Process for preparing enantiomerically enriched JAK inhibitors

Abstract

To provide a process for preparing enantiomerically enriched JAK inhibitors.SOLUTION: The invention provides a process for preparing (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (ruxolitinib) and deuterated forms thereof or salts thereof, and intermediates useful for synthesizing ruxolitinib and deuterated forms thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 802,129, filed on February 6, 2019, and U.S. Provisional Patent Application No. 62 / 850,981, filed on May 21, 2019. The entire contents of these applications are incorporated herein by reference in their entirety.

[0002] The present invention relates to a method for preparing an enantiomerically enriched JAK inhibitor.

Background Art

[0003] Ruxolitinib phosphate is a heteroaryl - substituted pyrrolo[2,3 - d]pyrimidine, also known as 3(R) - cyclopentyl - 3 - [4 - (7H - pyrrolo[2,3 - d]pyrimidin - 4 - yl) - 1H - pyrazol - 1 - yl]propanenitrile phosphate and (R) - 3 - (4 - (7H - pyrrolo[2,3 - d]pyrimidin - 4 - yl) - 1H - pyrazol - 1 - yl) - 3 - cyclopentylpropanenitrile phosphate, which inhibits JAK1 and JAK2, which are Janus - related kinases (JAKs). These kinases mediate the signaling of several cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves the recruitment of STAT (signal transducer and activator of transcription) to cytokine receptors, the activation of STAT leading to modulation of gene expression, and its subsequent localization to the cell nucleus.

[0004] Ruxolitinib phosphate has been approved in the United States and Europe for the treatment of myelofibrosis and polycythemia vera. Ruxolitinib is currently in clinical trials for the treatment of graft - versus - host disease and other conditions.

[0005] A deuterated analog of ruxolitinib phosphate (referred to herein as CTP - 543 or compound (I)) is currently in clinical trials for the treatment of alopecia areata.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] There is a continuing need for improved methods for synthesizing ruxolitinib and its deuterated forms for the beneficial activities of ruxolitinib and deuterated ruxolitinib analogs.

Means for Solving the Problems

[0008] The present invention provides an improved method for synthesizing ruxolitinib and its deuterated forms. The present invention further provides intermediates useful for synthesizing ruxolitinib and its deuterated forms.

[0009] That is, the gist of the present invention relates to the following. Item 1 A compound of formula I

Chemical Formula

Chemical Formula

Advantages of the Invention

[0010] The present invention can provide a method for preparing an enantiomerically enriched JAK inhibitor.

Modes for Carrying Out the Invention

[0011] In one aspect, the present invention provides a method for preparing a compound of formula I

Chemical Formula

Chemical Formula

[0012] In one aspect, the present invention provides a method for preparing a compound of formula I

Chemical formula

Chemical formula

[0013] In another aspect, the present invention provides a method for preparing a compound of formula II (or a salt thereof)

Chemical formula

Chemical formula

[0014] In another aspect, the present invention provides a method for preparing a compound of formula II’ (or a salt thereof)

Chemical formula

Chemical formula

[0015] In certain embodiments of the above method for producing a compound of formula II or II’, the hydrogenation catalyst includes, but is not limited to, transition metals including rhodium, ruthenium, and iridium. In certain embodiments, the hydrogenation catalyst includes a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L) according to formula IV below. In certain embodiments, the hydrogenation catalyst includes rhodium. In certain embodiments, the hydrogenation catalyst includes rhodium and a chiral phosphine ligand (L) according to formula IV

Chemical formula

[0016] In certain embodiments, each of R 2a , R 2b , R 3a , R 3b and R 4 is hydrogen and R 5 is norbornyl. In certain embodiments, each of R 2a , R 2b , R 3a , R 3b and R 4 is hydrogen, and R5 is cyclohexyl. In certain embodiments, the hydrogenation catalyst is present in an amount of 2.5 mol% or less. In certain embodiments, the hydrogenation catalyst is present in an amount of 1 mol% or less.

[0017] In certain embodiments, the hydrogen gas is present at a pressure of 15 bar or less. In certain embodiments, the hydrogen gas is present at a pressure of 10 bar or less. In certain embodiments, the step of reacting a compound of formula III or III’ with hydrogen gas in the presence of a hydrogenation catalyst is carried out in a solvent selected from dichloromethane (DCM), trifluorotoluene (TFT), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF), methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), isopropanol (iPrOH), hexafluoroisopropanol (HFIP), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), acetic acid (AcOH), and mixtures thereof. In certain embodiments, the solvent is trifluoroethanol (TFE). In certain embodiments, the compound of formula II or II’ has an enantiomeric excess of at least 95% of the (R)-enantiomer. In certain embodiments, the compound of formula II or II’ has an enantiomeric excess of at least 98% of the (R)-enantiomer.

[0018] In another aspect, the present invention provides a method for preparing a compound of formula III (or a salt thereof)

Chemical formula

Chemical formula

Chemical formula

[0019] In another aspect, the present invention provides a method for preparing a compound of formula III’ (or a salt thereof)

Chemical formula

Chemical formula

Chemical formula

[0020] Certain embodiments of the present invention relate to a method for preparing a compound of formula VIII (or a salt thereof) [Chemical Formula] which method comprises reacting, in the presence of a base, a compound of formula IX (or a salt thereof) [Chemical Formula] with a compound represented by the formula [Chemical Formula] (BPin - pyrazole) (or another pyrazole boronic acid ester) and a catalytic amount of a palladium catalyst (e.g., Pd(PPh 3 )) 4 ) wherein each R 1 is C 1 ~C 6 alkyl or two Rs together form a C 1 or C 2 or C 3 alkylene moiety; each R 6 is independently selected from H and a protecting group; and X is I, Br, Cl, or triflate. In certain embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0021] Certain embodiments of the present invention relate to a method for preparing a compound of formula VIII' (or a salt thereof) [Chemical Formula] which method comprises reacting, in the presence of a base, a compound of formula IX' (or a salt thereof) [Chemical Formula] with a compound represented by the formula [Chemical Formula] (BPin - pyrazole) (or another pyrazole boronic acid ester) and a catalytic amount of a palladium catalyst (e.g., Pd(PPh 3 )) 4 ), including reacting them; in Formulas VIII’ and IX’, each R 1’ is C 1 - C 10 alkyl (e.g., methyl or ethyl), or C 2 - C 10 alkenyl (e.g., allyl), or two Rs 1’ together with the oxygen atom to which they are attached form a 5 - 7 membered heterocyclic ring which may be optionally substituted (e.g., 1,3 - dioxolan - 2 - yl ring, or 1,3 - dioxan - 2 - yl ring, or 1,3 - benzodioxolan - 2 - yl ring); each R 6 is independently selected from H and a protecting group. In certain embodiments, each R 1’ is C 1 - C 10 alkyl; in a further embodiment, each R 1’ is methyl or ethyl. In certain embodiments, each R 6 is H. In certain embodiments, one R 6 is H and one R 6 is a protecting group. In certain embodiments, each R 6 is a protecting group. In certain embodiments, the protecting group is a t - butoxycarbonyl group. In certain embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0022] In any of the formulas described herein, in certain embodiments, the protecting group is selected from t - butoxycarbonyl (Boc), triflyl (Tf, SO 2 - CF 3 ), trifluoroacetyl (F 3 - Ac), and trityl (Tr, CPh 3 ). In certain embodiments, both Rs 6 are H. In certain embodiments, both Rs 1is methyl. In certain embodiments, both R 1 are ethyl. In certain embodiments, both R 1’ are methyl. In certain embodiments, both R 1’ are ethyl. In certain embodiments, Y 1 is hydrogen and Y 2 and Y 3 each are deuterium. In certain embodiments, Y 1 , Y 2 , and Y 3 each are hydrogen. In certain embodiments, the incorporation of deuterium at each position designated as deuterium is at least 90%, at least 95%, or at least 97%.

[0023] Certain aspects of the invention provide intermediates useful for preparing loxoribine and deuterated analogs of loxoribine. In one embodiment, the invention provides a compound represented by the structure

Chemical formula

[0024] In another embodiment, the invention provides a compound represented by the structure

Chemical formula

[0025] In another embodiment, the invention provides a compound represented by the structure

Chemical formula

[0026] In another embodiment, the invention provides a compound represented by the structure

Chemical formula

[0027] ​​ In another embodiment, the present invention relates to a structure

Chemical formula

[0028] In another embodiment, the present invention relates to a structure

Chemical formula

[0029] In another embodiment, the present invention relates to a structure

Chemical formula

[0030] In another embodiment, the present invention relates to a structure

Chemical formula

[0031] In another embodiment, the present invention relates to a structure

Chemical formula

[0032] In another embodiment, the present invention relates to a structure

Chemical formula

[0033] In another embodiment, the present invention relates to a structure

Chemical formula

[0034] In another embodiment, the present invention is a structure

Chemical formula

[0035] In certain embodiments, the deuterium incorporation at each position designated as deuterium in any compound of the present invention is at least 90%, at least 95%, or at least 97%.

[0036] Other aspects and embodiments of the present invention will be recognized from the detailed description and claims herein.

[0037] Detailed Description of the Invention Definitions The term "alkyl" refers to a monovalent saturated hydrocarbon group. C 1 ~C 6 -alkyl has 1 to 6 carbon atoms. In some embodiments, alkyl can be linear or branched. In some embodiments, alkyl can be primary, secondary, or tertiary. Non-limiting examples of alkyl groups include methyl; ethyl; propyl including n-propyl and isopropyl; butyl including n-butyl, isobutyl, sec-butyl, and t-butyl; pentyl including, for example, n-pentyl, isopentyl, and neopentyl; and hexyl including, for example, n-hexyl and 2-methylpentyl. Non-limiting examples of primary alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Non-limiting examples of secondary alkyl groups include isopropyl, sec-butyl, and 2-methylpentyl. Non-limiting examples of tertiary alkyl groups include t-butyl.

[0038] Unless otherwise specified, "alkylene" refers to a saturated straight-chain or branched divalent group having the stated number of carbon atoms, either by itself or as part of another substituent, and derived from the removal of two hydrogen atoms from the corresponding alkane. Examples of straight-chain and branched alkylene groups are -CH 2-(methylene), -CH 2 -CH 2 -(ethylene), -CH 2 -CH 2 -CH 2 -(propylene), -C(CH 3 ) 2 -, -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 -(butylene), -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -(pentylene), and -CH 2 -C(CH 3 ) 2 -CH 2 -and the like.

[0039] The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group, where the unsaturation is represented by a double bond. C 2 ~C 6 The alkenyl has 2 to 6 carbon atoms. The alkenyl may be linear or branched. Examples of alkenyl groups are CH 2 =CH-(vinyl), CH 2 =C(CH 3 )-, CH 2 =CH-CH 2 -(allyl), CH 3 -CH=CH-CH 2 -(crotyl), CH 3 -CH=C(CH 3 )-and CH 3 -CH=CH-CH(CH 3 )-CH 2 -. When double bond stereoisomerism is possible, the stereochemical configuration of the alkenyl can be (E), (Z), or a mixture thereof.

[0040] The term "alkynyl" refers to a monovalent unsaturated hydrocarbon group, where the unsaturation is represented by a triple bond. C 2 ~C 6 The alkynyl is an alkynyl having 2 to 6 carbon atoms. The alkynyl can be linear or branched. Examples of alkynyl groups are HC≡C-, CH 3 -C≡C-, CH 3 -CC-CH 2 -, CH 3 -C≡C-CH 2 -CH 2 - and CH 3 -C≡C-CH(CH 3 )-CH 2 .

[0041] The term "cycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C 3 ~C 10 cycloalkyl" refers to a cycloalkyl having 3 to 10 ring carbon atoms. C 3 ~C 10 Examples of cycloalkyl include C 3 ~C 6 cycloalkyl. The bicyclic ring system includes fused rings, bridged rings, and spiro ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cis- and trans-decalinyl, norbornyl, and spiro[4.5]decanyl.

[0042] The term "carbocyclic" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C 3 ~C 10 carbocyclic" refers to a carbocyclic having 3 to 10 ring carbon atoms. C 3 ~C 10 Examples of carbocyclic include C 3 ~C 6It includes a carbocyclic ring. The bicyclic ring system includes a fused ring, a bridged ring, and a spiro ring system. More specific examples of the carbocyclic ring group include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cis- and trans-decalinyl, norbornyl, norbornenyl, and spiro[4.5]decanyl.

[0043] The term "heterocycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated ring system, where 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of O, N, and S. The term "3- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl having 3 to 10 ring atoms. Examples of 3- to 10-membered heterocycloalkyl include 3- to 6-membered heterocycloalkyl. The bicyclic ring system includes a fused ring, a bridged ring, and a spiro ring system. More specific examples of the heterocycloalkyl group include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, and thiomorpholinyl.

