WO2009117278A2 - Processes for preparing (amino-pyrazolopyridinyl)methoxy substituted biaryl ethers - Google Patents

Abstract

Processes for preparing certain (amino-pyrazolopyridinyl)methoxy-substituted biaryl ethers and their salts are described. The substituted biaryl ethers are useful as HIV non-nucleoside reverse transcriptase inhibitors. The processes include coupling a biaryl ether with a suitably protected and activated pyrazolopyridinyl methanol and then removing the protective groups from the coupled product to provide the desired substituted biaryl ether in the form of a sulfonate salt or a sulfate salt. Earlier reaction steps and the intermediates employed and obtained therein are also described. Crystalline HCl and sulfate salts of a particular (amino-pyrazolopyridmyl)-methoxy~substituted biaryl ether are described as well.

Description

TITLE OF THE INVENTION

PROCESSES FOR PREPARING (AMINO-PYRAZOLOPYRIDINYL)METHOXY

SUBSTITUTED BIARYL ETHERS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos. 61/070,084 (filed March 20, 2008) and 61/195,262 (filed October 6, 2008), the disclosures of which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to processes for preparing certain

(amino-ρyrazolopyridinyl)methoxy-substituted biaryl ethers in protected and unprotected forms and salts thereof. The substituted biaryl ethers are useful as HIV non-nucleoside reverse transcriptase inhibitors. The present invention is also directed to certain compounds, including pyrazolopyridinyl methanols and related compounds, and their preparation, wherein these compounds are useful as intermediates in the processes for preparing the substituted biaryl ethers.

BACKGROUND OF THE INVENTION A class of diphenyl ethers mono-substituted with a (6-amino-l H-ρyrazolo[3,4- b]pyridin-3~yl)methoxy group are inhibitors of HIV reverse transcriptase. More particularly, these compounds can inhibit HIV type 1 (HIV-I) and HFV type 2 (HIV-2) reverse transcriptase enzymes. This class includes the compounds of Formula IX as defined and described below. These compounds and pharmaceutically acceptable salts thereof are useful in the treatment or prophylaxis of infection by HIV and in the treatment, prophylaxis, or delay in the onset or progression of AIDS. Representative compounds of this class are described in US 2007/0021442. Representative of the compounds of Formula IX disclosed in US 2007/0021442 is the compound of formula:

hereinafter referred to as Compound A.

Example 37 of US2007/0021442 discloses the following process (alternatively referred to herein as Process A) for preparing Compound A: Process A:

a§ (= Compound A)

Process A is suitable for the preparation of Compound A and its analogs (by appropriately changing the substituents in the diphenyl ether group Ar in ArOH), but the overall yield is typically less than about 0.1%. The 3-bromomethyl-6-fluoro-pyrazolopyridine intermediate a5 is difficult to prepare requiring 4 steps from 2,6-difIuoropyridine al with an overall yield of about 5-10%. Furthermore, a5 requires chromatographic purification and is inherently unstable at room temperature. In addition, the formation of a§ proceeds relatively slowly with average yields of only 20-30%. Accordingly, there is a need for an improved process that can provide a better yield and would be more suitable for the large-scale production of Compound A and its analogs.

SUMMARY OF THE INVENTION

The present invention is directed to processes for preparing certain

(amϊno-pyrazolopyridinyl)methoxy-substituted biaryl ethers in protected and unprotected forms and salts thereof. The substituted biaryl ethers are useful as HIV reverse transcriptase inhibitors. The present invention is also directed to certain compounds, including pyrazolopyridinyl methanols and related compounds, and their preparation, wherein these compounds are useful as intermediates in the process for preparing the substituted biaryl ethers. More particularly, the present invention includes a process (alternatively referred to herein as Process P) for preparing a compound of Formula VIII:

which comprises:

(F) contacting a compound of Formula VI:

with a biaryl ether of Formula VII:

in the presence of an iodide selected from alkali metal iodides and ammonium iodide and a base F to obtain the compound of Formula VIII; wherein: Rl i is:

(1) Ci-IO alkyl,

(2) phenyl, or

(3) Cl -4 alkyl substituted with 1 , 2 or 3 phenyl groups, wherein each phenyl in (2) or (3) is optionally and independently substituted with one or more substituents (e.g., from 1 to 3 substituents, or from 1 to 2 substituents) each of which is independently halogen, NO2, Ci, 6 alkyl, O-Ci-6 alkyl, Cμ6 fluoroalkyl, or 0-Ci-6 fluoroalkyl;

LG is a leaving group;

pG2 is a nitrogen-protective group;

R3 and R⁴ are each independently selected from the group consisting of hydrogen, halogen, C \ .5 alkyl and Ci_6 fluoroalkyl; and

R5, R6 and R? are each independently selected from the group consisting of hydrogen, halogen,

CN, Cl -6 alkyl and Cl -6 fluoroalkyl. Step F represents a significant improvement over the corresponding step disclosed in US2007/0021442 (i.e., the coupling of a5 with ArOH to obtain 36) in that it avoids the use of the 3-bromomethyl-6-fluoro-pyrazoloρyridine intermediate a5. The corresponding compounds of Formula VI are more stable and have the desired amino function (vs. F in a5) at the 6 position.

Thus, the method of the invention is more convergent Furthermore, compounds of Formula VI can be prepared on a large scale without the need for chromatographic purification (see, e.g.,

Example 3 below),

The compound of Formula VIII is a protected form of the desired substituted biaryl ether. The present invention also includes a process for preparing the desired substituted bϊaryl ethers from a compound of Formula VIII. More particularly, the present invention includes a process (Process Q) for preparing a compound of Formula IX in the form of a sulfonate salt:

which comprises conducting Step F as described above to obtain a compound of Formula VIlI; and

(G) treating the compound of Formula VIΪI with (ϊ) phosphoric acid or a carboxylic acid selected from the group consisting of oxalic acid, acetic acid and haloacetic acids and with (ii) an organic sulfonic acid to obtain the sulfonate salt of the compound of Formula IX.

The combination of Steps F and G in Process Q represents a significant improvement over the corresponding steps disclosed in US2007/0021442 (i.e., removing Boc from a6 to obtain a7, replacing the fluoro with the amino group to obtain a8, and then treating with acid to remove the amine protective group to obtain ag). Step G of Process Q removes the amine protective group and the pyrazolo nitrogen protective group in a single step to provide a the desired compound which can be conveniently recovered in the form of a sulfonate salt. Furthermore, the formation of a compound of Formula DC from the protected penultimate of Formula VIII proceeds more efficiently. For example, the formation of Compound A via the process of the invention proceeds with average yields of 50-70%, whereas as noted earlier the formation of a8 proceeds slowly with 20-30% average yields.

