Process for preparation of enantiomer enriched JAK inhibitors

Abstract

A method for preparing an enantiomerically enriched JAK inhibitor is disclosed. Disclosed are improved processes and intermediates for the preparation of rusotinib and deuterated analogs of rusotinib.

Description

This application is a divisional application of Chinese Patent Application No. 202080024598.1, filed on February 6, 2020, entitled "Method for preparing enantiomer-enriched JAK inhibitors". Cross-references to related applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 802,129, filed February 6, 2019, and U.S. Provisional Patent Application No. 62 / 850,981, filed May 21, 2019. The contents of these applications are incorporated herein by reference in their entirety. Background Technology

[0001] Ruxotinib 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]propionitrile phosphate and (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, which inhibits Janus-associated kinases (JAK) JAK1 and JAK2. These kinases mediate the signaling of many cytokines and growth factors important for hematopoietic and immune functions. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to the regulation of gene expression.

[0002] Ruxotinib phosphate has been approved in the United States and Europe for the treatment of myelofibrosis and polycythemia vera. Ruxotinib is currently in clinical trials for the treatment of graft-versus-host disease and other conditions.

[0003] A deuterated analogue of ruxotinib phosphate (referred to in this article as CTP-543 or compound (I)) is currently in clinical trials for the treatment of alopecia areata.

[0004] Due to the beneficial activity of ruxolitinib and its deuterated analogues, there is a continued need for improved methods for synthesizing ruxolitinib and its deuterated forms. Summary of the Invention

[0005] This invention provides an improved method for synthesizing ruxolitinib and its deuterated forms. This invention further provides intermediates that can be used to synthesize ruxolitinib and its deuterated forms.

[0006] In one aspect, the present invention provides a method for preparing compounds of formula I: or its salt method, This method involves making a compound of formula II: Or its salt reacts in the presence of an acid to form a compound of formula I; wherein in formulas I and II, Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; and in Formula II, each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety (i.e., the two Rs) 1 Together with the oxygen atoms attached to them, they form 5- or 6-membered heterocycles; and each R 6 The acid is independently selected from H and protecting groups. In some embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, trifluoroacetic anhydride (TFAA), or combinations thereof. In some embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or combinations thereof. In some embodiments, the acid is hydrochloric acid.

[0007] In one aspect, the present invention provides a method for preparing compounds of formula I: or its salt method, This method involves making a compound of formula II': Or its salt reacts in the presence of an acid to form a compound of formula I; wherein in formulas I and II', Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; and in formula II', each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring, each optionally substituted with one or more methyl groups); and each R 6 The acid is independently selected from H and protecting groups. In some embodiments, the acid is selected from hydrochloric acid, trifluoroacetic acid (TFA), phosphoric acid, or combinations thereof. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group.

[0008] In another aspect, the present invention provides a method for preparing compounds of formula II (or their salts): This method involves using a compound of formula III (or a salt thereof): Reaction with a hydrogen source (e.g., hydrogen gas) in the presence of a hydrogenation catalyst; wherein Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 It is independently selected from H and protecting groups.

[0009] In another aspect, the present invention provides a method for preparing compounds of formula II' (or salts thereof): This method involves using a compound of formula III' (or a salt thereof): Reaction with a hydrogen source (e.g., hydrogen gas) in the presence of a hydrogenation catalyst; wherein in formulas II' and III', Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group.

[0010] In some embodiments of the above methods for producing compounds of formula II or II', the hydrogenation catalyst comprises a transition metal, including but not limited to rhodium, ruthenium, and iridium. In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium and a chiral phosphine ligand (L) according to formula IV. In some embodiments, the hydrogenation catalyst comprises rhodium. In some embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand (L) according to formula IV: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl.

[0011] In some embodiments, R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is norborneol. In some embodiments, R 2a R 2b R 3a R3b and R 4 Each of them is hydrogen, and R 5 It is cyclohexyl. In some embodiments, the hydrogenation catalyst is present in an amount of 2.5 mol% or less. In some embodiments, the hydrogenation catalyst is present in an amount of 1 mol% or less.

[0012] In some embodiments, the hydrogen gas is present at a pressure of 15 bar or less. In some embodiments, the hydrogen gas is present at a pressure of 10 bar or less. In some embodiments, the step of reacting the compound of formula III or III' with hydrogen gas in the presence of a hydrogenation catalyst is carried out in a solvent, and the solvent is 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 some embodiments, the solvent is trifluoroethanol (TFE). In some embodiments, the compound of formula II or II' has an enantiomer excess of at least 95% of the (R)-enantiomer. In some embodiments, the compound of formula II or II' has an enantiomer excess of at least 98% of the (R)-enantiomer.

[0013] In another aspect, the present invention provides a method for preparing compounds of formula III (or their salts): This method involves making a compound of formula VIII (or a salt thereof): Compounds with Formula VII: The reaction occurs in the presence of a base, resulting in a compound of formula III; wherein Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 The base is independently selected from H and protecting groups. In some embodiments, the base is selected from tripotassium phosphate, tripotassium hydrate, and potassium carbonate.

[0014] In another aspect, the present invention provides a method for preparing compounds of formula III' (or salts thereof): This method involves making a compound of formula VIII' (or a salt thereof): Compounds with Formula VII: The reaction in the presence of a base results in the formation of a compound of formula III' (or a salt thereof); wherein in formulas III' and VII, Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; and in formulas III' and VIII', each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring, which may optionally be substituted with, for example, one or more methyl groups); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group. In some embodiments, the base is selected from tripotassium phosphate, hydrated tripotassium phosphate, and potassium carbonate. In some embodiments, the reaction step is carried out in a solvent. Non-limiting examples of solvents include dimethylacetamide (DMAc), water (H2O), and combinations thereof. In some embodiments, the solvent is a combination of dimethylacetamide and water, for example, dimethylacetamide and water in a ratio in the range of 7:1 DMac:water and 1:2 DMac:water (such as 7:1 DMac:water, 5:4 DMac / water, or 2:1 DMac / water). In some embodiments, the reaction is carried out at one or more temperatures in the range of 0°C to room temperature (e.g., in the range of 0°C to 23°C).

[0015] Some aspects of this invention relate to a method for preparing a compound of formula VIII (or a salt thereof): This method involves making a compound of formula IX (or a salt thereof):

[0016] With compounds represented by the following formula: (or another pyrazole borate ester) and a catalytic amount of palladium catalyst (such as Pd(PPh3)4) react in the presence of a base to form a compound of formula VIII; wherein each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; each R 6 The base is independently selected from H and the protecting group; and X is I, Br, Cl, or a trifluoromethanesulfonate. In some embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0017] Some aspects of this invention relate to a method for preparing compounds of formula VIII' (or salts thereof): This method involves making a compound of formula IX' (or a salt thereof): With compounds represented by the following formula: (or another pyrazole borate ester) and a catalytic amount of palladium catalyst (such as Pd(PPh3)4) react in the presence of a base to form a compound of formula VIII'; wherein in formulas VIII' and IX', each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 Independently selected from H and protecting groups. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group. In some embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0018] In any of the formulas described herein, in some embodiments, the protecting group is selected from tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and triphenylmethyl (Tr, CPh3). In some embodiments, the two R... 6 Both are H. In some embodiments, the two Rs 1 Both are methyl groups. In some embodiments, the two R groups... 1 Both are ethyl. In some embodiments, the two R... 1’ Both are methyl groups. In some embodiments, the two R groups... 1’ All are ethyl. In some embodiments, Y 1 It is hydrogen and Y 2 and Y 3 Each of them is deuterium. In some embodiments, Y 1 Y 2 and Y 3 Each of these is hydrogen. In some embodiments, the deuterium doping at each location designated as deuterium is at least 90%, at least 95%, or at least 97%.

[0019] Certain aspects of the present invention provide intermediates that can be used to prepare ruxolitinib and deuterated analogs of ruxolitinib. In one embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0020] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0021] In another embodiment, the present invention provides a compound represented by the following structure:

[0022] In another embodiment, the present invention provides a compound represented by the following structure:

[0023] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0024] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

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

[0026] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0027] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0028] In another embodiment, the present invention provides a compound represented by the following structure:

[0029] In another embodiment, the present invention provides a compound represented by the following structure:

[0030] In another embodiment, the present invention provides a compound represented by the following structure:

[0031] In some embodiments, the deuterium doping at each position specified as deuterium in any compound of the invention is at least 90%, at least 95%, or at least 97%.

[0032] Other aspects and embodiments of the invention will become apparent from the detailed description and claims herein. Detailed Implementation definition

[0033] The term "alkyl" refers to a monovalent saturated hydrocarbon group. C1-C6 alkyl groups are alkyl groups having 1 to 6 carbon atoms. In some embodiments, the alkyl group can be straight-chain or branched. In some embodiments, the alkyl group 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 tert-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 tert-butyl.

[0034] Unless otherwise specified, "alkylene" itself, or as part of another substituent, refers to a saturated straight-chain or branched divalent group having the stated number of carbon atoms and derived from the removal of two hydrogen atoms from the corresponding alkane. Examples of straight-chain and branched alkylenes include -CH2- (methylene), -CH2-CH2- (ethylene), -CH2-CH2-CH2- (propylene), -C(CH3)2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2- (butylene), -CH2-CH(CH3)-CH2-, -CH2-CH2-CH2-CH2-CH2- (pentylene), and -CH2-C(CH3)2-CH2-.

[0035] The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group, where the degree of unsaturation is represented by a double bond. C2-C6 alkenyl groups are alkenyl groups having 2 to 6 carbon atoms. Alkenyl groups can be straight-chain or branched. Examples of alkenyl groups include CH2=CH- (vinyl), CH2=C(CH3)-, CH2=CH-CH2- (allyl), CH3-CH=CH-CH2- (crotonyl), CH3-CH=C(CH3)-, and CH3-CH=CH-CH(CH3)-CH2-. Where double bond stereoisomerism is possible, the stereochemistry of the alkenyl group can be (E), (Z), or a mixture thereof.

[0036] The term "alkynyl" refers to a monovalent unsaturated hydrocarbon group, where the degree of unsaturation is represented by a triple bond. C2-C6 alkynyl groups are alkynyl groups having 2 to 6 carbon atoms. Alynyl groups can be straight-chain or branched. Examples of alkynyl groups include HC≡C-, CH3-C≡C-, CH3-C≡C-CH2-, CH3-C≡C-CH2-CH2-, and CH3-C≡C-CH(CH3)-CH2-.

[0037] The term "cycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C3-C"... 10"Cycloalkyl" refers to a cycloalkyl group in which the number of carbon atoms in the ring ranges from 3 to 10. (C3-C) 10 Examples of cycloalkyl groups include C3-C6 cycloalkyl groups. Bicyclic systems include fused, bridged, and spirocyclic systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cis- and trans-decahydronaphthyl, norbornyl, and spiro[4.5]decyl.

[0038] The term "carbocyclic group" refers to a monovalent saturated or non-aromatic unsaturated hydrocarbon ring system, whether monocyclic or bicyclic. The term "C3-C..." 10 A "carbocyclic group" refers to a carbocyclic group in which the number of ring carbon atoms ranges from 3 to 10. (C3-C) 10 Examples of carbocyclic groups include C3-C6 carbocyclic groups. Bicyclic systems include fused, bridged, and spirocyclic systems. More specific examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cis- and trans-decahydronaphthyl, norbornyl, norbornyl, and spiro[4.5]decyl.

[0039] The term "heterocyclic alkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated ring system, wherein one to four ring atoms are heteroatoms independently selected from the group consisting of O, N, and S. The term "3- to 10-membered heterocyclic alkyl" refers to a heterocyclic alkyl system in which the number of ring atoms ranges from 3 to 10. Examples of 3- to 10-membered heterocyclic alkyls include 3- to 6-membered heterocyclic alkyls. Bicyclic systems include fused, bridged, and spirocyclic systems. More specific examples of heterocyclic alkyls include azirmonyl heptyl, azirmonyl butyl, azirmonyl propaneyl, imidazolyl, morpholinyl, oxazolyl, oxazolyl, piperazine, piperidinyl, pyrazolyl, pyrrolidinyl, quininecycloyl, and thiomorpholinyl.

[0040] In the above heterocyclic alkyl substituents, the nitrogen, phosphorus, carbon, or sulfur atoms can 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 -SO2- (sulfone), respectively. For convenience, and particularly but not exclusively, nitrogen is not intended to include its corresponding N-oxide form, although this is not explicitly defined in certain instances. Thus, for compounds of the invention having, for example, a pyridine ring; the corresponding pyridyl-N-oxide is intended to be included as another compound of the invention. Furthermore, the cyclic nitrogen atom may optionally be quaternized; and the cyclic substituents may be partially or fully saturated or aromatic.

[0041] "Aryl" itself, or as part of another substituent, refers to a monocyclic or polycyclic monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C1). 14This refers to groups with 5 to 14 carbon atoms. Typical aryl groups include, but are not limited to, those derived from: anthracene, acenaphthene, acephenanthrylene, anthracene, azurite, benzene, etc. Aryl compounds include fluoranthene, fluorene, hexacene, hexaphene, hexene, as-indacene, s-indacene, dihydroindene, indene, naphthalene, octacene, octophene, octalene, ovalene, pentacene-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, pleiadene, pyrene, pyranthrene, rubicene, benzo[a]phenanthrene, and trinaphthalene. In specific embodiments, the aryl group is cyclopentadienyl, phenyl, or naphthyl. In more specific embodiments, the aryl group is phenyl or naphthyl.

[0042] "Arylalkyl" itself, or as part of another substituent, refers to a group containing a carbon atom (typically the terminal carbon atom or sp). 3 An aryl alkyl group is an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylvinyl-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylvinyl-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, etc. In one embodiment, the alkyl portion of the aryl alkyl group is (C1-C6) and the aryl portion is (C5-C6). 14 In a more specific embodiment, the alkyl group is (C1-C3), and the aryl moiety is (C5-C6). 10 ), such as (C6-C 10 ).

[0043] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon ring system in which at least one ring atom is a heteroatom independently selected from the group consisting of O, N, and S. In some embodiments, a heteroaryl has one or two rings. When a heteroaryl contains more than one heteroatom ring member, the heteroatoms can be the same or different. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolopyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrrololyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purine, carbazole, benzimidazolyl, indololinyl, etc. The term 5-membered heteroaryl refers to a heteroaryl group in which the number of ring atoms is 5. Non-limiting examples of 5-membered heteroaryl groups include pyrrole, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, furazolyl, imidazolyl, and triazolyl.

[0044] "Heteroarylalkyl" itself, or as part of another substituent, refers to a group containing a carbon atom (typically the terminal carbon atom or sp). 3 An acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In one embodiment, the alkyl portion of the heteroaryl alkyl group is (C1-C6) alkyl and the heteroaryl portion is a 5-14-membered heteroaryl group. In a more specific embodiment, the alkyl portion is (C1-C3) alkyl and the heteroaryl portion is a 5-10-membered heteroaryl group.

[0045] "Halogen" or "halogen group" refers to fluorine, chlorine, bromine, and iodine, or fluorine, chlorine, bromine, and iodine groups, either by themselves or as part of another substituent.

[0046] As used herein, the terms “contact” and “reaction” are as known in the art and generally refer to a combination of chemical reagents in a manner that allows them to interact at the molecular level to achieve a chemical or physical transformation. In some embodiments, a contact or reaction involves two (or more) reagents, wherein one or more equivalents of a second reagent are used relative to a first reagent. The reaction steps described herein can be carried out at times and under conditions suitable for the preparation of the identified product.

[0047] Compound (I) or CTP-543 is a deuterated analogue of ruxolitinib, known by 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-d8)propionitrile. Compound (I) may also be referred to herein as D8-ruxolitinib. Compound (I) is represented by the following structural formula:

[0048] It should be recognized that, depending on the source of the chemical materials used in the synthesis, some variation in the natural isotopic abundance occurs in the synthesized compounds. Therefore, the compounds disclosed herein will inherently contain small amounts of deuterated isotopes. The concentrations of naturally abundant stable hydrogen and carbon isotopes (despite this variation) are small and insignificant compared to the degree of stable isotopic substitution in the compounds of this invention. See, for example, Wada, E et al., Seikagaku [Japanese Biochemistry], 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol [Comparative Biochemistry and Physiology Molecular Integrative Physiology], 1998, 119:725.

[0049] In the compounds of this invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position should be understood to have hydrogen having its naturally abundant isotopic 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 is doped with ≤10% deuterium, ≤5% deuterium, ≤4% deuterium, ≤3% deuterium, ≤2% deuterium, or ≤1% deuterium. Similarly, unless otherwise specified, when a position is specifically designated as “D” or “deuterium”, the position shall be understood to have at least 3340 times the abundance of deuterium, which is 0.015%, that is, at least 50.1% deuterium incorporation.

