in an additional critical impurity.

[0024] The aim of our invention is to overcome the drawbacks of the state-of-the-art production processes of upadacitinib of formula (I) by a new shorter process, in a preferred embodiment, which provides a high purity isolated end product with a contamination profile better than that of the state-of- the-art processes, with a production equal to or better than the known literature, while at the same time in a manner that is reproducible, applicable on an industrial scale, environmentally friendly and cost- effective. The state of the art has so far failed to provide such a solution.

[0025] BRIEF DESCRIPTION OF THE INVENTION

[0026] The object of the present invention is a new process for the preparation of upadacitinib (I), which starts from two commercially available key intermediates of formulae (VIII) and (III) of the Y- synthesis described in the originator’s international patent application WO2017066775 according to Figure 2. As a first step, carbamate (VIII) is V-alkylated with a-bromo ketone as described by the originator. The Cbz protecting group is selectively removed from the intermediate (IX) and a substituent acting as a protecting group is introduced onto the resulting intermediate (XVI), where the said protecting group also carries the trifluoroethylcarbamoyl moiety which is characteristic of the upadacitinib end product. For this purpose, the secondary amine (XVIII) obtained by reductive amination of benzaldehyde of formula (XVII) with trifluoroethylamine is first reacted with triphosgene to form acid chloride of formula (XIX), and then the pyrrolidine nitrogen of intermediate (XVI) is carbamoylated with this acid chloride. The resulting derivative (XX) is reacted with TFAA, where the ring closure is accompanied by cleavage of the tosyl protecting group. In this step, depending on the substituents of the benzyl protecting group of the 2,2,2-trifluoroethylcarbamoyl function, we either obtain the end product of formula (I) directly, or the (XXI) derivative protected on the carbamoyl nitrogen of the end product. In the latter case, the substituted benzyl protecting group is removed in a separate step.

[0027] The process according to the invention is summarized in Figure 4.

[0028] Upadacitinib

[0029] Figure 4.

[0030] The aim of the process we have developed is to eliminate the drawbacks of the state-of-the-art solutions by obtaining a final product of higher chemical and enantiomeric purity, which is achieved in such a way that it is capable reducing the trans impurity formed during the originator process and of completely eliminating the carbamoylation on the pyrrole N atom of the final product.

[0031] Object of the present invention is a procedure for synthesis of upadacitinib of formula Upadacitinib

[0032] (I) where the compound of formula

[0033] (XVI) or its salt

[0034] (XVIxHA)

[0035] (XVIxHA) where (A) is trifluoroacetate, a halide ion, preferably chloride ion or bromide ion, or, where appropriate, one or more acetate derivatives substituted by halogen, such as CCI3-COO or CH3-COO , with the compound of formula

[0036] (XIX), where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl; R, R' is 2,3- or 3,4-position -O-(CH )2n-O-, where n=l,2; preferably R is 4-OMe, R' is H, or R is 3-OMe, R' is 4-OMe, is carbamoylated and the compound of formula

[0037] (XX) thus obtained where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H, or R represents 3-OMe, R' represents 4-OMe, after purification and crystallisation with 4 - 12 molar equivalents in excess of TFAA- applied, or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent in the presence of a base at room temperature to 100 °C, followed by either a. the compound of formula XXI) thus obtained, where R represents H, OR", NO2 ; R' represents H, OR", where R" represents Cl- C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2; preferably R is 4-OMe, R' is H, after purification and crystallisation in organic solvent, without solvent or with organic or mineral acid dissolved in organic solvent or water at a temperature of 0 - 100 °C, or b. without the preparation and isolation of compound of formula (XXI), compound of formula (I) is prepared, from which a pharmaceutically acceptable form of compound of formula (I) is obtained by crystallisation or salt formation.

[0038] The object of the present invention is also the above process, wherein the compound of formula

[0039] (XX) where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H, or R represents 3-OMe, R' represents 4-OMe, is prepared in such a way that compound

[0040] (XVI) or salts thereof

[0041]

[0042] (XVIxHA)

[0043] (XVIxHA) where (A) is trifluoroacetate, halogen ion, preferably chloride ion or bromide ion, or optionally one or more halogen-substituted acetate derivatives such as CCh-COO or CH3-COO , is reacted with a solution of an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably with DCM, to give compound

[0044] (XIX) where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2; preferably R is 4-OMe, R' is H, or R is 3-OMe, R' is 4-OMe, in a solution with an aprotic organic solvent such as THF, 2-Me- THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably with DCM.

[0045] In addition, the object of the present invention is a process according to the method described above according to point a., wherein the compound of formula (XX) where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n— O-, where n=l,2, preferably R represents 4-OMe, R' represents H, or R represents 3-OMe, R' represents 4-OMe, is converted to the compound of formula

[0046] (XXI) where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2; preferably R is- 4- OMe, R' is H, carried out by using 4 to 12 molar equivalents in excess of TFAA, or other perfluorocarboxylic acid anhydride reagent in aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably in acetonitrile, in the presence of a base, preferably pyridine, at room temperature to 100 °C, preferably 70 to 90 °C. In the present process, the conversion of the compound of formula (XXI) to the compound of formula (I) is carried out in an organic solvent, preferably ethanol, methanol, IP A, EtOAc, IP AC, dioxane, preferably DCM, or without solvent, or with organic or mineral acid dissolved in an organic solvent or in water, preferably with TFA, or dissolved in C1-C6 straight, branched or cyclic alcohols, with hydrochloric acid gas absorbed in the alcohol in question, or with aqueous hydrochloric acid solution, HBr absorbed in acetic acid or water, at a temperature between room temperature and 100 °C.

[0047] In addition, the subject of our invention is the procedure described above in point b. where the compound of formula (XX) where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l ,2, preferably R represents 4-OMe, R' represents H, or R represents 3-OMe, R' represents 4-OMe, is converted to a compound of formula (I) with 4 - 12 molar equivalent excesses of TFAA, or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably in ACN, in the presence of a base, preferably with pyridine, at room temperature to 100 °C, preferably at 70 to 90 °C.

[0048] The object of the present invention in addition, is the compound of formula

[0049] (XVI) and salts thereof

[0050] (XVlxHA) of formula (XVfxHA) where (A) is trifluoroacetate, a halogen ion, preferably chloride ion or bromide ion, optionally one or more halogen-substituted acetate derivatives such as CCI3-COO or CH3-COO .

[0051] The subject of our invention is the process for the preparation of compound of formula (XVI) and its salts of formula (XVlxHA), where compound (IX) is reacted with acid. In this process, the removal of the benzyloxycarbonyl protecting group is carried out with or without organic solvent, using mineral or organic acid absorbed in aqueous or organic solvent, preferably absorbing HC1 or HBr gas in 4.5 to 5 times the volume of trifluoroacetic acid, water, alcohols, acetic acid or ester type solvents, stirred at room temperature to 100 °C, preferably at 30 to 80 °C.

[0052] In addition, the compound of formula

[0053]

[0054] (XX) is a further object of the present invention, where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4- position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H or R represents 3- OMe, R' represents 4-OMe.

[0055] In a process for the preparation of a compound of formula (XX), which is also the object of the present invention, wherein the compound of formula (XVI) or a salt thereof of formula (XVIxHA) is carbamoylated with the compound of formula

[0056] (XIX), where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H. In this procedure, the carbamoylation is carried out by reacting a solution of the compound of formula (XVI) with an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably with DCM, with a solution of the compound of formula (XIX) with an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably with DCM.

