Processes and intermediates for the preparation of upadacitinib

Abstract

The present invention relates to a process for preparing compounds of formula (I) using Weinreb amide (III) or its equivalent as a key intermediate, which is a useful intermediate in the synthesis of upadacitinib and structurally related compounds. [Formula 1] TIFF2023510111000118.tif92157

Description

[Technical field]

[0001] The present invention relates to processes for the preparation of compounds that are useful intermediates in the synthesis of Upadacitinib. [Background technology]

[0002] (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (upadacitinib) is a Janus kinase (JAK) inhibitor. [ka]

[0003] Upadacitinib (also known as ABT-494) is a potent and selective JAK1 inhibitor developed by AbbVie. Upadacitinib is FDA-approved for the treatment of rheumatoid arthritis.

[0004] Several methods for the synthesis of upadacitinib have been described in the literature, all based largely on a similar approach, namely the preparation of so-called fragment A and fragment B (pyrrolidine derivatives) followed by coupling thereof, followed by cyclization to provide the imidazopyrrolopyrazine scaffold, which upon derivatization, yields upadacitinib. [ka]

[0005] WO 2013 / 043826 discloses in Example 12 a method for preparing cis-(3R,4S)-benzyl-4-ethyl-3-(2-bromoacetyl)pyrrolidine-1-carboxylate. [ka]

[0006] In this method, racemic cis-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid (5) is first prepared. The (3R,4S) enantiomers are then separated by formation of the diastereomeric (naphthalenyl)ethaneammonium salts. Finally, in step E, treatment of the intermediate acid chloride with trimethylsilyldiazomethane affords compound 7, which is unstable and highly toxic. [ka]

[0007] WO 2017 / 066775 discloses the preparation of cis-(3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylate by formation of the sulfoxonium salt followed by treatment with LiBr. [ka]

[0008] However, the inventors of the present invention have found that the basic conditions required for the preparation of the sulfoxonium salt and also for the subsequent bromine addition reaction result in partial isomerization to the trans isomer (see Comparative Experiments 19 and 20 herein), necessitating further purification to obtain the pure product, and the product thus obtained is in reduced yield.

[0009] WO 2017 / 066775 discloses the preparation of the starting material (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid by asymmetric hydrogenation. [ka]

[0010] Finally, WO 2019 / 016745 discloses a method for preparing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid using (1R)-2,10-camphorsultam as the chiral auxiliary. [ka]

[0011] This approach further requires the use of 2-pentynoic acid as a starting material, which is not easy to prepare and increases the cost of the process.

[0012] Therefore, there is a need to develop new processes for obtaining intermediates in the synthesis of upadacitinib and related compounds that overcome all or part of the problems associated with known processes in the art. Summary of the Invention

[0013] The present invention is directed to the problem of providing a novel process for the preparation of a compound of formula (I), which is a useful intermediate in the synthesis of upadacitinib and structurally related compounds. In particular, the inventors have found that by using a Weinreb amide of formula (III) or a triazine ester of formula (IV) as a key intermediate, the compound of formula (I) can be successfully obtained industrially, economically and without the need for highly toxic reagents.

[0014] Furthermore, the inventors have found that isomerization of the pyrrolidine ring to the trans isomer does not occur in the method of the present invention. In contrast, the conditions required in the method disclosed in WO 2017 / 06677 for the preparation of sulfoxonium salts and subsequent bromine addition reaction result in biased isomerization of cis-pyrrolidine to the trans isomer (see Comparative Experiments 19 and 20 herein).

[0015] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, - - - is a single bond or a double bond, X is a leaving group, and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof, comprising the steps of: (a) Formula (II): [ka] (In the formula, - - - is a single bond or a double bond, Y is OH, Cl, OR 2 and O.C.(O)R. 2 (R 2 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl), and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof, Formula (III) or Formula (IV): [ka] (In the formula, - - - is a single or double bond, and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof; and (b) the steps of: (bi) reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi, Formula (V): [ka] (In the formula, - - - is a single or double bond, and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof; (bii) a ketone of formula (V) or a salt or solvate thereof, Formula (VI) or Formula (VII): [ka] (In the formula, - - - is a single bond or a double bond, R 1 is selected from H and an amino protecting group; R 3 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)Alkyl, C6-C 15 aryl, COR′, and SiR′3, each R′ being independently selected from C 1~6 Alkyl, C3-C 10 Cycloalkyl, C 6~15 Aryl and (C6-C 15 ) aryl(C1-C6) alkyl), and R 4 and R 5 are independently C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; or a salt or solvate thereof, or an enamine or a salt or solvate thereof; and (biii) converting an enol ether of formula (VI) or a salt or solvate thereof, or an enamine of formula (VII) or a salt or solvate thereof, into a compound of formula (I) or a salt or solvate thereof, or (bi') reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to provide a compound of formula (I) or a salt or solvate thereof, or (bi″) reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof with R 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 React with O-CH2-MgBr Formula (VIII): [ka] (In the formula, - - - is a single bond or a double bond, R 1 is selected from H and an amino protecting group, and R 6 is selected from H, -COR' and -CONR'R'', where R' and R'' are independently C1-C6 alkyl, C6-C 15 Aryl, and (C6-C 15 ) aryl(C1-C6) alkyl) or a salt or solvate thereof; and (bii'') converting a compound of formula (VIII) or a salt or solvate thereof into a compound of formula (I) or a salt or solvate thereof converting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof, into a compound of formula (I) or a salt or solvate thereof, by a process comprising the steps of: The present invention is directed to a method comprising the steps of:

[0016] In another aspect, the present invention is directed to a process for preparing upadacitinib or a salt or solvate or stereoisomer thereof, comprising the steps of preparing a compound of formula (I) or a salt or solvate thereof by a process defined in the first aspect of the invention and converting said compound to upadacitinib.

[0017] In a further aspect, the present invention provides a compound of the formula: [ka] TIFF0007648027000015.tif131163 (in the formula, R 1 is selected from H and an amino protecting group; R 3 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)Alkyl, C6-C 15 aryl, COR′, and SiR′3, each R′ being independently selected from 1~6 Alkyl, C3-C 10 Cycloalkyl, C 6~15 Aryl and (C6-C 15 ) aryl(C1-C6) alkyl); R 4 and R 5 are independently C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; and R' is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl) or a salt or solvate thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The term "alkyl" refers to a straight or branched chain alkane derivative containing from 1 to 6 ("C1-C6 alkyl"), preferably 1 to 3 ("C1-C3 alkyl") carbon atoms and attached to another molecule by a single bond. Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, and hexyl.

[0019] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing from 2 to 6 ("C2-C6 alkenyl"), preferably from 2 to 3 carbon atoms, containing at least one double bond, and connected to another molecule by a single bond. Illustrative examples of alkenyl include ethenyl, propenyl, allyl, butenyl, and 1-methyl-2-buten-yl.

[0020] The term "haloalkyl" refers to an alkyl group, as defined above, in which at least one hydrogen atom is replaced with a halogen. Examples of haloalkyl groups include, but are not limited to, CF3, CCl3, CHF2, and CF2CF3.

[0021] The term "aryl" refers to an aromatic group having from 6 to 15, preferably from 6 to 10, carbon atoms and containing one, two or three aromatic nuclei fused together. Illustrative examples of aryl groups include phenyl, naphthyl, indenyl, phenanthryl, and the like. Preferably, the aryl group is phenyl.

[0022] "(C6~C 15 The term "aryl(C1-C6)alkyl" refers to an alkyl group, as defined above, substituted with an aryl group, as defined above. Examples of such groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and the like. Preferably, the (C6-C 15 ) The aryl(C1-C6)alkyl group is benzyl.

[0023] The term "halogen" refers to bromine, chlorine, iodine or fluorine.

[0024] "C3~C 10 The term "cycloalkyl" refers to a mono- or bicyclic ring system containing from 3 to 10, preferably 3 to 7, carbon atoms ("C3-C7 cycloalkyl"). Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing 3 to 15, preferably 3 to 10, more preferably 5 to 7 ring atoms containing one or more, especially 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, with the remaining ring atoms being carbon. Illustrative examples of heterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine, piperazine, piperidine, azepane and [1,4]dioxane.

[0026] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic or tricyclic system containing from 3 to 15, preferably from 3 to 10, more preferably from 5 to 7 ring atoms including one or more, particularly 1, 2, 3 or 4, ring heteroatoms independently selected from O, N and S, with the remaining ring atoms being carbon.

[0027] The term "amino protecting group" (APG) refers to a group that blocks an NH functionality for subsequent reaction that can be removed under controlled conditions. Amino protecting groups are well known in the art. Illustrative examples of amino protecting groups are described by Green TW et al. in "Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons. Virtually any amino protecting group can be used and incorporated in the practice of the present invention. Illustrative non-limiting examples of APGs include: -Carbamic acid ester [-COOR]. R is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6 alkyl)silane. Examples of carbamates include methyl carbamate (MOC), ethyl carbamate, t-butyl carbamate (Boc), benzyl carbamate (CBz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halobenzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate, trichloroethyl carbamate (Troc), trimethylsilylethyl carbamate (Teoc), trimethylsilyl carbamate, triisopropylsilyl carbamate; -amide [-COR]. R is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl. Examples of amides include acetamide, phenylacetamide, haloacetamide (e.g., chloroacetamide, trichloroacetamide, trifluoroacetamide), benzamide, picolinamide; -Amine [-R]. R is C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. Examples of amines include methylamine, tert-butylamine, benzylamine, p-methoxybenzylamine, 3,4-dimethoxybenzylamine, allylamine, methoxymethylamine, triphenylmethylamine, benzoylamine, dinitrophenylamine, p-methoxyphenylamine, o-methoxyphenylamine, trimethylsilylethoxymethylamine, triphenylmethylamine; -Sulfonamide [-SO2R]. R is C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15Aryl, (C6-C 15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl. Examples of sulfonamides include methanesulfonamide, trifluoromethanesulfonamide, t-butylsulfonamide, trimethylsilylethanesulfonamide, benzylsulfonamide, p-toluenesulfonamide, benzenesulfonamide, o- or p-nitrobenzenesulfonamide, dinitrobenzenesulfonamide, naphthalenesulfonamide, pyridine-2-sulfonamide; And, -silylamine [-Si(R)(R')(R'')]. R, R' and R'' are C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, and (C6-C 15 )aryl(C1-C6)alkyl. Examples of silylamines include trimethylsilylamine, triethylsilylamine, tert-butyldimethylsilylamine, tert-butyldiphenylsilylamine, tri-isopropylsilylamine, and triphenylsilylamine.

[0028] The term "leaving group" refers to a functional group or atom that can be replaced with another functional group in a substitution reaction, such as a nucleophilic substitution reaction. Suitable leaving groups are well known in the art. In certain embodiments, the leaving group is a halogen, a C1-C6 alkylsulfonic acid group, a C1-C6 haloalkylsulfonic acid group, a C6-C7 alkylsulfonic acid group, such as, for example, chlorine, bromine, iodine, mesylate, triflate, tosylate, nosylate, and the like. 10 Arylsulfonic acid group, and (C1-C6) alkyl (C6-C 10 ) arylsulfonic acid groups.

[0029] As is understood in the art, the radicals may have some degree of substitution. Thus, any of the radicals of the present invention may have substitution. The radicals may be substituted at one or more available positions with one or more substituents. The substituents include, by way of example and without limitation, C 1~6 Alkyl, C1-C6 haloalkyl, C 3~10 Cycloalkyl, C6-C 10 Aryl, (C6-C 10 )aryl(C1-C6)alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, halogen, -CN, NO2, CF3, -N(R a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f , -C(O)N(R g )(R h ), -OC(O)R i and R a , R b , R c , R d , R e , R f , R g , R h and the above R i are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, (C6-C 15 ) aryl(C1-C6)alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl and trifluoromethyl.

[0030] The present invention also provides "salts" of the compounds described herein. By way of example, the salts may be acid addition salts, base addition salts or metal salts, and may be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods known in the art. Such salts are generally prepared, for example, by reacting the compound in free acid or free base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are preferred. Illustrative examples of the acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and the like; organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, camphorsulfonate, and the like. Illustrative examples of base addition salts include inorganic basic salts, such as ammonium salts, and organic basic salts, such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, amino acid basic salts. Illustrative examples of metal salts include sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and lithium salts. In certain embodiments, the salt is an acid addition salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, or camphorsulfonate. Preferably, it is selected from the salts of HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citric acid, and fumaric acid.

[0031] Similarly, the compounds described herein can be obtained either as free compounds or as solvates (e.g., hydrates, alcoholates, etc.), and both forms are included within the scope of the present invention. Solvation methods are known in the art. Preferably, the solvate is a hydrate.

[0032] The term "organic solvent" includes, for example, cyclic and acyclic ethers (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g., pentane, hexane, heptane), halogenated solvents (e.g., dichloromethane, chloroform), aromatic solvents (e.g., toluene, xylene), ketones (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g., EtOAc, iPrOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA), alcohols (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), sulfoxides (DMSO), and mixtures thereof.

[0033] The term "aprotic organic solvent" refers to any organic solvent that does not generate a proton under reaction conditions. Suitable examples include, but are not limited to, cyclic and non-cyclic ethers (e.g., Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g., pentane, hexane, heptane), halogenated solvents (e.g., dichloromethane, chloroform), aromatic solvents (e.g., toluene, xylene), ketones (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g., EtOAc, iPrOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA), sulfoxides (DMSO) and mixtures thereof.

[0034] In a first aspect, the present invention is directed to a process (the process of the present invention) for preparing a compound of formula (I) or a salt or solvate thereof from a compound of formula (II) or a salt or solvate thereof.

[0035] In one embodiment, the method of the present invention comprises administering to a subject a compound of formula (I), - - - is a double bond, a compound of formula (I″)) or a salt or solvate thereof is reacted with a compound of formula (II) - - - is a double bond, the compound of formula (II″) or a salt or solvate thereof. Thus, in certain embodiments, - - - represents a double bond in the compounds of the present invention (compounds (I″), (II″), (III″), (IV″), (V″), (VI″), (VIII″)).

[0036] In a preferred embodiment, the method of the present invention comprises the step of: - - - is a single bond) or a salt or solvate thereof.

[0037] In one embodiment, the method of the present invention comprises administering to a subject a compound of formula (I), - - - is a single bond, a compound of formula (I') or a salt or solvate thereof is reacted with a compound of formula (II) - - - is a single bond), or a salt or solvate thereof. - - - represents a single bond in the compound of the present invention (compounds (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), and (VIII')). It is preferably a cis single bond, and more preferably a cis-3R single bond.

