Method and intermediate for manufacturing upadacitinib

Abstract

The present invention relates to a method for preparing a compound of formula (I) which is a useful intermediate in the synthesis of upadacitinib and structurally related compounds by using vainleb amide (III) or its equivalent as a major intermediate.

Description

Technology Field

[0001] The present invention relates to a method for preparing a compound that is an intermediate useful for the synthesis of upadacitinib. Background Technology

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

[0003]

[0004] Upadacitinib

[0005] Upadacitinib (also known as ABT-494) is a potent and selective JAK1 inhibitor developed by AbbVie. It has received FDA approval as a treatment for rheumatoid arthritis.

[0006] Although various methods for the synthesis of upadacitinib are described in the literature, they are all based primarily on the same approach: namely, preparing fragments referred to as Fragment A and Fragment B (a pyrrolidine derivative) and then combining them. Subsequent cyclicization and derivatization to provide an imidazopyrolopyrazine backbone then yield upadacitinib.

[0007]

[0008] Document WO 2013 / 043826 discloses a method for preparing cis-(3R,4S)-benzyl-4-ethyl-3-(2-bromoacetyl)pyrrolidine-1 carboxylate in Example 12.

[0009]

[0010] In this process, racemicis-1-benzyloxycarbonyl-4-ethylpyrrolidin-3-carboxylic acid (5) is first prepared. Then, the (3R,4S) enantiomer is separated by the formation of the diastereomer (naphthalenyl)etanamonium salt. Finally, the intermediate acid chloride is treated with the unstable and highly toxic trimethylsilyldiazomethane to obtain compound 7 in step E.

[0011]

[0012] The document WO 2017 / 066775 discloses the preparation of cis-(3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylate through the formation of a sulfoxonium salt and subsequent treatment with LiBr.

[0013]

[0014] However, the inventors of the present invention observed that the basic conditions required for the preparation of sulfoxonium salts and subsequent bromination reactions cause partial isomerization into trans isomers (see Comparative Experiments 19 and 20 of the present invention), which requires additional purification to obtain a pure product obtained in lower yields.

[0015] The preparation of starting (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid through asymmetric hydrogenation is disclosed in WO 2017 / 066775.

[0016]

[0017] Finally, document WO 2019 / 016745 discloses a method for preparing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, comprising the use of (1R)-2,10-camphorsulfam as a chiral auxiliary.

[0018]

[0019] This approach additionally requires the use of 2-pentinoic acid as a starting material, which is not easy to manufacture and increases process costs.

[0020] Therefore, it is necessary to develop a new process for obtaining intermediates in the synthesis of upadacitinib and related compounds that overcomes all or part of the problems associated with known processes belonging to the latest technology.

[0021] The present invention faces the problem of providing a new method for preparing a compound of formula (I), which is a useful intermediate in the synthesis of upadacitinib and structurally related compounds. In particular, the inventors have discovered that by using a weinreb amide of formula (III) or a triazine ester of formula (IV) as a major intermediate, the compound of formula I can be satisfactorily obtained in an industrially economical manner without requiring highly toxic reagents.

[0022] Additionally, the inventors observed that isomerization of the pyrrolidine ring to the trans isomer does not occur by the method of the present invention. In contrast, the conditions required by the method disclosed in WO 2017 / 06677 for the preparation of sulfoxonium salts and subsequent bromination reactions cause partial isomerization of cis-pyrrolidine to the trans isomer (see Comparative Experiments 19 and 20 of the present invention).

[0023] Accordingly, in the first aspect, the present invention relates to a method for preparing a compound of formula (I) or its salt or solvate, and

[0024]

[0025] (I)

[0026] food

[0027] is a single or double bond;

[0028] X is the leaving phase and

[0029] R 1is selected from H, and amino protecting groups;

[0030] This includes the following:

[0031] (a) a step of converting a compound of formula (II) or its salt or solvate into a compound of formula (III) or (IV) or its salt or solvate.

[0032]

[0033] (II)

[0034] food

[0035] is a single or double bond;

[0036] Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aryl; and

[0037] R 1 is selected from H, and amino protecting groups;

[0038]

[0039] (III) (IV)

[0040] food

[0041] is a single or double bond; and

[0042] R 1 is selected from H, and amino protecting groups; and

[0043] (b) a step of converting a compound of formula (III) or (IV), or its salt or solvate, into a compound of formula (I) or its salt or solvate by a method comprising the following:

[0044] (bi) a step of reacting a compound of formula (III) or (IV), or its salt or solvate, with MeMgCl, MeMgBr, or MeLi to provide a ketone of formula (V) or its salt or solvate.

[0045]

[0046] (V)

[0047] food

[0048] is a single or double bond; and

[0049] R 1 is selected from H, and amino protecting groups; and

[0050] (bii) A step of converting a ketone of formula (V), or its salt or solvate, into an enol ether of formula (VI) or an enamin of formula (VII) or its salt or solvate.

[0051]

[0052] (VI) (VII)

[0053] food

[0054] is a single or double bond; and

[0055] R 1 Is Selected from H, and amino protecting groups; and

[0056] R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; and

[0057] R 4 and R 5 is a C1-C6 alkyl, (C6-C15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or these form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and

[0058] (biii) a step of converting the enol ether of formula (VI) or the enamin of formula (VII), or its salt or solvate, into the compound of formula (I) or its salt or solvate;

[0059] or

[0060] (bi') a step of reacting a compound of formula (III) or (IV), or its salt or solvate, with X-CH2-Li, X-CH2-MgCl or X-CH2-MgBr to provide a compound of formula (I), or its salt or solvate;

[0061] or

[0062] (bi'') A compound of formula (III) or (IV), or its salt or solvate R 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 A step of reacting with O-CH2-MgBr to provide a compound of formula (VIII) or its salt or solvate;

[0063]

[0064] (VIII)

[0065] food

[0066] is a single or double bond;

[0067] R 1 is selected from H, and amino protecting groups; and

[0068] R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15Independently selected from aryl(C1-C6)alkyl;

[0069] and

[0070] (bii'') A step of converting a compound of formula (VIII) or its salt or solvate into a compound of formula (I) or its salt or solvate.

[0071] In another aspect, the present invention relates to a method for preparing upadacitinib, or its salt or solvate or stereoisomer, comprising the steps of preparing a compound of formula (I) or its salt or solvate through a method defined in the first aspect and converting said compound into upadacitinib.

[0072] In a further aspect, the present invention relates to a compound of the following chemical formula, or a salt or solvate thereof, and

[0073]

[0074] Food in progress:

[0075] R 1 is selected from H and amino protecting groups;

[0076] R 3 It is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl;

[0077] R 4 and R 5 It is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or they form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and

[0078] R' is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril. Specific details for implementing the invention

[0079] The term "alkyl" means a linear or branched 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 through single bonds. Exemplary examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, and hexyl.

[0080] The term "alkenyl" refers to a linear or branched hydrocarbon chain radical comprising 2 to 6 ("C1-C6 alkenyl"), preferably 2 to 3 carbon atoms, containing one or more double bonds, and attached to the rest of the molecule by single bonds. Exemplary examples of alkenyls include ethenyl, propenyl, allyl, butenyl, and 1-methyl-2-butenyl.

[0081] The term "haloalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogens. Examples of haloalkyl groups are CF3, CCl3, CHF2, and CF2CF3. Includes, but is not limited to.

[0082] The term "aryl" refers to an aromatic group having 6 to 15, preferably 6 to 10, carbon atoms comprising 1, 2, or 3 fused aromatic nuclei. Exemplary examples of aryl groups include phenyl, naphthyl, indenyl, phenanthryl, etc. Preferably, it is phenyl.

[0083] term "(C6-C 15"Aryl(C1-C6)alkyl" refers to an alkyl group as defined above that is substituted with an aryl group as defined above. Examples of such groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc. Preferably, it is benzyl.

[0084] The term "halogen" refers to bromine, chlorine, iodine, or fluorine.

[0085] Term "C3-C 10 "Cycloalkyl" refers to a monocyclic or bicyclic system containing 3 to 10, preferably 3 to 7 ("C3-C7-cycloalkyl") carbon atoms. Exemplary examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0086] The term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 15, preferably 3 to 10, more preferably 5 to 7 ring atoms, wherein the ring atoms comprise one or more, in particular 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbons. Exemplary examples of heterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine, piperazine, piperidine, azephan, and [1,4]dioxane.

[0087] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or tricyclic system containing 3 to 15, preferably 3 to 10, more preferably 5 to 7 ring atoms, wherein the ring atoms include one or more, in particular 1, 2, 3 or 4 ring heteroatoms, independently selected from O, N and S, and the remaining ring atoms are carbon.

[0088] The term "amino protecting group" (APG) refers to a group that blocks the NH function for a subsequent reaction, which can be removed under controlled conditions. Amino protecting groups are well known in the art. Exemplary examples of amino protecting groups are described in Green TW et al., "Protecting Groups in Organic Synthesis," 3rd ed. (1999), Ed. John Wiley & Sons. Virtually any amino protecting group may be used to practice the present invention. Exemplary and non-limiting examples of APGs include the following:

[0089] - Carbamate[-COOR]. R is a C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 It may be selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6alkyl)silane. Examples of carbamates include methyl carbamate (MOC), ethyl carbamate, t-butyl carbamate (Boc), benzyl carbamate (CBz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halobenzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate, trichloroethyl carbamate (Troc), trimethylsilylethyl carbamate (Teoc), trimethylsilyl carbamate, and triisopropylsilyl carbamate;

[0090] - amide [-COR]. R is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15It may be selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl. Examples of amides include acetamide, phenylacetamide, haloacetamide (e.g., chloroacetamide, trichloroacetamide, trifluoroacetamide), benzamide, and picolinamide;

[0091] - Amine [-R]. R is a C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 It may be selected from aryl(C1-C6)alkyl. Examples of amines include methylamine, tert-butylamine, benzylamine, p-methoxybenzylamine, 3,4-dimethoxybenzylamine, allylamine, methoxymethylamine, triphenylmethylamine, benzoylamine, dinitrophenylamine, p-methoxyphenylamine, o-methoxyphenylamine, trimethylsilylethoxymethylamine, and triphenylmethylamine;

[0092] - Sulfonamide[-SO2R]. R is a C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl, (C6-C 15 It may be selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyls, and 3- to 15-membered heteroaryls. Examples of sulfonamides include methanesulfonamide, trifluoromethanesulfonamide, t-butylsulfonamide, trimethylsilylethanesulfonamide, benzsulfonamide, p-toluenesulfonamide, benzenesulfonamide, o- or p-nitrobenzenesulfonamide, dinitrobenzenesulfonamide, naphthalenesulfonamide, and pyridine-2-sulfonamide;

[0093] and

[0094] - Silylamine [-Si(R)(R')(R'')]. R, R', and R'' are C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl and (C6-C 15It can be independently selected from aryl(C1-C6)alkyl groups. Examples of silylamines include trimethylsilylamine, triethylsilylamine, tert-butyldimethylsilamine, tert-butyldiphenylsilylamine, tri-isopropylsilylamine, and triphenylsilylamine.

[0095] The term "leaving group" refers to a functional group or atom that can be substituted for another functional group in a substitution reaction, such as a nucleophilic substitution reaction. Suitable leaving groups are well known in the art. In certain embodiments, the leaving group is a halogen, C1-C6 alkylsulfonate, C1-C6 haloalkylsulfonate, C6-C 10 Arylsulfonate and (C1-C6)alkyl (C6-C 10 ) It is selected from arylsulfonates, such as chloro, bromo, iodo, mesylate, triflate, tosylate, nosylate, etc.

[0096] As is understood in this art, the aforementioned radicals may have some degree of substitution. Accordingly, substitution may occur at any group of the present invention. The former groups may be substituted with one or more substituents at one or more acceptable positions. The substituents are, for example, C in a non-limiting sense. 1-6 Alkyl, C1-C6 haloalkyl, C 3-10 Cycloalkyl, C6-C 10 Aryl, (C6-C 10 )aryl(C1-C6)alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, halogen, -CN, NO2, CF3, -N(R a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f , -C(O)N(R g )(R h ), -OC(O)R i Includes; where R a , R b , R c, R d , R e , R f , R g , R h and R i is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, (C6-C 15 It is independently selected from aryl(C1-C6)alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, and trifluoromethyl.

[0097] The present invention also provides a “salt” of the compound described herein. By example, the salt may be an acid addition salt, a base addition salt, or a metal salt, and may be synthesized from a parent compound containing a basic or acid moiety by conventional chemical processes known in the art. Such salts are generally prepared by reacting the free acid or base form of the compound with a stoichiometric amount of a suitable base or acid, for example, in water or an organic solvent or a mixture of both. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol, or acetonitrile are generally preferred. Exemplary examples of the above acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, camphosulfonate, etc. Exemplary examples of base addition salts include inorganic base salts such as ammonium salts, etc., and organic base salts such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, amino acid base salts, etc. Examples of metal salts include sodium, potassium, calcium, magnesium, aluminum, and lithium salts.

[0098] In certain embodiments, the salt is an acid addition salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, maleate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, and camphosulfonate. Preferably, it is selected from HCl, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citrate, and fumarate salts.

[0099] Likewise, the compounds described herein may be obtained as either free compounds or as solvates (e.g., hydrates, alcoholates, etc.), and both forms are included within the scope of the present invention. Solvation methods are generally known in the art. Preferably, the solvate is a hydrate.

[0100] The term "organic solvent" refers, for example, cyclic and acyclic ethers (e.g., t2O, 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, t-butanol), sulfoxides (DMSO) and their Includes a mixture.