[0044] In the above heterocycloalkyl substituents, the nitrogen, phosphorus, carbon, or sulfur atoms may optionally be oxidized to various oxidation states. In a specific example, the group -S(O) 0~2 - refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO 2 -(sulfone), respectively. For convenience, nitrogen is meant to include, but is not limited to, their corresponding N-oxide forms, although not explicitly defined as such in a specific example. Thus, for example, for a compound of the present invention having a pyridyl ring, the corresponding pyridyl-N-oxide is meant to be included as another compound of the present invention. Further, the cyclic nitrogen atom may optionally be quaternized, and the ring substituents may be partially or fully saturated or aromatic.

[0045] "Aryl" refers to a monocyclic or polycyclic monovalent aromatic hydrocarbon group having the stated number of carbon atoms, either by itself or as part of another substituent (i.e., C 5 ~C 14 means 5 to 14 carbon atoms). Typical aryl groups include, but are not limited to, groups derived from acenanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octophene, octylene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthylene, etc. In certain embodiments, the aryl group is cyclopentadienyl, phenyl or naphthyl. In more specific embodiments, the aryl group is phenyl or naphthyl.

[0046] "Arylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 carbon atom, and the hydrogen atom bonded thereto are replaced by an aryl group, either by itself or as part of another substituent. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, etc. In one embodiment, the alkyl portion of the arylalkyl group is (C 1 ~C 6 ), and the aryl portion is (C 5 ~C 14 ). In more specific embodiments, the alkyl group is (C 1 ~C 3 ), and the aryl portion is (C 5 ~C 10 ), for example, (C 6 ~C 10 ).

[0047] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon ring system, where at least one ring atom is a heteroatom independently selected from the group consisting of O, N, and S. In some embodiments, the heteroaryl group has 1 or 2 rings. When the heteroaryl group contains multiple heteroatom ring members, the heteroatoms can be the same or different. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolopyrimidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. The term 5-membered heteroaryl refers to a heteroaryl where the number of ring atoms is 5. Non-limiting examples of 5-membered heteroaryl groups include pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furazanyl, imidazolinyl, and triazolyl.

[0048] "Heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced by a heteroaryl group. In one embodiment, the alkyl portion of the heteroarylalkyl is (C 1 ~C 6 )alkyl and the heteroaryl portion is a 5- to 14-membered heteroaryl. In a more specific embodiment, the alkyl portion is (C 1 ~C 3 )alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0049] "Halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine, or fluoro, chloro, bromo, and iodo, either by themselves or as part of another substituent.

[0050] As used herein, the terms "contacting" and "reacting" are used as known in the art and generally refer to combining chemical reagents in such a manner that their interaction at the molecular level enables a chemical or physical transformation to be achieved. In some embodiments, contacting or reacting involves two (or more) reagents, where one equivalent or multiple equivalents of a second reagent are used with respect to a first reagent. The reacting step of the methods described herein can be carried out under the time and conditions suitable for preparing the identified product.

[0051] "Compound (I)" or "CTP-543" is the deuterated analog of ruxolitinib known as the chemical name (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyclopentyl-2,2,3,3,4,4,5,5-d 8 )propanenitrile. Compound (I) may also be referred to herein as D 8 -ruxolitinib. Compound (I) has the following structural formula

Chemical formula

[0052] Some variations in the natural isotope abundances are recognized to occur in the synthesized compounds depending on the origin of the chemical materials used in the synthesis. Thus, the compounds disclosed herein inherently contain minor amounts of deuterated isotope substituents. The concentrations of the naturally abundant stable hydrogen and carbon isotopes are small and not significant compared to the degree of stable isotope substitution of the compounds of the invention, notwithstanding this variation. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0053] In the compounds of the invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its naturally occurring isotope composition. In some embodiments, when a position is specifically designated as "H" or "hydrogen", that position is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments, when a position is specifically designated as "H" or "hydrogen", that position incorporates ≦10% deuterium, ≦5% deuterium, ≦4% deuterium, ≦3% deuterium, ≦2% deuterium, or ≦1% deuterium. Unless otherwise noted, when a position is specifically designated as "D" or "deuterium", that position is understood to have deuterium at an abundance that is at least 3340 times the natural abundance of deuterium, which is 0.015% (i.e., incorporation of at least 50.1% deuterium).

[0054] The term "isotope enrichment factor", as used herein, means the ratio between the isotope abundance and the natural abundance of a particular isotope.

[0055] In other embodiments, the compounds of the invention have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0056] In some embodiments, the compounds of the invention have at least 52.5% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 60% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 67.5% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 75% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 82.5% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 90% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 95% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 97.5% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 99% deuterium incorporation at each designated deuterium atom. In some embodiments, the compounds of the invention have at least 99.5% deuterium incorporation at each designated deuterium atom.

[0057] The term "isotope substituent" refers to a species (molecule) whose chemical structure differs from another species (molecule) of the compounds of the present invention only in its isotope composition.

[0058] The term "compound", when referring to the compounds of the present invention, refers to a collection of molecules having the same chemical structure, except that isotope variations may exist among the constituent atoms of the molecules. Thus, for example, while compound (I) is represented by a specific chemical structure having deuterium atoms at eight designated positions, compound (I) contains molecules having deuterium at each of the eight designated positions and may also contain isotope substituents having hydrogen atoms at one or more of the designated deuterium positions in its structure. It will be apparent to those skilled in the art that the relative amounts of such isotope substituents in compound (I) are determined by several factors, including the isotopic purity of the deuterated reagents used to prepare the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0059] As used herein, the term "reacting" is used as known in the art and generally refers to combining chemical reagents in such a manner that their interactions at the molecular level enable a chemical or physical transformation to be achieved. In some embodiments, reacting involves two reagents, where one or more equivalents of a second reagent are used with respect to the first reagent. The reacting step of the methods described herein can be carried out under the time and conditions suitable for preparing the identified product.

[0060] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical reactions of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Thus, for example, a nitrogen atom can be protected as a carbamate, e.g., with a protecting group such as t-butoxycarbonyl (Boc); as a sulfonamide, e.g., with a protecting group such as triflyl (Tf, SO 2 -CF 3 ); as an amide, e.g., with a protecting group such as acetyl, benzoyl, or trifluoroacetyl (F 3 -Ac); as an amine, e.g., with a protecting group such as benzyl or trityl (Tr, -CPh 3 ); or as a silylamine (e.g., with a protecting group such as SiPh 2 Bu t ). The adjustment to the protecting groups and the formation and cleavage methods described herein can be adjusted as needed taking into account various substituents.

[0061] The reactions of the methods described herein can be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. The suitable solvent may be substantially non-reactive with the starting materials (reactants), intermediates, or products at a temperature in the range of the freezing temperature to the boiling temperature of the solvent, e.g., the temperature at which the reaction is carried out. A given reaction can be carried out in one solvent or a mixture of solvents. Depending on the particular reaction step, a suitable solvent for the particular reaction step can be selected. In some embodiments, the reaction can be carried out in the absence of a solvent, such as when at least one of the reagents is a liquid or a gas.

[0062] Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane (DCM), tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, trifluorotoluene (TFT), and mixtures thereof.

[0063] Suitable ether solvents include dimethoxymethane, tetrahydrofuran (THF), 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, and mixtures thereof. Further ether solvents include 2-methyltetrahydrofuran and cyclopentyl methyl ether (and mixtures thereof including other ether solvents described herein).

[0064] Suitable protic solvents can include, by way of example and not limitation, water, methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH), 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol (TFE), ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, hexafluoroisopropanol (HFIP), acetic acid (AcOH), and mixtures thereof.

[0065] Suitable aprotic solvents can include, by way of example and not limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate (EtOAc), sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, and mixtures thereof.

[0066] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, naphthalene, and mixtures thereof.

[0067] The reactions of the methods described herein can be carried out at a suitable temperature that can be readily determined by one of ordinary skill in the art. The reaction temperature can be, for example, the melting and boiling points of the reagents and solvents (if present); the thermodynamics of the reaction (e.g., an exothermic reaction may need to be carried out at a reduced temperature); and the kinetics of the reaction (e.g., a high activation energy barrier may require a high temperature). "High temperature" refers to a temperature above room temperature (about 22 °C).

[0068] The reactions of the methods described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques well known to those of ordinary skill in the art.

[0069] Examples of acids can be inorganic acids or organic acids. Non-limiting examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Non-limiting examples of organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinylacetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0070] Non-limiting examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, where alkoxides include the lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include the sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl, and cyclohexyl-substituted amides.

[0071] By preparing the compounds by the methods described herein, the desired products can be isolated using conventional isolation and purification operations such as concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography, and the like.

[0072] In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial separation can include, for example, a composition in which the compound of the invention is concentrated. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or a salt thereof. Methods for isolating compounds and their salts are conventional in the art.

[0073] The invention also includes salts of the compounds described herein. Salts of the compounds of the invention are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment, the acid addition salt can be a deuterated acid addition salt.

[0074] The term "pharmaceutically acceptable" as used herein refers to a component that is suitable for use in contact with the tissues of humans and other mammals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that can provide, directly or indirectly, the compounds of the invention upon administration to a recipient. "Pharmaceutically acceptable counterion" refers to the ionic portion of the salt that is not toxic when released from the salt upon administration to a recipient.

[0075] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, and related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates and other salts. In one embodiment, the pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and in particular, those formed with organic acids such as maleic acid. In one embodiment, the acids commonly used to form pharmaceutically acceptable salts include the inorganic acids listed above, where at least one hydrogen is replaced with deuterium.

[0076] The compounds of the present invention may contain asymmetric carbon atoms, for example, as a result of deuterium substitution or in other ways. Thus, unless otherwise described (or exemplified) herein, the compounds of the present invention can exist as individual enantiomers, or as a mixture of two enantiomers. Thus, the compounds of the present invention can exist as a racemic mixture or a scalemic mixture, or as individual stereoisomers substantially free of other possible stereoisomers. The term "substantially free of other stereoisomers" as used herein means that less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers, and most preferably less than 2% of other stereoisomers are present. In certain embodiments, a compound substantially free of other stereoisomers has an enantiomeric excess (e.e.) of at least about 90%. In other embodiments, a compound substantially free of other stereoisomers has an enantiomeric excess (e.e.) of at least about 95%, 96%, 97%, 98%, 99%, or 99.5%. Methods for obtaining or synthesizing the individual enantiomers of a given compound are known in the art and can be applied to the final compound, starting materials, or intermediates as appropriate.

[0077] Unless otherwise indicated, when a disclosed compound is named or shown by structure without specifying a stereochemical configuration and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0078] The term "stable compound" as used herein refers to compounds that have sufficient stability to allow their manufacture and maintain their integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in the production of therapeutic compounds, isolable or storable intermediate compounds, treating diseases or conditions responsive to therapeutic agents).

[0079] Both "D" and "d" refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "ER" or "er" refers to the enantiomeric ratio. "EE" or "ee" refers to the enantiomeric excess. "AUC" refers to the area under the curve. "Tert" and "t-" each refer to tertiary. "Sec" or "s-" each refer to secondary. "n-" refers to normal. "i-" refers to iso. "US" refers to the United States of America.

[0080] "Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with the corresponding number of deuterium atoms.

[0081] Throughout this specification, a variable part may be referred to generally (e.g., "each R") or specifically (e.g., R 1 , R 2 , R 3 etc.). Unless otherwise indicated, when a variable part is referred to generally, this means including all specific embodiments of that particular variable part.

[0082] Compound In one aspect, the present invention provides compounds and intermediates useful for preparing ruxolitinib and deuterated analogs of ruxolitinib.

[0083] In certain embodiments, the present invention provides a compound of any one of Formulas II, II', III, III', V, V', VIII, VIII', IX, IX', XI, or XI' as described herein; or a salt thereof.

[0084] In certain embodiments, the present invention provides a compound of Formula II'

Chemical Formula

[0085] In certain embodiments, each R 1 ’ is methyl or ethyl; one R 6 is H and the other is a protecting group. In certain embodiments, Y 1 is hydrogen. In certain embodiments, each Y 2 is the same and is deuterium; each Y 3 is the same and is deuterium. In other embodiments, each Y 2 is the same and is hydrogen; each Y 3 is the same and is hydrogen. In certain embodiments, each R 1 ’ is methyl. In certain embodiments, each R 1’ is ethyl. In certain embodiments, each R 6 is H. In certain embodiments, one R 6 is H and the other R 6 is a protecting group. In certain embodiments, the protecting group is a Boc group.

[0086] In certain embodiments, the present invention provides a compound of formula II

Chemical formula

[0087] In certain embodiments, the present invention provides a compound of formula III’

Chemical formula

[0088] In certain embodiments, the present invention provides a compound of formula III

Chemical formula

[0089] In certain embodiments, the present invention provides a compound of formula VII

Chemical formula

[0090] In another embodiment, the present invention provides a compound of formula VIII’ [Chemical Formula] wherein each R 1’ is C 1 -C 10 alkyl (e.g., methyl or ethyl), or C 2 -C 10 alkenyl (e.g., allyl), or two Rs 1’ together with the oxygen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring (e.g., 1,3-dioxolan-2-yl ring, or 1,3-dioxan-2-yl ring, or 1,3-benzodioxolan-2-yl ring); each R 6 is independently selected from H and a protecting group. In certain embodiments, Y 1 is hydrogen; each Y 2 is the same and is hydrogen; each Y 3 is the same and is hydrogen. In other embodiments, Y 1 is deuterium; each Y 2 is the same and is deuterium; each Y 3 is the same and is deuterium. In certain embodiments, each R 1’ is C 1 -C 10 alkyl; in a further embodiment, each R 1’ is methyl or ethyl. In certain embodiments, each R 6 is H. In certain embodiments, one R 6 is H and one R 6 is a protecting group. In certain embodiments, each R 6 is a protecting group. In certain embodiments, the protecting group is a t-butoxycarbonyl group.

