Process for the preparation of upadacitinib

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

[0002] The object of the invention is the preparation of upadacitinib drug substance 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.

[0003] STATE OF THE ART

[0004] The formula of the active substance upadacitinib or ABT-494, chemically known as (35,47?)-3-ethyl-4-{ l,5,7,10-tetraazatricyclo[7.3.0.02’6]dodeca-2(6),3,7,9,l l-pentaen-12-yl}- 7V-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide, developed by Abbott Laboratories (Abb Vie), 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 disease-modifying 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 psoriatis), axial spondyloarthritis, atopic dermatitis, ulcerative colitis.

[0006] The active substance and its method of manufacture were first described in international patent application WO2011068881 by Abbott Laboratories (Abb Vie).

[0007] In the synthesis Y described in international patent application WO2011068881, upon the preparation of the two key intermediates in the common branch of the synthesis, the tert- butylcarbamate intermediate of the formula (II) is N-alkylated with a-bromo ketone of the formula (III), than the protective oc-group is removed from the resulting adduct, and the secondary amine is subjected to a ring-closure reaction with Lawesson's reagent. The Cbz protecting group is removed from the tricyclic containing the tosyl group, and the V-tosyl protected pyrrolidine compound is / ' / -carbamoyl ated with imidazolide of the formula (Vila) prepared from CDI and 2,2,2-trifluoroethylamine. Finally, the tosyl protecting group is removed from the sulfamate thus prepared under alkaline conditions to yield the base upadacitinib of the 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 synthesis line, which are shown in Figure 2:

[0010]

[0011] Figure 2.

[0012] Instead of the previously preferred terc-butylcarbamate key intermediate of formula (II), the more crystallizable and thus more purifiable ethylcarbamate derivative, compound of formula (VIII), is used, the V-alkylation of which is achieved with a-bromo ketone of formula (III) and t-BuOLi. The cyclization of a-keto carbamate of the formula (IX) is carried out with trifluoroacetic anhydride and pyridine, followed by alkaline treatment to remove the tosyl protecting group to give the compound of the formula (X). The Cbz protecting group of the latter compound 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 compound of formula (Vila) which was already discussed above. The Z-(+)-tartaric acid salt of upadacitinib is also prepared from the resulting upadacitinib base.

[0013] Although the hydrochloric acid salt of the baseof the formula (XI) obtained by catalytic reduction of the protecting group from the compound of formula (X) in Figure 2 is a well purifiable entity, due to its production method it is heavily contaminated with palladium, the removal of which (as well as its reduction below regulatory levels causes serious problems not only at this point, but also in the contamination profile of the final product.

[0014] In the final step, carbamoylation of the dihydrochloride salt of compound of formula (XI) with compound of formula (Vila) also slightly carbamoylates the 3J / -imidazo-[l,2- a]pyrrolo[2,3-e]pyrazine ring at position 3, generating a characteristic dicarbamoyl impurity which is difficult to remove.

[0015] One of the aims of the procedure of the present invention is to eliminate these disadvantages.

[0016] The process described in Figure 2 is discussed in the article entitled Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib (Organic Process Research&Development 2022, 26, 949-962), in which the possibilities of coupling the intermediates of formula (VIII) and formula (III), of optimal realization of ring closure, and of achieving the most favorable impurity profile are examined.

[0017] 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), a compound containing the 2,2,2-trifluoroethylamine group of formula (XIII). The compound of the formula (XIV) thus obtained, is subjected to a ring-closing reaction with Lawesson's reagent and then converted to upadacitinib of formula (I) by removal of the protecting group. The synthesis described in international patent application WO2021005484 is shown in Figure 3.

[0018] (XII) (XIII) (XIV) (XV) (I)

[0019] Upadacitinib

[0020] Figure 3.

[0021] 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 of the compounds of formulae (VIII and III).

[0022] In the final step of the process, the removal of the acetyl group that is protecting the 3J / -imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at position 3, the cleavage of the 2,2,2- trifluoroethyl-carbamoyl group can occur more easily in the end product, than in the solution according to the present invention. In our process, the milder reaction conditions used to remove the tosyl protecting group, which has a significantly better leaving-group property, eliminate the risk of cleavage of the 2,2,2-trifluoroethyl carbamoyl group, whereas in the Mankind process, cleavage of the carbamoyl group of the final product results in an additional critical impurity.

[0023] The aim of our invention is to overcome the drawbacks of the state-of-the-art upadacitinib (I) production processes by a new and, in a preferred embodiment, shorter process, which provides a final isolated product with a high purity, having better contamination profile than the products of state-of-the-art processes, with an equal or better yield than the known literature, and which at the same time is reproducible, applicable on an industrial scale, in an environmentally friendly and cost-effective manner. The state of the art has so far failed to provide such a solution.

[0024] BRIEF DESCRIPTION OF THE INVENTION

[0025] The object of our invention is a novel process for the preparation of upadacitinib of formula (I), which starts from two purchasable key intermediates of formulae ((VIII) and (HI)) of the Y-synthesis which is described in originator’s international patent application WO2017066775 as shown in Figure 2. As a first step, carbamate compound of formula (VIII) is V-alkylated with the a-bromo ketone compound as described by the originator. The Cbz protecting group is selectively removed from the intermediate of formula (IX), and the resulting pyrrolidine derivative of formula (XVI) is V-carbamoylated with the compound of formula (Vila) and the intermediate of formula (XVII) is subjected to a ring-closing reaction with TFAA. The tosyl protecting group is then removed by alkaline hydrolysis to give the upadacitinib end product of formula (I). The process according to the present invention is summarized in Figure 4. Upadacitinib

[0026] Figure 4.

[0027] The aim of the process we have developed is to overcome the drawbacks of the previous solutions by obtaining a final product of higher chemical and diastereomeric purity, which is achieved in such a way that it is able to reduce the amount of trans impurity formed during the originator process, and to completely exclude the carbamoylation on the pyrrole N atom of the final product. The object of our invention is a process for the preparation of upadacitinib or its salt of formula (I), characterized in that the compound of formula (XVII) is formed to the compound of formula (I), which is then converted into a pharmaceutically acceptable form of formula (I) by crystallisation or salt formation, as appropriate.

[0028] The invention further relates to a process for the preparation of upadicitinib of formula (I), wherein the compound of formula (XVI) or its acid addition salt of general formula (XVI x HnA) wherein n is 1,2, or 3, is converted to a compound of formula (XVII), depending on the meaning of A, and then the compound of formula (XVII) is converted to the compound of formula (I), which is optionally converted by crystallisation or salt formation to a pharmaceutically acceptable form of the compound of formula (I).

[0029] A further subject of our inventio is a process for the preparation of the formula (I) upadicitinib, in which the Cbz protecting group is selectively cleaved from the general formula (IX) known from the literature, and the resulting compound of formula (XVI) or its acid addition salt of general formula (XVI x HnA), where n is 1,2, or 3, is reacted with the compound of formula (VIII) to give the compound of formula (XVII) depending on the meaning of A, and the compound of formula (XVII) is then converted to the compound of formula (I), which is optionally converted by crystallisation or salt formation to a pharmaceutically acceptable form of the compound of formula (I).

[0030] Further objects of the present invention are the intermediate compound of formula (XVI) or its acid-doped salt (XVI x HnA) and the compound of formula (XVII).