[0101] The term “aprotic organic solvent” means any organic solvent that does not generate protons under the above reaction conditions. Suitable examples include cyclic 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.

[0102] In the first aspect, the present invention relates to a method for preparing a compound of formula (I) or its salt or solvate from a compound of formula (II) or its salt or solvate (method of the present invention).

[0103] In one embodiment, the method of the present invention is a compound of formula (II), or a salt or solvate thereof, wherein is a double bond (compound of formula (II'')), from which is a compound of formula (I), or its salt or solvate, where This relates to the preparation of a double bond (a compound of formula (I''). Accordingly, in certain embodiments, represents a double bond in the compound of the method of the present invention (compounds (I''), (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII'')).

[0104] 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'))

[0105] In one embodiment, the method of the present invention is a compound of formula (II), or a salt or solvate thereof, wherein is a single bond. Preparation of a compound of formula (I), or its salt or solvate, from (a compound of formula (II') (where is a single bond. (It relates to a compound of chemical formula (I'). Accordingly, in certain embodiments, represents a single bond in the compound of the method of the present invention (compounds (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII')). Preferably, it is a cis single bond, more preferably a cis-3R single bond.

[0106] In another embodiment, the method of the present invention is derived from a compound of formula (II), or its salt or solvate, wherein is a double bond (compound of formula (II'), and preparation of a compound of formula (I), or its salt or solvate (where is a double bond. This relates to a method for preparing (a compound of chemical formula (I'). In this case, the method of the present invention further comprises a step of hydrogenating the double bond. Hydrogenation may occur at any step of the method, that is, before or after any step of the method of the present invention. For example, the hydrogenation step may be performed 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'').

[0107] In certain embodiments, the method of the present invention comprises the following:

[0108] - A compound of formula (II), or its salt or solvate (wherein hydrogenation of (where is a double bond) to form a compound of formula (II), or its salt or solvate (where is a single bond) a step of obtaining; and

[0109] - A compound of formula (II), or its salt or solvate (wherein (where is a single bond) is formed by the method of the present invention into a compound of formula (I), or its salt or solvate (wherein A step of converting to (which is a single bond), where is a single bond in all intermediate compounds.

[0110] In another embodiment, the method of the present invention comprises the following:

[0111] - A compound of formula (II), or its salt or solvate (wherein (where is a double bond) a compound of formula (III) or (IV), or its salt or solvate (where A step of converting to (which is a double bond);

[0112] - Compounds of formula (III) or (IV), or their salts or solvates (wherein hydrogenating the double bond (where is a double bond) to form a compound of formula (III) or (IV), or its salt or solvate (where The step of obtaining (is a single bond); and

[0113] - Compounds of formula (III) or (IV), or their salts or solvates (wherein (where is a single bond) by a method comprising the compound of formula (I) or its salt or solvate (wherein Step of converting to (which is a single bond):

[0114] (i) a compound of formula (III) or (IV), or its salt or solvate (wherein, (where is a single bond) is reacted with MeMgCl, MeMgBr, or MeLi to form a ketone of formula (V), or its salt or solvate (where, A step of enhancing (is a single combination);

[0115] (ii) a ketone of formula (V), or its salt or solvate (where, is a single bond) is an enol ether of formula (VI) or an enamin of formula (VII), or its salt or solvate (wherein, A step of converting to (which is a single combination); and

[0116] (iii) an enol ether of formula (VI) or an enamin of formula (VII), or its salt or solvate (wherein, is a single bond) with formula (I) or its salt or solvate (where, A step of converting to (which is a single bond);

[0117] or

[0118] (i') A compound of formula (III) or (IV), or its salt or solvate (wherein, (where is a single bond) is reacted with X-CH2-Li, X-CH2-MgCl, or X-CH2-MgBr to form a compound of formula (I), or its salt or solvate (wherein, A step of providing (which is a single combination);

[0119] or

[0120] (i'') A compound of formula (III) or (IV), or its salt or solvate (wherein, (is a single bond) R 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 React with O-CH2-MgBr to produce a compound of formula (VIII), or its salt or solvate (wherein, is a single combination) step providing; and

[0121] (ii'') A compound of formula (VIII) or its salt or solvate (where, is a single bond) a compound of formula (I) or its salt or solvate (where, A step of converting to (which is a single combination).

[0122] In another embodiment, the method of the present invention comprises the following:

[0123] - Chemicals of formula (II), or their salts or solvates (wherein, is a single bond) a compound of formula (III) or (IV), or its salt or solvate (where, A step of converting to (which is a double bond); and

[0124] - A compound of formula (III) or (IV), or its salt or solvate, by a method comprising the following (wherein, is a single bond) a compound of formula (I), or its salt or solvate (where, Step of converting to (which is a single bond):

[0125] (i) a compound of formula (III) or (IV), or its salt or solvate (wherein, (where is a double bond) is reacted with MeMgCl, MeMgBr, or MeLi to form a ketone of formula (V), or its salt or solvate (where, A step of providing (which is a double bond);

[0126] (ii) a compound of formula (V), or its salt or solvate, (wherein, hydrogenating the double bond) to form a compound of formula (V), or its salt or solvate (where, Step of obtaining (is a single bond);

[0127] (iii) a ketone of formula (V), or its salt or solvate, (where, is a single bond) enol ether of formula (VI) or enamin of formula (VII), or its salt or solvate, (where, A step of converting to (which is a single bond); and

[0128] (iv) an enol ether of formula (VI) or an enamin of formula (VII), or its salt or solvate, (wherein, is a single bond) a compound of formula (I) or its salt or solvate, (where, A step of converting to (which is a single combination).

[0129] In another embodiment, the method of the present invention comprises the following:

[0130] - A compound of formula (II), or its salt or solvate (where, is a double bond) a compound of formula (III) or (IV), or its salt or solvate, (where, A step of converting to (which is a double bond); and

[0131] - A compound of formula (III) or (IV), or its salt or solvate, by a method comprising the following (wherein, is a double bond) Chemical formula (I), a compound of, or its salt or solvate (where, Step of converting to (which is a single bond):

[0132] (i) a compound of formula (III) or (IV), or its salt or solvate, (wherein, (where is a double bond) reacts with MeMgCl, MeMgBr, or MeLi to form a ketone of formula (V), or its salt or solvate, (where, A step of providing (which is a double bond);

[0133] (ii) a ketone of formula (V), or its salt or solvate (where, is a double bond) to the enol ether of formula (VI) or the enamin of formula (VII), or its salt or solvate (wherein, A step of converting to (which is a double bond);

[0134] (iii) an enol ether of formula (VI) or an enamin of formula (VII), or its salt or solvate, (wherein, is a double bond) a compound of formula (I) or its salt or solvate, (where, A step of converting to (which is a double bond); and

[0135] (iv) a compound of formula (I), or its salt or solvate, (where, hydrogenating the double bond) to form a compound of formula (I), or its salt or solvate (where, Step of obtaining (is a single bond);

[0136] or

[0137] (i') A compound of formula (III) or (IV), or its salt or solvate, (where, (where is a double bond) reacts with X-CH2-Li, X-CH2-MgCl, or X-CH2-MgBr to form a compound of formula (I), or its salt or solvate, (where, A step of providing (which is a double bond); and

[0138] (ii') A compound of formula (I), or its salt or solvate, (where, hydrogenating the double bond to form a compound of formula (I), or its salt or solvate, (where, Step of obtaining (is a single bond);

[0139] or

[0140] (i'') A compound of formula (III) or (IV), or its salt or solvate, (where, R (which is a double bond) 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 React with O-CH2-MgBr to form a compound of formula (VIII), or its salt or solvate, (wherein, A step of providing (which is a double bond);

[0141] (ii'') A compound of formula (VIII), or its salt or solvate, (wherein, is a double bond) a compound of formula (I), or its salt or solvate, (where, A step of converting to (which is a double bond); and

[0142] (iii'') A compound of formula (I), or its salt or solvate, (where, hydrogenating the double bond) to form a compound of formula (I), or its salt or solvate, (where, Step to obtain (is a single bond).

[0143] In another embodiment, the method of the present invention comprises the following:

[0144] - A compound of formula (II), or its salt or solvate, (where, is a double bond) a compound of formula (III) or (IV), or its salt or solvate, (wherein, A step of converting to (which is a double bond); and

[0145] - A compound of formula (III) or (IV), or its salt or solvate, by a method comprising the following, (wherein, is a double bond) a compound of formula (I), or its salt or solvate, (where, Step of converting to (which is a single bond):

[0146] (i'') A compound of formula (III) or (IV), or its salt or solvate, (where, R (which is a double bond) 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 React with O-CH2-MgBr to form a compound of formula (VIII), or its salt or solvate, (wherein, A step of providing (which is a double bond);

[0147] (ii'') A compound of formula (VIII), or its salt or solvate, (where, hydrogenating the double bond) to form a compound of formula (VIII), or its salt or solvate, (where, is a single combination) a step of providing; and

[0148] (iii'') A compound of formula (VIII), or its salt or solvate, (where, is a single bond) a compound of formula (I), or its salt or solvate, (where, A step of converting to (which is a single combination).

[0149] The method of the present invention may include one or more of the following steps in any order, if necessary:

[0150] - Amino protecting group (R 1 Cutting of ), and / or

[0151] - Amino group (R 1 Protection of )

[0152] Any of these steps may be performed at any step of the method of the present invention. For example, protection of an amino group and / or an amino protecting group (R 1 The cutting of ) can be performed 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'').

[0153] The protection / cutting of the amino protecting group can be performed by any ordinary means known in the art (e.g., TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, 2007) and is disclosed herein.

[0154] For example, R 1 The amino protecting group of carbamate (R 1 In the case of =COOR), it can be easily deprotected by acid or basic hydrolysis according to well-established modern technical procedures. Suitable acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromide, 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 one embodiment, the reaction is carried out in the presence of water and an organic solvent, preferably an alcohol (e.g., methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, 2-butanol, 2-pentanol, 2-hexanol, 2-octanol, ethylene glycol). In one 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, more preferably between 40°C and 60°C. In one 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. R 1 The amino protecting group of amide (R 1In the case of =COR), it can preferably be deprotected by acid or basic hydrolysis under heat. Suitable acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromide, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, and 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 of 20°C to 120°C, preferably 50°C to 110°C, more preferably 60°C to 110°C, and can be carried out in the presence of an organic solvent, water, and mixtures thereof. R 1 The amino protecting group of is an alkyl, aryl, or arylalkyl amine (R 1 In the case where =R), it can be deprotected by treatment with acids, bases, oxidizing agents, or reducing agents, or by hydrolysis (in the case of aryl or arylalkyl amines), etc. R 1 The amino protecting group of silylamine (R 1 In the case where = Si(R)(R')(R'')), deprotection can be performed using fluoride salts or fluoride reagents such as HF, acidic media, oxidizing media, etc.

[0155] Preferably, Where is a single bond in any compound of the method of the present invention, said single bond has a cis arrangement, that is, the two hydrogen atoms on the carbon of said bond are located on the same side of the pyrrolidine ring. More preferably, In the case where a single bond is present in any of the compounds of the method of the present invention, said single bond has a cis-3R arrangement as shown below, that is, the two hydrogen atoms on the carbon of said bond are on the same side of the pyrrolidine ring and the carbon atom at position 3 of the pyrrolidine ring is the carbon atom to which the imidazopyrrolopyrazinyl ring is bonded in upadacitinib, thus having the arrangement required for the compound upadacitinib, i.e., the R arrangement. Therefore Where is a single bond in a compound of formula (I), (II), or (III), or (IV), or (V), or (VI), or (VII), or (VIII), preferably is 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 is 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:

[0156]

[0157] or his salt or solvate, where, X, Y, R 1 , R 3 , R 4 , R 5 and R 6 is as defined here.

[0158] In this specification, wedge-shaped joints and dotted-line joints ( ) is used to indicate the absolute alignment of the stereocenter (R or S), whereas and is used to indicate the relative arrangement of stereocenters (cis or trans).

[0159] Unless otherwise specified, the compounds disclosed herein include their stereoisomers, such as geometric isomers (cis / trans) and optical isomers (i.e., diastereomers, racemic mixtures, individual enantiomers, and mixtures of enantiomers in any proportion are included in the invention).

[0160] Preferably, When a single bond is represented in a compound of the method of the present invention, it comprises 80% or more of cis isomers, preferably 90% or more, more preferably 95%, and much more preferably 98% or more of cis isomers (for a cis+trans mixture). In a more preferred embodiment, it comprises only cis isomers as measured by NMR.

[0161] When the compound of the method of the present invention is an optically active compound, preferably the enantiomer excess rate is 80% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

[0162] In a preferred embodiment, the method of the present invention comprises the step of 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), as defined in the method of the present invention (all intermediates of the method are cis, more preferably cis-3R, corresponding compounds).

[0163] In certain embodiments, X is a leaving group. Preferred leaving groups are chloro, bromo, iodo, mesylate, triflate, tosylate, or nosylate; more preferably selected from Cl, Br, and I.

[0164] In one embodiment, Y is OH and OR 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 It is selected from aryls. In certain embodiments, Y is OH.

[0165] In one embodiment, R 1is an amino protecting group. As disclosed herein, suitable amino protecting groups include carbamates, amides, amines, sulfonamides, and silylamines. In a preferred embodiment, it is a carbamate. Accordingly, preferably R 1 is a group of the chemical formula -COOR, where R is a C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclil, 3- to 15-membered heteroaryl and tri(C1-C6alkyl)silane; selected from methyl carbamate (MOC), ethyl carbamate, t-butyl carbamate (Boc), benzyl carbamate (CBz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halobenzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate and trichloroethyl carbamate (Troc).

