Methods and intermediates for preparing upadacitinib

Abstract

The present invention relates to a process for preparing compounds of formula (I) by using Weinreb amide (III) or its equivalent as a key intermediate, which are useful intermediates in the synthesis of upadacitinib and structurally related compounds.

Description

Technical Field

[0001] The present invention relates to a method for preparing compounds which are useful intermediates in the synthesis of Upadacitinib. Background Art

[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.

[0003]

[0004] Upadacitinib (also known as ABT-494) is a potent and selective JAK1 inhibitor developed by AbbVie. It has been approved by the FDA for the treatment of rheumatoid arthritis.

[0005] Several methods for the synthesis of upadacitinib have been described in the literature, but they are all based on the same approach: preparation of what we call fragment A and fragment B (pyrrolidine derivatives), followed by their ligation. Subsequent cyclization to provide the imidazopyrrolopyrazine skeleton and derivatization yields upadacitinib.

[0006]

[0007] Document WO 2013 / 043826 discloses in Example 12 a process for preparing cis-(3R,4S)-benzyl-4-ethyl-3-(2-bromoacetyl)pyrrolidine-1-carboxylate.

[0008]

[0009] In this method, racemic cis-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid (5) is first prepared. Then, the (3R, 4S) enantiomer is separated by forming diastereoisomeric (naphthyl)ethylammonium salts. Finally, in step E, compound 7 is obtained by treating the intermediate acid chloride with unstable and highly toxic trimethylsilyldiazomethane.

[0010]

[0011] Document WO 2017 / 066775 discloses the preparation of cis-(3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylate by forming a sulfoxonium salt and subsequent treatment with LiBr.

[0012]

[0013] However, the inventors have observed that the basic conditions required for the preparation of the sulfonium oxide salt and also the subsequent bromination reaction lead to partial isomerization to the trans isomer (see comparative experiments 19 and 20 therein), requiring further purification to obtain the pure product, which is therefore obtained in lower yields.

[0014] WO 2017 / 066775 discloses the preparation of the starting (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid by asymmetric hydrogenation.

[0015]

[0016] Finally, document WO 2019 / 016745 discloses a process for preparing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, which comprises the use of (1R)-2,10-camphorsulfone as chiral auxiliary.

[0017]

[0018] The process further requires the use of 2-pentynoic acid as a starting material, which is inconvenient to prepare and increases the cost of the process.

[0019] Therefore, it is necessary to develop new methods for obtaining intermediates for the synthesis of upadacitinib and related compounds in order to overcome all or part of the problems associated with the known methods belonging to the prior art. Summary of the invention

[0020] The problem faced by the present invention is to provide a new process for preparing compounds of formula (I) which are useful intermediates for the synthesis of upadacitinib and structurally related compounds. In particular, the inventors have found that compounds of formula (I) can be obtained satisfactorily in an industrially economical manner and without the need for highly toxic reagents by using Weinreb amides of formula (III) or triazine esters of formula (IV) as key intermediates.

[0021] In addition, the inventors have observed that isomerization of the trans isomer of the pyrrolidine ring does not occur using the method of the present invention. In contrast, the method for preparing sulfonium oxide salts disclosed in WO 2017 / 06677 and the conditions required for the subsequent bromination reaction lead to partial isomerization of cis-pyrrolidine to the trans isomer (see comparative experiments 19 and 20 therein).

[0022] Therefore, in a first aspect, the present invention relates to a process for preparing a compound of formula (I) or a salt or solvate thereof

[0023]

[0024] in

[0025] is a single bond or a double bond;

[0026] X is a leaving group, and

[0027] R 1 is selected from H and an amino protecting group;

[0028] It includes:

[0029] (a) a compound of formula (II) or a salt or solvate thereof

[0030]

[0031] in

[0032] is a single bond or a double bond;

[0033] Y is selected from OH, Cl, OR 2 and OC(O)R 2 , where R 2 Selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 Aryl; and

[0034] R 1 is selected from H and an amino protecting group;

[0035] Converted into a compound of formula (III) or (IV) or a salt or solvate thereof

[0036]

[0037] in

[0038] is a single bond or a double bond; and

[0039] R 1 is selected from H and an amino protecting group; and

[0040] (b) converting a compound of formula (III) or (IV) or a salt or solvate thereof into a compound of formula (I) or a salt or solvate thereof by a process comprising:

[0041] (bi) reacting the compound of formula (III) or (IV) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V) or a salt or solvate thereof

[0042]

[0043] in

[0044] is a single bond or a double bond; and

[0045] R 1 is selected from H and an amino protecting group;

[0046] (bii) converting a ketone of formula (V) or a salt or solvate thereof into an enol ether of formula (VI) or an enamine of formula (VII) or a salt or solvate thereof

[0047]

[0048] in

[0049] is a single bond or a double bond; and

[0050] R 1 is selected from H and an amino protecting group;

[0051] R 3 Selected from C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl, C6-C 15 Aryl, COR' and SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl; and

[0052] R 4 and R 5 Independently selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 aryl groups or they together with the nitrogen atom form a 5- to 7-membered heterocyclic ring; and

[0053] (biii) converting an enol ether of formula (VI) or an enamine of formula (VII) or a salt or solvate thereof into a compound of formula (I) or a salt or solvate thereof

[0054] or

[0055] (bi') reacting the compound of formula (III) or (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;

[0056] or

[0057] (bi") reacting the compound of formula (III) or (IV) or its salt or solvate with R 6 O-CH2-Li、R 6O-CH2-MgCl or R 6 O-CH2-MgBr reaction to provide a compound of formula (VIII) or a salt or solvate thereof

[0058]

[0059] in

[0060] is a single bond or a double bond;

[0061] R 1 is selected from H and an amino protecting group; and

[0062] R 6 selected from H, -COR' and -CONR'R", wherein R' and R" are independently selected from C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 ) aryl(C1-C6)alkyl;

[0063] as well as

[0064] (bii") converting the compound of formula (VIII) or a salt or solvate thereof into a compound of formula (I) or a salt or solvate thereof.

[0065] In another aspect, the present invention relates to a method for preparing upadacitinib or a salt or solvate or stereoisomer thereof, the method comprising preparing a compound of formula (I) or a salt or solvate thereof by the method defined in the first aspect of the present invention, and converting the compound into upadacitinib.

[0066] In another aspect, the present invention relates to compounds of the formula

[0067]

[0068]

[0069] or a salt or solvate thereof, wherein:

[0070] R 1 is selected from H and an amino protecting group;

[0071] R 3 Selected from C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl, C6-C 15 Aryl, COR' and SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 ) aryl(C1-C6)alkyl;

[0072] R 4 and R 5 Independently selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 aryl groups or they together with the nitrogen atom form a 5- to 7-membered heterocyclic ring; and

[0073] R' is selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 Aryl. DETAILED DESCRIPTION

[0074] The term "alkyl" refers to a straight or branched chain alkane derivative containing 1 to 6 ("C1-C6 alkyl"), preferably 1 to 3 ("C1-C3 alkyl") carbon atoms and bonded to the rest of the molecule by a single bond. Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.

[0075] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical comprising 2 to 6 ("C1-C6 alkenyl"), preferably 2 to 3 carbon atoms, and containing at least one double bond and attached to the remainder of the molecule by a single bond. Illustrative examples of alkenyl include ethenyl, propenyl, allyl, butenyl, 1-methyl-2-buten-yl.

[0076] The term "haloalkyl" refers to an alkyl group as defined above in which at least one hydrogen atom has been replaced by a halogen. Examples of haloalkyl groups include, but are not limited to, CF3, CCl3, CHF2, CF2CF3.

[0077] The term "aryl" refers to an aromatic group having 6 to 15, preferably 6 to 10 carbon atoms, comprising 1, 2 or 3 aromatic nuclei fused to each other. Illustrative examples of aryl groups include phenyl, naphthyl, indenyl, phenanthrenyl, etc. Preferably, it is phenyl.

[0078] The term "(C6-C 15 )Aryl(C1-C6)alkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above. Examples of such groups include benzyl, phenethyl, phenylpropyl, naphthylmethyl, etc. Preferably, it is benzyl.

[0079] The term "halogen" refers to bromine, chlorine, iodine or fluorine.

[0080] The term "C3-C 10"Cycloalkyl" refers to a monocyclic or bicyclic ring system containing 3 to 10, preferably 3 to 7 ("C3-C7 cycloalkyl") carbon atoms. Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0081] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 15, preferably 3 to 10, more preferably 5 to 7 ring atoms, the ring atoms containing one or more, in particular one, two, three or four, ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon. Illustrative examples of heterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine, piperazine, piperidine, azepane and [1,4]dioxane.

[0082] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic or tricyclic ring system containing 3 to 15, preferably 3 to 10, more preferably 5 to 7 ring atoms, the ring atoms containing one or more, in particular one, two, three or four, ring heteroatoms independently selected from O, N and S, and the remaining ring atoms are carbon.

[0083] The term "amino protecting group" (APG) refers to a group that blocks the NH function in subsequent reactions and can be removed under controlled conditions. Amino protecting groups are well known in the art. Illustrative examples of amino protecting groups have been described by Green TW et al. in "Protective Groups in Organic Synthesis", 3rd edition (1999), edited by John Wiley & Sons. Virtually any amino protecting group may be used to practice the present invention. Illustrative, non-limiting examples of APGs include:

[0084] -carbamate [-COOR]. R can be selected from 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 heterocyclic group, 3- to 15-membered heteroaryl and tri (C1-C6 alkyl) silane. Examples of carbamates include methyl carbamate (MOC), ethyl carbamate, tert-butyl carbamate (Boc), benzyl carbamate (CBz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halogenated benzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate, trichloroethyl carbamate (Troc), trimethylsilylethyl carbamate (Teoc), trimethylsilyl carbamate, triisopropylsilyl carbamate;

[0085] -amide [-COR]. R can be selected from 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, halogenated acetamide (e.g., chloroacetamide, trichloroacetamide, trifluoroacetamide), benzamide, pyridineamide;

[0086] -amine [-R]. R can be selected from 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, benzamide, dinitroaniline, p-methoxyaniline, o-methoxyaniline, trimethylsilylethoxymethylamine, triphenylmethylamine;

[0087] -sulfonamide [-SO2R]. R can be selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl, (C6-C 15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclic group and 3- to 15-membered heteroaryl group. Examples of sulfonamides include methanesulfonamide, trifluoromethanesulfonamide, tert-butylsulfonamide, trimethylsilylethanesulfonamide, benzylsulfonamide, p-toluenesulfonamide, benzenesulfonamide, o- or p-nitrobenzenesulfonamide, dinitrobenzenesulfonamide, naphthalenesulfonamide, pyridine-2-sulfonamide;

[0088] as well as

[0089] -Silylamine [-Si(R)(R')(R")]. R, R' and R" can be independently selected from C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. Examples of the silylamine include trimethylsilylamine, triethylsilylamine, tert-butyldimethylsilylamine, tert-butyldiphenylsilylamine, triisopropylsilylamine, triphenylsilylamine.