[0031] Furthermore, the preparation of a compound of formula (XVI) or acid addition salts of the general formula (XVI x HnA) is the subject of our invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] ABBREVIATIONS:

[0033] ACN - acetonitrile

[0034] AcOH - acetic acid

[0035] Boc - tert-butoxycarbonyl

[0036] Cbz - benzyloxycarbonyl

[0037] CDI - 1,1 '-carbonyldiimidazole

[0038] DCM - dichloromethane

[0039] DIPE - diisopropyl ether

[0040] DIPEA - diisopropylethylamine

[0041] DMA - dimethyl acetamide

[0042] DMF - N,N-dimethylformamide

[0043] HBr - hydrogen bromide

[0044] HC1 - hydrogen chloride

[0045] K2 CO3 - potassium carbonate

[0046] K2 HPO4 - dipotassium hydrogen phosphate

[0047] KI - potassium iodide

[0048] KOH - potassium hydroxide

[0049] Lawesson's reagent - 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulphide

[0050] MgSO4 - magnesium sulphate

[0051] MTBE - methyl terc-butyl ether

[0052] 2-MeTHF - 2-methyl tetrahydrofuran

[0053] NaH - sodium hydride

[0054] NaH2BO4 - sodium perborate

[0055] NaOH - sodium hydroxide

[0056] Pd / C - bone-in palladium catalyst

[0057] Py - pyridine rt - room temperature t-BuOLi - lithium terc-butoxide

[0058] TEA - triethylamine

[0059] TFA - trifluoroacetic acid

[0060] TFAA - trifluoroacetic anhydride THF - tetrahydrofuran

[0061] 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 V-alkylated with a-bromo ketone of formula (III) in the presence of t-BuOLi. The resulting compound (IX) is moved to the next synthesis step without purification or, if necessary, after purification.

[0062] Then, the intermediate (XVI) and its salts which are not known from the prior art are prepared from the compound of formula (IX) by removing the Cbz protecting group. Surprisingly, we found that the removal of the benzyloxy carbonyl group with acid is a highly selective reaction, in which neither the other two protecting groups of the molecule, nor the chirality centres and the pyrrolo-pyrazine ring system are damaged.

[0063] In the elementary steps of Abbvie's application WO2017066775, trans contaminants are generated at several points, which are critical for the quality of the final product. This is not mentioned by the originator in its application, but the manuscript entitled Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib (Org. Process Res. Dev. 2022, 26, 949-962) explores the phenomenon in detail. Surprisingly to the chemistry expert, we have found that the rate of trans impurity formation in our process is significantly reduced, and thus our process yields an end product with overall higher diastereomeric and chemical purity than the originator’s process. This advantage is entirely due to the advantageous chemical properties of the new intermediates (XVI) and (XVII) that we have produced.

[0064] A further advantage of our process is that the (XVI x HnA) intermediate 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.

[0065] Moreover, surprisingly to the person skilled in chemistry, we found that no cleavage of the TV-ethoxy carbonyl or tosyl protecting group or other significant degradation or isomerization processes were observed during the preparation of our intermediate (XVI x HnA). In contrast to the state of the art, in our synthesis ring closure occurs only in the final step. However, the ring system, which is open for a substantial part of the process, remains stable in a way that is not obvious to the person skilled in the art, and the Cbz protecting group can be selectively removed, with no cleavage or partial cleavage of the other protecting groups, no significant isomerisation, and no other damage to the ring system. Surprisingly, we found that when TFA, sulphuric acid, phosphoric acid or aqueous HBr are used to prepare our intermediate (XVI x HnA), only the Cbz protecting group is hydrolysed, leaving the other structural elements of the molecule unaffected. In this step of the reaction for the preparation of upadacitinib according to the invention, the other structural units and protecting groups of the open chain molecule are not degraded or cleaved by the use of acids in a relatively high temperature range, so that the Cbz group is selectively removed.

[0066] Thus, the removal of the Cbz group of the compound of general formula (IX) is performed in or without organic solvent, with the use of mineral or organic acid absorbed or dissolved in aqueous or organic solvent, in water, in alcohols such as MeOH, EtOH, IP A, in acetic acid or in ether-type solvents such as diethyl ether, DIPE, MTBE, dioxane, absorbed HC1 or HBr gas, stirred at room temperature or under warm conditions, until the benzyloxycarbonyl protecting group is completely cleaved. Preferably, trifluoroacetic acid, sulphuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or one or more acetic acid derivatives substituted with halogen, such as CCh-COOH or CH3-COOH, more preferably trifluoroacetic acid, sulphuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide, most preferably trifluoroacetic acid, sulphuric acid, phosphoric acid or an aqueous solution of HBr is used. In a very preferred embodiment of the present invention, trifluoroacetic acid is used to remove the Cbz group of the compound of general formula (IX).

[0067] The subject of our invention is therefore a process for the preparation of upadacitinib, characterized in that the compound of formula (XVII) is reacted with TFAA or other perfluorocarboxylic acid anhydrides in an aprotic solvent in an inert atmosphere in the presence of an organic base, at a temperature close to the boiling point of the solvent used, and from the compound so obtained, optionally without isolation, in an aprotic solvent in the presence of organic or inorganic bases, preferably alkali metal bases, the crude compound of formula (I) is prepared, from which the pharmaceutically acceptable form of the compound of formula (I) is obtained by crystallisation or salt formation.

[0068] According to the present invention, the aprotic solvent in which the compound of formula (XVII) is reacted in the above described process is dioxane, THF, 2-MeTHF, toluene, DCM, DMF, preferably acetonitrile; the organic base is TEA, DIPEA, DMAP, dimethyl aniline, preferably pyridine.

[0069] The subject of our study is also a procedure for the preparation of upadacitinib of the formula (I) Upadacitinib where the compound of formula (XVI) or

[0070] (XVIxHnA)

[0071] (XVI x HnA), where n is 1, 2, or 3, depending on the meaning of A, where A is an anion, preferably a trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or an acetate derivative substituted by one or more halogen(s), such as CCh- COO'or CHs-COO", preferably trifluoroacetate, sulphate ion, phosphate ion, chloride ion or bromide ion, more preferably trifluoroacetate ion, or sulphate ion, most preferably trifluoroacetate ion, if applicable with the in situ prepared carbamoylation agent of formula (VII), where R may be chlorine, bromine, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazolyl, reacted in aqueous-organic solvent mixture, using an aqueous buffer, preferably using phosphate buffer, in basic medium at 10 to 30 °C or in organic solvent using organic base at 10 to 40 °C.

[0072] The compound of formula (XVII) in an inert atmosphere, in an aprotic solvent in the presence of an organic base, is reacted with TFAA or other perfluorocarboxylic acid anhydrides at a temperature up to the boiling point of the solvent used, and from the compound obtained, optionally without isolation, in an aprotic solvent in the presence of organic or inorganic bases, preferably alkali metal bases, the crude compound of formula (I) is prepared, from which the pharmaceutically acceptable form of the compound of formula (I) is obtained by crystallisation or salt formation.

[0073] In the above process according to the present invention for the preparation of the compound of formula (XVII), the reaction is carried out by a.) is carried out in a water - organic solvent mixture, preferably a water - aprotic organic solvent mixture, in the pH range 8.5 - 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane or DMF, preferably THF and where the water - organic solvent volume ratio in the mixture is 1 :0,5 - 1 :5, preferably 1 :2, or b.) is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and water, preferably in 2-MeTHF or THF, in the presence of organic bases, preferably in TEA, DIPEA, pyridine, DMAP, DBU, preferably in the presence of DIPEA or TEA in such way that the amount of the base used is 2-6 molar equivalent, preferably 2,5-3 molar equivalent.

[0074] In the preparation of the compound of formula (XVII), the reaction is carried out at a temperature between 10 and 40 °C, preferably between 15 and 25 °C.

[0075] In a further preferred embodiment of our invention, a process for the preparation of upadacitinib of formula (I) is carried out in such way that the compound of formula (XVI), or its salt of general formula (XVI*HnA), wherein n and A are as defined above, are used to prepare compound (XVII), by reacting compound (IX)

[0076] with acid.

[0077] Thus, in the most preferred embodiment of our method, upadacitinib of formula (I) is prepared from the known compound of formula (IX) by first selectively cleaving the Cbz protecting group of formula (IX) using acid, and then the compound of formula (XVI) or its salt thus obtained is reacted with the compound of formula (VII) to give the compound of formula (XVII), which is converted by ring-closure reaction to the compound of formula (I) upadacitinib or its salt. The preferred embodiments of each step of the process are described in detail in the following description and examples.