[0166] In one embodiment, R 3 It is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, COR' and SiR'3 Selected from, where each R' is C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )is independently selected from aryl(C1-C6)alkyl. In certain embodiments, R 3 is SiR'3, where each R' is C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 ) aryl(C1-C6)alkyl is selected from, for example, TMS, TES, TBS, and TBDPS.

[0167] R 4 and R 5When they form a 5- to 7-membered heterocyclic ring with the attached nitrogen atom, this is preferably a 5- to 7-membered heterocyclic ring containing one nitrogen atom or two nitrogen atoms, or one nitrogen and one oxygen atom, examples of which are pyrrolidine, piperidine, morpholine, piperazine, and azepan.

[0168] In certain embodiments, R 4 and R 5 They are independently selected from C1-C6 alkyls, or they form a 5- to 7-membered heterocyclic ring with a nitrogen atom. More preferably, they form a 5- to 7-membered heterocyclic ring 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 azephan.

[0169] R 6 is selected from H, -COR' and -CONR'R'', where R' and R'' are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )is independently selected from aryl(C1-C6)alkyl. In certain embodiments, R 6 is a group of the chemical formula -COR' and R' is preferably a C1-C6 alkyl. In a preferred embodiment, R 6 is the group of the chemical formula -COtBu(Piv).

[0170] Conversion of a compound of formula (II) into a compound of formula (III) or (IV)

[0171] The compound of formula (II) may be obtained by methods known to those skilled in the art or disclosed in the art. For example, by methods disclosed in WO 2011 / 068881, WO 2013 / 043826, WO 2017 / 066775 or WO 2019 / 016745. In one embodiment, the compound of formula (II), or its salt or solvate, may be obtained by a method comprising the following:

[0172] - Compound of formula (IX) or its salt or solvate and

[0173]

[0174] (IX)

[0175] food

[0176] Z is a halogen, C1-C6 alkylsulfonate, C1-C6 haloalkylsulfonate, C6-C 10 Arylsulfonate and (C1-C6)alkyl (C6-C 10 Selected from arylsulfonates;

[0177] R 1 is selected from H and amino protecting groups; and

[0178] Y is OH, Cl, OR 2 and OC(O)R 2 Selected from , and here R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril;

[0179] Reacts with Et2CuLi, Et2CuMgBr, or Et2CuMgCl to provide a compound of formula (II'') or its salt or solvate.

[0180]

[0181] (II'')

[0182] and

[0183] - If necessary (i.e., if a compound of formula (II') is needed), provide a compound of formula (II'), or its salt or solvate through hydrogenation of the double bond.

[0184] 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 or acyclic ether, more preferably a tetrahydrofuran.

[0185] Typically, the reaction can be carried out at a temperature of -50°C to 30°C, preferably -30°C to 20°C, more preferably -10°C to 10°C.

[0186] In one embodiment, Et2CuLi, Et2CuMgBr, or Et2CuMgCl are present in an amount of 1.0 to 5.0 molar equivalents, preferably 1.1 to 3.0 molar equivalents, with respect to the compound of formula (IX).

[0187] This method of preparing a compound of formula (II) may further include a step of converting Y of the compound of formula (II'') or (II') to another Y group before performing the process to prepare a compound of formula (I).

[0188] For example, Y OR 2 If a compound of the chemical formula (IX), or its salt or solvate, is used in the above method, an additional step may be included after reaction with the cuprate reagent or after hydrogenation of the double bond (if performed), for example OR 2The group is converted to an OH group. The conversion can be carried out under acid or base hydrolysis according to well-established procedures of the latest technology. Suitable acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromide, 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 one embodiment, the reaction is carried out at a temperature of 10°C to 120°C, preferably 30°C to 70°C, more preferably 40°C to 60°C.

[0189] In one embodiment, a compound of formula (II), or its salt or solvate, is obtained by a method comprising the following:

[0190] - Compound of formula (IX), or its salt or solvate and

[0191]

[0192] food

[0193] Z is a halogen, C1-C6 alkylsulfonate, C1-C6 haloalkylsulfonate, C6-C 10 Arylsulfonate and (C1-C6)alkyl (C6-C 10 Selected from arylsulfonates;

[0194] R 1 is selected from H and amino protecting groups; and

[0195] Y is OR 2 and, here R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15Selected from Aril;

[0196] Reaction with Et2CuLi, Et2CuMgBr, or Et2CuMgCl, providing the chemical formula (II'') or its salt or solvate.

[0197]

[0198] - Compound of chemical formula (II''), where Y is OR 2 , or by hydrolyzing its salt or solvate, a compound of formula (II''), wherein Y provides OH;

[0199] and

[0200] - If necessary (i.e., if a compound of formula (II') is needed), provide a compound of formula (II'), or its salt or solvate through hydrogenation of the double bond, where Y is OH.

[0201] Preparing the compound of formula (II) from the compound of formula (IX) is preferable to using the Suzuki reaction previously disclosed in the prior art. It is a cheaper alternative because it avoids the use of boron reagents (which are more expensive and cannot be stored for a long time) and palladium catalysts.

[0202] In a preferred embodiment, R in the compound of formula (II) 1 is an amino protecting group and Y is OH.

[0203] In an embodiment according to the method of the present invention, the compound of formula (II), or its salt or solvate is converted into the compound of formula (III), or its salt or solvate.

[0204] Means suitable for such conversion are well known in the art. In certain embodiments, such conversion may be carried out by reacting a compound of formula (II) or its salt or solvate with N,O-dimethylhydroxylamine or its salt, preferably N,O-dimethylhydroxylamine hydrochloride, optionally in the presence of an activator and / or base, and with an organic solvent.

[0205] Suitable activators or coupling agents are known to those skilled in the art and, in particular, include the following: N,N-carbonyldiimidazole (CDI), 1-propanephosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), N,N'-dicyclohexylcarbodiimide (DCC), benzotriazole-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-benzotriazole-1-yl-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), and bromo-tripyrrolidino-phosphonium hexa-fluorophosphate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylamium tetrafluoroborate (TBTU), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), Me2AlCl, Me3Al, iPrMgCl; preferably CDI.

[0206] Suitable bases include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine (DIPEA), pyridine (pyr), 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-rutidine, and mixtures thereof.

[0207] Preferably, the organic solvent is selected from aprotic organic solvents such as dichloromethane, tetrahydrofuran and mixtures thereof, preferably dichloromethane.

[0208] Typically, the reaction can be carried out at a temperature of -10°C to 70°C, preferably 0°C to 50°C, more preferably 10°C to 30°C.

[0209] In one 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, with respect to the compound of formula (II). In a specific embodiment, an 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, with respect to the compound of formula (II). In one embodiment, a base is present in an amount of 1.0 to 3.0 molar equivalents, preferably 1.1 to 2.0 molar equivalents, with respect to the compound of formula (II).

[0210] In certain embodiments, in the compound of formula (II), Y is Cl or OC(O)R 2 In the case of representing, the reaction with N,O-dimethylhydroxylamine or its salt is carried out in the presence of a base and optionally an organic solvent.

[0211] In another embodiment, where Y represents OH in the compound of formula (II), the reaction with N,O-dimethylhydroxylamine or its salt is carried out in the presence of an activator and optionally an organic solvent.

[0212] In another embodiment, in the compound of formula (II), Y is OR 2 In the case of representing N,O-dimethylhydroxylamine or its salt, the reaction is carried out in the presence of Me2AlCl, Me3Al or iPrMgCl, and optionally an organic solvent.

[0213] In another embodiment according to the method of the present invention, the compound of formula (II), or its salt or solvate is converted into the compound of formula (IV), or its salt or solvate.

[0214] Means suitable for such conversion are well known in the art. In certain embodiments, such conversion can be carried out by reacting a compound of formula (II) or its salt or solvate with 6-chloro-2,4-dimethoxy-1,3,5-triazine (CDMT) in the presence of optionally a base and an organic solvent.

[0215] Suitable bases include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine (DIPEA), pyridine (pyr), 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-rutidine, and mixtures thereof; preferably, NMM.

[0216] Preferably, the organic solvent is selected from protic organic solvents.

[0217] Generally, the reaction can be carried out at a temperature between -10℃ and 70℃.

[0218] Conversion of a compound of formula (III) or (IV) into a compound of formula (V)

[0219] In a preferred embodiment, R 1 is an amino protecting group in compounds of chemical formula (III) or (IV).

[0220] This transformation can optionally be carried out by reacting a compound of formula (III) or (IV), or its salt or solvate, with MeMgCl, MeMgBr, or MeLi in the presence of an organic solvent.

[0221] The organic solvent may be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably tetrahydrofuran.

[0222] Typically, the reaction can be carried out at a temperature between -50°C and 30°C, preferably between -30°C and 20°C, and more preferably between -10°C and 10°C.

[0223] In one 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, for the compound of formula (III) or (IV).

[0224] When a compound of formula (III) or (IV) exhibits a cis single bond, it reacts with MeMgCl, MeMgBr, or MeLi to produce a compound of formula (V), after which isomerization into a trans isomer is not observed.

[0225] Conversion of a compound of formula (V) into a compound of formula (VI)

[0226] In a preferred embodiment, R 1 is an amino protecting group in the compound of chemical formula (V).

[0227] In an embodiment according to the method of the present invention, a compound of formula (V), or its salt or solvate is converted into a compound of formula (VI), or its salt or solvate.

[0228] The inventors observed that the desired enol ether is obtained in a regioselective manner. Therefore, subsequent treatment of this compound allows an X group to be introduced at the terminal position without isomerization of the pyrrolidine carbon atom to which the carbonyl group is attached.

[0229] This reaction can be carried out by a well-known enol ether synthesis method. In one embodiment, R 3 The compound of formula (VI) of SiR'3 can be obtained by the reaction of the compound of formula (V), or its salt or solvate, with the compound of formula R'3SiZ, where each R' is C 1-6 Alkyl, C 6-10 Aryl and C 1-6 It is independently selected from alkoxy, and Z is a halogen or trilate in the presence of a base.

[0230] Suitable bases include tertiary amines such as Me3N, Et3N, DIPEA, Pyr, DMAP, NMM, 2,6-rutidine, and mixtures thereof. The reaction may be carried out in the presence of an organic solvent, preferably an aprotic organic solvent, and at a temperature of -30°C to 70°C, preferably -30°C to 20°C, more preferably -10°C to 10°C.

[0231] In another embodiment, R 3 This C 1-6 An alkyl compound of formula (VI) can be obtained by the reaction of a compound of formula (V), or its salt or solvate, with a trialkyl orthoformate in the presence of an acid. Suitable acids include acetic acid, trifluoroacetic acid, chloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, hydrochloric acid, hydrobromide, hydrofluoric acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid, ZnCl2, AlCl3, and BF3. The reaction may be carried out in the presence of an organic solvent and at a temperature of -20°C to 120°C, preferably 10°C to 90°C. In one embodiment, the reaction is carried out in the presence of methyl or ethyl orthoformate, an acid, and an organic solvent.

[0232] In another embodiment, R 3 The compound of formula (VI), which is Ac, can be obtained by reacting the compound of formula (V), or its salt or solvate, with isopropen acetate, 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 of 20°C to 120°C, preferably 40°C to 120°C.

[0233] In a preferred embodiment, R 1 is an amino protecting group and R 3 is SiR'3, where each R' is independently C in the compound of formula (VI). 1- 6-alkyl, C 6- 10 Aryl and C 1- It is selected from 6-alkoxy. In a more preferred embodiment, R 3 is SiR'3, where each R' is C such as TMS, TES, TBDMS, TIPS 1-6 It is independently selected from alkyls.

[0234] Conversion of the compound of formula (V) into the compound of formula (VII)

[0235] In a preferred embodiment, R 1 is an amino protecting group in the compound of chemical formula (V).

[0236] In an embodiment according to the method of the present invention, the compound of formula (V), or its salt or solvate is converted into the compound of formula (VII), or its salt or solvate.

[0237] This reaction can be carried out by a well-known method for preparing enamin from a corresponding ketone. In one embodiment, this conversion is optionally performed by converting a compound of formula (V), or its salt or solvate, of formula HN(R) in the presence of an acid and an organic solvent. 4 )R 5 This can be achieved by reacting with an amine.

[0238] Suitable acids include, for example, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, and hydrochloric acid. It may be possible to use the acid as a catalyst. In one embodiment, the reaction is carried out with 0.01 to 0.5 molar acid per mole of ketone of formula (V).

[0239] In one embodiment, amine HN(R 4 )R 5is used in an amount of 1.0 to 5.0 molar equivalents, preferably 1.1 to 3.0 molar equivalents, for the compound of formula (V).

[0240] This conversion can typically be performed at a temperature of 20°C to 180°C, preferably 50°C to 150°C, more preferably 60°C to 130°C.

[0241] In a preferred embodiment, R 1 is an amino protecting group, and R 4 and R 5 is independently selected from C1-C6 alkyls, or they form a 5- to 7-membered heterocyclic ring with a nitrogen atom in a compound of formula (VII). Preferably, the 5- to 7-membered heterocyclic ring is a 5- to 7-membered heterocyclic ring containing one nitrogen atom, two nitrogen atoms, or one nitrogen and one oxygen atom, e.g., pyrrolidine, piperidine, morpholine, piperazine, and azepan.