[0057] In addition, the compound of formula,

[0058] (XXI) is also an object of the present invention where R is H, OR", NO2 ; R' is H, OR", where R" is Cl- C6 straight or branched alkyl; R, R' represents 2,3- or 3,4- position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H or R represents 3-OMe, R' represents 4-OMe; and the preparation thereof, which is carried out by applying the compound of formula (XX) with a TFAA in 4 to 12 molar excess, or another perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably ACN, in the presence of a base, preferably pyridine, between room temperature and 100 °C, preferably at 70 - 90 °C.

[0059] DETAILED DESCRIPTION OF THE INVENTION

[0060] ABBREVIATIONS:

[0061] ACN - acetonitrile

[0062] AcOH - acetic acid

[0063] CDI - 1,1 '-carbonyldiimidazole

[0064] DCM - dichloromethane

[0065] DIPE - diisopropyl ether

[0066] DIPEA - diisopropylethylamine

[0067] DCM- dichloromethane

[0068] DMA - dimethyl acetamide

[0069] DMF - N,N-dimethylformamide

[0070] EtOAc - ethyl acetate

[0071] HBr - hydrogen bromide

[0072] HC1 - hydrogen chloride

[0073] IPA - isopropanol

[0074] IP AC - isopropyl acetate

[0075] K2CO3 - potassium carbonate

[0076] K2HPO4 - dipotassium hydrogen phosphate

[0077] KI - potassium iodide KOH - potassium hydroxide

[0078] Lawesson's reagent - 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulphide

[0079] MgSO4 - magnesium sulphate

[0080] MTBE - methyl terc-butyl ether

[0081] 2-Me-THF - 2-methyl tetrahydrofuran

[0082] NaH - sodium hydride

[0083] NaH2BO4 - sodium perborate

[0084] NaOH - sodium hydroxide

[0085] Pd / C - bone-in palladium catalyst

[0086] Py - pyridine rt - room temperature t-BuOLi - lithium terc-butoxide

[0087] TEA - triethylamine

[0088] TFA - trifluoroacetic acid

[0089] TFAA - trifluoroacetic anhydride

[0090] THF - tetrahydrofuran

[0091] The process we have developed starts with the step described in the originator's international patent application WO2017066775. Accordingly, two commercially available intermediates are reacted with each other, namely urethane of formula (VIII) is A-alkylated with a-bromo ketone of formula (III) in the presence of the compound of t-BuOLi. The resulting compound (IX) is passed to the next synthesis step without purification.

[0092] Then, the thus far unknown intermediate of formula (XVI) and its salts are prepared from the compound of formula (IX) by removing the Cbz protecting group. Surprisingly, we found that the removal of the benzyloxycarbonyl group with acid is a highly selective reaction, in which the other two protecting groups of the molecule are not damaged.

[0093] In the elementary steps of Abbvie's application WO2017066775, there is a potential for the generation of trans contaminants at several points, which is critical for the quality of the final product. This is not mentioned by the originator in its application, but is explored in detail in the article entitled Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib (Org. Process Res. Dev. 2022, 26, 949-962). In the originator's process, the inherently high trans content in the steps from the (IX) intermediate to the final product does not decrease and may even increase further under the conditions used. In contrast, using compounds of formulae (XX) and (XXI), the amount of trans impurity is much lower and, surprisingly, does not increase in the subsequent steps of our process, even though we are working at acidic pH, i.e. under conditions that result in partial cis-trans isomerization in the originator’s process. An additional advantage of our process is that the intermediate of formula (XVIxTFA) can be isolated as a well-crystallizable and purifiable salt, which allows the removal of impurities critical for the quality of the final product at a much earlier stage than the originator process.

[0094] Moreover, surprisingly for the person skilled in the art in chemistry, we found that neither cleavage of the V-ethoxycarbonyl or tosyl protecting groups, nor other degradation processes were observed during the preparation of intermediate of formula (XVIxTFA) according to the present invention.

[0095] Preparation of the intermediate of formula (XVI) and its salts are carried out, with or without organic solvent, using mineral or organic acid absorbed in aqueous or organic solvent, preferably HC1 or HBr gas absorbed in 4,5 to 5 times the volume of TFA, water, alcohols such as MeOH, EtOH, IPA, in acetic acid or ester type solvents such as diethyl ether, DIPE, MTBE, dioxane,, at room temperature to 100 °C, preferably at 30 to 80 °C, stirring, until the benzyloxycarbonyl protecting group is completely cleaved. The reaction time may be 12 to 72 hours depending on the acid.

[0096] The intermediate of formula (XVI) obtained by acid hydrolysis is overlaid with a substituent acting as a protecting group, which also carries the trifluoroethyl carbamoyl moiety characteristic of the upadacitinib of formula (I) end product.

[0097] Surprisingly, we found that when a substituted benzyl protecting group is used - where R stands for H, OR", NO2 ; R' stands for H, OR", where R" stands for C1C6 -straight or branched alkyl; R, R' represents 2,3- or 3,4- position -O-(CH2)n-O-, where n=l,2 - our procedure can be further simplified in such a way that both ring closure and removal of the tosyl and substituted benzyl protecting groups can be achieved in one step, directly resulting in the final product by the application of the appropriate acids.

[0098] To do this, first the benzaldehyde of formula (XVII) where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl- ; R, R' is 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, and trifluoroethylamine is reduced by amination to give the secondary amine of formula (XVIII) where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl; R, R' is 2,3- or 3,4-position- -O-(CH2)n-O-, where n=l,2. The compound of formula (XVIII) is then reacted with triphosgene to give the acid chloride of formula (XIX).

[0099] The reaction is illustrated in Figure 5.

[0100] Figure 5.

[0101] The compound of formula

[0102] (XIX), where R represents H, OR", NO2 ; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position- -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H, or R represents 3-OMe, R' represents 4-OMe.

[0103] Nitrogen of the intermediate pyrrolidine of formula (XVI) is protected with a compound of carbamoyl chloride of formula (XIX) dissolved in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably in DCM, and thus the new intermediate of formula (XX) is obtained. The solid crude product is purified and crystallised.

[0104] The purification of the solid crude product obtained by processing the reaction mixture is carried out in such way that it is dissolved in aprotic solvents or mixtures thereof, such as DCM, THF, 2-Me- THF, dioxane, ACN, EtOAc, IPAC, DMF, DIPE, MTBE, toluene, xylene, thenfiltered on a silica gel bed and finally crystallised from an ether type organic solvent such as THF, 2-Me-THF, dioxane, diethyl ether, DIPE, MTBE.

[0105] A ring closure is performed on the pyrrolo-pyrazine ring of the derivative of formula (XX), forming a heterocycle characteristic of the structure of the final product. The transformation is carried out with an excess of 4-12 molar equivalent TFAA or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably in acetonitrile, in the presence of a base, preferably pyridine, between room temperature and 100 °C, preferably at 70- 90 °C.

[0106] It was surprising to find that starting from compound (XX), where R= 4-OMe, R'= H, the isolated product no longer contains the tosyl protecting group, i.e. it was cleaved under acidic conditions. This is a more simple reaction than AbbVie's procedure because it is not necessary to remove the tosyl protecting group in a separate reaction step at different pH under basic conditions.