[0078] The compounds of formulae (XVI) and (XVII) used in the process are not known from the state of the art.

[0079] In addition, the compound of formula (XVI)

[0080] (XVIxHnA) salts of general formula (XVIxHnA) are also subjects of the present invention.

[0081] In a preferred embodiment of our invention n is as defined above, A is an anion, preferably a trifluoroacetate anion, a sulfate ion, a phosphate ion, a halide ion, preferably a chloride ion or bromide ion, or one or more halogen- substituted acetyl ions, such as CCh-COO" or CHa-COO". A more preferably means trifluoroacetate ion, sulphate ion, phosphate ion, chloride ion or bromide ion, more preferably trifluoroacetate ion or sulphate ion. Most preferably its meaning is trifluoroacetate ion.

[0082] The scope of present invention also includes a process for the preparation of the compound of formula (XVI) and

[0083] (XVIxHnA) salts thereof of general formula (XVI x HnA), wherein n is 1, 2, or 3, depending on the meaning of A, wherein A is an anion, preferably a trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or one or more halogen-substituted acetate derivatives, such as CCh-COO" or CHa-COO", more preferably trifluoroacetate, sulfate ion, phosphate ion, chloride ion or bromide ion, even more preferably trifluoroacetate or sulfate ion, most preferably trifluoroacetate ion, wherein the compound of formula (IX) is reacted with acid. In this process, the benzyloxycarbonyl protecting group is selectively removed with or without organic solvent, using a mineral or organic acid absorbed in aqueous or organic solvent or a mixture thereof, preferably trifluoroacetic acid, sulphuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or one or more halogen-substituted acetic acid derivatives, such as CCh-COOH or CH3-COOH, more preferably trifluoroacetic acid, sulphuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide, even more preferably trifluoroacetic acid, sulphuric acid, phosphoric acid, or aqueous solution of HBr, most preferably trifluoroacetic acid In a highly preferred embodiment of our invention, the compound and salts thereof in the general formula (XVI) or its salts can be prepared by removing the benzyloxycarbonyl protecting group of the compound of formula (IX) preferably in trifluoroacetic acid, or in aqueous sulfuric acid at a concentration of between 40 wt% and 98 wt%, preferably between 80 wt% and 98 wt%, most preferably between 95 wt% and 98 wt%, or in phosphoric acid at a concentration between 60 % and 85 % by weight, preferably between 75 % and 85 % by weight, or in an aqueous HBr solution at a concentration between 20 % and 48 % by weight, preferably between 40 % and 48 % by weight, most preferably 48 % by weight, , or in HC1 or HBr gas absorbed in alcohols, acetic acid or ether-type solvents.

[0084] In a highly preferred embodiment of the invention, the removal of the benzyloxycarbonyl protecting group according to the invention is preferably carried out in 4.5 to 5 times the volume of trifluoroacetic acid , in 10 to 12 times the volume of concentrated or diluted sulfuric acid, or in 12 to 16 times the volume of phosphoric acid solution, most preferably in 4.5 to 5 times the volume of trifluoroacetic acid.

[0085] The amount of acid used according to the present invention is defined in mass / volume ratio as 1 g of compound (IX) per ml of acid volume as defined above. As an example, 1 g of compound IX is preferably reacted with 4,5-5 ml of trifluoroacetic acid, or 10-12 ml of concentrated or diluted sulphuric acid, or 12-16 ml of phosphoric acid solution.

[0086] According to the preferred embodiment of our invention or depending on the acid used, it is carried out at a temperature between 0-80 °C. The choice of the preferred temperature depends on the acid and solvent used, which will enable the person skilled in the art to determine the most advantageous temperature range. In a highly preferred embodiment of our invention, wherein trifluoroacetic acid, sulfuric acid or aqueous hydrogen bromide solution is used to remove the protecting group, the reaction mixture is preferably carried out at 0-30 °C, more preferably at 20- 25 °C in TFA, 0-10 °C in sulfuric acid and 25-30 °C in HBr.

[0087] In another very preferred embodiment of our invention, where phosphoric acid is used, the reaction is carried out at temperatures between 30 - 80 °C, preferably between 50 - 60 °C.

[0088] The reaction takes 0.5 to 72 hours, depending on the acid used. The reaction in trifluoroacetic acid takes 48-60 hours, preferably 24-60 hours, the reaction in sulphuric acid takes 30-120 minutes, preferably 45-75 minutes, the reaction in phosphoric acid takes 2-10 hours, preferably 4-6 hours. In a highly preferred embodiment of the present invention, the selective removal of the benzyloxycarbonyl protecting group according to the invention is preferably carried out with aqueous sulfuric acid at a concentration of between 40 wt% and 98 wt%, preferably between 80 wt% and 98 wt%, most preferably between 95 wt% and 98 wt%, in such way that the compound of formula (IX) is reacted with preferably 10 to 12 times the volume of concentrated or dilute sulphuric acid at a temperature of between 0 and 30 °C, preferably between 0 and 15 °C, for 30 to 120 minutes, preferably for 45 to 75 minutes. In another highly preferred embodiment of the invention, the removal of the benzyloxy carbonyl protecting group according to the invention is preferably carried out with trifluoroacetic acid by reacting the compound of formula (IX) with preferably 4.5 to 5 times the volume of trifluoroacetic acid at 0-30 °C, preferably 20-25 °C for 48-60 hours, preferably 24-60 hours.

[0089] In another highly preferred embodiment of the present invention, the removal of the benzyloxycarbonyl protecting group according to the invention is carried out with phosphoric acid at a concentration of preferably between 60 wt% and 85 wt%, preferably between 75 wt% and 85 wt%, by reacting the compound of formula (IX) with preferably 12 to 16 times the volume of phosphoric acid at a temperature of between 30 to 80°C, preferably between 50 to 60°C for 2 to 10 hours, preferably 4 to 6 hours.

[0090] In another very preferred embodiment of the present invention, the removal of the benzyloxycarbonyl protecting groupis preferably carried out with an aqueous HBr solution of preferably 20 wt% to 48 wt%, more preferably 40 wt% to 48 wt%, most preferably 48 wt%.

[0091] Removing the Cbz group, the resulting compound of formula (XVI) can be salified to a base if required, or converted from the resulting base to another salt with another acid. The conversion of a compound of formula (XVI) from a base to a salt or from a salt to a base is within the general knowledge of the person skilled in the art.

[0092] The salt of the resulting compound (XVI) can be purified by crystallisation if necessary, or by mixing with a solvent in warm water, or by adding the salt to an aqueous solution and mixing cold with e.g. carbonates such as K- or Na-carbonates or aqueous solutions thereof, and extracting the base from the aqueous solution with a solvent which is slightly miscible or not miscible with water, and then separating the base from the resulting organic solvent solution with an acid of choice as a salt. These methods of purification are methods of general application in organic chemistry and belong to the general knowledge of the person skilled in the art, the salts thus obtained being generally within the scope of our patent. However, salts produced according to the present invention usually do not require further purification.

[0093] The compound of formula

[0094] (XVII) is also the object of the present invention.

[0095] Furthermore, other objectof the present invention is a process for the preparation of the compound of

[0096] (XVII), wherein a compound of formula (XVI) or a compound of general formula

[0097] (XVIxHnA)

[0098] (XVI x HnA), where n is 1, 2, or 3 , A is an anion of an organic or inorganic acid preferably trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or acetate derivative substituted by one or more halogens, such as CCh-COO" or CH3- COO", more preferably trifluoroacetate, sulphate ion, phosphate ion, chloride ion or bromide ion, most preferably trifluoroacetate, or sulphate ion is reacted with carbamoylation agent of formula (VII), (which is, if applicable, prepared in situ) where R may be chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazolyl.