The present invention also includes a process (Process R) for preparing a compound of Formula IX in the form of a sulfate salt, which comprises conducting Step F as described above to obtain a compound of Formula VIII; and

(H-I ) treating the compound of Formula VIII with sulfuric acid in the presence of a C i .16 alkanethiol or benzenethiol to obtain a sulfate salt of a compound of Formula VIII-A:

(H-2) treating the compound of Formula VIII-A with sulfuric acid to obtain the sulfate salt of a compound of Formula IX.

In contrast to Step G in Process Q, Steps H-I and H-2 in Process R remove the pyrazolo nitrogen protective group and the amine protective group sequentially (v. concurrently in Step G) to provide the desired compound in the form of a sulfate salt (v. sulfonate salt in Step G). Process R can be more efficient than Process Q₅ providing higher yields of Compound IX. For example, Process R can provide Compound A with 85-90% average yields.

The present invention also includes a process (Process S) for preparing a compound of Formula IX in the form of a sulfate salt, which comprises conducting Step F as described above to obtain a compound of Formula VIII; and

(K) treating the compound of Formula VIII with sulfuric acid to obtain the sulfate salt of a compound of Formula IX. Process S can achieve yields similar to those of Process Q (e.g., Process S can provide Compound A with yields of about 50-70%) with the employment of a single, comparatively low-cost reagent (i.e., H2SO4 v. in Process Q a carboxylic acid and a sulfonic acid). While Process S advantageously involves the use of a single reagent in a single finishing step (H2SO4 in Step K) versus two reagents and two finishing steps in Process R (i.e., H2SO4 and a thiol in Step H-I and H2SO4 in Step H-2), Process R typically can provide a higher yield of desired product. Process R is the preferred route to Compound A.

Other embodiments (e.g., embodiments of Process P and Process Q and Process R and Process S including additional process steps), aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the X-ray powder diffraction pattern for the Form I crystalline HCl salt of Compound A described in Example 4.

Figure 2 is the X-ray powder diffraction pattern for the Form II crystalline HCl salt of Compound A described in Example 4.

Figure 3 is the X-ray powder diffraction pattern for the crystalline sulfate salt of Compound P-A described in Part A of Example 6.

Figure 4 is the X-ray powder diffraction pattern for the crystalline sulfate salt of Compound A described in Part B of Example 6.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to processes for preparing certain

(amino-pyrazolopyridinyl)methoxy-substituted biaryl ethers and salts and intermediates thereof. The present invention includes Process P to obtain a compound of Formula VIE and Process Q to obtain a compound of Formula IX as set forth above in the Summary of the Invention. The present invention also includes Processes R and S₁ both to obtain a compound of Formula IX as set forth above in the Summary of the Invention. A compound of Formula VIII is alternatively referred to herein more simply as "Compound VIII", a compound of Formula VIII-A is alternatively referred to as "Compound VIII-A", and a compound of Formula IX is alternatively referred to as "Compound IX". Analogous nomenclature is employed for compounds of Formula I₃ II, III, IV, V, VI, VII and the like described below. A first embodiment of the present invention (alternatively referred to herein as

Embodiment El) is Process P or Process Q or Process R or Process S, wherein Rl is: (1) Ci.g alkyl, (2) phenyl,

(3) CH2-phenyl_s

(4) diphenylmethyl, or

(5) trityl wherein the phenyl in (2) or (3) is optionally substituted with one or more substitueπts (e.g., from 1 to 3 substituents, or from 1 to 2 substituents) each of which is independently Cl₁ Br, F, NO2, Ci-4 alkyl, O-Ci-4 alkyl, CF3, CH2CF3, OCF3, or OCH2CF3; and all other variables are as originally defined (i.e., as defined in the Summary of the Invention). A second embodiment of the present invention (Embodiment E2) is Process P or

Process Q or Process R or Process S, wherein Rl is:

(1) branched C3.8 alkyl,

(2) phenyl, or

(3) CH2-phenyl, wherein the phenyl in (2) or (3) is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, NO2, CH3, OCH3, CF3, CH2CF3, OCF3, or OCH2CF3; and all other variables are as originally defined.

A third embodiment of the present invention (Embodiment E3) is Process P or Process Q or Process R or Process S, wherein Rl is isopropyl, t-butyl, isobutyl, sec-butyl, isopentyl, neopentyl, 1,1-dimethylpropyl (also referred to as t-pentyl)₅ 1,1,3,3-tetramethylbutyl (also referred to as 2,4,4-trirnethyl-2-pentyl), or ben2yl in which the phenyl group is substituted in the para-position with Cl, Br, CH3, OCH3, or CF3; and all other variables are as originally defined. A fourth embodiment of the present invention (Embodiment E4) is Process P or

Process Q or Process R or Process S, wherein Rl is t-butyl; and all other variables are as originally defined.

A fifth embodiment of the present invention (Embodiment E5) is Process P or Process Q or Process R or Process S, wherein:

R3 and R4 are each independently selected from the group consisting of H, Cl, Br, F, Ci .4 alkyl,

CF3 and CH2CF3;

R5, R6 and R? are each independently selected from the group consisting of hydrogen, Cl, Br, F, CN, Ci-4 alkyl, CF3 and CH2CF3;

and all other variables are as originally defined or as defined in any of the preceding embodiments. A sixth embodiment of the present invention (Embodiment E6) is Process P or Process Q or Process R or Process S, wherein R3 is H; R4 is Cl, Br, F, Cj.3 alkyl, or CF3; R5 and Kr are each independently selected from the group consisting of hydrogen, Cl, Br₇ F, CN, C 1-3 alkyl and CF3; Rό is H; and all other variables are as originally defined or as defined in any of the preceding embodiments.

A seventh embodiment of the present invention (Embodiment E7) is Process P or Process Q or Process R or Process S, wherein R3 is H; R4 is Cl, Br, F, CH3, or CF3; R5 and R? are each independently selected from the group consisting of hydrogen, Cl, Br, F, CN, CH3, and CF3; Rό ts H; and all other variables are as originally defined or as defined in any of the preceding embodiments.

An eighth embodiment of the present invention (Embodiment E8) is Process P or Process Q or Process R or Process S, wherein LG is a halide, a sulfonate, a sulfinate, a phosphonate, a phosphinate, or an imidate; and all other variables are as originally defined or as defined in any of the preceding embodiments. A ninth embodiment of the present invention (Embodiment E9) is Process P or

Process Q or Process R or Process S, wherein L*J is X or Y, wherein X is halogen (esp. Cl₅ Br or

(2) -OS(=O)R2, (3) -OP(=O)(R2)2,

(4) -OP(=O)(OH)R2, or

(5) -OC(=NH)R2; wherein each R2 is independently Cl -6 alkyl, C\.β haloalkyl (e.g., CF3, CHF2, CCI3, CHCI2), or phenyl, wherein the phenyl is optionally substituted with one or more substituents (e.g., from 1 to 3 substituents, or from 1 to 2 substituents) each of which is independently halogen, Cl -6 alkyl, O-Ci-6 alkyl, Cj.g fluoroalkyl, or O-Ci-6 fluoroalkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments. A tenth embodiment of the present invention (Embodiment ElO) is Process P or

Process Q or Process R or Process S, wherein LG is OS(O)2R2, wherein R2 is CH3, CF3, or phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, OCH3, CF3, or OCF3; and all other variables are as originally defined or as defined in any of the preceding embodiments. An eleventh embodiment of the present invention (Embodiment El 1) is Process P or Process Q or Process R or Process S, wherein L<J is halo; and all other variables are as originally defined or as defined in any of the preceding embodiments. A twelfth embodiment of the present invention (Embodiment E 12) is Process P or Process Q or Process R or Process S, wherein L^ is chloro; and all other variables are as originally defined or as defined in any of the preceding embodiments.