[0242] Conversion of a compound of formula (VI) or (VII) into a compound of formula (I)

[0243] In an embodiment according to the method of the present invention, a compound of formula (VI) or (VII), or its salt or solvate, is converted into a compound of formula (I), or its salt or solvate. Means suitable for such conversion are well known in the art.

[0244] In certain embodiments, this conversion may be carried out by reacting a compound of formula (VI) or (VII), or its salt or solvate, with a halogenating agent in the presence of an optional organic solvent. According to this method, a compound of formula (I), or its salt or solvate, in which X is a halogen, is obtained.

[0245] Suitable halogenating agents include, in particular, thionyl chloride, oxalyl chloride, NCS, Br2, CBr4, NBS, I2, CI4, and NIS.

[0246] The organic solvent may be an aprotic organic solvent, preferably dichloromethane or cyclic or acyclic ether, more preferably tetrahydrofuran or dichloromethane.

[0247] Typically, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -50°C and 30°C, and more preferably between -20°C and 20°C.

[0248] In one 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, for the compound of formula (VI) or (VII).

[0249] In another embodiment, the conversion of a compound of formula (VI) or (VII), or its salt or solvate, to a compound of formula (I) or its salt or solvate involves epoxidizing the double bond of the enol ether of formula (VI) or the enamine of formula (VII), and then opening the ring to R 6 This is provided by providing a compound of the chemical formula (VIII) of which H is provided, or its salt or solvate, and

[0250]

[0251] Here, is a single bond and R 1 It is selected from H and amino protecting groups.

[0252] In one embodiment, the epoxidation reaction is carried out in the presence of a peroxycarboxylic acid, hydrogen peroxide, or oxone, preferably a peroxycarboxylic acid, e.g., mCPBA, benzoic acid, monoperphthalic acid, or magnesium monoperoxyphthalate (MMPP). The reaction may be carried out in the presence of an organic solvent and at a temperature of -40°C to 120°C, preferably -20°C to 40°C. In one embodiment, the reaction is carried out in the presence of mCPBA and an aprotic polar solvent, e.g., dichloromethane.

[0253] Ring opening of the generated epoxide can be carried out by treatment with water, an acid, or a fluoride source. Suitable acids include, for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromide, 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 at a temperature of -40°C to 120°C, preferably -20°C to 40°C.

[0254] R 6 A compound of formula (VIII) in which H is present, or its salt or solvate, can be converted into a compound of formula (I), or its salt or solvate, by methods well known in the art. In one embodiment, the conversion of the primary hydroxyl group to a leaving group is carried out by treatment with a halogenating agent, e.g., I2, NaI, Br2, CBr4, PBr3, Cl2, thionyl chloride, oxalyl chloride; or sulfonyl chloride, e.g., TsCl or MsCl. This 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.

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

[0256] In a preferred embodiment, the conversion of the compound of formula (V) or its salt or solvate to the compound of formula (I) or its salt or solvate is carried out as a one-pot process, that is, without isolating the intermediate compound of formula (VI) or (VII), or its salt or solvate.

[0257] Conversion of a compound of formula (III) or (IV) into a compound of formula (I)

[0258] In a preferred embodiment, R 1 is an amino protecting group in compounds of chemical formula (III) or (IV).

[0259] This transformation can be carried out by reacting a compound of formula (III) or (IV), or its salt or solvate, with a compound of formula X-CH2-Li, X-CH2-MgCl, or X-CH2-MgBr (where X is a leaving group) in the presence of an organic solvent.

[0260] The organic solvent may be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably tetrahydrofuran.

[0261] Typically, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -80°C and 0°C, and more preferably between -80°C and -20°C.

[0262] Typically, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -80°C and 0°C, and more preferably between -80°C and -20°C.

[0263] In one 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 for the compound of formula (III) or (IV), preferably 1.1 to 5.0 molar equivalents.

[0264] In a preferred embodiment, R 1 is an amino protecting group in the compound of chemical formula (I).

[0265] Conversion of a compound of formula (III) or (IV) into a compound of formula (VIII)

[0266] In a preferred embodiment, R 1 is an amino protecting group in compounds of chemical formula (III) or (IV).

[0267] This transformation is performed on a compound of formula (III) or (IV), or its salt or solvate, in the presence of any organic solvent of formula R 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 This can be carried out by reacting with an O-CH2-MgBr compound, where R 6 is selected from -COR' and -CONR'R'', where R' and R'' are optionally C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 ) It is independently selected from aryl(C1-C6)alkyl.

[0268] In certain embodiments, R 6 is a group of the chemical formula -COR, where R is a C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 It is selected from aryl(C1-C6)alkyl. Preferably, R 6 is the group of the chemical formula -COtBu(Piv).

[0269] The organic solvent may be an aprotic organic solvent, preferably a cyclic or acyclic ether, more preferably a tetrahydrofuran.

[0270] Typically, the reaction can be carried out at a temperature between -80°C and 30°C, preferably between -80°C and 0°C, and more preferably between -80°C and -20°C.

[0271] In one embodiment, 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 for the compound of formula (III) or (IV), preferably 1.1 to 5.0 molar equivalents.

[0272] In a preferred embodiment, R in the compound of formula (VIII) obtained after this reaction 1 is an amino protecting group and R6 The is selected from -COR' and -CONR'R'', preferably -COR', where R' and R'' are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )Selected from aryl(C1-C6)alkyl.

[0273] In an embodiment of the present invention, R 6 If a compound of formula VIII selected from -COR' and -CONR'R'', or its salt or solvate is obtained, it is converted into a compound of formula (VIII), or its salt or solvate, where R 6 is hydrogen before being converted into a compound of chemical formula (I), or its salt or solvate.

[0274] R 6 R of the compound of formula (VIII) which is -COR' or -CONR'R'', or its salt or solvate 6This conversion to a compound of formula (VIII), or its salt or solvate, which is hydrogen, can be carried out under acidic or basic hydrolysis reaction conditions. Suitable acids include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromide, 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, e.g., NaOH, KOH, NaOtBu, NaOMe, NaSMe. In one embodiment, the hydrolysis reaction is carried out in the presence of water and an organic solvent, preferably an alcohol (e.g., methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, 2-butanol, -pentanol, 2-hexanol, 2-octanol, ethylene glycol). In one embodiment, the reaction is carried out at a temperature of 10°C to 120°C, preferably 30°C to 70°C, more preferably 40°C to 60°C.

[0275] Conversion of the compound of formula (VIII) into the compound of formula (I)

[0276] In a preferred embodiment, R in the compound of formula (VIII) 1 is an amino protecting group and R 6 is H.

[0277] R 6The compound of formula (VIII), or its salt or solvate, which is H, can be converted into the compound of formula (I), or its salt or solvate, by methods widely known in the art. In one embodiment, the conversion of the primary hydroxyl group to the leaving group is performed using a halogenating agent, such as I2, NaI, Br2, CBr4, PBr3, Cl2, thionyl chloride, oxalyl chloride; or sulfonyl chloride such as TsCl or MsCl. This 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.

[0278] In a preferred embodiment, R 1 is an amino protecting group in the compound of chemical formula (I).

[0279] hydrogenation

[0280] The method of the present invention may include the step of hydrogenating the double bond of a pyrrolidine ring into a single bond.

[0281] In one embodiment, the method of the present invention From a compound of formula (II) in which is a double bond, or from a salt or solvate A method for preparing a compound of formula (I) in which is a single bond, or a salt or solvate thereof. In this case, the method of the present invention further comprises a step of hydrogenating the double bond.

[0282] Hydrogenation occurs at any step of the process, for example, after step (a), or after step (bi), or after step (bii), or after step (biii), or after step (bi'), or after step (bi'') or after step (bii'').

[0283] This reaction can be carried out by a well-known method of hydrogenating a double bond. In one embodiment, this reaction is The method of the present invention, in which the compound having a double bond is reacted with H2 in the presence of a transition metal catalyst and optionally an organic solvent.

[0284] Suitable transition metal catalysts or compounds are, for example, Pd, Pt, Ni, Rh, Ru, Ir, Mo, Cr, Co, Cu and Fe, for example, Pd / C, Pt / C, Pt / C, 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, It includes supported and unsupported catalysts of transition metals selected from bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)iridium tetrafluoroborate, bis(1,5-cyclooctadiene)diiridium dichloride, FeCl2, FeBr2, Fe(CH3CO2)2, [Fe(OH2)6](BF4)2, CuCl, and [CuH(Ph3)]6.

[0285] In certain embodiments, 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. Thus, in certain embodiments, this reaction is carried out in the presence of a transition metal compound, an optically active chiral ligand, and optionally an organic solvent This is carried out by reacting a compound of the method of the present invention, in which the bond is a double bond, with H2. When asymmetric hydrogenation is performed, an optically active compound, preferably a compound of the 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), is obtained.

[0286] Suitable transition metal compounds or catalysts are as defined above, and are preferably selected from Ru, Pd, Pt, Rh, and Ir compounds.

[0287] Optically active chiral ligands can be monodentate, bidentate, tridentate, or tetradentate. These include cyclic or acyclic heteroatoms containing metal-bonding functional groups such as phosphine, phosphite, phosphinate, phosphoramidite, sulfonamide-phosphoramidite, phosphine oxide, N-heterocyclic carbene, diamine, imidazole, amino alcohol, diol, oxazoline, imine, and amino acid.

[0288] Preferably, the optically active ligand is a P,P-, or P,N, or P,O, or P,S-bidentary ligand, preferably a P,P-bidentary ligand, more preferably a diphosphine ligand.

[0289] Suitable but not limited to optically active chiral ligands include (S)-BINAP, (S)-TolBINAP, (S)-XylBINAP, (S)-Cy-BINAP, (S)-H8-BINAP, (S)-MeOBIPHEP, di-tBu-MeOBIPHEP, (S)-SEGPHOS, (S)-DM-SEGPHOS, (S)-DTBM-SEGPHOS, (S)-QUINAP, (S,S)-BDPP, (S)-BIPHEMP, (S)-Me-BPE, (S,S)-DIOP, (S,S)-DIOP-OH, (S,S)-DIPAMP, (S)-SYNPHOS, (S,S)-CHIRAPHOS, (S,S)-Me-DuPHOS, (R)-(S)-BPPFA, (R)-(S)-BPPFOH, (2S,4S)-BPPM, (R)-(S)-JOSIPHOS, (R)-(S)-XYLIPHOS, (R)-PROPHOS, (R)-MeO-MOP, and their enantiomers.

[0290] In one embodiment, 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 one embodiment, the reaction is carried out in the presence of Ru(OAc)2 and (S)-SEGPHOS, for example, as disclosed in WO 2017 / 066775.

[0291] Transition metal catalysts It may be present in an amount of 0.01 to 50 weight%, preferably 1 to 10 weight%, relative to the amount of the compound having a double bond. When an optically active transition metal catalyst is used, the optically active ligand It can be used in an amount of 0.01 to 50 weight%, preferably 1 to 10 weight%, relative to the amount of the compound having a double bond.

[0292] The reaction is carried out in the presence of organic solvents such as 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, t-butanol), sulfoxides (DMSO), acids (AcOH), and mixtures thereof It can be performed.

[0293] This reaction is carried out in the presence of H2, preferably at a pressure of 1 to 100 atm, preferably 2 to 50 atm. In one embodiment, the reaction is carried out at a temperature of -80°C to 100°C, preferably -20°C to 90°C, more preferably 0°C to 50°C. The hydrogen source comprises H2, formic acid or its salt, and cyclohexene.

[0294] Preferably, the term optical activity as used herein refers to a compound having an enantiomer excess rate of 50% or more. More preferably, this means an enantiomer excess of 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

[0295] Preferably, the cis isomer is selectively obtained after the hydrogenation reaction. With respect to the hydrogenated compound, the term "selectively" means that the ratio of the cis isomer to the trans isomer is 80:20 or higher, preferably 90:10 or higher, more preferably 95:5 or higher, and even more preferably at least 98:2.

[0296] When asymmetric hydrogenation is performed, the desired isomer (e.g., cis-3R isomer) is obtained with an excess of at least 90%, at least 95%, preferably at least 98%, or at least 99% of the enantiomer.

[0297] manufacturing of upadacitinib

[0298] The method of the present invention may further include the conversion of a compound of formula (I), or its salt or solvate, into upadacitinib.

[0299] Accordingly, in another aspect, the present invention relates to a method for preparing upadacitinib, or a salt, solvate, or stereoisomer thereof, comprising the following, and

[0300] - A step of preparing a compound of formula (I) or its salt or solvate by the method defined herein; and

[0301]

[0302] food

[0303] is a single bond or a double bond;

[0304] X is the leaving group, and

[0305] R 1 is selected from H, and amino protecting groups;

[0306] - A step of converting the compound of formula (I), or its salt or solvate, into upadacitinib, or its salt or solvate.

[0307] 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 methods known in the art. For example, as disclosed in WO 2013 / 043826 or WO 2017 / 066775.

[0308] In certain embodiments, 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:

[0309] (i) react the compound of formula (I), or its salt or solvate, with the compound of formula (IX).

[0310]

[0311] food

[0312] R 7 C1-C6 alkyl, C1-C6 alkoxyl, C6-C 15 Aryl and (C6-C 15 )Selected from aryl(C1-C6)alkyl, preferably methyl or ethyl; and

[0313] R 8 is an amino protecting group, preferably Ts;

[0314] A step of providing a compound of formula (X) or its salt or solvate;

[0315]

[0316] food

[0317] is a single bond; and

[0318] R 1 is selected from H, and an amino protecting group; preferably, it is an amino protecting group, and

[0319] (ii) reacting a compound of formula (X) or its salt or solvate with a perfluoroacid anhydride and a base to form a compound of formula XI or its salt or solvate;

[0320]

[0321] (iii) R 1 In the case where this is an amino protecting group, R in the compound of formula (XI) or its salt or solvate 1A step of deprotecting the group to provide a compound of formula (XII) or its salt or solvate.