[0099] The procedure can also be done in such a way that it is carried out in a water - organic solvent mixture, preferably a water - aprotic organic solvent mixture, in the pH range 8.5 - 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane or DMF, preferably THF and where the water - organic solvent volume ratio in the mixture is 1 :0,5 - 1 :5, preferably 1 :2, or we can also proceed such that it is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and water, preferably in 2-MeTHF or THF, in the presence of organic bases, preferably in TEA, DIPEA, pyridine, DMAP, DBU, preferably in the presence of DIPEA or TEA in such way that the amount of base used is 2-6 molar equivalent, preferably 2,5-3 molar equivalent.

[0100] The reactiont for the preparation of the compound of formula (XVII) is carried out at a temperature between 10 and 40 °C, preferably between 15 and 25 °C.

[0101] If an aqueous buffer solution, preferably phosphate buffer is used, the reaction is preferably carried out at 10 - 30 °C, preferably at 15 - 20 °C.

[0102] If an organic base is used, the reaction is carried out between 10 - 40 °C, preferably between 15 - 25 °C.

[0103] In the most advantageous form of the procedure of the present invention is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and in water, preferably in 2-MeTHF or THF, in the presence of organic bases preferably TEA, DIPEA, pyridine, DMAP, DBU, more preferably in the presence of DIPEA or TEA, the amount of base used being 2-6 molar equivalent, preferably 2,5-3 molar equivalent, the reaction being carried out at a temperature between 10 and 40 °C, preferably between 15 and 25 °C.

[0104] The subject of our study is also a procedure for the preparation of upadacitinib of the formula (I) Upadacitinib where a compound of formula (IX)

[0105] is reacted with acid to give compound (XVI) or its salt of general formula

[0106] (XVIxHnA)

[0107] (XVI x HnA) where n is 1, 2, or 3, depending on the meaning of A, where A is an anion, preferably a trifluoroacetate ion, a sulfate ion, a phosphate ion, a halide ion, preferably a chloride ion or bromide ion, or acetate derivatives substituted by one or more halogens, such as CCh-COO" or CHa-COO", more preferably trifluoroacetate, sulphate ion, phosphate ion, chloride ion or bromide ion, most preferably trifluoroacetate, or sulphate ion, with the acetylating agent of formula (VII), (prepared in situ in that particular case) where R may be chlorine, bromine, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazole, in aqueous-organic solvent mixture, aqueous buffer, preferably using phosphate buffer in basic medium, at 10 to 30 °C, or in organic solvent using organic base, reacted at 10 to 40 °C, and the compound of formula (XVII) so obtained reacted in an inert atmosphere in an aprotic solvent in the presence of an organic base, in TFAA or other perfluorocarboxylic acid anhydrides at a temperature close to the boiling point of the solvent used and from the compound thus obtained, in some cases without isolation, in an aprotic solvent in the presence of organic or inorganic bases, preferably alkali metal bases, the crude compound of formula (I) is prepared, from which the pharmaceutically acceptable form of the compound of formula (I) is obtained by crystallisation or salt formation.

[0108] The pyrrolidine nitrogen of the compound of formula (XVI) is substituted with the 2,2,2-trifluoroethyl carbamoyl functional group of the final product by means of a carbamoylation agent of general formula (VII), prepared in situ, if desired. For the reaction, a carbamoylation agent known from the literature of the general formula (VII) is used, wherein R is chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazolyl. The compound containing imidazolyl is marked by formula (Vila).

[0109] The in situ synthesis of the compound of formula (Vila) is well known from the literature: to a suspension of CDI in THF under Ar, a solution of 2,2,2-trifluoroethylamine in THF is added upon cooling.

[0110] The procedure can also be done in such way that a.) it is carried out in a water - organic solvent mixture, preferably a water - aprotic organic solvent mixture, in the pH range 8.5 - 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane or DMF, preferably THF and where the water - organic solvent volume ratio in the mixture is 1 :0,5 - 1 :5, preferably 1 :2, or b.) it is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and water, preferably in 2-MeTHF or THF, in the presence of organic bases, preferably TEA DIPEA, pyridine, DMAP, DBU, more preferably in the presence of DIPEA or TEA, in a way that the amount of base used is 2-6 molar equivalent, preferably 2,5-3 molar equivalent.

[0111] The reaction is carried out at a temperature between 10 and 40 °C, preferably between 15 and 25 °C, to give the compound of formula (XVII). If an aqueous buffer solution, preferably phosphate buffer, is used, the reaction is preferably carried out at 10- 30 °C, preferably at 15 - 20 °C.

[0112] If an organic base is used, the reaction is carried out between 10 - 40 °C, preferably between 15 - 25 °C.

[0113] In the most advantageous form of the procedure, of the present invention, the reaction is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and in water, preferably in 2-MeTHF or THF, in the presence of organic bases preferably TEA, DIPEA, pyridine, DMAP, DBU, more preferably in the presence of DIPEA or TEA, in such way that the amount of base used is 2-6 molar equivalent, preferably 2,5-3 molar equivalent, at a temperature between 10 and 40 °C, preferably between 15 and 25 °C.

[0114] This process is more preferable compared to the aqueous buffer process, because the aqueous phosphate buffer system is cumbersome due to the continuous pH control and is less suitable for scale-up.

[0115] One advantage of our method is that the synthesis of the intermediate (XVI) synthetised just before the end product of formula (I) is Pd-free. In the originator's process shown in Figure 2, a heavy metal catalyst is used to produce the last intermediate (XI). Removing this catalyst and - reducing it to below the required 10 ppm level in the final product - causes serious technical problems and generates significant cost increases.

[0116] In the last step of our synthesis, we perform the ring closure of the intermediate of formula (XVII) and the removal of the tosyl protecting group.

[0117] According to a preferred embodiment of our method, the tosylated end product intermediate formed after ring closure is reacted without isolation and the tosyl protecting group is removed. The synthesis can also be carried out by isolating the tosylated intermediate after ring closure and then removing the protecting group.

[0118] The ring closure is carried out in an inert atmosphere, in an aprotic solvent, dioxane, THF, 2-MeTHF, toluene, DCM, DMF, preferably in acetonitrile, in the presence of organic base, TEA, DIPEA, DMAP, dimethyl aniline, preferably pyridine, using TFAA, or other perfluorocarboxylic acid anhydride coupling agent, at a temperature close to the boiling point of the solvent used. Removal of the tosyl group of the protected ring-closed intermediate is carried out in an aprotic solvent, dioxane, THF, acetonitrile, toluene, DCM, DMF, preferably 2-MeTHF, using basic conditions, in the presence of organic or inorganic bases, preferably in the presence of alkali metal bases, for example heated with an aqueous NaOH solution, preferably at 50-55 °C. The crude end product is converted into a pharmaceutically acceptable form by acid-alkaline processing followed by crystallisation or salt formation.

[0119] The cis-trans isomeric transformation occurs to a small extent in all steps with strong acidic or basic character, generating the critical trans impurity or its precursor. The originator's process also uses a basic medium in the last step, giving the possibility of an unfavourable chemical process. Although the last step of the process according to the present invention is also carried out in an alkaline medium, due to the advantageous chemical properties of the intermediate (XVII) produced by our method, the generation of critical impurities is reduced compared to the originator's process, with a beneficial effect on the purity of the final product.

[0120] Intermediates (XVI) and (XVI x HnA) and intermediate (XVII) can be produced by the methods of the present invention with a production of greater than 95% and a purity of greater than 99%. This results in the ring-closure step being carried out with a better impurity profile, without the appearance of impurities and degradation products normally produced in prior art reactions. In the processes described by the originator, significantly more impurities are generated.