[0038] In another embodiment, the method of the present invention comprises the step of: - - - is a single bond, a compound of formula (I') or a salt or solvate thereof is reacted with a compound of formula (II) - - -is a double bond) or a salt or solvate thereof. In that case, the process of the present invention further comprises the step of hydrogenating the double bond. The hydrogenation can be carried out at any stage of the process, i.e., before or after any of the steps of the process of the present invention. For example, the hydrogenation step can be carried out after step (a), or after step (bi), or after step (bii), or after step (biii), or after step (bi'), or after step (bi"), or after step (bii").

[0039] In certain embodiments, the method of the present invention comprises: - Formula (II) (in the formula - - - is a double bond), or a salt or solvate thereof, to obtain a compound of formula (II) - - - is a single bond), or a salt or solvate thereof; and - Formula (II) (in the formula - - - is a single bond), or a salt or solvate thereof, is - - - is a single bond), - - - is a single bond), or a salt or solvate thereof.

[0040] In another embodiment, the method of the present invention further comprises: - Formula (II) (in the formula - - - is a double bond), or a salt or solvate thereof, - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof; - Formula (III) (in formula - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof, to obtain a compound of formula (III) - - - is a single bond) or formula (IV) - - - is a single bond), or a salt or solvate thereof; and - The following steps: (i) Formula (III) (in the formula - - - is a single bond) or formula (IV) - - - is a single bond) or a salt or solvate thereof with MeMgCl, MeMgBr, or MeLi to obtain a compound of formula (V), - - - is a single bond), or a salt or solvate thereof; (ii) Formula (V) (in the formula - - - is a single bond), or a salt or solvate thereof, - - - is a single bond) or formula (VII) - - - is a single bond), into an enol ether or a salt or solvate thereof or an enamine or a salt or solvate thereof; and (iii) Formula (VI) (in the formula - - - is a single bond) or formula (VII) - - - is a single bond), or a salt or solvate thereof, or an enamine or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof; or (i') Formula (III) (in formula - - - is a single bond) or formula (IV) - - - is a single bond), or a salt or solvate thereof, with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to obtain a compound of formula (I), - - - is a single bond, or a salt or solvate thereof; or (i'') Formula (III) (in formula - - - is a single bond) or formula (IV) - - - is a single bond), or a salt or solvate thereof, 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 O-CH2-MgBr to give a compound of formula (VIII), - - -is a single bond, or a salt or solvate thereof; and (ii'') Formula (VIII) (in formula - - - is a single bond), or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof; by a process comprising the steps of: - - - is a single bond) or (IV) (wherein - - - is a single bond), or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof.

[0041] In another embodiment, the method of the present invention further comprises: - Formula (II) (in the formula - - - is a double bond), or a salt or solvate thereof, - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof; and - The following steps: (i) Formula (III) (in the formula - - - is a double bond) or formula (IV) - - - is a double bond) or a salt or solvate thereof with MeMgCl, MeMgBr, or MeLi to obtain a compound of formula (V), - - - is a double bond), or a salt or solvate thereof; (ii) Formula (V) (in the formula - - - is a double bond), or a salt or solvate thereof, to obtain a compound of formula (V), - - - is a single bond), or a salt or solvate thereof; (iii) Formula (V) (in the formula - - - is a single bond), or a salt or solvate thereof, - - - is a single bond) or formula (VII) - - -is a single bond), into an enol ether or a salt or solvate thereof or an enamine or a salt or solvate thereof; and (iv) Formula (VI) (in formula - - - is a single bond) or formula (VII) - - - is a single bond), or a salt or solvate thereof, or an enamine or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof; By a process including Formula (III) (in the formula - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof.

[0042] In another embodiment, the method of the present invention comprises: - Formula (II) (in the formula - - - is a double bond), or a salt or solvate thereof, - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof; and - The following steps: (i) Formula (III) (in the formula - - - is a double bond) or formula (IV) - - - is a double bond) or a salt or solvate thereof with MeMgCl, MeMgBr, or MeLi to obtain a compound of formula (V), - - - is a double bond), or a salt or solvate thereof; (ii) Formula (V) (in the formula - - - is a double bond), or a salt or solvate thereof, - - - is a double bond) or formula (VII) - - - is a double bond), (iii) Formula (VI) (in the formula - - - is a double bond) or formula (VII) - - - is a double bond), or a salt or solvate thereof, or an enamine or a salt or solvate thereof, - - - is a double bond), or a salt or solvate thereof; and (iv) Formula (I) (in the formula - - - is a double bond), or a salt or solvate thereof, to obtain a compound represented by formula (I), - - - is a single bond), or a salt or solvate thereof; or (i') Formula (III) (in formula - - - is a double bond) or formula (IV) - - - is a double bond) or a salt or solvate thereof with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to obtain a compound of formula (I), - - - is a double bond), or a salt or solvate thereof; and (ii') Formula (I) (in the formula - - - is a double bond), or a salt or solvate thereof, to obtain a compound represented by formula (I), - - - is a single bond), or a salt or solvate thereof; or (i'') Formula (III) (in formula - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof, 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 O-CH2-MgBr to give a compound of formula (VIII), - - - is a double bond, or a salt or solvate thereof; (ii'') Formula (VIII) (in formula - - - is a double bond), or a salt or solvate thereof, - - -is a double bond), or a salt or solvate thereof; and (iii') Formula (I) (in the formula - - - is a double bond), or a salt or solvate thereof, to obtain a compound represented by formula (I), - - - is a single bond), or a salt or solvate thereof; by a process comprising the steps of: - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof.

[0043] In another embodiment, the method of the present invention further comprises: - Formula (II) (in the formula - - - is a double bond), or a salt or solvate thereof, - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof; and - The following steps: (i'') Formula (III) (in formula - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof, 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 O-CH2-MgBr to give a compound of formula (VIII), - - - is a double bond, or a salt or solvate thereof; (ii'') Formula (VIII) (in formula - - - is a double bond), or a salt or solvate thereof, to obtain a compound of formula (VIII) - - - is a single bond, or a salt or solvate thereof; and (iii'') Formula (VIII) (in formula - - -is a single bond), or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof; by a process comprising the steps of: - - - is a double bond) or formula (IV) - - - is a double bond), or a salt or solvate thereof, - - - is a single bond), or a salt or solvate thereof.

[0044] The method of the invention may, if desired, include one or more of the following steps, in any order: - Amino protecting group (R 1 ) and / or - Amino group (R 1 ) protection.

[0045] Any of these steps can be carried out at any stage of the method of the invention. For example, protection of the amino group and / or addition of an amino protecting group (R 1 The removal of the amino protecting group can be carried out after step (a), or after step (bi), or after step (bii), or after step (biii), or after step (bi'), or after step (bi"), or after step (bii"). The protection / removal of the amino protecting group can be carried out by any conventional means known in the art (e.g., see TH Greene and PGM Wets, Protective Groups in Organic Synthesis, 4 th edition, John Wiley & Sons, 2007), and can be implemented as disclosed herein.

[0046] For example, R 1 The amino protecting group in 1=COOR), it can be easily deprotected by acid hydrolysis or base hydrolysis according to procedures established in the art. Suitable acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, fumaric acid, benzoic acid, TFA, MsOH, pTsOH, oxalic acid and succinic acid, preferably HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citric acid and fumaric acid. Suitable bases include alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, alkali metal thioalkoxides, and alkali metal hydroxide salts. In certain embodiments, the reaction is carried out in the presence of water and an organic solvent, preferably an alcohol (e.g., methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, 2-butanol, 2-pentanol, 2-hexanol, 2-octanol, ethylene glycol). In certain embodiments, the reaction is carried out at a temperature of 10° C. to the reflux temperature of the solvent, preferably 30° C. to 70° C., more preferably 40° C. to 60° C. In certain embodiments, the reaction is carried out in the presence of an acid selected from HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citrate, fumarate, and the like, preferably HCl, water, and an alcohol (preferably methanol), at a temperature of 30° C. to 70° C., preferably 40° C. to 60° C. R 1 The amino protecting group in 1=COR), it can be deprotected by acid hydrolysis or base hydrolysis, preferably with heating. Suitable acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid. Suitable bases include alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, and alkali metal hydroxide salts. The reaction can be carried out at a temperature of 20°C to 120°C, preferably 50°C to 110°C, more preferably 60°C to 110°C, and can be carried out in the presence of an organic solvent, water, and mixtures thereof. R 1 where the amino protecting group is an alkyl, aryl or arylalkylamine (R 1 =R), it can be deprotected by treatment with acid, base, oxidizing agent, reducing agent, hydrogenolysis (for aryl or arylalkylamines), etc. 1 The amino protecting group in 1 When =Si(R)(R')(R'') it can be deprotected, for example, by using a fluoride salt or a fluoride reagent such as HF, or an acidic or oxidizing medium.

[0047] Preferably, in any of the compounds of the method of the present invention - - - is a single bond, said single bond is in a cis configuration, i.e., the two hydrogen atoms attached to the carbon of said bond are located on the same side of the pyrrolidine ring. - - - is a single bond, said single bond is in the cis-3R configuration as shown below, i.e., the two hydrogen atoms attached to the carbon of said bond are located on the same side as the pyrrolidine ring, and the 3-position carbon atom of the pyrrolidine ring has the required conformation for the compound upadacitinib, i.e., the R configuration, at the carbon atom to which the imidazopyrrolopyrazinyl ring is attached in upadacitinib. Thus, in a compound of formula (I), or formula (II), or formula (III), or formula (IV), or formula (V), or formula (VI), or formula (VII), or formula (VIII), - - -is a single bond, it is preferably a compound of formula (I'-cis), or formula (II'-cis), or formula (III'-cis), or formula (IV'-cis), or formula (V'-cis), or formula (VI'-cis), or formula (VII'-cis), or formula (VIII'-cis), more preferably a compound of formula (I'-cis-3R), or formula (II'-cis-3R), or formula (III'-cis-3R), or formula (IV'-cis-3R), or formula (V'-cis-3R), or formula (VI'-cis-3R), or formula (VII'-cis-3R), or formula (VIII'-cis-3R): [ka] (In the formula, X, Y, R 1 , R 3 , R 4 , R 5 , and R 6 is as defined herein) or a salt or solvate thereof.

[0048] As used herein, wedge bonds and dashed bonds [ka] is used to indicate the absolute configuration (R or S) of the asymmetric center, while [ka] is used to indicate the relative configuration (cis or trans) of the asymmetric center.

[0049] Unless otherwise specified, the compounds disclosed herein include their stereoisomers, such as geometric isomers (cis / trans) and optical isomers (i.e., diastereoisomers, racemates, individual enantiomers, and mixtures of enantiomers in any ratio are encompassed by the present invention).

[0050] Preferably, - - -When represents a single bond in the compounds of the present invention, the cis isomer is included in an amount of at least 80%, preferably at least 90%, more preferably at least 95%, and even more preferably at least 98% (relative to the cis+trans mixture). In a more preferred embodiment, only the cis isomer confirmed by NMR is included.

[0051] When the compound of the method of the invention is an optically active compound, it is preferably in enantiomeric excess of at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%.

[0052] In a preferred embodiment, the process of the present invention comprises the step of preparing a compound of formula (I'-cis) from a compound of formula (II'-cis), more preferably from a compound of formula (II'-cis-3R), and is as defined in the process of the present invention (so that all intermediates in said process are the corresponding compounds in cis form, more preferably in cis-3R form).

[0053] In certain embodiments, X is a leaving group. Preferred leaving groups are chlorine, bromine, iodine, mesylate, triflate, tosylate, or nosylate, more preferably selected from Cl, Br, and I.

[0054] In some embodiments, Y is selected from the group consisting of OH and OR 2 wherein R is selected from 2 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 In certain embodiments, Y is selected from aryl.

[0055] In one embodiment, R 1is an amino protecting group. As disclosed herein, suitable amino protecting groups include carbamates, amides, amines, sulfonamides, and silylamines. In a preferred embodiment, the amino protecting group is a carbamate. Thus, R 1 is preferably a group of the formula -COOR, wherein R is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6 alkyl)silane, such as methyl carbamate (MOC), ethyl carbamate, t-butyl carbamate (Boc), benzyl carbamate (CBz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halobenzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate, and trichloroethyl carbamate (Troc).

[0056] In one embodiment, R 3 is C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, COR', and SiR'3, each R' being independently selected from C 1~6 Alkyl, C 6~15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. In certain embodiments, R 3 is a SiR' group, each R' being independently 1~6 Alkyl, C 6~15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl, such as TMS, TES, TBS, and TBDPS.

[0057] R 4 and R 5When they are taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered heterocycle, the 5- to 7-membered heterocycle preferably contains one nitrogen atom, or two nitrogen atoms, or one nitrogen atom and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine, and azepane.

[0058] In certain embodiments, R 4 and R 5 are independently selected from C1-C6 alkyl or together with the nitrogen atom form a 5- to 7-membered heterocycle. More preferably, R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle, preferably the 5- to 7-membered heterocycle contains one nitrogen atom, or two nitrogen atoms, or one nitrogen atom and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine, and azepane.

[0059] R 6 is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently C1-C6 alkyl, C6-C 15 Aryl, and (C6-C 15 )aryl(C1-C6)alkyl. In certain embodiments, R 6 is a group of formula -COR', where R' is preferably a C1-C6 alkyl. In a preferred embodiment, R 6 is a group of formula -COtBu (Piv).

[0060] Conversion of a compound of formula (II) to a compound of formula (III) or formula (IV) The compound of formula (II) can be obtained by methods known to those skilled in the art or disclosed in the art, for example by methods as disclosed in WO 2011 / 068881, WO 2013 / 043826, WO 2017 / 066775, or WO 2019 / 016745. In some embodiments, the compound of formula (II) or a salt or solvate thereof can be prepared by the following steps: -Formula (IX): [ka] (In the formula, Z is a halogen, a C1-C6 alkylsulfonic acid group, a C1-C6 haloalkylsulfonic acid group, a C6-C 10 Arylsulfonic acid group, and (C1-C6) alkyl (C6-C 10 ) arylsulfonic acid groups; R 1 is selected from H, and an amino protecting group, and Y is OH, Cl, OR 2 and O.C.(O)R. 2 (R 2 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl) or a salt or solvate thereof with Et2CuLi, Et2CuMgBr or Et2CuMgCl, Formula (II''): [ka] or a salt or solvate thereof; and - if necessary (i.e. if a compound of formula (II') is desired), hydrogenating the double bond to provide a compound of formula (II') or a salt or solvate thereof. The composition can be obtained by a process comprising the steps of:

[0061] The reaction with Et2CuLi, Et2CuMgBr or Et2CuMgCl is preferably carried out in the presence of an organic solvent, which can be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably tetrahydrofuran.