[0090] The term "leaving group" refers to a functional group or atom that can be displaced by another functional group in a substitution reaction (such as a nucleophilic substitution reaction). Suitable leaving groups are well known in the art. In a specific embodiment, the leaving group is selected from halogen, C1-C6 alkyl sulfonate, C1-C6 haloalkyl sulfonate, C6-C 10 Aryl sulfonate and (C1-C6) alkyl (C6-C 10) aryl sulfonate groups such as chloro, bromo, iodo, methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, nosylate, and the like.

[0091] As is understood in the art, some degree of substitution may be present in the above groups. Thus, substitution may be present in any group of the present invention. The above groups may be substituted at one or more available positions with one or more substituents. Such substituents include, for example and in a non-limiting sense, 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 heterocyclic group, 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 ; where R a , R b , R c , R d , R e , R f , R g , R h and R i independently selected from 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.

[0092] The present invention also provides "salt" of the compound described in this specification. In an exemplary manner, the salt may be an acid addition salt, a base addition salt or a metal salt, and may be synthesized by a parent compound comprising a base or acid moiety by conventional chemical methods known in the art. Such salts are usually prepared, for example, by reacting the free acid or base form of the compound with a stoichiometric amount of a suitable base or acid in water or an organic solvent or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are usually preferred. Illustrative examples of the acid addition salt include inorganic acid addition salts, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate, p-toluenesulfonate, trifluoroacetate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts, such as, for example, ammonium salts, and organic base salts, such as, for example, ethylenediamine, ethanolamine, N, N-dialkyleneethanolamine, triethanolamine, glutamine, amino acid base salts, etc. Illustrative examples of metal salts include, for example, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and lithium salts. In a specific embodiment, the salt is an acid addition salt, such as, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate, p-toluenesulfonate, trifluoroacetate, or camphorsulfonate. Preferably, it is selected from HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citrate, and fumarate.

[0093] Likewise, the compounds described in this specification may be obtained as free compounds or as solvates (e.g., hydrates, alcoholates, etc.), both of which are included within the scope of the present invention. Solvation methods are generally known in the prior art. Preferably, the solvate is a hydrate.

[0094] The term "organic solvent" includes, for example, cyclic ethers 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), alcohols (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, tert-butanol), sulfoxides (DMSO), and mixtures thereof.

[0095] The term "aprotic organic solvent" means any organic solvent that does not generate protons under the reaction conditions. Suitable examples include, but are not limited to, cyclic ethers and acyclic 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.

[0096] In a first aspect, the present invention relates to a process 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 (process of the present invention).

[0097] In an embodiment, the method of the present invention relates to the preparation of a compound of formula (I) or a salt or solvate thereof, wherein the compound of formula (II) or a salt or solvate thereof is a double bond (compound of formula (I")), wherein is a double bond (compound of formula (II")). Therefore, in a specific embodiment, represents a double bond in the compounds of the method of the present invention (compounds (I"), (II"), (III"), (IV"), (V"), (VI"), (VII"), (VIII")).

[0098] In a preferred embodiment, the method of the present invention relates to the preparation of a compound of formula (I) or a salt or solvate thereof, wherein is a single bond (compound of formula (I')).

[0099] In an embodiment, the method of the present invention relates to the preparation of a compound of formula (I) or a salt or solvate thereof, wherein the compound of formula (II) or a salt or solvate thereof is a single bond (compound of formula (I')), wherein is a single bond (compound of formula (II')). Therefore, in a specific embodiment, The single bond in the compounds (compounds (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII')) of the method of the present invention is preferably a cis single bond, and more preferably a cis-3R single bond.

[0100] In other embodiments, the method of the present invention is a method for preparing a compound of formula (I) or a salt or solvate thereof, wherein the compound of formula (II) or a salt or solvate thereof is a single bond (compound of formula (I')), wherein is a double bond (compound of formula (II")). In this case, the process of the present invention further comprises a step of hydrogenating the double bond. The hydrogenation may occur at any stage of the process, i.e., before or after any step of the process of the present invention. For example, the hydrogenation step may 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").

[0101] In a specific embodiment, the method of the present invention comprises:

[0102] - Hydrogenate a compound of formula (II) or a salt or solvate thereof (wherein is a double bond), to obtain a compound of formula (II) or a salt or solvate thereof (wherein is a single bond); and

[0103] - by the method of the present invention, the compound (II) or a salt or solvate thereof (wherein is a single bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single bond), where In all intermediate compounds there are single bonds.

[0104] In other embodiments, the method of the present invention comprises:

[0105] - Compound (II) or a salt or solvate thereof (wherein is a double bond) into a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond);

[0106] - Hydrogenate a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond) to obtain a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a single bond); and

[0107] - by a method comprising the following steps: is a single bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single key):

[0108] (i) a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a single bond) with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V) or a salt or solvate thereof (wherein is a single bond);

[0109] (ii) a ketone of formula (V) or a salt or solvate thereof (wherein is a single bond) into an enol ether of formula (VI) or an enamine of formula (VII) or a salt or solvate thereof (wherein is a single bond); and

[0110] (iii) enol ether of formula (VI) or enamine of formula (VII) or a salt or solvate thereof (wherein is a single bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single bond);

[0111] or

[0112] (i') making a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a single bond) with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to provide a compound of formula (I) or a salt or solvate thereof (wherein is a single bond);

[0113] or

[0114] (i") a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a single bond) and R 6 O-CH2-Li、R 6 O-CH2-MgCl or R 6 O-CH2-MgBr reaction to provide a compound of formula (VIII) or a salt or solvate thereof (wherein is a single bond); and

[0115] (ii") a compound of formula (VIII) or a salt or solvate thereof (wherein is a single bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single bond).

[0116] In other embodiments, the method of the present invention comprises:

[0117] - Compound (II) or a salt or solvate thereof (wherein is a double bond) into a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond); and

[0118] - by a method comprising the following steps: is a double bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single key):

[0119] (i) a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond) with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V) or a salt or solvate thereof (wherein is a double bond);

[0120] (ii) hydrogenating a compound of formula (V) or a salt or solvate thereof (wherein is a double bond) to obtain a compound of formula (V) or a salt or solvate thereof (wherein is a single key)

[0121] (iii) a ketone of formula (V) or a salt or solvate thereof (wherein is a single bond) into an enol ether of formula (VI) or an enamine of formula (VII) or a salt or solvate thereof (wherein is a single bond); and

[0122] (iv) enol ether of formula (VI) or enamine of formula (VII) or a salt or solvate thereof (wherein is a single bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single bond).

[0123] In other embodiments, the method of the present invention comprises:

[0124] - Compound (II) or a salt or solvate thereof (wherein is a double bond) into a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond); and

[0125] - by a method comprising the following steps: is a double bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single key):

[0126] (i) a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond) with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V) or a salt or solvate thereof (wherein is a double bond);

[0127] (ii) a ketone of formula (V) or a salt or solvate thereof (wherein is a double bond) into an enol ether of formula (VI) or an enamine of formula (VII) or a salt or solvate thereof (wherein is a double bond);

[0128] (iii) enol ether of formula (VI) or enamine of formula (VII) or a salt or solvate thereof (wherein is a double bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a double bond); and

[0129] (iv) hydrogenating a compound of formula (I) or a salt or solvate thereof (wherein is a double bond), to obtain a compound of formula (I) or a salt or solvate thereof (wherein is a single bond);

[0130] or

[0131] (i') making a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond) with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to provide a compound of formula (I) or a salt or solvate thereof (wherein is a double bond); and

[0132] (ii') hydrogenating a compound of formula (I) or a salt or solvate thereof (wherein is a double bond), to obtain a compound of formula (I) or a salt or solvate thereof (wherein is a single bond);

[0133] or

[0134] (i") a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond) and R 6 O-CH2-Li、R 6 O-CH2-MgCl or R 6 O-CH2-MgBr reaction to provide a compound of formula (VIII) or a salt or solvate thereof (wherein is a double bond);

[0135] (ii") a compound of formula (VIII) or a salt or solvate thereof (wherein is a double bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a double bond); and

[0136] (iii") hydrogenating a compound of formula (I) or a salt or solvate thereof (wherein is a double bond), to obtain a compound of formula (I) or a salt or solvate thereof (wherein is a single bond).

[0137] In other embodiments, the method of the present invention comprises:

[0138] - Compound (II) or a salt or solvate thereof (wherein is a double bond) into a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond); and

[0139] - by a method comprising the following steps: is a double bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single key):

[0140] (i") a compound of formula (III) or (IV) or a salt or solvate thereof (wherein is a double bond) and R 6 O-CH2-Li、R 6 O-CH2-MgCl or R 6 O-CH2-MgBr reaction to provide a compound of formula (VIII) or a salt or solvate thereof (wherein is a double bond);

[0141] (ii") hydrogenating a compound of formula (VIII) or a salt or solvate thereof (wherein is a double bond), to provide a compound of formula (VIII) or a salt or solvate thereof (wherein is a single bond); and

[0142] (iii") a compound of formula (VIII) or a salt or solvate thereof (wherein is a single bond) into a compound of formula (I) or a salt or solvate thereof (wherein is a single bond).

[0143] If necessary, the method of the present invention may include one or more of the following steps in any order:

[0144] -cleavage of the amino protecting group (R 1 ), and / or

[0145] - Protecting amino groups (R 1 ).

[0146] Any of these steps can be carried out at any stage of the method of the present invention. For example, the protection of the amino group and / or the amino protecting group (R 1 ) 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"). Protection / cleavage of the amino protecting group can be carried out by any conventional method known in the art (e.g., TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, 2007) and as disclosed herein.

[0147] For example, when R 1 The amino protecting group in the 1 =COOR), according to the established procedures of the prior art, it can be easily deprotected by acid or base hydrolysis. 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 hydroxides. In an embodiment, the reaction is carried out in water and an organic solvent, preferably in an alcohol (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, 2-pentanol, 2-hexanol, 2-octanol, ethylene glycol). In an embodiment, the reaction is carried out at a temperature between 10°C and the reflux temperature of the solvent, preferably between 30°C and 70°C, and more preferably between 40°C and 60°C. In an embodiment, the reaction is carried out at a temperature between 30°C and 70°C, preferably between 40°C and 60°C, in the presence of an acid (selected from HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citrate and fumarate, preferably HCl), water and an alcohol (preferably methanol). When R 1 The amino protecting group in the 1=COR), it can be deprotected by acid or base hydrolysis, preferably under 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 hydroxides. The reaction can be carried out at a temperature between 20°C and 120°C, preferably between 50°C and 110°C, more preferably between 60°C and 110°C, and can be carried out in the presence of an organic solvent, water and a mixture thereof. When R 1 The amino protecting group in the amine group is an alkyl, aryl or arylalkylamine (R 1 =R), it can be deprotected by treatment with an acid, a base, an oxidizing agent, a reducing agent, by hydrogenolysis (for an aryl or arylalkylamine), etc. 1 The amino protecting group in the 1 =Si(R)(R')(R")), it can be deprotected by using a fluoride reagent (such as a fluoride salt or HF), an acid medium, an oxidizing medium, and the like.

