Patent Description:
Activin receptor-like kinase-<NUM> (ALK2) is encoded by the Activin A receptor, type I gene (ACVR1). ALK2 is a serine/threonine kinase in the bone morphogenetic protein (BMP) pathway (<NPL>). Inhibitors of ALK2 and mutant forms of ALK2 have the potential to treat a number of diseases, including fibrodysplasia ossificans progressiva (FOP); heterotopic ossification (HO) induced by, for example, major surgical interventions, trauma (such as head or blast injuries), protracted immobilization, or severe burns; diffuse intrinsic pontine glioma (DIPG), a rare form of brain cancer; and anemia associated with chronic inflammatory, infectious or neoplastic disease.

<CIT>, discloses potent, highly selective inhibitors of ALK2 and mutant forms of ALK2. Also disclosed in <CIT> is Compound <NUM> as a key intermediate in the
<CHM>
synthesis of many of the disclosed ALK2 inhibitors. <CIT> discloses Suzuki reactions for the preparation of intermediates such as Compound <NUM>, as shown below:
<CHM>
which involve the coupling of a pyrrolo-pyridazine intermediate with a piperidinyl-pyridine compound.

It now has been found that the Suzuki coupling of <NUM>-pyrrolo-pyridazine and the (bis(pinacolato)diboron piperidinyl-pyridine to prepare Compound <NUM> results in a complicated purity profile, whereas the formation of by-products in the corresponding Negishi coupling is considerably reduced (Example <NUM>). The Negishi coupling has further advantages in that it requires smaller amounts of the expensive <NUM>-pyrrolo-pyridazine starting material, has only one isolation step and uses inexpensive reagents (ZnCh and i-propylmagnesiumchloride). Moreover, based on small scale reactions, it is expected that considerably higher yields will be obtained when the Negishi coupling is employed to prepare Compound <NUM> on an industrial scale than the Suzuki coupling. Based on these results, new and improved syntheses of important intermediate Compound <NUM> are disclosed.

In one embodiment, the disclosure provides a method of preparing a compound represented by formula (I):
<CHM>.

The method comprises reacting in a reaction mixture a first starting material represented by formula (II):
<CHM>
and a second starting material represented by formula (III) under Negishi conditions:
<CHM>
to form the compound of formula (I). R is an amine protecting group; Y is Cl, Br or I; and Z is Cl, Br, I or triflate (preferably Br). Amine protecting groups are well known in the art and are disclosed, for example, in <NPL>. Protecting groups may be added and removed using methods well known in the art. Examples of amine protecting groups include (<NUM>-Fluorenylmethyl carbamate), Cbz (Benzyl carbamate), Boc (t-Butyl carbamate), acetamide, benzyl, tosyl (p-Toluenesulfonamide). In one embodiment, the amine protecting group is Boc.

Another embodiment of the present disclosure is a compound represented by formula (II-A), or (II-B). The compound with formula (II) is not encompassed by the wording of the claims. The scope of the subject-matter for which protection is sought is defined by the claims. <CHM>
wherein Y, X, and X<NUM> are independently Cl, Br or I. In one embodiment, Y is Cl or I. The compounds represented by Formulas (II), (II-A) and (II-B) are intermediates in the disclosed Negishi Reaction, as described in greater detail below.

The present disclosure provides an improved method for preparing Compound <NUM> in a good yield and a high purity via a Negishi Reaction (also referred to herein as a "Negishi Coupling").