[0062] Typically, the reaction may be carried out at a temperature of -50°C to 30°C, preferably -30°C to 20°C, more preferably -10°C to 10°C.

[0063] In certain embodiments, Et2CuLi, Et2CuMgBr or Et2CuMgCl is present in an amount of 1.0 to 5.0 molar equivalents relative to the compound of formula (IX), preferably 1.1 to 3.0 molar equivalents.

[0064] This process for preparing a compound of formula (II) may further comprise the step of converting Y in the compound of formula (II″) or formula (II′) to a different Y group prior to carrying out the process of the invention for preparing a compound of formula (I).

[0065] For example, in the above method, a compound represented by formula (IX) (wherein Y is OR 2 or a salt or solvate thereof, is used, after reaction with a copper oxide reagent or after hydrogenation of the double bond (if performed), e.g. OR 2 The method may further comprise a step of converting the group to an OH group. The conversion may be carried out by acid hydrolysis or base hydrolysis according to established procedures in the art. Suitable acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, fumaric acid, benzoic acid, TFA, MsOH, pTsOH, oxalic acid and succinic acid, preferably HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citric acid and fumaric acid. Suitable bases include alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, alkali metal thioalkoxides and alkali metal hydroxide salts. In an embodiment, the reaction is carried out at a temperature of 10°C to 120°C, preferably 30°C to 70°C, more preferably 40°C to 60°C.

[0066] In one embodiment, the compound of formula (II) or a salt or solvate thereof can be prepared by the process of: -Formula (IX): [ka] (In the formula, Z is a halogen, a C1-C6 alkylsulfonic acid group, a C1-C6 haloalkylsulfonic acid group, a C6-C 10 Arylsulfonic acid group, and (C1-C6) alkyl (C6-C 10 ) arylsulfonic acid groups; R 1 is selected from H, and an amino protecting group, and Y is OR 2 (The above R 2 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl) or a salt or solvate thereof with Et2CuLi, Et2CuMgBr or Et2CuMgCl to obtain a compound of formula (II″): [ka] or a salt or solvate thereof; - Formula (I'') (wherein Y is OR 2 or a salt or solvate thereof to provide a compound of formula (II') wherein Y is OH; and - if necessary (i.e. if a compound of formula (II') is desired), hydrogenating the double bond to provide a compound of formula (II') (wherein Y is OH) or a salt or solvate thereof. The composition is obtained by a process comprising the steps of:

[0067] The preparation of compounds of formula (II) from compounds of formula (IX) is preferably carried out using the Suzuki reaction previously disclosed in the prior art, which is a cheaper option since it avoids the use of boron-based reagents (which are more expensive and cannot be stored for long periods) and the use of palladium catalysts.

[0068] In a preferred embodiment, in the compound of formula (II), R 1 is an amino protecting group and Y is OH.

[0069] In certain embodiments according to the method of the present invention, a compound of formula (II) or a salt or solvate thereof is converted to a compound of formula (III) or a salt or solvate thereof.

[0070] Suitable means for this conversion are well known in the art. In certain embodiments, this conversion can be carried out by reacting the compound of formula (II) or a salt or solvate thereof with N,O-dimethylhydroxylamine or a salt thereof, preferably with N,O-dimethylhydroxylamine hydrochloride, optionally in the presence of an activating agent and / or a base and an organic solvent.

[0071] Suitable activating or coupling agents are known to those skilled in the art and include, inter alia, N,N-carbonyldiimidazole (CDI), 1-propanephosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), N,N'-dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), triphenylphosphine, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphine, phosphate (HATU), O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), and bromo-tripyrrolidino-phosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), Me2AlCl, Me3Al, iPrMgCl are preferred.

[0072] Suitable bases include, for example, tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine (DIPEA), pyridine (pyr), 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, and mixtures thereof.

[0073] Preferably, the organic solvent is selected from aprotic organic solvents such as, for example, dichloromethane, tetrahydrofuran, and mixtures thereof, preferably dichloromethane.

[0074] Typically, the reaction may be carried out at a temperature of from -10°C to 70°C, preferably from 0°C to 50°C, more preferably from 10°C to 30°C.

[0075] In some embodiments, N,O-dimethylhydroxylamine or a salt thereof is present in an amount of 1.0 to 3.0 molar equivalents relative to the compound of formula (II), preferably 1.1 to 2.0 molar equivalents. In certain embodiments, the activating agent or coupling agent is present in an amount of 1.0 to 3.0 molar equivalents relative to the compound of formula (II), preferably 1.1 to 2.0 molar equivalents. In some embodiments, the base is present in an amount of 1.0 to 3.0 molar equivalents relative to the compound of formula (II), preferably 1.1 to 2.0 molar equivalents.

[0076] In certain embodiments, Y in the compound of formula (II) is Cl or OC(O)R 2 In the case where it is, the reaction with N,O-dimethylhydroxylamine or a salt thereof is carried out in the presence of a base and optionally an organic solvent.

[0077] In another embodiment, when Y in the compound of formula (II) is OH, the reaction with N,O-dimethylhydroxylamine or a salt thereof is carried out in the presence of an activating agent and optionally an organic solvent.

[0078] In another embodiment, Y in the compound of formula (II) is OR 2In the case where it is, the reaction with N,O-dimethylhydroxylamine or a salt thereof is carried out in the presence of Me2AlCl, Me3Al or iPrMgCl and optionally an organic solvent.

[0079] In another embodiment according to the method of the present invention, a compound of formula (II) or a salt or solvate thereof is converted to a compound of formula (IV) or a salt or solvate thereof.

[0080] Suitable means for this conversion are well known in the art. In certain embodiments, this conversion can be carried out by reacting the compound of formula (II) or a salt or solvate thereof with 6-chloro-2,4-dimethoxy-1,3,5-triazine (CDMT), optionally in the presence of a base and an organic solvent.

[0081] Suitable bases include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine (DIPEA), pyridine (pyr), 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, and mixtures thereof, preferably NMM.

[0082] Preferably, the organic solvent is selected from aprotic organic solvents.

[0083] Typically the reaction may be carried out at a temperature of from -10°C to 70°C.

[0084] Conversion of a compound of formula (III) or a compound of formula (IV) to a compound of formula (V) In a preferred embodiment, in the compound of formula (III) or in the compound of formula (IV), R 1 is an amino protecting group.

[0085] This conversion can be carried out by reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof, with MeMgCl, MeMgBr or MeLi, optionally in the presence of an organic solvent.

[0086] The organic solvent can be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably tetrahydrofuran.

[0087] Typically, the reaction may be carried out at a temperature of -50°C to 30°C, preferably -30°C to 20°C, more preferably -10°C to 10°C.

[0088] In certain embodiments, MeMgCl, MeMgBr or MeLi is present in an amount of 1.0 to 5.0 molar equivalents relative to the compound of formula (III) or the compound of formula (IV), preferably 1.1 to 3.0 molar equivalents.

[0089] In the compound of formula (III) or the compound of formula (IV), - - - It is important to note that when is a cis single bond, no isomerization to the trans isomer is observed after reaction with MeMgCl, MeMgBr or MeLi to provide compounds of formula (V).

[0090] Conversion of a compound of formula (V) to a compound of formula (VI) In a preferred embodiment, in the compound of formula (V), R 1 is an amino protecting group.

[0091] In certain embodiments according to the method of the present invention, a compound of formula (V) or a salt or solvate thereof is converted to a compound of formula (VI) or a salt or solvate thereof.

[0092] We have found that the desired enol ether is obtained regioselectively, such that subsequent processing of this compound leads to the introduction of the X group in a terminal position and without isomerization of the pyrrolidine carbon atom to which the carbonyl group is attached.

[0093] This reaction can be carried out by known methods for the synthesis of enol ethers. In one embodiment, the compound of formula (VI), 3is SiR'3) can be prepared by reacting a compound of formula (V) or a salt or solvate thereof with a compound of formula R'3SiZ, 1~6 Alkyl, C 6~10 Aryl and C 1~6 and Z is halogen or triflate) in the presence of a base. Suitable bases include tertiary amines such as Me3N, Et3N, DIPEA, Pyr, DMAP, NMM, 2,6-lutidine, and mixtures thereof. The reaction may be carried out in the presence of an organic solvent, preferably an aprotic solvent, and at a temperature between -30°C and 70°C, preferably between -30°C and 20°C, more preferably between -10°C and 10°C.

[0094] In another embodiment, the compound of formula (VI), 3 C 1~6 The compound of formula (V) or a salt or solvate thereof can be obtained by reacting a compound of formula (V) or a salt or solvate thereof with a trialkyl orthoformate in the presence of an acid. Suitable acids include acetic acid, trifluoroacetic acid, chloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid, ZnCl2, AlCl3, and BF3. The reaction may be carried out in the presence of an organic solvent and at a temperature between -20°C and 120°C, preferably between 10°C and 90°C. In an embodiment, the reaction is carried out in the presence of methyl or ethyl orthoformate, an acid, and an organic solvent.

[0095] In another embodiment, the compound of formula (VI), 3is Ac) can be obtained by reacting a compound of formula (V) or a salt or solvate thereof with isopropenyl acetate, or acetic anhydride, or an acetyl halide in the presence of an acid or base. Suitable acids include sulfuric acid, perchloric acid, pTsOH, and sulfonic acid. Suitable bases include pyridine, DMAP, Me3N, Et3N, and DIPEA. The reaction may be carried out in the presence of an organic solvent and at a temperature between 20°C and 120°C, preferably between 40°C and 120°C.

[0096] In a preferred embodiment, in the compound of formula (VI), R 1 is an amino protecting group, and R 3 is SiR'3, each R' is independently 1~6 Alkyl, C 6~10 Aryl and C 1~6 In a more preferred embodiment, R 3 is SiR'3, each R' is independently 1~6 alkyl, such as TMS, TES, TBDMS, TIPS, etc.

[0097] Conversion of a compound of formula (V) to a compound of formula (VII) In a preferred embodiment, in the compound of formula (V), R 1 is an amino protecting group.

[0098] In certain embodiments according to the method of the present invention, a compound of formula (V) or a salt or solvate thereof is converted to a compound of formula (VII) or a salt or solvate thereof.

[0099] This reaction can be carried out by known methods for preparing enamines from the corresponding ketones. In certain embodiments, this conversion can be carried out by reacting a compound of formula (V) or a salt or solvate thereof with a compound of formula HN(R 4 )R 5 with an amine of formula (I), optionally in the presence of an acid and an organic solvent.

[0100] Suitable acids include, for example, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid and hydrochloric acid. The acid may be used in catalytic amounts. In some embodiments, the reaction is carried out with 0.01 to 0.5 mol of acid per mol of ketone of formula (V).

[0101] In one embodiment, the amine HN(R 4 )R 5 is used in an amount of 1.0 to 5.0 molar equivalents, preferably 1.1 to 3.0 molar equivalents, relative to the compound of formula (V).

[0102] This conversion may typically be carried out at a temperature of from 20°C to 180°C, preferably from 50°C to 150°C, more preferably from 60°C to 130°C.

[0103] In a preferred embodiment, in the compound of formula (VII), R 1 is an amino protecting group, and R 4 and R 5 are independently selected from C1-C6 alkyl, or together with the nitrogen atom form a 5- to 7-membered heterocycle. Preferably, the 5- to 7-membered heterocycle is a 5- to 7-membered heterocycle containing one nitrogen atom or two nitrogen atoms, or one nitrogen atom and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine, and azepane.

[0104] Conversion of a compound of formula (VI) or a compound of formula (VII) to a compound of formula (I) In certain embodiments according to the method of the present invention, a compound of formula (VI) or a salt or solvate thereof, or a compound of formula (VII) or a salt or solvate thereof is converted to a compound of formula (I) or a salt or solvate thereof. Suitable means for this conversion are well known in the art.

[0105] In certain embodiments, this conversion can be carried out by reacting a compound of formula (VI) or a salt or solvate thereof, or a compound of formula (VII) or a salt or solvate thereof with a halogenating agent, optionally in the presence of an organic solvent, to obtain a compound of formula (I) where X is a halogen, or a salt or solvate thereof.

[0106] Suitable halogenating agents include thionyl chloride, oxalyl chloride, NCS, Br2, CBr4, NBS, I2, CI4, NIS, among others.

[0107] The organic solvent may be an aprotic organic solvent, preferably dichloromethane or a cyclic or acyclic ether, more preferably tetrahydrofuran or dichloromethane.

[0108] Typically, the reaction may be carried out at a temperature of -80°C to 30°C, preferably -50°C to 30°C, more preferably -20°C to 20°C.

[0109] In certain embodiments, the halogenating agent is present in an amount of 1.0 to 5.0 molar equivalents relative to the compound of Formula (VI) or the compound of Formula (VII), preferably 1.1 to 3.0 molar equivalents.

[0110] In another embodiment, the conversion of a compound of formula (VI) or a salt or solvate thereof, or a compound of formula (VII) or a salt or solvate thereof, to a compound of formula (I) or a salt or solvate thereof is carried out by epoxidation of the double bond of the enol ether of formula (VI) or the enamine of formula (VII) followed by ring opening to give a compound of formula (VIII), 6 is H): [ka] (In the ceremony - - - is a single or double bond, and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof.

[0111] In certain embodiments, the epoxidation reaction is carried out in the presence of a percarboxylic acid, hydrogen peroxide or oxone, preferably in the presence of a percarboxylic acid such as mCPBA, benzoic acid, monoperphthalic acid or magnesium monoperoxyphthalate (MMPP). The reaction may be carried out in the presence of an organic solvent and may be carried out at a temperature of from -40° C. to 120° C., preferably from -20° C. to 40° C. In certain embodiments, the reaction is carried out in the presence of mCPBA and an aprotic polar solvent such as dichloromethane.

[0112] The ring opening of the resulting epoxide may be carried out by treatment with water and an acid or a fluoride source. Suitable acids include, for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid and succinic acid. Suitable fluoride sources include HF and fluoride salts such as, for example, CsF, RbF, NaF and TBAF. The reaction may be carried out in the presence of an organic solvent and at a temperature between -40°C and 120°C, preferably between -20°C and 40°C.

[0113] Formula (VIII) (wherein R 6 is H) or a salt or solvate thereof can be converted to a compound of formula (I) or a salt or solvate thereof by methods well known in the art. In certain embodiments, the conversion of the primary hydroxyl group to a leaving group is carried out by treatment with a halogenating agent, e.g., I2, NaI, Br2, CBr4, PBr3, Cl2, thionyl chloride, oxalyl chloride, and the like, or with a sulfonyl chloride, e.g., TsCl or MsCl. The reaction is preferably carried out at a temperature of -78°C to 80°C, preferably -40°C to 40°C, in the presence of an organic solvent.