[0322]

[0323] food

[0324] is a single bond; and

[0325] R 8 is selected from H, and amino protecting groups;

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

[0327]

[0328] (VIII)

[0329] Food R 8 is selected from H, and amino protecting groups;

[0330] (v) If necessary, i.e., R 8 In the case where this is an amino protecting group, deprotects the compound of formula (XIII) or its salt or solvate by R 8 A step of providing a compound of chemical formula (XIII) which is H, or its salt or solvate.

[0331] If necessary, that is If the compound of formula (I) represents a double bond, the method further includes a hydrogenation step at any step of upadacitinib synthesis. For example, after step (i), or after step (ii), or after step (iii), or after step (iv), or after step (v).

[0332] In one embodiment, the method comprises the following:

[0333] (i) reacting a compound of formula (I), or its salt or solvate, with a compound of formula (IX) as defined above to provide a compound of formula (X) or its salt or solvate as defined above,

[0334] (ii) reacting a compound of formula (X) as defined above, or its salt or solvate, with a perfluoroacid anhydride and a base to form a compound of formula (XI) or its salt or solvate.

[0335]

[0336] (XI)

[0337] (iii) a step of deprotecting the compound of formula (XI) or its salt or solvate to provide the compound of formula (XII') or its salt or solvate.

[0338]

[0339] (XII')

[0340] (iv) a step of converting the compound of formula (XII), or its salt or solvate, into the compound of formula (XIII'), or its salt or solvate.

[0341]

[0342] (XIII')

[0343] If necessary, that is If the compound of formula (I) represents a double bond, the method further includes a hydrogenation step at any step of upadacitinib synthesis. For example, after step (i), or after step (ii), or after step (iii), or after step (iv).

[0344] In a preferred embodiment, the compound of formula (I) is compound (I-cis-3R) and thus a method for preparing upadacitinib or its salt or solvate comprises the following:

[0345] (i) R 1 A step of reacting a compound of formula (I-cis-3R), which is this amino protecting group, or its salt or solvate, with a compound of formula (IX) to provide a compound of formula (X-cis-3R) or its salt or solvate.

[0346]

[0347] (X-Sys-3R)

[0348] food

[0349] R 1 is selected from H and amino protecting groups;

[0350] R 7 C1-C6 alkyl, C1-C6 alkoxyl, C6-C 15 Aryl and (C6-C 15 )Selected from aryl(C1-C6)alkyl, preferably methyl or ethyl; and

[0351] R 8 is an amino protecting group, preferably Ts;

[0352] (ii) a step of reacting a compound of formula (X-cis-3R), or its salt or solvate, with a perfluoroacid anhydride and a base to form a compound of formula (XI-cis-3R), or its salt or solvate.

[0353]

[0354] (XI-Sys-3R)

[0355] (iii) R 1 In the case where this is an amino protecting group, R in a compound of the chemical formula (XI-cis-3R) or its salt or solvate 1 A step of deprotecting a group to provide a compound of the chemical formula (XII-cis-3R), a salt, or a solvate thereof.

[0356]

[0357] (XII-Sis-3R)

[0358] food

[0359] R 8 is selected from H, and amino protecting groups;

[0360] (iv) a step of converting a compound of formula (XII-cis-3R), or its salt or solvate, into a compound of formula (XIII-cis-3R), or its salt or solvate.

[0361]

[0362] (XIII-Sis-3R)

[0363] Food R 8 is selected from H, and amino protecting groups;

[0364] (v) If necessary, i.e., R 8 In the case where this is an amino protecting group, a step of deprotecting a compound of the chemical formula (XIII-cis-3R) or its salt or solvate to provide upadacitinib or its salt or solvate.

[0365] In certain embodiments, this method includes the following:

[0366] (i) R 1 A step of reacting a compound of the formula (I-cis-3R), which is this amino protecting group, or its salt or solvate, with a compound of the formula (IX) to provide a compound of the formula (X-cis-3R) or its salt or solvate as defined above.

[0367] (ii) a step of reacting a compound of the formula (X-cis-3R) as defined above, or its salt or solvate, with a perfluoroacid anhydride and a base to form a compound of the formula (XI-cis-3R) or its salt or solvate,

[0368]

[0369] (XI-Sys-3R)

[0370] (iii) a step of deprotecting a compound of formula (XI-cis-3R) or its salt or solvate to provide a compound of formula (XII'-cis-3R) or its salt or solvate.

[0371]

[0372] (XII'-Sis-3R)

[0373] (iv) A step of converting a compound of the chemical formula (XII'-cis-3R), or its salt or solvate, into upadacitinib or its salt or solvate.

[0374] In a preferred embodiment, the compound of formula (I) is a compound (I-cis-3R), e.g., compound 10, and

[0375]

[0376] 10

[0377] A method for preparing upadacitinib or its salt or solvate includes the following:

[0378] (i) react a compound of formula (I-cis-3R), e.g., compound 10, or its salt or solvate with a compound of formula (IX), e.g., compound 20

[0379]

[0380] 20

[0381] A step of providing a compound of the chemical formula (X-cis-3R) or its salt or solvate, e.g., compound 21

[0382]

[0383] 21

[0384] (ii) a step of reacting a compound of the formula (X-cis-3R), e.g., compound 21, or its salt or solvate, with a perfluoroacid anhydride and a base to form a compound of the formula (XI-cis-3R), e.g., compound 22, or its salt or solvate:

[0385]

[0386] 22

[0387] (iii) a step of deprotecting a compound of formula (XI-cis-3R), e.g., compound 22, or its salt or solvate, to provide a compound of formula (XII-cis-3R), e.g., compound 23, or its salt or solvate.

[0388]

[0389] 23

[0390] (iv) a step of converting a compound of formula (XII), e.g., compound 23, or its salt or solvate, into upadacitinib or its salt or solvate.

[0391] Conditions suitable for transformation (i)-(v) are disclosed in the prior art (e.g., WO 2017 / 066775) or are known to those skilled in the art.

[0392] In one embodiment, step (i) may be performed 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.

[0393] Step (ii) may be performed in the presence of perfluoroacid anhydride, optionally in the presence of a perfluorocarboxylic acid, and optionally in the presence of an organic solvent. Suitable perfluorocarboxylic acids include, for example, trifluoroacetic acid, pentafluoropropionic acid, and heptafluorobutyric acid.

[0394] Suitable perfluoroacid anhydrides include, for example, trifluoroacetic anhydride, pentafluoropropionic anhydride, and heptafluorobutyric anhydride.

[0395] Steps (iii) and (v) may be performed by any ordinary means known in the art for cleaving amino protecting groups (e.g., TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, 2007) and as disclosed herein.

[0396] Step (iv) can be carried out by reaction with 2,2,2-trifluoroethylamine in the presence of CDI and optionally an organic solvent.

[0397] Intermediate compounds

[0398] Compounds of formulas (III), (IV), (V), (VI), and (VII), and their salts or solvates are useful intermediates for the preparation of the compound of formula (I) and thus for the synthesis of upadacitinib and structurally related compounds.

[0399] In another aspect, the present invention relates to a compound of the following chemical formula or its salt or solvate:

[0400]

[0401] During food, R 1 is selected from H and amino protecting groups;

[0402] R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Aryl, COR' and SiR'3 Selected from, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl;

[0403] R 4 and R 5 is a C1-C6 alkyl, (C6-C 15)aryl(C1-C6)alkyl and C6-C 15 They are independently selected from aryls or they form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and

[0404] R' is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril.

[0405] R', R 1 , R 3 , R 4 and R 5 Suitable and preferred embodiments for the method of the present invention are as defined herein.

[0406] In one embodiment, R 1 is selected from the following:

[0407] - COOR a , during food R a is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 Selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl, and tri(C1-C6alkyl)silane;

[0408] - COR b , during food R b is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 Selected from )aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl and 3- to 15-membered heteroaryl;

[0409] - R c , during food R c is a C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 Selected from aryl(C1-C6)alkyl;

[0410] - SO2R d , during food R d is a C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl, (C6-C 15 )Selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; and

[0411] - Si(R e )(R f )(R g ), during food R e , R f and R g is a C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl and (C6-C 15 ) It is independently selected from aryl(C1-C6)alkyl.

[0412] Preferably, R' is selected from C1-C6 alkyl; more preferably, from tBu.

[0413] Preferably, R 1 is a group of the chemical formula COOR, where R is a C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or 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; methyl carbamate (MOC), ethyl carbamate, t-butyl carbamate (Boc), benzyl carbamate (Cbz), p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, halobenzyl carbamate, phenylethyl carbamate, allyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), chloroethyl carbamate and trichloroethyl carbamate (Troc). In one embodiment, it is selected from Cbz and Boc.

[0414] Preferably, R 3 It is a C1-C6 alkyl, (C6-C 15)Selected from aryl(C1-C6)alkyl, COR' and SiR'3, where each R' is independently C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl. More preferably, R 3 is a SiR'3 group, where each R' is independently C 1-6 Alkyl, C 6-15 Aryl and (C6-C 15 )aryl(C1-C6)alkyl, such as TMS, TES, TBS, and TBDPS.

[0415] In certain embodiments, R 4 and R 5 The molecules are independently selected from C1-C6 alkyls, or they form a 5- to 7-membered heterocyclic ring with a nitrogen atom. More preferably, they form a 5- to 7-membered heterocyclic ring with an attached nitrogen atom, preferably a 5- to 7-membered heterocyclic ring containing one nitrogen atom, two nitrogen atoms, or one nitrogen and one oxygen atom, such as pyrrolidine, piperidine, morpholine, piperazine, and azephan.

[0416] In a particular embodiment, the present invention relates to a compound of the following formula or a salt or solvate thereof.

[0417]

[0418] It should be understood that the scope of this disclosure includes all possible combinations of the embodiments disclosed herein.

[0419] Examples

[0420] Examples 1: Sis - from carboxylic acid (1) Sis - Vine Level Synthesis of amide (2)

[0421]

[0422] 6 g (21.63 mmol) of cis-compound (1) was dissolved in 40 ml of dichloromethane under an argon atmosphere and then cooled to 0–5°C using an ice bath. 4.56 g of CDI (1.3 equivalents) was added to the solution little by little. The reaction mixture was stirred for 20 minutes and then allowed to warm to room temperature. Then, 2.74 g of N,O - Dimethylhydroxylamine (1.3 equivalents) was added. Once the reaction was confirmed to be complete by TLC, it was quenched with 1 M aqueous solution of HCl and 100 ml of AcOEt until the pH reached 4-6. The organic layer was washed with water (60 ml) and the solvent was evaporated under reduced pressure to obtain 6.86 g of cis-compound (2) in oil form. The obtained compound was sufficiently pure to be used directly in subsequent reaction steps. 1 H NMR (500 MHz, CDCl3) δ 7.26 (s, 5H), 5.23-5.05 (m, 2H), 3.79-3.71 (m, 1H), 3.71-3.66 (m, 3H), 3.63-3.54 (m, 2H), 3.50 (dd, J=14.7, 9.2 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).

[0423] Examples 2: Sis - Vine Level from amide (2) Sis - Synthesis of ketone (3)

[0424]

[0425] 5.96 g (18.6 mmol) of cis compound (2) was dissolved in 60 ml of dry THF under an argon atmosphere, and the resulting solution was cooled to 0-5°C in an ice bath. 12.4 ml of a 3 M solution of MeMgCl dissolved in THF (2 equivalents) was slowly added so that the temperature did not exceed 5°C. The reaction mixture was stirred for 15-30 minutes, and then TLC was performed. Then, it was quenched with sat. aq. NH4Cl and extracted with 100 ml of EtOAc. The organic layer was washed with water (20-30 ml) and the solvent was evaporated under reduced pressure to obtain 4.8 g of brown oil. The resulting oil was extracted by adding 40-100 ml of hot heptane to obtain an undissolved colorless residue. The heptane extract was evaporated under reduced pressure to obtain 4.7 g of pure cis compound (3) (91% yield). 1 H NMR (500 MHz, CDCl3) δ 7.26 (s, 5H), 5.13 (qd, J=12.5, 3.8 Hz, 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, 7.4 Hz, 3H).

[0426] Examples 3: Sis - From ketone (3) Sis -Silyl Enol Synthesis of ether (4)

[0427]

[0428] 5.55 g (20.6 ml) of cis-compound (3) was dissolved in 100 ml of anhydrous dichloromethane under an argon atmosphere and then cooled to 0-5°C in an ice bath. 6.7 ml of trimethylsilyl trilate (1.8 equivalents) was added, followed by the addition of 5.62 ml of anhydrous trimethylamine (2 equivalents). The reaction mixture was stirred until complete (15-60 minutes) by TLC. The reaction was quenched by adding 100 ml of 7% NaHCO3 aqueous solution and extracted with 100 ml of dichloromethane. The solvent was evaporated under reduced pressure to obtain oil (6.9 g), which was used directly in a subsequent reaction. 1 H NMR (500 MHz, CDCl3) δ 7.43-7.28 (m, 5H), 5.24-5.04 (m, 2H), 4.00 (dd, J=26.5, 7.0 Hz, 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).