[0091] In another embodiment, the present invention provides a compound of formula VIII [Chemical Formula] or a salt thereof; Wherein, R 1 and R 6 are as defined for Compound II. In certain embodiments, Y 1 is hydrogen. In certain embodiments, each Y 2 is the same and is deuterium; each Y 3 is the same and is deuterium. In other embodiments, each Y 2 is the same and is hydrogen; each Y 3 is the same and is hydrogen. In certain embodiments, each R 1 is methyl. In certain embodiments, each R 1 is ethyl. In certain embodiments, each R 6 is H. In certain embodiments, one R 6 is H and the other R 6 is a protecting group. In certain embodiments, the protecting group is a Boc group.

[0092] In yet another embodiment, the present invention provides a compound of Formula XI, or a salt thereof

Chemical formula

[0093] In another embodiment, the present invention provides a compound of formula XI’ or a salt thereof

Chemical formula

[0094] In one embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0095] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0096] ​In another embodiment, the present invention provides a compound represented by the structure [Chemical formula] or a salt thereof.

[0097] In another embodiment, the present invention provides a compound represented by the structure [Chemical formula]

[0098] In another embodiment, the present invention provides a compound represented by the structure [Chemical formula] or a salt thereof.

[0099] In another embodiment, the present invention provides a compound represented by the structure [Chemical formula] or a salt thereof.

[0100] In another embodiment, the present invention provides a compound represented by the structure [Chemical formula] or a salt thereof.

[0101] In another embodiment, the present invention provides a compound represented by the structure [Chemical formula] or a salt thereof.

[0102] In another embodiment, the present invention provides a compound represented by the structure [Chemical formula] or a salt thereof.

[0103] ​ In another embodiment, the present invention relates to a structure

Chemical formula

[0104] In another embodiment, the present invention relates to a structure

Chemical formula

[0105] In another embodiment, the present invention relates to a structure

Chemical formula

[0106] In another embodiment, the present invention relates to a structure

Chemical formula

[0107] In another embodiment, the present invention relates to a structure

Chemical formula

[0108] In another embodiment, the present invention relates to a structure

Chemical formula

[0109] In another embodiment, the present invention relates to a structure

Chemical formula

[0110] In another embodiment, the present invention relates to a structure

Chemical formula

[0111] In another embodiment, the present invention relates to a structure

Chemical formula

[0112] In another embodiment, the present invention relates to a structure

Chemical formula

[0113] In another embodiment, the present invention relates to a structure

Chemical formula

[0114] In another embodiment, the present invention relates to a structure

Chemical formula

[0115] In another embodiment, the present invention relates to a structure

Chemical formula

[0116] In another embodiment, the present invention relates to a structure

Chemical formula

[0117] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0118] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0119] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0120] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0121] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0122] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0123] In another embodiment, the present invention provides a compound represented by the structure

Chemical formula

[0124] In another embodiment, the present invention provides a compound represented by a structure

Chemical formula

[0125] In another embodiment, the present invention provides a compound represented by a structure

Chemical formula

[0126] In yet another embodiment, the present invention provides a compound of formula I (e.g., a compound of formula I prepared by any of the methods disclosed herein) for use in the manufacture of a medicament for the treatment of JAK1- or JAK2-related disorders, including alopecia cicatrisata.

[0127] Method In one aspect, the present invention provides a method for preparing ruxolitinib. In certain embodiments, the method comprises the steps shown below.

Chemical formula

[0128] In one aspect, a method for preparing ruxolitinib or a salt thereof comprises reacting a compound represented by formula E-6 or a salt thereof under conditions such that ruxolitinib or a salt thereof is formed in the presence of an acid. In certain embodiments, the compound represented by formula E-6 or a salt thereof is a D-DBTA salt. In certain embodiments, when the compound represented by formula E-6 or a salt thereof is a salt, the method further comprises contacting the salt of the compound represented by formula E-6 with a base prior to the step of reacting in the presence of an acid. In certain embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl). In certain embodiments, the acid is HCl. In certain embodiments, the acid is present in a molar excess relative to the compound represented by formula E-6 or a salt thereof. In certain embodiments, the step of reacting the compound represented by formula E-6 or a salt thereof in the presence of an acid is carried out in a solvent. In certain embodiments, the solvent is an aprotic solvent. In certain embodiments, the solvent is toluene. In certain embodiments, the solvent is a mixture of solvents, for example, a mixture of aprotic solvents, for example, toluene and an alcoholic solvent, for example, isopropanol. In one embodiment, the solvent is a mixture of toluene and isopropanol. In certain embodiments, the acid is provided in an aqueous solvent and the step of reacting the compound represented by formula E-6 or a salt thereof in the presence of an acid is carried out in a biphasic reaction mixture. In certain embodiments, the step of reacting the compound represented by formula E-6 or a salt thereof in the presence of an acid is carried out at a temperature in the range of 15 to 40 °C, for example, about 25 °C. In certain embodiments, the method further comprises contacting ruxolitinib or a salt thereof with a base, for example, an inorganic base, for example, potassium phosphate, after the step of reacting the compound represented by formula E-6 or a salt thereof in the presence of an acid. In certain embodiments, the base is provided in an aqueous solvent and the step of reacting the compound represented by formula E-6 or a salt thereof in the presence of an acid is carried out in a biphasic reaction mixture.In certain embodiments, the method further comprises, after the step of contacting ruxolitinib, or a salt and a base thereof, with a second acid, such as phosphoric acid, to provide a salt of ruxolitinib, such as a phosphate. In certain embodiments, the step of contacting ruxolitinib with the second acid comprises contacting ruxolitinib with 85% phosphoric acid, optionally in a solvent such as isopropanol or an isopropanol / water mixture.

[0129] In another aspect, the present invention provides a method for preparing CTP-543, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises the steps shown below.

Chemical formula

[0130] Phosphoric acid (H 3 PO 4 ) treatment of CTP-543 produced by the above method yields the phosphate of CTP-543. In certain embodiments, E-5’ is converted to E-6’ via intermediate E-7’ (illustrative embodiments are shown).

Chemical formula

[0131] In one aspect, a method for preparing CTP-543, or a salt thereof, includes reacting a compound represented by formula E-6’, or a salt thereof, in the presence of an acid under conditions such that CTP-543, or a salt thereof, is formed. In certain embodiments, the compound represented by formula E-6’, or a salt thereof, is a D-DBTA salt. In certain embodiments, when the compound represented by formula E-6’, or a salt thereof, is a salt, the method includes an additional step of contacting the salt of the compound represented by formula E-6’ with a base prior to the step of reacting in the presence of an acid. In certain embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl). In certain embodiments, the acid is HCl. In certain embodiments, the acid is present in a molar excess relative to the compound represented by formula E-6’, or a salt thereof. In certain embodiments, the step of reacting the compound represented by formula E-6’, or a salt thereof, in the presence of an acid is carried out in a solvent. In certain embodiments, the solvent is an aprotic solvent. In certain embodiments, the solvent is toluene. In certain embodiments, the solvent is a mixture of solvents, e.g., a mixture of aprotic solvents, e.g., toluene and an alcoholic solvent, e.g., isopropanol. In one embodiment, the solvent is a mixture of toluene and isopropanol. In certain embodiments, the acid is provided in an aqueous solvent and the step of reacting the compound represented by formula E-6’, or a salt thereof, in the presence of an acid is carried out in a biphasic reaction mixture. In certain embodiments, the step of reacting the compound represented by formula E-6’, or a salt thereof, in the presence of an acid is carried out at a temperature in the range of 15 to 40 °C, e.g., about 25 °C. In certain embodiments, the method includes an additional step of contacting CTP-543, or a salt thereof, with a base, e.g., an inorganic base, e.g., potassium phosphate, after the step of reacting the compound represented by formula E-6’, or a salt thereof, in the presence of an acid. In certain embodiments, the method further includes an additional step of contacting CTP-543 with a second acid, e.g., phosphoric acid, to provide a salt of CTP-543, e.g., a phosphate, after the step of contacting CTP-543, or a salt thereof, with a base.In certain embodiments, the step of contacting CTP-543 with a second acid comprises contacting CTP-543 with 85% phosphoric acid, optionally in a solvent such as isopropanol or an isopropanol / water mixture.

[0132] In another aspect, the present invention provides CTP-543, or a salt thereof, prepared by the methods shown above, or by any method disclosed herein for producing CTP-543, or a salt thereof, or a compound of formula I.

[0133] In another aspect, the present invention is a compound of formula I

Chemical formula

Chemical formula

[0134] In certain embodiments, each Y 1 , Y 2 and Y 3 is deuterium. In certain embodiments, Y 1 is hydrogen, and each Y 2 and Y 3 is deuterium. In certain embodiments, Y 1 is hydrogen, and each Y 2 and Y 3 is hydrogen. In certain embodiments, the reacting step comprises reacting a compound of Formula II, or a salt thereof, in the presence of an acid. In certain embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, trifluoroacetic anhydride (TFAA), or combinations thereof. In certain embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or combinations thereof. In certain embodiments, the acid is hydrochloric acid.

[0135] In certain embodiments, the compound of formula II, or a salt thereof, is the D-DBTA salt. In certain embodiments, when the compound of formula II, or a salt thereof, is a salt, the method includes an additional step of contacting the salt of the compound of formula II with a base prior to the step of reacting in the presence of an acid. In certain embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl); in certain embodiments, the acid is HCl. In certain embodiments, the acid is present in a molar excess relative to the compound of formula II or a salt thereof. In certain embodiments, the step of reacting the compound of formula II, or a salt thereof, in the presence of an acid is carried out in a solvent. In certain embodiments, the solvent is an aprotic solvent. In certain embodiments, the solvent is toluene. In certain embodiments, the solvent is a mixture of solvents, e.g., a mixture of aprotic solvents, e.g., toluene, and an alcoholic solvent, e.g., isopropanol. In one embodiment, the solvent is a mixture of toluene and isopropanol. In certain embodiments, the acid is provided in an aqueous solvent and the step of reacting the compound of formula II, or a salt thereof, in the presence of the acid is carried out in a biphasic reaction mixture. In certain embodiments, the step of reacting the compound of formula II, or a salt thereof, in the presence of an acid is carried out at a temperature in the range of 15 to 40 °C, e.g., about 25 °C. In certain embodiments, the method includes an additional step of contacting nilotinib, or a salt thereof, with a base, e.g., an inorganic base, e.g., potassium phosphate, after the step of reacting the compound of formula II, or a salt thereof, in the presence of an acid. In certain embodiments, the base is provided in an aqueous solvent and the step of reacting the compound of formula II, or a salt thereof, in the presence of an acid is carried out in a biphasic reaction mixture. In certain embodiments, the method further includes an additional step of contacting nilotinib with a second acid, e.g., phosphoric acid, after the step of contacting nilotinib, or a salt thereof, with a base to provide a salt of nilotinib, e.g., a phosphate. In certain embodiments, the step of contacting nilotinib with the second acid includes contacting nilotinib with 85% phosphoric acid, optionally in a solvent, e.g., isopropanol.

[0136] In one aspect, the present invention provides a method for preparing a compound of formula I

Chemical formula

Chemical formula

[0137] In certain embodiments, the compound of formula II', or a salt thereof, is a D-DBTA salt. In certain embodiments, when the compound of formula II', or a salt thereof, is a salt, the method includes the further step of contacting the salt of the compound of formula II' with a base prior to the step of reacting in the presence of an acid. In certain embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl). In certain embodiments, the acid is HCl. In certain embodiments, the acid is present in a molar excess relative to the compound of formula II' or a salt thereof. In certain embodiments, the step of reacting the compound of formula II', or a salt thereof, in the presence of an acid is carried out in a solvent. In certain embodiments, the solvent is an aprotic solvent. In certain embodiments, the solvent is toluene. In certain embodiments, the solvent is a mixture of solvents, for example, a mixture of aprotic solvents, for example, toluene, and an alcoholic solvent, for example, isopropanol. In one embodiment, the solvent is a mixture of toluene and isopropanol. In certain embodiments, the acid is provided in an aqueous solvent, and the step of reacting the compound of formula II', or a salt thereof, in the presence of an acid is carried out in a biphasic reaction mixture. In certain embodiments, the step of reacting the compound of formula II', or a salt thereof, in the presence of an acid is carried out at a temperature in the range of 15 to 40 °C, for example, about 25 °C. In certain embodiments, the method includes the further step of contacting nilotinib, or a salt thereof, with a base, for example, an inorganic base, for example, potassium phosphate, after the step of reacting the compound of formula II', or a salt thereof, in the presence of an acid. In certain embodiments, the base is provided in an aqueous solvent, and the step of reacting the compound of formula II', or a salt thereof, in the presence of an acid is carried out in a biphasic reaction mixture. In certain embodiments, the method further includes the further step of contacting nilotinib with a second acid, for example, phosphoric acid, after the step of contacting nilotinib, or a salt thereof, with a base, to provide a salt of nilotinib, for example, a phosphate. In certain embodiments, the step of contacting nilotinib with the second acid includes contacting nilotinib with 85% phosphoric acid, optionally in a solvent, for example, isopropanol.