[0107] The intermediate of formula (XXI), where R= 4-OMe, R'= H, obtained by processing the reaction mixture is purified in aprotic solvent or in a mixture of aprotic solvents such as DCM, THF, 2- Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, toluene, xylene, then filtered on a silica gel bed and finally crystallized from an ether type organic solvent such as THF, 2-Me-THF, dioxane, diethyl ether, DIPE, MTBE.

[0108] From the intermediate thus obtained, only the 4-methoxybenzyl group needs to be removed to obtain the upadacitinib end product of formula (I). The removal of the protecting group is carried out in organic solvents such as ethanol, methanol, IP A, EtOAc, IP AC, dioxane, DCM, added without solvent, or with organic solvent or organic or mineral acid dissolved in water, at room temperature to 100 °C. The reaction may preferably be carried out, for example, in DCM, TFA, or dissolved in C1-C6 straight or branched chain or cyclic alcohols with hydrochloric acid gas absorbed in the alcohol, aqueous hydrochloric acid solution, HBr absorbed in acetic acid or water, at room temperature to 100 °C. If the aim is to obtain the pharmaceutically acceptable salt form of upadacitinib of formula (I), the reaction is carried out directly from the intermediate of formula (XXI) (R= 4-OMe, R'= H) in one of the solvents listed above or in mixtures thereof, at room temperature or with heating, using the organic or mineral acid required for salt formation as acid.

[0109] It was even more surprising to find that starting from the intermediate of formula (XX), where R= 3-OMe, R'= 4-OMe, the product obtained by evaporation of the reaction mixture no longer contains either the tosyl or the 3,4-dimethoxybenzyl protecting group, i.e. it is the crude end product of upadacitinib of formula (I)itself. The conversion is carried out with excess TFAA or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably in acetonitrile, in the presence of a base, preferably pyridine, at room temperature to 100 °C, preferably at 70 to 90 °C. The crude end product is converted into a pharmaceutically acceptable form by acid-alkaline processing followed by crystallisation or salt formation.

[0110] An additional advantage of our process compared to the originator's process in Figure 2 is that we have eliminated the use of Pd or other heavy metal catalysts. In state of the art processes where Pd catalyst is used, its removal or reduction in the final product to below the required level of 10 ppm creates a serious technical problem and a significant cost increase.

[0111] In the final step of the procedure illustrated in Figure 2, the carbamoylation of the dihydrochloride salt of compound (XI) with compound (VII) also slightly carbamoylates the 3H- imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at position 3, generating a characteristic dicarbamoyl impurity which is difficult to remove. An advantage of the process according to the present invention is that it eliminates the formation of dicarbamoyl impurity, such that position 3 is still protected by a tosyl protecting group during the carbamoylation step.

[0112] The final step in Mankind's procedure is the removal of the 3H-imidazo-[l,2-a]pyrrolo[2,3- e]pyrazine ring's 3 -position acetyl protecting group in an alkaline medium, which also causes a slight cleavage of the carbamoyl group of the final product, resulting in a critical impurity corresponding to the base of the intermediate (XI). In contrast, in our procedure all protecting groups are removed at acidic pH, reaction conditions which leave the carbamoyl function intact.

[0113] EXAMPLES

[0114] Further details of the solution according to our invention are shown in the examples below, without limiting the scope of protection of our invention in any way to those examples.

[0115] Example 1: Process for preparation of benzyl-(37?,4S)-3-{2-[(ethoxycarbonyl)[5-(4- methylbenzenesulfonyl)-5 / / -pyrrolo[2,3-b]pyrazin-2-yl]amino]acetyl}-4-ethylpyrrolidine-l- carboxylate of formula (IX)

[0116] 10.6 g of compound of formula (VIII) is measured under Ar and dissolved in 51 ml of dry DMA. Into the resulting dilute suspension, which is kept at -10 °C under Ar, we simultaneously add 3.28 g of t-BuOLi dissolved in 26.5 ml of dry DMA and 15.37 g of formula (III) in 24.5 ml of DMA.. The solution is stirred at -10 °C for 2 hours and the reaction is checked by HPLC. To the resulting mixture 0.88 ml of acetic acid is added coldly. Then stop cooling and 87.5 ml of ethanol is added to the reaction mixture. The temperature of the suspension formed is raised to 20 °C and 11 ml of distilled water is added. The suspension is stirred at 50 °C for 10 minutes, then allowed to cool and this procedure is repeated. The suspension is filtered, washed with aqueous ethanol and diethyl ether. The product is dried to constant weight.

[0117] Yield: 17.9 g (98.1%), white crystal

[0118] Mp.: 138-138.5 °C

[0119] IR (KBr): 3136, 1729, 1707, 1383, 1371, 1235, 1176, 679

[0120] 1HNMR (CDC13, 600 MHz): 8.98 (b, 1H), 8.02 (m, 2H), 7.89 / 7.87 (d, J=4A Hz, 1H), 7.34 (m, 2H), 7.33 (m, 2H), 7.29 (m, 1H), 7.29 (m, 2H), 6.62 / 6.49 (d, J=4.Q Hz, 1H), 5.14 / 5.13 (d, J=12A Hz, 1H), 5.08 / 5.06 (d, J=12A Hz, 1H), 4.85 (d, J=18 Hz, 1H), 4.78 / 4.77 (d, J=18 Hz, 1H), 4.28 / 4.27 (q, J=7.0 Hz, 2H), 3.83 / 3.75 (m, 1H), 3.60 (m, 1H), 2.58 / 3.55 (m, 1H), 3.42 / 3.35 (m, 1H), 3.35 / 3.32 (m, 1H), 2.40 (m, 1H), 2.38 (s, 3H), 1.52 (m, 1H), 1.39 (m, 1H), 1.29 / 1.28 (t, J=7.2 Hz, 3H), 0.97 / 0.95 (t, 150 MHz): 204.03 / 203.60, 154.72 / 154.65, 154.40 / 154.37, 147.07, 145.78 / 154.74, 37.97 / 137.87, 137.13 / 137.10, 136.73 / 136.67, 134.87, 134.76 / 134.74, 130.21 / 130.18, 129.89, 128.37, 27.89, 127.85, 127.80 / 127.78, 105.74 / 105.50, 66.79 / 66.76, 62.97, 55.79, 50.18 / 50.15, 49.84 / 48.60, 47.90 / 46.73, 44.02 / 42.89, 21.61, 21.21 / 21.18, 14.29, 12.85 / 12.74

[0121] COSY: 8.02-7.29, 7.89 / 7.87-6.62 / 6.49, 7.34-7.33-7.29-2.38, (5.14 / 5.13, 5.08 / 5.06), (4.85, 4.78 / 4.77), 4.28 / 4.27-1.29 / 1.28, (3.83 / 3.75, 3.58 / 3.55)-3.35 / 3.32-2.40*-(3.60, 3.42 / 3.35), 2.40*-(1.52, 1.39)- 0.97 / 0.95

[0122] NOESY: 3.35 / 3.32-(3.58 / 3.55, 2.40), 2.40-(3.60, 3.35 / 3.32)