[0121] In the final step of the process illustrated in Figure 2, the carbamoylation of the dihydrochloride salt of compound (XI) with compound (VII) also slightly carbamoylates the 3J / -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.

[0122] The final step of the procedure of the present invention is the removal of the protective group of the 3J / -imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at position 3 in alkaline medium. Removal of the tosyl protecting group as a last step allows to obtain a more pure product than the final product obtained by the procedure shown in Figure 3. While the process in Figure 3 uses an acetyl protecting group, we use a tosyl protecting group with a significantly better leaving-group property. The removal of this group requires milder conditions, thus reducing the cleavage of the 2,2,2-trifluoroethylcarbamoyl group in the final product.

[0123] The enantiomeric purity of our process meets the definition of the ICH Q3 Guideline. According to ICH Q3A(R2) guideline, the total procedure should have a maximum of 0.15% specified impurity, a maximum of 0.10% unspecified impurity, a maximum of 0.5% total impurity and an expected purity >99.50%.

[0124] The process according to the present invention, i.e. the production of upadacitinib from the active compound (XVI), can be achieved with a particularly high production yield of more than 70%.

[0125] EXAMPLES

[0126] Further details of the solution according to the present invention are set out in the examples below, without limiting the scope of protection of our invention in any way to those examples.

[0127] Example 1:

[0128] Preparation of benzyl (37?,45)-3-{2-[(ethoxycarbonyl)[5-(4-methylbenzenesulfonyl)-5JT- pyrrolo[2,3-b]pyrazin-2-yl]amino]acetyl}-4-ethylpyrrolidine-l-carboxylate of formula (IX)

[0129] 10.6 g of compound of the formula (VIII) is added into a 500 ml 4-necked flask under Ar and dissolved in 51 ml of dry DMA. Into the resulting dilute suspension, a solution of 3.28 g of LiOtBu in 26.5 ml of dry DMA and a solution of 15.37 g of compound of formula (III) in 24.5 ml of DMA are simultaneously injected at -10 °C under Ar for 30 minutes. 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 in cold condition. Afterwards, the cooling is stopped and 87.5 ml 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 it is allowed to cool down and the procedure is repeated. Filter the suspension, wash with aqueous ethanol and diethyl ether. The product is dried to constant weight.

[0130] Yield: 17.9 g (98.1%), white crystal

[0131] Mp.: 138-138.5 °C

[0132] IR (KBr): 3136, 1729, 1707, 1383, 1371, 1235, 1176, 679 'HNMR (CDCh , 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=18.3 Hz, 1H), 4.78 / 4.77 (d, J=18.3 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, J=7.3 Hz, 3H)

[0133] °CNMR (CDCh, 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

[0134] 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

[0135] NOESY: 3.35 / 3.32-(3.58 / 3.55, 2.40), 2.40-(3.60, 3.35 / 3.32)

[0136] 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

[0137] 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-

[0138] (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)-(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) Example 2:

[0139] Preparation of trifluoroacetic acid salt (XVIxTFA) of the Formula (XVI) compound ethyl N- {2-[(37?,45)-4-ethylpyrrolidin-3-yl]-2-oxoethyl}-7V-[5-(4-methylbenzenesulfonyl)-5J / - pyrrolo[2,3-b]pyrazin-2-yl]carbamate

[0140] Measure 17.8 g of compound (IX) into a flask under Ar and dissolve in 85 ml of anhydrous TFA. The resulting solution is stirred at room temperature for 48 hours. The reaction is checked by HPLC Phenomenex Kinetex F5 column / NH4 OAc / ACN / water = 5 / 95 - ACN / 235 nm). After the reaction has taken place, the reaction mixture is diluted with 510 ml DCM, washed with water and saturated NaCl solution, dried on Na2SO4 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 at 50 °C to constant weight at 10 mbar.

[0141] Yield: 15.76 g (93%), white crystal

[0142] Mp.: 186.5-187 °C

[0143] 'HNMR (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=7A 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).

[0144] °CNMR (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=299.7 Hz), 106.09, 62.71, 56.65, 48.53, 48.34, 45.47, 42.99, 21.32, 20.13, 14.31, 12.59

[0145] 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*

[0146] 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 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, 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, 20.13)

[0147] Example 3:

[0148] Preparation of ethyl A-{2-[(3A,45)-4-ethyl-l-[(2,2,2-trifluoroethyl)carbamoyl]pyrrolidin-3- yl]-2-oxoethyl}-A-[5-(4-methylbenzenesulfonyl)-5Z7-pyrrolo[2,3-b]pyrazin-2-yl]carbamate of formula (XVII)

[0149] 1.

[0150] Suspend 4.35 g CDI in 30 ml dry THF under Ar. Cool the suspension to 8-10 °C and drop in the solution of 1.8 ml trifluoroethylamine made with 5 ml dry THF. The reaction mixture is stirred at room temperature for 1 hour.

[0151] 2.

[0152] Into a mixture of 16 ml dist. water and 36 ml THF, 9.20 g (XVIxTFA) and 4.0 g K2HPO4 are measured under Ar at room temperature. The pH of the mixture is adjusted to 8.5 - 9- by adding a 10% KOH solution. Into the resulting two-phase mixture, the solution of compound N-(2,2,2-trifluoroethyl)-lH-imidazole-l -carboxamide (Vila) prepared according to 1. is added at 15 - 20 °C. During the addition, the pH of the aqueous phase is checked several times and maintained between 8.5 and 9 by adding a 10 % KOH solution. The reaction mixture is stirred for a further 3 hours at room temperature at that pH. The reaction is checked by HPLC (Phenomenex Kinetex F 5 column / NH4 O Ac / ACN / water = 5 / 95 -ACN / 235 nm). The resulting suspension is cooled to 0 - 4 °C and stirred for further 1 hour at this temperature, filtered and washed with DIPE. The filtrate is concentrated, stirred at 0 - 4 °C for 1 hour and 16 ml of cold water is added. Filter the suspension, wash with cold water and DIPE. The two solid fractions are combined, suspended in a mixture of MTBE and toluene, stirred overnight, filtered, washed with MTBE and finally dried to constant weight. Add 22 ml DMA to the crude product and heat to 60 - 70 °C. After complete dissolution, add 30 ml of warm ethanol. The resulting suspension is stirred under warm conditions for a few minutes and allowed to cool slowly. Then heat to 55 - 60 °C, cool slowly to 20 - 22 °C, filter, wash with cold ethanol and MTBE and dry to constant weight.

[0153] Yield: 6.70 g (73%), off-white crystal

[0154] Mp.: 206.5-207 °C

[0155] 1HNMR (DMSO, 600 MHz): 8.79 (s, 1H), 8.25 (d, .J 43) Hz, 1H), 8.00 (~d, J=8.3 Hz, 2H), 7.45 (~d, J=8A Hz, 2H), 6.84 (b, 1H), 6.83 (d, J=4A Hz, 1H), 4.82 (s, 2H), 4.18 (q, J=7 A Hz, 2H), 3.78 (m, 2H), 3.55 (m, 1H), 3.50 (m, 1H), 3.40 (m, 1H), 3.38 (m, 1H), 3.16 (m, 1H), 2.43 (m, 1H), 2.35 (s, 3H), 1.45 (m, 1H), 1.22 (m, 1H), 1.20 (t, J=7 A Hz, 3H), 0.90 (t, . / 7.3 Hz, 3H)

[0156] °CNMR (DMS0, 150 MHz): 204.96, 155.89, 154.40, 147.61, 146.39, 137.88, 136.70, 134.94, 134.32, 131.75, 130.50, 127.72, 125.32 (q, J=279.2 Hz), 106.14, 62.63, 56.08, 49.75, 47.18, 42.84, 41.20 (q, J=33.3 Hz), 21.32, 20.96, 14.27, 12.74