[0148] Preferably, when When a single bond is present in any of the compounds of the method of the present invention, the single bond has a cis configuration, i.e., the two hydrogen atoms on the carbon of the bond are located on the same side of the pyrrolidine ring. More preferably, when When a single bond is present in any compound of the method of the invention, the single bond has a cis-3R configuration as shown below, i.e., the two hydrogen atoms on the carbon of the bond are located on the same side of the pyrrolidine ring, and the carbon atom at position 3 of the pyrrolidine ring has the desired configuration of the compound upadacitinib, i.e., the R configuration, on the carbon atom to which the imidazopyrrolopyrazine ring in upadacitinib is bonded. Thus, when When it is a single bond in a compound of formula (I), or (II), or (III), or (IV), or (V), or (VI), or (VII), or (VIII), it is preferably a compound of formula (I'-cis), or (II'-cis), or (III'-cis), or (IV'-cis), or (V'-cis), or (VI'-cis), or (VII'-cis), or (VIII'-cis); more preferably a compound of formula (I'-cis-3R), or (II'-cis-3R), or (III'-cis-3R), or (IV'-cis-3R), or (V'-cis-3R), or (VI'-cis-3R), or (VII'-cis-3R), or (VIII'-cis-3R) as defined herein:

[0149]

[0150] or a salt or solvate thereof, wherein X, Y, R 1 , R3 , R 4 , R 5 and R 6 As defined herein.

[0151] As used herein, wedge-shaped keys and dashed keys is used to indicate the absolute configuration (R or S) of a stereocenter, and and Used to indicate the relative configuration (cis or trans) of a stereocenter.

[0152] Unless otherwise indicated, the compounds disclosed herein include their stereoisomers, such as geometric isomers (cis / trans) and optical isomers (ie, diastereomers, racemates, individual enantiomers and mixtures of enantiomers in any ratio are all encompassed by the present invention).

[0153] Preferably, when When representing a single bond in a compound of the method of the present invention, it comprises at least 80% of the cis isomer, preferably at least 90%, more preferably 95%, even more preferably at least 98% of the cis isomer (on a cis+trans mixture). In a more preferred embodiment, it comprises only the cis isomer as determined by NMR.

[0154] When the compounds of the method of the invention are optically active compounds, preferably they have an enantiomeric excess of at least 80%, at least 90%, at least 95%, at least 98% or at least 99%.

[0155] In a preferred embodiment, the method of the present invention comprises preparing a compound of formula (I'-cis) from a compound of formula (II'-cis); more preferably, preparing a compound of formula (I'-cis-3R) from a compound of formula (II'-cis-3R), and as defined in the method of the present invention (such that all intermediates in the method are cis, more preferably cis-3R, corresponding compounds).

[0156] In a specific embodiment, X is a leaving group. Preferred leaving groups are chloro, bromo, iodo, mesylate, trifluoromethanesulfonate, tosylate or m-nitrobenzenesulfonate; more preferably, they are selected from Cl, Br and I.

[0157] In an embodiment, Y is selected from OH and OR 2 , where R 2 Selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 In a specific embodiment, Y is OH.

[0158] In an embodiment, R1 is an amino protecting group. As disclosed herein, suitable amino protecting groups include carbamates, amides, amines, sulfonamides, and silylamines. In a preferred embodiment, it is a carbamate. Thus, preferably, R 1 is a group of the formula -COOR, wherein R is selected from 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-C6alkyl)silane; such as methyl carbamate (MOC), ethyl carbamate, tert-butyl carbamate (Boc), benzyl carbamate (CBz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halogenated benzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate and trichloroethyl carbamate (Troc).

[0159] In an embodiment, R 3 Selected from C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, COR' and SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. In a specific embodiment, R 3 is a group SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl, such as TMS, TES, TBS and TBDPS.

[0160] When R 4 and R 5 When forming a 5- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached, they are preferably a 5- to 7-membered heterocyclic ring containing one nitrogen atom, or two nitrogen atoms, or one nitrogen and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine and azepane.

[0161] In a specific embodiment, R 4 and R 5 are independently selected from C1-C6 alkyl, or they form a 5- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached. More preferably, they form a 5- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached, preferably a 5- to 7-membered heterocyclic ring containing one nitrogen atom, or two nitrogen atoms, or one nitrogen and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine and azepane.

[0162] R 6 selected from H, -COR' and -CONR'R", wherein R' and R" are independently selected from C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. In a specific embodiment, R 6 is a group of formula -COR' and R' is preferably a C1-C6 alkyl group. 6 It is a group of formula -COtBu(Piv).

[0163] The compound of formula (II) is converted into a compound of formula (III) or (IV)

[0164] The compound of formula (II) can be obtained by methods known to the skilled person or disclosed in the art. For example, by methods disclosed in WO 2011 / 068881, WO 2013 / 043826, WO2017 / 066775 or WO2019 / 016745. In an embodiment, the compound of formula (II) or a salt or solvate thereof can be obtained by a method comprising:

[0165] - a compound of formula (IX) or a salt or solvate thereof

[0166]

[0167] in

[0168] Z is selected from halogen, C1-C6 alkyl sulfonate, C1-C6 haloalkyl sulfonate, C6-C 10 Aryl sulfonate and (C1-C6) alkyl (C6-C 10 ) aryl sulfonate group;

[0169] R 1 is selected from H and an amino protecting group; and

[0170] Y is selected from OH, Cl, OR 2 and OC(O)R 2 , where R 2 Selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 Aryl;

[0171] Reaction with Et2CuLi, Et2CuMgBr or Et2CuMgCl to provide a compound of formula (II") or a salt or solvate thereof

[0172]

[0173] as well as

[0174] - If necessary (ie 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.

[0175] The reaction with Et2CuLi, Et2CuMgBr or Et2CuMgCl is preferably carried out in the presence of an organic solvent. The organic solvent may be an aprotic organic solvent, preferably a cyclic ether or a non-cyclic ether, more preferably tetrahydrofuran.

[0176] Generally, the reaction can be carried out at a temperature between -50°C and 30°C, preferably between -30°C and 20°C, more preferably between -10°C and 10°C.

[0177] In an embodiment, Et2CuLi, Et2CuMgBr or Et2CuMgCl is present 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 (IX).

[0178] The method for preparing the compound of formula (II) may further comprise the step of converting Y in the compound of formula (II") or (II') into a different Y group before carrying out the method for preparing the compound of formula (I) of the present invention.

[0179] For example, if a compound of formula (IX) or a salt or solvate thereof is used in the above method, wherein Y is OR 2 , an additional step may be included after the reaction with the cuprate reagent or after the double bond hydrogenation (if performed), for example, to 2 Converted into group OH. The conversion can be carried out under acid or base hydrolysis according to the established procedures of the prior 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 hydroxides. In an 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.

[0180] In an embodiment, the compound of formula (II) or a salt or solvate thereof is obtained by a process comprising:

[0181] - a compound of formula (IX) or a salt or solvate thereof

[0182]

[0183] in

[0184] Z is selected from halogen, C1-C6 alkyl sulfonate, C1-C6 haloalkyl sulfonate, C6-C 10 Aryl sulfonate and (C1-C6) alkyl (C6-C 10 ) aryl sulfonate group;

[0185] R 1 is selected from H and an amino protecting group; and

[0186] Y is OR 2 , where R 2 Selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 Aryl;

[0187] Reaction with Et2CuLi Et2CuMgBr or Et2CuMgCl to provide a compound of formula (II") or a salt or solvate thereof

[0188]

[0189] - hydrolyzed compound of formula (II") or a salt or solvate thereof, wherein Y is OR 2 , to provide a compound of formula (II"), wherein Y is OH;

[0190] as well as

[0191] - If necessary (ie 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, wherein Y is OH.

[0192] The preparation of compounds of formula (II) from compounds of formula (IX) is advantageous over the use of the Suzuki reaction previously disclosed in the prior art. It is a cheaper alternative as it avoids the use of boronic acid reagents (which are more expensive and cannot be stored for long periods of time) and the use of palladium catalysts.

[0193] In a preferred embodiment, in the compound of formula (II), R 1 is an amino protecting group and Y is OH.

[0194] In an embodiment of the process according to the invention, the compound of formula (II) or a salt or solvate thereof is converted into a compound of formula (III) or a salt or solvate thereof.

[0195] Suitable methods for this transformation are well known in the art. In a specific embodiment, the transformation can be carried out by reacting a compound of formula (II) or a salt or solvate thereof with N,O-dimethylhydroxylamine or a salt thereof, preferably N,O-dimethylhydroxylamine hydrochloride, optionally in the presence of an activator and / or a base and an organic solvent.

[0196] Suitable activators 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 hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N,N-tetrakis(2-nitropropene)pyridine, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), ... Methyluronium hexafluorophosphate (HBTU) and bromo-tripyrrolidino-phosphonium hexafluorophosphate, 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate (TBTU), 1-cyano-2-ethoxy-2-oxyylideneethylaminooxy)dimethylaminomorpholinocarbon hexafluorophosphate (COMU), Me2AlCl, Me3Al, iPrMgCl; preferably CDI.

[0197] 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.

[0198] Preferably, the organic solvent is selected from aprotic organic solvents such as dichloromethane, tetrahydrofuran and mixtures thereof, preferably dichloromethane.

[0199] Generally, the reaction can be carried out at a temperature between -10°C and 70°C, preferably between 0°C and 50°C, more preferably between 10°C and 30°C.

[0200] In an embodiment, N,O-dimethylhydroxylamine or its salt is present in an amount of 1.0 to 3.0 molar equivalents, preferably 1.1 to 2.0 molar equivalents, relative to the compound of formula (II). In a specific embodiment, the activator or coupling agent is present in an amount of 1.0 to 3.0 molar equivalents, preferably 1.1 to 2.0 molar equivalents, relative to the compound of formula (II). In an embodiment, the base is present in an amount of 1.0 to 3.0 molar equivalents, preferably 1.1 to 2.0 molar equivalents, relative to the compound of formula (II).

[0201] In a specific embodiment, when Y in the compound of formula (II) represents Cl or OC(O)R 2 When the reaction is carried out with N,O-dimethylhydroxylamine or a salt thereof, the reaction is carried out in the presence of a base and optionally an organic solvent.

[0202] In other embodiments, when Y in the compound of formula (II) represents 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.

[0203] In other embodiments, when Y in the compound of formula (II) represents OR 2 When the reaction is carried out with N,O-dimethylhydroxylamine or a salt thereof, the reaction is carried out in the presence of Me2AlCl, Me3Al or iPrMgCl and optionally an organic solvent.

[0204] In a further embodiment of the process according to the invention, the compound of formula (II) or a salt or solvate thereof is converted into a compound of formula (IV) or a salt or solvate thereof.

[0205] Suitable methods for this transformation are well known in the art. In a specific embodiment, the transformation can be carried out by reacting a 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.

[0206] 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.

[0207] Preferably, the organic solvent is selected from aprotic organic solvents.

[0208] Typically, the reaction can be carried out at a temperature between -10°C and 70°C.