[0114] In a preferred embodiment, in the compound of formula (I), R 1 is an amino protecting group.

[0115] In a preferred embodiment, the conversion of a compound of formula (V) or a salt or solvate thereof to a compound of formula (I) or a salt or solvate thereof is carried out in a one-pot process, i.e. without isolation of an intermediate compound of formula (VI) or a salt or solvate thereof or an intermediate compound of formula (VII) or a salt or solvate thereof.

[0116] Conversion of a compound of formula (III) or a compound of formula (IV) to a compound of formula (I) In a preferred embodiment, in the compound of formula (III) or in the compound of formula (IV), R 1 is an amino protecting group.

[0117] This conversion can be carried out by reacting a compound of formula (III) or a salt or solvate thereof or a compound of formula (IV) or a salt or solvate thereof with a compound of formula X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr, wherein X is a leaving group, optionally in the presence of an organic solvent.

[0118] The organic solvent can be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably tetrahydrofuran.

[0119] Typically, the reaction may be carried out at a temperature of -80°C to 30°C, preferably -80°C to 0°C, more preferably -80°C to -20°C.

[0120] In certain embodiments, the compound X-CH2-Li, the compound X-CH2-MgCl, or the compound X-CH2-MgBr is present in an amount of 1.0 to 8.0 molar equivalents relative to the compound of formula (III) or the compound of formula (IV), preferably 1.1 to 5.0 molar equivalents.

[0121] In a preferred embodiment, in the compound of formula (I), R 1is an amino protecting group.

[0122] Conversion of a compound of formula (III) or a compound of formula (IV) to a compound of formula (VIII) In a preferred embodiment, in the compound of formula (III) or in the compound of formula (IV), R 1 is an amino protecting group.

[0123] This conversion can be carried out by reacting a compound of formula (III) or a salt or solvate thereof or a compound of formula (IV) or a salt or solvate thereof with a compound of formula R 6 O-CH2-Li, formula R 6 O-CH2-MgCl, or formula R 6 The compound O-CH2-MgBr (see above R 6 is selected from -COR' and -CONR'R'', where R' and R'' are independently C1 to C6 alkyl, C6 to C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl) optionally in the presence of an organic solvent.

[0124] In certain embodiments, R 6 is represented by the formula -COR (wherein R is C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl). Preferably, R 6 is a group of formula -COtBu (Piv).

[0125] The organic solvent can be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably tetrahydrofuran.

[0126] Typically, the reaction may be carried out at a temperature of -80°C to 30°C, preferably -80°C to 0°C, more preferably -80°C to -20°C.

[0127] In one embodiment, compound R 6 O-CH2-Li, compound R 6O-CH2-MgCl, or compound R 6 The O-CH2-MgBr is present in an amount of 1.0 to 8.0 molar equivalents relative to the compound of formula (III) or the compound of formula (IV), preferably 1.1 to 5.0 molar equivalents.

[0128] In a preferred embodiment, in the compound of formula (VIII) obtained after this reaction, R 1 is an amino protecting group, and R 6 is selected from -COR' and -CONR'R'', preferably -COR', and the R' and the R'' are independently C1 to C6 alkyl, C6 to C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl.

[0129] In one embodiment of the present invention, a compound represented by formula (VIII) (wherein R 6 is selected from -COR' and -CONR'R'' or a salt or solvate thereof, which can be represented by the formula (VIII) 6 is hydrogen) or a salt or solvate thereof, which is then converted to a compound of formula (I) or a salt or solvate thereof.

[0130] Formula (VIII) (wherein R 6 is -COR' or -CONR'R''), or a salt or solvate thereof, 6is hydrogen) or its salt or solvate can be carried out under acidic or basic hydrolysis reaction conditions. Suitable acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, fumaric acid, benzoic acid, TFA, MsOH, pTsOH, oxalic acid and succinic acid, preferably HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citric acid and fumaric acid. Suitable bases include alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, alkali metal thioalkoxides, and alkali metal hydroxide salts, such as NaOH, KOH, NaOtBu, NaOMe, NaSMe, etc. In one embodiment, the hydrolysis reaction is carried out in the presence of water and an organic solvent, preferably an alcohol (e.g., methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, 2-butanol, 2-pentanol, 2-hexanol, 2-octanol, ethylene glycol). In one embodiment, the reaction is carried out at a temperature between 10°C and 120°C, preferably between 30°C and 70°C, more preferably between 40°C and 60°C.

[0131] Conversion of a compound of formula (VIII) to a compound of formula (I) In a preferred embodiment, in the compound of formula (VIII), R 1 is an amino protecting group, and R 6 is H.

[0132] Formula (VIII) (wherein R 6is H) or a salt or solvate thereof can be converted to a compound of formula (I) or a salt or solvate thereof by methods well known in the art. In certain embodiments, the conversion of the primary hydroxyl group to a leaving group is carried out by treatment with a halogenating agent, e.g., I2, NaI, Br2, CBr4, PBr3, Cl2, thionyl chloride, oxalyl chloride, and the like, or with a sulfonyl chloride, e.g., TsCl or MsCl. The reaction is preferably carried out at a temperature of -78°C to 80°C, preferably -40°C to 40°C, in the presence of an organic solvent.

[0133] In a preferred embodiment, in the compound of formula (I), R 1 is an amino protecting group.

[0134] Hydrogenation Reaction The process of the invention may include the step of hydrogenating the double bond in the pyrrolidine ring to a single bond.

[0135] In one embodiment, the method of the present invention comprises the step of: - - - is a single bond), or a salt or solvate thereof, - - - is a double bond), or a salt or solvate thereof. In that case, the process of the invention further comprises the step of hydrogenating the double bond. The hydrogenation can be carried out at any stage of the process, for example after step (a), or after step (bi), or after step (bii), or after step (biii), or after step (bi'), or after step (bi"), or after step (bii").

[0136] This reaction can be carried out by well-known methods for hydrogenating double bonds. In certain embodiments, this reaction is carried out by reacting a compound of the process of the present invention, - - - is a double bond) with H2.

[0137] Suitable transition metal catalysts or compounds include, for example, supported and unsupported catalysts of transition metals selected from Pd, Pt, Ni, Rh, Ru, Ir, Mo, Cr, Co, Cu and Fe, such as Pd / C, Pt / C, Pt / C, Pd / CaCO3, Pd / Al2O3, Pd / BaCO3, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, Pd(CF3CO2)2, Pd(CH3CO2)2, Pt / Al2O3, PtO2, Ra-Ni, Ru / C, Ru / Al2O3, Ru(OH)2, Ru(OAc)2, [RuCl2(p-Si)], [Ru ... [Menen]2, bis(1,5-cyclooctadiene)ruthenium(II) polymer, dichlorobenzeneruthenium(II) dimer, dibromobenzeneruthenium(II) dimer, RhCl(PPh3)3, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)iridium tetrafluoroborate, bis(1,5-cyclooctadiene)diiridium dichloride, FeCl2, FeBr2, Fe(CH3CO2)2, [Fe(OH2)6](BF4)2, CuCl, and [CuH(Ph3)]6.

[0138] In a particular embodiment, the reaction is an asymmetric hydrogenation reaction. In that case, the reaction uses an optically active catalyst. The optically active catalyst is an optically active transition metal compound obtained by mixing a transition metal compound with an optically active chiral ligand. Thus, in a particular embodiment, the reaction is carried out by reacting a compound of the method of the present invention, - - - is a double bond) with H2. When the asymmetric hydrogenation is carried out, an optically active compound is obtained, preferably a compound of formula (I'-cis-3R), or formula (II'-cis-3R), or formula (III'-cis-3R), or formula (IV'-cis-3R), or formula (V'-cis-3R), or formula (VI'-cis-3R), or formula (VII'-cis-3R), or formula (VIII'-cis-3R).

[0139] Preferred transition metal compounds or catalysts are as defined above and are preferably selected from compounds of Ru, Pd, Pt, Rh and Ir.

[0140] Optically active chiral ligands can be monodentate, bidentate, tridentate, or tetradentate. They include cyclic or acyclic heteroatom-containing metal binding functional groups, such as phosphines, phosphites, hypophosphites, phosphoramidites, sulfonamide-phosphoramidites, phosphine oxides, N-heterocyclic carbenes, diamines, imidazoles, amino alcohols, diols, oxazolines, imines, and amino acids.

[0141] Preferably, the optically active ligand is a P,P-bidentate ligand, or a P,N-bidentate ligand, or a P,O-bidentate ligand, or a P,S-bidentate ligand, preferably a P,P-bidentate ligand, more preferably a diphosphine ligand.

[0142] Non-limiting examples of suitable optically active chiral ligands include (S)-BINAP, (S)-TolBINAP, (S)-XylBINAP, (S)-Cy-BINAP, (S)-H8-BINAP, (S)-MeOBIPHEP, di-tBu-MeOBIPHEP, (S)-SEGPHOS, (S)-DM-SEGPHOS, (S)-DTBM-SEGPHOS, (S)-QUINAP, (S,S)-BDPP, (S)-BIPHEMP, (S)-M e-BPE, (S,S)-DIOP, (S,S)-DIOP-OH, (S,S)-DIPAMP, (S)-SYNPHOS, (S,S)-CHIRAPHOS, (S,S)-Me-DuPHOS, (R)-(S)-BPPFA, (R)-(S)-BPPFOH, (2S,4S)-BPPM, (R)-(S)-JOSIPHOS, (R)-(S)-XYLIPHOS, (R)-PROPHOS, (R)-MeO-MOP, and their enantiomers.

[0143] In certain embodiments, the asymmetric hydrogenation is carried out in the presence of a Ru compound, such as Ru(OAc)2, an optically active chiral ligand, preferably a diphosphine ligand, such as (S)-SEGPHOS, and an organic solvent, preferably an alcohol. In certain embodiments, the reaction is carried out in the presence of Ru(OAc)2 and (S)-SEGPHOS, for example as disclosed in WO 2017 / 066775.

[0144] The transition metal catalyst is a compound represented by the formula - - - is a double bond), the amount of the optically active ligand may be present in an amount of 0.01 to 50% by weight, preferably 1 to 10% by weight, based on the amount of the compound (wherein - - - is a double bond), preferably in an amount of 0.01 to 50% by weight, more preferably 1 to 10% by weight.

[0145] The reaction may be carried out in the presence of an organic solvent such as, for example, ethers (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g., pentane, hexane, heptane), halogenated solvents (e.g., dichloromethane, chloroform), aromatic solvents (e.g., toluene, xylene), ketones (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g., EtOAc, iPrOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA), alcohols (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), sulfoxides (DMSO), acids (AcOH) and mixtures thereof.

[0146] The reaction is preferably carried out in the presence of H2 at a pressure of 1 to 100 atm, preferably 2 to 50 atm. In an embodiment, the reaction is carried out at a temperature of -80° C. to 100° C., preferably -20° C. to 90° C., more preferably 0° C. to 50° C. Sources of hydrogen include H2, formic acid or its salts, and cyclohexene.

[0147] Preferably, as used herein, the term optically active refers to compounds having an enantiomeric excess of at least 50%, more preferably at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%.

[0148] Preferably, after the hydrogenation reaction, the cis isomer is obtained selectively. The term "selectively" in reference to the hydrogenated compound means that the ratio of cis to trans isomer is at least 80:20, preferably at least 90:10, more preferably at least 95:5, and even more preferably at least 98:2.

[0149] Asymmetric hydrogenation is preferably carried out to provide the desired isomer (eg, the cis-3R isomer) in an enantiomeric excess of at least 90%, at least 95%, preferably at least 98%, or at least 99%.

[0150] Preparation of Upadacitinib The process of the present invention may further comprise converting the compound of formula (I) or a salt or solvate thereof to upadacitinib.

[0151] Thus, in another aspect, the present invention provides a process for preparing upadacitinib, or a salt, solvate, or stereoisomer thereof, comprising the steps of: - Formula (I): [ka] (In the formula, - - -is a single bond or a double bond, X is a leaving group, and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof, preparing by the method defined herein; and - converting a compound of formula (I) or a salt or solvate thereof into upadacitinib or a salt or solvate or stereoisomer thereof. The present invention is directed to a method comprising the steps of:

[0152] The conversion of a compound of formula (I) or a salt or solvate thereof to upadacitinib or a salt or solvate or stereoisomer thereof can be carried out by methods known in the art, for example as disclosed in WO 2013 / 043826 or WO 2017 / 066775.

[0153] In certain embodiments, converting a compound of formula (I) or a salt or solvate thereof to upadacitinib or a salt or solvate or stereoisomer thereof comprises the steps of: (i) a compound of formula (I) or a salt or solvate thereof, Formula (IX): [ka] (In the formula, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C6-C 15 Aryl, and (C6-C 15 ) aryl(C1-C6) alkyl (preferably methyl or ethyl), and R 8 is an amino protecting group, preferably Ts or a salt or solvate thereof, Formula (X): [ka] (In the formula, - - - is a single or double bond, and R 1 is selected from H and an amino protecting group (preferably an amino protecting group). or a salt or solvate thereof; (ii) reacting a compound of formula (X) or a salt or solvate thereof with a perfluorinated acid anhydride and a base, Formula (XI): [ka] or a salt or solvate thereof; (iii)R 1 is an amino protecting group, R in the compound of formula (XI) or a salt or solvate thereof 1 Deprotection of the group, Formula (XII): [ka] (In the formula, - - - is a single or double bond, and R 8 is selected from H and an amino protecting group. or a salt or solvate thereof; (iv) reacting a compound of formula (XII) or a salt or solvate thereof with Formula (XIII): [ka] (In the formula, R 8 is selected from H and an amino protecting group. or a salt or solvate thereof; (v) If necessary, i.e. R 8 is an amino protecting group, the compound of formula (XIII) or a salt or solvate thereof may be deprotected to give a compound of formula (XIII) 8 is H, or a salt or solvate thereof. The method can be carried out by a process comprising:

[0154] If necessary, i.e. in the compound of formula (I) - - - When is a double bond, the process may further comprise a hydrogenation step at any stage of the synthesis of upadacitinib, for example after step (i), or after step (ii), or after step (iii), or after step (iv), or after step (v).