[0123] HSQC (140 Hz): 8.98-134.87, 8.02-127.89, 7.89 / 7.87-130.21 / 130.18, 7.34-127.80 / 127.78, 7.33-128.37, 7.29-127.85, 7.29-129.89, 6.62 / 6.49-105.74 / 105.50, (5.14 / 5.13, 5.08 / 5.06)-66.79 / 66.76, (4.85, 4.78 / 4.77)-55.79, 4.28 / 4.27-62.97, (3.83 / 3.75, 3.58 / 3.55)-47.90 / 46.73, (3.60, 3.42 / 3.35)-50.18 / 50.15, 3.35 / 3.32-49.84 / 48.60, 2.40-44.02 / 42.89, 2.38-21.61, (1.52, 1.39)-21.21 / 21.18, 1.29 / 1.28-14.29, 0.97 / 0.95-12.85 / 12.74

[0124] HMBC (8 Hz, 140 Hz): 8.02-(145.78 / 145.74, 127.89), 7.89 / 7.87-(137.97 / 137.87, 137.13 / 137.10, 105.24 / 105.50, 7.34-(127.85, 127.80 / 127.78, 66.79 / 66.76), 7.33-(136.73 / 136.67, 128.37), 7.29- 127.80 / 127.78, 7.29-(134.76 / 134.74, 129.89, 21.61), 6.62 / 6.49-(137.13 / 137.10, 130.21 / 130.18), (5.14 / 5.13, 5.08 / 5.06)-(154.72 / 154.65, 136.73 / 136.67, 127.80 / 127.78), (4.85, 4.78 / 4.77)-

[0125] (204.03 / 203.60, 154.40 / 154.37, 147.07), 4.28 / 4.27-(154.40 / 154.37, 14.29), (3.83 / 3.75, 3.58 / 3.55)- (204.03 / 203.60, 50.18 / 50.15, 44.02 / 42.89, 49.84 / 48.60, 44.02 / 42.89), (3.60, 3.42 / 3.35)-(49.84 / 48.60, 44.02 / 42.89), 3.35 / 3.32-(204.03 / 203.60, 44.02 / 42.89, 21.21 / 21.18), 2.40-(204.03 / 203.60, 49.84 / 48.60, 21.21 / 21.18), 2.38-(145.78 / 145.74, 129.89), (1.52, 1.39)-(49.84 / 48.60, 44.02 / 42.89, 12.85 / 12.74), 1.29 / 1.28-62.97, 0.97 / 0.95-(44.02 / 42.89, 21.21 / 21.18)

[0126] Example 2: Preparation of ethyl JV-{2-[(37?,45)-4-ethylpyrrolidin-3-yl]-2-oxoethyl}-7V-[5-(4- methylbenzenesulfonyl)-5 / 7-pyrrolo[2,3-b]pyrazin-2-yl]carbamate trifluoroacetic acid salt of formula (XVI)

[0127] 17.8 g of compound of formula (IX) is measured into a flask under Ar and dissolved in 85 ml of anhydrous TFA. The resulting solution is stirred at room temperature for 48 hours. The reaction is checked by HPLC. After the reaction has taken place, the reaction mixture is diluted with 510 ml DCM, washed with water and saturated NaCl solution, dried on Na2SC>4 and evaporated. The residue is suspended in 135 ml MTBE and stirred at room temperature for 18 hours. The suspension is filtered and the product washed with 25 ml MTBE, followed by 25 ml DIPE and -dried to constant weight at 50°C under 10 mbar.

[0128] Yield: 15.76 g (93%), white crystal

[0129] Mp.: 186.5-187 °C

[0130] 1HNMR (DMSO, 600 MHz): 9.58 (b, 1H), 9.29 (b, 1H), 8.77 9s, 1H), 8.28 (d, J=4A Hz, 1H), 8.01 (~d, J=8.3 Hz, 2H), 7.46 (~d, J=8.3 Hz, 2H), 6.84 (d, J=4A Hz, 1H), 4.89 (d, J=19A Hz, 1H), 4.88 (d, J=19A Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.66 (m, 1H), 3.30 (m, 2H), 3.29 (m, 1H), 3.00 (m, 1H), 2.53 (m, 1H), 2.36 (s, 3H), 1.47 (m, 1H), 1.25 (m, 1H), 1.21 (t, J=7A Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).

[0131] 13CNMR (DMSO, 150 MHz): 204.89, 158.41 (q, J=30.9 Hz), 154.32, 147.52, 146.42, 137.91, 136.80, 135.30, 134.30, 131.85, 130.51, 127.76, 117.44 (q, J=299 l Hz), 106.09, 62.71, 56.65, 48.53, 48.34, 45.47, 42.99, 21.32, 20.13, 14.31, 12.59

[0132] COSY: 8.28-6.84, 8.01-7.46, (4.89, 4.88), 4.19-1.21, 3.66*-3.30-(9.58, 9.29)-(3.29, 3.00)-2.53*-(1.47, 1.25)-0.91, 3.66*-2.53*

[0133] HSQC (140 Hz): 8.77-135.30, 8.28-131.85, 8.01-127.76, 7.46-130.51, 6.84-106.09, 4.89-56.65, 4.88- 56.65, 4.19-62.71, 3.66-48.53, 3.30-45.47, 3.29-48.34, 3.00-48.34, 2.53-42.99, 2.36-21.32, 1.47-20.13, 1.25-20.13, 1.21-14.31, 0.91-12.59

[0134] HMBC (8 Hz, 140 Hz): 8.77-(147.52, 136.80), 8.28-(137.91, 136.80, 106.09), 8.01-(146.42, 127.76), 7.46-(134.30, 130.51, 21.32), 6.84-(137.91, 136.80, 131.85), (4.89, 4.88)-(204.89, 154.32, 147.52), 4.19-(154.32, 14.31), 3.66-(204.89, 48.34, 45.47, 42.99, 20.13), (3.29, 3.00)-20.13, 2.53-(204.89, 48.34,

[0135] 20.13), 2.36-(146.42, 130.51), (1.47, 1.25)-(48.53, 48.34, 142.99, 12.59), 1.21-62.71, 0.91-(42.99,

[0136] 20.13)

[0137] Example 3: Preparation of ethyl Y-{2-[(37?,4S)-4-ethyl-l-{[(4-methoxyphenyl)methyl](2,2,2- trifluoroethyl)carbamoyl}pyrrolidin-3-yl]-2-oxoethyl}-JV-[5-(4-methylbenzenesulfonyl)-5H- pyrrolo[2,3-b]pyrazin-2-yl]carbamate of formula (XX) (R= 4-OMe, R'= H)

[0138] In 60 ml dry DCM under Ar 4.70 g TFA salt of compound formula (XVI) is suspendedDCM. To the suspension 2.70 ml of TEA is added and 15 ml solution of 3 g of compound (XIX), where R = 4OMe-, R'= H, in 15 ml of dry DCM added dropwise into the resulting solution at 2 - 5 °C aDCM. After addition, the reaction mixture is stirred at room temperature for 18 hours. Then the mixture is diluted with 200 ml DCM, washed with saturated NaHCOa solution, water and saturated NaCl solution, dried on MgSC>4- and evaporated. The resulting material is suspended in DIPE / MTBE / tohiene=l / l / 0.1 and stirred for 5 hours at room temperature, filtered and dried. The resulting crude product is dissolved in 50 ml DCM / EtOAc=10 / l and filtered through a silica gel bed. The filtrate is dried on MgSC>4 and evaporated. The residue is suspended in DIPE, filtered, washed with DIPE and dried to constant weight.