The Negishi Reaction is a transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, thereby forming carbon-carbon bonds (c-c) in the process. The transition metal catalyst is typically palladium or nickel. In the case of palladium, the catalytic species is Pd(<NUM>) in the form of, for example, Pd(X<NUM>)<NUM>; X<NUM>is a phosphine ligand. Alternatively, Pd(<NUM>) can be generated in situ from a Pd+<NUM> species in the form of, for example, Pd(X<NUM>)<NUM>Cl<NUM>. Exemplary phosphine ligands include <NUM>,<NUM>'-Bis(di-tert-butylphosphino)ferrocene (dtbpf), <NUM>,<NUM>'-Bis(di-tert-butylphosphino)ferrocene (dcypf), <NUM>,<NUM>'-Bis(diphenylphosphino)ferrocene (dppf), <NUM>-Di-tert-butylphosphino-<NUM>',<NUM>',<NUM>'-triisopropylbiphenyl (t-BuXPhos), [<NUM>-(Di-<NUM>-adamantylphosphino)-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>,<NUM>-dimethoxybiphenyl] [<NUM>-(<NUM>'-amino-<NUM>,<NUM> '-biphenyl)]palladium(II) methanesulfonate (AdBrettPhos), <NUM>-Dicyclohexylphosphino-<NUM>',<NUM>'-dimethoxybiphenyl (SPhos), (<NUM>-Dicyclohexylphosphino-<NUM>',<NUM>'-diisopropoxy-<NUM>,<NUM>'-biphenyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate (RuPhos), [<NUM>-Dicyclohexylphosphino-<NUM>',<NUM>',<NUM>'-triisopropylbiphenyl] (XPhos), [(<NUM>-Di-cyclohexylphosphino-<NUM>,<NUM>-dimethoxy-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>,<NUM>'-biphenyl)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate methanesulfonate (BrettPhos), [(<NUM>-{Bis[<NUM>,<NUM>-bis(trifluoromethyl)phenyl]phosphine}-<NUM>,<NUM>-dimethoxy- <NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>,<NUM>'-biphenyl )-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate (JackiePhos), [(<NUM>-Di-tert-butylphosphino-<NUM>,<NUM>-dimethoxy-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>,<NUM>'-biphenyl)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos), Mesyl(<NUM>-(di-tert-butylphosphino)-<NUM>,<NUM>'-binaphthyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium (TrixiePhos), (<NUM>-Biphenyl)di-tert-butylphosphine, (<NUM>-Biphenylyl)di-tert-butylphosphine (JohnPhos), <NUM>'-(Di-tert-butylphosphino)-N,N-dimethylbiphenyl-<NUM>-amine (t-BuDavePhos), <NUM>-Di-tert-butylphosphino-<NUM>'-methylbiphenyl (t-BuMePhos), Chloro(<NUM>-dicyclohexylphosphino-<NUM>,<NUM>'-biphenyl)[<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)]palladium(II) (CyJohnPhos), <NUM>-Dicyclohexylphosphino-<NUM>'-(N,N-dimethylamino)biphenyl (DavePhos), <NUM>-Dicyclohexylphosphino-<NUM>'-methylbiphenyl (MePhos), <NUM>-Dicyclohexylphosphino-<NUM>'-(N,N-dimethylamino)biphenyl (PhDavePhos), <NUM>-Dicyclohexylphosphino-<NUM>'-methoxy-<NUM>',<NUM>'-di-tert-butylbiphenyl (VPhos), <NUM>-[(tert-Butyl)phenylphosphino]-<NUM>',<NUM>'-bis(N,N-dimethylamino)biphenyl. (PhCPhos), [(<NUM>-Dicyclohexylphosphino-<NUM>',<NUM>'-bis(N,N-dimethylamino) -<NUM>,<NUM>'-biphenyl)-<NUM>-(<NUM>'-amino-<NUM>,<NUM>'-biphenyl)] palladium(II) methanesulfonate (CPhos), Methanesulfonato[<NUM>-diethylphosphino-<NUM>',<NUM>'-bis(dimethylamino)-<NUM>,<NUM>-biphenyl](<NUM>'-amino-<NUM>,<NUM>'-biphenyl-<NUM>-yl)palladium(II) (EtCPhos), <NUM>-Di(tert-butyl)phosphino-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>-methoxy-<NUM>-methylbiphenyl (RockPhos), Di-<NUM>-adamantyl(<NUM>"-butyl-<NUM>",<NUM>",<NUM>",<NUM>"-tetrafluoro-<NUM>',<NUM>',<NUM>'-triisopropyl-<NUM>-methoxy-meta-terphenyl)phosphine (AlPhos) and <NUM>-(t-Butylphenylphosphino)-<NUM>',<NUM>'-dimethylamino-<NUM>,<NUM>'-biphenyl, ((t-Bu)PhCPhos).