[0050] As used in this article, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance.

[0051] In other embodiments, the compounds of the present invention have an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) for each specified deuterium atom.

[0052] In some embodiments, the compounds of the present invention have at least 52.5% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 60% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 67.5% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 75% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 82.5% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 90% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 95% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 97.5% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 99% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of the present invention have at least 99.5% deuterium doping at each specified deuterium atom.

[0053] The term "isotope" refers to a substance (molecule) whose chemical structure differs from that of the compound of the present invention only in its isotopic composition.

[0054] When referring to the compounds of the present invention, the term "compound" means a collection of molecules having a consistent chemical structure, except that isotopic variations may exist in the constituent atoms of the molecules. Thus, for example, it will be apparent to those skilled in the art that although compound (I) is represented by a specific chemical structure having deuterium atoms at eight designated positions, compound (I) will contain molecules having deuterium at each of the eight designated positions, and may also contain isotopes having hydrogen atoms at one or more designated deuterium positions in the structure. The relative amounts of such isotopes in compound (I) will depend on a variety of factors, including the isotopic purity of the deuterating agent used to prepare the compound and the deuteration incorporation efficiency in the various synthetic steps used to prepare the compound.

[0055] As used herein, the term "reaction" as is known in the art and generally refers to a combination of chemical reagents in a manner that allows them to interact at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reaction involves two reagents, wherein one or more equivalents of a second reagent are used relative to a first reagent. The reaction steps described herein can be carried out at times and under conditions suitable for the preparation of the identified product.

[0056] The preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4th ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Thus, for example, a nitrogen atom can be protected with a protecting group such as tert-butoxycarbonyl (Boc) to form a carbamate; with a protecting group such as trifluoromethanesulfonyl (Tf, SO2-CF3) to form a sulfonamide; with a protecting group such as acetyl, benzoyl, or trifluoroacetyl (F3-Ac) to form an amide; with a protecting group such as benzyl or triphenylmethyl (Tr, -CPh3) to form an amine; or with a protecting group such as SiPh2Bu t The protecting group is silylamine. The protecting group described herein, as well as the formation and cleavage methods, can be adjusted as needed according to various substituents.

[0057] The reactions described herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are those that are substantially unreactive with the starting materials (reactants), intermediates, or products at temperatures in which the reaction takes place (e.g., temperatures ranging from the freezing point to the boiling point of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent can be selected for that specific reaction step. In some embodiments, the reaction can be carried out in the absence of a solvent (e.g., when at least one reagent is a liquid or gas).

[0058] Suitable solvents may include halogenated solvents such as carbon tetrachloride, dichlorobromodichloromethane, 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.

[0059] 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, tert-butyl methyl ether, and mixtures thereof. Other ether solvents include 2-methyltetrahydrofuran and cyclopentylmethyl ether (and mixtures thereof, including mixtures with other ether solvents described herein).

[0060] By way of example and without limitation, suitable proton solvents may include, but are not limited to, 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, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-, 2- or 3-pentanol, neopentanol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, hexafluoroisopropanol (HFIP), acetic acid (AcOH), and mixtures thereof.

[0061] By way of example and without limitation, suitable aprotic solvents may include 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-imidazolinone (DMI), N-methylpyrrolidone (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.

[0062] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, meta-, or o- or p-xylene, octane, indane, nonane, naphthalene, and mixtures thereof.

[0063] The reactions described herein can be carried out at appropriate temperatures that can be readily determined by a skilled technician. The reaction temperature will depend on, for example, the melting and boiling points of the reagents and solvents (if present); the thermodynamics of the reaction (e.g., a violently exothermic reaction may require a lower temperature); and the kinetics of the reaction (e.g., a high activation barrier may require an elevated temperature). "Elevated temperature" refers to a temperature above room temperature (approximately 22°C).

[0064] The reactions described herein can be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are fully reactive with air can be carried out using air-sensitive synthesis techniques well known to skilled technicians.

[0065] Examples of acids can be inorganic or organic. 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, butyric acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propynic acid, butyric acid, 2-butynic acid, vinylacetic acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0066] Non-limiting examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some exemplary strong bases include, but are not limited to, hydroxides, alkoxides, amino metals, metal hydrides, dialkylamino metals, and arylamines, wherein; alkoxides include sodium and potassium salts of methyl, ethyl, and tert-butyl oxides; amino metals include sodium amide, potassium amide, and lithium amide; amino metals include sodium hydride, potassium hydride, and lithium hydride; and dialkylamino metals include sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl, and cyclohexyl-substituted amino compounds.

[0067] When preparing compounds according to the methods described herein, common separation and purification operations (such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, etc.) can be used to separate the desired product.

[0068] In some embodiments, the compounds of the present invention and their salts are substantially separated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may include, for example, compositions rich in the compounds of the present invention. Substantially separated may include compositions containing, by weight, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% of the compounds of the present invention or their salts. Methods for separating the compounds and their salts are conventional in the art.

[0069] This invention also includes salt forms of the compounds described herein. Salts of the compounds of this invention are formed between an acid and a basic group (such as an amino functional group) of the compound or between a base and an acidic group (such as a carboxyl functional group) of the compound. According to one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment, the acid addition salt may be a deuterated acid addition salt.

[0070] As used herein, the term "pharmaceutically acceptable" means a component suitable for use in contact with human and other mammalian tissues within the bounds of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention. "Pharmaceutically acceptable counterion" is the ionic portion of a salt that is non-toxic upon release from the salt upon administration to a recipient.

[0071] 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 p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric 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, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid; as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, and butyn-1,4-diacids. Hexyne-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with inorganic acids (such as hydrochloric acid and hydrobromic acid), and especially those formed with organic acids (such as maleic acid). In one embodiment, acids commonly used to form pharmaceutically acceptable salts include the inorganic acids listed above, wherein at least one hydrogen atom is replaced by deuterium.

[0072] The compounds of the present invention may contain asymmetric carbon atoms, for example, due to deuterium substitution or otherwise. Therefore, unless otherwise stated (or explained) herein, the compounds of the present invention may exist as a single enantiomer or a mixture of two enantiomers. Thus, the compounds of the present invention may exist as racemic or scalemic mixtures, or as a single stereoisomer substantially free of another possible stereoisomer. As used herein, the term "substantially free of other stereoisomers" means the presence of 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. In some embodiments, the compound substantially free of other stereoisomers has an enantiomer excess (ee) of at least about 90%. In other embodiments, the compound substantially free of other stereoisomers has an enantiomer excess (ee) of at least about 95%, 96%, 97%, 98%, 99%, or 99.5%. Methods for obtaining or synthesizing individual enantiomers of a given compound are known in the art and can be applied, in practice, to the final compound or to the starting material or intermediate.

[0073] Unless otherwise indicated, when a disclosed compound is named or described by an unspecified stereochemical structure and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound.

[0074] As used herein, the term "stable compound" means a compound having sufficient stability to allow the manufacture of the compound and to maintain the integrity of the compound for a sufficient period of time for which it can be used for the purposes detailed herein (e.g., formulation of therapeutic products, intermediates for the production of therapeutic compounds, separable or storable intermediate compounds, treatment of diseases or conditions in response to therapeutic agents).

[0075] Both "D" and "d" refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "ER" or "er" refers to the enantiomer ratio. "EE" or "ee" indicates an enantiomer in excess. "AUC" refers to the area under the curve. "Tert" and "t-" each refer to tert-. "Sec" or "s" - “Each refers to Zhong.” - " indicates positive. "i-" indicates negative. "US" refers to the United States.

[0076] "Replaced by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms. Throughout this specification, variables may refer generally (e.g., "each R") or may refer precisely (e.g., R0). 1 R 2 R3 (etc.). Unless otherwise indicated, when a variable is referred to generally, it is intended to include all specific embodiments of that particular variable. compound

[0077] In one aspect, the present invention provides compounds and intermediates that can be used to prepare ruxolitinib and deuterated analogs of ruxolitinib.

[0078] In some embodiments, the present invention provides compounds of any one of formulas II, II', III, III', V, V', VIII, VIII', IX, IX', XI, or XI' as described herein; or salts thereof.

[0079] In some embodiments, the present invention provides compounds of formula II'. or its salt, Each Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 It is independently selected from H and protecting groups.

[0080] In some embodiments: each R 1 'Is methyl or ethyl; and one R 6 One is H and the other is a protecting group. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1 'Is methyl.' In some embodiments, each R 1’ It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group.

[0081] In some embodiments, the present invention provides a compound of formula II: or its salt, Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and each of R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 Independently selected from H or protecting groups. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1 It is methyl. In some embodiments, each R 1 It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group.

[0082] In some embodiments, the present invention provides a compound of formula III':

[0083] or its salt; Where Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group.

[0084] In some embodiments, the present invention provides a compound of formula III: or its salt, Where Y 1 Y 2 Y 3 R 1 and R 6 Each of these is as defined in Equation II. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1 It is methyl. In some embodiments, each R 1 It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group. Y 3 It is deuterium.

[0085] In some embodiments, the present invention provides a compound of formula VII: Where Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium. In some embodiments, Y 1It is hydrogen. In some embodiments, each Y 2 They are the same and are hydrogen. In some embodiments, each Y 2 They are the same and are deuterium. In some embodiments, each Y 3 They are the same and are hydrogen. In some embodiments, each Y 3 They are the same and are deuterium. In some embodiments, each Y 2 And Y 3 It is hydrogen. In some embodiments, each Y 2 And Y 3 It is deuterium. In one embodiment, Y 1 It is hydrogen and each Y 2 and Y 3 It is hydrogen. In another embodiment, Y 1 It is hydrogen and each Y 2 and Y 3 It is deuterium.

[0086] In another embodiment, the present invention provides a compound of formula VIII': Each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group.

[0087] In another embodiment, the present invention provides a compound of formula VIII: or its salt; Where R 1 and R 6 It is as defined for compound II. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1 It is methyl. In some embodiments, each R 1 It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group.

[0088] In yet another embodiment, the present invention provides a compound of formula XI: or a salt thereof; or its salt, Where Y 2 Y 3 R 1 and R 6 Each of these is as defined in Equation II. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1 It is methyl. In some embodiments, each R 1 It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group.

[0089] In another embodiment, the present invention provides a compound of formula XI': or a salt thereof; or its salt, Where Y 2 Y 3 R 1 and R 6 Each of them is as defined in Equation II'. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1’ It is methyl. In some embodiments, each R 1’ It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group.

[0090] In one embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0091] In another embodiment, the present invention provides a compound represented by the following structure:

[0092] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0093] In another embodiment, the present invention provides a compound represented by the following structure:

[0094] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0095] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0096] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0097] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0098] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0099] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0100] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0101] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0102] In another embodiment, the present invention provides a compound represented by the following structure:

[0103] In another embodiment, the present invention provides a compound represented by the following structure:

[0104] In another embodiment, the present invention provides a compound represented by the following structure:

[0105] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0106] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0107] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0108] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0109] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0110] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0111] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0112] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0113] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0114] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0115] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0116] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0117] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0118] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0119] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0120] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0121] In another embodiment, the present invention provides a compound represented by the following structure: Or its salt.

[0122] 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 treating JAK1 or JAK2-related disorders, including alopecia areata. method

[0123] In one aspect, the present invention provides a method for preparing ruxolitinib. In some embodiments, the method includes the steps shown below:

[0124] In one aspect, a method for preparing ruxolitinib or a salt thereof includes the step of reacting a compound represented by formula E-6 or a salt thereof in the presence of an acid under conditions that cause the formation of ruxolitinib or a salt thereof. In some embodiments, the compound represented by formula E-6 or a salt thereof is a D-DBTA salt. In some embodiments, when the compound represented by formula E-6 or a salt thereof is a salt, the method includes a further 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 some embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl); in some embodiments, the acid is HCl. In some embodiments, the acid is present in a molar excess relative to the compound represented by formula E-6 or a salt thereof. In some 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 some embodiments, the solvent is an aprotic solvent; in some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of solvents, such as a mixture of an aprotic solvent (e.g., toluene) and an alcohol solvent (e.g., isopropanol). In one embodiment, the solvent is a mixture of toluene and isopropanol. In some embodiments, the acid is provided in an aqueous solvent, and the step of reacting the compound represented by formula E-6 or its salt in the presence of the acid is carried out in a biphasic reaction mixture. In some embodiments, the step of reacting the compound represented by formula E-6 or its salt in the presence of the acid is carried out at a temperature in the range of 15°C to 40°C (e.g., at about 25°C). In some embodiments, the method includes, after the step of reacting the compound represented by formula E-6 or its salt in the presence of the acid, an additional step of contacting ruxolitinib or its salt with a base (such as an inorganic base (such as potassium phosphate)). In some embodiments, the base is provided in an aqueous solvent, and the step of reacting the compound represented by formula E-6 or its salt in the presence of the acid is carried out in a biphasic reaction mixture. In some embodiments, the method further includes, after the step of contacting ruxolitinib or its salt with the base, a further step of contacting ruxolitinib with a second acid (such as phosphoric acid) to provide a salt of ruxolitinib (such as a phosphate). In some embodiments, the step of contacting ruxolitinib with the second acid includes contacting ruxolitinib with 85% phosphoric acid optionally in a solvent (such as isopropanol or an isopropanol / water mixture).

[0125] In another aspect, the present invention provides a method for preparing CTP-543 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes the steps shown below: CTP-543 produced by the above method is treated with phosphoric acid (H3PO4) to produce CTP-543 phosphate. In some embodiments, E-5' is converted to E-6' via intermediate E-7' (an exemplary embodiment is shown):

[0126] In one aspect, a method for preparing CTP-543 or a salt thereof includes the step of reacting a compound represented by formula E-6' or a salt thereof in the presence of an acid under conditions that cause the formation of CTP-543 or a salt thereof. In some embodiments, the compound represented by formula E-6' or a salt thereof is a D-DBTA salt. In some embodiments, when the compound represented by formula E-6' or a salt thereof is a salt, the method includes a further 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 some embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl); in some embodiments, the acid is HCl. In some embodiments, the acid is present in a molar excess relative to the compound represented by formula E-6' or a salt thereof. In some 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 some embodiments, the solvent is an aprotic solvent; in some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of solvents, such as a mixture of an aprotic solvent (such as toluene) and an alcohol solvent (such as isopropanol). In one embodiment, the solvent is a mixture of toluene and isopropanol. In some 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 the acid is carried out in a biphasic reaction mixture. In some embodiments, the step of reacting the compound represented by formula E-6' or a salt thereof in the presence of the acid is carried out at a temperature in the range of 15°C to 40°C (e.g., at about 25°C). In some embodiments, the method includes, after the step of reacting the compound represented by formula E-6' or a salt thereof in the presence of the acid, an additional step of contacting CTP-543 or a salt thereof with a base (such as an inorganic base (such as potassium phosphate)). In some embodiments, the method further includes, after the step of contacting CTP-543 or a salt thereof with a base, a further step of contacting CTP-543 with a second acid (such as phosphoric acid) to provide a salt of CTP-543 (such as a phosphate). In some embodiments, the step of contacting CTP-543 with the second acid includes contacting CTP-543 with 85% phosphoric acid optionally in a solvent (such as isopropanol or an isopropanol / water mixture).

[0127] In another aspect, the present invention provides CTP-543 or a salt thereof prepared by the method shown above or by any method disclosed herein for producing CTP-543 or a salt thereof or a compound of formula I.

[0128] In another aspect, the present invention provides a method for preparing compounds of formula I: or its salt; Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 They are the same and are either hydrogen or deuterium; This method involves making a compound of formula II: or its salt in Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and Each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and Each R 6 Independently selected from H or protecting groups; The reaction occurs under conditions that allow the formation of a compound of formula I.

[0129] In some embodiments, each Y 1 Y 2 and Y 3 It is deuterium. In some embodiments, Y 1 It is hydrogen and each Y 2 and Y 3 It is deuterium. In some embodiments, Y 1 It is hydrogen and each Y 2 and Y 3 It is hydrogen. In some embodiments, the reaction step includes reacting a compound of formula II or a salt thereof in the presence of an acid. In some embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, trifluoroacetic anhydride (TFAA), or combinations thereof. In some embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or combinations thereof. In some embodiments, the acid is hydrochloric acid.