[0209] The compound of formula (III) or (IV) is converted into a compound of formula (V)

[0210] In a preferred embodiment, R1 is an amino protecting group in the compound of formula (III) or (IV).

[0211] This conversion can be carried out by reacting a compound of formula (III) or (IV) or a salt or solvate thereof with MeMgCl, MeMgBr or MeLi, optionally in the presence of an organic solvent.

[0212] The organic solvent may be an aprotic organic solvent, preferably a cyclic ether or a non-cyclic ether, more preferably tetrahydrofuran.

[0213] Generally, the reaction can be carried out at a temperature between -50°C and 30°C, preferably between -30°C and 20°C, more preferably between -10°C and 10°C.

[0214] In an embodiment, MeMgCl, MeMgBr or MeLi is present 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 (III) or (IV).

[0215] It is worth noting that when When representing a cis single bond in compounds of formula (III) or (IV), isomerization to the trans isomer is not observed upon reaction with MeMgCl, MeMgBr or MeLi to provide compounds of formula (V).

[0216] The compound of formula (V) is converted into the compound of formula (VI)

[0217] In a preferred embodiment, R 1 is the amino protecting group in the compound of formula (V).

[0218] In an embodiment of the process according to the invention, the compound of formula (V) or a salt or solvate thereof is converted into a compound of formula (VI) or a salt or solvate thereof.

[0219] The present inventors have observed that the desired enol ether is obtained in a regioselective manner. Thus, subsequent treatment of this compound leads to the introduction of the X group in the terminal position and isomerization of the pyrrolidine carbon atom to which the carbonyl group is not attached.

[0220] The reaction can be carried out by well-known methods for synthesizing enol ethers. 3 The compound of formula (VI) which is SiR'3 can be obtained by reacting a compound of formula (V) or a salt or solvate thereof with a compound of formula R'3SiZ in the presence of a base, wherein each R' is independently selected from C 1-6 Alkyl, C 6-10 Aryl and C 1-6Alkoxy, and Z is halogen or triflate. Suitable bases include tertiary amines such as Me3N, Et3N, DIPEA, Pyr, DMAP, NMM, 2,6-lutidine and mixtures thereof. The reaction can be carried out in the presence of an organic solvent, preferably an aprotic organic solvent, and can be carried out at a temperature between -30°C and 70°C, preferably between -30°C and 20°C, more preferably between -10°C and 10°C.

[0221] In other embodiments, wherein R 3 It is C 1-6 The compound of formula (VI) of alkyl can be obtained by reacting the compound of formula (V) or its salt or solvate with trialkyl orthoformate in the presence of acid. Suitable acid includes 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, ZnCl , AlCl and BF . The reaction can be carried out in the presence of an organic solvent, and can be carried out at a temperature between -20 ℃ and 120 ℃, preferably between 10 ℃ and 90 ℃. In an embodiment, the reaction is carried out in the presence of methyl orthoformate or ethyl orthoformate, acid and an organic solvent.

[0222] In other embodiments, wherein R 3 The compound of formula (VI) of Ac can be obtained by reacting a compound of formula (V) or a salt or solvate thereof with isopropenyl acetate, or acetic anhydride or acetyl halide in the presence of an acid or a base. Suitable acids include sulfuric acid, perchloric acid, pTsOH and sulfonic acid. Suitable bases include pyridine, DMAP, Me3N, Et3N and DIPEA. The reaction can 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.

[0223] In a preferred embodiment, in the compound of formula (VI), R 1 is an amino protecting group and R 3 is SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-10 Aryl and C 1-6 In a more preferred embodiment, R 3 is SiR'3, wherein each R' is independently selected from C 1-6 Alkyl groups such as TMS, TES, TBDMS, TIPS.

[0224] The compound of formula (V) is converted into the compound of formula (VII)

[0225] In a preferred embodiment, R 1is the amino protecting group in the compound of formula (V).

[0226] In an embodiment of the process according to the invention, the compound of formula (V) or a salt or solvate thereof is converted into a compound of formula (VII) or a salt or solvate thereof.

[0227] The reaction can be carried out by well-known methods for preparing enamines from corresponding ketones. In an embodiment, the 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 The reaction is carried out by reacting an amine, optionally in the presence of an acid and an organic solvent.

[0228] Suitable acids include, for example, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid and hydrochloric acid. A catalytic amount of the acid may be used. In an embodiment, the reaction is carried out using 0.01 to 0.5 mol of acid per mol of ketone of formula (V).

[0229] In an embodiment, relative to the compound of formula (V), the amine HN (R 4 )R 5 It is used in an amount of 1.0 to 5.0 molar equivalents, preferably 1.1 to 3.0 molar equivalents.

[0230] The conversion may generally be carried out at a temperature between 20°C and 180°C, preferably between 50°C and 150°C, more preferably between 60°C and 130°C.

[0231] In a preferred embodiment, in the compound of formula (VII), R 1 is an amino protecting group and R 4 and R 5 Independently selected from C1-C6 alkyl or they form a 5- to 7-membered heterocyclic ring together with the nitrogen atom. Preferably, the 5- to 7-membered heterocyclic ring is a 5- to 7-membered heterocyclic ring containing one nitrogen atom or two nitrogen atoms or one nitrogen and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine and azepane.

[0232] The compound of formula (VI) or (VII) is converted into the compound of formula (I)

[0233] In an embodiment of the method according to the invention, the compound of formula (VI) or (VII) or a salt or solvate thereof is converted into a compound of formula (I) or a salt or solvate thereof. Suitable methods for this conversion are well known in the art.

[0234] In a specific embodiment, the conversion can be carried out by reacting a compound of formula (VI) or (VII) or a salt or solvate thereof with a halogenating agent, optionally in the presence of an organic solvent. According to this method, a compound of formula (I) or a salt or solvate thereof is obtained, wherein X is a halogen.

[0235] Suitable halogenating agents include thionyl chloride, oxalyl chloride, NCS, Br2, CBr4, NBS, I2, CI4, NIS, among others.

[0236] The organic solvent may be an aprotic organic solvent, preferably dichloromethane or a cyclic ether or a non-cyclic ether, more preferably tetrahydrofuran or dichloromethane.

[0237] Generally, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -50°C and 30°C, more preferably between -20°C and 20°C.

[0238] In an embodiment, the halogenating agent is present 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 (VI) or (VII).

[0239] In other embodiments, a compound of formula (VI) or (VII), or a salt or solvate thereof, is converted to a compound of formula (I), or a salt or solvate thereof, by epoxidizing the double bond of an enol ether of formula (VI) or an enamine of formula (VII), followed by ring opening to provide a compound of formula (VIII) (wherein R 6 Yes H)

[0240]

[0241] or a salt or solvate thereof, wherein is a single bond or a double bond and R 1 is selected from H and an amino protecting group.

[0242] In an embodiment, the epoxidation reaction is carried out in the presence of a peroxycarboxylic acid, hydrogen peroxide or potassium peroxysulfate (oxone), preferably a peroxycarboxylic acid such as mCPBA, benzoic acid, monoperphthalic acid or magnesium monoperphthalate (MMPP). The reaction may be carried out in the presence of an organic solvent and may be carried out at a temperature between -40°C and 120°C, preferably between -20°C and 40°C. In an embodiment, the reaction is carried out in the presence of mCPBA and an aprotic polar solvent such as dichloromethane.

[0243] The ring opening of the resulting epoxide can be carried out by treating with water and an acid or 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 CsF, RbF, NaF and TBAF. The reaction can be carried out in the presence of an organic solvent and can be carried out at a temperature between -40°C and 120°C, preferably between -20°C and 40°C.

[0244] Where R 6 The compound of formula (VIII) or its salt or solvate of H can be converted into the compound of formula (I) or its salt or solvate by methods known in the art. In an embodiment, the conversion of the primary hydroxyl group to the leaving group is carried out by using a halogenating agent (such as I2, NaI, Br2, CBr4, PBr3, Cl2, thionyl chloride, oxalyl chloride); or using a sulfonyl chloride (such as TsCl or MsCl) to treat. The reaction is preferably carried out in the presence of an organic solvent at a temperature of -78°C to 80°C, preferably -40°C to 40°C.

[0245] In a preferred embodiment, R 1 is the amino protecting group in the compound of formula (I).

[0246] In a preferred embodiment, the conversion of the compound of formula (V) or its salt or solvate into the compound of formula (I) or its salt or solvate is carried out in a one-pot process, that is, the intermediate compound of formula (VI) or (VII) or its salt or solvate is not isolated.

[0247] The compound of formula (III) or (IV) is converted into a compound of formula (I)

[0248] In a preferred embodiment, R 1 is an amino protecting group in the compound of formula (III) or (IV).

[0249] The conversion can be carried out by reacting a compound of formula (III) or (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.

[0250] The organic solvent may be an aprotic organic solvent, preferably a cyclic ether or a non-cyclic ether, more preferably tetrahydrofuran.

[0251] Generally, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -80°C and 0°C, more preferably between -80°C and -20°C.

[0252] In an embodiment, the compound X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr is present in an amount of 1.0 to 8.0 molar equivalents, preferably 1.1 to 5.0 molar equivalents, relative to the compound of formula (III) or (IV).

[0253] In a preferred embodiment, R 1 is the amino protecting group in the compound of formula (I).

[0254] The compound of formula (III) or (IV) is converted into the compound of formula (VIII)

[0255] In a preferred embodiment, R 1 is an amino protecting group in the compound of formula (III) or (IV).

[0256] This conversion can be carried out by reacting a compound of formula (III) or (IV) or a salt or solvate thereof with a compound of formula R 6 O-CH2-Li、R 6 O-CH2-MgCl or R 6 O-CH2-MgBr compound, optionally in the presence of an organic solvent, wherein R 6 Selected from -COR' and -CONR'R", wherein R' and R" are independently selected from C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl.

[0257] In a specific embodiment, R 6 is a group of formula -COR, wherein R is selected from C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. Preferably, R 6 It is a group of formula -COtBu(Piv).

[0258] The organic solvent may be an aprotic organic solvent, preferably a cyclic ether or a non-cyclic ether, more preferably tetrahydrofuran.

[0259] Generally, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -80°C and 0°C, more preferably between -80°C and -20°C.

[0260] In an embodiment, relative to the compound of formula (III) or (IV), compound R 6 O-CH2-Li、R 6 O-CH2-MgCl or R 6 O-CH2-MgBr is present in an amount of 1.0 to 8.0 molar equivalents, preferably 1.1 to 5.0 molar equivalents.

[0261] In a preferred embodiment, in the compound of formula (VIII) obtained after the reaction, R 1 is an amino protecting group and R 6 -COR' and -CONR'R", preferably -COR', wherein R' and R" are independently selected from C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl.

[0262] In an embodiment of the present invention, when a compound of formula (VIII) or a salt or solvate thereof is obtained, wherein R 6 When it is selected from -COR' and -CONR'R", it is converted into a compound of formula (VIII) or a salt or solvate thereof, wherein before converting it into a compound of formula (I) or a salt or solvate thereof, R 6 It's hydrogen.