[0138] In another aspect, the present invention provides a method for preparing a compound of formula II

Chemical formula

Chemical formula

[0139] In another aspect, the present invention provides a method for preparing a compound of formula II

Chemical formula

Chemical formula

[0140] In another aspect, the present invention provides a process for preparing a compound of formula II’

Chemical formula

Chemical formula

[0141] In certain embodiments of the above method for producing a compound of formula II or II’, the hydrogenation catalyst includes transition metals including, but not limited to, rhodium, ruthenium, and iridium. In certain embodiments, the hydrogenation catalyst includes a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L) according to the following formula IV. In certain embodiments, the hydrogenation catalyst includes rhodium. In certain embodiments, the hydrogenation catalyst includes rhodium and a chiral phosphine ligand (L) according to formula IV

Chemical formula

[0142] In certain embodiments, each of R 2a 、R 2b 、R 3a 、R 3b 、and R 4 is hydrogen, and R 5 is norbornyl. In certain embodiments, R 2a 、R 2b 、R 3a 、R 3b 、and R4 Each of them is hydrogen, and R 5 is cyclohexyl. In certain embodiments, the hydrogenation catalyst is present in an amount of 2.5 mol% or less. In certain embodiments, the hydrogenation catalyst is present in an amount of 1 mol% or less.

[0143] In certain embodiments, hydrogen gas is present at a pressure of 15 bar or less. In certain embodiments, hydrogen gas is present at a pressure of 10 bar or less. In certain embodiments, in the presence of a hydrogenation catalyst, the step of reacting a compound of formula III or III' with hydrogen gas is carried out in a solvent selected from dichloromethane (DCM), trifluorotoluene (TFT), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF), methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), isopropanol (iPrOH), hexafluoroisopropanol (HFIP), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), acetic acid (AcOH), and mixtures thereof. In certain embodiments, the solvent is trifluoroethanol (TFE). In certain embodiments, the compound of formula II or II' has an enantiomeric excess of at least 95% of the (R)-enantiomer. In certain embodiments, the compound of formula II or II' has an enantiomeric excess of at least 98% of the (R)-enantiomer.

[0144] In another aspect, the present invention provides a method for preparing a compound of formula III' (or a salt thereof)

Chemical formula

Chemical formula

Chemical formula

[0145] In certain aspects, the present invention provides a method and a compound for preparing a compound of formula I

Chemical formula

[0146] In certain embodiments, the method for preparing the compound of formula I comprises reacting a compound of formula II

Chemical formula

[0147] Certain aspects of the present invention are directed to methods of synthesizing compounds of formula II, which are useful as intermediates for the synthesis of JAK inhibitors, including ruxolitinib and, for example, CTP-543, as disclosed herein. In certain embodiments, the methods include asymmetric hydrogenation to generate an enantiomeric excess of the (R)-enantiomer of the intermediate.

[0148] Some embodiments include a compound of formula II [ka] or a salt thereof, wherein Y 1 is hydrogen or deuterium, and each Y 2is the same and is hydrogen or deuterium, each Y 3 is the same and is hydrogen or deuterium; each R 1 is C 1 ~C 6 alkyl, or together two Rs 1 is C 2 or C 3 form an alkylene moiety; each R 6 is independently selected from H or a protecting group. In certain embodiments, the method comprises reacting a compound of formula III

Chemical formula

[0149] In another aspect, the present invention provides a method for preparing a compound of formula II' (or a salt thereof)

Chemical formula

Chemical formula

[0150] In certain embodiments of the method for preparing a compound of formula II or formula II', the hydrogenation catalyst includes transition metals including, but not limited to, rhodium, ruthenium, and iridium. In certain embodiments, the hydrogenation catalyst is a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand selected from Walphos W022-1 (CAS#849925-29-7), Walphos W003-1 (CAS#565184-29-4), Walphos W002-1 (CAS#565124-32-9), Walphos W005-1 (CAS#494227-30-4), Walphos W006-1 (CAS#894771-25-6), Walphos W008-1 (CAS#821009-34-1), Walphos W009-1 (CAS#894771-28-9), Walphos W012-1 (CAS#565184-30-7), Walphos W029-1 (CAS#18540687-50-7), Walphos W030-1 (CAS#1854067-62-1), Josiphos J002-1 (CAS#155830-69-6), Josiphos J003-1 (CAS#167416-28-6), Josiphos J006-1 (CAS#292638-88-1), Josiphos J007-1 (CAS#360048-63-1), Josiphos J009-1 (CAS#158923-11-6), Mandyphos M 002-1 (CAS#494227-35-), and Taniaphos T002-1 (CAS#1156547-61-3). In certain embodiments, the hydrogenation catalyst is a rhodium-containing catalyst containing rhodium.In certain embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand selected from Walphos W022-1 (CAS#849925-29-7), Walphos W003-1 (CAS#565184-29-4), Walphos W002-1 (CAS#565124-32-9), Walphos W005-1 (CAS#494227-30-4), Walphos W006-1 (CAS#894771-25-6), Walphos W008-1 (CAS#821009-34-1), Walphos W009-1 (CAS#894771-28-9), Walphos W012-1 (CAS#565184-30-7), Walphos W029-1 (CAS#18540687-50-7), Walphos W030-1 (CAS#1854067-62-1), Josiphos J002-1 (CAS#155830-69-6), Josiphos J003-1 (CAS#167416-28-6), Josiphos J006-1 (CAS#292638-88-1), Josiphos J007-1 (CAS#360048-63-1), Josiphos J009-1 (CAS#158923-11-6), Mandyphos M002-1 (CAS#494227-35-), and Taniaphos T002-1 (CAS#1156547-61-3). In certain embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L) according to Formula IV below. In certain embodiments, the hydrogenation catalyst comprises rhodium and Formula IV. [Chemical Formula] and a chiral phosphine ligand (L) according to, wherein R 2a , R 2b , R 3a , R 3b , and R 4 are each independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; R 5 is secondary alkyl, tertiary alkyl, or cycloalkyl.

[0151] In certain embodiments, the reaction of the compound of Formula III to form the compound of Formula II is carried out in the presence of a catalyst / ligand of a Rh catalyst and a ligand (e.g., Walphos W022-1) in an amount of about 0.25 mol% to about 10 mol%. In certain embodiments, the solvent is trifluoroethanol. In certain embodiments, the pressure of hydrogen gas is 10 bar. In certain embodiments, the temperature is in the range of 15 to 25 °C. In certain embodiments, the compound of Formula II has an e.e. of at least 90%, 95%, 96%, 97%, 98%, 99% or 99.5% of the (R)-enantiomer. In another aspect, the present invention provides a method for preparing a compound of Formula II, the method comprising rhodium, and Formula VI

Chemical formula

Chemical formula

[0152] In another aspect, the present invention provides a method for preparing a compound of Formula II', the method comprising rhodium, and Formula VI [Chem.] In the presence of a hydrogenation catalyst comprising a chiral phosphine ligand (L') according to the formula V', a compound of the formula V' [Chem.] or a salt thereof (wherein each of Y 1 , Y 2 , Y 3 , R 1 and R 6 is as defined in formula II') is reacted with hydrogen gas, comprising the step of: wherein each of R 2a , R 2b , R 3a , R 3b , and R 4 is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; R 5is secondary alkyl, tertiary alkyl, or cycloalkyl. In certain embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand according to Formula VI above. In some embodiments, the method for preparing a compound of Formula II or II’ comprises reacting a mixture comprising ≧80% of a compound of Formula III (for preparing a compound of Formula II) or III’ (for preparing a compound of Formula II’) as disclosed herein and ≦20% of a compound of Formula V (for preparing a compound of Formula II) or V’ (for preparing a compound of Formula II’) as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L) according to Formula IV as disclosed herein. In some embodiments, the method comprises reacting a mixture comprising ≧90% of a compound of Formula III (for preparing a compound of Formula II) or III’ (for preparing a compound of Formula II’) as disclosed herein and ≦10% of a compound of Formula V or V’ as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L) according to Formula IV as disclosed herein. In certain embodiments, the method comprises reacting a mixture comprising ≧95% of a compound of Formula III or III’ as disclosed herein and ≦5% of a compound of Formula V or V’ as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L) according to Formula IV as disclosed herein. In certain embodiments, the compound of Formula I has an e.e. of at least 90%, 95%, 96%, 97%, 98%, 99% or 99.5% (of the (R)-enantiomer). In certain embodiments, the hydrogenation catalyst disclosed above comprises a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L) according to Formula IV as disclosed herein.In certain embodiments, a method for preparing a compound of Formula II comprises reacting a mixture comprising a molar ratio of ≧80% of a compound of Formula V and ≦20% of a compound of Formula III as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L’) of Formula VI as disclosed herein. In some embodiments, the method comprises reacting a mixture comprising a molar ratio of ≧90% of a compound of Formula V and ≦10% of a compound of Formula III as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L’) of Formula VI as disclosed herein. In some embodiments, the method comprises reacting a mixture comprising a molar ratio of ≧95% of a compound of Formula V and ≦5% of a compound of Formula III as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L’) of Formula VI as disclosed herein. In certain embodiments, the hydrogenation catalyst disclosed above comprises a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L’) of Formula VI as disclosed herein.

[0153] In certain embodiments, a method for preparing a compound of formula II’ comprises reacting a mixture comprising a molar ratio of ≧80% of a compound of formula V as disclosed herein and ≦20% of a compound of formula III’ as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L’) of formula VI as disclosed herein. In some embodiments, the method comprises reacting a mixture comprising a molar ratio of ≧90% of a compound of formula V as disclosed herein and ≦10% of a compound of formula III’ as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L’) of formula VI as disclosed herein. In some embodiments, the method comprises reacting a mixture comprising a molar ratio of ≧95% of a compound of formula V as disclosed herein and ≦5% of a compound of formula III’ as disclosed herein with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L’) of formula VI as disclosed herein. In certain embodiments, the hydrogenation catalyst disclosed above comprises a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L’) of formula VI as disclosed herein.

[0154] In some embodiments of the formulas described herein, R 5 is selected from norbornyl, cyclohexyl, cyclopentyl, and tert-butyl. In some embodiments, R 5 is norbornyl. In some embodiments, R 5 is cyclohexyl.

[0155] In some embodiments of the formulas described herein, each of R 2a , R 2b , R 3a , R 3b , and R 4 is hydrogen. In some embodiments, R 2a , R 2b , and R 4Each of them is hydrogen, and R 3a and R 3b are each methyl or each trifluoromethyl. In some embodiments, R 2a and R 2b each are hydrogen, R 4 is methoxy, and R 3a and R 3b are each methyl. In some embodiments, R 2a , R 2b , R 3a , and R 3b each are hydrogen, and R 4 is methoxy, trifluoromethyl, or methyl. In some embodiments, R 3a , R 3b , and R 4 each are hydrogen, one of R 2a and R 2b is hydrogen, and the other of R 2a and R 2b is methyl. In some embodiments, R 2a , R 2b , R 3a , R 3b , and R 4 each are hydrogen, and R 5 is selected from norbornyl, cyclohexyl, cyclopentyl, and tert-butyl. In some embodiments, R 2a , R 2b , R 3a , R 3b , and R 4 each are hydrogen, and R 5 is norbornyl. In some embodiments, R 2a , R 2b , R 3a , R 3b , and R 4 each are hydrogen, and R 5 is cyclohexyl.

[0156] In some embodiments of the formulas described herein, the hydrogenation catalyst is of the formula [Rh(L 1 )(L 2 )] + NC- formed by mixing a rhodium precatalyst with a chiral phosphine ligand (L) of formula IV or (L’) of formula VI; wherein L 1 and L 2 are the same or different, and L 1 and L 2 are each independently a pair of monodentate ligands or bidentate ligands, where the monodentate ligand is selected from alkene ligands and solvent ligands, and the bidentate ligand is a diene; NC - is a non-coordinating counterion selected from tetrafluoroborate, triflate, hexafluorophosphate, hexafluoroantimonate, and perchlorate. In some embodiments, the alkene ligand may have 1, 2, 3, 4, or more double bonds. In some embodiments, the alkene ligand is selected from ethylene, cyclooctene, and norbornene. In some embodiments, the solvent ligand is selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, trifluoroethanol, and isopropanol. In some embodiments, the diene ligand is selected from 1,5-cyclooctadiene (COD), 1,5-hexadiene, and norbornadiene. In some embodiments, the rhodium precatalyst is bis(norbornadiene)rhodium(I) tetrafluoroborate or [Rh(COD) 2 + BF 4 - In some embodiments, the rhodium precatalyst is [Rh(COD) 2 + BF 4 - .