Exemplary palladium catalysts include Pd(dppe)<NUM> (Bis[<NUM>,<NUM>-bis(diphenylphosphino)ethane]palladium(<NUM>)),Pd(dba)<NUM> (Bis(dibenzylideneacetone)palladium(<NUM>)), CX-<NUM> (<NUM>,<NUM>-Bis(<NUM>,<NUM>-diisopropylphenyl)imidazol-<NUM>-ylidene(<NUM>,<NUM>-naphthoquinone)palladium(<NUM>) dimer), CX-<NUM> (<NUM>,<NUM>-Bis(<NUM>,<NUM>,<NUM>-trimethylphenyl)imidazol-<NUM>-ylidene (<NUM>,<NUM>-naphthoquinone)palladium(<NUM>) dimer), Pd(t-Bu<NUM>P)<NUM> (Bis(tri-tert-butylphosphine)palladium(<NUM>)), Pd(PCy<NUM>)<NUM> (Bis(tricyclohexylphosphine)palladium(<NUM>)), Pd(PPh<NUM>)<NUM> (Tetrakis(triphenylphosphine)palladium(<NUM>)),Pd<NUM>(dba)<NUM> (Tris(dibenzylideneacetone)dipalladium(<NUM>)), Pd(OAc)<NUM> (Palladium (II) acetate), PdCl<NUM>(PPh<NUM>)<NUM> (Dichlorobis(triphenylphosphine)palladium(II)), PdCl<NUM>(Amphos)<NUM> (Bis(di-tert-butyl(<NUM>-dimethylaminophenyl)phosphine)dichloropalladium(II)), Pd(MeCN)<NUM>Cl<NUM> (Bis(acetonitrile)dichloropalladium(II)), PdCl<NUM>(P(o-Tol)<NUM>)<NUM> (Dichlorobis(tri-o-tolylphosphine)palladium(II)), Pd(dppf)Cl<NUM> (<NUM>,<NUM>'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)), Pd(MeCN)<NUM>(BF<NUM>)<NUM> (Tetrakis(acetonitrile)palladium(II) tetrafluoroborate), Pd-PEPPSI-IPent (Dichloro[<NUM>,<NUM>-bis(<NUM>,<NUM>-Di-<NUM>-pentylphenyl)imidazol-<NUM>-ylidene](<NUM>-chloropyridyl)palladium(II)), Pd-PEPPSI-IPr([<NUM>,<NUM>-Bis(<NUM>,<NUM>-Diisopropylphenyl)imidazol-<NUM>-ylidene](<NUM>-chloropyridyl)palladium(II) dichloride) and Pd-PEPPSI-SIPr ((<NUM>,<NUM>-Bis(<NUM>,<NUM>-Diisopropylphenyl)imidazolidene) (<NUM>-chloropyridyl) palladium(II) dichloride).

Alternatively, the palladium catalyst is selected from Pd(MeCN)<NUM>Cl<NUM>, Pd[P(o-Tol)<NUM>]<NUM>Cl<NUM>, PdCl<NUM>(Amphos)<NUM> and Pd(dba)<NUM>. In another alternative, the palladium catalyst is selected from Pd<NUM>(dba)<NUM>/P(R<NUM>)<NUM>, Pd(PPh<NUM>)<NUM>, Pd(PPh<NUM>)<NUM>Cl<NUM>, Pd(MeCN)<NUM>Cl<NUM>, Pd[P(o-Tol)<NUM>]<NUM>Cl<NUM>, PdCl<NUM>(Amphos)<NUM>, Pd(PtBu<NUM>)<NUM>, Pd(dppf)Cl<NUM>, Pd(dba)<NUM>, Pd<NUM>(dba)<NUM> and Pd(XPhos); each R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM>cycloalkyl, benzyl or phenyl and wherein the benzyl or phenyl is each optionally and independently substituted with one or more groups selected from halogen, C<NUM>-C<NUM>alkyl and C<NUM>-C<NUM> alkoxy. In another alternative, the palladium catalyst is Pd<NUM>(dba)<NUM> In yet another alternative, the palladium catalyst is PdP(tBu)<NUM>.