A thirteenth embodiment of the present invention (Embodiment El 3) is Process P or Process Q or Process R or Process S, wherein PG2 i_s;

(1) C 1-6 alkyloxycarbonyl,

(2) tetrahydropyran-2-yl,

(3) tetrahydrofuran-2-yl,

*^OR^C

(4) R^A R^B _; wherein RA, RB and RC are each independently a Ci .4 alkyl; or alternatively RC is Cl -4 alkyl, and RA and RB together with the carbon to which they are both attached form Cs_6 cycloalkyl, C4.5 oxacycloalkyl, C4_5 thiacycloalkyl, or C4..5 azacycloalkyl in which the aza nitrogen is substituted with C i_4 alkyl, or

(5) R R^RJ _? RK is C 1 ,4 alkyl, and RJ and RL₅ together with the carbon to which RL is attached and the O to which RJ is attached form C4-5 oxacycloalkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.

A fourteenth embodiment of the present invention (Embodiment E 14) is Process P or Process Q or Process R or Process S, wherein pG2 _ls: (I) t-butyloxycarbonyl,

(2) tetrahydropyran-2-yl,

(3) tetrahydrofuran-2-yl, or

*^OCH₃

(4) R^A R^B ; and all other variables are as originally defined or as defined in any of the preceding embodiments.

A fifteenth embodiment of the present invention (Embodiment El 5) is Process P or Process Q or Process R or Process S, wherein PG2 is;

(1) t-butyloxycarbonyl,

(2) tetrahydropyran-2-yl, or

and all other variables are as originally defined or as defined in any of the preceding embodiments.

A sixteenth embodiment of the present invention (Embodiment E 16) is Process P or Process Q or Process R or Process S, wherein pG2 is tetrahydropyran-2-yl; and all other variables are as originally defined or as defined in any of the preceding embodiments. As used herein, the term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "C 1-8 alkyl" (or "Ci-Cg alkyl") refers to any of the octyi, heptyl, hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl. As another example, "Ci_6 alkyl" (or "Ci-Cg alkyl") refers to any of the hexyl and pentyl alkyl isomers as well as n-_f iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl. As another example, "Ci _4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example;, "Ci_3 alkyl" refers to n-propyl, isopropyl, ethyl and methyl.

The term "alkane" refers to both linear and branched alkanes corresponding to the alkyl groups defined above. The term "branched alkyl" refers to an alkyl group as defined above except that straight chain alkyl groups in the specified range are excluded. As defined herein, branched alkyl includes alkyl groups in which the alkyl is attached to the rest of the compound via a secondary or tertiary carbon; e.g., isopropyl is a branched alkyl group.

The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fiuoro, chloro, bromo, and iodo).

The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and/or I). Thus, for example, "Ci-6 haloalkyl" (or "Cl-C$ haloalkyl") refers to a Cl to Cg linear or branched alkyl group as defined above with one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoro-n-propyl, etc.). A fluoroalkyl of particular interest is CF3. The term "cycloalkyl" refers to any monovalent monocyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C5.7 cycloalkyl" (or "C5-C7 cycloalkyl") refers to cyclopentyl, cyclohexyl, and cycloheptyl and "C5-6 cycloalkyl" refers to cyclopentyl and cyclohexyl.

The term "azacycloalkyl" refers to a cycloalkyl as just defined in which one of the ring carbons is replaced with N-R wherein R is H or C 1 _g alkyl.

The term "oxacycloalkyl" refers to a cycloalkyl as just defined in which one of the ring carbons is replaced with an oxygen.

The term "thiacycloalkyl" refers to a cycloalkyl as just defined in which one of the ring carbons is replaced with a sulfur. The term "C(O)" refers to carbonyl. The terms "S(O)2" and "SO2" each refer to sulfonyl. The term "S(O)" refers to sulfmyl.

An asterisk ("*") as the end of an open bond in a chemical group denotes the point of attachment of the group to the rest of the compound.

Combinations of substituents and/or variables are permissible only if such combinations result in a stable compound.

Unless expressly stated to the contrary, substitution, by a named substituent is permitted on any atom in a ring (e.g., phenyl) provided such ring substitution is chemically allowed and results in a stable compound.

Unless expressly stated to the contrary, all ranges cited herein are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. For example, a phenyl ring described as optionally substituted with " 1 to 3 substituents" is intended to include as aspects thereof, a ring substituted with 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent. As another example, a phenyl ring substituted with "one or more" substituents is intended to include as aspects thereof a phenyl ring substituted with 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substituents, 4 to 5 substituents, 1 to 4 substituents, 2 to 4 substituents, and so forth. As still another example, temperature ranges, ranges of equivalents, and the like described below include the upper and lower limits of the range and any value in the continuum therebetween.

In reference to the compounds employed as reactants or reagents in the process of the invention (e.g., Compounds II, IH, and IV), a "stable" compound is one whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow its use in the process of the invention so as to achieve the preparation of Compound VIII, Compound VIII-A and/or Compound IX. In reference to Compound IX and its salts, a "stable" compound is a compound which can be prepared in accordance with the process of the present invention and then isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for its intended purpose; e.g., for the therapeutic administration to a subject who has an HIV infection or AIDS. The process of the present invention is limited to the use and/or preparation of such stable compounds.