[0157] In some embodiments, the hydrogenation catalyst comprises [Rh(L 1 )(L)] + BF 4 - wherein (L 1 ) is a pair of monodentate ligands or bidentate ligands, and (L) is

Chemical formula

[0158] In some embodiments, the hydrogenation catalyst is [Rh(L 1 )(L’)] + BF 4 - and includes, wherein (L 1 ) is a pair of monodentate ligands or bidentate ligands, and (L’) is

Chemical formula

[0159] In some embodiments, the hydrogenation catalyst is [Rh(L 1 )(L)] + BF 4 - and includes, wherein (L 1 ) is a pair of monodentate ligands or bidentate ligands, and (L) is

Chemical formula

[0160] In some embodiments, the hydrogenation catalyst is [Rh(L 1 )(L’)] + BF 4 - and includes, wherein (L 1 ) is a pair of monodentate ligands or bidentate ligands, and (L’) is

Chemical formula

[0161] R 5 In some embodiments where R is norbornyl, the norbornyl group is attached to the phosphorus atom in any of the following configurations shown in Table 1 below.

[0162]

Table 1

[0163] Here, (1S)-exo-norbornyl is

Chemical formula

Chemical formula

[0164] In certain embodiments, the present invention provides a method for preparing a compound of formula II [Chem.] or a salt thereof; wherein Y 1 is hydrogen; each Y 2 is the same and is hydrogen or deuterium; each Y 3 is the same and is hydrogen or deuterium; each R 1 is C 1 ~C 6 alkyl or two R 1 together form a C 2 or C 3 alkylene moiety; each R 6 is independently selected from H or a protecting group. In certain embodiments, this method comprises reacting a compound of formula XI [Chem.] or a salt thereof (wherein Y 2 , Y 3 , R 1 , and R 6each of which is as defined in Formula II) and hydrogen gas to form a compound of Formula II. In certain embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium. In certain embodiments, the hydrogenation catalyst has the formula VI [Chemical Formula] (wherein R 2a , R 2b , R 3a , R 3b , and R 4 are each independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; R 5 is aryl, secondary alkyl, tertiary alkyl, or cycloalkyl), and Formula XII [Chemical Formula] (wherein R 2a , R 2b , R 3a , R 3b , and R 4 are each independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; R 5 is secondary alkyl, tertiary alkyl, or cycloalkyl)), and further comprises a chiral phosphine ligand selected from). In certain embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand selected from Walphos W002-2 (CAS#1854067-25-6) and Josiphos J002-1 (CAS#155830-69-6). In certain embodiments, the compound of Formula I has an e.e. of at least 90%, 95%, 96%, 97%, 98%, 99% or 99.5% of the (R)-enantiomer.

[0165] In certain embodiments, the present invention provides a method for preparing a compound of Formula II' [Chemical Formula] or a salt thereof; wherein Y1 is hydrogen, and Y 2 , Y 3 , R 1 and R 6 are defined above for formula II'. In certain embodiments, the method involves, in the presence of a hydrogenation catalyst, a compound of formula XI'

Chemical formula

Chemical formula

Chemical formula

[0166] In some embodiments of the above method for preparing a compound of Formula II or II', the amount of the hydrogenation catalyst containing rhodium and the chiral phosphine ligand, or the amount of the hydrogenation catalyst containing rhodium, or the amount of the chiral phosphine ligand is 0.1 - 10 mol%, 0.5 - 8 mol%, 1 - 6 mol%, 1.5 - 5 mol%, 2 - 4 mol%, or 2.5 - 3 mol%. In some embodiments, the amount of the hydrogenation catalyst containing rhodium and the chiral phosphine ligand, or the amount of the hydrogenation catalyst containing rhodium, or the amount of the chiral phosphine ligand is 5 mol% or less, 2.5 mol% or less, 2 mol% or less, 1.5 mol% or less, 1 mol% or less, or 0.5 mol% or less. In some embodiments, the amount is 5 mol% or less. In some embodiments, the amount is 2.5 mol% or less. In some embodiments, the amount is 1 mol% or less. In some embodiments, the amount of the hydrogenation catalyst disclosed above includes the amount of the hydrogenation catalyst containing a transition metal selected from rhodium, ruthenium, and iridium, and the chiral phosphine ligand, or the amount of the hydrogenation catalyst containing a transition metal selected from rhodium, ruthenium, and iridium.

[0167] In some embodiments, the reacting step further includes treating with an additive (non-limiting examples of which are tetrafluoroboric acid (HBF 4 ). In some embodiments, HBF 4The amount is in the range of 0.5 to 1.0 equivalents.

[0168] In some embodiments, the reacting step is carried out in a solvent. Non-limiting examples of the solvent include dichloromethane (DCM), trifluorotoluene (TFT), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF), methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), isopropanol (iPrOH), hexafluoroisopropanol (HFIP), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), acetic acid (AcOH), and mixtures thereof. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is trifluoroethanol. In some embodiments, the solvent is hexafluoroisopropanol (HFIP). In some embodiments, the solvent is DCM and the reacting step further comprises treatment with HBF 4 In some embodiments, the solvent is TFE and the reacting step further comprises treatment with HBF 4 In some embodiments, the reacting step further comprises treatment with HBF.

[0169] In certain embodiments, the solvent is present in an amount of 1 to 50 volumes (vol), 2.5 to 20 volumes, 5 to 15 volumes, or 5 to 10 volumes. In certain embodiments, the solvent is present in an amount of 10 volumes. In certain embodiments, the solvent is present in an amount of 5 volumes. In certain embodiments, the solvent is present in an amount of 2.5 volumes.

[0170] In certain embodiments, hydrogen gas is present at a pressure in the range of 1 to 200 bar, 5 to 100 bar, 10 to 50 bar, or 15 to 30 bar in the reaction step. In certain embodiments, hydrogen gas is present at a pressure of 50 bar or less in the reaction step. In certain embodiments, hydrogen gas is present at a pressure of 20 bar or less in the reaction step. In certain embodiments, hydrogen gas is present at a pressure of 15 bar or less. In certain embodiments, hydrogen gas is present at a pressure of 10 bar or less. In certain embodiments, hydrogen gas is present at a pressure of 5 bar or less.

[0171] In certain embodiments, the method forms a compound of formula II or II' having an enantiomeric excess of at least 80% of the (R)-enantiomer. In some embodiments, the method forms a compound of formula II or II' having an enantiomeric excess of at least 90% of the (R)-enantiomer. In some embodiments, the method forms a compound of formula II or II' having an enantiomeric excess of at least 95% of the (R)-enantiomer. In some embodiments, the method forms a compound of formula II or II' having an enantiomeric excess of at least 97% of the (R)-enantiomer. In some embodiments, the method forms a compound of formula II or II' having an enantiomeric excess of at least 98% of the (R)-enantiomer. In some embodiments, the method forms a compound of formula II or II' having an enantiomeric excess of at least 99% of the (R)-enantiomer.

[0172] In certain embodiments of the above method for preparing a compound of formula II or II', the method includes the further step of treating the compound of formula II or II' with an acid to form a salt of the compound of formula II or II'.

[0173] Certain embodiments of the present invention are directed to a method for synthesizing a compound of Formula III that is useful as an intermediate for the synthesis of ruxolitinib and JAK inhibitors, such as CTP-543 as disclosed herein.

[0174] In certain embodiments, the present invention provides a method for preparing a compound of Formula III

Chemical formula

Chemical formula

Chemical formula

[0175] In another aspect, the present invention provides a method for preparing a compound of formula III’ (or a salt thereof)

Chemical formula

Chemical formula

Chemical formula

[0176] Certain aspects of the present invention are directed to a method for synthesizing a compound of formula XI that is useful as an intermediate for the synthesis of ruxolitinib and JAK inhibitors, including, for example, CTP-543 as disclosed herein. In certain embodiments, the present invention provides a compound of formula XI [Chemical] or a method for preparing its salt; a compound of formula III [Chemical] or its salt; reacting with a base to form a compound of formula XI; wherein Y 1 is hydrogen or deuterium, each Y 2 is the same and is hydrogen or deuterium, each Y 3 is the same and is hydrogen or deuterium, each R 1 is C 1 ~C 6 alkyl, or two Rs together form a C 1 is C 2 or C 3 alkylene moiety; each R 6 is independently selected from H or a protecting group. Non-limiting examples of the base include lithium hydroxide, sodium hydroxide, and potassium hydroxide. In some embodiments, the reacting step is performed in a solvent. Non-limiting examples of the solvent include dimethylacetamide (DMAc), water (H 2 2O), and combinations thereof. In some embodiments, the reaction is performed at one or more temperatures in the range from 0 °C to room temperature, for example, in the range from 0 to 23 °C.

[0177] Certain aspects of the present invention are directed to a method for synthesizing a compound of formula XI, which is useful as an intermediate for the synthesis of ruxolitinib and JAK inhibitors, including, for example, CTP-543 as disclosed herein. In certain embodiments, the present invention provides a compound of formula XI' [Chemical] or a method for preparing its salt; this method comprises a compound of formula III' [Chemical] or its salt; reacting with a base to form a compound of formula XI'; wherein Y 1 is hydrogen or deuterium, and Y 2 , Y 3 , R 1’ , and R 6 each is as defined in formula II'. In certain embodiments, Y 1 is hydrogen. In certain embodiments, each Y 2 is the same and is deuterium; each Y 3 is the same and is deuterium. In other embodiments, each Y 2 is the same and is hydrogen; each Y 3 is the same and is hydrogen. In certain embodiments, each R 1’ is methyl. In certain embodiments, each R 1’ is ethyl. In certain embodiments, each R 6 is H. In certain embodiments, one R 6 is H and the other R 6 is a protecting group. In certain embodiments, the protecting group is a Boc group. Non-limiting examples of the base include lithium hydroxide, sodium hydroxide, and potassium hydroxide. In some embodiments, the reacting step is carried out in a solvent. Non-limiting examples of the solvent include dimethylacetamide (DMAc), water (H 2 O), and combinations thereof. In some embodiments, the reaction is carried out at one or more temperatures in the range from 0 °C to room temperature, for example, at a temperature in the range from 0 to about 23 °C.

[0178] Certain aspects of the present invention are directed to a method for synthesizing a compound of formula VIII that is useful as an intermediate for the synthesis of ruxolitinib and JAK inhibitors including, for example, CTP-543 as disclosed herein. In certain embodiments, the method for preparing a compound of formula VIII (or a salt thereof)

Chemical formula

[0179] Certain embodiments of the present invention relate to a method for preparing a compound of formula VIII' (or a salt thereof) [Chemical formula] which method comprises reacting a compound of formula IX' (or a salt thereof) [Chemical formula] with a compound represented by the formula [Chemical formula] (BPin-pyrazole) (or another pyrazole boronic acid ester) and a catalytic amount of a palladium catalyst (e.g., Pd(PPh 3 ) 4 ) in the presence of a base; in formulas VIII' and IX', each R 1’ is C 1 ~C 10 alkyl (e.g., methyl or ethyl), or C 2 ~C 10 alkenyl (e.g., allyl), or two Rs 1’together with the oxygen atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclic ring (e.g., 1,3-dioxolan-2-yl ring, or 1,3-dioxan-2-yl ring, or 1,3-benzodioxolan-2-yl ring); each R 6 is independently selected from H and a protecting group. In certain embodiments, each R 1’ is C 1 ~C 10 alkyl; in a further embodiment, each R 1’ is methyl or ethyl. In certain embodiments, each R 6 is H. In certain embodiments, one R 6 is H and one R 6 is a protecting group. In certain embodiments, each R 6 is a protecting group. In certain embodiments, the protecting group is a t-butoxycarbonyl group. In certain embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0180] In certain embodiments of Formula IX or IX’, X is Cl. In certain embodiments, the palladium catalyst is Pd(PPh 3 ) 4 or a combination of Pd 2 (dba) 3 and XPhos. In certain embodiments, the catalytic amount of the palladium catalyst ranges from 0.1 to 10 mol%, 0.5 to 5 mol%, 3 to 6 mol%, or 1 to 2.5 mol%. In certain embodiments, non-limiting examples of the base include potassium carbonate and disodium hydrogen phosphate dihydrate. In some embodiments, the step of reacting is carried out in a solvent. Non-limiting examples of the solvent include n-butanol, 1,4-dioxane, THF, and combinations thereof. In some embodiments, the reaction is carried out at a temperature ranging from room temperature to 120 °C, or 60 to 90 °C, or one or more temperatures of the reflux temperature of the solvent.

[0181] In certain embodiments of Formulas II, II', III, III', V, V', VIII, VIII', IX, IX', XI or XI', the protecting group is t-butoxycarbonyl (Boc), triflyl (Tf, SO 2 -CF 3 ), trifluoroacetyl (F 3 -Ac), and trityl (Tr, CPh 3 ). In certain embodiments, both R 6 are t-butoxycarbonyl (Boc). In certain embodiments, one R 6 is t-butoxycarbonyl (Boc) and the other R 6 is H. In certain embodiments, one R 6 is triflyl (Tf) and the other R 6 is H. In certain embodiments, one R 6 is trifluoroacetyl (F 3 -Ac) and the other R 6 is H. In certain embodiments, one R 6 is trityl (Tr) and the other R 6 is H. In certain embodiments, both R 6 are H.