[0130] In some embodiments, the compound of Formula II or a salt thereof is a D-DBTA salt. In some embodiments, when the compound of Formula II or a salt thereof is a salt, the method includes a 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 some embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl); in some embodiments, the acid is HCl. In some embodiments, the acid is present in a molar excess relative to the compound of Formula II or a salt thereof. In some 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 some embodiments, the solvent is an aprotic solvent; in some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of solvents, such as a mixture of an aprotic solvent (such as toluene) and an alcohol solvent (such as isopropanol). In one embodiment, the solvent is a mixture of toluene and isopropanol. In some 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 two-phase reaction mixture. In some 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°C to 40°C (e.g., at about 25°C). In some embodiments, the method includes, after the step of reacting the compound of formula II or a salt thereof in the presence of an acid, an additional step of contacting ruxolitinib or a salt thereof with a base (such as an inorganic base (such as potassium phosphate)). In some 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 some embodiments, the method further includes, after the step of contacting ruxolitinib or a salt thereof with a base, a further step of contacting ruxolitinib with a second acid (such as phosphoric acid) to provide a salt of ruxolitinib (such as a phosphate). In some embodiments, the step of contacting ruxolitinib with a second acid includes contacting ruxolitinib with 85% phosphoric acid optionally in a solvent (such as isopropanol).

[0131] In one aspect, the present invention provides a method for preparing compounds of formula I: or its salt method, This method involves making a compound of formula II': Or its salt reacts in the presence of an acid to form a compound of formula I; wherein in formulas I and II', Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; and in formula II', each R 1’ It is C1-C 10Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The acid is independently selected from H and protecting groups. In some embodiments, the acid is selected from hydrochloric acid, trifluoroacetic acid (TFA), phosphoric acid, or combinations thereof. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group.

[0132] In some embodiments, the compound of formula II' or a salt thereof is a D-DBTA salt. In some embodiments, when the compound of formula II' or a salt thereof is a salt, the method includes a 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 some embodiments, the acid is trifluoroacetic acid or hydrochloric acid (HCl); in some embodiments, the acid is HCl. In some embodiments, the acid is present in a molar excess relative to the compound of formula II' or a salt thereof. In some 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 some embodiments, the solvent is an aprotic solvent; in some embodiments, the solvent is toluene. In some embodiments, the solvent is a mixture of solvents, such as a mixture of an aprotic solvent (such as toluene) and an alcohol solvent (such as isopropanol). In one embodiment, the solvent is a mixture of toluene and isopropanol. In some 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 two-phase reaction mixture. In some 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°C to 40°C (e.g., at about 25°C). In some embodiments, the method includes, after the step of reacting the compound of formula II' or a salt thereof in the presence of an acid, an additional step of contacting ruxolitinib or a salt thereof with a base (such as an inorganic base (such as potassium phosphate)). In some 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 some embodiments, the method further includes, after the step of contacting ruxolitinib or a salt thereof with a base, a further step of contacting ruxolitinib with a second acid (such as phosphoric acid) to provide a salt of ruxolitinib (such as a phosphate). In some embodiments, the step of contacting ruxolitinib with a second acid includes contacting ruxolitinib with 85% phosphoric acid optionally in a solvent (such as isopropanol).

[0133] In another aspect, the present invention provides a method for preparing compounds of formula II: or its salt method in Y 1 It is hydrogen or deuterium; Each Y 2 They are the same and are either hydrogen or deuterium; Each Y 3 The same and is either hydrogen or deuterium; and Each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6Independently selected from H or protecting groups; This method involves making a compound of formula III: Or its salt reacts with hydrogen in the presence of a hydrogenation catalyst, wherein Y 1 Y 2 Y 3 R 1 and R 6 Each of them is as defined in Equation II.

[0134] In another aspect, the present invention provides a method for preparing compounds of formula II: or its salt method, in Y 1 It is hydrogen or deuterium; Each Y 2 They are the same and are either hydrogen or deuterium; Each Y 3 The same and is either hydrogen or deuterium; and Each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 Independently selected from H or protecting groups; This method involves making a compound of formula XI: or its salt, It reacts with hydrogen in the presence of a hydrogenation catalyst, wherein Y 2 Y 3 R 1 and R 6 Each of them is as defined in Equation II.

[0135] In another aspect, the present invention provides a method for preparing compounds of formula II': or its salt method, in Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring, each optionally substituted, for example, with one or more methyl groups); and each R 6 The compounds are independently selected from H and protecting groups; the method involves making compounds of formula XI': or its salt, The reaction occurs with a hydrogen source (such as hydrogen gas) in the presence of a hydrogenation catalyst (e.g., a rhodium-containing hydrogenation catalyst), wherein Y... 2 Y 3 R 1 and R 6 Each of them is as defined in Equation II'.

[0136] In some embodiments of the above methods for producing compounds of formula II or II', the hydrogenation catalyst comprises a transition metal, including but not limited to rhodium, ruthenium, and iridium. In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium and a chiral phosphine ligand (L) according to formula IV. In some embodiments, the hydrogenation catalyst comprises rhodium. In some embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand (L) according to formula IV: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl.

[0137] In some embodiments, R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is norborneol. In some embodiments, R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is cyclohexyl. In some embodiments, the hydrogenation catalyst is present in an amount of 2.5 mol% or less. In some embodiments, the hydrogenation catalyst is present in an amount of 1 mol% or less.

[0138] In some embodiments, the hydrogen gas is present at a pressure of 15 bar or less. In some embodiments, the hydrogen gas is present at a pressure of 10 bar or less. In some embodiments, the step of reacting the compound of formula III or III' with hydrogen gas in the presence of a hydrogenation catalyst is carried out in a solvent, and the solvent is 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 some embodiments, the solvent is trifluoroethanol (TFE). In some embodiments, the compound of formula II or II' has an enantiomer excess of at least 95% of the (R)-enantiomer. In some embodiments, the compound of formula II or II' has an enantiomer excess of at least 98% of the (R)-enantiomer.

[0139] In another aspect, the present invention provides a method for preparing compounds of formula III' (or salts thereof): This method involves making a compound of formula VIII' (or a salt thereof): Compounds with Formula VII: The reaction in the presence of a base results in the formation of a compound of formula III' (or a salt thereof); wherein in formulas III' and VII, Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; and in formulas III' and VIII', each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is tert-butoxycarbonyl. In some embodiments, the base is selected from tripotassium phosphate, hydrated tripotassium phosphate, and potassium carbonate. In some embodiments, the step of reacting the compound of formula VIII' with the compound of formula VII occurs in a solvent. Non-limiting examples of solvents include dimethylacetamide (DMAc), water (H2O), and combinations thereof. In some embodiments, the solvent is a combination of dimethylacetamide and water, for example, dimethylacetamide and water in a ratio between 7:1 DMAc:water and 1:2 DMAc:water (such as 7:1 DMAc:water, 5:4 DMAc / water, or 2:1 DMAc / water). In some embodiments, the reaction is carried out at one or more temperatures in the range of 0°C to room temperature (e.g., in the range of 0°C to 23°C).

[0140] In some respects, the present invention provides for the preparation of compounds of formula I: or its salts, methods and compounds Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 They are the same and are either hydrogen or deuterium.

[0141] In some embodiments, the method for preparing compounds of formula I includes making compounds of formula II: or its salt, Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and each of R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6The reaction is independently selected from H or protecting groups; and is carried out under conditions that cause the formation of a compound of formula I. In some embodiments, the reaction step includes contacting a compound of formula II with an acid (such as trifluoroacetic acid, phosphoric acid, trifluoroacetic anhydride, or combinations thereof) under conditions that cause the formation of a compound of formula I. In some embodiments, the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or combinations thereof. In some embodiments, the acid is hydrochloric acid. In some embodiments, the reaction step includes contacting a compound of formula II with phosphoric acid, wherein the compound of formula I is formed as a phosphate. In some embodiments, the reaction is carried out at a temperature from room temperature (or about 20°C-22°C) to about 100°C. In some embodiments, the reaction is carried out in a solvent (such as toluene, dichloromethane, isopropanol, or combinations thereof). In some embodiments, the compound of formula I has at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the (R)-enantiomer ee. In some embodiments, the compound of formula I is ruxolitinib or a salt thereof. In some embodiments, the compound of Formula I is CTP-543 or a salt thereof.

[0142] Certain aspects of this invention relate to methods for synthesizing compounds of formula II, which can be used as intermediates for the synthesis of JAK inhibitors, including, for example, ruxotinib and CTP-543 as disclosed herein. In some embodiments, the method includes asymmetric hydrogenation, which produces an enantiomeric excess of the (R)-enantiomer of its intermediate.

[0143] Some examples provide a method for preparing compounds of formula II: or its salt method, Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and each of R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 The components are independently selected from H or protecting groups. In some embodiments, the method includes the step of: making the compound of formula III: or its salt, (where Y) 1 Y 2 Y 3 R 1 and R 6 Each of them (as defined in Formula II) reacts with hydrogen in the presence of a hydrogenation catalyst to form a compound of Formula II.

[0145] In another aspect, the present invention provides a method for preparing compounds of formula II' (or salts thereof): This method involves using a compound of formula III' (or a salt thereof): Reaction with a hydrogen source (e.g., hydrogen gas) in the presence of a hydrogenation catalyst; wherein in formulas II' and III', Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2 The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group.

[0146] In some embodiments of the method for preparing compounds of formula II or II', the hydrogenation catalyst comprises a transition metal, including but not limited to rhodium, ruthenium, and iridium. In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium and a chiral phosphine ligand selected from: Walphos W022-1 (CAS No. 849925-29-7), Walphos W003-1 (CAS No. 565184-29-4), Walphos W002-1 (CAS No. 565124-32-9), Walphos W005-1 (CAS No. 494227-30-4), Walphos W006-1 (CAS No. 894771-25-6), Walphos W008-1 (CAS No. 821009-34-1), Walphos W009-1 (CAS No. 894771-28-9), Walphos The following are listed: W012-1 (CAS No. 565184-30-7), Walphos W029-1 (CAS No. 18540687-50-7), Walphos W030-1 (CAS No. 1854067-62-1), Josiphos J002-1 (CAS No. 155830-69-6), Josiphos J003-1 (CAS No. 167416-28-6), Josiphos J006-1 (CAS No. 292638-88-1), Josiphos J007-1 (CAS No. 360048-63-1), Josiphos J009-1 (CAS No. 158923-11-6), Mandyphos M002-1 (CAS No. 494227-35-), and Taniaphos T002-1 (CAS No. 1156547-61-3). In some embodiments, the hydrogenation catalyst is a rhodium-containing catalyst.In some embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand selected from the following: Walphos W022-1 (CAS No. 849925-29-7), Walphos W003-1 (CAS No. 565184-29-4), Walphos W002-1 (CAS No. 565124-32-9), Walphos W005-1 (CAS No. 494227-30-4), Walphos W006-1 (CAS No. 894771-25-6), Walphos W008-1 (CAS No. 821009-34-1), Walphos W009-1 (CAS No. 894771-28-9), Walphos W012-1 (CAS No. 565184-30-7), Walphos W029-1 (CAS No. 18540687-50-7), Walphos The following catalysts are used: W030-1 (CAS No. 1854067-62-1), Josiphos J002-1 (CAS No. 155830-69-6), Josiphos J003-1 (CAS No. 167416-28-6), Josiphos J006-1 (CAS No. 292638-88-1), Josiphos J007-1 (CAS No. 360048-63-1), Josiphos J009-1 (CAS No. 158923-11-6), Mandyphos M002-1 (CAS No. 494227-35-), and Taniaphos T002-1 (CAS No. 1156547-61-3). In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium and a chiral phosphine ligand (L) according to Formula IV. In some embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand (L) according to formula IV. Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl.

[0147] In some embodiments, the reaction forming the compound of formula II into the compound of formula III is carried out in the presence of about 0.25 mol% to about 10 mol% of an Rh catalyst and a catalyst / ligand amount (such as Walphos WO22-1). In some embodiments, the solvent is trifluoroethanol. In some embodiments, the hydrogen pressure is 10 bar. In some embodiments, the temperature is in the range of 15°C to 25°C. In some embodiments, the compound of formula II has at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the (R)-enantiomer ee. In another aspect, the present invention provides a method for preparing a compound of formula II, the method comprising the step of: reacting a compound of formula V with: or its salt (Y) 1 Y 2 Y 3 R 1 and R 6 Each of the following (as defined in Formula II) reacts with hydrogen in the presence of a hydrogenation catalyst containing rhodium and a chiral phosphine ligand (L') according to Formula VI: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl group. In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand according to Formula VI above.

[0148] In another aspect, the present invention provides a method for preparing a compound of formula II', the method comprising the steps of: preparing a compound of formula V': or its salt (Y) 1 Y 2 Y 3 R 1 and R 6 Each of these (as defined in Formula II') reacts with hydrogen in the presence of a hydrogenation catalyst containing rhodium and a chiral phosphine ligand (L') according to Formula VI:

[0149] Where R 2a R 2b R 3a R 3band R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5It is a secondary alkyl, tertiary alkyl, or cycloalkyl group. In some 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, a method for preparing a compound of formula II or II' comprises the step of 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') 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') disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L) according to formula IV disclosed herein. In some embodiments, the method includes the step of reacting a mixture comprising ≥90% of a compound of formula III (for the preparation of compounds of formula II) or III' (for the preparation of compounds of formula II') and ≤10% of a compound of formula V or V' disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L) according to formula IV disclosed herein. In some embodiments, the method includes the step of reacting a mixture comprising ≥95% of a compound of formula III or III' disclosed herein with ≤5% of a compound of formula V or V' disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L) according to formula IV disclosed herein. In some embodiments, the compound of formula I has at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% ((R)-enantiomer) of ee. In some embodiments, the hydrogenation catalysts disclosed above comprise a transition metal selected from rhodium, ruthenium, and iridium, and a chiral phosphine ligand (L) according to Formula IV as disclosed herein. In some embodiments, a method for preparing a compound of Formula II comprises the step of reacting a mixture comprising ≥80% of a compound of Formula V as disclosed herein and ≤20% of a compound of Formula III as disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L') according to Formula VI as disclosed herein. In some embodiments, the method comprises the step of reacting a mixture comprising ≥90% of a compound of Formula V as disclosed herein and ≤10% of a compound of Formula III as disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L') according to Formula VI as disclosed herein. In some embodiments, the method includes the step of reacting a mixture comprising ≥95% of a compound of formula V as disclosed herein and ≤5% of a compound of formula III as disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L') according to formula VI as disclosed herein.In some 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 VI as disclosed herein.

[0150] In some embodiments, a method for preparing a compound of formula II' includes the step of reacting a mixture comprising ≥80% of a compound of formula V disclosed herein and ≤20% of a compound of formula III' disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L') according to formula VI disclosed herein. In some embodiments, the method includes the step of reacting a mixture comprising ≥90% of a compound of formula V disclosed herein and ≤10% of a compound of formula III' disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L') according to formula VI disclosed herein. In some embodiments, the method includes the step of reacting a mixture comprising ≥95% of a compound of formula V disclosed herein and ≤5% of a compound of formula III' disclosed herein with hydrogen in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand (L') according to formula VI disclosed herein. In some 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 VI as disclosed herein.

[0151] In some embodiments of the formula described herein, R 5 Selected from norbornel, cyclohexyl, cyclopentyl, and tert-butyl. In some embodiments, R 5 It is norborneol. In some embodiments, R 5 It is cyclohexyl.

[0152] In some embodiments of the formula described herein, R 2a R 2b R 3a R 3b and R 4 Each of these is hydrogen. In some embodiments, R 2a R 2b and R 4 Each of them is hydrogen, and R 3a and R 3b Each is either methyl or trifluoromethyl. In some embodiments, R 2a and R 2b Each of them is hydrogen, R 4 It is a methoxy group, and R 3a and R 3b Each is a methyl group. In some embodiments, R 2a R 2b R 3a and R 3bEach of them is hydrogen, and R 4 It is methoxy, trifluoromethyl, or methyl. In some embodiments, R 3a R 3b and R 4 Each of them is hydrogen, R 2a and R 2b One of them is hydrogen and R 2a and R 2b The other one is methyl. In some embodiments, R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 Selected from norbornel, cyclohexyl, cyclopentyl, and tert-butyl. In some embodiments, R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is norborneol. In some embodiments, R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is cyclohexyl.

[0153] In some embodiments of the formula described herein, by making the formula [Rh(L1)(L2)] + NC - A rhodium precatalyst is mixed with a chiral phosphine ligand of formula IV (L) or formula VI (L') to form a hydrogenation catalyst; wherein L1 and L2 are the same or different, and L1 and L2 are each independently a pair of monodentate or bidentate ligands, wherein the monodentate ligands are selected from alkene ligands and solvent ligands, and wherein the bidentate ligands are dienes; and wherein NC - It is a noncoordinate counterion selected from tetrafluoroborate, trifluoromethanesulfonate, hexafluorophosphate, hexafluoroantimonate, and perchlorate. In some embodiments, the alkene ligand may have one, two, three, four, 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]. + BF4 -In some embodiments, the rhodium precatalyst is [Rh(COD)2]. + BF4 - .

[0154] In some embodiments, the hydrogenation catalyst comprises [Rh(L1)(L)] + BF4 - Where (L1) is a pair of monodentate or bidentate ligands, and (L) is: (1S)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene (CAS No. 565184-29-4), where R 5 It is cyclohexyl. In some embodiments, the hydrogenation catalyst comprises [Rh(COD)(565184-29-4)]. + BF4 - .