[0155] In one embodiment, the method comprises: (i) reacting a compound of formula (I) or a salt or solvate thereof with a compound of formula (IX) as defined above to provide a compound of formula (X) as defined above or a salt or solvate thereof; (ii) reacting a compound of formula (X) as defined above or a salt or solvate thereof with a perfluorinated acid anhydride and a base, Formula (XI): [ka] or a salt or solvate thereof; (iii) deprotecting the compound of formula (XI) or a salt or solvate thereof, Formula (XII'): [ka] or a salt or solvate thereof; (v) reacting a compound of formula (XII) or a salt or solvate thereof with Formula (XIII'): [ka] or a salt or solvate thereof.

[0156] If necessary, i.e. in the compound of formula (I) - - -When is a double bond, the process further comprises a hydrogenation step at any stage of the synthesis of upadacitinib, for example after step (i), or after step (ii), or after step (iii), or after step (iv).

[0157] In a preferred embodiment, the compound of formula (I) is the compound (I-cis-3R), therefore the process for preparing upadacitinib, or a salt or solvate thereof, comprises: (i) a compound of formula (I-cis-3R) (wherein R 1 is an amino protecting group), or a salt or solvate thereof, with a compound of formula (IX), Formula (X-cis-3R): [ka] (In the formula, R 1 is selected from H and an amino protecting group; R 7 is C1-C6 alkyl, C1-C6 alkoxy, C6-C 15 Aryl, and (C6-C 15 ) aryl(C1-C6) alkyl, preferably methyl or ethyl; and R 8 is an amino protecting group, preferably Ts or a salt or solvate thereof; (ii) reacting a compound of formula (X-cis-3R) or a salt or solvate thereof with a perfluorinated anhydride and a base, Formula (XI-cis-3R): [ka] or a salt or solvate thereof; (iii)R 1 is an amino protecting group, R in the compound of formula (XI-cis-3R) or a salt or solvate thereof 1 Deprotection of the group, Formula (XII-cis-3R): [ka] (In the formula, R 8 is selected from H and an amino protecting group. or a salt or solvate thereof; (iv) a compound of formula (XII-cis-3R) or a salt or solvate thereof, Formula (XIII-cis-3R): [ka] (In the formula, R 8 is selected from H and an amino protecting group. or a salt or solvate thereof; (v) If necessary, i.e. R 8 is an amino protecting group, deprotecting the compound of formula (XIII-cis-3R) or a salt or solvate thereof to provide upadacitinib or a salt or solvate thereof.

[0158] In certain embodiments, the method comprises: (i) a compound of formula (I-cis-3R) (wherein R 1 is an amino protecting group) or a salt or solvate thereof, with a compound of formula (IX) to provide a compound of formula (X-cis-3R) as defined above or a salt or solvate thereof; (ii) reacting a compound of formula (X-cis-3R) as defined above or a salt or solvate thereof with a perfluorinated anhydride and a base, Formula (XI-cis-3R): [ka] or a salt or solvate thereof; (iii) deprotecting the compound of formula (XI-cis-3R) or a salt or solvate thereof, Formula (XII'-cis-3R): [ka] or a salt or solvate thereof; (iv) converting a compound of formula (XII'-cis-3R) or a salt or solvate thereof into upadacitinib or a salt or solvate thereof.

[0159] In a preferred embodiment, the compound of formula (I) is, for example, compound 10: [ka] and the like (I-cis-3R), And the method for preparing upadacitinib or a salt or solvate thereof comprises: (i) reacting a compound of formula (I-cis-3R), such as, for example, compound 10, or a salt or solvate thereof, with, for example, compound 20: [ka] With a compound of formula (IX), such as For example, compound 21: [ka] or a salt or solvate thereof, (ii) reacting a compound of formula (X-cis-3R), such as compound 21, or a salt or solvate thereof, with a perfluorinated anhydride and a base to give, for example, compound 22: [ka] or a salt or solvate thereof, (iii) deprotecting a compound of formula (XI-cis-3R), such as, for example, 22, or a salt or solvate thereof, to obtain, for example, compound 23: [ka] or a salt or solvate thereof, (iv) converting a compound of formula (XII) or a salt or solvate thereof, such as compound 23, into upadacitinib or a salt or solvate thereof.

[0160] Suitable conditions for the conversion of (i) to (v) are disclosed in the prior art (e.g., WO 2017 / 066775) or known to the skilled artisan.

[0161] In certain embodiments, step (i) may be carried out in the presence of a base such as, for example, NaH, tBuOLi, tBuONa or tBuOK, optionally in the presence of an organic solvent, preferably an aprotic organic solvent.

[0162] Step (ii) may be carried out in the presence of a perfluoroacid anhydride, optionally in the presence of a perfluorocarboxylic acid, and optionally in the presence of an organic solvent. Suitable perfluorocarboxylic acids include, for example, trifluoroacetic acid, pentafluoropropionic acid, and heptafluorobutyric acid.

[0163] Suitable perfluoroanhydrides include, for example, trifluoroacetic anhydride, pentafluoropropionic anhydride, and heptafluorobutyric anhydride.

[0164] Steps (iii) and (v) can be carried out by any conventional means known in the art for the removal of amino protecting groups (e.g., see T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 4 th edition, John Wiley & Sons, 2007), and can be performed as disclosed herein.

[0165] Step (iv) may be carried out by reacting with 2,2,2-trifluoroethylamine in the presence of CDI and optionally an organic solvent.

[0166] intermediate compound The compounds of formula (III) or salts or solvates thereof, the compounds of formula (IV) or salts or solvates thereof, the compounds of formula (V) or salts or solvates thereof, the compounds of formula (VI) or salts or solvates thereof, and the compounds of formula (VII) or salts or solvates thereof are useful intermediates in the preparation of compounds of formula (I) and thus in the synthesis of upadacitinib and structurally related compounds.

[0167] In another aspect, the present invention provides a compound of the formula: [ka] TIFF0007648027000045.tif136167 (in the formula, R 1 is selected from H and an amino protecting group; R 3 is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)Alkyl, C6-C 15 aryl, COR′, and SiR′3, each R′ being independently selected from 1~6 Alkyl, C3-C 10 Cycloalkyl, C 6~15 Aryl and (C6-C 15 ) aryl(C1-C6) alkyl); R 4 and R 5 are independently C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; and R' is C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl and C6-C 15 aryl) or a salt or solvate thereof.

[0168] R', R 1 , R 3 , R 4 and R5 Suitable and preferred embodiments for are as defined herein for the method of the invention.

[0169] In one embodiment, R 1 but, -COOR a (The above R a is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 ) selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6 alkyl)silane; -COR b (The above R b is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 ) aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; -R c (The above R c is C1-C6 alkyl, C6-C 15 Aryl, and (C6-C 15 ) aryl(C1-C6) alkyl); -SO2R d (The above R d is C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl, (C6-C 15 ) aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and -Si(R e )(R f )(R g ) (R e , R f and the above R g are independently C1 to C6 alkyl, C3 to C 10 Cycloalkyl, C6-C15 Aryl, and (C6-C 15 ) aryl(C1-C6) alkyl) is selected from.

[0170] Preferably, R' is selected from C1-C6 alkyl, more preferably tBu.

[0171] R 1 is preferably a group of the formula COOR, wherein R is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6 alkyl)silane, such as methyl carbamate (MOC), ethyl carbamate, t-butyl carbamate (Boc), benzyl carbamate (Cbz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halobenzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate, and trichloroethyl carbamate (Troc). In some embodiments, it is selected from Cbz and Boc.

[0172] R 3 is C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, COR' and SiR'3, each R' being independently selected from C 1~6 Alkyl, C 6~15 Aryl, and (C6-C 15 )aryl(C1-C6)alkyl. R 3 is more preferably a SiR' group, each R' being independently 1~6 Alkyl, C 6~15 Aryl and (C6-C 15)aryl(C1-C6)alkyl, such as TMS, TES, TBS, and TBDPS.

[0173] In certain embodiments, R 4 and R 5 are independently selected from C1-C6 alkyl or together with the nitrogen atom form a 5- to 7-membered heterocycle. More preferably, R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle, preferably the 5- to 7-membered heterocycle contains one nitrogen atom, or two nitrogen atoms, or one nitrogen atom and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine, and azepane.

[0174] In certain embodiments, the present invention provides a compound of the formula: [ka] The present invention relates to a compound represented by TIFF0007648027000047.tif83161 or a salt or solvate thereof.

[0175] It is to be understood that the scope of the present disclosure includes all possible combinations of the embodiments disclosed herein. EXAMPLES

[0176] Example 1: Synthesis of cis-Weinreb amide (2) from cis-carboxylic acid (1) [ka] Under argon atmosphere, 6 g of cis-compound (1) (21.63 mmol) was dissolved in 40 ml of dichloromethane, and the resulting solution was cooled to 0-5°C in an ice bath. 4.56 g of CDI (1.3 equiv.) was slowly added to the solution in several portions. The reaction mixture was stirred for 20 min and then allowed to warm to room temperature. 2.74 g of N,O-dimethylhydroxylamine (1.3 equiv.) was then added. The reaction was confirmed to be complete by TLC, and quenched with 1 M aqueous HCl to pH 4-6 and 100 ml of AcOEt. The organic layer was washed with water (60 ml), and the solvent was evaporated under reduced pressure to give 6.86 g of cis-compound (2) as an oil. The resulting compound was pure enough to be used directly in the next reaction step. 1 H NMR(500MHz,CDCl3)δ 7.26(s,5H),5.23-5.05(m,2H),3.79-3.71(m,1H),3.71-3.66(m,3H),3.63-3.54(m,2H),3.50(dd,J=14.7,9.2Hz,1H),3. 45-3.33(m,1H),3.24-3.13(m,3H),2.41-2.30(m,1H),1.56-1.36(m,1H),1.36-1.20(m,1H),0.91(dd,J=14.0,7.3Hz,3H).

[0177] Example 2: Synthesis of cis-ketone (3) from cis-Weinreb amide (2) [ka] Under argon atmosphere, 5.96 g of cis-compound (2) (18.6 mmol) was dissolved in 60 ml of dry THF and the resulting solution was cooled to 0-5 °C in an ice bath. 12.4 ml (2 eq.) of a 3 M solution of MeMgCl in THF was added slowly, ensuring that the temperature did not exceed 5 °C. The reaction mixture was stirred for 15-30 min and monitored by TLC. It was then quenched with saturated aqueous NH4Cl and extracted with 100 ml of EtOAc. The organic layer was washed with water (20-30 ml) and the solvent was evaporated under reduced pressure to give 4.8 g of a brown oil. The resulting oil was extracted by adding 40-100 ml of hot heptane to give an insoluble colorless residue. The heptane extract was evaporated under reduced pressure to give 4.7 g of pure cis-compound (3) (91% yield).1 H NMR(500MHz,CDCl3)δ 7.26(s,5H),5.13(qd,J=12.5,3.8Hz,2H),3.88-3.17(m,5H),2.42-2.29(m,1 H),2.18(s,3H),1.66(s,1H),1.44-1.17(m,2H),0.94(dd,J=15.9,7.4Hz,3H).

[0178] Example 3: Synthesis of cis-silyl enol ether (4) from cis-ketone (3) [ka] Under argon atmosphere, 5.55 g of cis-compound (3) (20.6 ml) was dissolved in 100 ml of anhydrous dichloromethane and the resulting solution was cooled to 0-5°C in an ice bath. 6.7 ml of trimethylsilyl triflate (1.8 eq.) was added followed by 5.62 ml of anhydrous trimethylamine (2 eq.). The reaction mixture was stirred until complete by TLC (15-60 min). The reaction was quenched by the addition of 100 ml of 7% aqueous NaHCO3 and extracted with 100 ml of dichloromethane. The solvent was removed under reduced pressure to give an oil (6.9 g) which was used directly in the next reaction. 1 H NMR(500MHz,CDCl3)δ 7.43-7.28(m,5H),5.24-5.04(m,2H),4.00(dd,J=26.5,7.0Hz,2H),3.58-3.42(m,3H),3.28-3.08(m,1H),2.8 3-2.65(m,1H),2.30-2.00(m,1H),1.52-1.37(m,1H),1.43-1.16(m,1H),1.02-0.77(m,3H),0.31-0.04(m,9H).

[0179] Example 4: Synthesis of cis-compound (5) from cis-silyl enol ether (4) [ka] The oil (4) obtained in the previous example was dissolved in 50 ml of dry THF under argon atmosphere and 2 g of NaHCO3 (1.21 eq.) was added. The resulting suspension was cooled to 0-5°C in an ice bath, and then 4.3 g of NBS (1.21 eq.) was added in several portions while controlling the temperature. The reaction proceeded quickly and was monitored by TLC. The reaction was quenched by adding 100 ml of a 7% aqueous solution of NaHCO3 and extracted with 100 ml of AcOEt. The solvent was distilled off under reduced pressure to obtain 8.5 g of an oil, which was purified by column chromatography to obtain 5.5 g of a white solid (77% yield from ketone (3)). 1 H NMR(400MHz,CDCl3)δ 7.45-7.28(m,5H),5.25-4.99(m,2H),3.99-3.82(m,2H),3.81-3.66(m,1H),3.63-3.48(m,3H) ,3.38(ddd,J=24.8,10.7,7.0Hz,1H),2.53-2.27(m,1H),1.46-1.17(m,2H),1.05-0.85(m,3H).

[0180] Example 5: Synthesis of cis-hydroxyketone (6) from cis-Weinreb amide (2) [ka] Preparation of ((pivaloyloxy)methyl)magnesium chloride (0.4 M): To a solution of iodomethyl pivalate (14.5 g, 60 mmol, 1.0 equiv) in dry THF (67 mL) pre-cooled to −65 to −75° C. under an argon atmosphere was added a solution of iPrMgCl (2.0 M in THF, 66.0 mL, 132 mmol, 2.2 equiv) The reaction mixture was stirred until formation of the desired reagent was complete, while maintaining the temperature below −65° C.

[0181] To a solution of Weinreb amide (2) (0.3 g, 0.93 mmol, 1.0 equiv.) in dry THF (5 mL) under argon atmosphere was added a freshly prepared solution of ((pivaloyloxy)methyl)magnesium chloride (0.4 M, 4.68 mL, 1.87 mmol, 2 equiv.) at 0° C. After 30 min, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×10 mL). The dried (MgSO4) extract was filtered, concentrated under reduced pressure, and the resulting oily residue was purified by flash column chromatography to give the desired product as a yellow oil (0.10 g, 32%). A better yield could be achieved by adding MeONa before quenching the reaction mixture. 1 H NMR(400MHz,chloroform-d)δ 7.44-7.29(m,5H),5.24-5.02(m,2H),4.40-4.11(m,2H),3.77-3.65(m,1H),3.65-3.48(m,2H),3.45-3 .27(m,1H),3.25-3.03(m,1H),2.36(d,J=5.9Hz,1H),1.46-1.20(m,2H),0.93(dd,J=13.1,7.0Hz,3H).