[0182] In certain embodiments of Formulas II, II', III, III', V, VIII, IX, IX', XI, or XI', each R 1 or R 1’ is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, both R 1 or R 1’ are methyl. In certain embodiments, two R 1 or R 1’ together form a C 2 or C 3 alkylene moiety to form a heterocyclic ring selected from

Chemical Formula

[0183] In certain embodiments of Formula I, II, II', III, III', V, V', VII, or VII', Y 1 , Y 2 , and Y 3 are each hydrogen. In certain embodiments of Formula I, II, II', III, III', V, V', VII, or VII', Y 1 , Y 2 , and Y 3 are each deuterium. In certain embodiments of Formula I, II, III, V, or VII, Y 1 is hydrogen and Y 2 and Y 3 are each deuterium. In certain embodiments of Formula I, II, II', III, III', V, V', VII, or VII', Y 1 is at least 95% hydrogen. In certain embodiments of Formula I, II, II', III, III', V, V', VII, or VII', Y 1 is at least 96% hydrogen. In some embodiments, Y 1 is at least 97% hydrogen. In some embodiments, Y 1 is at least 98% hydrogen. In some embodiments, Y 1 is at least 99% hydrogen.

[0184] In certain embodiments, a compound of formula I, II, II’, III, III’, V, V’, VII, VII’, XI or XI’ has at least 90% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of formula I, II, II’, III, III’, V, V’, VII, VII’, XI or XI’ has at least 95% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of formula I, II, II’, III, III’, V, V’, VII, VII’, XI or XI’ has at least 97.5% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of formula I, II, II’, III, III’, V, V’, VII, VII’, XI or XI’ has at least 98% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of formula I, II, II’, III, III’, V, V’, VII, VII’, XI or XI’ has at least 99% deuterium incorporation at each of the designated deuterium atoms.

[0185] In certain aspects, the invention provides a compound of formula I

Chemical formula

Chemical formula

Chemical formula

[0186] The present invention further provides a method for preparing a compound of the present invention, such as a compound of formula I, or a compound of formula II or II', or a compound of formula III or III', or a compound of formula VII, or a compound of formula VIII or VIII', using a plurality of the methods described herein. For example, the present invention first prepares a compound of VIII or VIII' as disclosed herein, and subsequently prepares a compound of formula III or III' from the compound of formula VIII or VIII' as disclosed herein, and then prepares a compound of formula I from the compound of formula III or III' as disclosed herein, thereby providing a method for preparing a compound of formula I.

[0187] The present invention further provides a method for preparing a compound of the present invention, such as a compound of formula I, or a compound of formula II or II', or a compound of formula III or III', or a compound of formula VII, or a compound of formula VIII or VIII', using a plurality of the methods described herein. For example, the present invention first prepares a compound of VIII or VIII' as disclosed herein, and subsequently prepares a compound of formula III or III' from the compound of formula VIII or VIII' as disclosed herein, and then prepares a compound of formula I from the compound of formula III or III' as disclosed herein, thereby providing a method for preparing a compound of formula I.

[0188] Certain embodiments of the method of the present invention relate to a compound of formula I that is substantially free of impurities, wherein Y 1 , Y 2 , and Y 3Each of them provides a compound defined as in Formula II (e.g., CTP-543 or ruxolitinib), or a pharmaceutically acceptable salt thereof (e.g., CTP-543 phosphate or ruxolitinib phosphate). In some embodiments, the compound of Formula I has a purity of at least 98%, 98.5%, 99.0%, 99.5%, 99.8%, 99.9%, or 99.95% (as measured by HPLC and / or NMR). In some embodiments, the compound of Formula I contains less than 0.30%, less than 0.15%, less than 0.10%, less than 0.05%, less than 0.01%, less than 0.005%, less than 0.001%, less than 0.0005%, or less than 0.0001% of the compound of Formula X, where Y 1 , Y 2 , and Y 3 each of which is defined as in Formula II.

Chemical Structure

[0189] Some embodiments provide CTP-543 containing a compound represented by a structure of less than 0.30%, less than 0.15%, less than 0.10%, less than 0.05%, less than 0.01%, less than 0.005%, less than 0.001%, less than 0.0005%, or less than 0.0001%

Chemical Structure

Chemical Structure

[0190] or a compound of E-6’

Chemical Structure

[0191] In another aspect, the present invention provides a compound 15 [Chem.] or 15' [Chem.] Provided is a method for purifying. This method includes contacting compound 15 or 15' with an acid to form a salt of the compound of formula 15 or 15', and crystallizing the crystalline salt of the compound of formula 15 or 15'. In certain embodiments, the acid is a chiral acid, for example, D-dibenzoyl tartaric acid. In certain embodiments, the step of contacting the compound of formula 15 or 15' with the acid is carried out in a solvent. In certain embodiments, the solvent is trifluoroethanol, acetonitrile, isopropyl acetate, or a mixture thereof. In certain embodiments, the crystalline salt of the compound of formula 15 or 15' has an enantiomeric ratio (er) of at least 99:1, or at least 99.5:0.5, or at least 99.6:0.4.

[0192] Intermediate Certain embodiments of the present invention are directed to further intermediates useful, for example, in the preparation of compounds of formula I.

[0193] In certain embodiments, the intermediate is a compound of formula II

Chemical formula

Chemical formula

[0194] In certain embodiments, the intermediate is a compound of formula III

Chemical formula

[0195] In certain embodiments of Formula II, III, or XI, the protecting group is selected from t-butoxycarbonyl (Boc), triflyl (Tf, SO 2 -CF 3 ), trifluoroacetyl (F 3 -Ac), and trityl (Tr, CHPh 3 ). In certain embodiments, both Rs 6 are t-butoxycarbonyl (Boc). In certain embodiments, one R 6 is t-butoxycarbonyl (Boc) and the other R 6 is H. In certain embodiments, one R 6 is triflyl (Tf) and the other R 6 is H. In certain embodiments, one R 6 is trifluoroacetyl (F 3 -Ac) and the other R 6 is H. In certain embodiments, one R 6 is trityl (Tr) and the other R 6 is H. In certain embodiments, both Rs 6 are H.

[0196] In certain embodiments of Formula II, III, or XI, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments of Formula II, III, or XI, R 1 is methyl or ethyl. In certain embodiments of Formula II, III, or XI, both Rs1 is methyl.

[0197] In another embodiment, the present invention provides a compound of formula VII

Chemical formula

Chemical formula

Chemical formula

[0198] In certain embodiments of formula II, III or VII, or formula I, II', II', or VII', each of Y 1 , Y 2 , and Y 3 is hydrogen. In certain embodiments of formula II, III or VII, or formula I, II', II', or VII', each of Y 1 , Y 2 , and Y 3 is deuterium. In certain embodiments of formula II, III or VII, or formula I, II', II', or VII', Y 1 is hydrogen, and each of Y 2 and Y 3 is deuterium. In certain embodiments of formula II, III or VII, or formula I, II', II', or VII', Y 1is at least 95% hydrogen. In certain embodiments of Formula II, III, or VII, or Formula I, II’, II’, or VII’, Y 1 is at least 96% hydrogen. In some embodiments, Y 1 is at least 97% hydrogen. In some embodiments, Y 1 is at least 98% hydrogen. In some embodiments, Y 1 is at least 99% hydrogen.

[0199] In certain embodiments, a compound of Formula II, III, VII, or XI, or Formula I, II’, II’, VII’, or XI’ has at least 90% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of Formula II, III, VII, or XI, or Formula I, II’, II’, VII’, or XI’ has at least 95% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of Formula II, III, VII, or XI, or Formula I, II’, II’, VII’, or XI’ has at least 97% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of Formula II, III, VII, or XI, or Formula I, II’, II’, VII’, or XI’ has at least 98% deuterium incorporation at each of the designated deuterium atoms. In certain embodiments, a compound of Formula II, III, VII, or XI, or Formula I, II’, II’, VII’, or XI’ has at least 99% deuterium incorporation at each of the designated deuterium atoms.

[0200] In another series of embodiments of the formulas described herein, any atom not designated as deuterium in any of the embodiments described herein is present at its natural isotopic abundance.

[0201] In another embodiment, the invention is a compound of Formula VIII

Chemical formula

[0202] In certain embodiments of Formula VIII, the protecting group is selected from t-butoxycarbonyl (Boc), triflyl (Tf, SO 2 -CF 3 ), trifluoroacetyl (F 3 -Ac), and trityl (Tr, CHPh 3 ). In certain embodiments, both Rs 6 are t-butoxycarbonyl (Boc). In certain embodiments, one R 6 is t-butoxycarbonyl (Boc) and the other R 6 is H. In certain embodiments, one R 6 is triflyl (Tf) and the other R 6 is H. In certain embodiments, one R 6 is trifluoroacetyl (F 3 -Ac) and the other R 6 is H. In certain embodiments, one R 6 is trityl (Tr) and the other R 6 is H. In certain embodiments, both Rs 6 are H. In certain embodiments of Formula VIII, both Rs 1 are methyl.

[0203] In another embodiment, the present invention provides a compound of Formula IX

Chemical formula

[0204] In certain embodiments of Formula IX, the protecting group is selected from t-butoxycarbonyl (Boc), triflyl (Tf, SO 2 -CF 3 ), trifluoroacetyl (F 3 -Ac), and trityl (Tr, CHPh 3 ). In certain embodiments, both Rs 6 are t-butoxycarbonyl (Boc). In certain embodiments, one R 6 is t-butoxycarbonyl (Boc) and the other R 6 is H. In certain embodiments, one R 6 is triflyl (Tf) and the other R 6 is H. In certain embodiments, one R 6 is trifluoroacetyl (F 3 -Ac) and the other R 6 is H. In certain embodiments, one R 6 is trityl (Tr) and the other R 6 is H. In certain embodiments, both Rs 6 are H. In certain embodiments of Formula IX, both Rs 1 are methyl. In certain embodiments of Formula XI, R 1 is not ethyl.

[0205] In certain embodiments of Formula IX, X is Cl.

[0206] In another embodiment, the invention provides a compound of Formula IX’

Chemical Formula

[0207] In certain embodiments of Formula IX, the protecting group is selected from t-butoxycarbonyl (Boc), triflyl (Tf, SO 2 -CF 3 ), trifluoroacetyl (F 3 -Ac), and trityl (Tr, CPh 3 ). In certain embodiments, both Rs 6 are t-butoxycarbonyl (Boc). In certain embodiments, one R 6 is t-butoxycarbonyl (Boc) and the other R 6is H. In certain embodiments, one R 6 is triflyl (Tf), and the other R 6 is H. In certain embodiments, one R 6 is trifluoroacetyl (F 3 -Ac), and the other R 6 is H. In certain embodiments, one R 6 is trityl (Tr), and the other R 6 is H. In certain embodiments, both Rs 6 are H. In certain embodiments of formula IX’, both Rs 1 are methyl. In certain embodiments of formula IX’, X is Cl. In certain embodiments of formula XI’, R 1’ is not ethyl.

[0208] The synthesis of the compounds of formulas II - XII can be readily achieved by one of ordinary skill in synthetic chemistry by reference to the exemplary syntheses disclosed herein.

[0209] Such methods can be carried out using the corresponding deuterated reagents and / or intermediates, and optionally other isotope-containing reagents and / or intermediates, which synthesize the compounds described herein, or by implementing standard synthetic protocols known in the art for introducing isotope atoms into chemical structures.

[0210] As used herein, the terms method and process are interchangeable.

Example

[0211] Scheme 1: Preparation of Ruxolitinib Phosphate

Chem.

[0212] Scheme 2: Preparation of D8-Ruxolitinib (CTP-543)

Chem.

[0213] Scheme 3: Preparation of Enol Triflates (2-Cyano-1-(cyclopentyl)vinyl Trifluoromethanesulfonate and 2-Cyano-1-(2,2,3,3,4,4,5,5-D8-cyclopentyl)vinyl Trifluoromethanesulfonate)

Chemical Structure

[0214] As shown in Scheme 3 above, 2-Cyano-1-(cyclopentyl)vinyl trifluoromethanesulfonate (enol triflate 16) can be prepared from the corresponding beta-ketonitrile, which can be prepared from cyclopentanecarboxylic acid, methyl ester (readily available from commercially available cyclopentanecarboxylic acid). Enol triflate 16 is synthesized as a mixture of Z and E isomers, which can optionally be separated into 16Z and 16E. Similarly, deuterated enol triflate 16' can be prepared from the corresponding deuterated precursor. Enol triflate 16' is synthesized as a mixture of Z and E isomers, which can optionally be separated into 16Z' and 16E'. Deuterated enol triflate 16', 16Z', or 16E' can replace enol triflate 16, 16Z, or 16E in any of the syntheses disclosed herein to produce CTP-543 or a pharmaceutically acceptable salt thereof.