[0155] In some embodiments, the hydrogenation catalyst comprises [Rh(L1)(L')] + BF4 - Where (L1) is a pair of monodentate or bidentate ligands, and (L') is: (1R)-1-[(1S)-1-(dicyclohexylphosphino)ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene (CAS No. 849925-19-5), where R 5 It is cyclohexyl. In some embodiments, the hydrogenation catalyst comprises [Rh(COD)(849925-19-5)]. + BF4 - .

[0156] In some embodiments, the hydrogenation catalyst comprises [Rh(L1)(L)] + BF4 - Where (L1) is a pair of monodentate or bidentate ligands, and (L) is: (1S)-1-[(1R)-1-[bis(bicyclo[2.2.1]hept-2-yl)phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene (CAS No. 849925-29-7), wherein R 5 It is norborneol. In some embodiments, the hydrogenation catalyst comprises [Rh(COD)(849925-29-7)]. + BF4 - .

[0157] In some embodiments, the hydrogenation catalyst comprises [Rh(L1)(L')] + BF4 -Where (L1) is a pair of monodentate or bidentate ligands, and (L') is: (1R)-1-[(1S)-1-[bis(bicyclo[2.2.1]hept-2-yl)phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene (CAS No. 849925-45-7), wherein R 5 It is norborneol. In some embodiments, the hydrogenation catalyst comprises [Rh(COD)(849925-45-7)]. + BF4 - .

[0158] In which R 5 In some embodiments of norbornene, the norbornene is bonded to a phosphorus atom in any of the following configurations shown in Table 1: Table 1 Among them, (1S)-exo-norborneol is (1R)-Exo-norborneol is (1S)-endo-norbornyl is And (1R)-endo-norborneol is In some embodiments, where R 5 It is a chiral phosphine ligand (L) of formula III of norbornel or (L') of formula VI containing a single isomer selected from Table 1 or a mixture containing two, three, four or more isomers selected from Table 1. The P(Nb1)(Nb2) column provides the stereochemical configuration of the phosphorus atom.

[0159] In some embodiments, the present invention provides a method for preparing compounds of formula II: or its salt method; Where Y 1 It is hydrogen; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and either hydrogen or deuterium; and each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 The components are independently selected from H or protecting groups. In some embodiments, the method includes the step of: making the compound of formula XI: or its salt; Where Y 2 Y 3 R 1 and R 6Each of the following (as defined in Formula II) reacts with hydrogen in the presence of a hydrogenation catalyst to form a compound of Formula II. In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium. In some embodiments, the hydrogenation catalyst further comprises a chiral phosphine ligand selected from: Formula VI: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is an aryl, secondary alkyl, tertiary alkyl, or cycloalkyl group; and formula XII: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl group. In some embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand selected from Walphos W002-2 (CAS No. 1854067-25-6) and Josiphos J002-1 (CAS No. 155830-69-6). In some embodiments, the compound of formula I has at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the (R)-enantiomer ee.

[0160] In some embodiments, the present invention provides a method for preparing compounds of formula II': or its salt method; Where Y 1 It is hydrogen and Y 2 Y 3 R 1 and R 6 This is as defined above for formula II'. In some embodiments, the method includes the step of: making the compound of formula XI': or its salt; (where Y) 2 Y 3 R 1’ and R 6Each of these is a compound of formula II that reacts with a hydrogen source (such as hydrogen) in the presence of a hydrogenation catalyst to form a compound of formula II. In some embodiments, the hydrogenation catalyst comprises a transition metal selected from rhodium, ruthenium, and iridium. In some embodiments, the hydrogenation catalyst further comprises a chiral phosphine ligand selected from the following: Formula VI: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is an aryl, secondary alkyl, tertiary alkyl, or cycloalkyl group; and formula XII: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl group. In some embodiments, the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand selected from Walphos W002-2 (CAS No. 1854067-25-6) and Josiphos J002-1 (CAS No. 155830-69-6). In some embodiments, the compound of formula I has at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the (R)-enantiomer ee.

[0161] In some embodiments of the methods described above for preparing compounds of formula II or II', the amount of hydrogenation catalyst containing rhodium and chiral phosphine ligands, or the amount of hydrogenation catalyst containing rhodium, or the amount of chiral phosphine ligands 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 hydrogenation catalyst containing rhodium and chiral phosphine ligands, or the amount of hydrogenation catalyst containing rhodium, or the amount of chiral phosphine ligands 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 hydrogenation catalyst disclosed above includes an amount of hydrogenation catalyst comprising a transition metal selected from rhodium, ruthenium, and iridium and a chiral phosphine ligand; or an amount of hydrogenation catalyst comprising a transition metal selected from rhodium, ruthenium, and iridium.

[0162] In some embodiments, the reaction step further includes treatment with an additive, a non-limiting example of which is tetrafluoroboric acid (HBF4). In some embodiments, the amount of HBF4 is in the range of 0.5 to 1.0 equivalents.

[0163] In some embodiments, the reaction 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 reaction step further includes treatment with HBF4. In some embodiments, the solvent is TFE and the reaction step further includes treatment with HBF4.

[0164] In some embodiments, the solvent is present in 1-50 volumes (vol), 2.5-20 volumes, 5-15 volumes, or 5-10 volumes. In some embodiments, the solvent is present in 10 volumes. In some embodiments, the solvent is present in 5 volumes. In some embodiments, the solvent is present in 2.5 volumes.

[0165] In some embodiments, hydrogen is present in the reaction step at a pressure ranging from 1-200 bar, 5-100 bar, 10-50 bar, or 15-30 bar. In some embodiments, hydrogen is present in the reaction step at a pressure of 50 bar or less. In some embodiments, hydrogen is present in the reaction step at a pressure of 20 bar or less. In some embodiments, hydrogen is present at a pressure of 15 bar or less. In some embodiments, hydrogen is present at a pressure of 10 bar or less. In some embodiments, hydrogen is present at a pressure of 5 bar or less.

[0166] In some embodiments, the method forms a compound of formula II or II' having an enantiomer excess of at least 80% (R)-enantiomers. In some embodiments, the method forms a compound of formula II or II' having an enantiomer excess of at least 90% (R)-enantiomers. In some embodiments, the method forms a compound of formula II or II' having an enantiomer excess of at least 95% (R)-enantiomers. In some embodiments, the method forms a compound of formula II or II' having an enantiomer excess of at least 97% (R)-enantiomers. In some embodiments, the method forms a compound of formula II or II' having an enantiomer excess of at least 98% (R)-enantiomers. In some embodiments, the method forms a compound of formula II or II' having an enantiomer excess of at least 99% (R)-enantiomers.

[0167] In some embodiments of the above methods for preparing compounds 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'.

[0168] Some aspects of the present invention relate to methods for synthesizing compounds of formula III, which can be used as intermediates for the synthesis of JAK inhibitors, including, for example, ruxolitinib and CTP-543 as disclosed herein.

[0169] In some embodiments, the present invention provides a method for preparing compounds of formula III: or its salt method; This method involves making a compound of formula VIII: or its salt; Compounds with Formula VII: The reaction takes place in the presence of a base to form a compound of formula III; wherein Y 1 Is it hydrogen or deuterium, each Y2 The same and either hydrogen or deuterium, each Y 3 The same and either hydrogen or deuterium, each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 The base is independently selected from H or the protecting group. The base can be an inorganic base, such as sodium phosphate or potassium phosphate, or sodium carbonate or potassium carbonate. Non-limiting examples of bases include tripotassium phosphate, such as hydrated tripotassium phosphate and potassium carbonate. In some embodiments, the reaction step is carried out in a solvent. Non-limiting examples of solvents include dimethylacetamide (DMAc), water (H2O), and combinations thereof. In some embodiments, the solvent is a combination of dimethylacetamide and water, for example, dimethylacetamide and water in a ratio between 7:1 DMac:water and 1:2 DMac:water (such as 7:1 DMac:water, 5:4 DMac / water, or 2:1 DMac / water). In some embodiments, the reaction is carried out at one or more temperatures in the range of 0°C to room temperature (e.g., in the range of 0°C to 23°C).

[0170] In another aspect, the present invention provides a method for preparing compounds of formula III' (or salts thereof): This method involves making a compound of formula VIII' (or a salt thereof): Compounds with Formula VII: The reaction in the presence of a base results in the formation of a compound of formula III' (or a salt thereof); wherein in formulas III' and VII, Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; and in formulas III' and VIII', each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 The components are independently selected from H and protecting groups. In some embodiments, Y... 1 It is hydrogen; each Y 2The same and is hydrogen; and each Y 3 It is the same and is hydrogen. In other embodiments, Y 1 It is deuterium; each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6 The protecting group is a tert-butoxycarbonyl group. In some embodiments, the protecting group is a tert-butoxycarbonyl group. The base can be an inorganic base, such as sodium phosphate or potassium phosphate, or sodium carbonate or potassium carbonate. Non-limiting examples of bases include tripotassium phosphate, such as tripotassium hydrate and potassium carbonate. In some embodiments, the reaction step is carried out in a solvent. Non-limiting examples of solvents include dimethylacetamide (DMAc), water (H2O), and combinations thereof. In some embodiments, the solvent is a combination of dimethylacetamide and water, for example, dimethylacetamide and water in a ratio between 7:1 DMAc:water and 1:2 DMAc:water (such as 7:1 DMAc:water, 5:4 DMAc / water, or 2:1 DMAc / water). In some embodiments, the reaction is carried out at one or more temperatures in the range of 0°C to room temperature (e.g., in the range of 0°C to 23°C).

[0171] Certain aspects of this invention relate to methods for synthesizing compounds of formula XI, which can be used as intermediates for the synthesis of JAK inhibitors, including, for example, ruxolitinib and CTP-543 as disclosed herein. In some embodiments, this invention provides a method for preparing compounds of formula XI: or its salt method; This method involves making a compound of formula III: or its salt; It reacts with a base to form a compound of formula XI; wherein Y 1 Is it hydrogen or deuterium, each Y 2 The same and either hydrogen or deuterium, each Y 3 The same and either hydrogen or deuterium, each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6The base is independently selected from H or a protecting group. Non-limiting examples of bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide. In some embodiments, the reaction step is carried out in a solvent. Non-limiting examples of solvents include dimethylacetamide (DMAc), water (H2O), and combinations thereof. In some embodiments, the reaction is carried out at one or more temperatures in the range of 0°C to room temperature (e.g., in the range of 0°C to 23°C).

[0172] Certain aspects of this invention relate to methods for synthesizing compounds of formula XI, which can be used as intermediates for the synthesis of JAK inhibitors, including, for example, ruxolitinib and CTP-543 as disclosed herein. In some embodiments, this invention provides a method for preparing compounds of formula XI': or its salt method; This method involves making a compound of formula III': or its salt; It reacts with a base to form a compound of formula XI'; wherein Y 1 It is hydrogen or deuterium and where Y 2 Y 3 R 1’ and R 6 Each of them is as defined in Equation II'. In some embodiments, Y 1 It is hydrogen. In some embodiments, each Y 2 The same and is deuterium; and each Y 3 They are the same and are deuterium. In other embodiments, each Y 2 The same and is hydrogen; and each Y 3 They are the same and are hydrogen. In some embodiments, each R 1’ It is methyl. In some embodiments, each R 1’ It is ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and another R 6 It is a protecting group. In some embodiments, the protecting group is a Boc group. Non-limiting examples of bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide. In some embodiments, the reaction step is carried out in a solvent. Non-limiting examples of solvents include dimethylacetamide (DMAc), water (H2O), and combinations thereof. In some embodiments, the reaction is carried out at one or more temperatures in the range of 0°C to room temperature (e.g., temperatures in the range of 0°C to about 23°C).

[0173] Certain aspects of this invention relate to methods for synthesizing compounds of formula VIII, which can be used as intermediates for the synthesis of JAK inhibitors, including, for example, ruxolitinib and CTP-543 as disclosed herein. In some embodiments, methods for preparing compounds of formula VIII (or salts thereof) include: Including compounds of formula IX: or its salt; and (or another pyrazole-4-ylboronic acid ester) and a catalytic amount of palladium catalyst react in the presence of a base to form a compound of formula VIII; wherein each R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; each R 6 It is independently selected from H or a protecting group; and X is I, Br, Cl, or a trifluoromethanesulfonate.

[0174] Some aspects of this invention relate to a method for preparing compounds of formula VIII' (or salts thereof): This method involves making a compound of formula IX' (or a salt thereof): With compounds represented by the following formula: (or another pyrazole borate ester) and a catalytic amount of palladium catalyst (such as Pd(PPh3)4) react in the presence of a base to form a compound of formula VIII'; wherein in formulas VIII' and IX', each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring); and each R 6 Independently selected from H and protecting groups. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R 6It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group. In some embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0175] In some embodiments of formula IX or IX', X is Cl. In some embodiments, the palladium catalyst is a combination of Pd(PPh3)4 or Pd2(dba)3 and XPhos. In some embodiments, the catalytic amount of the palladium catalyst is in the range of 0.1-10 mol%, 0.5-5 mol%, 3-6 mol%, or 1-2.5 mol%. In some embodiments, non-limiting examples of the base include potassium carbonate and disodium hydrogen phosphate dihydrate. In some embodiments, the reaction step is carried out in a solvent. Non-limiting examples of solvents include n-butanol, 1,4-dioxane, THF, and combinations thereof. In some embodiments, the reaction is carried out at one or more temperatures within the range of room temperature to 120°C, or 60°C to 90°C, or the reflux temperature of the solvent.

[0176] In some embodiments of formulas II, II', III, III', V, V', VIII, VIII', IX, IX', XI, or XI', the protecting group is selected from tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and triphenylmethyl (Tr, CPh3). In some embodiments, the two R... 6 All are tert-butoxycarbonyl (Boc). In some embodiments, one R 6 It is tert-butoxycarbonyl (Boc) and another R 6 It is H. In some embodiments, an R 6 It is trifluoromethanesulfonyl (Tf) and another R 6 It is H. In some embodiments, an R 6 It is trifluoroacetyl (F3-Ac) and another R 6 It is H. In some embodiments, an R 6 It is triphenylmethyl (Tr) and another R 6 It is H. In some embodiments, two Rs 6 Both are H.

[0177] In some embodiments of formulas II, II', III, III', V, VIII, IX, IX', XI, or XI', each R 1 or R 1’ It is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, two R... 1 or R 1’ Both are methyl groups. In some embodiments, the two R groups... 1 or R 1’Together they form a C2 or C3 alkylene moiety to form a selection from and Heterocyclic compounds.

[0178] In some embodiments of formulas I, II, II', III, III', V, V', VII, or VII', Y 1 Y 2 and Y 3 Each of them is hydrogen. In some embodiments of formulas I, II, II', III, III', V, V', VII, or VII', Y 1 Y 2 and Y 3 Each of these is deuterium. In some embodiments of formulas I, II, III, V, or VII, Y 1 It is hydrogen and Y 2 and Y 3 Each of these is deuterium. In some embodiments of formulas I, II, II', III, III', V, V', VII, or VII', Y 1 It is at least 95% hydrogen. In some embodiments of formula I, II, II', III, III', V, V', VII, or VII', Y 1 It is at least 96% hydrogen. In some embodiments, Y 1 It is at least 97% hydrogen. In some embodiments, Y 1 It is at least 98% hydrogen. In some embodiments, Y 1 It is at least 99% hydrogen.

[0179] In some embodiments, the compounds of formulas I, II, II', III, III', V, V', VII, VII', XI, or XI' have at least 90% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of formulas I, II, II', III, III', V, V', VII, VII', XI, or XI' have at least 95% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of formulas I, II, II', III, III', V, V', VII, VII', XI, or XI' have at least 97.5% deuterium doping at each specified deuterium atom. In some embodiments, the compounds of formulas I, II, II', III, III', V, V', VII, VII', XI, or XI' have at least 98% deuterium doping at each specified deuterium atom. In some embodiments, compounds of formulas I, II, II', III, III', V, V', VII, VII', XI, or XI' have at least 99% deuterium doping at each specified deuterium atom.

[0180] In some respects, the present invention provides for the preparation of compounds of formula I: Methods and compounds thereof, or their salts; The method includes the following steps: Where Y 1 Y 2 Y 3 R 1 and R 6 As defined in Formula II, and each reactant and reaction condition is as defined for each transformation herein. In some embodiments, the compound of Formula III is converted to the compound of Formula II via an intermediate compound of Formula XI;

[0181] The present invention further provides methods for preparing compounds of the present invention (e.g., compounds of formula I, or compounds of formula II or II', or compounds of formula III or III', or compounds of formula VII, or compounds of formula VIII or VIII') using more than one method described herein. For example, the present invention provides a method for producing a compound of formula I by first preparing a compound of formula VIII or VIII' as disclosed herein, then preparing a compound of formula III or III' from a compound of formula VIII or VIII' as disclosed herein, and then preparing a compound of formula I from a compound of formula III or III' as described herein.