[0182] Example 6: Synthesis of cis-3R Weinreb amide (8) from cis-3R carboxylic acid (7) [ka] Compound (7) (6.00 g, 21.63 mmol, 1.0 equiv) and CDI (4.56 g, 28.13 mmol, 1.3 equiv) were mixed under an argon atmosphere. Dry CHCl (40 mL) was added and the suspension was stirred at 0° C. for 10 min. N,O-dimethylhydroxylamine hydrochloride (0.99 g, 10.20 mmol, 1.5 equiv) was then added and the resulting mixture was stirred at room temperature for another 12 h until the reaction was complete. The suspension was quenched with aqueous HCl (0.5 M, 20 mL) and the organic layer was extracted and washed twice with saturated brine (2×20 mL). The combined organic layers were dried over anhydrous MgSO, filtered and evaporated under reduced pressure to give the pure title product as a brown oil (6.86 g, 21.41 mmol, 99%). 1H NMR(500MHz,chloroform-d)δ 7.26(s,5H),5.23-5.05(m,2H),3.79-3.71(m,1H),3.71-3.66(m,3H),3.63-3.54(m,2H),3.50(dd,J=14.7,9.2Hz,1H),3. 45-3.33(m,1H),3.24-3.13(m,3H),2.41-2.30(m,1H),1.56-1.36(m,1H),1.36-1.20(m,1H),0.91(dd,J=14.0,7.3Hz,3H).

[0183] Example 7: Synthesis of cis-3R ketone (9) from cis-3R Weinreb amide (8) [ka] To a solution of compound (8) (5.96 g, 17.74 mmol, 1.0 equiv) in dry THF (60 mL) under argon atmosphere was added MeMgCl (3 M, 11.80 mL, 35.47 mmol, 2 equiv) at 0° C. After 15 min, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×10 mL). The dried (MgSO4) extract was filtered, concentrated under reduced pressure, and extracted with hot heptane to give the desired product as a brown oil (4.37 g, 89%). 1 H NMR(500MHz,chloroform-d)δ 7.26(s,5H),5.13(qd,J=12.5,3.8Hz,2H),3.73-3.64(m,1H),3.59-3.52(m,1H),3.48(td,J=11.5,5.9Hz,1H),3.42(dd,J=10.9, 5.1Hz,1H),3.22(ddd,J=16.0,13.3,6.9Hz,1H),2.42-2.29(m,1H),2.18(s,3H),1.44-1.17(m,2H),0.94(dd,J=15.9,7.4Hz,3H).

[0184] Example 8: Synthesis of cis-3R compound (10) from cis-3R ketone (9) [ka] A solution of compound (9) (1.0 g, 3.63 mmol, 1.0 equiv) in dry CHCl (15 mL) was cooled to 0 °C under argon atmosphere. To this solution was added TMSOTf (1.18 mL, 6.54 mmol, 1.8 equiv), EtN (1.01 mL, 7.27 mmol, 2.0 equiv) and stirring was continued for 10 min until the formation of the intermediate silyl enol ether was complete. NaHCO (0.37 g, 4.40 mmol, 1.2 equiv) and NBS (0.84 mg, 2.07 mmol, 1.3 equiv) were then added at 0 °C. After 1 h, the reaction was quenched with saturated aqueous NaHCO and extracted with CHCl (2 × 10 mL). The organic layer was then washed with 5% aqueous NaSO. The dried (MgSO4) organic layer was filtered, concentrated under reduced pressure and purified by chromatography on silica gel to afford the title product (0.96 g, 77%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.45-7.28 (m, 5H), 5.25-4.99 (m, 2H), 3.99-3.82 (m, 2H), 3.81-3.66 (m, 1H), 3.63-3.48 (m, 3H), 3.38 (ddd, J=24.8, 10.7, 7.0 Hz, 1H), 2.53-2.27 (m, 1H), 1.46-1.17 (m, 2H), 1.05-0.85 (m, 3H).

[0185] Example 9: Synthesis of cis-3R compound (11) from cis-3R Weinreb amide (8) [ka] To a solution of compound (8) (0.3 g, 0.94 mmol, 1.0 equiv.) in dry THF (5 mL) cooled to -78 °C was added ICHCl (0.27 mL, 3.70 mmol, 4.0 equiv.), followed by dropwise addition of MeLi·LiBr complex (1.5 M solution in EtO, 1.88 mL, 2.82 mmol, 3.0 equiv.) over 5 min. The resulting solution was stirred at that temperature for 2 h, then saturated aqueous NHCl was added at -78 °C. The mixture was allowed to warm to room temperature and washed with EtO (10 mL) and saturated brine (10 mL). The two resulting phases were separated and the organic phase was dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to give the pure desired product as a yellow oil (0.18 g, 63%). 1 H NMR (500 MHz, chloroform-d) δ 7.44-7.23 (m, 5H), 5.25-4.94 (m, 2H), 4.17-4.00 (m, 2H), 3.97-3.14 (m, 5H), 2.52-2.28 (m, 1H), 1.47-1.16 (m, 2H), 0.93 (qd, J=7.43, 1.90 Hz, 3H).

[0186] Example 10: Synthesis of cis-3R hydroxyl ketone (12) from cis-3R ketone (9) [ka] Step 1: A solution of methyl ketone (12) (1.0 g, 3.63 mmol, 1.0 equiv) in dry CHCl (10 mL) under argon atmosphere was cooled to 0° C. To this solution was added TMSOTf (1.18 mL, 6.54 mmol, 1.8 equiv) and EtN (1.0 mL, 7.26 mmol, 2.0 equiv) and stirring was continued for 1 h until the formation of the silyl enol ether was complete. The reaction was quenched with saturated aqueous NaHCO and extracted with ether (3×10 mL). The dried (MgSO) extract was concentrated under reduced pressure to give the intermediate silyl enol ether as a brown oil, which was used in the next step without further purification (1.3 g, 99%).

[0187] Step 2: The crude silyl enol ether (1.0 g, 2.87 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and m-CPBA (0.75 g, 4.3 mmol, 1.5 equiv) was added in one portion at room temperature. After 1 h, the reaction was quenched with 5% aqueous Na2S2O3. This solution was extracted with DCM (3 x 10 mL). The organic phase was then washed with saturated aqueous K2CO3, dried (NaSO4), filtered, and concentrated under reduced pressure to give the pure product as a yellow oil (0.66 g, 80%). 1 H NMR(400MHz,chloroform-d)δ 7.44-7.29(m,5H),5.24-5.02(m,2H),4.40-4.11(m,2H),3.77-3.65(m,1H),3.65-3.48(m,2H),3.45-3 .27(m,1H),3.25-3.03(m,1H),2.36(d,J=5.9Hz,1H),1.46-1.20(m,2H),0.93(dd,J=13.1,7.0Hz,3H).

[0188] Example 11: Synthesis of Weinreb amide (14) from carboxylic acid (13) [ka] Compound (13) (1.80 g, 6.80 mmol, 1.0 equiv) and CDI (1.66 g, 10.20 mmol, 1.5 equiv) were mixed under argon atmosphere. Dry CHCl (20 mL) was added and the suspension was stirred at 0° C. for 5 min. N,O-Dimethylhydroxylamine hydrochloride (0.99 g, 10.20 mmol, 1.5 equiv) was then added and the resulting mixture was stirred at room temperature for another 5 h until the reaction was complete. The suspension was quenched with aqueous HCl (0.5 M, 10 mL) and the organic layer was extracted and washed twice with saturated brine (2×10 mL). The combined organic layers were dried over anhydrous MgSO, filtered and evaporated under reduced pressure to give the pure title product as a yellow oil (2.12 g, 14.11 mmol, 98%). 1H NMR(400MHz,chloroform-d)δ 7.44-7.29(m,5H),5.16(s,2H),4.45(dt,J=15.91,4.11Hz,2H),4.26(dt,J=15.91,4.11Hz,2H),3. 65(d,J=4.09Hz,3H),3.24(d,J=1.06Hz,3H),2.34(q,J=7.62Hz,2H),1.07(td,J=7.64,5.07Hz,3H).

[0189] Example 12: Synthesis of ketone (15) from Weinreb amide (14) [ka] To a solution of compound (14) (0.50 g, 1.57 mmol, 1.0 equiv) in dry THF (10 mL) under argon atmosphere was added MeMgCl (3 M, 0.90 mL, 2.67 mmol, 1.7 equiv) at 0° C. and the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×10 mL). The dried (MgSO4) extract was filtered and concentrated under reduced pressure to give the title product (0.42 g, 98%) as a brown oil. 1 H NMR(500MHz,chloroform-d)δ 7.43-7.30(m,5H),5.16(s,2H),4.55-4.25(m,4H),2.69-2.51(m,2H),2.25(d,J=9.19Hz,3H),1.10(dt,J=16.34,7.62Hz,3H).

[0190] Example 13: Synthesis of compound (16) from ketone (15) [ka] A solution of compound (15) (0.1 g, 0.36 mmol, 1.0 equiv) in dry CHCl (2 mL) under argon atmosphere was cooled to 0 °C. To this solution was added TMSOTf (0.12 mL, 0.65 mmol, 1.8 equiv), EtN (0.1 mL, 0.72 mmol, 2.0 equiv) and stirring was continued for 1 h until the formation of the intermediate silyl enol ether was complete. NaHCO (0.03 g, 0.43 mmol, 1.2 equiv) and NBS (0.04 mg, 0.43 mmol, 1.2 equiv) were then added at 0 °C. After 1 h, the reaction was quenched with saturated aqueous NaHCO and extracted with EtOAc (2 × 10 mL). The organic layer was then washed with 5% aqueous NaSO. The dried (Mg2SO4) organic layer was filtered, concentrated under reduced pressure and purified by column chromatography on silica gel to afford the title product as a yellow oil (0.09 g, 73%). 1 H NMR(500MHz,chloroform-d)δ 7.41-7.30(m,5H),5.18(d,J=1.17Hz,2H),4.64-4.44(m,2H),4.43-4.32(m,2 H),3.93(d,J=5.63Hz,2H),2.77-2.48(m,2H),1.12(dt,J=15.12,7.63Hz,3H).

[0191] Example 14: Synthesis of compound (17) from Weinreb amide (14) [ka] To a solution of compound (14) (0.3 g, 0.94 mmol, 1.0 equiv.) in dry THF (5 mL) cooled to −78 °C, ICHCl (0.28 mL, 3.80 mmol, 4.0 equiv.) was added, followed by dropwise addition of MeLi·LiBr complex (1.5 M solution in EtO, 1.5 mL, 2.82 mmol, 3.0 equiv.) over 5 min. The resulting solution was stirred at that temperature for 2 h, then saturated aqueous NHCl was added at −78 °C. The mixture was allowed to warm to room temperature and washed with EtO (10 mL) and saturated brine (10 mL). The two resulting phases were separated, and the organic phase was dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to give the pure desired product as a yellow oil (0.13 g, 48%). 1 H NMR(500MHz,chloroform-d)δ 7.54-7.28(m,5H),5.17(s,2H),4.63-4.45(m,2H),4.38(dt,J=24.39,4.20Hz, 2H),4.17(d,J=2.84Hz,2H),2.77-2.57(m,2H),1.12(dt,J=13.57,7.62Hz,3H).

[0192] Example 15: Hydrogenation of Weinreb amide (14) to cis compound (2) [ka] To a solution of compound (14) (0.3 g, 0.94 mmol, 1.0 equiv) in glacial AcOH (2 mL) was added PtO2 (0.08 g, 0.35 mmol). The reaction mixture was stirred at room temperature under H2 (10 bar) for 12 h. The solution was filtered through a pad of Celite and evaporated under reduced pressure to give a brown oil. The crude oil was purified by column chromatography to give the desired reduction product. 1H NMR(500MHz,chloroform-d)δ 7.26(s,5H),5.23-5.05(m,2H),3.79-3.71(m,1H),3.71-3.66(m,3H),3.63-3.54(m,2H),3.50(dd,J=14.7,9.2Hz,1H),3. 45-3.33(m,1H),3.24-3.13(m,3H),2.41-2.30(m,1H),1.56-1.36(m,1H),1.36-1.20(m,1H),0.91(dd,J=14.0,7.3Hz,3H).

[0193] Example 16: Hydrogenation of ester (18) to cis compound (19) [ka] To a solution of compound (18) (0.5 g, 1.50 mmol, 1.0 equiv) in glacial AcOH (2 mL) was added PtO2 (0.08 g, 0.35 mmol). The reaction mixture was stirred at room temperature under H2 (10 bar) for 12 h. The solution was filtered through a pad of Celite and evaporated under reduced pressure to give a brown oil. The crude oil was purified by column chromatography to give the desired reduction product. 1 H NMR(500MHz,chloroform-d)δ 7.39-7.27(m,5H),5.24-5.00(m,2H),3.78-3.64(m,1H),3.57(ddd,J=16.1,10.4,7.3Hz,1H),3.48(ddd,J=11.6,7.1,5.1Hz,1H),3.2 4(ddd,J=19.8,10.4,8.7Hz,1H),2.95(dtd,J=13.8,7.0,3.5Hz,1H),2.27(dddd,J=15.1,8.4,6.7,1.6Hz,1H),1.52-1.44(m,2H),1.43 (s,9H),0.97(td,J=7.4,4.8Hz,3H).

[0194] Example 17: Synthesis of ester (18) from enol triflate (20) [ka] To a suspension of CuI (0.84 g, 4.4 mmol, 2 equiv) in dry THF (20 mL) cooled to 0 °C was added EtMgBr (3.0 M, 3.0 mL, 8.85 mmol, 4 equiv) dropwise. The reaction mixture was observed to turn dark purple and was stirred at 0 °C for 30 min. A solution of methyl ketone (1.0 g, 2.2 mmol, 1.0 equiv) in THF (20 mL) was then added dropwise at that temperature. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 x 50 mL). The organic phase was then washed with saturated aqueous NaCl, dried (MgSO4), filtered through a pad of Celite, and concentrated under reduced pressure to give the title product (0.73 g, 98%) as a brown oil. 1H NMR(500MHz,chloroform-d)δ 7.45-7.27(m,5H),5.16(d,J = 4.46Hz,2H),4.47-4.19(m,4H),2.66-2.54(m,2H),1.49(d,J=2.14Hz,9H),1.08(q,J=7.50Hz,3H).