Step F involves the coupling of pyrazolopyridine VI with a hydroxy-substituted biaryl ether VII in the presence of an iodide reagent and base to obtain a coupled product VIII. Biaryl ethers of Formula VII can be prepared as described in U S 2007/0021442. Step F is conducted in organic solvent F. Organic solvent F is an aprotic solvent and typically a polar aprotic solvent. The aprotic solvent can be, for example, a dialkyl ether, a dialkoxyalkane, a bis(alkoxyalkyl)ether, a cyclic ether or diether, a phenyl alkyl ether, phenyl alkyl thioether, a tertiary alkyl amine, a tertiary cyclic amine or diamine, an aliphatic nitrile, an aromatic nitrile, a tertiary carboxylic amide, a dialkyl sulfoxide, a cyclic sulfone, a N,N'-dialkyl cyclic urea, a hexaalkylphosphoramide, an alkyl acetate, a haloalkane, an aromatic hydrocarbon, or a halogenated aromatic hydrocarbon. A class of suitable solvents consists of dialkyl ethers wherein each alkyl is independently a C1-C5 alkyl; Ci -5 alkyl C5-6 cycloalkyl ethers; C1-C5 alkanes substituted with two -O-C1-C4 alkyl groups which are the same or different; bis (Ci .4 alkoxy-Ci-5 alkyl)ethers; C4-Cg cyclic ethers and diethers in which the cyclic ring is optionally substituted with C 1.4 alkyl; phenyl C1-C4 alkyl ethers; phenyl Ci -C4 alkyl thioethers; C2-C4 aliphatic nitriles; C7-C9 aromatic nitriles; tri-Ci-4 alkyl amines in which the alkyl groups are the same or different; C4-.6 azacycloalkanes and diazacycloalkanes in which one of the ring carbons is optionally replaced with O or S and wherein each of the ring nitrogens is substituted with Ci .4 alkyl; N,N-di-Ci_4 alkyl Cl -.4 alkylcarboxamides; tertiary C4_6 lactams; di-Ci.4 alkylsulfoxides; C4.6 cyclic sulfones; N,N'-di-Ci-4 alkyl-N,N'-(di- or tri- or tetra-methylene)ureas; hexa(C]-4 alkyl)phosphoramides; Cl -.5 alkyl acetates; C 1.4 haloalkanes; C7-9 aromatic hydrocarbons; and halogenated C7.9 aromatic hydrocarbons.

In one aspect, the solvent employed in Step F is diethyl ether, MTBE, DME, cyclopentyl methyl ether, bis(2-methoxyethyl)ether, THF, 2-methyl-THF, dioxolane, dioxane, am sole, thioanisole, acetonitrile, propionitrile, benzonitrile, o-tolunitrile, p-tolunitrile, triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, DMF, DMAc, NMP, DMSO₅ sulfolane, DMPU, HMPA, IPAc, dichloromethane, toluene, or trifluorotoluene. hi a feature of this aspect, the solvent employed in Step F is NMP or DMAc. In another feature of this aspect, the solvent employed in Step F is DMAc. In still another feature of this aspect, the solvent employed in Step F is acetonitrile. In still another feature of this aspect, the solvent employed in Step F is a combination of acetonitrile and 2-methyl-THF. The iodide reagent is selected from the group consisting of alkali metal iodides and ammonium iodide. The iodide employed in Step F is suitably LiI, NaI, KI₅ CsI or NH4I. In one aspect of Step F the iodide is KI.

Base F (i.e., the base employed in Step F) can be any base capable of neutralizing acid by-product resulting from the coupling reaction. The base can be, for example, an alkali metal fluoride, a metal carbonate, a metal bicarbonate, or a tertiary amine. Suitable bases include NaF, KF, CsF, Na carbonate, K carbonate, Cs carbonate, Na bicarbonate, K bicarbonate, Cs bicarbonate, and Hunig's base, hi one aspect the base is cesium carbonate, Na carbonate, K carbonate, or CsF. In a feature of this aspect, the base employed in Step F is K carbonate or CsF. In another feature of this aspect, the base is K carbonate.

Compound VI, Compound VII, iodide (e.g., KI) and base F can be employed in any amounts which result in the formation of at least some of Compound VIII. Optimal conversion of Compound VI and optimal formation of Compound VIII are normally desired in Step F₅ and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed. In one embodiment of Step F, the equivalents of iodide employed is approximately equal to or in excess of the equivalents of Compound VI. In this embodiment, the iodide (e.g., KI) can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 0.95 equivalent, or at least about 1 equivalent) per equivalent of the compound of Formula VI, is typically employed in an amount in a range of from about 1 to about 3 equivalents per equivalent of Compound VI, and is more typically employed in an amount in a range of from about 1.2 to about 2 equivalents per equivalent of Compound VI. In one aspect of this embodiment, the iodide is employed in an amount of from about 1.5 to about 2 equivalents (e.g., about 1.7 equivalents) per equivalent of Compound VI. An equal or excess amount of the iodide is suitably employed, for example, when the leaving group in Compound VI is a sulfonate such as mesylate.

In another embodiment of Step F, iodide is employed in a sub-stoichiometric amount. In this embodiment, the iodide (e.g., KJ) can suitably be employed in an amount of at least about 0.05 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula VI, is typically employed in an amount in a range of from about 0.1 to about 0,9 equivalents per equivalent of Compound VI, and is more typically employed in an amount in a range of from about 0.1 to about 0.5 equivalent per equivalent of Compound VI. In one aspect of this embodiment, the iodide is employed in an amount of from about 0.1 to about 0.3 equivalent (e.g., about 0.2 equivalent) per equivalent of Compound VI. A sub-stoichiometric amount of the iodide is suitably employed, for example, when the leaving group in Compound VI is a halide such as chloride.

The base F can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula VI, is typically employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound VI, and is more typically employed in an amount in a range of from about 2 to about 8 equivalents per equivalent of Compound VI. In one aspect, the base is employed in an amount in a range of from about 4 to about 6 equivalents per equivalent of Compound VL

Compound VII can suitably be employed in an amount of at least about 0.8 equivalent (e.g., at least about 0.9 equivalent, or at least about 1 equivalent) per equivalent of the compound of Formula VI, is typically employed in an amount in a range of from about 0.8 to about 1.5 equivalents per equivalent of Compound VI₅ and is more typically employed in an amount in a range of from about 0.8 to about 1.2 equivalents per equivalent of Compound VI. In one aspect, Compound VII is employed in an amount in a range of from about 0.9 to about 1.1 equivalents per equivalent of Compound VI.

Step F can be conducted at any temperature at which the reaction forming Compound VIII can detectably proceed. In one embodiment, the reaction can suitably be conducted at a temperature in a range of from about 0⁰C to about 50°C and is typically conducted at a temperature in a range of from about 10⁰C to about 40⁰C. In an aspect of this embodiment, Step F is conducted at a temperature in a range of from about 15⁰C to about 30⁰C. Temperatures in this range are, for example, suitable when the leaving group in Compound VI is a sulfonate such as mesylate.

In another embodiment, the reaction can suitably be conducted at a temperature in a range of from about 30⁰C to about 80⁰C and is typically conducted at a temperature in a range of from about 40⁰C to about 70⁰C. In an aspect of this embodiment, Step F is conducted at a temperature in a range of from about 5O⁰C to about 65⁰C. Temperatures in this range are, for example, suitable when the leaving group in Compound VI is a halide such as chloride.

The reaction time for Step F can vary widely depending upon (i) the choice and relative proportions of Compound VI, Compound VII, iodide (e.g., KI), and base, (ii) the choice of solvent, (iii) the choice of reaction temperature, (iv) the overall scale of the reaction, (v) the level of conversion desired, and so forth. Nonetheless, the reaction can. usually be completed (i.e., 100% conversion) in about 48 hours or less, and is typically complete in about 24 hours or less, and is often complete in from about 12 to about 24 hours.