In another embodiment, the palladium catalyst can be combined with a phosphine ligand, e.g., the palladium catalyst is Pd<NUM>(dba) combined with P(tBu)<NUM>.

In the case of nickel, the catalytic species is Ni(<NUM>); and Ni(<NUM>) can be generated in situ from Ni+<NUM> species such as NiCl<NUM>. Exemplary nickel catalyst include Ni(acac)<NUM>, Ni(cod)<NUM>, Ni(PCy<NUM>)2Cl2, NiBr<NUM>, NiI<NUM>, Ni(OAc)<NUM>, Ni(OTf)<NUM>, Ni(BF4)<NUM>, NiCl2(PPh<NUM>)<NUM>.

The organic halide or organic triflate in the Negishi Reaction can be an alkenyl, aryl, allyl, alkynyl or propargyl halide or triflate; and the organozinc compound is R-Zn-X in which X is chloride, bromide or iodide and R is an alkenyl, aryl, allyl, alkyl, benzyl, homoallyl or homopropargyl group. Conditions for carrying out the Negishi Reaction are described in, for example, <NPL>; <NPL>; <NPL>; <NPL>;<NPL>; <NPL>;<NPL>; <NPL>; <NPL>; <NPL>; <NPL>; <NPL>; and<NPL>.

Aryl zincs can be prepared using mild reaction conditions via a Grignard or organolithium intermediate with zinc metals such as ZnCh or ZnBr<NUM>. See, for example, <NPL>. In some instances, the organozinc compound can be prepared directly by reacting with ZnCh.

The term "under Negishi conditions" means the transition metal catalyzed cross-coupling, carbon-carbon bond forming reaction between an organic halide and an organozinc compound. "Under Negishi conditions" also includes the formation of the organozinc compound, such as by reaction of a Grignard or oganolithium intermediate with a zinc halide.

In one aspect, i) the first starting material of formula (II) is converted into an organozinc intermediate represented by formula (II-B):
<CHM>.

The organozinc intermediate of formula (II-B) is reacted with the second starting material of formula (III) in the presence of the palladium catalyst to form the compound of formula (I). X is Cl, Br or I. Alternatively, X in the organozinc intermediate (formula (II-B) is Cl; and Y in the first starting material (formula II) is Br. Suitable solvents for this reaction include ethereal solvents such as tetrahydrofuran, methyltetrahydrofuran, anisole and mixtures thereof. The organozinc intermediate of formula (II-B) is often reacted with the second starting material of formula (III) without isolation of the organozinc intermediate of formula (II-B). In one aspect, a solution of an alkoxide or amine base in an ethereal solvent is combined with the organozinc intermediate of formula (II-B) before reaction with the second starting material of formula (III). Adding the base to the reaction mixture has the advantage of reducing by-product formation. Examples of suitable bases include potassium tert-butoxide (KOtBu), morpholine, piperazine, benzylpiperazine, NH<NUM>, NH<NUM>Cl, and hexamethyldisilazane. KotBu is commonly used. In one aspect, between <NUM> and <NUM> equivalents of base relative to the first starting material of formula (II). In one aspect, between <NUM> and <NUM> equivalents of base relative to the first starting material of formula (II). Methyl tetrahydrofuran is a commonly used ethereal solvent. In yet another aspect, the reaction with the organozinc intermediate of formula (II-B) and the second starting material of formula (III) is carried out in the presence of polar aprotic solvent such as N-methyl-<NUM>-pyrrolidinone, dimethylformamide or dimethyl sulfoxide. N-methyl-<NUM>-pyrrolidinone is commonly used. In one aspect, between <NUM> to <NUM> volumes or mL per gram starting material of the polar aprotic solvent are used. In another aspect, the reaction mixture comprising the reaction product of the organozinc intermediate of formula (II-B) and the second starting material of formula (III) is extracted with a basic aqueous solution of N-acetyl-L-cysteine after formation of the compound of formula (I). The concentration of the N-acetyl-L-cysteine solution is generally less than <NUM> gram per <NUM> water. "Extraction" of the reaction mixture refers washing the reaction mixture directly with the N-acetyl-L-cysteine solution to form an aqueous phase and organic phase. The organic phase, which contains Compound <NUM>, is then separated from the aqueous phase. Alternatively, "extraction" refers to quenching the reaction mixture with an aqueous solution to form an aqueous phase and organic phase. The organic phase, which contains Compound <NUM>, is then separated from the aqueous phase, which is then extracted with the N-acetyl-L-cysteine solution. The N-acetyl-L-cysteine solution extraction has the advantage of reducing residual palladium in the final reaction product (Compound <NUM>). In another aspect, the organozinc intermediate of formula (II-B) is obtained by reacting the first starting material of formula (II) with a Grignard reagent R'MgX<NUM>, to form an organometallic intermediate represented by formula (II-A):
<CHM>.