[0429] Examples 4: Sis -Silyl Enol from ether (4) Sis - Synthesis of compound (5):

[0430]

[0431] The oil obtained in the previous example (4) was dissolved in 50 ml of dry THF under an argon atmosphere, and 2 g of NaHCO3 (1.21 equivalents) was added. The resulting suspension was cooled to 0-5°C in an ice bath, and 4.3 g of NBS (1.21 equivalents) was partially added while controlling the temperature. The reaction proceeded rapidly and was followed by TLC. 100 ml of 7% NaHCO3 The reaction was quenched by adding an aqueous solution and extracted with 100 ml of AcOEt. The solvent was evaporated under reduced pressure to obtain 8.5 g of oil purifiable by column chromatography, and 5.5 g of white solid was obtained (77% yield from ketone (3)). 1 H NMR (400 MHz, CDCl3) δ 7.45-7.28 (m, 5H), 5.25-4.99 (m, 2H), 3.99-3.82 (m, 2H), 3.81-3.66 (m, 1H), 3.63-3.48 (m, 3H), 3.38 (ddd, J =24.8, 10.7, 7.0 Hz, 1H), 2.53-2.27 (m, 1H), 1.46-1.17 (m, 2H), 1.05-0.85 (m, 3H).

[0432] Examples 5: Sis - Vine Level from amide (2) Sis - Hydroxy Synthesis of ketones (6)

[0433]

[0434] Preparation of ((pivaloyloxy)methyl)magnesium chloride (0.4M): A solution of iPrMgCl (2.0M in THF, 66.0mL, 132 mmol, 2.2 equivalents) was added to a solution of iodomethyl pivalate (14.5g, 60 mmol, 1.0 equivalent) in dry THF (67mL) that had been pre-cooled to -65°C to -75°C under an argon atmosphere. The reaction mixture was stirred while maintaining the temperature below -65°C until the desired reagent was fully formed.

[0435] Under an argon atmosphere at 0°C, ((pivaloyloxy)methyl)magnesium chloride (0.4M, 4.68mL, 1.87 mmol, 2 equivalents) was added to a solution of valine amide (2) (0.3g, 0.93 mmol, 1.0 equivalent) in dry THF (5mL). After 30 minutes, the reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3 x 10 mL). The dried (MgSO4) extract was filtered and concentrated under vacuum, and the resulting oil residue was purified by flash column chromatography to obtain the desired product (0.10g, 32%) as a yellow oil. A better yield can be 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).

[0436] Examples 6: Sis -3R from carboxylic acid (7) Sis -3R Vine Level Synthesis of amide (8)

[0437]

[0438] Compound (7) (6.00 g, 21.63 mmol, 1.0 equivalent) and CDI (4.56 g, 28.13 mmol, 1.3 equivalent) were mixed under an argon atmosphere. Dry CH2Cl2 (40 mL) was added, and the suspension was stirred at 0°C for 10 minutes. Subsequently, N,O- Dimethylhydroxylamine hydrochloride (0.99 g, 10.20 mmol, 1.5 equivalents) was added, and the resulting mixture was stirred at room temperature for 12 hours until the reaction was complete. The suspension was quenched with an aqueous HCl solution (0.5 M, 20 mL) to extract the organic layer, and washed twice with an aqueous brine solution (2 x 20 mL). The organic layer was collected, dried with anhydrous MgSO4, filtered, and evaporated under reduced pressure to obtain the pure product of the title as a brown oil (6.86 g, 21.41 mmol, 99%). 1 ¹H 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).

[0439] Examples 7: Sis -3R Vine Level from amide (8) Sis Synthesis of -3R ketone (9)

[0440]

[0441] MeMgCl (3M, 11.80 mL, 35.47 mmol, 2 equivalents) was added to a solution of compound (8) (5.96 g, 17.74 mmol, 1.0 equivalent) in dry THF (60 mL) under an argon atmosphere at 0°C. After 15 minutes, the reaction was quenched with sat.aq. NH4Cl and extracted with EtOAc (3 x 10 mL). The dried (MgSO4) extract was filtered, concentrated under vacuum, and extracted with hot heptane to obtain the desired product (4.37 g, 89%) as a brown oil. 1 ¹H NMR (500 MHz, chloroform- d ) δ 7.26 (s, 5H), 5.13 (qd, J =12.5, 3.8 Hz, 2H), 3.73-3.64 (m, 1H), 3.59-3.52 (m, 1H), 3.48 (td, J =11.5, 5.9 Hz, 1H), 3.42 (dd, J =10.9, 5.1 Hz, 1H), 3.22 (ddd, J =16.0, 13.3, 6.9 Hz, 1H), 2.42-2.29 (m, 1H), 2.18 (s, 3H), 1.44-1.17 (m, 2H), 0.94 (dd, J =15.9, 7.4 Hz, 3H).

[0442] Examples 8: Sis -3R from ketone (9) Sis Synthesis of -3R compound (10)

[0443]

[0444] A solution of compound (9) (1.0 g, 3.63 mmol, 1.0 equivalent) in dry CH2Cl2 (15 mL) under an argon atmosphere was cooled to 0°C. TMSOTf (1.18 mL, 6.54 mmol, 1.8 equivalents) and Et3N (1.01 mL, 7.27 mmol, 2.0 equivalents) were added to this solution, and stirring was continued for 10 minutes until the intermediate silyl enol ether was fully formed. Then, NaHCO3 (0.37 g, 4.40 mmol, 1.2 equivalents) and NBS (0.84 mg, 2.07 mmol, 1.3 equivalents) were added at 0°C. After 1 hour, the reaction was treated with sat. aq. NaHCO3 and CH2Cl2 Extraction was performed with (2 x 10 mL). Subsequently, the organic layer was washed with 5% aq Na2S2O3. The dried (MgSO4) organic layer was filtered, concentrated under vacuum, and purified by chromatography on silica gel to obtain the title product (0.96 g, 77%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform- d ) δ 7.45-7.28 (m, 5H), 5.25-4.99 (m, 2H), 3.99-3.82 (m, 2H), 3.81-3.66 (m, 1H), 3.63-3.48 (m, 3H), 3.38 (ddd, J =24.8, 10.7, 7.0 Hz, 1H), 2.53-2.27 (m, 1H), 1.46-1.17 (m, 2H), 1.05-0.85 (m, 3H).

[0445] Examples 9: Sis -3R Vine Level from amide (8) Sis Synthesis of -3R compound (11)

[0446]

[0447] ICH2Cl (0.27 mL, 3.70 mmol, 4.0 equivalents) was added to a solution of compound (8) (0.3 g, 0.94 mmol, 1.0 equivalent) in dry THF (5 mL) cooled to -78°C, and then a MeLi·LiBr complex (1.88 mL, 2.82 mmol, 3.0 equivalents, 1.5 M solution in Et2O) was added dropwise over 5 minutes. The resulting solution was stirred at that temperature for 2 hours, and then a saturated aqueous solution of NH4Cl 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 resulting phases were separated, the organic phase was dried with anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel to obtain the desired pure product (0.18 g, 63%) as a yellow oil. 1 ¹H 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).

[0448] Examples 10: Sis -3R from ketone (9) Sis -3R Hydroxyl Synthesis of ketones (12)

[0449]

[0450] Step 1: A solution of methyl ketone (12) (1.0 g, 3.63 mmol, 1.0 equivalent) in dry CH2Cl2 (10 mL) under an argon atmosphere was cooled to 0°C. TMSOTf (1.18 mL, 6.54 mmol, 1.8 equivalents) and Et3N (1.0 mL, 7.26 mmol, 2.0 equivalents) were added to this solution and stirred continuously for 1 hour until the silyl enol ether was fully formed. The reaction was quenched with sat. aq. NaHCO3 and extracted with ether (3 x 10 mL). The dried (MgSO4) extract was concentrated under vacuum to yield the intermediate silyl enol ether, which was used as a brown oil in the next step without further purification (1.3 g, 99%).

[0451] Step 2: Unpurified silyl enol ether (1.0 g, 2.87 mmol, 1.0 equivalent) was dissolved in DCM (10 mL), and m-CPBA (0.75 g, 4.3 mmol, 1.5 equivalents) was added all at once at room temperature. After 1 hour, the reaction was 5% aq Na2S2O3 It was quenched with water. The above solution was extracted with DCM (3 x 10 mL). Subsequently, the organic phase was saturated with aq. K2CO3 The product was washed with a solution, dried (NaSO4), filtered, and concentrated under vacuum to obtain a pure product (0.66 g, 80%) as 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).

[0452] Examples 11: from carboxylic acid (13) Vine Level Synthesis of amide (14)

[0453]

[0454] Compound (13) (1.80 g, 6.80 mmol, 1.0 equivalent) and CDI (1.66 g, 10.20 mmol, 1.5 equivalent) were mixed under an argon atmosphere. Dry CH2Cl2 (20 mL) was added, and the suspension was stirred at 0°C for 5 minutes. Subsequently, N,O - Dimethylhydroxylamine hydrochloride (0.99 g, 10.20 mmol, 1.5 equivalents) was added, and the resulting mixture was stirred at room temperature for 5 more hours until the reaction was complete. The suspension was quenched with an aqueous HCl solution (0.5 M, 10 mL) to extract the organic layer, and washed twice with an aqueous brine solution (2 x 10 mL). The organic layer was collected, dried with anhydrous MgSO4, filtered, and evaporated under reduced pressure to obtain the pure product (2.12 g, 14.11 mmol, 98%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform- d ) δ 7.44-7.29 (m, 5H), 5.16 (s, 2H), 4.45 (dt, J =15.91, 4.11 Hz, 2H), 4.26 (dt, J =15.91, 4.11 Hz, 2H), 3.65 (d, J =4.09 Hz, 3H), 3.24 (d, J =1.06 Hz, 3H), 2.34 (q, J =7.62 Hz, 2H), 1.07 (td, J =7.64, 5.07 Hz, 3H).

[0455] Examples 12: Vine Level Ketone from amide (14) 15) of synthesis

[0456]

[0457] MeMgCl (3M, 0.90 mL, 2.67 mmol, 1.7 equivalents) was added to a solution of compound (14) (0.50 g, 1.57 mmol, 1.0 equivalent) in dry THF (10 mL) under an argon atmosphere at 0°C, and the reaction was stirred for 12 hours to reach room temperature. The reaction was extracted with sat. aq. NH4Cl and EtOAc (3 x 10 mL). The dried (MgSO4) extract was filtered and concentrated under vacuum to obtain the title product (0.42 g, 98%) as a brown oil. 1 ¹H 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).

[0458] Examples 13: from ketones (15) Synthesis of compound (16)

[0459]

[0460] Dry CH2Cl2 under an argon atmosphere A solution of compound (15) (0.1 g, 0.36 mmol, 1.0 equivalent) in (2 mL) was cooled to 0°C. TMSOTf (0.12 mL, 0.65 mmol, 1.8 equivalents) and Et3N (0.1 mL, 0.72 mmol, 2.0 equivalents) were added to this solution, and stirring was continued for 1 hour until the intermediate silyl enol ether was completely formed. Then, NaHCO3 (0.03g, 0.43mmol, 1.2 equivalents) and NBS (0.04mg, 0.43mmol, 1.2 equivalents) were added at 0°C. After 1 hour, the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc (2 x 10 mL). Subsequently, the organic layer was washed with 5% aq. Na2S2O3. The dried (Mg2SO4) organic layer was filtered, concentrated under vacuum, and purified by silica gel chromatography to obtain the title product (0.09g, 73%) as a yellow oil. 1 ¹H NMR (500 MHz, chloroform- d ) δ 7.41-7.30 (m, 5H), 5.18 (d, J =1.17 Hz, 2H), 4.64-4.44 (m, 2H), 4.43-4.32 (m, 2H), 3.93 (d, J =5.63 Hz, 2H), 2.77-2.48 (m, 2H), 1.12 (dt, J =15.12, 7.63 Hz, 3H).

[0461] Examples 14: Vine Level From amide (14) Compound (17) synthesis

[0462]

[0463] ICH2Cl (0.28 mL, 3.80 mmol, 4.0 equivalents) was added to a solution of compound (14) (0.3 g, 0.94 mmol, 1.0 equivalent) in dry THF (5 mL) cooled to -78°C, and then MeLi·LiBr complex (1.5 mL, 2.82 mmol, 3.0 equivalents, 1.5 M solution in Et2O) was added dropwise over 5 minutes. The resulting solution was stirred at that temperature for 2 hours, and then a saturated aqueous solution of NH4Cl 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 resulting phases were separated, the organic phase was dried with anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel to obtain the desired pure product (0.13 g, 48%) as a yellow oil. 1 ¹H NMR (500 MHz, chloroform- d ) δ 7.54-7.28 (m, 5H), 5.17 (s, 2H), 4.63-4.45 (m, 2H), 4.38 (dt, J =24.39, 4.20 Hz, 2H), 4.17 (d, J =2.84 Hz, 2H), 2.77-2.57 (m, 2H), 1.12 (dt, J =13.57, 7.62 Hz, 3H).

[0464] Examples 15: Vine Level of amide (14) Sis -Compound ( 2) to hydrogenation

[0465]

[0466] 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 glacial AcOH (2 mL). The reaction mixture was stirred at room temperature under an H2 (10 bar) atmosphere for 12 hours. The solution was filtered through a Celite pad and evaporated under vacuum to obtain brown oil. The crude oil was purified by column chromatography to obtain the desired reduction product. 1 ¹H 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).