The order of addition of the reactants and reagents to the reaction vessel (alternatively referred to herein as the reaction "pot") in Step F is not critical. Step F can be conducted, for example, in the following manner: Compound VII, iodide reagent (e.g., KI), base F and organic solvent F are sequentially charged to a flask after which Compound VI in solvent F is charged to the flask. The resulting mixture is brought to reaction temperature and aged at reaction temperature until the desired degree of conversion is achieved. Complete conversion of Compound VI is typically desired. The reaction mixture is optionally but typically agitated (e.g., stirred) during addition of the reactants and reagents to the reaction vessel and during the subsequent ageing. Compound VIII formed in Step F can be recovered by conventional means. For example, Compound VIII can be recovered by diluting the reaction mixture with water and a suitable solvent, separating and concentrating the organic layer to precipitate Compound VILI, and separating Compound Viπ by filtration. Alternatively, the organic layer containing Compound VIH can be used directly in Step G or Step H-I or the layer can be subjected to a solvent switch for subsequent use in Step G or Step H-I. Step G in Process Q involves deprotecting Compound VIII with (i) phosphoric acid or a carboxylic acid selected from the group consisting of oxalic acid, acetic acid and haloacetic acids and (ii) an organic sulfonic acid to provide a sulfonate salt of Compound IX.

Step G is conducted in organic solvent G, which is a polar aprotic solvent. The polar aprotic solvent can be, for example, a dialkyl ether, a dialkoxyalkane, a bis(alkoxyalkyl)ether, a cyclic ether or diether, a phenyl alkyl ether, phenyl alkyl thioether, a tertiary alkyl amine, a tertiary cyclic amine or diamine, an aliphatic nitrile, an aromatic nitrile, a tertiary carboxylic amide, a dialkyl sulfoxide, a cyclic sulfone, a N,N'-dialkyl cyclic urea, a hexaalkylphosphoramide, an alkyl acetate, a haloalkane, or a halogenated aromatic hydrocarbon. A class of suitable solvents consists of dialkyl ethers wherein each alkyl is independently a C1-C5 alkyl; Ci-5 alkyl C5.6 cycloalkyl ethers; C1-C5 alkanes substituted with two -O-C1-C4 alkyl groups which are the same or different; bis (Ci-4 alkoxy-Cl-5 alkyl)ethers; C4-C8 cyclic ethers and diethers in which the cyclic ring is optionally substituted with Cl -4 alkyl; phenyl Q-C4 alkyl ethers; phenyl C1-C4 alkyl thioethers; C2-C4 aliphatic nitriles; C7-C9 aromatic nitrites; tri-Ci-4 alkyl amines in which the alkyl groups are the same or different; C4.6 azacycloalkanes and diazacycloalkanes in which one of the ring carbons is optionally replaced with O or S and wherein each of the ring nitrogens is substituted with C 1.4 alkyl; N,N-di-Ci_4 alkyl C 1.4 alkylcarboxamides; tertiary C4-6 lactams; di-Cj-4 alkylsulfoxides; C4_g cyclic sulfones; N,N¹-di-Ci_4 alkyl-N,N'-(di- or tri- or tetra-methylene)ureas; hexa(Ci_4 alkyl)phosphoramides; Ci-5 alkyl acetates; Cl -.4 haloalkanes; and halogenated C7.9 aromatic hydrocarbons.

In one aspect, the solvent employed in Step G is diethyl ether, MTBE, DME, cyclopentyl methyl ether, bis(2-methoxyethyl)ether, THF, 2-methyl-THF, dioxolane, dioxane, anisole, thioanisole, acetonitrile, propionitrile, benzonitrile, o-tolunitrile, p-tolunitrile, triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, DMF, DMAc, NMP, DMSO, sulfotane, DMPU, HMPA₅ IPAc, dichloromethane, or trifluorotoluene. In a feature of this aspect, the solvent employed in Step G is acetonitrile, proprionitrile, MTBE, or anisole. In a feature of this aspect, solvent G is acetonitrile. In still another feature of this aspect, the solvent employed in Step G is a combination of acetonitrile and 2-methyl-THF. Compound VIII is treated in Step G with (i) phosphoric acid or a carboxylic acid selected from the group consisting of oxalic acid, acetic acid and haloacetic acids and with (ii) an organic sulfonic acid. The haloacetic acid is acetic acid in which the acetyl group is substituted with one or more halogens. A class of suitable acids for use in Step G includes phosphoric acid, oxalic acid, acetic acid, trichloroacetic acid, dichloroacetic acid, trifhioroacetic acid, and difluoroacelic acid. In one aspect of this class, the acid employed in Step G is a carboxylϊc acid. In a feature of this aspect, the carboxylic acid is dichloroacetic acid or trifluoroacetic acid. In another feature of this aspect, the acid is trifluoroacetic acid. In another aspect of this class, the acid is oxalic acid. In still another aspect of this class, the acid is phosphoric acid.

The organic sulfonic acid can be, for example, a Cj.6 alkanesulfonic acid, a C\.β haloalkanesulfonic acid, or a benzenesulfonic acid in which the benzene is optionally substituted with one of more substituents (e.g., from 1 to 3 substituents) each of which is independently C 1-6 alkyl, O-Ci-6 alkyl, or halogen. Suitable organic sulfonic acids include, for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, trifiuoromethanesulfonic acid, 1,1,2,2-tetrafluoroethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, and p-methoxybenzenesulfonic acid. In one aspect, the organic sulfonic acid is benzenesulfonic acid or toluenesulfonic acid. In a feature of this aspect, the organic sulfonic acid is benzenesulfonic acid. Compound VIII, carboxylic acid (or phosphoric acid), and organic sulfonic acid can be employed in any amounts which result in the formation of at least some sulfonate salt of Compound IX. Optimal conversion of Compound VIII and optimal formation of Compound IX salt are normally desired in Step G, and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed. The phosphoric acid or carboxylic acid (i.e., oxalic acid, acetic acid or a haloacetic acid) can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula VIII, is typically employed in an amount in a range of from about 2 to about 50 equivalents per equivalent of Compound VIII, and is more typically employed in an amount in a range of from about 10 to about 20 equivalents per equivalent of Compound VIII. In one aspect, the carboxylic acid is employedϊn an amount of from about 12 to about 18 equivalents (e.g., about 15 equivalents) per equivalent of Compound VIII. In another aspect, the phosphoric acid or carboxylic acid is employed in an amount of from about 6 to about 16 equivalents (e.g., either about 7 equivalents or about 15 equivalents) per equivalent of Compound VIII.