The organometallic intermediate of formula (II-A) is then reacted with ZnX<NUM> to form the organozinc intermediate of formula (II-B). R' is a C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkenyl, C<NUM>-C<NUM> alkynyl, phenyl, benzyl or monocyclic heteroaryl; the phenyl, benzyl or heteroaryl is each optionally and independently substituted with one or more groups selected from halogen, C<NUM>-C<NUM>alkyl and C<NUM>-C<NUM> alkoxy group; and X<NUM> is Cl, Br or I. In one aspect, the Grignard reagent is iso-propyl magnesium chloride (i-PrMgCl). Conveniently, the organometallic intermediate of formula (II-A) is reacted with ZnX<NUM> without isolation of the organometallic intermediate of formula (II-A). The reaction of the first starting material of formula (II) with the Grignard reagent can be carried out in ethereal solvents. One commonly used ethereal solvent is tetrahydrofuran. In one aspect, the reaction of the first starting material of formula (II) with the Grignard reagent is carried out in a mixture comprising anisole and an ethereal solvent. Utilizing anisole in the reaction mixture has the advantage of reducing by-products. In one aspect, the reaction of the first starting material of formula (II) with the Grignard reagent is carried out in a mixture comprising an aromatic solvent such as benzene, toluene, xylene, and a mixture thereof.

Specific conditions for preparing Compound <NUM> by the methods of the present disclosure are provided in Examples <NUM> and <NUM>. Compound <NUM> can be readily converted into ALK-<NUM> inhibitors by first removing the amine protecting group and then carbamoylating the resulting free amine into the desired ALK-<NUM> inhibitor. Suitable conditions for these two transformations are disclosed in <CIT>. Specific conditions for the removal of a Boc protecting group are provided in Example <NUM> below; and in Examiner <NUM> for the carbamoylation.

The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure.

Compound <NUM> was prepared from starting materials <NUM>-isopropylpiperidin-<NUM>-one and <NUM>-bromo-<NUM>-iodopyridine via a synthetic route as shown in the scheme above. It was also commercially available from Acceledev.

A mixture of <NUM>-bromopyrrolo[<NUM>,<NUM>-b]pyridazine-<NUM>-ol (<NUM>, <NUM> mol) and triethylamine (<NUM>, <NUM> equiv) in acetonitrile (<NUM>, <NUM> volumes) is agitated at -<NUM>. To this mixture was added trifluoromethanesulfonic anhydride (<NUM>, <NUM> equiv) with an additional rinse of acetonitrile (<NUM>, <NUM> volumes). The reaction was agitated until reaction completion, at which time trimethylsilyl chloride (<NUM>, <NUM> equiv) is added. To the mixture is then added, triethylamine (<NUM>, <NUM> equiv) and N-Boc-piperazine (<NUM>, <NUM> equiv) with additional acetonitrile rinses (<NUM>, <NUM> volumes). The reaction was heated to <NUM>-<NUM> until reaction completion. The reaction mixture was concentrated at <NUM>-<NUM> and diluted with water before cooling to <NUM>-<NUM> to crystalize the product. The product was filtered and washed with isopropanol (<NUM> × <NUM>, <NUM> × <NUM> volumes) to give <NUM> (<NUM>% yield).