[0263] A compound of formula (VIII) or a salt or solvate thereof (wherein R 6 is -COR' or -CONR'R") to a compound of formula (VIII) or a salt or solvate thereof (wherein R 6 The conversion of (i.e., hydrogen) can be carried out under acidic or alkaline hydrolysis reaction conditions. Suitable acid includes 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, H PO , H SO , MsOH, pTsOH, TFA, citric acid and fumaric acid. Suitable alkali includes alkali carbonate, alkali phosphate, alkali alkoxide, alkali thioalkoxide and alkali hydroxide, such as NaOH, KOH, NaOtBu, NaOMe, NaSMe. In an embodiment, the hydrolysis reaction is carried out in water and an organic solvent, preferably in an alcohol (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-butanol, 2-pentanol, 2-hexanol, 2-octanol, ethylene glycol). In an 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.

[0264] The compound of formula (VIII) is converted into the compound of formula (I)

[0265] In a preferred embodiment, in the compound of formula (VIII), R 1 is an amino protecting group and R 6 It's H.

[0266] Where R6 The compound of formula (VIII) or its salt or solvate of H can be converted into the compound of formula (I) or its salt or solvate by methods known in the art. In an embodiment, the conversion of the primary hydroxyl group to the leaving group is carried out by using a halogenating agent (such as I2, NaI, Br2, CBr4, PBr3, Cl2, thionyl chloride, oxalyl chloride); or using a sulfonyl chloride (such as TsCl or MsCl) to treat. The reaction is preferably carried out in the presence of an organic solvent at a temperature of -78°C to 80°C, preferably -40°C to 40°C.

[0267] In a preferred embodiment, R 1 is the amino protecting group in the compound of formula (I).

[0268] Hydrogenation reaction

[0269] The process of the present invention may include the step of hydrogenating the double bonds in the pyrrolidine ring into single bonds.

[0270] In an embodiment, the method of the present invention is a method for preparing a compound of formula (I) or a salt or solvate thereof, wherein the compound of formula (II) or a salt or solvate thereof is a single bond, where is a double bond. In this case, the method of the present invention further comprises a step of hydrogenating the double bond. The hydrogenation can occur at any stage of the method, 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").

[0271] The reaction can be carried out by well-known methods of hydrogenating double bonds. In an embodiment, the reaction is carried out by reacting a compound of the method of the present invention (wherein is a double bond) and react with H2.

[0272] Suitable transition metal catalysts or compounds include, for example, supported and unsupported catalysts of transition metals selected from the group consisting of 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-cymene)]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)iridium dichloride, FeCl2, FeBr2, Fe(CH3CO2)2, [Fe(OH2)6](BF4)2, CuCl, [CuH(Ph3)]6.

[0273] In a specific embodiment, the reaction is an asymmetric hydrogenation reaction. In this case, an optically active catalyst is used in the reaction. The optically active catalyst is an optically active transition metal compound obtained by mixing a transition metal compound with an optically active chiral ligand. Therefore, in a specific embodiment, the reaction is carried out by reacting a compound of the method of the present invention (wherein When asymmetric hydrogenation is carried out, an optically active compound is obtained, preferably a compound of formula (I'-cis-3R), or (II'-cis-3R), or (III'-cis-3R), or (IV'-cis-3R), or (V'-cis-3R), or (VI'-cis-3R), or (VII'-cis-3R), or (VIII'-cis-3R).

[0274] Suitable transition metal compounds or catalysts are as defined above and are preferably selected from Ru, Pd, Pt, Rh and Ir compounds.

[0275] 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, phosphinates, phosphoramidites, sulfonamide-phosphoramidites, phosphine oxides, N-heterocyclic carbenes, diamines, imidazoles, amino alcohols, diols, oxazolines, imines and amino acids.

[0276] Preferably, the optically active ligand is a P,P- or P,N- or P,O- or P,S-bidentate ligand, preferably a P,P-bidentate ligand, more preferably a diphosphine ligand.

[0277] Suitable but non-limiting examples of optically active chiral ligands are (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 enantiomers thereof.

[0278] In an embodiment, 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 an embodiment, the reaction is carried out in the presence of Ru(OAc)2 and (S)-SEGPHOS, for example as disclosed in WO 2017 / 066775.

[0279] Relative to which The amount of the compound having a double bond, the transition metal catalyst may be present in an amount between 0.01 and 50 wt%, preferably between 1 and 10 wt%. If an optically active transition metal catalyst is used, then relative to the amount of The optically active ligand may be used in an amount between 0.01 and 50 wt %, preferably between 1 and 10 wt %, based on the amount of the compound having a double bond.

[0280] The reaction can be carried out in the presence of an organic solvent such as an ether (e.g., Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran)), a hydrocarbon solvent (e.g., pentane, hexane, heptane), a halogenated solvent (e.g., dichloromethane, chloroform), an aromatic solvent (e.g., toluene, xylene), a ketone (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g., EtOAc, iPrOAc), a nitrile (e.g., acetonitrile, benzonitrile), an amide (e.g., DMF, DMA, HMPA), an alcohol (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, tert-butanol), a sulfoxide (DMSO), an acid (AcOH), and a mixture thereof.

[0281] The reaction is carried out in the presence of H2, preferably at a pressure between 1 and 100 atm, preferably between 2 and 50 atm. In an embodiment, the reaction is carried out at a temperature between -80°C and 100°C, preferably between -20°C and 90°C, more preferably between 0°C and 50°C. The hydrogen source includes H2, formic acid or a salt thereof, and cyclohexene.

[0282] Preferably, the term optical activity as used herein refers to a compound with an enantiomeric excess of at least 50%. More preferably, it refers to an enantiomeric excess of at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99%.

[0283] Preferably, the cis isomer is selectively obtained after the hydrogenation reaction. The term "selective" with respect to the hydrogenated compound means that the cis isomer is obtained in a ratio of at least 80:20 relative to the trans isomer, preferably at least 90:10, more preferably at least 95:5, even more preferably at least 98:2.

[0284] When carrying out an asymmetric hydrogenation, the desired isomer (eg the cis-3R isomer) is preferably obtained in an enantiomeric excess of at least 90%, at least 95%, preferably at least 98% or at least 99%.

[0285] Preparation of Upadacitinib

[0286] The method of the present invention may further comprise converting the compound of formula (I) or a salt or solvate thereof into upadacitinib.

[0287] Therefore, in another aspect, the present invention relates to a method for preparing upadacitinib or a salt or solvate or stereoisomer thereof, the method comprising:

[0288] - by a method as defined herein

[0289]

[0290] in

[0291] is a single bond or a double bond;

[0292] X is a leaving group, and

[0293] R 1 is selected from H and an amino protecting group;

[0294] preparing a compound of formula (I) or a salt or solvate thereof; and

[0295] - converting the compound of formula (I) or a salt or solvate thereof into upadacitinib or a salt or solvate or a stereoisomer thereof.

[0296] The conversion of the compound of formula (I) or a salt or solvate thereof into 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 WO2017 / 066775.

[0297] In a specific embodiment, the conversion of the compound of formula (I) or its salt or solvate into upadacitinib or its salt or solvate or stereoisomer may be carried out by a method comprising the following:

[0298] (i) reacting a compound of formula (I) or a salt or solvate thereof with a compound of formula (IX)

[0299]

[0300] in

[0301] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, C6-C 15 Aryl and (C6-C 15 ) aryl(C1-C6)alkyl, preferably it is methyl or ethyl; and

[0302] R 8 is an amino protecting group, preferably Ts;

[0303] To provide a compound of formula (X) or a salt or solvate thereof

[0304]

[0305] in

[0306] is a single bond or a double bond; and

[0307] R 1 is selected from H and an amino protecting group; preferably an amino protecting group,

[0308] (ii) reacting a compound of formula (X) or a salt or solvate thereof with perfluoroanhydride and a base to form a compound of formula (XI) or a salt or solvate thereof

[0309]

[0310] (iii) When R 1 When R in the compound of formula (XI) or its salt or solvate is 1 The group is deprotected to provide a compound of formula (XII) or a salt or solvate thereof

[0311]

[0312] in

[0313] is a single bond or a double bond; and

[0314] R 8 is selected from H and an amino protecting group;

[0315] (iv) converting the compound of formula (XII) or its salt or solvate into the compound of formula (XIII) or its salt or solvate

[0316]

[0317] Where R 8 is selected from H and an amino protecting group;

[0318] (v) If necessary, when R 8 When it is an amino protecting group, the compound of formula (XIII) or a salt or solvate thereof is deprotected to provide a compound of formula (XIII) (wherein R 8 is H) or a salt or solvate thereof.

[0319] If necessary, When represents a double bond in the compound of formula (I), 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), or after step (v).

[0320] In an embodiment, the method comprises:

[0321] (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,

[0322] (ii) reacting a compound of formula (X) as defined above, or a salt or solvate thereof, with perfluoroanhydride and a base to form a compound of formula (XI) or a salt or solvate thereof

[0323]

[0324] (iii) deprotecting the compound of formula (XI) or a salt or solvate thereof to provide a compound of formula (XII') or a salt or solvate thereof

[0325]

[0326] (iv) converting the compound of formula (XII) or its salt or solvate into the compound of formula (XIII') or its salt or solvate

[0327]

[0328] If necessary, When represents a double bond in the compound of formula (I), 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).

[0329] In a preferred embodiment, the compound of formula (I) is compound (I-cis-3R), and thus the method for preparing upadacitinib or a salt or solvate thereof comprises:

[0330] (i) Make R 1 A compound of formula (I-cis-3R) or a salt or solvate thereof having an amino protecting group is reacted with a compound of formula (IX) to provide a compound of formula (X-cis-3R) or a salt or solvate thereof

[0331]

[0332] in

[0333] R 1 is selected from H and an amino protecting group;

[0334] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, C6-C 15 Aryl and (C6-C 15 ) aryl(C1-C6)alkyl, preferably it is methyl or ethyl; and

[0335] R 8 is an amino protecting group, preferably Ts;

[0336] (ii) reacting a compound of formula (X-cis-3R) or a salt or solvate thereof with perfluoroanhydride and a base to form a compound of formula (XI-cis-3R) or a salt or solvate thereof

[0337]

[0338] (iii) When R 1 When it is an amino protecting group, R 1 The group is deprotected to provide a compound of formula (XII-cis-3R) or a salt or solvate thereof

[0339]

[0340] in

[0341] R 8 is selected from H and an amino protecting group;

[0342] (iv) converting the compound of formula (XII-cis-3R) or its salt or solvate into the compound of formula (XIII-cis-3R) or its salt or solvate

[0343]

[0344] Where R 8 is selected from H and an amino protecting group;

[0345] (v) If necessary, when R 8 When is an amino protecting group, the compound of formula (XIII-cis-3R) or a salt or solvate thereof is deprotected to provide upadacitinib or a salt or solvate thereof.