The organic sulfonic acid can. suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula VIII, is typically employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound VIII, and is more typically employed in an amount in a range of from about 4 to about 6 equivalents (e.g., about 5 equivalents) per equivalent of Compound VIII. Step G can be conducted at any temperature at which the reaction forming the Compound IX sulfonate salt can detectably proceed. The reaction can suitably be conducted at a temperature in a range of from about 2O⁰C to about 80⁰C and is typically conducted at a temperature in a range of from about 6O⁰C to about 80⁰C. In an aspect of the present invention, Step G is conducted at a temperature in a range of from about 65°C to about 75°C (e.g., at 7O⁰C). The reaction time for Step G can vary widely depending upon (i) the choice and relative proportions of Compound VIII, phosphoric acid or carboxylic acid (e.g., acetic acid or a haloacetic acid), and organic sulfonic acid, (U) the choice of solvent, (iii) the choice of reaction temperature, (iv) the overall scale of the reaction, (v) the level of conversion desired, and so forth. Nonetheless, the reaction can usually be completed (i.e., 100% conversion) in about 24 hours or less, and is typically complete in from about 12 hours or less, and is often complete in from about 1 to about 8 hours.

The order of addition of the reactants and reagents to the reaction vessel in Step G is not critical. Step G can be conducted, for example, in the following manner: Organic sulfonic acid and carboxylic acid (or phosphoric acid) are added concurrently or sequentially in either order to a reaction vessel containing Compound VIII dissolved in solvent G, and the mixture is brought (e.g., heated) to reaction temperature and aged at that temperature until the desired degree of conversion is achieved. Complete conversion of Compound VIII is typically desired. The reaction mixture is optionally but typically agitated (e.g., stirred) during addition of the reactants and reagents to the reaction vessel and during the subsequent ageing. The reaction is typically conducted under anhydrous conditions. Compound IX sulfonate salt formed in Step G can be recovered by conventional means. For example, Compound IX sulfonate salt can be recovered by cooling the reaction mixture, diluting the cooled mixture with water, ageing the resulting slurry, filtering, and washing and then drying the resulting wet cake. The dried salt can typically be purified further by re-crystallization.

Step H-I in Process R involves removal of the nitrogen protecting group pG2 from Compound VIII by contact with sulfuric acid in the presence of a Ci- 16 alkanethiol or benzenethiol to obtain a sulfate salt (e.g., a bis sulfate salt) of a compound of Formula VIII-A. A class of the suitable thiols consists of the C6-12 alkanethiols. In an aspect of this class, the thiol is octanethiol, decanethiol or dodecanethϊol. In another aspect of this class, the alkanethiol is octanethiol.

Step H-I is conducted in organic solvent Hl, which can be, for example, a dialkyl ether, a dialkoxyalkane, a bis(alkoxyalkyl)ether, a cyclic ether or diether, a phenyl alkyl ether, a phenyl alkyl thioether, or an aliphatic nitrile. A class of suitable solvents consists of dialkyl ethers wherein each alkyl is independently a Ci -C5 alkyl; Cl-5 alkyl C5-6 cycloalkyl ethers; C1-C5 alkanes substituted with two -O-C 1-C4 alkyl groups which are the same or different; bis (Ci-4 alkoxy-Cl-5 alkyl)ethers; C4-CS cyclic ethers and diethers in which the cyclic ring is optionally substituted with Cl .4 alkyl; phenyl C1-C4 alkyl ethers; and C2-C4 aliphatic nitriles. In one aspect, the solvent employed in Step H-I is diethyl ether, MTBE, DME, cyclopentyl methyl ether, bis(2-methoxyethyl)ether, THF, 2-methyl-THF, dioxolane, dioxane, anisole, acetonitrile, or propionitrile. In a feature of this aspect, the solvent employed in Step H-I is acetonitrile, proprionitrile, MTBE, or anisole. In a feature of this aspect, solvent Hl is acetonitrile. Compound VIII, sulfuric acid and thiol (i.e., alkanethiol or benzenethiol) can be employed in any amounts which result in the formation of at least some sulfate salt of Compound VIII-A. Optimal conversion of Compound VIII and optimal formation of Compound VIII-A salt are normally desired in Step H-I, and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed. Sulfuric acid can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula VIII, is typically employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound VIII, and is more typically employed in an amount in a range of from about 1.5 to 3 equivalents per equivalent of Compound VIII. In one aspect, sulfuric acid is employed in an amount of from about 2 to 2.5 equivalents (e.g., about 2.2 equivalents) per equivalent of Compound VIII. The alkanethiol or benzene thiol can suitably be employed in an amount at least equivalent to the amount of sulfuric acid. The ratio of equivalents of the thiol to equivalents of sulfuric acid is typically in a range of from about 0.9:1 to about 1.1:1 and is more typically about 1:1. Step H-I can be conducted at any temperature at which the reaction forming the

Compound VIII-A sulfate salt can detectably proceed. The reaction can suitably be conducted at a temperature in a range of from about 10⁰C to about 4O⁰C and is typically conducted at a temperature in a range of from about 15°C to about 30⁰C. In an aspect of the present invention, Step G is conducted at a temperature in a range of from about 15⁰C to about 25°C. The reaction time for Step H-I can vary widely depending upon (i) the choice of

Compound VIII, (ii) the choice of thiol, (iii) the relative proportions of Compound VIII, sulfuric acid, and thiol, (iv) the choice of solvent, (v) the choice of reaction temperature, (vi) the overall scale of the reaction, (vii) the level of conversion desired, and so forth. Nonetheless, the reaction can usually be completed (i.e., 100% conversion) in about 24 hours or less, and is typically complete in from about 12 hours or less, and is often complete in from about 1 to about 8 hours.

The order of addition of the reactants and reagents to the reaction vessel in Step H-I is not critical. Step H-I can be conducted, for example, in the following manner: The thiol (e.g., an alkanethiol such as octanethiol or dodecanethiol) is added to a reaction vessel containing Compound VIII dissolved in solvent Hl (e.g., acetonitrile), followed by the addition of the sulfuric acid. The reaction mixture is brought to reaction temperature (note: heat generated during the addition of sulfuric acid can by itself raise the temperature of the mixture to the desired reaction temperature and/or can require cooling to maintain the mixture at the desired temperature) and aged at that temperature until the desired degree of conversion is achieved. Complete conversion of Compound VIII is typically desired. The reaction mixture is optionally but typically agitated (e.g., stirred) during addition of the reactants and reagents to the reaction vessel and during the subsequent ageing. Compound VIII-A sulfate salt formed in Step H-I can be recovered by conventional means. For example, the sulfate salt can be recovered by adding one or more anti-solvents to form a slurry of the crystalline the salt, filtering the slurry to provide a wet cake, and then washing and drying the wet cake.