<NUM>-Bromo-<NUM>-(<NUM>-ethoxy-<NUM>-isopropylpiperidin-<NUM>-yl)pyridine (Compound <NUM>, <NUM>, prepared as disclosed in <CIT>) was dissolved in anisole (<NUM>). The resulting solution was heated to <NUM>-<NUM> and partially distilled to lower water content. The remaining reaction solution was cooled to <NUM>-<NUM> and isopropylmagnesium chloride (<NUM>% in tetrahydrofuran, <NUM>) was added. Once complete conversion was observed a solution of zinc chloride (<NUM>% in methyltetrahydrofuran, <NUM>) was added while continuing heating. The resulting zinc organyl (Intermediate <NUM>) solution was then charged with potassium tert-butoxide (<NUM>% in methyltetrahydrofuran, <NUM>), Pd<NUM>(dba)<NUM> (<NUM>) and tert-Bu<NUM>P•HBF<NUM> (<NUM>). Additionally, N-methyl-<NUM>-pyrrolidone (<NUM>) was added followed by tert-butyl <NUM>-(<NUM>-bromopyrrolo[<NUM>,<NUM>-b]pyridazin-<NUM>-yl)piperazine-<NUM>-carboxylate (Compound <NUM>, prepared as disclosed in <CIT>) as a solution in tetrahydrofuran (<NUM> Compound <NUM> in <NUM> of tetrahydrofuran). Heating was continued until complete conversion to Compound <NUM>.

Compound <NUM> prepared as described in Example <NUM> was used without purification or isolation from the reaction mixture. The reaction mixture was diluted with tetrahydrofuran (<NUM>) and <NUM>% hydrochloric acid (<NUM>) in water (<NUM>) was added. The acidic aqueous mixture containing the product was washed with methyltetrahydrofuran (<NUM>) and then isopropyl acetate (<NUM> × <NUM>). The aqueous solution was then diluted with isopropyl acetate (<NUM>) and basified with ammonia (<NUM>%, <NUM>). The organic phase was separated and washed with acetylcysteine (<NUM> × <NUM>) and water (<NUM> × <NUM>). The organic solution was seeded and heptane (<NUM>) was added to crystalize the product that was then isolated by filtration to give approximately <NUM> of Compound <NUM> after drying.

To the reactor was added <NUM>,<NUM>-carbonyldiimidazol (<NUM>), isopropyl acetate (<NUM>), and the alcohol R-OH (e.g., <NUM> equivalents relative to <NUM>,<NUM>-carbonyldiimidazol). The reaction was agitated <NUM> minutes at <NUM>-<NUM> until reaction completion. The reaction was heated to <NUM>-<NUM> and filtered, washing the filter with isopropyl acetate (<NUM>). This diluted mixture was charged with ammonia (<NUM>%, <NUM>) and Compound <NUM> (<NUM>) was added. The reaction was heated to <NUM>-<NUM> and distilled under vacuum. The mixture was further diluted with isopropyl acetate (<NUM>) and reaction completion confirmed. At this time, the reaction mixture was diluted with water (<NUM>) and isopropyl acetate (<NUM>) and agitated. The mixture was allowed to settle, and organic phase separated. The organic solution was further washed with water (<NUM> ×<NUM>). The organic phase after final separation was diluted with isopropyl acetate (<NUM>) and distilled at <NUM>-<NUM> under vacuum to reduce the water content. The organic solvent can then be removed to isolate the ALK-<NUM> inhibitor.