[0139] Yield: 4.45 g (79.7%), ochre yellow crystal

[0140] Mp.: 94-95 °C

[0141] 1HNMR (DMSO, 600 MHz): 8.78 (s, 1H), 8.26 (d, J=3.9 Hz, 1H), 8.00 (~d, J=8.2 Hz, 2H), 7.44 (~d, J=8.2 Hz, 2H), 7.11 (~d, J=8A Hz, 2H), 6.83 (~d, J=8A Hz, 2H), 6.78 (d, J=4A Hz, 1H), 4.78 (s, 2H), 4.40 (d, J=15.6 Hz, 1H), 4.33 (d, J=75.6 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.92 (m, 1H), 3.85 (m, 1H), 3.69 (s, 3H), 3.62 (m, 1H), 3.49 (m, 1H), 3.48 (m, 1H), 3.47 (m, 1H), 3.33 (m, 1H), 2.41 (m, 1H), 2.35 (s, 3H), 1.39 (m, 1H), 1.20 (t, .7=7.1 Hz, 3H), 1.12 (m, 1H), 0.87 (t, J=7.2 Hz, 3H)13CNMR (DMSO, 150 MHz): 204.49, 161.22, 158.80, 154.38, 147.58, 146.38, 137.86, 136.70, 135.02, 134.31, 131.76, 130.49, 129.05, 129.00, 127.72, 125.55 (q, J=280.Q Hz), 122.78, 114.08, 106.06, 62.61, 55.84, 55.18, 52.63, 52.17, 49.23, 48.46, 46.91 (q, J=32.0 Hz), 45.77, 42.63, 21.31, 20.63, 14.26, 12.50 COSY: 8.26-6.78, 8.00-7.44, 7.11-6.83, (4.40, 4.33), 4.17-1.20, (3.92, 3.85), (3.62, 3.47)-3.48-2.41*- (3.49, 3.33), 2.41*-(1.39, 1.12)-0.87 ROE: 2.41-3.48

[0142] HSQC (140 Hz): 8.78-135.02, 8.26-131.76, 8.00-127.72, 7.44-130.49, 7.11-129.00, 6.83-114.08, 6.78- 106.06, 4.78-55.84, (4.40, 4.33)-52.63, 4.17-62.61, (3.92, 3.85)-46.91, 3.69-55.18, (3.62, 3.47)-48.46, (3.49, 3.33)-52.17, 3.48-49.23, 2.41-42.63, 2.35-21.31, (1.39, 1.12)-20.63, 1.20-14.26, 0.87-12.50 HMBC (8 Hz, 140 Hz): 8.78-(147.58, 136.70), 8.26-(137.86, 136.70, 106.06), 8.00-(146.38, 127.72), 7.44-(134.31, 130.49, 21.31), 7.11-(158.80, 129.00, 52.63), 6.83-(158.80, 129.05, 114.08), 6.78- (137.86, 136.70, 131.76), 4.78-(204.49, 154.38, 147.58), (4.40, 4.33)-(161.22, 129.05, 129.00, 46.91), 4.17-(154.38, 14.26), (3.92, 3.85)-(161.22, 125.55, 52.63), 3.69-158.80, (3.62, 3.47)-(204.49, 49.23, 42.63), (3.49, 3.33)-(49.23, 48.46, 42.63, 20.63), 3.48-(204.49, 48.46, 42.63), 2.35-(146.38, 130.49), (1.39, 1.12)-(52.17, 42.63, 12.50), 1.20-62.61, 0.87-(42.63, 20.63)

[0143] Example 4: Process for the reparation of Ethyl-V-{2-[(37?,4S)-4-ethyl-l-{[(3,4-dimethoxyphenyl) methyl](2,2,2-trifluoroethyl)carbamoyl}pirrolidin-3-yl]-2-oxoethyl}-JV-[5-(4-methylbenzenesulfonyl)- 5H-pirrolo[2,3-b]pyrazin-2-yl]carbamate (Formula (XX) ( R= 3-OMe, R'= 4-OMe )

[0144] In 12 ml dry DCM under Ar 1.0 g TFA salt of compound formula (XVI) is suspended. To the suspension 0.57 ml of TEA is added and into the resulting solution at 2 - 5 °C a solution of 0.68 g of [(3,4-dimethoxyphenyl)methyl](2,2,2-trifluoroethyl)amine of formula (XIX) (R= 3- OMe, R- 4-OMe) in 15 ml of dry DCM is added dropwise. After addition, the reaction mixture is stirred at room temperature for 30 hours. Subsequently the mixture is diluted with 40 ml DCM and saturated NaHCOs, water and saturated NaCl solution, dried on MgSO4- and evaporated. The resulting material is suspended in DIPE / MTBE / toluene=l / l / 0.1, stirred at room temperature for 6 hours, filtered and dried. The resulting crude product is dissolved in 10 ml of mixture of DCM / EtOAc=10 / l and filtered through a silica gel bed. The filtrate is dried on MgSO4 and evaporated. Suspend the residue in DIPE, filter, wash with DIPE and dry to constant weight.

[0145] Yield: 1.04 g (83.9%), light brown crystal

[0146] Mp.: 107-108 °C Example 5: Process for preparation of (3S,47?)-3-ethyl-JV-[(4-methoxyphenyl)methyl]-4-{l,5,7,10- tetraazatricyclo[7.3.0.0.0A{2,6} ]dodeca-2(6), 3,7,9, 11 -pentaen-12-yl} -7V-(2, 2,2- trifluoroethyl)pyrrolidin-l -carboxamide of formula (XXI) (R= 4-OMe, R'= H)

[0147] In a 100 ml flask under inert atmosphere in 58 ml ACN 4.40 g of intermediate of formula (XX) is suspended, where R= 4-OMe, R- H, . To the suspension 1.57 ml pyridine are added, followed by 5.55 ml TFAA while cooling on ice. Then the mixture is heated to 75 - 78 °C. Stirred at this temperature for 5 hours and then at room temperature for a further 16 hours. The reaction is checked by HPLC. The reaction mixture is evaporated and redissolved in 65 ml DCM, and washed with saturated NaHCOs , water and saturated NaCl solution. The solution is stirred with a mixture of activated carbon and silica gel for 1 hour and filtered through a silica gel layer. The filtrate is evaporated, the residue is suspended in DIPE, and stirred at room temperature, filtered, washed with DIPE and dried to constant weight.