[0157] COSY: 8.25-6.83, 8.00-7.45, 6.84-3.78, 4.18-1.20, (3.55, 3.38)-3.50-2.43*-(3.40, 3.16), 2.43*- (1.45, 1.22)-0.90

[0158] ROESY: 2.43-(3.50, 3.40)

[0159] HSQC (140 Hz): 8.79-134.94, 8.25-131.75, 8.00-127.72, 7.45-130.50, 6.83-106.14, 4.82-56.08, 4.18-62.63, 3.78-41.20, 3.55-47.18, 3.50-49.75, 3.40-49.75, 3.38-47.18, 3.16-49.75, 2.453- 42.84, 2.35-21.32, 1.45-20.96, 1.22-20.96, 1.20-14.27, 0.90-12.74

[0160] HMBC (8 Hz, 140 Hz): 8.79-(147.61, 136.70), 8.25-(137.88, 136.70, 106.14), 8.0-(146.39, 127.72), 7.45-(134.32, 130.53, 21.32), 6.84-155.89, 6.83-(137.88, 136.70, 131.75), 4.82- (204.96, 154.40, 147.61), 4.18-(154.40, 14.27), 3.78-155.89, (3.55, 3.38)-204.96, (3.40, 3.16)- (204.96, 20.96), 2.43-204.96, 2.35-(146.39, 130.50), (1.45, 1.22)-49.75, 1.20-62.63, 0.90- (42.84, 20.96)

[0161] Example 4: Preparation of the (I) formula ((35,4A)-3-ethyl-4-{ l,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) hemihydrate end product (1*14 H2O)

[0162] In a 100 ml flask, 4.0 g of compound formula (XVII) is suspended in 60 ml ACN under inert atmosphere. To the suspension 1.57 ml pyridine is added, followed by the dropwise addition of 5.50 ml TFAA while the mixture was cooling on ice. The mixture is then heated to 75-80 °C and stirred at this temperature for 5 hours and then at room temperature for a further 16 hours. The reaction is checked by HPLC (X-Bridge BEH C18 column / ACN / water / HCOOH = 5 / 95 / 0, 05 - 95 / 5 / 0, 05 / 235 mi).

[0163] The resulting mixture is filtered, the filtrate is evaporated and the residue dissolved in 40 ml 2- MeTHF. 11 ml of 20% NaOH solution is added to the mixture and stirred at 55 °C for 2 hours. The reaction mixture is then cooled and the phases separated. The organic phase is washed with saturated NaCl solution, dried on MgSC , filtered on a celite bed, washed with 2-MeTHF and evaporated. From the evaporation residue n-heptane is evaporated. The resulting material is dissolved in EtOAc, extracted with phosphoric acid and recycled to the organic phase by alkalinisation. The organic phase is washed with a saturated NaCl solution, dried on MgSCU, filtered and evaporated to dryness.

[0164] The resulting 2.20 g of the 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 under vacuum at 45 °C- to constant weight.

[0165] Yield: 1.55 g (62.7%) of off-white crystal

[0166] Mp.: 163-164 °C

[0167] IR (KBr): 3431, 3177, 1656, 1616, 1548, 1399, 1147, 890

[0168] 'HNMR (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) °CNMR (DMSO, 150 MHz): 156.10, 139.13, 134.55, 134.03, 131.65, 125.51, 125.42 (q, J=279A Hz), 121.97, 114.82, 95.01, 49.97, 49.37, 43.28, 41.29 (q, J=33.2 Hz), 37.42, 21.69, 12.3

[0169] COSY: 12.31-7.46-7.02, 7.00-3.89, (3.83, 3.79)-4.37-2.57*-(3.70, 3.28), 2.57*-(l.l l, 0.82)- 0.64.

[0170] NOESY: 4.37-2.57

[0171] 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, 3.83-49.97, 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

[0172] 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-(l 56.10, 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)

[0173] Example 5:

[0174] Ethyl A-{2-[(3A,45)-4-ethylpyrrolidin-3-yl]-2-oxoethyl}-A-[5-(4-methylbenzenesulfonyl)- 5J / -pyrrolo[2,3-b]pyrazin-2-yl]carbamate sulphate salt

[0175] Into a 500 ml 3-necked flask, 250 ml (96%) cc of sulphuric acid is measured and cooled to 0- 10°C. To the concentrated acid, 25 g of benzyl (3A,45)-3-{2-[(ethoxycarbonyl)[5-(4- methylbenzenesulphonyl)-5J / -pyrrolo[2,3-b]pyrazin-2-yl]amino]acetyl}-4-ethylpyrrolidine-l- carboxylate compound of formula (IX) is added in parts with vigorous stirring and then stirred for 30-60 min keeping cold then the processed. The competition of the reaction is checked by HPLC. The cc. sulphuric acid solution is poured slowly over 3 kg of ice water with vigorous stirring, stirred for 2-4 hours and the suspension is filtered. The filtered product is washed with water and, after drying, washed with MTBE. The resulting crude product is taken up in 290 ml of IP A and stirred at 60-70 °C for 2-4 hours and then at room temperature for 6-10 hours. Then filtered and washshed with IPA followed by MTBE, and dried. m= 23.3 g (slightly hygroscopic white powder)

[0176] T~ 99 %

[0177] HPLC: 99.45% Ethyl A-{2-[(3A,45)-4-ethylpyrrolidin-3-yl]-2-oxoethyl}-7V-[5-(4- methylbenzenesulfonyl)-5J / -pyrrolo[2,3-b]pyrazin-2-yl]carbamate sulfuric acid salt + 0.39% trans- Ethyl A-{2-[(35,4A)-4-ethylpyrrolidin-3-yl]-2-oxoethyl}-7V-[5-(4- methylbenzenesulfonyl)-57 / -pyrrolo[2,3-b]pyrazin-2-yl]carbamate sulfuric acid salt Imp. + 0.16% Benzyl-ethyl-7V-{2-[(3A,45)-4-ethyl-l-[(2,2,2-trifluorethyl)carbamoyl]pyrrolidin-3-yl]- 2-oxoethyl }- / ' / -[5-(4-methyl-benzenesulphonyl)-57 / -pyrrolo[2,3-b]pyrazin-2-yl]carbamate Imp.

[0178] Mp.: 157.5-158.5 °C

[0179] IR(KBr): 3435, 1729, 1376, 1225, 1171, 1090, 1063, 591, 574.

[0180] 'HNMR (DMSO, a600): 8.01 (b, 2H), 8.76 (s, 1H), 8.28 (d, J=3.8 Hz, 1H), 8.01 (~d, J=8.0 Hz, 2H), 7.46 (~d, J=7.9 Hz, 2H), 6.83 (d, J=3.8 Hz, 1H), 4.90 (d, J=19.5 Hz, Ih), 4.88 (d, J=19.5 Hz, IH), 4.19 (q, J=6.9 Hz, 2H), 3.67 (m, IH), 3.32 (m, IH), 3.31 (m, 2H), 3.00 (m, IH), 2.54 (m, IH), 2.36 (s, 3H), 1.50 (m, IH), 1.24 (m, IH), 1.21 (t, J=6.9 Hz, 3H), 0.92 (t, J=7.1 Hz, 3H)

[0181] 13CNMR: 205.19, 154.32, 147.53, 146.44, 137.91, 136.81, 135.33, 134.31, 131.88, 130.53, 127.78, 106.10, 62.73, 56.74, 48.68, 48.34, 46.13, 43.03, 21.34, 20.18, 14.33, 12.63.