[0182] The present invention further provides methods for preparing compounds of the present invention (e.g., compounds of formula I, or compounds of formula II or II', or compounds of formula III or III', or compounds of formula VII, or compounds of formula VIII or VIII') using more than one method described herein. For example, the present invention provides a method for producing a compound of formula I by first preparing a compound of formula VIII or VIII' as disclosed herein, then preparing a compound of formula III or III' from a compound of formula VIII or VIII' as disclosed herein, and then preparing a compound of formula I from a compound of formula III or III' as described herein.

[0183] Some aspects of the method of the present invention provide that Y 1 Y 2 and Y 3Each of the compounds in Formula I as defined in Formula II is substantially free of impurities (e.g., CTP-543 or ruxotinib) or a pharmaceutically acceptable salt thereof (e.g., CTP-543 phosphate or ruxotinib phosphate). In some embodiments, the compounds of Formula I have 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 compounds of Formula I contain 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 Y. 1 Y 2 and Y 3 Each of these is a compound of formula X as defined in formula II: Some embodiments provide CTP-543, which comprises 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 a compound represented by the following structure: Some embodiments provide ruxolitinib comprising 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 a compound represented by the following structure:

[0184] On the other hand, the present invention provides a purified E-6: Or E-6': A method for obtaining a compound of formula E-6 or E-6'. The method includes contacting a compound of formula E-6 or E-6' with an acid to form a salt of the compound of formula E-6 or E-6', and crystallizing the crystalline salt of the compound of formula E-6 or E-6'. In some embodiments, the acid is a chiral acid, such as D-dibenzoyl tartaric acid. In some embodiments, the step of contacting the compound of formula E-6 or E-6' with the acid is carried out in a solvent; in some embodiments, the solvent is trifluoroethanol, acetonitrile, isopropyl acetate, or a mixture thereof. In some embodiments, the crystalline salt of the compound of formula E-6 or E-6' has an enantiomeric ratio (er) of at least 99:1, or at least 99.5:0.5, or at least 99.6:0.4.

[0185] In another aspect, the present invention provides a purified compound 15: Or 15': The method comprises 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 some embodiments, the acid is a chiral acid, such as D-dibenzoyl tartaric acid. In some embodiments, the step of contacting the compound of formula 15 or 15' with the acid is carried out in a solvent; in some embodiments, the solvent is trifluoroethanol, acetonitrile, isopropyl acetate, or a mixture thereof. In some 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. intermediate

[0186] Some aspects of the present invention relate to additional intermediates that can be used, for example, to prepare compounds of formula I.

[0187] In some embodiments, the intermediate comprises a compound of formula II: or its salt; Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and each of R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 The intermediate is independently selected from H or a protecting group. In some embodiments, the intermediate comprises a compound of formula III: or its salt; Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and each of R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 It is independently selected from H or a protecting group.

[0188] In some embodiments, the intermediate comprises a compound of formula III: or its salt; Each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and each of R 1 It is a C1-C6 alkyl group, or both of the R groups. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 It is independently selected from H or a protecting group.

[0189] In some embodiments of formula II, III, or XI, the protecting group is selected from tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and triphenylmethyl (Tr, CHPh3). In some embodiments, the two R 6 All are tert-butoxycarbonyl (Boc). In some embodiments, one R 6 It is tert-butoxycarbonyl (Boc) and another R 6 It is H. In some embodiments, an R 6 It is trifluoromethanesulfonyl (Tf) and another R 6 It is H. In some embodiments, an R 6 It is trifluoroacetyl (F3-Ac) and another R 6 It is H. In some embodiments, an R 6 It is triphenylmethyl (Tr) and another R 6 It is H. In some embodiments, two Rs 6 Both are H.

[0190] In some embodiments of formulas II, III, or XI, R 1 It is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments of formula II, III, or XI, R 1 It is methyl or ethyl. In some embodiments of formula II, III, or XI, both R 1 All are methyl groups.

[0191] In another embodiment, the present invention provides a compound of formula VII: Where Y 1 Is it hydrogen or deuterium, each Y 2 The same and is either hydrogen or deuterium, and each Y 3 The same and is either hydrogen or deuterium; and OTf is trifluoromethanesulfonate (-OSO2CF3). In some embodiments, the compound of formula VII is the compound of formula VIIa: In some embodiments, the compound of formula VII is a compound of formula VIIb: In some embodiments, the compound of formula VII is a mixture of compounds of formula VIIa and formula VIIb.

[0192] In some embodiments of formulas II, III, or VII, or formulas I, II', II', or VII', Y 1 Y 2 and Y 3 Each of them is hydrogen. In some embodiments of formula II, III, or VII, or formula I, II', II', or VII', Y 1 Y 2 and Y 3 Each of these is deuterium. In some embodiments of formulas II, III, or VII, or formulas I, II', II', or VII', Y 1 It is hydrogen and Y 2 and Y 3 Each of these is deuterium. In some embodiments of formulas II, III, or VII, or formulas I, II', II', or VII', Y 1 It is at least 95% hydrogen. In some embodiments of formula II, III, or VII, or formula I, II', II', or VII', Y 1 It is at least 96% hydrogen. In some embodiments, Y 1 It is at least 97% hydrogen. In some embodiments, Y 1 It is at least 98% hydrogen. In some embodiments, Y 1 It is at least 99% hydrogen.

[0193] In some embodiments, compounds of formulas II, III, VII, or XI, or formulas I, II', II', VII', or XI', have at least 90% deuterium doping at each specified deuterium atom. In some embodiments, compounds of formulas II, III, VII, or XI, or formulas I, II', II', VII', or XI', have at least 95% deuterium doping at each specified deuterium atom. In some embodiments, compounds of formulas II, III, VII, or XI, or formulas I, II', II', VII', or XI', have at least 97% deuterium doping at each specified deuterium atom. In some embodiments, compounds of formulas II, III, VII, or XI, or formulas I, II', II', VII', or XI', have at least 98% deuterium doping at each specified deuterium atom. In some embodiments, compounds of formula II, III, VII, or XI, or formula I, II', II', VII', or XI', have at least 99% deuterium doping at each specified deuterium atom.

[0194] In another set of embodiments of the formulas described herein, any atom not designated as deuterium in any of the embodiments set forth herein exists in its natural isotopic abundance.

[0195] In another embodiment, the present invention provides a compound of formula VIII: or its salt; Each R 1 It is methyl, propyl, butyl, pentyl, hexyl, or both of these R. 1 Together they form a C2 or C3 alkylene moiety; and each R 6 It is independently selected from H or a protecting group.

[0196] In some embodiments of Formula VIII, the protecting group is selected from tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and triphenylmethyl (Tr, CHPh3). In some embodiments, the two R 6 All are tert-butoxycarbonyl (Boc). In some embodiments, one R 6 It is tert-butoxycarbonyl (Boc) and another R 6 It is H. In some embodiments, an R 6 It is trifluoromethanesulfonyl (Tf) and another R 6 It is H. In some embodiments, an R 6 It is trifluoroacetyl (F3-Ac) and another R 6 It is H. In some embodiments, an R 6 It is triphenylmethyl (Tr) and another R 6 It is H. In some embodiments, two Rs 6 Both are H. In some embodiments of formula VIII, the two Rs 1 All are methyl groups.

[0197] In another embodiment, the present invention provides a compound of formula IX: or its salt; Each R 1 It is methyl, propyl, butyl, pentyl, hexyl, or both of these R. 1 Together they form a C2 or C3 alkylene moiety; each R 6 It is independently selected from H or a protecting group; and X is I, Br, Cl, or a trifluoromethanesulfonate.

[0198] In some embodiments of Formula IX, the protecting group is selected from tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and triphenylmethyl (Tr, CHPh3). In some embodiments, the two R 6 All are tert-butoxycarbonyl (Boc). In some embodiments, one R 6 It is tert-butoxycarbonyl (Boc) and another R 6 It is H. In some embodiments, an R 6 It is trifluoromethanesulfonyl (Tf) and another R 6 It is H. In some embodiments, an R 6 It is trifluoroacetyl (F3-Ac) and another R 6 It is H. In some embodiments, an R 6 It is triphenylmethyl (Tr) and another R 6 It is H. In some embodiments, two Rs 6 Both are H. In some embodiments of Formula IX, the two Rs 1 All are methyl groups. In some embodiments of formula XI, R 1 It is not ethyl.

[0199] In some embodiments of Formula IX, X is Cl.

[0200] In another embodiment, the present invention provides a compound of formula IX': or its salt; Each R 1’ It is C1-C 10 Alkyl (e.g., methyl or ethyl), or C2-C 10 Alkenyl (e.g., allyl), or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted (e.g., 1,3-dioxolane-2-yl ring, or 1,3-dioxane-2-yl ring, or 1,3-benzodioxolane-2-yl ring, each of which may be substituted, for example, with one or more methyl groups); and each R 6 Independently selected from H and protecting groups; and X is I, Br, Cl, or trifluoromethanesulfonate. In some embodiments, each R 1’ It is C1-C 10 Alkyl; in further embodiments, each R 1’ It is methyl or ethyl. In some embodiments, each R 6 It is H. In some embodiments, an R 6 It is H and an R 6 It is a protecting group. In some embodiments, each R6 It is a protecting group. In some embodiments, the protecting group is a tert-butoxycarbonyl group. In some embodiments, the base is selected from potassium carbonate and disodium hydrogen phosphate dihydrate.

[0201] In some embodiments of Formula IX, the protecting group is selected from tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and triphenylmethyl (Tr, CPh3). In some embodiments, the two R 6 All are tert-butoxycarbonyl (Boc). In some embodiments, one R 6 It is tert-butoxycarbonyl (Boc) and another R 6 It is H. In some embodiments, an R 6 It is trifluoromethanesulfonyl (Tf) and another R 6 It is H. In some embodiments, an R 6 It is trifluoroacetyl (F3-Ac) and another R 6 It is H. In some embodiments, an R 6 It is triphenylmethyl (Tr) and another R 6 It is H. In some embodiments, two Rs 6 Both are H. In some embodiments of formula IX', the two Rs 1 All are methyl groups. In some embodiments of formula IX', X is Cl. In some embodiments of formula XI', R... 1’ It is not ethyl.

[0202] The synthesis of compounds of formulas II-XII can be readily performed by those skilled in the art with reference to the exemplary synthesis disclosed herein.

[0203] The compounds described herein can be synthesized using appropriate deuterating agents and optionally other isotopic reagents and / or intermediates, or by employing standard synthetic methods known in the art for introducing isotopic atoms into chemical structures.

[0204] As used in this article, the terms method and process are used interchangeably. Example Option 1: Preparation of ruxotinib phosphate Option 2: Preparation of D8-Ruxotinib (CTP-543) Scheme 3: Preparation of enol trifluoromethanesulfonates (2-cyano-1-(cyclopentyl)vinyltrifluoromethanesulfonate and 2-cyano-1-(2,2,3,3,4,4,5,5-D8-cyclopentyl)vinyltrifluoromethanesulfonate)

[0205] As shown in Scheme 3 above, 2-cyano-1-(cyclopentyl)vinyltrifluoromethanesulfonate (enol trifluoromethanesulfonate 16) can be prepared from the corresponding β-keto nitrile, which in turn can be prepared from methyl cyclopentanecarboxylate (easily obtained from commercially available cyclopentanecarboxylic acid). Enol trifluoromethanesulfonate 16 is synthesized as a mixture of Z and E isomers, which can optionally be separated into 16Z and 16E. Similarly, deuterated enol trifluoromethanesulfonate 16' can be prepared from the corresponding deuterated precursor. Enol trifluoromethanesulfonate 16' is synthesized as a mixture of Z and E isomers, which can optionally be separated into 16Z' and 16E'. In any of the syntheses disclosed herein, deuterated enol trifluoromethanesulfonate 16', 16Z', or 16E' can replace enol trifluoromethanesulfonate 16, 16Z, or 16E to produce CTP-543 or a pharmaceutically acceptable salt thereof. A) Preparation of β-ketonitrile

[0206] A solution of NaHMDS in THF (173 mL, 343.2 mmol, 2.2 equivalents; 2 M solution in THF) was added via syringe to a 3-necked 500-mL European-style flask equipped with a mechanical stirrer and thermocouple and rinsed with nitrogen. The yellow solution was then cooled to -14.6 °C under N2. A solution of methyl cyclopentanecarbamate (20 g, 156 mmol, 1.0 equivalent) in MeCN (9.8 mL, 187.2 mmol, 1.2 equivalents) was added dropwise via syringe to the cold solution. The flask was rinsed with anhydrous THF (10 mL) and the rinsing solution was added to the reaction mixture over 50 min, during which time the internal temperature was maintained below -3 °C and the mixture became a cloudy and thin slurry. The mixture was stirred at approximately -10 °C for 10 min and then warmed to 20 °C over a period of 1 h. The mixture was stirred continuously overnight at 24°C to form a very thick slurry with a hardened top layer. The mixture was cooled to approximately 3°C, and then cold 6N HCl (approximately 5°C, 130 mL) was added in batches to maintain the internal temperature primarily below 27°C. After quenching, the mixture was stirred and warmed to 22°C, then transferred to a separatory funnel to collect the organic and aqueous layers. The aqueous layer (140 mL) was extracted with MTBE (2 x 55 mL). The combined organic layers were washed with saturated NaHCO3 (60 mL), 1N HCl (2 x 50 mL), and 20% NaCl aqueous solution (50 mL), followed by a final wash with water (2 x 50 mL). The resulting organic layers were concentrated in a rotary evaporator (45°C) to remove volatile organic compounds, and further MTBE (2X) was used for azeotropic removal of residual water. A crude product as an amber liquid was obtained, weighing 20.09 g. 1 ¹H NMR (CDCl₃) showed the desired product with a very clear characteristic profile. Molar yield = 93%. 1 ¹H NMR (CDCl₃) δ: 3.50 (s, 3H), 3.07 (quintet, J = 8 Hz, 1H), 1.98–1.54 (m, 8H). B) Preparation of 2-cyano-1-(cyclopentyl)vinyltrifluoromethane sulfonate 16

[0207] A β-ketonitrile solution (50 g, 364 mmol, solution weight = 213.6 g, w% = 23.4%) in toluene was added to a 1-L jacketed reactor equipped with a mechanical stirrer and thermocouples under nitrogen atmosphere. The solution was cooled to 0 °C, and then N-methylmorpholine (50.1 g, 455.5 mmol, 1.25 equivalents) was added while maintaining the batch temperature below 2 °C. Tf₂O (111.5 g, 395.2 mmol, 1.09 equivalents) was added dropwise to the mixture over an 80-minute period at approximately 0 °C to maintain the batch temperature below 5 °C. The reaction mixture was stirred under cold for approximately 2 h. GC analysis showed >99.8% conversion. Water (300 mL) was added to the cold mixture, and the resulting cold two-phase mixture was warmed to ambient temperature. The upper organic layer was collected and washed with water (300 mL), and then partially concentrated in a rotary evaporator to obtain an enol-trifluoromethanesulfonate solution (163.2 g) in toluene. 1 ¹H NMR (CDCl₃) analysis indicated a w / w percentage of 55% for enol-trifluoromethanesulfonate 16, as a mixture of E / Z isomers (Z:E approximately 89:11). Corrected weight = 88.9 g, molar yield = 91%. 1 ¹H NMR (CDCl₃)δ: 16Z-isomer---5.33(d,J=4Hz,1H),2.99(dq,J=8Hz,4Hz,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=8Hz,1H),2.18-1.51(m,8H).