[0148] Yield: 2.33 g (79.8%), brown crystal

[0149] Mp.: 100-101°C

[0150] IR (KBr): 3416, 3175, 1644, 1514, 1404, 1152, 1088, 832

[0151] 1HNMR (CDC13, 600 MHz): 10.84 / 10.79 (b, 1H), 8.75 (s, 1H), 7.52 (s, 1H), 7.33 (~t, J=3A Hz, 1H), 7.18 (~d, J=8.7 Hz, 2H), 6.91 (~d, J=8.7 Hz, 2H), 6.79 (dd, Ji =2.2 Hz, J2=3.4 Hz, 1H), 4.57 (d, J=15A Hz, 1H), 4.51 (d, J=15A Hz, 1H), 4.26 (~q, J=6.3 Hz, 1H), 4.06 (dd, J}=7.0 Hz, J2=10.7 Hz), 3.97 (m, 1H), 3.94 (dd, Ji =5.8 Hz, J2=10.6 Hz, 1H), 3.82 (s, 3H), 3.82 (m, 1H), 3.80 (m, 1H), 3.52 (dd, Ji =6.6 Hz, J2=10.6 Hz, 1H), 2.60 (m, 1H), 1.30 (m, 1H), 0.87 (m, 1H), 0.76 (t, .7=7.4 Hz, 3H)

[0152] 13CNMR (CDC13, 150 MHz): 162.52, 159.41, 139.71, 135.53, 134.17, 132.40, 129.11, 127.89, 125.41, 125.15 (q, J=280.0 Hz), 120.84, 115.33, 114.38, 95.09, 55.31, 52.91, 52.47, 52.32, 46.03 (q, J=33.2 Hz), 43.98, 38.22, 21.58, 12.30

[0153] ROE: 2.60-(4.26, 4.06, 3.82)

[0154] COSY: 10.84 / 10.79-7.33-6.79, 7.18-6.91, (4.57, 4.51), (4.06, 3.94)-4.26-2.60*-((3.82, 3.52), (3.97, 3.80), 2.60*-(1.30, 0.87)-0.76

[0155] HSQC (140 Hz): 8.75-135.53, 7.52-132.40, 7.33-120.84, 7.18-129.11, 6.91-114.38, 6.79-95.09, 4.57- 52.91, 4.51-52.91, 4.26-38.22, 4.06-52.47, 3.97-46.03, 3.94-52.47, 3.82-55.31, 3.82-52.32, 3.80-46.03, 3.52-52.32, 2.60-43.98, 1.30-21.58, 0.87-21.58, 0.76-12.30

[0156] HMBC (8 Hz, 140 Hz): 10.84 / 10.79-(l 15.33, 95.09), 8.75-(139.71, 134.17), 7.52-139.71, 7.33-(134.17, 115.33, 95.09), 7.18-(159.41, 129.11), 6.91-(159.41, 127.89, 114.38), 6.79-(134.17, 120.84), (4.57, 4.51)-(162.52, 129.11, 127.89, 46.03), 4.26-(132.40, 125.41, 52.47, 52.32, 43.98, 21.58), (4.06, 3.94)- (162.52, 125.41, 43.98, 38.22), (3.97, 3.80)-(162.52, 125.15, 52.91), 3.82-159.41, (3.82, 3.52)- (162.52,43.98, 38.22, 21.58), 2.60-(125.41, 52.47, 52.32, 38.22, 12.30), (1.30, 0.87)-(52.32, 43.98, 12.30), 0.76-(43.98, 21.58) Example 6: Process for preparation of (I) ((3S,4R)-3-ethyl-4-{l,5,7,10- tetraazatricyclo[7.3.0.0A{2,6} ]dodeca-2(6),3,7,9, 11 -pentaen- 12-yl} -N-(2, 2,2- trifluoroethyl)pyrrolidine-l -carboxamide) hemihydrate (Ixl / 2 H2 O) end product

[0157] Into a 100 ml flask under inert atmosphere, place 2.0 g of (3S,47?)-3-ethyl- V-[(4- methoxyphenyl)methyl]-4-{l,5,7,10-tetraazatricyclo[7.3.0.0A{2,6}]dodeca-2(6),3,7,9,l l-pentaen-12- yl}-Y-(2,2,2-trifluoroethyl)pyrrolidine-l -carboxamide of formula (XXI) ((R= 4-OMe, R'= H)) is dissolved in a mixture of 15 ml DCM and 3 ml TFA. The mixture is stirred at room temperature for 6 hours. The reaction is checked by HPLC. The mixture is evaporated and the residue is dissolved in 24 ml EtOAc and washed with sturated NaHCOa solution. The resulting solution is extracted with phosphoric acid then recycled into the organic phase, by alkalinization, washed with saturated NaCl solution, dried on MgSC>4 and evaporated to dryness.

[0158] The resulting 1.38 g of crude product is dissolved in 3% aqueous EtOAc and inoculated with upadacitinib Form C, a few drops of n-heptane are added to the resulting suspension and stirred for 1 hour. The suspension is filtered, washed with a mixture of aqueous EtOAc and n-heptane, and finally dried in vacuo at 45 °C- to constant weight.

[0159] Yield: 1.22 g (41.3%), crushed white crystal

[0160] Mp.: 163-164 °C

[0161] IR (KBr): 3431, 3177, 1656, 1616, 1548, 1399, 1147, 890

[0162] 1HNMR (DMSO, 600 MHz): 12.31 (b, 1H), 8.56 (s, 1H), 7.49 (s, 1H), 7.46 (d, J=3.1 Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 7.00 (bt, J=6A Hz, 1H), 4.37 (m, 1H), 3.89 (m, 1H), 3.83 (m, 1H), 3.79 (m, 1H), 3.70 (m, 1H), 3.28 (m, 1H), 2.57 (m, 1H), 1.11 (m, 1H), 0.82 (m, 1H), 0.64 (t, J=7A Hz, 3H)13CNMR (DMSO, 150 MHz): 156.10, 139.13, 134.55, 134.03, 131.65, 125.51, 125.42 (q, J=279 A Hz),

[0163] 121.97, 114.82, 95.01, 49.97, 49.37, 43.28, 41.29 (q, J=332 Hz), 37.42, 21.69, 12.36

[0164] COSY: 12.31-7.46-7.02, 7.00-3.89, (3.83, 3.79H.37-2.57*-(3.70, 3.28), 2.57*-(l.l l, 0.82)-0.64 NOESY: 4.37-2.57

[0165] HSQC (140 Hz): 8.56-134.55, 7.49-131.65, 7.46-121.97, 7.02-95.01, 4.37-37.42, 3.89-41.29, 3.83-

[0166] 49.97, 3.79-49.97, 3.70-49.37, 3.28-49.37, 2.57-43.28, 1.11-21.69, 0.82-21.69, 0.64-12.36

[0167] HMBC (8 Hz, 140 Hz): 12.31-(134.03, 121.97, 114.82, 95.01), 8.56-(139.13, 134.03), 7.49-139.13, 7.46-(134.03, 114.82, 95.01), 7.02-(134.02, 121.97, 114.82), 7.00-(156.10, 41.29), 4.37-(131.65, 125.51, 49.97, 21.69), 3.89-(156.10, 125.42), (3.83, 3.79)-125.51, 49.37, 43.28, 37.42), (3.70, 3.28)- (49.97, 43.28, 37.42, 21.69), (1.11, 0.82)-(49.37, 43.28, 37.42, 12.36), 0.64-(43.28, 21.69) Example 7: Preparation of ((3S,4R)-3-ethyl-4-{l,5,7,10-tetraazatricyclo[7.3.0.0A{2,6}]dodeca- 2(6),3,7,9,l l-pentaen-12-yl}-7V-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide) hemihydrate (I* 'A H2 O) end product

[0168] In 12 ml ACN 0.90 g of (XX) (R= 3-OMe, R'= 4-OMe) ethyl-A-{2-[(3R,45)-4-ethyl-l-{[(3,4- dimethoxyphenyl)methyl](2,2,2-trifluoroethyl)carbamoyl}pyrrolidin-3-yl]-2-oxoethyl}-JV-[5-(4- methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]carbamate is suspended in a 100 ml flask under inert atmosphere. To the suspension 0.30 ml pyridine is added, followed by 1.68 ml TFAA with ice cooling. Then heated to 75 - 78 °C. At this temperature is stirred for 8 hours and then at room temperature for a further 18 hours. The reaction is checked by HPLC. The reaction mixture is evaporated and the residue dissolved in 15 ml EtOAc, and washed with saturated NaHCCh, water and saturated NaCl solution. The solution is stirred with a mixture of activated carbon and silica gel for 2 hours and filtered through a silica gel layer. The resulting solution is extracted with phosphoric acid and the product is recycled to the organic phase by alkalization washed with saturated NaCl solution, dried on MgSC>4 and evaporated to dryness.