Step H-2 in Process R involves removal of Rl from Compound VIII-A by treatment with sulfuric acid Io obtain a sulfate salt of a compound of Formula IX. The sulfuric acid employed in Step H-2 is typically concentrated sulfuric acid. Step H-2 is conducted in organic solvent H2, which can be suitably and independently selected from any of the solvents suitable for use as organic solvent Hl . In other words, it is understood that solvent H2 independently has a general description, classes, aspects and features corresponding to those set forth above for Solvent Hl and that solvent H2 can independently be selected from among the solvents described above as suitable for use as Solvent Hl . In a separate aspect, solvent H2 is an aliphatic nitrile such as acetonitrile or propionitrile. In a feature of this aspect solvent H2 is acelonitrile.

Step H-2 is preferably conducted in the presence of water, wherein the amount of water employed is less than about 10 volume percent based on the total volumes of water and solvent H2 being employed. In one embodiment, Step H-2 is conducted using acetonitrile and water. In an aspect of this embodiment, the amount of water employed is no more than about 7 vol.%, is typically in a range of from about 2 to about 6 vol.%, and is more typically in a range of from about 3 to about 5 vol.% (e.g., about 4 vol.%).

Step H-2 can be conducted at any temperature at which the reaction forming the Compound IX sulfonate salt can detectably proceed. The reaction can suitably be conducted at a temperature in a range of from about 20°C to about 9O⁰C and is typically conducted at a temperature in a range of from about 50⁰C to about 80⁰C. In an aspect of the present invention, Step H-2 is conducted at a temperature in a range of from about 65⁰C to about 75⁰C (e.g., at about 70⁰C). Compound VIII-A and sulfuric acid can be employed in any amounts which result in the formation of at least some sulfate salt of Compound IX. Optimal conversion of Compound VIII-A and optimal formation of Compound IX sulfate salt are normally desired in Step H-2, and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed. Sulfuric acid can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula VIII-A, is typically employed in an amount in a range of from about 2 to about 20 equivalents per equivalent of Compound VIII-A, and is more typically employed in an amount in a range of from about 3 to about 12 equivalents per equivalent of Compound VIII-A. In one aspect, sulfuric acid is employed in an amount of from about 5 to about 10 equivalents (e.g., about 7 eqmvalents) per equivalent of Compound VIII-A.

The reaction time for Step H-2 can vary widely depending upon (i) the choice of Compound VIII-A. (ii) the relative proportions of Compound VIII-A and sulfuric acid, (in) the choice of solvent, (iv) the choice of reaction temperature, (v) the overall scale of the reaction, (vi) the level of conversion desired, and so forth. Nonetheless, the reaction can usually be completed (i.e., 100% conversion) in about 12 hours or less, and is typically complete in from about 2 to about 8 hours.

The order of addition of the reactants and reagents to the reaction vessel in Step H-2 is not critical. Step H-2 can be conducted, for example, in the following manner:

Concentrated sulfuric acid is added to a reaction vessel containing a solution of Compound VIII-A in solvent H2 (e.g., acetonitrile) and optionally water, and the resulting reaction mixture is brought to and maintained at the chosen reaction temperature until the desired degree of conversion is achieved. Complete conversion is typically desired. The reaction mixture is optionally but typically agitated (e.g., stirred) during addition of the sulfuric acid and during the subsequent reaction. Compound VIII sulfate salt formed in Step H-2 can be recovered by conventional means. For example, the sulfate salt can be recovered by cooling the reaction mixture to ambient temperature, diluting the mixture with water, ageing the resulting slurry, filtering the slurry, and then washing and drying the resulting wet cake. Step K in Process S involves removal of Rl and the nitrogen protecting group pG2 from Compound VIII by treatment with sulfuric acid to obtain a sulfate salt of a compound of Formula IX. Step K is generally conducted using solvents, reaction conditions, and amounts of reactants analogous to those described above for Step H-2. Thus, for example, Step K is conducted in organic solvent K optionally in the presence of a small amount of water, wherein solvent K is suitably and independently selected from any of the solvents suitable for use as organic solvent H2 (e.g., acetonitrile optionally in combination with a small amount — 2 to about 6 vol.% — of water); and Step K is conducted using amounts of sulfuric acid and at reaction temperatures as described above for Step H-2, Ln other words, the description provided above for the conduct of Step H-2 applies equally to Step K. The present invention also includes a process for preparing a compound of

Formula VIII or a sulfonate salt of Compound IX or a sulfate salt of Compound IX which comprises Process P or Process Q or Process R or Process S as described above, and which further comprises:

(E) contacting a compound of Formula V :

with an L^-producing agent to obtain a compound of Formula VI.

Step E is directed to the activation of the pyrazolopyridine methanol of Formula V. It is understood that Embodiments El to El 6 directed to LG, pG2, RI _; R3 , R4_S R5, R6 and I*? and variables incorporated therein (e.g., R2, RA_? RB_? RC_; etc.) also apply to the process comprising Steps E and F, the process comprising Steps E, F and G, the process comprising Steps E, F, H-I and H-2, and the process comprising Steps E, F and K. It is also understood that Step E is conducted prior to Step F; i.e., the order of the steps in these processes is Step E, followed by Step F, and then, optionally, either Step G or Steps H- 1 and H-2 or Step K.

Step E is conducted in organic solvent E which is an aprotic solvent. The aprotic solvent can be, for example, a haloalkane, a dialkyl ether, a dialkoxyalkane, a bis(alkoxyalkyl)ether, a cyclic ether or diether, an aliphatic nitrile, an aromatic nitrile, a tertiary carboxylic amide, a carboxylic ester, an aromatic hydrocarbon, or a halogenated aromatic hydrocarbon. A class of suitable aprotic solvents consists of C1-C4 haloaϊkanes; dialkyl ethers wherein each alkyl is independently a Q-C4 alkyl; C1-C4 alkanes substituted with two -O-C1-C4 alkyl groups which are the same or different; his (C}_4 alkoxy-Ci-4 alkyl)ethers; C4-C8 cyclic ethers and diethers in which the cyclic ring is optionally substituted with Cl .4 alkyl; C2-C4 aliphatic nitriles; C7-C9 aromatic nitriles; N,N-di-Ci-4 alkyl Q-4 alkylcarboxamides; tertiary C4.6 lactams; Ci .4 alkyl C 1.4 alkylcarboxylates; Cγ.α aromatic hydrocarbons; and mono-, di- and tri-halobenzenes. In one aspect, the organic solvent employed in Step E is methylene chloride, diethyl ether, MTBE, DME, bis(2-methoxyethyl)ether, THF, 2-methyI-THF, dioxolane, dioxane, acetonitrile, propionitrile, benzonitrile, o-tolunitrile.. p-tolunitrile, DMF, DMAc, NMP, EtOAc, IPAc, toluene, xylenes (i.e., 0-, m-, and p-xylene individually or in mixtures), or chlorobenzene. In a feature of this aspect, the solvent employed in Step E is methylene chloride, acetonitrile, DMF, THF, 2-methyl-THF, MTBE, NMP₅ EtOAc, IPAc, or toluene.