[0467] Examples 16: of Esther (18) Sis -Compound ( to 19) hydrogenation

[0468]

[0469] 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 glacial AcOH (2 mL). The reaction mixture was stirred at room temperature under an H2 (10 bar) atmosphere for 12 hours. The solution was filtered through a Celite pad and evaporated under vacuum to obtain brown oil. The crude oil was purified by column chromatography to obtain the desired reduction product. 1 ¹H NMR (500 MHz, chloroform- d) δ 7.39-7.27 (m, 5H), 5.24-5.00 (m, 2H), 3.78-3.64 (m, 1H), 3.57 (ddd, J =16.1, 10.4, 7.3 Hz, 1H), 3.48 (ddd, J =11.6, 7.1, 5.1 Hz, 1H), 3.24 (ddd, J =19.8, 10.4, 8.7 Hz, 1H), 2.95 (dtd, J =13.8, 7.0, 3.5 Hz, 1H), 2.27 (dddd, J =15.1, 8.4, 6.7, 1.6 Hz, 1H), 1.52-1.44 (m, 2H), 1.43 (s, 9H), 0.97 (td, J =7.4, 4.8 Hz, 3H).

[0470] Examples 17: From the enol triplate (20) Synthesis of ester (18)

[0471]

[0472] EtMgBr (3.0M, 3.0mL, 8.85 mmol, 4 equivalents) was added dropwise to a suspension of CuI (0.84 g, 4.4 mmol, 2 equivalents) in dry THF (20 mL) cooled to 0°C. The reaction mixture turned dark purple and was stirred at 0°C for 30 minutes. Then, a solution of methyl ketone (1.0 g, 2.2 mmol, 1.0 equivalent) in THF (20 mL) was added dropwise at the same temperature. The reaction mixture was allowed to reach room temperature and stirred for 4 hours. Subsequently, the reaction was extracted with sat. aq. NH4Cl and EtOAc (2 x 50 mL). The organic phase was washed with sat. aq. NaCl, dry (MgSO4), filtered through a Celite pad, and concentrated under vacuum to obtain the title product (0.73 g, 98%) as a brown oil. 1H NMR (500 MHz, chloroform-d) δ 7.45-7.27 (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).

[0473] Examples 18: From ester (18) carboxylic acid (13) synthesis

[0474]

[0475] In a round-bottom flask, formic acid (8 ml) was added to a crude sample (2 g, 0.6 mmol) of t-butyl ester (18), and the reaction mixture was stirred at 45°C until complete (TLC control, 3–4 hours). Residual formic acid was removed by vacuum distillation and redissolved in 20 ml of EtOAc until a residue was obtained, and washed with 12 ml of NaCl. The resulting organic phase was then washed with 20 ml of Na2CO3 A new extraction was applied using a sat. aq. solution, in which the product migrated to the aqueous phase as a sodium salt and the organic phase was expelled. The basic and colored aqueous phases were acidified with HCl cc. The desired product precipitated as a beige solid, which was filtered, washed with water, and dried to obtain the title product (1.4 g, 85%).

[0476] Examples 19: benzyl ( 3R,4S )-3-(N-( Burst - Butoxycarbonyl )-N-(5-Tosil- 5H- Pirrol Synthesis of [2,3-b]pyrazine-2-yl)glycyl)-4-ethylpyrrolidine-l-carboxylate (21)

[0477]

[0478] 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]pyrazine-2-yl)carbamate (11 g) in dimethylformamide (30 mL) was added to the mixture at 0°C and stirred for 120 minutes at the same temperature. A mixture of benzyl(3R,4S)-3-(2-bromoacetyl)-4-ethylpyrrolidin-1-carboxylate (10 g) in tetrahydrofuran (10 mL) was added to the reaction mixture at 0°C and stirred for 1 hour at the same temperature. After the reaction was finished, acetic acid (0.8 ml) was added to the reaction mixture. The solution was added to cold water (750 mL), and the solid was filtered and dried to obtain a crude product. Yield: 75%; 1 H NMR (400MHz, d-DMSO): δ 8.74 (s,1H), 8.21-8.17 (m,1H), 8.00-7.97 (m,2H), 7.44-7.42 (m,2H), 7.34-7.27 (m,5H),6.79-6.66 (m,1H), 5.06-5.05 (m,2H), 4.74 (s,2H), 3.65-3.58 (m,1H), 3.52-3.43 (m, 3H), 3.21-3.16 (m, 1H), 2.40-2.38 (m, 1H), 2.34 (s, 3H), 1.29-1.46 (m, 10H), 1.29-1.23 (m, 1H), 0.91-0.86 (m,3H).

[0479] Examples 20: benzyl ( 3S,4R )-3-ethyl-4-(3-tosyl-3H- imidazo[l,2-a]pyrrolo[2,3-e]pyrazine -8-day) Synthesis of pyrrolidine-l-carboxylate (22)

[0480]

[0481] To a mixture of crude benzyl (3R,4S)-3-(N-(tert-butoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-yl)glycyl)-4-ethylpyrrolidin-1-carboxylate (10 g) and acetonitrile (100 mL), trifluoroacetic anhydride (6.3 mL) and trifluoroacetic acid (1.6 mL) were added at 20 / 25°C. The reaction mixture was heated to 70°C and stirred at this temperature for 4 hours. The reaction mixture was distilled and added to a 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 under vacuum to obtain a crude solid, which was purified by crystallization with methanol (50 mL). Yield: 40%; 1 H NMR (400MHz, d-DMSO) δ 8.77 (s,1H), 8.04-8.02 (m,2H), 7.98-7.97 (m,1H), 7.70 (s,1H), 7.44-7.29 (m,1H), 5.16-5.08 (m,2H), 4.35-4.30 (m,1H), 3.87-3.70 (m,3H),3.34-3.27 (m,1H), 2.47-2.46 (m, 1H), 2.33 (s, 3H), 0.99-0.75 (m, 2H), 0.60-0.45 (m, 3H).

[0482] Examples 21: 8 -(( 3S,4R )-4- Ethylpyrrolidine -3-day)-3-Tosil-3H- Imidajo[l,2-a]pi Synthesis of rollo[2,3- e]pyrazine (23)

[0483]

[0484] To a solution of benzyl (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)pyrrolidin-1-carboxylate (10 g) in isopropanol (20 mL), a concentrated aqueous HCl solution (20 mL) was slowly added at 20 / 25°C and heated to 80°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 x 100 mL). The pH of the aqueous layer was adjusted to 7.5 using sodium bicarbonate, and then extracted with dichloromethane (2 x 100 mL). The organic layer was concentrated at 20 / 25°C under reduced pressure until a suspension was obtained and filtered to obtain a moist pale yellow solid. Yield: 100%. 1H NMR (400MHz, MeOD) δ 9.06 (s,1H), 8.49 (s,1H), 8.30-8.29 (m,1H), 8.10 (d,2H), 7.58-7.57 (m,1H), 7.42 (d,2H), 4.67-4.65 (m,1H), 3.99-3.94 (m,1H), 3.84-3.78 (m,2H), 3.43-3.38 (m, 1H), 2.84-2.82 (m,1H), 2.38 (s,3H), 1.15 -1.08 (m, 2H), 0.82-0.76 (m, 3H).

[0485] Examples 22: ( 3S,4R )-3-ethyl-4-(3-tosyl-3H- Imidazō[1,2-a]pyrrolo[2,3-e]py Synthesis of razine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (24)

[0486]

[0487] 2,2,2-trifluoroethylamine (2.2 ml) was added to a mixture of 1,1-carbonyl diimidazole (CDI) (4.1 g) and tetrahydrofuran (50 mL) at 0 / 5°C and stirred for 2 hours. The reaction mixture was added to a mixture of 8-((3S,4R)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (7.5 g) and dichloromethane (100 mL) and heated to 30 / 35°C. The reaction mixture was stirred until the reaction was complete. A 10% HCl solution was added to water (100 ml) and the aqueous phase was discarded. The resulting organic phase was washed with water (100 ml), and the final organic phase was concentrated by distillation to 30 ml. Heptane (300 ml) was added to obtain a suspension, which was then filtered and dried to obtain a light brown solid. Yield: 80%. 1 HNMR (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).

[0488] Examples 23: Upadacitinib's manufacturing

[0489]

[0490] A 10% solution of sodium hydroxide in 15 ml of water was added to a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2-trifluoroethyl)pyrrolidin-1-carboxamide (10 g) in tetrahydrofuran (50 mL), and the mixture was heated to 50°C. The reaction mixture was stirred for 5 hours and cooled to 25°C. A 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 HCl solution (100 ml) was added and stirred for 30 minutes. The organic phase was removed, and the resulting aqueous acid phase was extracted with dichloromethane (100 ml). The final aqueous phase was cooled to 0 / 5°C and filled with a 10% NaOH solution to a pH of 10 / 12. The resulting suspension was filtered and washed with water (2 x 50 mL). The cake was drained and dried under vacuum at 30 / 40°C to obtain a nearly white amorphous solid. Yield: 80%. 1 H NMR (400MHz, d-DMSO) δ12.27 (s,1H), 8.58 (s,1H),7.47-7.43 (m,2H), 7.00-6.94 (m,2H), 4.38 -4.33 (m,1H), 3.92-3.67 (m,5H), 3.33-3.25 (m,1H), 2.59-2.54 (m,1H),1.14-1.08 (m,1H), 0.86-0.78 (m, 1H), 0.65-0.62 (m, 3H).

[0491] Examples 24: Upadacitinib's manufacturing

[0492] Upadacitinib (0.25 g) was dissolved in ethanol (1 mL). This solution was added to an aqueous solution (25 mL) containing 0.5% ethanol that had been pre-cooled to 0-5°C. A solid was observed immediately. The suspension was stirred at 0-5°C for 20 minutes and then filtered. The wet cake was dried overnight at 50°C under forced air to obtain a nearly white amorphous solid.

[0493] Examples 25: Upadacitinib Tartrate manufacturing

[0494] A 10% solution of sodium hydroxide in water (15 ml) was added to a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide (10 g) in tetrahydrofuran (50 mL), and the mixture was heated to 50°C. The reaction mixture was stirred for 5 hours and cooled to 25°C. A saturated sodium chloride solution (100 ml) was added to the reaction mixture and extracted with dichloromethane (100 ml). The organic phase was separated and washed with water (100 mL). The organic phase was concentrated to obtain a crude substance dissolved in isopropanol (30 mL). L-(+) tartaric acid (1,2 mol / mol) was added and the mixture was heated to 30 / 40°C. The solution was cooled to 20 / 25°C and slowly added to isopropyl acetate (300 ml). The suspension was stirred overnight, and water was added (2 mol / mol). The resulting suspension was evaporated to 100 ml, filtered, and dried to obtain a light brown solid. Yield: 80%.

[0495] comparison Examples

[0496] To further compare the method of the present invention with that disclosed in WO 2017 / 066975, the synthetic approach disclosed under condition e in Examples 3A and 3B of the said document was reproduced as follows.

[0497]

[0498] comparison Examples 26: Sis - From compound (1) dimethylsulfonium (25) synthesis

[0499]

[0500] Preparation of trimethylsulfoxonium anion (slurry 1)

[0501] 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 under reflux for 2 hours and then cooled below 0°C.

[0502] Preparation of carbonyldiimidazole (Solution 2):

[0503] A solution of cis-compound (1) (1.15 g, 4.18 mmol) in anhydrous THF (3.5 ml) was slowly (over 30 minutes) added to a solution of CDI (1.02 g, 1.5 equivalents) in anhydrous THF (3.5 ml), and the resulting mixture was stirred for 1 hour. Slurry 1 was slowly (over 15 minutes), and a newly prepared solution 2 was added while maintaining the temperature below -1°C. The resulting mixture was stirred at room temperature for 20 minutes until the reaction was complete. The solvent was partially evaporated under reduced pressure, and AcOEt (11 ml) and a 5% aqueous solution of NaCl (11 ml) were added. The two layers were separated, and the aqueous layer was extracted again with AcOEt (11 ml). The combined organic layer was washed with a 12% aqueous solution of NaCl. The organic layer was evaporated under reduced pressure to obtain 1.46 g. This oil was analyzed by HPLC and found to be a 68 / 32 mixture of cis / trans isomers. Therefore, isomerization occurs under the reaction conditions required for the process disclosed in WO 2017 / 066775. The resulting oil was purified by chromatography to separate the two isomers.

[0504] Cis isomer (0.75 g): 1 H NMR (500 MHz, DMSO) δ: 7.41-7.25 (m, 5H), 5.11-4.93 (m, 2H), 4.76 (s, 1H), 3.54-3.23 (m, 9H), 3.15 (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).

[0505] Trans isomer (0.3 g): 1 H NMR (500 MHz, 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).

[0506] comparison Examples 27: Sis - Synthesis of compound (5) from compound (25)

[0507]

[0508] p-toluenesulfonic acid monohydrate (0.447 g, 1.1 equivalents) was added 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 equivalents). The resulting mixture was heated 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 a 7% aqueous solution (13 ml) of NaHCO3 were added. The two layers were separated, and the organic layer was washed with water (5 ml). Finally, the organic layer was evaporated under reduced pressure to obtain 0.71 g of oil formed from a 38 / 62 mixture of cis / trans isomers. The resulting oil was purified by chromatography to separate the two isomers.

[0509] Cis isomer (0.063 g): 1 H NMR (400 MHz, CDCl3) δ 7.45-7.28 (m, 5H), 5.25-4.99 (m, 2H), 3.99-3.82 (m, 2H), 3.81-3.66 (m, 1H), 3.63-3.48 (m, 3H), 3.38 (ddd, J =24.8, 10.7, 7.0 Hz, 1H), 2.53-2.27 (m, 1H), 1.46-1.17 (m, 2H), 1.05-0.85 (m, 3H).