[0346] In a specific embodiment, the method comprises:

[0347] (i) Make R 1 A compound of formula (I-cis-3R) or a salt or solvate thereof having an amino protecting group is reacted with a compound of formula (IX) to provide a compound of formula (X-cis-3R) or a salt or solvate thereof as defined above,

[0348] (ii) reacting a compound of formula (X-cis-3R) as defined above, or a salt or solvate thereof, with perfluoroanhydride and a base to form a compound of formula (XI-cis-3R) or a salt or solvate thereof

[0349]

[0350] (iii) deprotecting the compound of formula (XI-cis-3R) or a salt or solvate thereof to provide a compound of formula (XII'-cis-3R) or a salt or solvate thereof

[0351]

[0352] (iv) converting the compound of formula (XII'-cis-3R) or a salt or solvate thereof into upadacitinib or a salt or solvate thereof.

[0353] In a preferred embodiment, the compound of formula (I) is compound (I-cis-3R), such as compound 10

[0354]

[0355] And the method for preparing upadacitinib or its salt or solvate comprises:

[0356] (i) reacting a compound of formula (I-cis-3R) (such as compound 10) or a salt or solvate thereof with a compound of formula (IX) (such as compound 20),

[0357]

[0358] To provide a compound of formula (X-cis-3R) or a salt or solvate thereof, such as compound 21

[0359]

[0360] (ii) reacting a compound of formula (X-cis-3R) (such as compound 21) or a salt or solvate thereof with perfluoroanhydride and a base to form a compound of formula (XI-cis-3R) (such as compound 22) or a salt or solvate thereof

[0361]

[0362] (iii) deprotecting a compound of formula (XI-cis-3R) (such as compound 22) or a salt or solvate thereof to provide a compound of formula (XII-cis-3R) (such as compound 23) or a salt or solvate thereof

[0363]

[0364] (iv) converting a compound of formula (XII) (such as compound 23) or a salt or solvate thereof into upadacitinib or a salt or solvate thereof.

[0365] Suitable conditions for transformations (i)-(v) are disclosed in the prior art (eg WO 2017 / 066775) or are known to those skilled in the art.

[0366] In an embodiment, step (i) may be carried out in the presence of a base such as NaH, tBuOLi, tBuONa or tBuOK, optionally in the presence of an organic solvent, preferably an aprotic organic solvent.

[0367] Step (ii) can be carried out in the presence of a perfluoroanhydride, 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, heptafluorobutyric acid.

[0368] Suitable perfluoroanhydrides include, for example, trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride.

[0369] Steps (iii) and (v) may be performed by any conventional method for cleavage of amino protecting groups known in the art (eg TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, 2007) and as disclosed herein.

[0370] Step (iv) can be carried out by reacting with 2,2,2-trifluoroethylamine in the presence of CDI and optionally an organic solvent.

[0371] Intermediate Compounds

[0372] Compounds of formula (III), (IV), (V), (VI) and (VII) and 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.

[0373] In another aspect, the invention relates to compounds of the formula:

[0374]

[0375]

[0376] or a salt or solvate thereof, wherein:

[0377] R 1 is selected from H and an amino protecting group;

[0378] R 3 Selected from C1-C6 alkyl, (C6-C 15 )Aryl(C1-C6)alkyl, C6-C 15 Aryl, COR' and SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15Aryl and (C6-C 15 ) aryl(C1-C6)alkyl;

[0379] R 4 and R 5 Independently selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 aryl groups or they together with the nitrogen atom form a 5- to 7-membered heterocyclic ring; and

[0380] R' is selected from C1-C6 alkyl, (C6-C 15 ) aryl (C1-C6) alkyl and C6-C 15 Aryl.

[0381] R'、R 1 , R 3 , R 4 and R 5 Suitable and preferred embodiments are as defined herein for the method of the invention.

[0382] In an embodiment, R 1 Selected from:

[0383] -COOR a , where R a Selected from 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;

[0384] -COR b , where R b Selected from 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;

[0385] -R c , where R c Selected from C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 ) aryl(C1-C6)alkyl;

[0386] -SO2R d , where R d Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C15 Aryl, (C6-C 15 ) aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl; and

[0387] -Si(R e )(R f )(R g ), where R e , R f and R g Independently selected from C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl.

[0388] Preferably, R' is selected from C1-C6 alkyl; more preferably tBu.

[0389] Preferably, R 1 is a group of formula COOR, wherein R is selected from 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, tert-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 an embodiment, it is selected from Cbz and Boc.

[0390] Preferably, R 3 Selected from C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, COR' and SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. More preferably, R 3 is a group SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl, such as TMS, TES, TBS and TBDPS.

[0391] In a specific embodiment, R4 and R 5 are independently selected from C1-C6 alkyl, or they form a 5- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached. More preferably, they form a 5- to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached, preferably a 5- to 7-membered heterocyclic ring containing one nitrogen atom, or two nitrogen atoms, or one nitrogen and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine and azepane.

[0392] In a specific embodiment, the present invention relates to a compound of the formula

[0393]

[0394]

[0395] or a salt or solvate thereof.

[0396] It should be understood that the scope of the present disclosure includes all possible combinations of the embodiments disclosed herein.

[0397] Example

[0398] Example 1: Synthesis of cis-Weinreb amide (2) from cis-carboxylic acid (1)

[0399]

[0400] Under argon atmosphere, 6g cis-compound (1) (21.63mmol) was dissolved in 40ml dichloromethane, and the resulting solution was cooled to 0-5°C with an ice bath. 4.56g of CDI (1.3 equivalents) was slowly added to the solution in batches. The reaction mixture was stirred for 20min, and then allowed to warm to room temperature. Then, 2.74g of N, O-dimethylhydroxylamine (1.3 equivalents) was added. When the reaction was found to be complete by TLC, it was quenched with 1M HCl aqueous solution until pH 4-6 and 100ml of AcOEt. The organic layer was washed with water (60ml) and the solvent was evaporated under reduced pressure to obtain 6.86g of cis-compound (2), which was an oil. The purity of the resulting compound was sufficient to be used directly in the subsequent reaction steps. 1H NMR(500MHz, CDCl3)δ7.26(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=14.7,9.2 Hz,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).

[0401] Example 2: Synthesis of cis-ketone (3) from cis-Weinreb amide (2)

[0402]

[0403] Under argon atmosphere, 5.96g cis-compound (2) (18.6mmol) is dissolved in 60ml dry THF, and the resulting solution is cooled to 0-5°C with an ice bath. 12.4ml of 3M MeMgCl solution in THF (2 equivalents) is slowly added so that the temperature does not exceed 5°C. The reaction mixture is stirred for 15-30min, and TLC is subsequently performed. Then, it is quenched with a saturated NH4Cl aqueous solution and extracted with 100ml of EtOAc. The organic layer is washed with water (20-30ml) and the solvent is evaporated under reduced pressure to produce 4.8g of brown oil. The resulting oil is extracted by adding 40-100ml of hot heptane to obtain an insoluble colorless residue. The heptane extract is evaporated under reduced pressure to obtain 4.7g of pure cis-compound (3) (91% yield). 1 H NMR (500MHz, CDCl3) δ7.26 (s, 5H), 5.13 (qd, J=12.5, 3.8Hz, 2H), 3.88-3.17 (m, 5H), 2.42 -2.29(m,1H),2.18(s,3H),1.66(s,1H),1.44-1.17(m,2H),0.94(dd,J=15.9,7.4Hz,3H).

[0404] Example 3: Synthesis of cis-silyl enol ether (4) from cis-ketone (3)

[0405]

[0406] Under argon atmosphere, 5.55g cis-compound (3) (20.6ml) was dissolved in 100ml anhydrous dichloromethane, and the resulting solution was cooled to 0-5°C with an ice bath. 6.7ml trifluoromethanesulfonic acid trimethylsilyl ester (1.8 equivalents) was added, followed by 5.62l anhydrous trimethylamine (2 equivalents). The reaction mixture was stirred until completed by TLC (15-60min). The reaction was quenched by adding 100ml of NaHCO 7% aqueous solution and extracted with 100ml dichloromethane. The solvent was evaporated under reduced pressure to obtain an oil (6.9g), which was directly used in subsequent reactions. 1 H NMR (500MHz, CDCl3) δ7.43-7.28(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),2.83-2.65(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).

[0407] Example 4: Synthesis of cis-compound (5) from cis-silyl enol ether (4):

[0408]

[0409] Under argon atmosphere, the oil obtained in the above example (4) was dissolved in 50 ml of anhydrous THF and 2 g of NaHCO (1.21 equivalents) were added. The resulting suspension was cooled to 0-5° C. with an ice bath and then 4.3 g of NBS (1.21 equivalents) were added in portions to control the temperature. The reaction proceeded rapidly and was followed by TLC. The reaction was quenched by adding 100 ml of a 7% aqueous solution of NaHCO and extracted with 100 ml of AcOEt. The solvent was evaporated under reduced pressure to give 8.5 g of an oil which was purified by column chromatography to give 5.5 g of a white solid (77% yield starting from ketone (3)). 1 H NMR (400MHz, CDCl3) δ7.45-7.28(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).

[0410] Example 5: Synthesis of cis-hydroxyketone (6) from cis-Weinreb amide (2)

[0411]

[0412] Preparation of ((pivaloyloxy)methyl)magnesium chloride (0.4 M): To a solution of iodomethyl pivalate (14.5 g, 60 mmol, 1.0 eq) in dry THF (67 mL) precooled to -65 to -75°C under argon atmosphere was added iPrMgCl solution (2.0 M in THF, 66.0 mL, 132 mmol, 2.2 eq). The reaction mixture was stirred, keeping the temperature below -65°C, until the desired reagent was completely formed.

[0413] To a solution of weinreb amide (2) (0.3 g, 0.93 mmol, 1.0 equiv) in dry THF (5 mL) 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 under argon atmosphere. After 30 min, the reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 10 mL). The dried (MgSO4) extracts were filtered and concentrated in vacuo, and the obtained oily residue was purified by flash column chromatography to give the desired product (0.10 g, 32%) as a yellow oil. Better yields were obtained by adding MeONa before quenching the reaction mixture. 1 H NMR (400 MHz, 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 = 5.9 Hz, 1H), 1.46-1.20 (m, 2H), 0.93 (dd, J = 13.1, 7.0 Hz, 3H).

[0414] Example 6: Synthesis of cis-3R-Weinreb amide (8) from cis-3R carboxylic acid (7)

[0415]

[0416] Compound (7) (6.00 g, 21.63 mmol, 1.0 eq.) and CDI (4.56 g, 28.13 mmol, 1.3 eq.) were mixed under an argon atmosphere. Dry CH2Cl2 (40 mL) was added, and the suspension was stirred at 0°C for 10 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (0.99 g, 10.20 mmol, 1.5 eq.) was added, and the resulting mixture was further stirred at room temperature for 12 h until the reaction was completed. The suspension was quenched with an aqueous solution of HCl (0.5 M, 20 mL), and the organic layer was extracted and washed twice with an aqueous solution of brine (2×20 mL). The organic layer was collected, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give the title pure product as a brown oil (6.86 g, 21.41 mmol, 99%). 1 H NMR (500 MHz, 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, 9.2 Hz, 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, 7.3 Hz, 3H).