[0169] The resulting 0.37 g of the crude product is dissolved in 3% EtOAc and inoculated with upadacitinib Form C, a few drops of n-heptane are added to the resulting suspension and stirred for 1 hour. The suspension is filtered, washed with a mixture of aqueous EtOAc and n-heptane and dried under vacuum at 45 °C to constant weight.

[0170] Yield: 0.27 g (62.8%), crushed white crystal

[0171] Mp.: 163-164 °C

[0172] IR (KBr): 3431, 3177, 1656, 1616, 1548, 1399, 1147, 890

[0173] 1HNMR (DMSO, 600 MHz): 12.31 (b, 1H), 8.56 (s, 1H), 7.49 (s, 1H), 7.46 (d, J=3A Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 7.00 (bt, J=6A Hz, 1H), 4.37 (m, 1H), 3.89 (m, 1H), 3.83 (m, 1H), 3.79 (m, 1H), 3.70 (m, 1H), 3.28 (m, 1H), 2.57 (m, 1H), 1.11 (m, 1H), 0.82 (m, 1H), 0.64 (t, J=7A Hz, 3H)13CNMR (DMSO, 150 MHz): 156.10, 139.13, 134.55, 134.03, 131.65, 125.51, 125.42 (q, J=279 A Hz),

[0174] 121.97, 114.82, 95.01, 49.97, 49.37, 43.28, 41.29 (q, J=332 Hz), 37.42, 21.69, 12.36

[0175] COSY: 12.31-7.46-7.02, 7.00-3.89, (3.83, 3.79) .37-2.57*-(3.70, 3.28), 2.57*-(l.l l, 0.82)-0.64 NOESY: 4.37-2.57

[0176] HSQC (140 Hz): 8.56-134.55, 7.49-131.65, 7.46-121.97, 7.02-95.01, 4.37-37.42, 3.89-41.29, 3.83-

[0177] 49.97, 3.79-49.97, 3.70-49.37, 3.28-49.37, 2.57-43.28, 1.11-21.69, 0.82-21.69, 0.64-12.36

[0178] HMBC (8 Hz, 140 Hz): 12.31-(134.03, 121.97, 114.82, 95.01), 8.56-(139.13, 134.03), 7.49-139.13, 7.46-(134.03, 114.82, 95.01), 7.02-(134.02, 121.97, 114.82), 7.00-(156.10, 41.29), 4.37-(131.65, 125.51, 49.97, 21.69), 3.89-(156.10, 125.42), (3.83, 3.79)425.51, 49.37, 43.28, 37.42), (3.70, 3.28)- (49.97, 43.28, 37.42, 21.69), (1.11, 0.82)-(49.37, 43.28, 37.42, 12.36), 0.64-(43.28, 21.69) Example 8: Process for preparation of [(4-methoxyphenyl)methyl](2,2,2-trifluoroethyl)amine of formula (XVIII) (R= 4-OMe, R'= H)

[0179] In 90 ml MeOH under an inert atmosphere 5.45 ml of trifluoroethylamine are dissolved.. To this solution 8.30 ml of anise aldehyde (XVII: R= 4-OMe, R- H) is added and the reaction mixture is stirred at room temperature for 4 hours. Then cool the solution to 0 °C and add 4 g NaBFU. The mixture is heated to room temperature and stirred for 24 hours. The reaction is checked by HPLC. The reaction mixture is evaporated, dissolved in 120 ml DCM and washed with saturated Na2 CO3 solution, water and saturated NaCl solution, dried on MgSO4 and evaporated.

[0180] Yield: 13.70 g (94.4%), pale yellow oil

[0181] 1HNMR (CDCI3 , 600 MHz): 7.23 (~d, J=8.5 Hz, 2H), 6.87 (~d, J=8.6 Hz, 2H), 3.83 (s, 2H), 3.80 (s, 3H), 3.15 (q, J=9.5 Hz, 2H)

[0182] 13CNMR (CDC13, 150 MHz): 158.89, 131.12, 129.28, 128.60, 125.66 (q, J=279.5 Hz), 113.87, 64.94, 55.21, 52.33, 49.29 (q, J=312 Hz)

[0183] HSQC (140 Hz): 7.23-129.28, 6.87-113.87, 3.83-52.33, 3.80-55.21, 3.15-49.29

[0184] HMBC (8 Hz, 140 Hz): 7.23-(158.89, 129.28, 52.33), 6.87-(131.12, 113.87), 3.83-(131.12, 129.28, 49.29), 3.80-158.89, 3.15-(125.66, 52.33)

[0185] The formula XVIII (R= 3-OMe, R'= 4-OMe) [(3,4-dimethoxyphenyl)methyl](2,2,2- trifluoroethyl)amine is prepared as above.

[0186] Example 9: Process for preparation of V-[(4-methoxyphenyl)methyl]-JV-(2,2,2- trifluoroethyl)carbamoyl chloride of formula (XIX) (R= 4-OMe, R - H)

[0187] Dissolve 8.23 g of intermediate of the formula (XVIII) (R= 4-OMe, R'= H) in 90 ml of dry DCM under inert atmosphere. Then 7.70 ml of TEA is added, the solution is cooled to 0 - 5 °C, and 6.80 g of triphosgene is added dissolved in 17 ml of dry DCM dropwise. Allow the reaction mixture to reach room temperature and stir for 24 hours. Cool the mixture to ice and add 60 ml of cold water. The phases are separated, the organic phase is washed with water, dried on MgSC>4 and evaporated.

[0188] Yield: 9.80 g (~100%), brown oil, mixture of A and B rotamer

[0189] 1HNMR (CDCI3 , 600 MHz):

[0190] A: 7.20 (~d, 2H), 6.90 (~d, 2H), 4.68 (s, 2H), 3.98 (q, J=8A Hz, 2H), 3.82 (s, 3H)

[0191] B: 7.19 (~d, 2H), 6.92 (~d, 2H), 4.82 (s, 2H), 3.88 (q, J=8.1 Hz, 2H), 3.82 (s, 3H)13CNMR (CDCh , 150 MHz): A: 159.87, 150.37, 130.06, 126.00, 123.83 (q, J=281.3 Hz), 114.47, 55.31, 52.07, 49.15 (q, J=34.5 Hz) B: 159.84, 150.91, 128.97, 125.67, 123.93 (q, J=280.1 Hz), 114.54, 55.29, 54.00, 47.11 (q, J=34.5 Hz) COSY:

[0192] A: 7.20-6.90

[0193] B: 7.19-6.92

[0194] HSQC (140 Hz):

[0195] A: 7.20-130.06, 6.90-114.47, 4.68-52.07, 3.98-49.15, 3.82-55.31

[0196] B: 7.19-128.97, 6.92-114.54, 4.82-54.00, 3.88-47.11, 3.82-55.29

[0197] HMBC (8 Hz, 140 Hz):

[0198] A: 7.20-(159.84, 130.06, 52.08), 6.90-(126.00, 114.47), 4.68-(150.37, 130.06, 126.00), 3.82-159.87

[0199] B: 7.19-(159.84, 128.97, 54.00), 6.92-(125.67, 114.54), 4.82-(150.91, 128.97, 125.67), 3.88-(150.91, 123.93, 54.00), 3.82-159.84

[0200] NHMBC (5 Hz):

[0201] A: 4.68-110.9, 3.98-110.9

[0202] B: 4.82-108.3, 3.88-108.3

[0203] The JV-[(3,4-dimethoxyphenyl)methyl]-7V-(2,2,2-trifluoroethyl)carbamoyl chloride of formula XIX (R= 3-OMe, R'= 4-OMe) is prepared similarly as above.