[0195] Example 18: Synthesis of carboxylic acid (13) from ester (18) [ka] To a crude sample of t-butyl ester (18) (2 g, 0.6 mmol) in a round bottom flask, formic acid (8 ml) was added and the reaction mixture was stirred at 45 °C until completion (TLC controlled, 3-4 h). The remaining formic acid was removed by distillation under reduced pressure until a residue was obtained, which was redissolved in 20 ml EtOAc and washed with 12 ml NaCl. The remaining organic phase was freshly extracted during this procedure with 20 ml saturated aqueous Na2CO3, transferring the product as the sodium salt to the aqueous phase and removing the organic phase. The basic and colored aqueous phase was then acidified with HCl cc. The desired product precipitated as a light brown solid, which was filtered, washed with water and dried to give the title product (1.4 g, 85%).

[0196] Example 19: Synthesis of (3R,4S)-3-(N-(tert-butoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)-4-ethylpyrrolidine-1-carboxylate benzyl (21) [ka] A mixture of sodium hydride (1.1 g) (60%, oil dispersion) and dimethylformamide (100 mL) was cooled to 0° C. A solution of tert-butyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (11 g) in dimethylformamide (30 ml) was added to the above mixture at 0° C. and stirred at the same temperature for 120 minutes. A mixture of benzyl (3R,4S)-3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate (10 g) in tetrahydrofuran (10 mL) at 0° C. was added to the above reaction mixture and stirred at the same temperature for 1 hour. After completion of the reaction, acetic acid (0.8 ml) was added to the reaction mixture. The solution was added to cold water (750 ml) and the solid was filtered and dried to obtain the crude product. Yield: 75%, 1H NMR (400MHz, d-DMSO): δ 8.74(s,1H),8.21-8.17(m,1H),8.00-7.97(m,2H),7.44-7.42(m,2H) ,7.34-7.27(m,5H),6.79-6.66(m,1H),5.06-5.05(m,2H),4.74(s,2H) ,3.65-3.58(m,1H),3.52-3.43(m,3H),3.21-3.16(m,1H),2.40-2.38( m,1H),2.34(s,3H),1.29-1.46(m,10H),1.29-1.23(m,1H),0.91-0.86 (m,3H).

[0197] Example 20: Synthesis of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-l-carboxylate benzyl (22) [ka] Trifluoroacetic anhydride (6.3 ml) and trifluoroacetic acid (1.6 ml) were added to a mixture of crude benzyl (3R,4S)-3-(N-(tert-butoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)-4-ethylpyrrolidine-1-carboxylate (10 g) and acetonitrile (100 ml) at 20 / 25° C. The reaction mixture was warmed to 70° C. and stirred at this temperature for 4 h. The reaction mixture was distilled and added to cooled saturated sodium bicarbonate solution (100 ml) and dichloromethane (100 ml) and the organic layer was separated. The organic layer was washed again with water (100 ml) and separated. The organic layer was concentrated under reduced pressure to give a crude solid, which was purified by crystallization from methanol (50 ml). Yield: 40%, 1H NMR (400MHz, d-DMSO)δ 8.77(s,1H),8.04-8.02(m,2H),7.98-7.97(m,1H),7.70(s,1H),7.44-7.29(m,1H),5.16-5.08(m,2H),4.35-4.30( m,1H),3.87-3.70(m,3H),3.34-3.27(m,1H),2.47-2.46(m,1H),2.33(s,3H),0.99-0.75(m,2H),0.60-0.45(m,3H).

[0198] Example 21: Synthesis of 8-((3S,4R)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (23) [ka] To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate benzyl (10 g) in isopropanol (20 mL) was added concentrated aqueous HCl (20 mL) slowly at 20 / 25° C. and heated to 80° C. The reaction mixture was stirred at the same temperature for 5 h and cooled to 20 / 25° C. Water (100 ml) and dichloromethane (100 mL) were added to the reaction mixture and the organic layer was separated and removed. The aqueous layer was washed with dichloromethane (2×100 mL). The pH of the aqueous layer was adjusted to 7.5 with sodium bicarbonate and then extracted with dichloromethane (2×100 mL). The organic layer was concentrated under reduced pressure at 20 / 25° C. until a suspension was obtained and the suspension was filtered to give a moist pale yellow solid. Yield: 100%. 1H NMR (400MHz,MeOD)δ 9.06(s,1H),8.49(s,1H),8.30-8.29(m,1H),8.10(d,2H),7.58-7.57(m,1H),7.42(d,2H),4.67-4.65 (m,1H),3.99-3.94(m,1H),3.84-3.78(m,2H),3.43-3.38(m,1H),2.84-2.82(m,1H),2.38(s,3H),1.15 -1.08(m,2H),0.82-0.76(m,3H).

[0199] Example 22: Synthesis of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (24) [ka] 2,2,2-trifluoroethylamine (2.2 ml) was added to a mixture of 1,1-carbonyldiimidazole (CDI) (4.1 g) and tetrahydrofuran (50 mL) at 0 / 5° C. and stirred for 2 hours. The reaction mixture was added to a mixture of 8-((3S,4R)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (7.5 g) and dichloromethane (100 mL) and heated to 30 / 35° C. The reaction mixture was stirred until the reaction was complete. 10% aqueous HCl (100 ml) was added, the aqueous phase was removed, the resulting organic phase was washed with water (100 mL), and the final organic phase was concentrated to 30 ml by distillation and added to heptane (300 ml) to obtain a suspension, which was filtered and dried to obtain a light brown solid. Yield: 80%. 1HNMR (400MHz,d-DMSO)δ8.77(s,1H),8.05(d,2H),7.98(d,1H),7.59(s,1H),7.46-7.43(m,3H),6.94(t,1H),4.34-4.29(m,1H),3. 88-3.65(m,5H),3.27-3.23(m,1H),2.46-2.54(m,1H),2.35(s,3H),1.04-0.99(m,1H),0.82-0.77(m,1H),0.63-0.60(m,3H).

[0200] Example 23: Preparation of Upadacitinib [ka] To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (10 g) in tetrahydrofuran (50 mL) was added 10% aqueous sodium hydroxide (15 mL) and heated to 50° C. The reaction mixture was stirred for 5 hours and cooled to 25° C. Saturated sodium chloride solution (100 mL) was added to the reaction mixture and extracted with dichloromethane (100 mL). The organic phase was separated and washed with water (100 mL). 2.5% aqueous HCl (100 mL) was added and stirred for 30 minutes. The organic phase was removed and the resulting acidic aqueous phase was extracted with dichloromethane (100 mL). The final aqueous phase was cooled to 0 / 5° C. and 10% NaOH solution was added until pH 10 / 12. The resulting suspension was filtered and washed with water (2×50 mL). The filter cake was stripped of water and dried under reduced pressure at 30 / 40° C. to give an almost white amorphous solid. Yield: 80%. 1H NMR (400MHz,d-DMSO)δ12.27(s,1H),8.58(s,1H),7.47-7.43(m,2H),7.00-6.94(m,2H),4.38-4.33(m,1H),3.92 -3.67(m,5H),3.33-3.25(m,1H),2.59-2.54(m,1H),1.14-1.08(m,1H),0.86-0.78(m,1H),0.65-0.62(m,3H).

[0201] Example 24: Preparation of Upadacitinib Upadacitinib (0.25 g) was dissolved in ethanol (1 mL). This solution was added to a solution of 0.5% ethanol in water (25 mL) pre-cooled to 0 / 5°C. A solid was obtained immediately. The suspension was stirred at 0-5°C for 20 minutes, after which filtration was continued. The wet filter cake was dried overnight at 50°C under forced air to obtain an almost white amorphous solid.

[0202] Example 25: Preparation of Upadacitinib Tartrate To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (10 g) in tetrahydrofuran (50 mL) was added 10% aqueous sodium hydroxide (15 ml) and heated to 50°C. The reaction mixture was stirred for 5 h and cooled to 25°C. Saturated sodium chloride solution (100 mL) was added to the reaction mixture and extracted with dichloromethane (100 ml). The organic phase was separated and washed with water (100 mL). The organic phase was concentrated to give the crude product which was dissolved in isopropanol (30 mL). L-(+)-tartaric acid (1.2 mol / mol) was added and heated to 30 / 40°C. The solution was cooled to 20 / 25°C and slowly added to isopropyl acetate (300ml). The suspension was stirred overnight and water was added (2mol / mol). The resulting suspension was evaporated to 100ml and the resulting suspension was filtered and dried to give a light brown solid. Yield: 80%.

[0203] Comparative experiment To further compare the method of the present invention with the method disclosed in WO 2017 / 066775, the disclosed synthetic method was reproduced as follows under the conditions disclosed in Examples 3A and 3B of said document. [ka]

[0204] Comparative Example 26: Synthesis of dimethylsulfoxonium (25) from cis compound (1) [ka] Preparation of trimethylsulfoxonium anion (slurry 1) A slurry of trimethylsulfoxonium chloride (1.84 g, 2 eq.) and KOtBu (0.96 g, 2 eq.) in anhydrous THF (13.8 ml) was heated to reflux for 2 h, then cooled to below 0°C.

[0205] Preparation of carbonyldiimidazole (solution 2) To a solution of CDI (1.02 g, 1.5 equiv.) in anhydrous THF (3.5 ml) was slowly added (over 30 min) a solution of cis compound (1) (1.15 g, 4.18 mmol) in anhydrous THF (3.5 ml) and the resulting mixture was stirred for 1 h.

[0206] Freshly prepared solution 2 was slowly added (over 15 min) to slurry 1, maintaining the temperature below -1°C. The resulting mixture was stirred at room temperature for 20 min until the reaction was complete. The solvent was partially evaporated under reduced pressure and AcOEt (11 ml) and 5% aqueous NaCl (11 ml) were added. The two layers were separated and the aqueous layer was extracted again with AcOEt (11 ml). The combined organic layers were washed with 12% aqueous NaCl. The organic layer was evaporated under reduced pressure to give 1.46 g. The oil was analyzed by HPLC and found to be a 68 / 32 mixture of cis / trans isomers. Thus, isomerization occurs under the reaction conditions required for the method disclosed in WO2017 / 066775. The resulting oil was purified by chromatography to separate the two isomers.

[0207] Cis isomer (0.75g): 1 H NMR(500MHz,DMSO)δ:7.41-7.25(m,5H),5.11-4.93(m,2H),4.76(s,1H),3.54-3.23(m,9H),3.1 5(dd,1H),2.91-2.72(m,1H),2.26-2.02(m,1H),1.57-1.39(m,1H),1.20(tq,1H),0.88(td,3H).

[0208] Trans isomer (0.3 g): 1 H NMR(500MHz,CDCl3)δ:7.4(m,5H),5.1(d,2H),4.42(d,1H),3.60-3.77(m,2H),3.47(m, 1H),3.39(m,6H),2.99(m,1H),2.53(q,1H),2.33(m,1H),1.56(m,1H),1.29(m,1H),0.9 (qd,3H).

[0209] Comparative Example 27: Synthesis of compound (5) from cis compound (25) [ka] To a solution of cis-dimethylsulfoxonium (25) (0.75 g, 2.13 mmol) and lithium bromide (0.222 g, 1.2 equiv.) in THF (7.5 ml) was added p-toluenesulfonic acid monohydrate (0.447 g, 1.1 equiv.). The resulting mixture was warmed to 40° C. and stirred overnight. A white solid precipitate formed. The slurry was cooled to room temperature and the solvent was partially evaporated under reduced pressure. AcOEt (30 ml) and 7% aqueous NaHCO3 (13 ml) were added. The two layers were separated and the organic layer was washed with water (5 ml). Finally, the organic layer was evaporated under reduced pressure to give 0.71 g of an oil formed of a 38 / 62 mixture of cis / trans isomers. The resulting oil was purified by chromatography to separate the two isomers.

[0210] Cis isomer (0.063g): 1 H NMR(400MHz,CDCl3)δ 7.45-7.28(m,5H),5.25-4.99(m,2H),3.99-3.82(m,2H),3.81-3.66(m,1H),3.63-3.48(m, 3H),3.38(ddd,J=24.8,10.7,7.0Hz,1H),2.53-2.27(m,1H),1.46-1.17(m,2H),1.05-0.85 (m,3H).

[0211] Trans isomer (0.373g): 1 H NMR(500 MHz,CDCl3)δ 7.42-7.28(m,5H),5.13(s,2H),3.98-3.87(m,2H),3.88-3.64(m,2H),3.48(dd,J=10.9,8.0Hz,1H),3.25(dd,J=1 4.6,7.8Hz,1H),3.18-3.04(m,1H),2.55-2.34(m,1H),1.54(td,J=13.5,6.8Hz,1H),1.44-1.19(m,1H),1.00-0.87 (m,3H). The present invention is as follows. [1] Formula (I): [ka] (In the formula, - - - is a single bond or a double bond, X is a leaving group, and R 1 is selected from H and an amino protecting group. or a salt or solvate thereof, comprising the steps of: (a) Formula (II):

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[10] In the compound of formula (I), or formula (II), or formula (III), or formula (IV), or formula (V), or formula (VI), or formula (VII), or formula (VIII), where - - - is a single bond, the compound is a compound of formula (I'-cis), or formula (II'-cis), or formula (III'-cis), or formula (IV'-cis), or formula (V'-cis), or formula (VII'-cis), or formula (VIII'-cis), preferably a compound of formula (I'-cis-3R), or formula (II'-cis-3R), or formula (III'-cis-3R), or formula (IV'-cis-3R), or formula (V'-cis-3R), or formula (VI'-cis-3R), or formula (VII'-cis-3R), or formula (VIII'-cis-3R):

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[11] The process of: -Formula (IX):

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[10] , wherein the compound of formula (II) or a salt or solvate thereof is obtained by a process comprising the steps of:

[12] A method for preparing upadacitinib, or a salt, solvate, or stereoisomer thereof, comprising: - Formula (I):

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[11] above; and - converting a compound of formula (I) or a salt or solvate thereof into upadacitinib or a salt or solvate or stereoisomer thereof. The method comprising:

[13] Formula (I'-cis-3R):

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[12] , comprising:

[14] The following formula: [ka] TIFF0007648027000116.tif131164 (In the formula, R 1 is selected from H and an amino protecting group; R 3 is C 1 ~C 6 Alkyl, (C 6 ~C 15 )Aryl(C 1 ~C 6 ) Alkyl, C 6 ~C 15 Aryl, COR', and SiR' 3 wherein each R′ is independently selected from1~6 Alkyl, C 3 ~C 10 Cycloalkyl, C 6~15 Aryl and (C 6 ~C 15 )Aryl(C 1 ~C 6 ) alkyl), R 4 and R 5 is independently C 1 ~C 6 Alkyl, (C 6 ~C 15 )Aryl(C 1 ~C 6 ) alkyl and C 6 ~C 15 aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; and R' is C 1 ~C 6 Alkyl, (C 6 ~C 15 )Aryl(C 1 ~C 6 ) alkyl and C 6 ~C 15 aryl) or a salt or solvate thereof.