[0510] Trans isomer (0.373 g): 1 H NMR (500 MHz, CDCl3) δ 7.42-7.28 (m, 5H), 5.13 (s, 2H), 3.98-3.87 (m, 2H), 3.88-3.64 (m, 2H), 3.48 (dd, J=10.9, 8.0 Hz, 1H), 3.25 (dd, J=14.6, 7.8 Hz, 1H), 3.18-3.04 (m, 1H), 2.55-2.34 (m, 1H), 1.54 (td, J=13.5, 6.8 Hz, 1H), 1.44-1.19 (m, 1H), 1.00-0.87 (m, 3H).

Claims

Claim 1 Method for preparing a compound of the chemical formula (I'-cis) or its salt or solvate: (I'-cis)form X is the leaving phase, and R 1 is selected from H, and an amino protecting group; this comprises: (a) a step of converting a compound of formula (II) or its salt or solvate into a compound of formula (III) or (IV) or its salt or solvate. (II) Food is a cis single or double bond; Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aryl; and R 1 is selected from H, and amino protecting groups; (III) (IV) Food is a cis single bond or double bond; and R 1 is selected from H, and an amino protecting group; and (b) a step of converting a compound of formula (III) or (IV), or its salt or solvate, into a compound of formula (I'-cis) or its salt or solvate by a method comprising: (bi) reacting the compound of formula (III) or (IV), or its salt or solvate, with MeMgCl, MeMgBr, or MeLi to provide a ketone of formula (V) or its salt or solvate. (V) Food is a cis single bond or double bond; and R 1 is selected from H, and an amino protecting group; (bii) a step of converting a ketone of formula (V), or its salt or solvate, into an enol ether of formula (VI) or an enamin of formula (VII) or its salt or solvate. (VI) (VII) Food is a cis single bond or double bond; and R 1 Is Selected from H, and amino protecting groups;R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; and R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or these form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and (biii) a step of converting an enol ether of formula (VI) or an enamin of formula (VII), or its salt or solvate, into a compound of formula (I'-cis) or its salt or solvate; or (bi') a step of reacting a compound of formula (III) or (IV), or its salt or solvate, with X-CH2-Li, X-CH2-MgCl, or X-CH2-MgBr to provide a compound of formula (I'-cis) or its salt or solvate; or (bi'') a step of converting a compound of formula (III) or (IV), or its salt or solvate, into R 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 A step of reacting with O-CH2-MgBr to provide a compound of formula (VIII) or its salt or solvate; (VIII) Food is a cis single bond or double bond and;;R 1 is selected from H, and amino protecting groups; and R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 ) independently selected from aryl(C1-C6)alkyl; and (bii'') a step of converting a compound of formula (VIII) or its salt or solvate into a compound of formula (I'-cis) or its salt or solvate. Claim 2 In claim 1, from the compound of chemical formula (II), or its salt or solvate is a double bond, and the method further comprises a hydrogenation step after step (a), or (bi), or (bii), or (biii), or (bi'), or (bi''), or (bii''). Claim 3 In claim 1, of the compounds of chemical formulas (II), (III), (IV), (V), (VI), (VII) and (VIII) A manufacturing method in which the cis single bond is Claim 4 In paragraph 3, A method of preparation characterized in that a compound of formula (II) having a cis single bond, or its salt or solvate, is obtained by hydrogenation of a compound of formula (II'') or its salt or solvate. (II'') In the formula Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, and R in food 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril; and R 1 is selected from H, and amino protecting groups. Claim 5 A method of manufacturing according to claim 1 or 2, comprising the following: (a) a step of converting a compound of formula (II'') or its salt or solvate into a compound of formula (III'') or (IV'') or its salt or solvate. (II'') In the formula Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aryl; and R 1 is selected from H, and amino protecting groups; (III'') (IV''); (b1) a step of hydrogenating a compound of formula (III'') or (IV''), or its salt or solvate, to provide a compound of formula (III'-cis) or (IV'-cis) or its salt or solvate. (III'-cis) (IV'-cis) and (b2) a step of converting a compound of formula (III'-cis) or (IV'-cis) or its salt or solvate into a compound of formula (I'-cis) or its salt or solvate by a method comprising the following: (bi) reacting a compound of formula (III'-cis) or (IV'-cis), or its salt or solvate, with MeMgCl, MeMgBr, or MeLi to provide a ketone of formula (V'-cis) or its salt or solvate. (V'-cis) (bii) A step of converting a ketone of formula (V'-cis), or its salt or solvate, into an enol ether of formula (VI'-cis) or an enamine of formula (VII'-cis) or its salt or solvate. (VI'-cis) (VII'-cis) Food R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; and R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or these form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and (biii) a step of converting an enol ether of formula (VI'-cis) or an enamine of formula (VII'-cis), or its salt or solvate, into a compound of formula (I'-cis) or its salt or solvate; or (bi') a step of reacting a compound of formula (III'-cis) or (IV'-cis), or its salt or solvate, with X-CH2-Li, X-CH2-MgCl, or X-CH2-MgBr to provide a compound of formula (I'-cis) or its salt or solvate; or (bi'') a step of R of a compound of formula (III'-cis) or (IV'-cis), or its salt or solvate 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 A step of reacting with O-CH2-MgBr to provide a compound of the chemical formula (VIII'-cis) or its salt or solvate; (VIII'-cis) Food R 1 is selected from H, and amino protecting groups; and R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 ) independently selected from aryl(C1-C6)alkyl; and (bii'') a step of converting a compound of formula (VIII'-cis) or its salt or solvate into a compound of formula (I'-cis) or its salt or solvate. Claim 6 A method of manufacturing according to claim 1 or 2, comprising the following: (a) a step of converting a compound of formula (II'') or its salt or solvate into a compound of formula (III'') or (IV'') or its salt or solvate. (II'') In the equation, Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril; and R 1 is selected from H, and amino protecting groups; (III'') (IV''); and (b) a step of converting a compound of formula (III'') or (IV''), or its salt or solvate, into a compound of formula (I'-cis) or its salt or solvate by a method comprising the following: (bi1) reacting a compound of formula (III'') or (IV''), or its salt or solvate, with MeMgCl, MeMgBr, or MeLi to provide a ketone of formula (V'') or its salt or solvate. (V''); (bi2) a step of hydrogenating a ketone of formula (V''), or its salt or solvate, to provide a ketone of formula (V'-cis), or its salt or solvate; A step of converting a ketone of formula (V'-cis)(bii), or its salt or solvate, into an enol ether of formula (VI'-cis) or an enamine of formula (VII'-cis) or its salt or solvate. (VI'-cis) (VII'-cis) Food R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; and R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 A step of independently selecting from an aryl, or forming a 5- to 7-membered heterocyclic ring with a nitrogen atom; and (biii) converting an enol ether of formula (VI'-cis) or an enamine of formula (VII'-cis), or its salt or solvate, into a compound of formula (I'-cis) or its salt or solvate. Claim 7 A method of manufacturing according to claim 1 or 2, comprising the following: (a) a step of converting a compound of formula (II'') or its salt or solvate into a compound of formula (III'') or (IV'') or its salt or solvate. (II'') In the formula Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril; and R 1 is selected from H, and amino protecting groups; (III'') (IV''); (b) a step of converting a compound of formula (III'') or (IV''), or its salt or solvate, into a compound of formula (I'-cis) or its salt or solvate by a method comprising the following: (bi) reacting a compound of formula (III'') or (IV''), or its salt or solvate, with MeMgCl, MeMgBr, or MeLi to provide a ketone of formula (V'') or its salt or solvate. (V''); (bii) A step of converting a ketone of formula (V''), or its salt or solvate, into an enol ether of formula (VI'') or an enamin of formula (VII'') or its salt or solvate; (VI'') (VII'') Food R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; and R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or these form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and (biii) a step of converting an enol ether of formula (VI'') or an enamin of formula (VII''), or its salt or solvate, into a compound of formula (I'') or its salt or solvate; (I'') In the formula X is the departure phase, and R 1 is selected from H, and an amino protecting group; and (biv) a step of hydrogenating a compound of formula (I''), or its salt or solvate, to provide a compound of formula (I'-cis), or its salt or solvate; or (bi') a step of reacting a compound of formula (III'') or (IV''), or its salt or solvate, with X-CH2-Li, X-CH2-MgCl, or X-CH2-MgBr, where X is a leaving group, to provide a compound of formula (I''), or its salt or solvate; (I'') and (bii') a step of hydrogenating a compound of formula (I''), or its salt or solvate, to provide a compound of formula (I'-cis), or its salt or solvate; or (bi'') a step of providing a compound of formula (III'') or (IV''), or its salt or solvate, R 6 O-CH2-Li, R 6 O-CH2-MgCl or R 6 A step of reacting with O-CH2-MgBr to provide a compound of formula (VIII'') or its salt or solvate; (VIII'') Food R 1 is selected from H, and amino protecting groups; and R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 ) independently selected from aryl(C1-C6)alkyl; (bii'') a step of converting a compound of formula (VIII'') or its salt or solvate into a compound of formula (I'') or its salt or solvate. (I'') and (biii'') a step of hydrogenating a compound of formula (I''), or its salt or solvate, to provide a compound of formula (I'-cis) or its salt or solvate. Claim 8 In any one of paragraphs 1 to 4, wherein: - X is selected from Cl, Br, and I; and / or - R 1 is an amino protecting group; and / or -Y is OH and OR 2 Selected from, and R in food 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from aryl; and / or- R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 A method of preparation independently selected from aryl(C1-C6)alkyl. Claim 9 In any one of claims 1 to 4, of a compound having the formula (I'-cis), or (II), or (III), or (IV), or (V), or (VI), or (VII), or (VIII) A method of preparation in which the compound is a cis single bond, and the compound is a compound of the 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), or a salt or solvate thereof. In the formula, X is the leaving group; Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, where R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril;R 1 is selected from H, and amino protecting groups;;R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or these form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 A manufacturing method characterized by being independently selected from aryl(C1-C6)alkyl. Claim 10 A method of preparation characterized in that, in any one of claims 1 to 4, the compound of formula (II), or its salt or solvate is obtained by a method comprising the following: - reacting the compound of formula (IX), or its salt or solvate, with Et2CuLi, Et2CuMgBr, or Et2CuMgCl to provide the compound of formula (II) or its salt or solvate, wherein the formula is a double bond; and (IX) Z in the formula is a halogen, C1-C6 alkylsulfonate, C1-C6 haloalkylsulfonate, C6-C 10 Arylsulfonate and (C1-C6)alkyl (C6-C 10 Selected from arylsulfonates; R 1 is selected from H and amino protecting groups; and Y is OH, Cl, OR 2 and OC(O)R 2 Selected from , and here R 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aryl; - if necessary (i.e., (If a compound of formula (II) having a cis single bond is required), hydrogenate the double bond to A step of providing a compound of formula (II) in which ga is a cis single bond, or a salt or solvate thereof, Claim 11 A method of preparation characterized in that, in any one of claims 1 to 4, the compound of the chemical formula (I'-cis), or its salt or solvate, is converted into upadacitinib, or its salt or solvate or stereoisomer. Claim 12 A method of preparation according to any one of claims 1, 3, or 4, wherein the compound of the chemical formula (I'-cis) or its salt or solvate is a compound of the chemical formula (I'-cis-3R) or its salt or solvate. (I-Cis-3R) Formula X is the departure phase, and R 1 is selected from H, and amino protecting groups; and where the compounds of formulas (II), (III), (IV), (V), (VI), (VII) and (VIII) are, respectively, compounds of formulas (II'-cis-3R), (III'-cis-3R), (IV'-cis-3R), (V'-cis-3R), (VI'-cis-3R), (VII'-cis-3R), or (VIII'-cis-3R). In the formula, X is the leaving group; Y is OH, Cl, OR 2 and OC(O)R 2 Selected from, and R in food 2 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected from Aril;R 1 Is Selected from H, and amino protecting groups; R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or these form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and R 6 is selected from H, -COR' and -CONR'R'', and R' and R'' in the formula are C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 A manufacturing method characterized by being independently selected from aryl(C1-C6)alkyl. Claim 13 A compound selected from the following, or its salt or solvate: Food in progress: R 1 is an amino protecting group;R 3 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl, C6-C 15 Selected from aryl, COR' and SiR'3, where each R' is C 1-6 Alkyl, C3-C 10 Cycloalkyl, C 6-15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl; R 4 and R 5 is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Independently selected from aryls, or they form a 5- to 7-membered heterocyclic ring with a nitrogen atom; and R' is a C1-C6 alkyl, (C6-C 15 )aryl(C1-C6)alkyl and C6-C 15 Selected by Aril. Claim 14 In Paragraph 13, R in food 1 A manufacturing method selected from the following:- COOR a , during food R a is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 Selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heteroaryl and tri(C1-C6alkyl)silane;- COR b , during food R b is C1-C6 alkyl, C2-C6 alkenyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl, (C6-C 15 )Selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl and 3- to 15-membered heteroaryl;- R c , during food R c is a C1-C6 alkyl, C6-C 15 Aryl and (C6-C 15 )Selected from aryl(C1-C6)alkyl;- SO2R d , during food R d is a C1-C6 alkyl, C1-C6 haloalkyl, C6-C 15 Aryl, (C6-C 15 )Selected from aryl(C1-C6)alkyl, 3- to 15-membered heterocyclyl, and 3- to 15-membered heteroaryl; and- Si(R e )(R f )(R g ), during food R e , R f and R g is a C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 15 Aryl and (C6-C 15 Independently selected from aryl(C1-C6)alkyl. Claim 15 delete

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