Claims

PATENT CLAIMS1. Process for the preparation of upadacitinib of formulaUpadacitinib(I) characterized in that the compound of formula(XVI) or its salt of general formula(XVIxHA)(XVIxHA), where (A) is trifluoroacetate, a halide ion, preferably chloride ion or bromide ion, or, where appropriate, one or more acetate derivatives substituted by halogen, such as CCI3-COO or CHs-COO", is carbamoylated with the compound of formula(XIX), where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl; R, R' is 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2; preferably R is 4-OMe, R' is H, or R is 3-OMe, R' is 4- OMe, and the compound of formula(XX) thus obtained, where R is H, OR", NO2 ; R' is H, OR", where R" is C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H, or R represents 3-OMe, R' represents 4-OMe, after purification and crystallisation reacted with 4 - 12 molar equivalents in excess of TFAA, or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent in the presence of a base at room temperature to 100 °C, then either the compound of formula(XXI) thus obtained, where R represents H, OR", NO2 ; R' represents H, OR", where R" represents Cl- C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2;preferably R is 4-OMe, R' is H, after purification and crystallization in organic solvent, without solvent, or with organic or mineral acid dissolved in organic solvent or water at a temperature of 0 - 100 °C, or without preparation and isolation of compound of formula (XXI) to give compound of formula (I), from which the pharmaceutically acceptable form of compound (I) is obtained by crystallization or salt formation.

2. The process according to claim 1 , characterized in that the compound of formula(XX), where R and R' are as defined in claim 1 , is prepared in such a way that a solution of a compound of formula(XVI) or its salts of formula(XVIxHA)(XVIxHA), wherein meaning of (A) is as in Claim 1 dissolved in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably in DCM reacted with a solution of the compound of the formula(XIX) where R and R' meaning are as of claim 1 in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IPAC, DMF, preferably in DCM.

3. A process according to claim 1, characterized in that the transformation of compound of formula(XX), where R and R' meaning according to Claim 1 to the compound of formula(XXI), where R and R' are as defined in claim 1, is carried out with a 4 to 12 molar excess of TFAA or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably in acetonitrile, in the presence of a base, preferably pyridine, at room temperature to 100 °C, preferably at 70 to 90 °C.

4. A process according to point a. of claim 1, characterized in that the compound of formulawhere the meaning of R and R' are according to Claim 1, which is transferred to compound of formula (I), which reaction is carried out in an organic solvent, preferably in ethanol, methanol, IP A, EtOAc, IP AC, dioxane, preferably DCM or without a solvent, with an organic or mineral acid without solvent, or dissolved in an organic solvent or in water, preferably with TFA, or dissolved in Ci-Cs straight, branched or cyclic alcohols, with hydrochloric acid gas absorbed in the alcohol in question, or with aqueous hydrochloric acid solution, HBr absorbed in acetic acid or water, at a temperature between room temperature and 100 °C.

5. A process according to point b. of claim 1 characterised in that the compound of formula(XX) is transformed into a compound of formula (I) with 4 to 12 molar excess of TFAA or other perfluorocarboxylic acid anhydride reagent in aprotic organic solvents such as THF, 2-Me-THF, dioxane, ACN, DMF, preferably in ACN, in the presence of a base, preferably with pyridine, at room temperature to 100 °C, preferably at 70 to 90 °C.

6. Compound of formula(XVI) and its salts of general formula(XVlxHA)(XVIxHA) where (A) is trifluoroacetate, a halogen ion, preferably chloride ion or bromide ion, optionally one or more halogen-substituted acetate derivatives such as CCh-COO or CHs-COO".

7. Procedure for the compound of formula(XVI) according to claim 6 and its salts of general formula(XVIxHA)(XVIxHA), wherein (A) is trifluoroacetate, a halogen ion, preferably chloride ion or bromide ion, one or more halogen-substituted acetate derivatives such as CCh-COO or CHa-COO" characterized in that the compound of formula(IX) is reacted with acid.

8. A process according to claim 7, characterized in that the removal of the benzyloxycarbonyl protecting group is carried out with or without an organic solvent, using a mineral or organic acid absorbed in an aqueous or organic solvent, preferably in 4.5 to 5 times the volume of trifluoroacetic acid, water, alcohols, acetic acid or ester-type solvents, using HC1 or HBr gas absorbed in water, alcohols, acetic acid or ester-type solvents, stirred at room temperature to 100 °C, preferably at 30 to 80 °C.

9. A compound of formula(XX), where R represents H, OR", NO2; R' represents H, OR", where R" represents Ci-Ce straight or branched alkyl; R, R' represents 2,3- or 3,4-position — O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H or R represents 3-OMe, R' represents 4-OMe.

10. Process for preparation of the compound of formula(XX) according to claim 9 characterized in that the compound of formula(XVI) or one of its salts of general formula(XVIxHA)(XVIxHA), wherein (A) is trifluoroacetate, a halogen ion, preferably chloride ion or bromide ion, one or more halogen-substituted acetate derivatives such as CCh-COO" or CHa-COO", is carbamoylated with the compound of formula(XIX), where R represents H, OR", NO2; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H.

11. The process according to claim 10, characterized in that the carbamoylation comprises reacting the compound of formula (XVI) dissolved in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IP AC, DMF, preferably DCM with the compound of formula (XIX) dissolved in an aprotic organic solvent such as THF, 2-Me-THF, dioxane, ACN, EtOAc, IPAC, DMF, preferably in DCM.

12. A compound of formula (XXI),where R represents H, OR", NO2; R' represents H, OR", where R" represents C1-C6 straight or branched alkyl; R, R' represents 2,3- or 3,4-position -O-(CH2)n-O-, where n=l,2, preferably R represents 4-OMe, R' represents H or R represents 3-OMe, R' represents 4-OMe.

13. Process for the preparation of the formula(XXI) according to Claim 12 characterized in that the compound of formula(XX) wherein R and R' are as defined in claims 1 and 9, is reacted with TFAA in a 4 to 12 molar excess, or other perfluorocarboxylic acid anhydride reagent in an aprotic organic solvent such as THF, 2-Me- THF, dioxane, ACN, DMF, preferably ACN, in the presence of a base, preferably pyridine, at room temperature to 100 °C, preferably at 70 to 90 °C.

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