[0182] COSY: 8.28-6.83, 8.01-7.46, (4.90, 4.88), 4.19-1.21, 3.31-3.67-3.54*-(3.32, 3.00), 2.54*- (1.50, 1.24)-0.92

[0183] HSQC (140 Hz): 8.76-135.33, 8.28-131.88, 8.01-127.78, 7.46-130.53, 6.83-106.10, 4.90- 56.74, 4.88-56.74, 4.19-62.73, 3.67-48.34, 3.32-48.68, 3.31-46.13, 3.00-48.68, 2.54-43.03, 2.36-21.34, 1.50-20.18, 1.24-20.18, 1.21-14.33, 0.92-12.63

[0184] HMBC (8 Hz, 140 Hz): 8.76-(147.53, 136.81), 8.28-(137.91, 136.81, 106.10), 8.01-(146.44, 127.78), 7.46-(134.31, 130.53, 21.34), 6.83-(136.81, 131.88), (4.90, 4.88)-(205.19, 154.32), 4.19-(154.32, 14.33), 3.67-(205.19, 48.68, 46.13, 43.03), (3.32, 3.00)-48.34, 46.13, 43.03), 3.31 -(205.19, 48.34), 2.36-(146.44, 130.53), (1.50, 1.24)-(48.68, 48.34, 43.03), 1.21-62.73, 0.92-43.09

[0185] Example 6:

[0186] Preparation of ethyl A-{2-[(3A,4A)-4-ethyl-l-[(2,2,2-trifluoroethyl)carbamoyl]pyrrolidin-3- yl]-2-oxoethyl}-7V-[5-(4-methylbenzenesulfonyl)-5J / -pyrrolo[2,3-b]pyrazin-2-yl]carbamate of Formula (XVII):

[0187] 1.

[0188] In a 250 ml flask, 12 g of CDI is measured under Ar and suspended in 85 ml of dry 2-MeTHF. The solution of 6.25 ml trifluoroethylamine in 30 ml 2-MeTHF is injected into the suspension over 20-25 minutes while cooling with water (5-10 °C). After addition, the reaction mixture is stirred for 1-2 hours at room temperature.

[0189] 2.

[0190] Into a 1000 ml 3-necked flask at room temperature, 25 g UP D32, 400 ml 2-MeTHF and 21.60 ml DIPEA are added under Ar. The resulting yellow suspension is stirred at room temperature for 15 minutes, then the solution prepared in point 1 is slowly added under Ar at 10-15 °C and the reaction mixture is stirred at room temperature for 2-4 hours. Then 200 ml of water is added, stirred for 30-45 minutes and the reaction is checked by HPLC measurement. The reaction mixture is extracted with DCM and the organic phase is evaporated on a rotation film evaporator. The resulting material is suspended in MTBE, stirred at room temperature for 8-12 hours, filtered, washed with water and MTBE, dried. m= 24.35 g (white powder)

[0191] Yield:- 94.1 %

[0192] HPLC: 99.76% Etil-A-{2-[(3A,4Y)-4-etil-l-[(2,2,2-trifluoretil)karbamoil]pirrolidin-3-yl]-2- oxoetil}-A-[5-(4-metil-benzolszulfonil)-5J7-pirrolo[2,3-b]pirazin-2-il]karbamat + 0.11% transz-Etil-A-{2-[(35,4A)-4-etil-l-[(2,2,2-trifluoretil)karbamoil]pirrolidin-3-yl]-2-oxoetil}-A- [5-(4-metil-benzol-szulfonil)-5J / -pirrolo[2,3-b]pirazin-2-il]karbamat Imp. + 0.02% Benzil-etil- A-{2-[(3A,45)-4-etil-l-[(2,2,2-trifluoretil)karbamoil]pirrolidin-3-il]-2-oxoetil}-A-[5-(4-metil- benzolszulfonil)-5J7-pirrolo[2,3-b]pirazin-2-il]karbamat Imp.

[0193] Mp.: 191-192 °C

[0194] Example 7:

[0195] Form C compound of formula (I) ((35,4A)-3-ethyl-4-{ l,5,7,10-tetraazatricyclo[7.3.0.02’6]dodeca-2(6),3,7,9,l l-pentaen-12-yl}-A-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide)

[0196] Into a 500 mL reactor under Ar, 30.0 g of ethyl A-{2-[(3A,45)-4-ethyl-l-[(2,2,2- trifluoroethyl)carbamoyl]pyrrolidin-3-yl]-2-oxoethyl}-A-[5-(4-methylbenzenesulphonyl)-5JT- pyrrolo[2,3-b]pyrazin-2-yl]carbamate of formula (XVII) is loaded and suspended in 360 mL ACN. 12.95 ml of pyridine, then subsequently 45.8 ml of TFAA are slowly added under argon while cooling on ice. Then the mixture is heated to 75-80 °C, stirred at this temperature for 6- 8 hours, and stirred at room temperature for a further 8-12 hours. The reaction is checked by HPLC X-Bridge BEH C18 column / ACN / water / HCOOH = 5 / 95 / 0.05 - 95 / 5 / 0.05 / 235 nm). The reaction mixture is evaporated on a rotary evaporator and the thick oily cream is dissolved in 300 ml 2-MeTHF and stirred with 90 ml fresh 20 % NaOH at 50-60 °C for 1-2 hours. Then separate the phases, wash the organic part with saturated NaCl, then stirred with mixture of Na2SO4, celite and silica gel and filtered.

[0197] To the 2-MeTHF solution 360 ml of 0.5 M H3PO4 solution is added. Bubble argon over the mixture and stir for 20 minutes. The phases are then separated. The extraction is repeated until the product is visible in the organic phase. To the combined phosphoric acid solution EtOAc is added then pH is adjusted to 6 with 2M NaOH and the phases are separated after 20 minutes of stirring. To the aqueous phase EtOAc is added again and separated after a few minutes of mixing. The pH of the aqueous phase is then adjusted to 6.5 with 2M NaOH and extracted with EtOAc. The extraction is repeated until a product is visible in the aqueous phase.

[0198] The combined EtOAc phase is washed with saturated NaCl, dried, filtered and concentrated to 65.1 ml. To the concentrated EtOAc solution 1.20 ml of water is added with vigorous stirring. The resulting suspension is stirred for 1-2 hours at room temperature, then 7.92 ml of n-heptane is added and stirred for 2-4 hours. The suspension is filtered and washed with EtAc / water / n- heptane=90 / l / 20, and finally the filtrate is dried. m= 13.7 g (grey powder)

[0199] Yield: 74 %

[0200] HPLC : 99.96% upadacitinib product + 0.04% ethyl-upadacitinib Imp.

[0201] Morphology: form C

[0202] Enantiomer: 100 % ee

[0203] KF: 2.39%

[0204] GC OVI:

[0205] ACN: 18 ppm

[0206] 1-acetate: 2169 ppm

[0207] Me-THF: 17 ppm n-Heptane: 6 ppm pyridine: 77 ppm

[0208] The Form C modalities of upadacitinib as described in international patent application WO2017066775 were tested using the following apparatus and method of measurement: Equipment: PANalytical Empyrean X-ray powder diffractometer

[0209] Measurement setup: Transmission

[0210] X-ray tube

[0211] Type: Empyrean long fine focus, high resolution tube

[0212] Anode: Cu

[0213] Wavelength: Ka (1.541874 A)

[0214] Focus: line focus

[0215] Source-side optical elements

[0216] Divergence gap: Fixed gap 1 / 2°

[0217] Mirror: Focusing elliptical mirror

[0218] Soller gap: 0,04 rad

[0219] Anti-dispersion gap: Fixed gap 1 / 2 °

[0220] Diffracted side optical elements

[0221] Anti-spill gap: Programmable gap in fixed mode: 1 / 2 °

[0222] Soller gap: 0,04 rad

[0223] Sample table

[0224] Type: Reflective-transmissive, with rotating sample holders

[0225] Rotation speed: 1 revolution per second

[0226] Direct beam pliers

[0227] ("beam knife"): Transmission

[0228] Detector

[0229] Type: PIXcel 3D 1 ^ 1 area detector

[0230] Operating mode: Sweeping line detector (ID) mode

[0231] Active detector window dimension: 3.3473°

[0232] Sample preparation: inserting samples between two Mylar films, without powdering Measurement conditions

[0233] Temperature: room temperature

[0234] Accelerating voltage: 45 kV

[0235] Anode current: 40 mA

[0236] Method of scan: continuous (9 / 9) sweep

[0237] Range: 2.0000 - 34.9964 29°

[0238] Step interval: 0.0131 29°

[0239] Time per step: 109.650 seconds

[0240] Number of measurement cycles: 1

[0241] Measurement time: 20 minutes

Claims

PATENT CLAIMS1. A process for the preparation of upadacitinib, characterized in that the compound of formula (XVII)is reacted in an inert atmosphere in an aprotic solvent in the presence of an organic base with TFAA or other perfluorocarboxylic acid anhydrides at a temperature close to the boiling point of the solvent used and the compound thus obtained, optionally without isolation, in an aprotic solvent in the presence of organic or inorganic bases, preferably alkali metal bases, the crude compound of formula (I) is prepared, from which the pharmaceutically acceptable form of the compound of formula (I) is obtained by crystallisation or salt formation.