[15] R 1 but, -COOR a (The above R a is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 3 ~C 10 Cycloalkyl, C 6 ~C 15 Aryl, (C 6 ~C 15 )Aryl(C 1 ~C 6 )alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C 1 ~C 6 alkyl)silanes, -COR b (The above R b is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 3 ~C 10 Cycloalkyl, C 6 ~C 15 Aryl, (C 6 ~C 15 )Aryl(C 1 ~C 6 ) alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; -R c (The above R c is C 1 ~C 6 Alkyl, C 6 ~C 15 Aryl, and (C 6 ~C 15 )Aryl(C 1 ~C 6 ) alkyl), -SO 2 R d (The above R d is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 6 ~C 15 Aryl, (C 6 ~C 15 )Aryl(C 1 ~C 6 ) selected from alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; and -Si(R e )(R f )(R g ) (R e , R f and the above R g is independently 1 ~C 6 Alkyl, C 3 ~C 10 Cycloalkyl, C 6 ~C 15 Aryl, and (C6 ~C 15 )Aryl(C 1 ~C 6 ) alkyl) The compound according to the above

[14] , selected from the group consisting of

Claims

1. Formula (I'-cis): 【Chemistry 1】 (In the formula, X is a leaving group, and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, comprising the steps of: (a) Formula (II): 【Chemistry 2】 (In the formula, - - - is a cis single or double bond, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, Formula (III) or Formula (IV): 【Chemistry 3】 (In the formula, - - - is a cis single or double bond, and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, and (b) the steps of: (bi) reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi, Formula (V): 【Chemistry 4】 (In the formula, - - - is a cis single or double bond, and R １ is selected from H and an amino protecting group. or a salt or solvate thereof; (bii) reacting a ketone of formula (V) or a salt or solvate thereof with Formula (VI) or Formula (VII): 【Chemistry 5】 (In the formula, - - - is a cis single or double bond, R １ is selected from H and an amino protecting group; R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′ and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), and R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; or a salt or solvate thereof, or an enamine or a salt or solvate thereof; and (biii) converting an enol ether of formula (VI) or a salt or solvate thereof, or an enamine of formula (VII) or a salt or solvate thereof, to a compound of formula (I'-cis) or a salt or solvate thereof, or (bi') reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof with a compound represented by the formula (III) or a salt or solvate thereof, with a compound represented by the formula (IV) or a salt or solvate thereof, ２ -Li, X-CH ２ -MgCl or X-CH ２ - MgBr to provide a compound of formula (I'-cis) or a salt or solvate thereof; or (bi″) reacting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof with R ６ O-CH ２ - Li, R ６ O-CH ２ -MgCl or R ６ O-CH ２ -MgBr, Formula (VIII): 【Chemistry 6】 (In the formula, - - - is a cis single or double bond, R １ is selected from H and an amino protecting group, and R ６ is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently １ ~C ６ Alkyl, C ６ ~C １５ Aryl, and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl) or a salt or solvate thereof; and (bii'') converting a compound of formula (VIII) or a salt or solvate thereof into a compound of formula (I'-cis) or a salt or solvate thereof. converting a compound of formula (III) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof, into a compound of formula (I'-cis) or a salt or solvate thereof, by a process comprising: The method comprising:

2. 2. The process according to claim 1, further comprising a hydrogenation step after step (a), or (bi), or (bii), or (biii), or (bi'), or (bi"), or (bii"), and wherein in the compound of formula (II) or a salt or solvate thereof, - - - is a double bond.

3. The method according to claim 1, wherein in the compounds of formula (II), (III), (IV), (V), (VI), (VII) and (VIII), or salts or solvates thereof, - - - is a cis single bond.

4. A compound of formula (II) (wherein - - - is a cis single bond) or a salt or solvate thereof, Formula (II''): 【Chemistry 7】 (In the formula, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), and R １ is selected from H and an amino protecting group. or a salt or solvate thereof.

5. (a) Formula (II″): 【Chemistry 8】 (In the formula, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, Formula (III″) or Formula (IV″): 【Chemistry 9】 or a salt or solvate thereof, (b1) hydrogenating a compound of formula (III″) or a salt or solvate thereof, or a compound of formula (IV″) or a salt or solvate thereof, Formula (III'-cis) or Formula (IV'-cis): 【Chemistry 10】 or a salt or solvate thereof; and (b2) the steps of: (bi) reacting a compound of formula (III'-cis) or a salt or solvate thereof, or a compound of formula (IV'-cis) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi, Formula (V'-cis): 【Chemistry 11】 or a salt or solvate thereof; (bii) reacting a ketone of formula (V'-cis) or a salt or solvate thereof with Formula (VI'-cis) or Formula (VII'-cis): 【Chemistry 12】 (In the formula, R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′, and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), and R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; or a salt or solvate thereof, or an enamine or a salt or solvate thereof; and (biii) converting an enol ether of formula (VI'-cis) or a salt or solvate thereof, or an enamine of formula (VII'-cis) or a salt or solvate thereof, to a compound of formula (I'-cis) or a salt or solvate thereof, or (bi') reacting a compound of formula (III'-cis) or a salt or solvate thereof, or a compound of formula (IV'-cis) or a salt or solvate thereof with X-CH ２ -Li, X-CH ２ -MgCl or X-CH ２ - MgBr to provide a compound of formula (I'-cis) or a salt or solvate thereof; or (bi'') a compound of formula (III'-cis) or a salt or solvate thereof, or a compound of formula (IV'-cis) or a salt or solvate thereof, ６ O-CH ２ - Li, R ６ O-CH ２ -MgCl or R ６ O-CH ２ -MgBr, Formula (VIII'-cis): 【Chemistry 13】 (In the formula, R １ is selected from H and an amino protecting group, and R ６ is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently １ ~C ６ Alkyl, C ６ ~C １５ Aryl, and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl) or a salt or solvate thereof; and (bii'') converting a compound of formula (VIII'-cis) or a salt or solvate thereof into a compound of formula (I'-cis) or a salt or solvate thereof, converting a compound of formula (III'-cis) or a salt or solvate thereof, or a compound of formula (IV'-cis) or a salt or solvate thereof, into a compound of formula (I'-cis) or a salt or solvate thereof, by a process comprising: The method according to claim 1 or 2, comprising:

6. (a) Formula (II″): 【Chemistry 14】 (In the formula, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, Formula (III″) or (IV″): 【Chemistry 15】 or a salt or solvate thereof, and (b) the steps of: (bi1) reacting a compound of formula (III″) or a salt or solvate thereof, or a compound of formula (IV″) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi, Formula (V''): 【Chemistry 16】 or a salt or solvate thereof; (bi2) hydrogenating a compound of formula (V″) or a salt or solvate thereof, Formula (V'-cis): 【Chemistry 17】 or a salt or solvate thereof; (bii) reacting a ketone of formula (V'-cis) or a salt or solvate thereof with a compound of formula (VI'-cis) or formula (VII'-cis): 【Chemistry 18】 (In the formula, R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′, and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), and R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; or a salt or solvate thereof, or an enamine or a salt or solvate thereof; and (biii) converting an enol ether of formula (VI'-cis) or a salt or solvate thereof, or an enamine of formula (VII'-cis) or a salt or solvate thereof, into a compound of formula (I'-cis) or a salt or solvate thereof. converting a compound of formula (III″) or a salt or solvate thereof, or a compound of formula (IV″) or a salt or solvate thereof, into a compound of formula (I′-cis) or a salt or solvate thereof, by a process comprising: The method according to claim 1 or 2, comprising:

7. (a) Formula (II″): 【Chemistry 19】 (In the formula, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, Formula (III″) or (IV″): 【Chemistry 20】 or a salt or solvate thereof, and (b) the steps of: (bi) reacting a compound of formula (III″) or a salt or solvate thereof, or a compound of formula (IV″) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi, Formula (V''): 【Chemistry 21】 or a salt or solvate thereof; (bii) reacting a ketone of formula (V″) or a salt or solvate thereof with Formula (VI″) or Formula (VII″): 【Chemical 22】 (In the formula, R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′, and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), and R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; or a salt or solvate thereof, or an enamine or a salt or solvate thereof; and (biii) reacting an enol ether of formula (VI″) or a salt or solvate thereof, or an enamine of formula (VII″) or a salt or solvate thereof, with Formula (I″): 【Chemistry 23】 (In the formula, X is a leaving group, and R １ is selected from H and an amino protecting group. or a salt or solvate thereof; and (biv) hydrogenating a compound of formula (I″) or a salt or solvate thereof to provide a compound of formula (I′-cis) or a salt or solvate thereof; or (bi′) reacting a compound of formula (III″) or a salt or solvate thereof, or a compound of formula (IV″) or a salt or solvate thereof with a compound represented by the formula (III″) or a salt or solvate thereof, with a compound represented by the formula (IV″) or a salt or solvate thereof, ２ -Li, X-CH ２ -MgCl or X-CH ２ -MgBr, where X is a leaving group, Formula (I″): 【Chemistry 24】 or a salt or solvate thereof; and (bii') hydrogenating a compound of formula (I'') or a salt or solvate thereof to provide a compound of formula (I'-cis) or a salt or solvate thereof; or (bi'') reacting a compound of formula (III'') or a salt or solvate thereof, or a compound of formula (IV'') or a salt or solvate thereof with R ６ O-CH ２ - Li, R ６ O-CH ２ -MgCl or R ６ O-CH ２ -MgBr, Formula (VIII''): 【Chemistry 25】 (In the formula, R １ is selected from H and an amino protecting group, and R ６ is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently １ ~C ６ Alkyl, C ６ ~C １５ Aryl, and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl) or a salt or solvate thereof; (bii″) reacting a compound of formula (VIII′) or a salt or solvate thereof with Formula (I″): 【Chemistry 26】 or a salt or solvate thereof, and (biii') hydrogenating a compound of formula (I'') or a salt or solvate thereof to provide a compound of formula (I'-cis) or a salt or solvate thereof; converting a compound of formula (III″) or a salt or solvate thereof, or a compound of formula (IV″) or a salt or solvate thereof, into a compound of formula (I′-cis) or a salt or solvate thereof, by a process comprising: The method according to claim 1 or 2, comprising:

8. In the above formula: -X is selected from Cl, Br and I, and / or -R １ is an amino protecting group, and / or -Y is OH and OR ２ wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl; and / or -R ６ is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently １ ~C ６ Alkyl, C ６ ~C １５ Aryl, and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), The method according to any one of claims 1 to 7.

9. In the compound of formula (I'-cis), or formula (II), or formula (III), or formula (IV), or formula (V), or formula (VI), or formula (VII), or formula (VIII), where - - - is a cis single bond, the compound has the formula (I'-cis-3R), or formula (II'-cis-3R), or formula (III'-cis-3R), or formula (IV'-cis-3R), or formula (V'-cis-3R), or formula (VI'-cis-3R), or formula (VII'-cis-3R), or formula (VIII'-cis-3R): 【Chemical 27】 (In the formula, X is a leaving group, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), R １ is selected from H and an amino protecting group; R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′, and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; and R ６ is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently １ ~C ６ Alkyl, C ６ ~C １５ Aryl, and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl) or a salt or solvate thereof.

10. The following steps: -Formula (IX): 【Chemistry 28】 (In the formula, Z is halogen, C １ ~C ６ Alkyl sulfonic acid group, C １ ~C ６ Haloalkylsulfonic acid group, C ６ ~C １０ Arylsulfonic acid group, and (C １ ~C ６ ) alkyl(C ６ ~C １０ ) arylsulfonic acid groups; R １ is selected from H and an amino protecting group, and Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl) or a salt or solvate thereof, ２ CuLi, Et ２ CuMgBr or Et ２ with CuMgCl to provide a compound of formula (II) (wherein - - - is a double bond) or a salt or solvate thereof; - if necessary (i.e. if a compound of formula (II) where - - - is a cis single bond is desired), hydrogenating said double bond to provide a compound of formula (II) where - - - is a cis single bond or a salt or solvate thereof. The method according to any one of claims 1 to 9, wherein the compound of formula (II) or a salt or solvate thereof is obtained by a process comprising:

11. The method of any one of claims 1 to 10, wherein the compound of formula (I'-cis) or a salt or solvate thereof is converted to upadacitinib or a salt or solvate or stereoisomer thereof.

12. The compound of the formula (I'-cis) or a salt or solvate thereof, Formula (I'-cis-3R): 【Chemical Formula 29】 (In the formula, X is a leaving group, and R １ is selected from H and an amino protecting group. or a salt or solvate thereof, and The compounds of the formula (II), (III), (IV), (V), (VI), (VII) and (VIII) or salts or solvates thereof are represented by the formula (II'-cis-3R), the formula (III'-cis-3R), the formula (IV'-cis-3R), the formula (V'-cis-3R), the formula (VI'-cis-3R), the formula (VII'-cis-3R) and the formula (VIII'-cis-3R): 【Chemistry 30】 (In the formula, X is a leaving group, Y is OH, Cl, OR ２ and O.C.(O)R ２ (wherein R ２ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl), R １ is selected from H and an amino protecting group; R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′, and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; and R ６ is selected from H, -COR' and -CONR'R'', wherein R' and R'' are independently １ ~C ６ Alkyl, C ６ ~C １５ Aryl, and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl) or a salt or solvate thereof, The method according to any one of claims 1, 3, 4 and 8 to 11.

13. The following formula: 【Chemistry 31】 【change】 (In the formula, R １ teeth, -COORa, wherein Ra is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C10 cycloalkyl, C6-C15 aryl, (C6-C15)aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6 alkyl)silane; -COR b , wherein R b is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, C 6 -C 15 aryl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; -Rc, wherein Rc is selected from C1-C6 alkyl, C6-C15 aryl, and (C6-C15)aryl(C1-C6)alkyl; -SO2Rd, where Rd is selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C15 aryl, (C6-C15)aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; and -Si(R e )(R f )(R g ), wherein R e , R f and R g are independently selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 15 aryl, and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl; is an amino protecting group selected from R ３ is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl, C ６ ~C １５ Aryl, COR′, and SiR′ ３ wherein each R′ is independently selected from １～６ Alkyl, C ３ ~C １０ Cycloalkyl, C ６～１５ Aryl and (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl), R ４ and R ５ is independently C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl, or together with the nitrogen atom form a 5- to 7-membered heterocycle; and R' is C １ ~C ６ Alkyl, (C ６ ~C １５ ) Aryl (C １ ~C ６ ) alkyl and C ６ ~C １５ aryl) or a salt or solvate thereof.

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