[0215] A) Preparation of Beta-Ketonitrile To a three-necked 500 mL European style flask equipped with a mechanical stirrer and a thermocouple and flushed with nitrogen, a THF solution of NaHMDS was added via syringe (173 mL, 343.2 mmol, 2.2 equivalents; 2 M solution in THF), and then the yellow solution was added with N 2It was cooled to -14.6 °C below. To the cold solution, a solution of methylcyclopentanecarboxylate (20 g, 156 mmol, 1.0 equiv) in MeCN (9.8 mL, 187.2 mmol, 1.2 equiv) was added dropwise via a syringe; the flask was rinsed with anhydrous THF (10 mL), and the rinsing solution was added to the reaction mixture. The addition time was 50 minutes, and during that period, the internal temperature was maintained below -3 °C, which resulted in a turbid dilute slurry. The mixture was stirred at about -10 °C for 10 minutes and then warmed to 20 °C over a 1-hour period. Stirring was continued overnight at 24 °C, and a very thick slurry with a crusty top layer was formed. The mixture was cooled to about 3 °C, and then cold 6N HCl (about 5 °C, 130 mL) was added little by little, keeping the internal temperature mainly below 27 °C. After quenching was complete, the mixture was stirred, warmed to 22 °C, transferred to a separatory funnel, and the organic and aqueous layers were collected. The aqueous layer (140 mL) was extracted with MTBE (2 × 55 mL). The combined organic layers were washed with saturated NaHCO 3 (60 mL), 1N HCl (2 × 50 mL), 20% aqueous NaCl solution (50 mL), and finally water (2 × 50 mL). The thus-obtained organic layer was concentrated in a rotary evaporator (45 °C) to remove organic volatiles, and residual water was azeotroped using additional MTBE (2 ×). The crude product was obtained as an amber liquid (weight = 20.09 g). 1 1H NMR (CDCl 3 ) showed the desired product with a very clean profile. Molar yield = 93%. 1 1H NMR (CDCl 3 ) δ: 3.50 (s, 3H), 3.07 (quintet, J = 8 Hz, 1H), 1.98 - 1.54 (m, 8H)

[0216] B) Preparation of 2-cyano-1-(cyclopentyl)vinyl trifluoromethanesulfonate 16 A 1 L jacketed reactor equipped with a mechanical stirrer and a thermocouple was charged with a solution of β-ketonitrile in toluene (50 g, 364 mmol, solution weight = 213.6 g, w% = 23.4%) under nitrogen. The solution was cooled to 0 °C, and subsequently N-methylmorpholine (50.1 g, 455.5 mmol, 1.25 eq) was added while maintaining the batch temperature below 2 °C. At approximately 0 °C, Tf 2 O (111.5 g, 395.2 mmol, 1.09 eq) was added dropwise over an 80-minute period while maintaining the batch temperature below 5 °C. The reaction mixture was stirred at low temperature for approximately 2 hours. GC analysis showed >99.8% conversion. Water (300 mL) was added to the cold mixture, and the cold biphasic mixture thus obtained was warmed to ambient temperature. The upper organic layer was collected, washed with water (300 mL), and then partially concentrated in a rotary evaporator to give a solution of enol-triflate in toluene (163.2 g). 1 1H NMR (CDCl 3 ) assay analysis showed that the w / w% for enol-triflate 16 was 55% as a mixture of E / Z isomers (Z:E, approximately 89:11). Corrected weight = 88.9 g, molar yield = 91%. 1 1H NMR (CDCl 3 ) δ: 16Z-isomer---5.33 (d, J = 4 Hz, 1H), 2.99 (dq, J = 8 Hz, 4 Hz, 1H), 2.18 - 1.99 (m, 2H), 1.89 - 1.68 (m, 4H), 1.67 - 1.51 (m, 2H); 16E-isomer---5.54 (s, 1H), 3.37 (q, J = 8 Hz, 1H), 2.18 - 1.51 (m, 8H).

[0217] The corresponding D8-deuterated compound 16’ (2-cyano-1-(2,2,3,3,4,4,5,5-D8-cyclopentyl)vinyl trifluoromethanesulfonate) can be prepared using a similar procedure starting from methyl 2,2,3,3,4,4,5,5-D8-cyclopentanecarboxylic acid (which can be prepared in a manner similar to the preparation of 1,2,2,3,3,4,4,5,5-D9-cyclopentanecarboxylic acid; see, for example, U.S. Patent No. 9,249,149). Similar to enol triflate 16, 2-cyano-1-(2,2,3,3,4,4,5,5-D8-cyclopentyl)vinyl trifluoromethanesulfonate 16’ is synthesized as a mixture of isomers, which can optionally be separated into 16Z’ and 16E’.

[0218] Scheme 4: Preparation of Ruxolitinib (Free Base)

Chemical formula

[0219] Example 1: Step 1: Preparation of 4,6-dichloro-5-(2,2-dimethoxyethyl)pyrimidine (C-2)

Chemical formula

[0220] b) Toluene, TsOH (1 mol%): To a suspension of Compound B-1 (635 g, 88% assay, 2.93 mol) in toluene (2988 g) was added trimethyl orthoformate (371 g, 3.50 mol, 1.2 eq). The batch was cooled to 20 °C and solid TsOH·H 2 O (5.76 g, 0.03 mol, 0.01 eq) was added. The jacket temperature was lowered to 16 °C for 10 minutes during a slight exotherm to maintain the batch temperature, and then adjusted to 20 °C. The suspension was stirred at 20 °C for 2 hours, then the jacket temperature was raised to 40 °C over 11.5 hours, and then the jacket was returned to 20 °C. HPLC indicated consumption of the starting material. The assay of the brown solution achieved a concentration of C-2 of approximately 136 mg / mL (total volume approximately 4.40 L, 597 - 631 g of product, 86% yield).

[0221] Prior to use in the next step, the batch was filtered through a coarse glass frit.

[0222] Step 2: Preparation of 6-chloro-5-(2,2-dimethoxyethyl)pyrimidin-4-amine (C-3)

Chemical formula

[0223] b) Toluene / iPA: In a 10 L glass reactor with a jacket (jacket temperature 20 °C, stirring speed 130 RPM, cooler temperature: -5 °C), an ammonium hydroxide solution (235 g) was added to a toluene solution of C-2 (4.40 L, approximately 136 mg / mL). The mixture showed an exotherm that raised the batch temperature to 3 °C. The mixture was stirred for 4 hours, after which stirring was stopped to allow removal of the aqueous layer (dark brown, lower layer, 376 g). The reactor jacket was set to 40 °C. An ammonium hydroxide solution (298 g) was added and the batch was held for 2 days. Further ammonium hydroxide (200 g) and isopropanol (4 L) were added and the reactor jacket was set to 70 °C. Further ammonium hydroxide solution (421 g) was added periodically over the next 24 hours and after 6 days of stirring at 70 °C, the reaction was considered complete. The batch was cooled to 20 °C and water (1.0 L) was added to the batch. Stirring was stopped and the aqueous cut was removed. The batch was discharged into a drum and treated with activated carbon (78 g). After standing for 3 hours, the batch was filtered into a clean reactor. A distillation apparatus was attached and the batch was distilled down to a volume of 2.5 L. Toluene was added (876 g). After further distillation (1023 g, after distillation), the reactor jacket was cooled to 10 °C over 4 hours. Heptane (100 g) was added and the batch was stirred for 4 hours. The batch was suction filtered onto three disposable polypropylene frit funnels to obtain a yellow-brown solid. The reactor was washed with 280 g of toluene. Each filter cake was washed with 100 mL of toluene. Each filter cake was dried to a transferable solid by suction and then combined in a drying tray. The solid was dried under vacuum with a nitrogen stream to obtain a yellow-brown solid (343.2 g, 94.6 wt%, 55% yield).

[0224] Step 3: Preparation of 5-(2,2-dimethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-amine (E-4):

Chemical formula

[0225] b) Large batch Into a 500 mL reactor with overhead stirring and nitrogen purge, C-3 (50.32 g) was charged, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.14 g), disodium hydrogen phosphate dihydrate (170.76 g) and n-butanol (250 mL) were charged into the reactor, and the reactor headspace was purged while stirring for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.62 g) was charged into the reactor. The reactor jacket was set to 100 °C while stirring. The reaction seemed to be complete after 13 hours (HPLC / UV, 210 nm). Water (250 mL) was pumped in over 1 hour. The batch was stirred until all salts were dissolved and then cooled to 20 °C. Stirring was stopped and the phases were separated. The aqueous layer was drained and discarded. A distillation apparatus was attached to the reactor and the batch was distilled under reduced pressure with a jacket temperature of 100 °C until the total reaction volume reached approximately 200 mL. The batch was cooled to 40 °C and then heptane (800 mL) was added over 1 hour. The jacket was set to 100 °C and the batch was warmed to this temperature for 4 hours and then cooled to 20 °C over 4 hours. The resulting suspension was filtered and dried by suction for 1 hour to obtain E-4 (52.0 g, 85% w / w, 77% yield) containing 3.3 wt% of pinacol.

[0226] The batch was dissolved in 500 mL of methanol, filtered and returned to a clean 500 mL reactor. The batch was distilled to a total volume of 200 mL. Tetrahydrofuran (800 mL) was added and the batch was distilled to a total volume of 200 mL. Heptane (100 mL) was added. The suspension was filtered and the filter cake was washed with 1:1 THF / heptane (50 mL). The filter cake was dried by suction for 1 hour to obtain a yellowish-brown powder of E-4 (41.4 g, 88% w / w, 82% recovery) having <0.1% w / w of pinacol. Acetonitrile (100 mL) was charged into a part of the resulting low-pinacol E-4 (21.4 g). The batch was warmed to 40 °C while stirring and then cooled to 23 °C over 1 hour. The suspension was filtered and dried by suction for 2 hours to obtain purified E-4 (19.04 g, 94% w / w, 96% recovery). 1 H-NMR (400 MHz, methanol-d 4 5% acetic acid in -d 4 ):δ 8.31(s,1H),8.07(s,2H),4.70(t,J=5.2Hz,1H),3.40(s,6H),2.98(d,J=5.2Hz,2H). 13 C-NMR (101 MHz, methanol-d 4 5% acetic acid in -d 4 ):δ 165.52,156.08,155.64,136.00,119.25,111.03,105.62,54.84,33.17.

[0227] c) Alternative reaction conditions to form E-4: [ka] A mixture of C-3 (0.5 g, 2.3 mmol) and BPin-pyrazole (0.58 g, 2.99 mmol, 1.3 equiv.) in dioxane (5 ml) was added to 2 ml of K 2 CO 3 Aqueous solution (0.952 g, 6.89 mmol, 3.0 equiv.) was added at room temperature. The solution was degassed by passing a stream of nitrogen through the solution for 15 min, after which Pd 2 (dba) 3 (32 mg, 0.0344 mmol, 0.03 equiv) and XPhos (35 mg, 0.069 mmol, 0.06 equiv). The resulting reaction mixture was then heated at 90° C. for 3 h. The reaction mixture was allowed to reach room temperature and then diluted with ethyl acetate (30 ml) and water (15 ml). The two layers were separated and the aqueous layer was further extracted with ethyl acetate (10 ml). The combined organic extracts were washed with water (2×5 ml), brine (10 ml) and anhydrous Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure. The crude residue was purified by ISCO to give E-4 as a white solid (0.47 g, 82% yield).

[0228] Step 4: Preparation of (Z)-3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile (E-5):

Chemical formula

[0229] Alternatively, the reaction mixture was quenched to pH about 8 with 0.4 vol of phosphoric acid (85 wt%). 5 vol of DMAc was added and the mixture was warmed to 55 °C for 30 minutes. The basic aqueous layer was separated at about 55 °C and then 11 vol of water was charged at 55 °C over 30 minutes. At the end of the water addition, a large amount of solid precipitated. The slurry was cooled to 22 °C over 35 minutes and then the solid was filtered. The filter cake was washed with 5 vol of 2:3 DMAc / water. The solid E-5 was then washed with 5 vol of water by displacement and the solid was dried under vacuum suction. 1 1H-NMR (DMSO-d6, 400 MHz): δ 8.65 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 6.73 (s, NH 2, 2H), 5.72 (s, 1H), 4.63 (t, J = 4.0 Hz, 1H), 3.41 (q, J = 8.0 Hz, 1H), 3.27 (s, 6H), 2.94 (d, J = 4.0 Hz, 2H), 1.99 - 1.89 (m, 2H), 1.77 - 1.47 (m, 6H).

[0230] a) Alternative reaction conditions for forming E-5:

Chemical formula

[0231] Step 5: Preparation of (R)-3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (E-6): a) Hydrogenation without additives at 10 bar

Chemical formula

[0232] Alternative reaction solvents were tested, and the results are shown in Table 1 below.

[0233]

Table 2

[0234] Alternative amounts of catalyst and ligand were tested in TFE, and the results are shown in Table 2 below.