[0208] The corresponding D8 deuterated compound 16' (2-cyano-1-(2,2,3,3,4,4,5,5-D8-cyclopentyl)vinyltrifluoromethanesulfonate) can be prepared using a similar procedure 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, US Patent No. 9,249,149). Similar to enol trifluoromethanesulfonate 16, 2-cyano-1-(2,2,3,3,4,4,5,5-D8-cyclopentyl)vinyltrifluoromethanesulfonate 16' is synthesized as a mixture of isomers, which can optionally be separated into 16Z' and 16E'. Scheme 4: Preparation of ruxolitinib (free base) Example 1: Step 1: Preparation of 4,6-dichloro-5-(2,2-dimethoxyethyl)pyrimidine (C-2) a) MeOH, TsOH (10 mol%):

[0209] A mixture of compound B-1 (10 g, 52.4 mmol), trimethyl orthoformate (6.67 g, 62.8 mmol, 1.2 equivalents), and TsOH·H₂O (0.902 g, 5.24 mmol, 0.10 equivalents) in MeOH (50 mL) was stirred at 40 °C for 1.5 h. The reaction mixture was cooled to room temperature, and an aqueous solution of Na₂CO₃ (20 mL) was added to adjust the pH to 8, followed by extraction with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (20 mL) and brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give C-2 (11.9 g, 96% yield) as a brown solid. b) Toluene, TsOH (1 mol%):

[0210] Trimethyl orthoformate (371 g, 3.50 mol, 1.2 equivalents) was added to a suspension of compound B-1 (635 g, 88% determination, 2.93 mol) in toluene (2988 g). The batch was cooled to 20 °C and solid TsOH·H₂O (5.76 g, 0.03 mol, 0.01 equivalents) was added. The batch temperature was maintained by lowering the jacket temperature to 16 °C for 10 minutes during a small exothermic process, and then adjusting it to 20 °C. After stirring the suspension at 20 °C for 2 hours, the jacket temperature was raised to 40 °C for 11.5 hours, and then lowered to 20 °C. HPLC indicated that the starting material was consumed. The determination of the brown solution provided a concentration of C-2 of approximately 136 mg / mL (total volume approximately 4.40 L, 597–631 g product, 86% yield). The batch is filtered through coarse glass frit and then used in the next step. Step 2: Preparation of 6-chloro-5-(2,2-dimethoxyethyl)pyrimidine-4-amine (C-3) a) Isopropanol (iPA):

[0211] The mixture of compound C-2 (6.0 g, 25.3 mmol) and NH4OH (30 ml) in iPA (30 ml) was stirred at 70 °C for 8 h. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (2 x 60 ml). The combined organic extracts were washed with water (20 ml) and brine (15 ml) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give C-3 (5.3 g, 96%) as a light brown solid. b) Toluene / iPA:

[0212] Ammonium hydroxide solution (235 g) was added to a 4.40 L (approximately 136 mg / mL) toluene solution of C-2 in a 10 L jacketed glass reactor (jacket temperature 20 °C, stirring rate 130 RPM, condenser temperature: -5 °C). The mixture exhibited exothermic reaction, raising the batch temperature by 3 °C. The mixture was stirred for 4 hours, then agitation was stopped to allow removal of the aqueous phase (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. Additional ammonium hydroxide (200 g) and isopropanol (4 L) were added, and the reactor jacket was set to 70 °C. Ammonium hydroxide solution (421 g) was added periodically over the next 24 hours, and the reaction was considered complete after stirring at 70 °C for 6 days. The batch was cooled to 20 °C and water (1.0 L) was added to the batch. Agitation was stopped, and the aqueous fraction was removed. The batch was discharged into a drum and treated with activated carbon (78 g). After standing for three hours, the batch was filtered into a clean reactor. A distillation apparatus was attached and the batch was distilled to a volume of 2.5 L. Toluene (876 g) was added. After a further distillation (1023 g distillation), the reactor jacket was cooled to 10°C for 4 hours. Heptane (100 g) was added and the batch was stirred for 4 hours. The batch was filtered under suction onto three disposable polypropylene sintered funnels to obtain a 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 under suction to a transferable solid and then combined into a drying tray. The solid was dried under vacuum with a nitrogen stream to obtain a brown solid (343.2 g, 94.6 wt%, 55% yield). Step 3: Preparation of 5-(2,2-dimethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidine-4-amine (E-4): a) Small batch

[0213] C-3 (9.95 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrazole (12.12 g), and disodium hydrogen phosphate dihydrate (35.02 g) were charged into a 100 mL reactor equipped with a top stirrer and nitrogen purging. 50 mL of n-butanol was added to the reactor, and the top space was purged while stirring for 15 min. Tetra(triphenylphosphine)palladium(0) (0.498 g) was added to the reactor. The reactor jacket was set to 100 °C while stirring. After 16.5 hours under reflux, the reaction appeared to be complete (HPLC / UV, 210 nm). The batch was cooled to 25 °C, and then 50 mL of water was added. The batch was stirred until all the salts dissolved. The batch was transferred to a separatory funnel and allowed to separate the phases. The aqueous layer was removed from the organics. The organics were returned to the reactor and washed with 30 mL of n-butanol. Attach a distillation apparatus and distill the batch until a total of 35 mL is collected. Filter the batch to remove precipitated salts and return it to a clean reactor rinsed with n-butanol (10 mL). Distill the batch to a total volume of 20 mL. Cool the reactor to 20°C while adding n-butanol (20 mL) and heptane (80 mL). Add E-4 seed crystals and heat the batch to 50°C, then cool to 25°C over 10 minutes. Filter the suspension under suction. Wash the filter cake twice with a 1:5 mixture of n-butanol and heptane (25 mL) and dry under suction for an additional hour to provide a brick-red solid (9.848 g, 70%) containing a 2:1 molar mixture of E-4 and pinacol. Pinacol can be removed by dissolving the product in n-butanol and continuously distilling the n-butanol until the pinacol is azeotropically removed. b) large quantities

[0214] C-3 (50.32 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrazole (60.14 g), and disodium hydrogen phosphate dihydrate (170.76 g) were charged into a 500 mL reactor equipped with a top stirrer and nitrogen purging. n-Butanol (250 mL) was added to the reactor, and the top space was purged while stirring for 5 minutes. Tetra(triphenylphosphine)palladium(0) (2.62 g) was added to the reactor. The reactor jacket was set to 100 °C while stirring. After 13 hours, the reaction appeared to be complete (HPLC / UV, 210 nm). Water (250 mL) was pumped in after 1 hour. The batch was stirred until all the salts dissolved, then cooled to 20 °C. Stirring was stopped, and the phases were allowed to separate. The aqueous layer was drained and discarded. A distillation apparatus was attached to the reactor and the batch was distilled under reduced pressure at 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 at this temperature for 4 hours, followed by cooling to 20°C over 4 hours. The resulting suspension was filtered and dried under suction for 1 hour to provide E-4 (52.0 g, 85% w / w, 77% yield) containing 3.3 wt% pinacol.

[0215] 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 under suction for 1 hour to provide a brownish powder of E-4 with <0.1% w / w pinacol (41.4 g, 88% w / w, 82% recovery). Acetonitrile (100 mL) was added to a portion of the resulting low-pinacol E-4 (21.4 g), and the batch was heated to 40 °C with stirring, then cooled to 23 °C for 1 hour. The suspension was filtered and dried under suction for 2 hours to provide purified E-4 (19.04 g, 94% w / w, 96% recovery). 1 ¹H-NMR (400 MHz, in methanol-d⁴, 5% acetic acid-d⁴): δ 8.31 (s, 1H), 8.07 (s, 2H), 4.70 (t, J = 5.2 Hz, 1H), 3.40 (s, 6H), 2.98 (d, J = 5.2 Hz, 2H). 13C-NMR (101 MHz, in methanol-d4 with 5% acetic acid-d4): δ 165.52, 156.08, 155.64, 136.00, 119.25, 111.03, 105.62, 54.84, 33.17. c) Alternative reaction conditions for the formation of E-4:

[0216] At room temperature, 2 mL of an aqueous K₂CO₃ solution (0.952 g, 6.89 mmol, 3.0 equivalence) was added to a mixture of C-3 (0.5 g, 2.3 mmol) and BPin-pyrazole (0.58 g, 2.99 mmol, 1.3 equivalence) in dioxane (5 mL). The solution was degassed by passing a nitrogen stream through it for 15 min, and then treated with Pd₂(dba)₃ (32 mg, 0.0344 mmol, 0.03 equivalence) and XPhos (35 mg, 0.069 mmol, 0.06 equivalence). 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 x 5 mL) and brine (10 mL), dried over anhydrous Na₂SO₄, 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). Step 4: (Z)-3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- Preparation of 3-cyclopentylacrylonitrile (E-5):

[0217] Compound E-4 (3 g, 11.4 mmol, 95% pure) and enol trifluoromethanesulfonate 16 (5.37 g, 12.1 mmol, 1.06 wt% in toluene) were added via syringe to a stirred solution of dimethylacetamide (DMAc, 15 mL) in 12 mL of water containing pre-dissolved K3PO4·H2O (7.89 g, 3.0 wt%). The resulting biphasic mixture was then allowed to reach room temperature (approximately 22 °C) and stirred for 15 h. As the reaction proceeded, the reaction mixture became a heterogeneous biphasic mixture (products slowly precipitated from the reaction mixture). DI water (30 mL, 10 vol) was added to the crude mixture, resulting in further precipitate formation. The slurry was stirred at ambient temperature for 1 h, the solids were filtered off, and the wet cake was then washed with a premixed solution (1 x 15 mL) of DMAc (5 vol) and water (14 vol). The resulting beige wet cake was vacuum-dried for 2 hours to obtain product E-5 (3.6 g, 86% yield).

[0218] Alternatively, the reaction mixture was quenched to approximately pH 8 with 0.4 volumes of phosphoric acid (85 wt%). Five volumes of DMAc were added, and the mixture was heated to 55°C for 30 minutes. The alkaline aqueous layer was separated at approximately 55°C, and then 11 volumes of water were added at 55°C for 30 minutes. At the end of the water addition, a large amount of solids precipitated. The slurry was cooled to 22°C for 35 minutes and then the solids were filtered. The filter cake was washed with 5 volumes of a 2:3 DMAc / water solution. The solids E-5 were then washed with 5 volumes of water and dried under vacuum. 1 H-NMR (DMSO-d6, 400MHz): δ8.65(s,1H),8.28(s,1H),8.16(s,1H),6.73(s,NH2,2H),5.72(s,1H),4.63(t,J= 4.0Hz, 1H), 3.41 (q, J = 8.0Hz, 1H), 3.27 (s, 6H), 2.94 (d, J = 4.0Hz, 2H), 1.99-1.89 (m, 2H), 1.77-1.47 (m, 6H). a) Alternative reaction conditions for the formation of E-5:

[0219] At 0 °C, 2.5 mL of an aqueous solution of K₂CO₃ (1.39 g, 50.3 mmol, 3.8 equivalents, dissolved in DI water) was added to a stirred solution of compound E-4 (0.64 g, 2.64 mmol) and enol trifluoromethanesulfonate 16 (0.9 g, 3.16 mmol, 1.2 equivalents, 92% pure) in DMAc (5 mL). The resulting mixture was allowed to reach room temperature and stirred for 13 h, during which most of the product slowly precipitated from the solution. Then, 10 mL of DI water was added dropwise over 5 min to the resulting brown reaction mixture. The solid was then filtered off and washed with DMAc:H₂O (1:1) to give product E-5 (0.44 g, 88% yield, 96% pure) as a light brown solid. Step 5: (R)-3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)- Preparation of 3-cyclopentylpropionitrile (E-6):

[0220] a) Additive-free hydrogenation at 10 bar

[0221] Rh catalyst (5.52 mg, 0.025 equivalence), Walphos ligand (9.42 mg, 0.025 equivalence), and olefin E-5 (200 mg, 0.516 mmol) were added to glass vials used in a 7-vial reactor. The solids were dissolved in trifluoroethanol (TFE, 1.0 mL, 5 volumes) and the vials were placed in the reactor. The reactor was sealed, connected to a hydrogen tank, and the system was purged three times with H2 and then pressurized to 10 bar. The reaction was stirred magnetically at room temperature for 17 h. After 17 h, the stirring was turned off and the reactor was vented. The reaction progress was checked by HPLC and it was determined that the reaction had proceeded to 95% completion. The TFE was then evaporated from the vials under a nitrogen stream, and the crude product was analyzed by chiral HPLC (IA column, 1 mL / min flow rate, 50:25:25 hexane:MeOH:EtOH containing 0.1% diethylamine), showing a product selectivity of 99.4:0.6 er. 1 ¹H NMR (400MHz, chloroform-d): δ 8.45 (s, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 5.56 (s, NH₂), 4.67 (t, J = 4.8 Hz, 1H), 4.21 (ddd, J = 10.1, 8.6, 4.0 Hz, 1H), 3.44 (s, 6H), 3.08 (dd, J = 17.0, 8.6 Hz, 1H), 3.01 (d, J = 4.8 Hz, 2H), 2.92 (dd, J = 17.0, 4.0 Hz, 1H), 2.55 (m, 1H), 1.95 (m, 1H), 1.79–1.51 (overlapping peak, 5H), 1.36–1.15 (overlapping peak, 2H).

[0222] Such methods can use alternative reaction solvents that are being tested, and the results are shown in Table 1 below: Table 1

[0223] Alternative catalysts and ligand amounts were tested in TFE, and the results are shown in Table 2 below: Table 2 In subsequent experiments, it was found that 0.25 mol% catalyst resulted in a conversion rate of more than 95% and an enantiomer ratio of more than 99:1.

[0224] Alternative reaction conditions were tested at 50 bar H2, and the results are shown in Table 3 below: Table 3 Alternative pathways for olefins E-6 or E-6':

[0225] In some embodiments, olefin E-5 or deuterated olefin E-5' can be isomerized to olefin E-7 or deuterated olefin E-7', and then can be asymmetrically hydrogenated to provide enantiomer-enriched E-6 or E-6'. a) Isomerization of E-5'

[0226] Olefin E-5' (20 g, 53.1 mmol) was dissolved in 100 mL of DMAc. A solution of lithium hydroxide (5000 mg, 80 mL) was added, and the resulting suspension was stirred overnight at room temperature. The reaction mixture was then filtered, and the solid cake was washed with water and dried under vacuum to give E-7' (19.0 g, 95.2% yield, 100% purity). 1 H-NMR (400MHz, DMSO-d6): δ8.29(d,J=0.7Hz,1H),8.25(s,1H),8.00(d,J=0.7Hz,1H),6. 64(s,2H),4.63(t,J=5.5Hz,1H),3.89(s,2H),3.26(s,6H),2.98-2.90(d,J=5.5Hz,2H). b) In the chiral ligand Walphos Asymmetric hydrogenation of E-7' in the case of SL-W002-2

[0227] At room temperature and under 50 bar hydrogen, a pressure reactor was used to stir 5 mL of Rh catalyst (53.5 mg, 0.132 mmol, 0.05 equivalents), chiral ligand Walphos SL-W002-2 (CAS No. 1854067-25-6) (87.4 mg, 0.133 mmol, 0.05 equivalents), and olefin E-7' substrate (1.0 g, 2.66 mmol, 1.0 equivalents) in trifluoroethanol. After 65 hours, product E-6' was formed in a yield of 21%, as determined by HPLC. Chiral HPLC analysis (Chiralpak IE-3 column, eluted with 50% hexane containing 0.1% diethylamine and 50% 1:1 ethanol / methanol containing 0.1% diethylamine) showed a chiral selectivity of approximately 83:17. c) Asymmetric hydrogenation of E-7' in the case of chiral ligand SL-J002-1

[0228] At room temperature and under 50 bar hydrogen, in a pressure reactor, Rh catalyst (53.3 mg, 0.131 mmol, 0.05 equivalents), chiral ligand Josiphos SL-J002-1 (CAS No. 155830-69-6) (34.4 mg, 0.063 mmol, 0.024 equivalents), and olefin E-7' substrate (1.0 g, 2.66 mmol, 1.0 equivalents) were prepared in 5 mL of trifluoroethanol. After 65 hours, product E-6' was formed in 79% yield, as determined by HPLC. Chiral HPLC analysis (Chiralpak IE-3 column, eluted with 50% hexane containing 0.1% diethylamine and 50% 1:1 ethanol / methanol containing 0.1% diethylamine) showed a chiral selectivity of approximately 89:11. Salt formation in E-6:

[0229] E-6 is an oily substance. For ease of purification and handling, E-6 can also be separated into solid acid salts. In subsequent reactions, the E-6 acid salt can replace the free E-6 base. acid:

[0230] For 4-nitrobenzoic acid, orotic acid, 1-hydroxy-2-naphtholic acid, benzoic acid, citric acid, 2-bromophenylacetic acid, and toluenesulfonic acid:

[0231] Add 50 mg (0.126 mmol) of E-6 to an HPLC vial. Dissolve the solid in 5 vol (0.25 mL) of isopropanol. Add 1 equivalent (0.126 mmol) of acid and 5 vol (0.25 mL) of 4:1 IPA / water to the E-6 solution. Stir the mixture at room temperature for 18 hours. After 18 hours, transfer all visible suspensions to filtered centrifuge tubes and rotate at 14,000 RPM for 1 min. Sample both the solid and the mother liquor for HPLC analysis, and sample the solid for NMR analysis and microscopy imaging.

[0232] For 4-bromobenzoic acid, (+)-tartaric acid, mucilage, and salicylic acid:

[0233] Add 50 mg (0.126 mmol) of E-6 to an HPLC vial. Dissolve the solid in 5 vol (0.25 mL) of isopropanol. Add 1 equivalent (0.126 mmol) of acid to a separate vial. Add 5 vol (0.25 mL) of 4:1 IPA / water to the acid. If the solid acid dissolves, add the acid solution to the E-6 solution and stir the mixture at room temperature. If the solid acid does not dissolve, add the E-6 solution to the acid suspension, heat the mixture until dissolved, and then cool the reaction to room temperature while stirring. Leave the vial at room temperature with stirring for 24 hours.