To <NUM> equivalents <NUM>-bromo-<NUM>-(<NUM>-ethoxy-<NUM>-isopropylpiperidin-<NUM>-yl)pyridine (Compound <NUM>) were added <NUM> volumes toluene and the mixture was heated to jacket temperature (JT) <NUM>° C<NUM>. At internal temperature (IT) <NUM>-<NUM>° C <NUM> volumes toluene were distilled. At IT <NUM>° C <NUM> equivalents iso-propyl magnesium chloride (<NUM> in tetrahydrofuran) were added in total to reach reaction completion. At that time, <NUM> equivalents ZnCh (<NUM> in tetrahydrofuran) was added at <NUM>° C and the mixture was stirred at JT <NUM>° C for <NUM> hours. At IT <NUM>° C were added <NUM> volumes N-methyl-<NUM>-pyrroldinone, <NUM> mol% Pd<NUM>(dba)<NUM>, <NUM> mol% tBu<NUM>P•HBF<NUM>. A solution of <NUM> equivalents Compound <NUM> (<NUM>) in <NUM> volumes methyltetrahydrofuran (MeTHF) was added over <NUM> minutes at IT <NUM>° C. After <NUM> additional <NUM> equivalents Compound <NUM> in <NUM> volumes tetrahydrofuran was added. The mixture was stirred for <NUM> hours at IT <NUM>° C, transferred to another reaction vessel, rinsed with <NUM> volumes MeTHF and then added over <NUM> minutes to a solution of <NUM> equivalents K<NUM>CO<NUM> in <NUM> volumes water at <NUM>° C. Then, <NUM> volumes <NUM>%-w/w NaOH were added, the aq. phase was separated and the organic phase split into three portions. Each portion was washed with <NUM> × <NUM> volumes of either (i) potassium carbonate, (ii) <NUM>,<NUM>,<NUM>-trimercapto-<NUM>,<NUM>,<NUM>-triazine (TMT), or (iii) N-acetylcysteine. Then <NUM> volumes water and <NUM> volumes <NUM> HCl were added and the organic phase was separated. Subsequently <NUM> volumes <NUM>%-w/w NaOH and Norit CGP super (approx. <NUM>) were added. The mixture was stirred at IT <NUM>° C for <NUM> hours, filtered, and washed with <NUM> volumes MeTHF. The organic phase was washed with <NUM> × <NUM> volumes water. Boc<NUM>O (<NUM> vol, <NUM>) was added and the mixture was stirred for <NUM> minutes at <NUM>° C. MeTHF was distilled at JT <NUM>-<NUM>° C while n-heptane was added (<NUM> × <NUM> volumes). The brown slurry was cooled to <NUM>° C, stirred for <NUM> minutes, filtered, and washed with <NUM> × <NUM> volumes n-heptane (re-slurry washings). <NUM> Equivalents and volumes are all relative to Compound <NUM>, in which one equivalent is <NUM>. Volume is <NUM>/<NUM> gram of reference material, in this case Compound <NUM>.

The quenched reaction mixture split into three portions and the palladium content determined by inductively coupled plasma mass spectrometry (IPC-MS) to be: Reference (K<NUM>CO<NUM>): <NUM>'<NUM> ppm Pd; <NUM> × extraction with TMT: <NUM>'<NUM> ppm Pd; and <NUM> × extraction with N-acetylcysteine: <NUM> ppm Pd.

To a vessel containing Compound <NUM> (<NUM>) in water <NUM> (<NUM> vol) and <NUM>,<NUM>-dioxane (<NUM>, <NUM> vol) was added <NUM> (<NUM> eq) of <NUM>-bromo-<NUM>-(<NUM>-ethoxy-<NUM>-isopropylpiperidin-<NUM>-yl)pyridine (Compound <NUM>) , K<NUM>CO<NUM> (<NUM>, <NUM> eq), and Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> eq). The reaction was heated to <NUM> until reaction completion was observed by HPLC (<FIG>).

To <NUM> of <NUM>-bromo-<NUM>-(<NUM>-ethoxy-<NUM>-isopropylpiperidin-<NUM>-yl)pyridine (Compound <NUM>) was added <NUM> vol toluene and <NUM> eq iPrMgCl (<NUM> in THF). The mixture was heated to JT <NUM>. After reaching reaction completion, <NUM> eq ZnCl<NUM> (<NUM> in MeTHF) was added and the reaction held at <NUM>-<NUM>. At <NUM>, Compound <NUM> was added with PdP(tBu<NUM>)<NUM> (<NUM> eq) with THF (<NUM> vol) and the mixture agitated until reaction completion by HPLC (<FIG>).

Claim 1:
A method of preparing a compound represented by formula (I):
<CHM>
comprising reacting in a reaction mixture a first starting material represented by formula (II):
<CHM>
and a second starting material represented by formula (III) under Negishi conditions:
<CHM>
to form the compound of formula (I), wherein R is an amine protecting group; Y is Cl, Br or I; and Z is Cl, Br, I or triflate.