[0417] Example 7: Synthesis of cis-3R Ketone (9) from cis-3R Weinreb Amide (8)

[0418]

[0419] To a solution of compound (8) (5.96 g, 17.74 mmol, 1.0 eq) in dry THF (60 mL) was added MeMgCl (3 M, 11.80 mL, 35.47 mmol, 2 eq) under argon at 0°C. After 15 min, the reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 10 mL). The dried (MgSO4) extracts were filtered and concentrated in vacuo and extracted with hot heptane to give the desired product (4.37 g, 89%) as a brown oil. 1H NMR(500MHz, chloroform-d)δ7.26(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).

[0420] Example 8: Synthesis of cis-3R compound (10) from cis-3R ketone (9)

[0421]

[0422] Under argon atmosphere, a solution of compound (9) (1.0 g, 3.63 mmol, 1.0 eq.) in dry CH2Cl2 (15 mL) was cooled to 0°C. TMSOTf (1.18 mL, 6.54 mmol, 1.8 eq.), Et3N (1.01 mL, 7.27 mmol, 2.0 eq.) were added to the solution and stirring was continued for 10 min until the intermediate silyl enol ether was completely formed. Then, NaHCO3 (0.37 g, 4.40 mmol, 1.2 eq.) and NBS (0.84 mg, 2.07 mmol, 1.3 eq.) were added at 0°C. After 1 h, the reaction was quenched with saturated NaHCO3 aqueous solution and extracted with CH2Cl2 (2×10 mL). The organic layer was then washed with 5% Na2S2O3 aqueous solution. The dried (MgSO4) organic layer was filtered and concentrated in vacuo and purified by silica gel chromatography to give the title product (0.96 g, 77%) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ7.45-7.28 (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).

[0423] Example 9: Synthesis of cis-3R compound (11) from cis-3R Weinreb amide (8)

[0424]

[0425] To a solution of compound (8) (0.3 g, 0.94 mmol, 1.0 equiv) in dry THF (5 mL) cooled at -78 ° C was added ICH2Cl (0.27 mL, 3.70 mmol, 4.0 equiv), and then, MeLi·LiBr complex (1.5 M solution in Et2O, 1.88 mL, 2.82 mmol, 3.0 equiv) was added dropwise over 5 min. The resulting solution was stirred at this temperature for 2 h, and then NH4Cl saturated aqueous solution was added at -78 ° C. The mixture was allowed to reach room temperature and washed with Et2O (10 mL) and brine (10 mL). The two phases obtained were separated, and the organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to obtain the desired pure product (0.18 g, 63%) as a yellow oil. 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).

[0426] Example 10: Synthesis of cis-3R hydroxyketone (12) from cis-3R ketone (9)

[0427]

[0428] Step 1: Under argon atmosphere, a solution of methyl ketone (12) (1.0 g, 3.63 mmol, 1.0 equiv) in dry CH2Cl2 (10 mL) was cooled to 0°C. TMSOTf (1.18 mL, 6.54 mmol, 1.8 equiv) and Et3N (1.0 mL, 7.26 mmol, 2.0 equiv) were added to the solution and stirring was continued for 1 h until the silyl enol ether was completely formed. The reaction was quenched with saturated NaHCO3 aqueous solution and extracted with ether (3×10 mL). The dried (MgSO4) extracts were concentrated in vacuo to provide the intermediate silyl enol ether, which was used in the next step without further purification (1.3 g, 99%) as a brown oil.

[0429] Step 2: Dissolve the crude silyl enol ether (1.0 g, 2.87 mmol, 1.0 equiv) in DCM (10 mL) and add m-CPBA (0.75 g, 4.3 mmol, 1.5 equiv) in one portion at room temperature. After 1 h, the reaction was quenched with 5% aqueous Na2S2O3 solution. The solution was extracted with DCM (3×10 mL). The organic phase was then washed with saturated aqueous K2CO3 solution, dried (NaSO4), filtered and concentrated in vacuo to give the pure product (0.66 g, 80%) as a yellow oil. 1 H NMR (400 MHz, 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 = 5.9 Hz, 1H), 1.46-1.20 (m, 2H), 0.93 (dd, J = 13.1, 7.0 Hz, 3H).

[0430] Example 11: Synthesis of Weinreb amide (14) from carboxylic acid (13)

[0431]

[0432] Compound (13) (1.80 g, 6.80 mmol, 1.0 eq.) and CDI (1.66 g, 10.20 mmol, 1.5 eq.) were mixed under an argon atmosphere. Dry CH2Cl2 (20 mL) was added, and the suspension was stirred at 0 °C for 5 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (0.99 g, 10.20 mmol, 1.5 eq.) was added, and the resulting mixture was further stirred at room temperature for 5 h until the reaction was completed. The suspension was quenched with an aqueous solution of HCl (0.5 M, 10 mL), and the organic layer was extracted and washed twice with an aqueous solution of brine (2×10 mL). The organic layer was collected, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give the title pure product (2.12 g, 14.11 mmol, 98%) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ7.44-7.29(m,5H),5.16(s,2H),4.45(dt,J=15.91,4.11Hz,2H),4.26(dt,J=15.91,4.11H z, 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).

[0433] Example 12: Synthesis of Ketone (15) from Weinreb Amide (14)

[0434]

[0435] To a solution of compound (14) (0.50 g, 1.57 mmol, 1.0 equiv) in dry THF (10 mL) was added MeMgCl (3 M, 0.90 mL, 2.67 mmol, 1.7 equiv) at 0°C under argon atmosphere and the reaction was allowed to reach room temperature and stirred for 12 h. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 10 mL). The dried (MgSO4) extracts were filtered and concentrated in vacuo to give the title product (0.42 g, 98%) as a brown oil. 1 H NMR (500 MHz, 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 = 9.19 Hz, 3H), 1.10 (dt, J = 16.34, 7.62 Hz, 3H).

[0436] Example 13: Synthesis of Compound (16) from Ketone (15)

[0437]

[0438] Under argon atmosphere, a solution of compound (15) (0.1 g, 0.36 mmol, 1.0 eq) in dry CH2Cl2 (2 mL) was cooled to 0°C. TMSOTf (0.12 mL, 0.65 mmol, 1.8 eq) and Et3N (0.1 mL, 0.72 mmol, 2.0 eq) were added to the solution and stirring was continued for 1 h until the intermediate silyl enol ether was completely formed. Then, NaHCO3 (0.03 g, 0.43 mmol, 1.2 eq) and NBS (0.04 mg, 0.43 mmol, 1.2 eq) were added at 0°C. After 1 h, the reaction was quenched with saturated NaHCO3 aqueous solution and extracted with EtOAc (2×10 mL). The organic layer was then washed with 5% Na2S2O3 aqueous solution. The dried (Mg2SO4) organic layer was filtered, concentrated in vacuo and purified by silica gel chromatography to give the title product (0.09 g, 73%) as a yellow oil. 1HNMR (500MHz, chloroform-d) δ7.41-7.30 (m, 5H), 5.18 (d, J = 1.17Hz, 2H), 4.64-4.44 (m, 2H), 4.43 -4.32(m,2H),3.93(d,J=5.63Hz,2H),2.77-2.48(m,2H),1.12(dt,J=15.12,7.63Hz,3H).

[0439] Example 14: Synthesis of Compound (17) from Weinreb Amide (14)

[0440]

[0441] To a solution of compound (14) (0.3 g, 0.94 mmol, 1.0 equiv) in dry THF (5 mL) cooled at -78 ° C was added ICH2Cl (0.28 mL, 3.80 mmol, 4.0 equiv), and then, MeLi·LiBr complex (1.5 M solution in Et2O, 1.5 mL, 2.82 mmol, 3.0 equiv) was added dropwise over 5 min. The resulting solution was stirred at this temperature for 2 h, and then NH4Cl saturated aqueous solution was added at -78 ° C. The mixture was allowed to reach room temperature and washed with Et2O (10 mL) and brine (10 mL). The two phases obtained were separated, and the organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to obtain the desired pure product (0.13 g, 48%) as a yellow oil. 1 H NMR (500MHz, chloroform-d) δ7.54-7.28(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).

[0442] Example 15: Hydrogenation of Weinreb amide (14) to cis-compound (2)

[0443]

[0444] PtO2 (0.08 g, 0.35 mmol) was added to a solution of compound (14) (0.3 g, 0.94 mmol, 1.0 equivalent) in icy AcOH (2 mL). The reaction mixture was stirred at room temperature for 12 h under an atmosphere of H2 (10 bar). The solution was filtered through a diatomaceous earth pad and evaporated in vacuo to give a brown oil. The crude oil was purified by column chromatography to give the desired reduced product.1 H NMR (500 MHz, CHLOROFORM-d) δ7.26 (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, 9.2 Hz, 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, 7.3 Hz, 3H).

[0445] Example 16: Hydrogenation of ester (18) to cis-compound (19)

[0446]

[0447] PtO2 (0.08 g, 0.35 mmol) was added to a solution of compound (18) (0.5 g, 1.50 mmol, 1.0 equivalent) in icy AcOH (2 mL). The reaction mixture was stirred at room temperature for 12 h under an atmosphere of H2 (10 bar). The solution was filtered through a diatomaceous earth pad and evaporated in vacuo to give a brown oil. The crude oil was purified by column chromatography to give the desired reduced product. 1 HNMR (500 MHz, chloroform-d) δ7.39-7.27 (m, 5H), 5.24-5.00 (m, 2H), 3.78-3.64 (m, 1H), 3.57 (ddd, J = 16.1, 10.4, 7.3 Hz, 1H), 3.48 (ddd, J = 11.6, 7.1, 5.1 Hz, 1H), 3.24 (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).

[0448] Example 17: Synthesis of ester (18) from enol triflate (20)

[0449]

[0450] EtMgBr (3.0M, 3.0mL, 8.85mmol, 4 equivalents) was added dropwise to a suspension of CuI (0.84g, 4.4mmol, 2 equivalents) in dry THF (20mL) cooled at 0°C. The reaction mixture turned dark purple and was stirred at 0°C for 30 minutes. Then, a solution of methyl ketone (1.0g, 2.2mmol, 1.0 equivalents) in THF (20mL) was added dropwise at this temperature. The reaction mixture was allowed to reach room temperature and was stirred for 4h. The reaction was then quenched with a saturated NH4Cl aqueous solution and extracted with EtOAc (2×50mL). The organic phase was washed with a saturated NaCl aqueous solution, dried (MgSO4), filtered through a diatomaceous earth pad and concentrated in vacuo to give the title product (0.73g, 98%) as a brown oil. 1H NMR (500 MHz, CHLOROFORM-d) δ7.45-7.27 (m, 5H), 5.16 (d, J = 4.46 Hz, 2H), 4.47-4.19 (m, 4H), 2.66-2.54 (m, 2H), 1.49 (d, J = 2.14 Hz, 9H), 1.08 (q, J = 7.50 Hz, 3H).