[0234] After 24 hours, all visible suspension samples were taken for microscopic imaging, and the slurry was then transferred to filtered centrifuge tubes and rotated at 14,000 RPM for 1 min. Both the solids and the mother liquor were sampled for HPLC analysis, and the solids were sampled for NMR analysis.

[0235] Based on NMR and HPLC analysis, E-6 forms crystalline solids with the following acids: orotic acid, 4-nitrobenzoic acid, 1-hydroxy-2-naphthoic acid, salicylic acid, and 4-bromobenzoic acid. Salt formation in E-6':

[0236] Salts of compound E-6' can be formed with any of the acids listed above for the formation of salts of E-6. In one embodiment, d-benzoyl tartrate of E-6' is formed with excellent recovery and improved enantiomeric ratio (er). A solution of E-6' (15 mL, 167 mg / mL in trifluoroethanol, directly from the reduction of E-5', 2.50 g net) is stirred at 25 °C under nitrogen. d-benzoyl tartrate (2.50 g, 1.05 wt.) is dissolved in acetonitrile (15 mL, 6 vol), and a 20% d-benzoyl tartrate solution (3 mL) is added to the E-6' solution. The reaction mixture is inoculated with E-6' D-DTBA salt (5-6 mg, 0.002 wt.). The suspension is maintained for 20 minutes with stirring. The remaining d-dibenzoyl tartaric acid solution was added to the E-6' solution over 1 hour. The precipitate was filtered, washed with acetonitrile (10 mL, 4 vol), and dried to provide an off-white powder (4.739 g, 98.6% w / w determined, 99.69:0.31 er, 96.1% corrected yield).

[0237] 1H-NMR (400MHz, DMSO-d6): δ8.30(d,J=8.6Hz,2H),8.10-7.98(m,4H),7.94(s,1H),7.79-7.67(m,2H),7.59(t,J=7.7Hz,4H),6.88(br s,2H),5.86(s,2H),4.61(t,J=5.5Hz,1H),4.48(td,J=9.5,4.3Hz,1H),3. 25(s,6H),3.23-3.08(m,2H),2.95(d,J=5.5Hz,2H),2.33(d,J=9.8Hz,1H). Step 6: Preparation of ruxolitinib (free base):

[0238] Trifluoroacetic acid (0.23 mL, 1 volume) and trifluoroacetic anhydride (0.023 mL, 0.1 volume) were added to a solution of aminoacetal E-6 (230 mg, 0.621 mmol) in toluene (2.3 mL, 10 volumes). The plate was set to 100 °C, and the reaction was allowed to be stirred. The reaction was monitored by HPLC. After 30 minutes, a sample was taken, which showed >90% conversion to the product. The reaction was allowed to be stirred for another 30 minutes, and then the heating was turned off. Once the reaction reached 30 °C, triethylamine (0.46 mL, 2 volumes) was added to neutralize the reaction. The mixture was then diluted with EtOAc and washed twice with water. The organic phase was concentrated, and the crude product was purified by rapid chromatography (eluting with 20%–100% EtOAc in heptane) to give a product as a white foam (61% yield). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.10 (s, NH), 8.79 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J = 3.6, 2.4Hz, 1H), 6.98 (dd, J = 3.6, 1.7Hz, 1H), 4.54 (ddd, J = 9.7, 9.7, 4.2Hz, 1H), 3.27 (dd, J = 17.2, 9.6Hz, 1H), 3.18 (dd, J = 17.1, 4.2Hz, 1H), 2.42 (m, 1H), 1.81 (m, 1H), 1.67–1.13 (overlapping peak, 7H). Step 6 (alternative): Preparation of ruxolitinib (HCl salt)

[0239] 6.0 mL of toluene (9.8 vol) was added to 50 mL of RBF containing brown, foamy solid E-6 (612 mg, 1.65 mmol). The mixture was magnetically stirred to obtain a yellow solution; then 6.0 mL of 2N HCl (9.8 vol, 7.27 equivalent) was added dropwise via syringe at ambient temperature. The resulting biphasic mixture was stirred at room temperature for 2 h. Some oily droplets were observed. More HCl (0.5 mL, 6N HCl) and MeOH (2 mL) were added to the mixture to aid dissolution. The mixture was stirred overnight at room temperature. Aliquots were taken from the lower aqueous layer, showing a conversion of 99.2% with a very clean purity profile: the desired product (ruxotinib HCl salt) AUC = 97.9%. Scheme 5: Preparation of ruxotinib (free base) via acetal (10) Step 1: Preparation of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (10):

[0240] The mixture of compound 9 (B-1 in Scheme 1 above) (1.5 g, 7.51 mmol), triethyl orthoformate (1.34 g, 9.02 mol, 1.2 equivalents), and TsOH (0.194 g, 1.13 mmol, 0.15 equivalents) in EtOH (15 ml) was stirred at 40 °C for 1.5 h. The reaction mixture was cooled to room temperature, and an aqueous solution of Na₂CO₃ was added to adjust the pH to 8. The solvent was removed under reduced pressure, and the residue was extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with water (20 ml) and brine (15 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 10 (2.0 g, 92% yield) as a colorless oil. Step 2: Preparation of 6-chloro-5-(2,2-diethoxyethyl)pyrimidine-4-amine (11):

[0241] The mixture of compound 10 (2.0 g, 7.51 mmol) and NH4OH (10 mL) in EtOH (12 mL) was stirred at 70 °C for 20 h. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (20 mL) and brine (15 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 11 (1.72 g, 93%) as a yellow oil. Step 3: (tert-butoxycarbonyl)(6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl) Preparation of tert-butyl carbamate (12)

[0242] Et3N (2 mL, 14.3 mmol, 2.2 equivalences), (Boc)2O (2.91 g, 13.3 mmol, 2.05 equivalences), and DMAP (80 mg, 0.651 mmol, 0.1 equivalences) were sequentially added to a stirred solution of compound 11 (1.6 g, 6.51 mmol) in CH2Cl2 (18 mL) at 0 °C. The resulting mixture was allowed to reach room temperature and stirred for 62 h. The reaction mixture was then treated with water and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 12 (2.78 g, 95% yield) as a yellow solid. Step 4: (tert-butoxycarbonyl)(5-(2,2-diethoxyethyl)-6-(1H-pyrazol-4-yl) Preparation of tert-butyl pyrimidin-4-yl)carbamate (13):

[0243] At room temperature, 3 mL of an aqueous K₂CO₃ solution (0.937 g, 6.73 mmol, 3.0 equivalence) was added to a mixture of 12 (1 g, 2.24 mmol) and BPin-pyrazole (0.57 g, 2.92 mmol, 1.3 equivalence) in dioxane (10 mL). The solution was degassed by passing a nitrogen stream through it for 15 min, then treated with Pd(PPh₃)₄ (52 mg, 0.044 mmol, 0.02 equivalence), and the resulting reaction mixture was heated at 90 °C for 1 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 (20 mL). The combined organic extracts were washed with water (2 x 10 mL) and brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 13 (0.85 g, 80% yield) as a colloidal oil. Step 5: (Z)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-yl)- Preparation of 5-(2,2-diethoxyethyl)pyrimidin-4-yl)carbamate tert-butyl ester (14):

[0244] 3.5 mL of an aqueous solution of K₂CO₃ (1.06 g, 7.67 mmol, 3.8 equivalents) was added to a stirred solution of compounds 13 (0.964 g, 2.02 mmol) and 16 (0.652 g, 2.42 mmol, 1.2 equivalents) in DMAc (18 mL) at 0 °C. The resulting mixture was allowed to reach room temperature and stirred for 5 h. The reaction mixture was then treated with water and extracted with MTBE (2 x 50 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 14 (0.98 g, 82% yield) as a yellow oil. Step 6: (R)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5- Preparation of (2,2-diethoxyethyl)pyrimidin-4-yl)carbamate tert-butyl ester (15):

[0245] 14 (80 mg, 0.134 mmol), Rh(COD)₂BF₄ (2.75 mg, 0.0068 mmol, 5 mol%), Walphos SL-W022-1 (4.73 mg, 0.0068 mmol, 5 mol%), and dichloromethane (0.80 mL, 10 volumes) were added to a stirred glass vial in a pressure reactor. The pressure reactor was sealed and the system was purged three times with hydrogen, then pressurized to 15 bar. The reaction was then stirred at room temperature for 22 hours. After purging the reactor, the crude reaction mixture was dissolved in a small amount of dichloromethane and purified by ISCO automated chromatography (eluting with 0-50% EtOAc in heptane). Fractions containing the product were combined, concentrated, and dried under vacuum to give 15 (50 mg, 62.3% yield). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.97 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 4.64 (t, J = 5.6Hz, 1H), 4.53 (ddd, J = 9.4, 9.4, 4.5Hz, 1H), 3.56 (m, 2H), 3.41–3.26 (overlapping peak, 2H), 3.21 (dd, J = 17.2, 9.2 Hz, 1H), 3.15 (dd, J = 17.1, 4.5 Hz, 1H), 2.97 (dd, J = 5.8, 1.7 Hz, 2H), 2.38 (m, 1H), 1.79 (m, 1H), 1.67-1.14 (overlapping peak, 7H), 1.41 (s, 18H), 1.01 (td, J = 7.0, 4.0 Hz, 6H).

[0246] Other catalyst systems used in the hydrogenation step were also tested, and the results are shown below:

[0247] All ligands are available from Solvias AG (Kaiserlauster, Switzerland) and / or StremChemicals (Newburyport, Massachusetts, USA). Step 7: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile Preparation of (ruxolitinib):

[0248] Add 20 μL of 85% phosphoric acid to a stirred round-bottom flask containing 15 (20 mg, 0.033 mmol), dichloromethane (0.40 mL, 20 volumes), and isopropanol (0.10 mL, 5 volumes). Stir the reaction at room temperature for 1 hour, then add another 30 μL of 85% phosphoric acid. After stirring at room temperature for 1 hour, add another 50 μL of 85% phosphoric acid. Allow the reaction to proceed overnight at room temperature with stirring. After stirring overnight, monitor the reaction progress by LCMS. Determine the reaction has reached 77% conversion by UV. Quench the crude cyclization mixture with water containing a saturated aqueous solution of potassium carbonate. Then extract the quenched reaction with DCM, dry over sodium sulfate, and evaporate the solvent. Evaluate the crude product by chiral HPLC. Chiral HPLC (AD-H column, 1 mL / min flow rate, 50:50 MeOH: EtOH containing 0.1% diethylamine) showed an enantiomer ratio of 97:3 for ruxolitinib to ruxolitinib-X (the undesirable enantiomer). Option 6a: Preparation of ruxotinib phosphate via methylal Option 6b: Preparation of ruxotinib phosphate via methylal Step 1A: Preparation of 4,6-dichloro-5-(2,2-dimethoxyethyl)pyrimidine (17): a) MeOH, TsOH (10 mol%):

[0249] Such a method involves stirring a mixture of compound 9 (10 g, 52.4 mmol), trimethyl orthoformate (6.67 g, 62.8 mmol, 1.2 equivalents), and TsOH·H₂O (0.902 g, 5.24 mmol, 0.10 equivalents) in MeOH (50 mL) at 40 °C for 1.5 h. The reaction mixture is cooled to room temperature, and an aqueous solution of Na₂CO₃ (20 mL) is added to adjust the pH to 8, followed by extraction with EtOAc (2 x 50 mL). The combined organic extracts are washed with water (20 mL) and brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 17 (11.9 g, 96% yield) as a brown solid. b) Toluene, TsOH (1 mol%):

[0250] Trimethyl orthoformate (371 g, 3.50 mol, 1.2 equivalents) was added to a suspension of compound 9 (635 g, 88% determination, 2.93 mol) in toluene (2988 g). The batch was cooled to 20 °C and solid TsOH·H₂O (5.76 g, 0.03 mol, 0.01 equivalents) was added. The batch temperature was maintained by lowering the jacket temperature to 16 °C for 10 minutes during a small exothermic process, and then adjusting it to 20 °C. After stirring the suspension at 20 °C for 2 hours, the jacket temperature was raised to 40 °C for 11.5 hours, and then lowered to 20 °C. HPLC indicated that the starting material was consumed. The determination of the brown solution provided a concentration of approximately 136 mg / mL of compound 9 (total volume approximately 4.40 L, 597–631 g product, 86% yield). The batch is filtered through coarse glass frit and then used in the next step. Step 2A: Preparation of 6-chloro-5-(2,2-dimethoxyethyl)pyrimidine-4-amine (18): a) Procedure 1: iPA:

[0251] The mixture of compound 17 (6.0 g, 25.3 mmol) and NH4OH (30 ml) in IPA (30 ml) was stirred at 70 °C for 8 h. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (2 x 60 ml). The combined organic extracts were washed with water (20 ml) and brine (15 ml) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 18 (5.3 g, 96%) as a light brown solid. b) Toluene / iPA:

[0252] Ammonium hydroxide solution (235 g) was added to a 17% toluene solution (4.40 L, approximately 136 mg / mL) in a 10 L jacketed glass reactor (jacket temperature 20 °C, stirring rate 130 RPM, condenser temperature: -5 °C). The mixture exhibited exothermic reaction, raising the batch temperature by 3 °C. The mixture was stirred for 4 hours, then agitation was stopped to allow removal of the aqueous phase (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. Additional ammonium hydroxide (200 g) and isopropanol (4 L) were added, and the reactor jacket was set to 70 °C. Ammonium hydroxide solution (421 g) was added periodically over the next 24 hours, and the reaction was considered complete after stirring at 70 °C for 6 days. The batch was cooled to 20 °C and water (1.0 L) was added to the batch. Agitation was stopped, and the aqueous fraction was removed. The batch was discharged into a drum and treated with activated carbon (78 g). After standing for three hours, the batch was filtered into a clean reactor. A distillation apparatus was attached and the batch was distilled to a volume of 2.5 L. Toluene (876 g) was added. After a further distillation (1023 g distillation), the reactor jacket was cooled to 10°C for 4 hours. Heptane (100 g) was added and the batch was stirred for 4 hours. The batch was filtered under suction onto three disposable polypropylene sintered funnels to obtain a 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 under suction to a transferable solid and then combined into a drying tray. The solid was dried under vacuum with a nitrogen stream to obtain a brown solid (343.2 g, 94.6 wt%, 55% yield). Step 3A: (tert-butoxycarbonyl)(6-chloro-5-(2,2-dimethoxyethyl)pyrimidin-4-yl) Preparation of tert-butyl carbamate (19): a) CH2Cl2, DMAP (10 mol%):

[0253] Et3N (6.55 mL, 47.3 mmol, 2.2 equivalences), (Boc)2O (9.56 g, 43.8 mmol, 2.05 equivalences), and 4-dimethylaminopyridine (DMAP) (261 mg, 2.14 mmol, 0.1 equivalences) were sequentially added to a stirred solution of compound 18 (4.65 g, 21.4 mmol) in CH2Cl2 (25 mL) at 0 °C. The resulting mixture was brought to room temperature and stirred for 8 h. The reaction mixture was then treated with water and extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 19 (8.1 g, 95% yield) as a pale yellow solid. b)THF:

[0254] Add 50 mL of THF to a stirred solution of compound 18 (11.12 g, 51.1 mmol) and (Boc)₂O (22.9 g, 105 mmol, 2.05 equivalences). Add Et₃N (15 mL, 47.3 mmol, 2.1 equivalences) and DMAP (625 mg, 5.1 mmol, 0.1 equivalences). Note the slight exothermic reaction (2 °C). Warm the batch to 40 °C for 20 minutes, then cool to 20 °C. HPLC indicates the reaction is >97% complete. Add N-methylpiperazine (0.56 mL, 5.1 mmol, 0.1 equivalences) and stir the batch for 30 minutes. Add potassium dihydrogen phosphate solution (1 M, 100 mL, 100 mmol, 2 equivalences) and THF (40 mL). After brief stirring, remove the aqueous fraction. Add potassium dihydrogen phosphate solution (1M, 50 mL, 50 mmol, 1 equivalent) and THF (20 mL). Add water (20 mL) as a final rinse to remove residual salts. Use the product solution (130 mL) in aliquots for the next step. Step 4A: (tert-butoxycarbonyl)(5-(2,2-dimethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl) Preparation of tert-butyl carbamate (20): a) 1,4-Dioxane (8 vol), H₂O (4 vol), 2 mol% Pd(PPh₃)₄, 70℃:

[0255] At room temperature, 15 mL of an aqueous solution of K₂CO₃ (5.46 g, 39.5 mmol, 3.0 equivalence dissolved in DI water) was added to a mixture of 19 (5.8 g, 13.9 mmol) and BPin-pyrazole (3.32 g, 17.1 mmol, 1.3 equivalence) in 1,4-dioxane (40 mL). The solution was degassed by passing a nitrogen stream through it for 15 min, then treated with Pd(PPh₃)₄ (304 mg, 0.263 mmol, 0.02 equivalence), and the resulting reaction mixture was heated at 70 °C for 2 h. The reaction mixture was allowed to reach room temperature, and the yellow solid was filtered off. The filtrate was diluted with ethyl acetate (50 mL) and water (15 mL). The two layers were separated, and the aqueous layer was further extracted with ethyl acetate (40 mL). The combined organic extracts were washed with water (2 x 15 ml) and brine (15 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 20 (crude product weight approximately 6 g) as a colloidal oil, which was used in the next conjugate addition reaction without any further purification. b)THF (10vol), H2O (4vol), 2mol% Pd(PPh3)4, 60℃:

[0256] At room temperature, 1 mL of an aqueous solution of K₂CO₃ (0.248 g, 1.79 mmol, 3.0 equivalent dissolved in DI water) was added to a mixture of 19 (0.25 g, 0.598 mmol) and BPin-pyrazole (0.151 g, 0.778 mmol, 1.3 equivalent) in THF (2.5 mL). The solution was degassed by passing a nitrogen stream through it for 15 min, then treated with Pd(PPh₃)₄ (14 mg, 0.0119 mmol, 0.02 equivalent), and the resulting reaction mixture was heated at 60 °C for 12 h. After 12 h, the characteristic spectra were those of the starting material (18%) and product 20 (82%). Step 5A: (Z)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylvinyl)- Preparation of 1H-pyrazol-4-yl)-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate tert-butyl ester:

[0257] 25 mL of an aqueous solution of K₂CO₃ (6.95 g, 50.3 mmol, 3.8 equivalents, dissolved in DI water) was added to a stirred solution of compound 20 (5.95 g, 13.2 mmol) and enol trifluoromethanesulfonate (4.28 g, 15.9 mmol, 1.2 equivalents, 92% pure) in DMAc (48 mL) at 0 °C. The resulting mixture was allowed to reach room temperature and stirred for 6 h. Then, 50 mL of DI water was slowly added to the resulting brown reaction mixture over one hour using a syringe pump. The product precipitated from the reaction mixture. The solid was then filtered off and washed with DMAc:H₂O (1:4) to give a product as a light brown solid (6.4 g, 90% pure, 85% yield after two steps). The product was recrystallized from IPA. Notice: 1) Add water until you can no longer see any product precipitate; this requires approximately 10-12 vol. of water. 2) The standard compound (>99% pure) is a white crystalline solid. 3) For recrystallization, add 3 vol. of IPA. The product is sparingly soluble, then heat at 50°C. At 50°C, the product completely dissolves, then allow it to reach room temperature. Step 6A: (R)-(tert-butoxycarbonyl)(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5- Preparation of (2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate tert-butyl ester:

[0258] An olefin (1.0 g, 1.76 mmol), Rh(COD)₂BF₄ (35.7 mg, 0.0878 mmol, 5 mol%), Walphos SL-W022-1 (61.1 mg, 0.0879 mmol, 5 mol%), and dichloromethane (10.0 mL, 10 volumes) were added to a stirred glass vial in a pressure reactor. The pressure reactor was sealed and the system was purged three times with hydrogen, then pressurized to 15 bar. The reaction was then stirred at room temperature for 16 hours. After purging the reactor, the crude reaction mixture was dissolved in a small amount of dichloromethane and purified by ISCO automated chromatography (eluting with 0-50% EtOAc in heptane). Fractions containing the product were combined, concentrated, and dried under vacuum to give the product (600 mg, 59.8% yield). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.96 (s, 1H), 8.57 (d, J = 0.7Hz, 1H), 8.16 (s, 1H), 4.56–4.49 (overlapping peak, 2H), 3.22 (dd, J = 17.3, 9.2Hz, 1H), 3.20 (s, 3H), 3.19 (s, 3H), 3.16 (dd, J = 17.5, 4.9Hz, 1H), 3.00 (d, J = 5.6Hz, 2H), 2.38 (m, 1H), 1.80 (m, 1H), 1.64–1.14 (overlapping peak, 7H), 1.41 (s, 18H). Step 7A: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropyl Preparation of nitriles (ruxotinib free base):

[0259] Toluene (0.80 mL, 10 volumes) was added to an HPLC vial containing aminoacetal (80 mg, 0.140 mmol) to dissolve the material. Trifluoroacetic acid (0.08 mL, 1 volume) was then added to the flask, and the plate was set to 100 °C with stirring allowed. The reaction was monitored by HPLC. After 15 minutes, a sample was taken, showing >90% conversion to the product. The reaction was allowed to cool to 40 °C, and then trifluoroacetic anhydride (0.08 mL, 1 volume) was added to the vial. After 15 minutes, the reaction had reached completion. Water (0.80 mL, 10 volumes) was added to quench the reaction. The mixture was neutralized with Na₂CO₃ and extracted with EtOAc. The crude product was dried over sodium sulfate and concentrated to give a white, foamy product (27 mg, 62.9% yield). Chiral HPLC (AD-H column, 1 mL / min flow rate, 50:50 MeOH: EtOH containing 0.1% diethylamine) showed an enantiomer ratio of 97.8:2.2 for ruxolitinib and the undesirable enantiomer. Step 1B: Preparation of tert-butyl (6-chloro-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)carbamate (21):

[0260] 2M NaHMDS (1 ml, 1.976 mmol, 2.0 equivalent, 2M in THF) was added to a stirred solution of compound 18 (215 mg, 0.988 mmol) in THF (2 ml) at 0 °C. After stirring at 0 °C for 30 min, a solution of (Boc)₂O (194 mg, 0.889 mmol, 0.9 equivalent) in THF (1.5 ml) was added at 0 °C. The resulting mixture was allowed to reach room temperature and stirred for 8 h. The reaction was 90% complete according to LC. 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 rapid chromatography (0 to 30% EtOAc in heptane) to give a single Boc product (21) (370 mg, 87% yield) as a white solid. Step 2B: (5-(2,2-dimethoxyethyl)-6-(1H-pyrazol-4-yl)pyrimidin-4-yl)tert-butyl carbamate Preparation of (22): Step 3B: (Z)-(6-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-yl)-5-(2,2-dimethoxy) Preparation of tert-butyl pyrimidin-4-yl)carbamate: Step 4B: (R)-(6-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5-(2,2-dimethoxy) Preparation of tert-butyl ethyl (ethyl)pyrimidin-4-yl)carbamate:

[0261] An olefin (0.50 g, 1.01 mmol), Rh(COD)₂BF₄ (20.5 mg, 0.0505 mmol, 5 mol%), Walphos SL-W022-1 (35.1 mg, 0.0505 mmol, 5 mol%), and dichloromethane (5.0 mL, 10 volumes) were added to a stirred glass vial in a pressure reactor. The pressure reactor was sealed and the system was purged three times with hydrogen, then pressurized to 10 bar. The reaction was then stirred at room temperature for 17 hours. After purging the reactor, the crude reaction mixture was dissolved in a small amount of dichloromethane and purified by ISCO automated chromatography (eluting with 0-50% EtOAc in heptane). Fractions containing the product were combined, concentrated, and dried under vacuum to give the product (531 mg, 52.4% yield). 1¹H NMR (400MHz, DMSO-d⁶) δ 9.43 (s, NH), 8.73 (s, 1H), 8.44 (s, 1H), 8.01 (s, 1H), 4.58 (t, J = 5.2Hz, 1H), 4.52 (ddd, J = 9.5, 9.5, 4.5Hz, 1H), 3.25–3.16 (overlapping peak, 2H), 3.23 (s, 6H), 3.12 (d, J = 5.3Hz, 2H), 2.37 (m, 1H), 1.80 (m, 1H), 1.63–1.13 (overlapping peak, 7H), 1.48 (s, 9H).

[0262] Alternative protecting groups were also tested, as shown in Table 4 below: Table 4

[0263] Other catalyst systems used in the hydrogenation step were also tested, and the results are shown below: 100% conversion rate, 99.6:0.4er 100% conversion rate, 91:9er All ligands are available from Solvias AG (Kaiserlauster, Switzerland) and / or StremChemicals (Newburyport, Massachusetts, USA). Step 5B: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropyl Preparation of nitriles (ruxotinib):

[0264] Toluene (0.508 mL, 10 volumes) was added to an HPLC vial containing aminoacetal (50 mg, 0.108 mmol) to dissolve the material. Trifluoroacetic acid (0.0508 mL, 1 volume) was then added to the flask, and the plate was set to 100 °C with stirring allowed. The reaction was monitored by HPLC. After 15 minutes, a sample was taken, showing >90% conversion to the product. The reaction was allowed to cool to 40 °C, and then trifluoroacetic anhydride (0.0508 mL, 1 volume) was added to the vial. After 15 minutes, the reaction had reached completion. Triethylamine (0.0508 mL, 1 volume) was added to neutralize the reaction. The mixture was then diluted with EtOAc, and the organic phase was washed twice with 10 volumes of water. The crude product was dried over sodium sulfate and concentrated to give a product that appeared as white foam. Chiral HPLC (AD-H column, 1 mL / min flow rate, 50:50 MeOH: EtOH containing 0.1% diethylamine) showed an enantiomer ratio of 99.6:0.4 for ruxolitinib and the undesirable enantiomer. 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.69 (s, 1H), 8.66 (d, J = 0.8 Hz, 1H), 8.39 (s, 1H), 7.55 (d, J = 3.7 Hz, 1H), 6.99 (d, J = 3.7 Hz, 1H), 4.50 (ddd, J = 9.8, 9.8, 4.0 Hz, 1H), 3.23 (dd, J = 17.1, 9.6 Hz, 1H), 3.12 (dd, J = 17.2, 4.1 Hz, 1H), 2.55 (m, 1H), 1.95 (m, J = 12.0, 7.6, 4.1 Hz, 1H), 1.82–1.17 (overlapping peak, 7H).

[0265] Without further description, it is believed that those skilled in the art can use the foregoing description and illustrative examples to manufacture and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples present only 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 invention.

Claims

1. A method for preparing a compound of formula I: or its salt method, The method includes making Compounds of formula II': Or its salt reacts in the presence of an acid to form a compound of formula I; wherein in formulas I and II', Y 1 It is hydrogen or deuterium; Each Y 2 They are the same and are either hydrogen or deuterium; Each Y 3 They are the same and are either hydrogen or deuterium; And in equation II', Each R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; and Each R 6 It is independently selected from H and protecting groups.

2. The method of claim 1, wherein the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or combinations thereof.

3. A compound for the preparation of formula II': or its salt method; This method involves making a compound of formula III': or its salt; It reacts with hydrogen in the presence of a hydrogenation catalyst; in: Y 1 It is hydrogen or deuterium; Each Y 2 They are the same and are either hydrogen or deuterium; Each Y 3 They are the same and are either hydrogen or deuterium; Each R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; and Each R 6 It is independently selected from H and protecting groups.

4. The method of claim 3, wherein the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand (L) according to formula IV: Where R 2a R 2b R 3a R 3b and R 4 Each of these is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 It is a secondary alkyl, tertiary alkyl, or cycloalkyl.

5. The method of claim 4, wherein R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is norborneol.

6. The method of claim 4, wherein R 2a R 2b R 3a R 3b and R 4 Each of them is hydrogen, and R 5 It is cyclohexyl.

7. The method according to any one of claims 3-6, wherein the hydrogenation catalyst is present in an amount of 2.5 mol% or less.

8. The method according to any one of claims 3-6, wherein the hydrogenation catalyst is present in an amount of 1 mol% or less.

9. The method of any one of claims 3-8, wherein the hydrogen gas is present at a pressure of 15 bar or less.

10. The method of any one of claims 3-8, wherein the hydrogen gas is present at a pressure of 10 bar or less.

11. The method according to any one of claims 3-10, wherein the reaction step is carried out in a solvent, and the solvent is 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.

12. The method of claim 11, wherein the solvent is trifluoroethanol (TFE).

13. The method according to any one of claims 3-12, wherein the compound of formula II' has an enantiomer excess of at least 95% of the (R)-enantiomer.

14. The method according to any one of claims 3-12, wherein the compound of formula II' has an enantiomer excess of at least 98% of the (R)-enantiomer.

15. The method according to any one of claims 4-12, further comprising the step of treating the compound of formula II' with an acid to form a salt of the compound of formula II'.

16. The method of claim 15, wherein the acid is selected from D-dibenzoyl tartaric acid, orotic acid, 4-nitrobenzoic acid, 1-hydroxy-2-naphthoic acid, salicylic acid, and 4-bromobenzoic acid.

17. A compound for the preparation of formula III': or its salt method; This method involves making a compound of chemical formula VIII': or its salt; Compounds with Formula VII: or its salt; The reaction occurs in the presence of a base, resulting in the formation of a compound of formula III or a salt thereof; in: Y 1 It is hydrogen or deuterium; Each Y 2 They are the same and are either hydrogen or deuterium; Each Y 3 They are the same and are either hydrogen or deuterium; Each R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; and Each R 6 It is independently selected from H and protecting groups.

18. The method of claim 17, wherein the base is selected from tripotassium phosphate, hydrated tripotassium phosphate, and potassium carbonate.

19. An aid for preparing compounds having formula VIII': or its salt method; This method involves making a compound of formula IX': and (BPin-pyrazole) and a catalytic amount of Pd(PPh3)4 react in the presence of a base to form a compound of formula VIII' or a salt thereof; in: Each R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; Each R 6 Independently selected from H and protecting groups; and X is I, Br, Cl, or trifluoromethanesulfonate.

20. The method of claim 19, wherein the base is selected from potassium carbonate and disodium hydrogen phosphate.

21. A compound for the preparation of formula II': or its salt method; This method involves making a compound of formula XI': or its salt; It reacts with hydrogen in the presence of a hydrogenation catalyst; in: Y 1 It is hydrogen or deuterium; Each Y 2 They are the same and are either hydrogen or deuterium; Each Y 3 They are the same and are either hydrogen or deuterium; Each R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; and Each R 6 It is independently selected from H and protecting groups.

22. The method of claim 21, wherein the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand selected from Josiphos J002-1 (CAS No. 155830-69-6) and Walphos W002-2 (CAS No. 1854067-25-6).

23. A compound for the preparation of formula XI': or its salt method; This method involves making a compound of formula III': or its salt; Reacts with a base to form a compound of formula XI or a salt thereof; wherein Y 1 It is hydrogen or deuterium; each Y 2 The same and either hydrogen or deuterium; each Y 3 The same and is either hydrogen or deuterium; R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; and each R 6 It is independently selected from H or a protecting group.

24. The method of claim 23, wherein the base is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.

25. The method of any one of claims 1-24, wherein the protecting group is selected from tert-butoxycarbonyl, trifluoromethanesulfonyl, trifluoroacetyl, and triphenylmethyl.

26. The method of any one of claims 1-24, wherein the two R 6 Both are H.

27. The method of any one of claims 1-26, wherein the two R 1 All are methyl groups.

28. The method of any one of claims 1-27, wherein Y 1 It is hydrogen and Y 2 and Y 3 Each of them is deuterium.

29. The method of any one of claims 1-27, wherein Y 1 Y 2 and Y 3 Each of them is hydrogen.

30. The method of any one of claims 1-28, wherein the deuterium doping at each designated deuterium location is at least 90%.

31. The method of any one of claims 1-28, wherein the deuterium doping at each designated deuterium location is at least 95%.

32. The method of any one of claims 1-28, wherein the deuterium doping at each designated deuterium location is at least 97%.

33. A compound represented by formula VIII': in Each R 1’ It is C1-C 10 Alkyl, or C2-C 10 alkenyl, or both R 1’ Together with the oxygen atoms to which they are attached, they form 5-7 membered heterocycles that can be optionally substituted; and Each R 6 It is independently selected from H and protecting groups.

34. A compound represented by the following structure: Or its salt.

35. A compound represented by the following structure: Or its salt.

36. A compound represented by the following structure:

37. A compound represented by the following structure:

38. A compound represented by the following structure: Or its salt.

39. A compound represented by the following structure: Or its salt.

40. A compound represented by the following structure: Or its salt.

41. A compound represented by the following structure:

42. A compound represented by the following structure: Or its salt.

43. A compound represented by the following structure: Or its salt.

44. A compound represented by the following structure:

45. A compound represented by the following structure:

46. ​​A compound represented by the following structure:

47. A compound represented by the following structure: Or its salt.

48. The compound of any one of claims 41-47, wherein the deuterium doping at each designated deuterium site is at least 90%.

49. The compound of any one of claims 41-47, wherein the deuterium doping at each designated deuterium site is at least 95%.

50. The compound of any one of claims 41-47, wherein the deuterium doping at each designated deuterium site is at least 97%.

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