[0235]

Table 3

[0236] In subsequent experiments, it was found that 0.25 mol% of the catalyst resulted in a conversion of over 95% with an enantiomeric ratio of over 99:1.

[0237] Alternative reaction conditions were tested at 50 bar of H 2 and the results are shown in Table 3 below.

[0238]

Table 4

[0239] Alternative route to alkene E-6 or E-6’: In certain embodiments, alkene E-5 or deuterated alkene E-5’ can isomerize to alkene E-7 or deuterated alkene E-7’, which can then be asymmetrically hydrogenated to obtain enantiomerically enriched E-6 or E-6’.

[0240] a) Isomerization of E-5’

Chemical formula

[0241] b) Asymmetric hydrogenation of E-7’ with chiral ligand Walphos SL-W002-2

Chemical formula

[0242] c) Asymmetric hydrogenation of E-7' with chiral ligand SL-J002-1

Chemical Structure

[0243] Formation of the salt of E-6: E-6 is an oil. To simplify purification and handling, E-6 can also be isolated as a solid acid salt. The E-6 acidic salt can replace the E-6 free base in subsequent reactions.

Chemical Structure

[0244] For 4-nitrobenzoic acid, orotic acid, 1-hydroxy-2-naphthoic acid, benzoic acid, citric acid, 2-bromophenylacetic acid, and toluenesulfonic acid: To an HPLC vial, 50 mg (0.126 mmol) of E-6 was added. The solid was dissolved in 5 vol (0.25 mL) of isopropanol. To the solution of E-6, 1 equivalent (0.126 mmol) of the acid and 5 vol (0.25 mL) of 4:1 IPA / water were added. The mixture was stirred at room temperature for 18 hours. After 18 hours, all visible suspension was transferred to a filter centrifuge tube and rotated at 14,000 RPM for 1 minute. Samples of both the solid and the mother liquor were taken for HPLC analysis, and samples of the solid were taken for NMR analysis and microscopic imaging.

[0245] For 4-bromobenzoic acid, (+)-tartaric acid, mucic acid, and salicylic acid: To an HPLC vial, 50 mg (0.126 mmol) of E-6 was added. The solid was dissolved in 5 vol (0.25 mL) of isopropanol. In separate vials, 1 equivalent (0.126 mmol) of the acid was added. To the acid, 5 vol (0.25 mL) of 4:1 IPA / water was added. If the solid acid dissolved, the acid solution was added to the E-6 solution and the mixture was stirred at room temperature. If the solid acid did not dissolve, the E-6 solution was added to the acid suspension, the mixture was heated until dissolved, then the reaction was cooled to room temperature and stirred. The vial was stirred at room temperature for 24 hours.

[0246] After 24 hours, all visible suspension was sampled for microscopic imaging, then the slurry was transferred to a filter centrifuge tube and rotated at 14,000 RPM for 1 minute. Samples of both the solid and the mother liquor were taken for HPLC analysis, and samples of the solid were taken for NMR analysis.

[0247] Based on NMR and HPLC analysis, E-6 formed crystalline solids with the following acids: orotic acid, 4-nitrobenzoic acid, 1-hydroxy-2-naphthoic acid, salicylic acid, and 4-bromobenzoic acid.

[0248] Formation of salts of E-6':

Chem.

[0249] Step 6: Preparation of ruxolitinib (free base):

Chem.

[0250] Step 6 (Alternative): Preparation of ruxolitinib (HCl salt):

Chemical Structure

[0251] Scheme 5: Preparation of ruxolitinib (free base) via ethyl acetal (10)

Chemical formula

Chemical formula

[0252] Step 2: Preparation of 6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-amine (11):

Chem.

[0253] Step 3: Preparation of tert-butyl (tert-butoxycarbonyl)(6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)carbamate (12):

Chem.

[0254] Step 4: Preparation of tert-butyl (tert-butoxycarbonyl)(5-(2,2-diethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (13):

Chem.

[0255] Step 5: Preparation of tert-butyl (Z)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-5-(2,2-diethoxyethyl)pyrimidin-4-yl)carbamate (14):

Chem.

[0256] Step 6: Preparation of tert-butyl (R)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5-(2,2-diethoxyethyl)pyrimidin-4-yl)carbamate (15):

Chemical formula

[0257] Additional catalyst systems were also tested for the hydrogenation step, and the results are shown below.

Chemical formula

[0258]

Table 5

[0259]

Chemical formula

[0260] All ligands are available from Solvias AG (Kaiseraugst, Switzerland) and / or Strem Chemicals (Newburyport, MA, USA).

[0261] Step 7: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (lucitanib):

Chemical formula

[0262] Scheme 6a: Preparation of Luxolitinib Phosphate via Methyl Acetal

Chemical Structure

[0263] Scheme 6b: Preparation of Luxolitinib Phosphate via Methyl Acetal

Chemical Structure

Chemical Structure

[0264] b) Toluene, TsOH (1 mol%): Trimethyl orthoformate (371 g, 3.50 mol, 1.2 eq) was charged to a suspension of compound 9 (635 g, 88% assay, 2.93 mol) in toluene (2988 g). The batch was cooled to 20 °C, and solid TsOH·H 2 O (5.76 g, 0.03 mol, 0.01 eq) was charged. Before adjusting to 20 °C, the batch temperature was maintained by lowering the jacket temperature to 16 °C for 10 min during a slight exotherm. The suspension was stirred at 20 °C for 2 h, then the jacket temperature was raised to 40 °C for 11.5 h, and then the jacket was returned to 20 °C. HPLC indicated consumption of the starting material. The assay of the brown solution achieved a concentration of 17 of approximately 136 mg / mL (total volume approximately 4.40 L, 597 - 631 g of product, 86% yield).

[0265] Before use in the next step, the batch was filtered through a coarse glass frit.

[0266] Step 2A: Preparation of 6-chloro-5-(2,2-dimethoxyethyl)pyrimidin-4-amine (18):

Chemical formula

[0267] b) Toluene / iPA: Ammonium hydroxide solution (235 g) was added to a solution of 17 in toluene (4.40 L, approximately 136 mg / mL) in a 10 L glass reactor with jacket (jacket temperature 20 °C, stirring speed 130 RPM, cooler temperature: -5 °C). The mixture showed an exotherm that increased the batch temperature to 3 °C. The mixture was stirred for 4 hours, after which stirring was stopped to allow removal of the aqueous layer (dark brown, lower layer, 376 g). The reactor jacket was set to 40 °C. Ammonium hydroxide solution (298 g) was added and the batch was held for 2 days. Further ammonium hydroxide (200 g) and isopropanol (4 L) were added and the reactor jacket was set to 70 °C. Further ammonium hydroxide solution (421 g) was added periodically over the next 24 hours and after stirring at 70 °C for 6 days, the reaction was considered complete. The batch was cooled to 20 °C and water (1.0 L) was added to the batch. Stirring was stopped and the aqueous cut was removed. The batch was discharged into a drum and treated with activated carbon (78 g). After standing for 3 hours, the batch was filtered into a clean reactor. A distillation apparatus was installed and the batch was distilled to a volume of 2.5 L. Toluene was added (876 g). After further distillation (1023 g, after distillation), the reactor jacket was cooled to 10 °C over 4 hours. Heptane (100 g) was added and the batch was stirred for 4 hours. The batch was filtered by suction onto three disposable polypropylene frit funnels to obtain a yellowish-brown solid. The reactor was washed with 280 g of toluene. Each filter cake was washed with 100 mL of toluene. Each filter cake was dried to a transferable solid by suction and then combined in a drying tray. The solid was dried under vacuum with a nitrogen stream to obtain a yellowish-brown solid (343.2 g, 94.6 wt%, 55% yield).

[0268] Step 3A: Preparation of tert-butyl (tert-butoxycarbonyl)(6-chloro-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate (19):

Chemical formula

[0269] b) THF: To a stirred solution of compound 18 (11.12 g, 51.1 mmol) and (Boc) 2 O (22.9 g, 105 mmol, 2.05 equivalents), THF (50 ml) was added. Et 3N (15 mL, 47.3 mmol, 2.1 eq) and DMAP (625 mg, 5.1 mmol, 0.1 eq) were charged. A small exotherm was noted (2 °C). The batch was warmed to 40 °C for 20 min and then cooled to 20 °C. HPLC indicated that the reaction was >97% complete. N-Methylpiperazine (0.56 mL, 5.1 mmol, 0.1 eq) was charged and the batch was stirred for 30 min. Potassium dihydrogen phosphate solution (1 M, 100 mL, 100 mmol, 2 eq) and THF (40 mL) were charged. After brief stirring, the aqueous cut was removed. Potassium dihydrogen phosphate solution (1 M, 50 mL, 50 mmol, 1 eq) and THF (20 mL) were charged. Water (20 mL) was charged as a final rinse to remove residual salts. The product solution (130 mL) was used in portions in the next step.

[0270] Step 4A: Preparation of tert-Butyl (tert-butoxycarbonyl)(5-(2,2-dimethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (20):

Chemical formula

[0271] b) THF (10 vol), H 2 O (4 vol), 2 mol% Pd(PPh 3 ) 4 , 60 °C: To a mixture of 19 (0.25 g, 0.598 mmol) and BPin-pyrazole (0.151 g, 0.778 mmol, 1.3 eq) in THF (2.5 ml) was added 1 ml of an aqueous K 2 CO 3 solution (0.248 g, 1.79 mmol, 3.0 eq, dissolved in deionized water) at room temperature. The solution was degassed by passing a stream of nitrogen through the solution for 15 min, after which it was treated with Pd(PPh 3 ) 4 (14 mg, 0.0119 mmol, 0.02 eq) and the resulting reaction mixture was heated at 60 °C for 12 h. After 12 h, the reaction profile was starting material (18%) and product 20 (82%).

[0272] Step 5A: Preparation of tert-butyl (Z)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate:

Chemical formula

[0273] Step 6A: Preparation of tert-butyl (R)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate:

Chem.

[0274] Step 7A: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (the free base of lxolitinib):

Chemical Structure

[0275] Step 1B: Preparation of tert-butyl (6-chloro-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate (21): [Chemical formula] To a stirred solution of compound 18 (215 mg, 0.988 mmol) in THF (2 ml) at 0 °C, 2 M NaHMDS (1 ml, 1.976 mmol, 2.0 equivalents, 2 M in THF) was added. After stirring at 0 °C for 30 minutes, (Boc) 2A solution of O (194 mg, 0.889 mmol, 0.9 equiv) in THF (1.5 ml) was added at 0 °C. The mixture thus obtained was brought to room temperature and stirred for 8 h. From LC, the reaction was 90% complete. The reaction mixture was then treated with water (2 ml) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with water (10 ml) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (0 - 30% EtOAc in heptane) to give the mono-Boc product (21) as a white solid (370 mg, 87% yield).

[0276] Step 2B: Preparation of tert-butyl (5-(2,2-dimethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)carbamate (22):

Chem.

[0277] Step 3B: Preparation of tert-butyl (Z)-(6-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate:

Chem.

[0278] Step 4B: Preparation of tert-butyl (R)-(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate:

Chem.

[0279] As shown in Table 4 below, alternative protecting groups were also tested.

Chemical Structure

[0280]

Table 6

[0281] Additional catalyst systems were also tested for the hydrogenation step, and the results are shown below.

Chemical Structure

[0282]

Table 7

[0283] All ligands are available from Solvias AG (Kaiseraugst, Switzerland) and / or Strem Chemicals (Newburyport, MA, USA).

[0284] Step 5B: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (ruxolitinib):

Chemical formula

[0285] Without further elaboration, it is believed that one of ordinary skill in the art can, using the foregoing description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing description and examples merely provide a detailed description of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the present invention.

[0286] The following are examples of aspects of the present invention. Item 1 A compound of formula I [Chemical formula] or a salt thereof, comprising reacting a compound of formula II' in the presence of an acid such that a compound of formula I is formed [Chemical formula] or a salt thereof; In formula I and formula II', Y 1 is hydrogen or deuterium; each Y 2 is the same and is hydrogen or deuterium; each Y 3 is the same and is hydrogen or deuterium; In formula II', each R 1’ is C1 ~C 10 alkyl, or C 2 ~C 10 is alkenyl, or two Rs 1’ together with the oxygen atom to which they are attached form a 5- to 7-membered heterocyclic ring which may be optionally substituted; each R 6 is independently selected from H and a protecting group, a method. Item 2 The method according to item 1, wherein the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or a combination thereof. Item 3 A compound of formula II’

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Claims

[Claim 1] Compounds of Formula I 【Chemistry 1】 or a salt thereof, comprising the steps of: In the presence of an acid, a compound of formula II' is reacted with a compound of formula I to form a compound of formula I. 【Chemistry 2】 or a salt thereof; In Formula I and Formula II', Y １ is hydrogen or deuterium; Each Y ２ are the same and are hydrogen or deuterium; Each Y ３ are the same and are hydrogen or deuterium; In formula II′, Each R １’ is C １ ~C １０ Alkyl, or C ２ ~C １０ alkenyl, or two R １’ together with the oxygen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring; Each R ６ is independently selected from H and a protecting group.

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