[0451] Example 18: Synthesis of carboxylic acid (13) from ester (18)

[0452]

[0453] In a round-bottom flask, formic acid (8 ml) was added to a crude sample of the tert-butyl ester (18) (2 g, 0.6 mmol) and the reaction mixture was stirred at 45 ° C until completion (TLC control, 3-4 h). The remaining formic acid was removed by vacuum distillation until a residue was obtained, which was redissolved in 20 ml of EtOAc and washed with 12 ml of NaCl. The resulting organic phase was freshly extracted with 20 ml of saturated Na2CO3 aqueous solution, in which operation the product was transferred to the aqueous phase as a sodium salt and the organic phase was discharged. The alkaline and colored aqueous phase was then acidified with concentrated HCl. The desired product was precipitated as a beige solid, which was filtered, washed with water and dried to give the title product (1.4 g, 85%).

[0454] Example 19: Synthesis of (3R,4S)-3-(N-(tert-butoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)-4-ethylpyrrolidine-l-carboxylic acid benzyl ester (21)

[0455]

[0456] A mixture of sodium hydride (1.1 g) (60% dispersion in oil) 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 (3R,4S)-3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate (10 g) in tetrahydrofuran (10 mL) was added to the above reaction mixture at 0°C and stirred at the same temperature for 1 hour. After the reaction was completed, acetic acid (0.8 ml) was added to the reaction mixture. The corresponding solution was added to cold water (750 ml), and the solid was filtered and dried to obtain a crude product. Yield: 75%; 1H NMR (400MHz, d-DMSO): δ8.74(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).

[0457] Example 20: Synthesis of benzyl (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (22)

[0458]

[0459] Trifluoroacetic anhydride (6.3 ml) and trifluoroacetic acid (1.6 ml) were added to a mixture of crude (3R,4S)-3-(N-(tert-butoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)glycyl)-4-ethylpyrrolidine-l-carboxylic acid benzyl ester (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 hours. The reaction mixture was distilled and added to cold 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 corresponding organic layer was concentrated in vacuo to give a crude solid, which was purified by crystallization from methanol (50 ml). Yield: 40%; 1H NMR (400 MHz, d-DMSO) δ8.77 (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).

[0460] Example 21: Synthesis of 8-((3S,4R)-4-ethylpyrrolidin-3-yl)-3-toluenesulfonyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (23)

[0461]

[0462] To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)pyrrolidine-1-carboxylic acid benzyl ester (10 g) in isopropanol (20 mL) was slowly added concentrated aqueous HCl solution (20 mL) and heated to 80 ° C at 20 / 25 ° C. The reaction mixture was stirred at the same temperature for 5 hours 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 discarded. The aqueous layer was washed with dichloromethane (2×100 mL). The pH of the aqueous layer was adjusted to 7.5 using 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, which was filtered to obtain a wet light yellow solid. Yield: 100%. 1H NMR(400MHz,MeOD)δ9.06(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).

[0463] Example 22: Synthesis of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide (24)

[0464]

[0465] To a mixture of 1,1-carbonyldiimidazole (CDI) (4.1 g) and tetrahydrofuran (50 mL) was added 2,2,2-trifluoroethylamine (2.2 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. A solution of 10% HCl in water (100 ml) was added, the aqueous phase was discarded, the organic phase was washed with water (100 mL), and the final organic phase was concentrated by distillation to 30 ml and added to obtain a suspension on heptane (300 ml), 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).

[0466] Example 23: Preparation of Upadacitinib

[0467]

[0468] To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide (10 g) in tetrahydrofuran (50 mL) was added a 10% solution of sodium hydroxide in water (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). A 2.5% aqueous solution of 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 cake was drained and dried under vacuum 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),3.9 2-3.67(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).

[0469] Example 24: Preparation of Upadacitinib

[0470] Upadacitinib (0.25 g) was dissolved in ethanol (1 mL). The solution was added to an aqueous solution (25 mL) containing 0.5% ethanol pre-cooled to 0 / 5°C. Solids were immediately observed. The suspension was stirred at 0-5°C for 20 minutes and then subsequently filtered. The wet cake was dried overnight at 50°C under forced air to obtain an almost white amorphous solid.

[0471] Example 25: Preparation of Upadacitinib Tartrate

[0472] To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide (10g) in tetrahydrofuran (50mL) was added a 10% solution of sodium hydroxide in water (15ml) and heated to 50°C. The reaction mixture was stirred for 5 hours and cooled to 25°C. Saturated sodium chloride solution (100mL) was added to the reaction mixture and extracted with dichloromethane (100mL). The organic phase was separated and washed with water (100mL). The organic phase was concentrated to obtain a crude product, which was dissolved in isopropanol (30mL). L-(+) tartaric acid (1,2mol / 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 (2 mol / mol) was added. The resulting suspension was evaporated to 100 ml, and the resulting suspension was filtered and dried to give a light brown solid. Yield; 80%.

[0473] Comparative Experiment

[0474] In order to further compare the method of the present invention with the method disclosed in WO 2017 / 066975, the synthesis method disclosed in the conditions e disclosed in Examples 3A and 3B of said document is reproduced as follows.

[0475]

[0476] Comparative Example 26: Synthesis of dimethylsulfoxonium (25) from cis-compound (1)

[0477]

[0478] Preparation of trimethylsulfoxonium anion (slurry 1):

[0479] 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 and then cooled to below 0 °C.

[0480] Preparation of carbonyldiimidazole (Solution 2):

[0481] To a solution of CDI (1.02 g, 1.5 eq.) 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.

[0482] Freshly prepared solution 2 was slowly added (within 15 min) to slurry 1 and the temperature was kept 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% NaCl aqueous solution (11 ml) were added. The two layers were separated, and the aqueous layer was extracted with AcOEt (11 ml) again. The combined organic layer was washed with 12% NaCl aqueous solution. The organic layer was evaporated under reduced pressure to obtain 1.46 g. The oil was analyzed by HPLC and found to be a 68 / 32 mixture of cis / trans isomers. Therefore, under the reaction conditions required for the method disclosed in WO 2017 / 066775, isomerization occurs. The resulting oil was purified by chromatography to separate the two isomers.

[0483] Cis isomer (0.75 g): 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).

[0484] Trans isomer (0.3g): 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).

[0485] Comparative Example 27: Synthesis of Compound (5) from Cis-Compound (25)

[0486]

[0487] To a THF (7.5 ml) solution of cis-dimethylsulfoxonium (25) (0.75 g, 2.13 mmol) and lithium bromide (0.222 g, 1.2 eq) was added p-toluenesulfonic acid monohydrate (0.447 g, 1.1 eq). The resulting mixture was warmed to 40 ° C and stirred overnight. A white solid precipitate was formed. The slurry was cooled to room temperature and the solvent was partially evaporated under reduced pressure. AcOEt (30 ml) and 7% NaHCO3 aqueous solution (13 ml) were added. The two layers were separated and the organic layer was washed with water (5 ml). The organic layer was finally evaporated under reduced pressure to produce 0.71 g of an oily substance formed by a 38 / 62 mixture of cis / trans isomers. The resulting oily substance was purified by chromatography to separate the two isomers.

[0488] Cis isomer (0.063 g): 1 H NMR (400MHz, CDCl3) δ7.45-7.28(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).

[0489] Trans isomer (0.373 g): 1 H NMR (500MHz, CDCl3) δ7.42-7.28(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(d d,J=14.6,7.8Hz,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).

Claims

1. A method for preparing a compound of formula (I'-cis) or a salt thereof in X is a halogen, and R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; The method comprises: (a) a compound of formula (II'-cis) or a salt thereof in Y is selected from OH and OR 2 , where R 2 is C1-C6 alkyl; and R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; Converted into a compound of formula (III'-cis) or a salt thereof in R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and (b) converting a compound of formula (III'-cis) or a salt thereof into a compound of formula (I'-cis) or a salt thereof by a process comprising: ( bi) reacting the compound of formula (III'-cis) or a salt thereof with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V'-cis) or a salt thereof in R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; (bii) converting a ketone of formula (V'-cis) or a salt thereof into an enol ether of formula (VI'-cis) or a salt thereof in R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and R 3 is SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and (biii) converting an enol ether of formula (VI'-cis) or a salt thereof into a compound of formula (I'-cis) or a salt thereof; or (bi') reacting the compound of formula (III'-cis) or a salt thereof with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to provide a compound of formula (I'-cis) or a salt thereof.

2. The method according to claim 1, wherein the compound of formula (II'-cis) or a salt thereof is obtained by hydrogenating a compound of formula (II") or a salt thereof, in Y is selected from OH and OR 2 , where R 2 is C1-C6 alkyl; and R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl.

3. The method according to any one of claims 1 to 2, wherein: -X is selected from Cl, Br and I; and / or -R 1 It is COOR a An amino protecting group, wherein R a It is C6-C 15 Aryl C1-C6 alkyl.

4. The method according to any one of claims 1 to 2, wherein the compound of formula (I'-cis), or (II'-cis), or (III'-cis), or (V'-cis), or (VI'-cis) is a compound of formula (I'-cis-3R), or (II'-cis-3R), or (III'-cis-3R), or (V'-cis-3R), or (VI'-cis-3R) respectively. or a salt thereof, wherein X is a halogen; Y is selected from OH and OR 2 , where R 2 is a C1-C6 alkyl group; R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and R 3 is SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and C6-C 15 Aryl C1-C6 alkyl.

5. The method according to any one of claims 1 to 2, wherein the compound of formula (II'-cis) or a salt thereof is obtained by a method comprising: - a compound of formula (IX) or a salt thereof in Z is selected from C1-C6 alkyl sulfonate groups and C1-C6 haloalkyl sulfonate groups; R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and Y is selected from OH and OR 2 , where R 2 is a C1-C6 alkyl group; Reaction with Et2CuLi, Et2CuMgBr or Et2CuMgCl to provide a compound of formula (II") or a salt thereof; as well as - hydrogenating the double bond to provide a compound of formula (II'-cis) or a salt thereof.

6. The method according to any one of claims 1 to 2, wherein The compound of formula (I'-cis) or a salt thereof is converted into upadacitinib or a salt thereof.

7. The method according to any one of claims 1 to 2, wherein the compound of formula (I'-cis) or a salt thereof is a compound of formula (I'-cis-3R) or a salt thereof in X is a halogen, and R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; And wherein the compounds of formula (II'-cis), (III'-cis), (V'-cis) and (VI'-cis) are compounds of formula (II'-cis-3R), (III'-cis-3R), (V'-cis-3R) and (VI'-cis-3R) respectively or a salt thereof, wherein X is a halogen; Y is selected from OH and OR 2 , where R 2 is a C1-C6 alkyl group; R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and R 3 is SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and C6-C 15 Aryl C1-C6 alkyl.

8. A compound selected from: or a salt thereof, wherein: R 1 It is COOR a An amino protecting group, wherein R a Selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl and C6-C 15 Aryl C1-C6 alkyl; and R 3 is SiR'3, wherein each R' is independently selected from C 1-6 Alkyl, C 6-15 Aryl and C6-C 15 Aryl C1-C6 alkyl.

9. The compound according to claim 8, wherein R a It is C6-C 15 Aryl C1-C6 alkyl.

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