2. The process according to claim 1 for preparation of upadacitinib of formula (I)Upadacitinib characterised in that the compound of formula (XVII) is prepared by reacting the compound of formula (XVI)or(XVIxHnA) its salt of general formula (XVI x HnA), where n is 1, 2, or 3, depending on the meaning of A, where A is an anion, preferably a trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or acetate derivative substituted by one or more halogens, such as CCh-COO'or CHa-COO", more preferably trifluoroacetate, sulphate ion, phosphate ion, chloride ion or bromide ion, even more preferably trifluoroacetate, or sulphate ion, with the carbamoylation agent of formula (VII), prepared in situ if applicable,where R may be chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably reacted with an imidazolyl group.

3. The process according to claim 2 for the preparation of upadacitinib (I) characterized in that the compound of formula (XVI) or its salt of general formula (XVI x HnA) wherein n and A are as defined in claim 2, is prepared by reacting the compound of formula (IX)with acid.

4. A process according to any one of claims 1-3 for the preparation of upadacitinib of formula (I) characterized in that the aprotic solvent in which the compound of formula (XVII) is reacted is dioxane, THF, 2-MeTHF, toluene, DCM, DMF, preferably acetonitrile; and the organic base is TEA, DIPEA, DMAP, dimethyl aniline, preferably pyridine.

5. A process according to any one of claims 2-4 for the preparation of upadacitinib of formula (I) characterised in that the compound of formula (XVII) is prepared by carrying out the reaction in a way in which a.) it is carried out in a water - organic solvent mixture, preferably a water - aprotic organic solvent mixture, in the pH range 8.5 - 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane or DMF, preferably THF and where the water - organic solvent volume ratio in the mixture is 1 :0.5 - 1 :5, preferably 1 :2, or b.)it is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and water, preferably in 2-MeTHF or THF, in the presence of organic bases, preferably TEA, DIPEA, pyridine, DMAP, DBU, more preferably in the presence of DIPEA or TEA, and the amount of base used being 2-6 molar equivalent, preferably 2.5-3 molar equivalent.

6. A process according to any one of claims 2 to 5 for the preparation of upadacitinib of formula (I), characterized in that during the preparation of compound of formula (XVII) the reaction is carried out at a temperature of between 10 and 40 °C, preferably between 15 and 25 °C.

7. A process according to any one of claims 3 to 6 for the preparation of upadacitinib of formula (I) characterized in that the Cbz protecting group of the compound of formula (IX) is cleaved in an organic solvent or without it, with a mineral or organic acid absorbed or dissolved in an aqueous or organic solvent or a mixture thereof, preferably with trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or with acetic acid derivatives substituted by one or more halogens, preferably with CCh-COOH or CH3-COOH, more preferably with trifluoroacetic acid, sulphuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide, most preferably with trifluoroacetic acid, sulphuric acid, phosphoric acid or an aqueous solution of HBr, and the resulting compound of general formula (XVI) is recovered as a base or a salt of general formula (XVI x HnA).

8. A process according to claim 7 for the preparation of upadacitinib of formula (I) characterized in that the cleavage of the Cbz protecting group of the compound of formula (IX) is carried out in trifluoroacetic acid, or in aqueous sulfuric acid of a concentration of between 40 wt% and 98 wt%, preferably between 80 wt% and 98 wt%, most preferably between 95 wt% and 98 wt%, or in phosphoric acid of a concentration between 60 wt% and 85 wt%, preferably between 75 % and 85 % by weight, or in an aqueous HBr solution of between 20 % and 48 % by weight, preferably between 40 % and 48 % by weight, most preferably 48 % by weight, or in HC1 or HBr gas absorbed in alcohols, acetic acid or ether-type solvents.

9. Compound of formula (XVI)and salt with the general formula(XVIxHnA)(XVI x HnA), where n is 1, 2, or 3, A is an anion of an organic or inorganic acid, and a compound of formula(XVII)10. Process for the preparation of compound of formula (XVI) and its salts according to claim 9, characterized in that the Cbz protecting group of the compound of formula (IX) in an organic solvent or without it, is reacted with a mineral or organic acid absorbed or dissolved in anaqueous or organic solvent or a mixture thereof, preferably with trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or with acetic acid derivatives substituted by one or more halogens, preferably with CCh-COOH or CH3-COOH, more preferably with trifluoroacetic acid, sulphuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide, most preferably with trifluoroacetic acid, sulphuric acid, phosphoric acid or an aqueous solution of HBr, and the resulting compound of general formula (XVI) is recovered as a base or a salt of general formula (XVI x HnA).

11. A process of claim 9 for the preparation of the compound of formula (XVI) and salts thereof, characterized in that the cleavage of Cbz protecting group of the compound of formula (IX) is carried out in trifluoroacetic acid, or in aqueous sulfuric acid at a concentration of between 40 wt% and 98 wt%, preferably between 80 wt% and 98 wt%, most preferably between 95 wt% and 98 wt%, or in phosphoric acid at a concentration between 60 % and 85 % by weight, preferably between 75 % and 85 % by weight, or in an aqueous HBr solution between 20 % and 48 % by weight, preferably between 40 % and 48 % by weight, most preferably 48 % by weight, or in HC1 or HBr gas absorbed in alcohols, acetic acid or ether-type solvents.

12. Process for the preparation of the compound of formula(XVII) according to claim 9 characterised in that the compound of formula (XVI) or its salt form of the general formula (XVI x HnA), wherein n is 1,2 or 3, depending on the meaning of A, and A is an anion, preferably a trifluoroacetate ion, a sulphate ion, a phosphate ion, a halide ion, preferably a chloride ion or a bromide ion, or an acetate derivative with one or more substituted halogens, such as CCh-COO'or CHs-COO", preferably trifluoroacetate, sulfate ion,phosphate ion, chloride ion or bromide ion, most preferably trifluoroacetate, or sulfate ion, is reacted with the carbamoylation agent of formula (VII), optionally prepared in situ,where R is chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably an imidazolyl group.

13. A process according to claim 12 for the preparation of a compound of formula (XVII), characterised in that the process comprises wherein a.) it is carried out in a water - organic solvent mixture, preferably a water - aprotic organic solvent mixture, in the pH range 8.5 - 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane or DMF, preferably THF and where the water - organic solvent volume ratio in the mixture is 1 :0.5 - 1 :5, preferably 1 :2, or b.) it is carried out in water-miscible and non-miscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IP Ac and water, preferably in 2-MeTHF or THF, in the presence of organic bases, DIPEA, pyridine, DMAP, DBU, preferably in the presence of DIPEA or TEA, wherein the amount of base used being 2-6 molar equivalent, preferably 2.5-3 molar equivalent.

14. The process according to any one of claims 12 and 13 for producing the compound of formula (XVII), characterized in that the reaction is carried out at a temperature between 10 and 40°C, preferably between 15 and 25 °C.

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