The LG-producing agent can be any agent which under the conditions of Step E will result in the placement of a leaving group LG at the hydroxymethyl position of pyrazolopyridine V. Suitable LG-producing agents include the hydrogen halides to provide LG = halogen, sulfonyl halides for LG = sulfonate, sulfinyl halides for LG = sulfonates, phosphonyl halides for LG = phosphonates, phosphinyl halides for L^ = phosphinates, and cyanides for LG = imidates. A class of suitable LG-producing agents consists of R2-S(O)2Z, R2-S(O)Z, (R2)2-P(O)Z, R2-P(O)(OH)Z, and R2-CN, wherein Z is halogen, to provide the leaving groups -OS(=O)2R2, -OS(=O)R2, -OP(=O)(R2)2, -OP(=O)(OH)R2_S and -0C(=NH)R2 respectively. In one aspect, the LG is -OS(=O)2R², and the corresponding LG-producing agent is R2-S(O)2Z. In a feature of this aspect, R2 is CH3, CF3, or phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl₉ Br₅ F, CH3, OCH3, CF3, or OCF3. In another feature of this aspect, the LG-producing agent is methanesulfonyl halide, trifiuoromethanesulfonyl halide, p-toluenesulfonyl halide, benzenesulfonyl halide, or p-methoxybenzenesulfonyl halide. Yet another feature of this aspect is identical to the preceding feature, except that the sulfonyl halides are restricted to sulfonyl chlorides, In another aspect, LG is -OC(HNH)R2 and the corresponding LG-producing agent is R.2-CN. In a feature of this aspect, R.2 is Q-4 alkyl or Q-4 haloalkyl. In another feature of this aspect, LG is -OC(=NH)CCl3 and the corresponding LG-producing agent is CI3C-CR

When the LG-producing agent is a sulfonate, sulfonate, phosphonate, or phosphinate, Compound V is typically contacted with the LG-producing agent in the presence of a base (referred to herein as base E). Base E can be any base capable of neutralizing acid by-product resulting from the reaction. The base can be, for example, a metal hydroxide, a metal carbonate, a metal bicarbonate, a tertiary amine, or a pyridine. A class of suitable bases consists of alkali metal hydroxides and tertiary amines. A sub-class of suitable bases consists of tri-Ci_4 alkyl amines and C4-6 azacycloalkanes and diazacycloalkanes in which one of the ring carbons is optionally replaced with O or S and wherein each of the ring nitrogens is substituted with Cl -4 alkyl. In one aspect the base is LiOH, KOH, NaOH, cesium carbonate, Na carbonate, K carbonate, NMM, NEM, TEA, DIPEA, DABCO, pyridine or collidine. In a feature of this aspect, the base employed in Step E is NMM₁ NEM, TEA, DIPEA, DABCO, Na carbonate, or K carbonate. In another feature of this aspect, the base is DIPEA.

When the LG-producing agent is an imidate, Compound V is typically contacted with the LG-producing agent in the presence of an acid (referred to herein as acid E). Acid E can be a Lewis acid such as a BF3-Et2θ complex.

Compound V, the LG-producing agent, and, depending on the choice of LG-producing agent, acid E or base E can be employed in any amounts which result in the formation of at least some of Compound VL Optimal conversion of Compound V and optimal formation of Compound VI are normally desired in Step E₅ and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed. LG-producing agent can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 0.95 equivalent, or at least about 1 equivalent) per equivalent of the compound of Formula V, is typically employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound V, and is more typically employed in an amount in a range of from about 1 to about 2 equivalents per equivalent of Compound V. In one aspect, LG-producing agent is employed in an amount in a range of from about 1 to about 1.5 equivalents per equivalent of Compound V. In another aspect, agent LG-producing agent is employed in an amount in a range of from about 1 to about 1.2 equivalents per equivalent of Compound V.

Base E can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 1 equivalent) per equivalent of the compound of Formula V, is typically employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound V, and is more typically employed in an amount in a range of from about 1 to about 2 equivalents per equivalent of Compound V. In one aspect, the base is employed in an amount in a range of from about 1 to about 1.5 equivalents per equivalent of Compound V. In another aspect, the base is employed in an amount in a range of from about 1 to about 1.2 equivalents per equivalent of Compound V.

Acid E is typically employed in a catalytic amount. Acid E can be employed, for example,, in an amount in a range of from about 0.01 to about 0.2 equivalents per equivalent of Compound V.

Step E can be conducted at any temperature at which the reaction forming Compound VI can detectably proceed. In one embodiment, the reaction can suitably be conducted at a temperature in a range of from about -20°C to about 40⁰C and is typically conducted at a temperature in a range of from about -5⁰C to about 10⁰C. In an aspect of this embodiment, Step E is conducted at a temperature in a range of from about O⁰C to about 8⁰C. In another embodiment, the reaction can suitably be conducted with the temperature profile described in the next paragraph.

Compounds of Formula VI having LG = halogen can also be obtained by using a sulfonyl halide as the lA-producing agent as follows: The sulfonyl halide (e.g., mesyl chloride) is initally reacted with Compound V in the presence of base (e.g., a trialkyl amine such as Hunig's base) at a relatively low temperature (e.g., less than about 3O⁰C such as in a range of from about 15°C to about 3O⁰C) and then reacted at an elevated temperature (e.g., from about 40⁰C to about 70⁰C) for a time and in an amount (e.g., at least about 1 equivalent of the sulfonyl halide per equivalent of Compound V) sufficient to obtain Compound VI with LG = halogen. Without wishing to be bound by any particular theory, it is believed that the Compound VI mesylate forms initially and then converts quantitatively to the Compound VI halide under the specified reaction conditions.

The reaction time for Step E can vary widely depending upon (i) the choice and relative proportions of Compound V, LG-producing agent and base, (ii) the choice of solvent, (iii) the choice of reaction temperature, (iv) the scale of the reaction, (v) the level of conversion desired, and so forth. Nonetheless, the reaction can usually be completed (i.e., 100% conversion) in about 24 hours or less (e.g., about 12 hours or less), and is typically complete in about 8 hours or less, and is often complete in about 4 hours or less (e.g., in from about 0.1 to about 2 hours). The order of addition of the reactants and reagents to the reaction vessel in Step E is not critical. Step E can be conducted, for example, in the following manner: Compound V and solvent E are charged to a reaction vessel and brought (e.g., cooled) to reaction temperature, after which base E (or acid E) is added. A suitable LG-producing agent is then added while maintaining the mixture at reaction temperature (e.g., added slowly to avoid an increase in temperature due to exothermic effects), and the reaction mixture is then aged at the reaction temperature until the desired degree of conversion is achieved. Complete conversion of Compound V is typically desired. The Step E reaction mixture is optionally but typically agitated (e.g., stirred) during addition of the reactants and reagents to the reaction vessel and during any subsequent ageing. Compound VI formed in Step E can be recovered as a solid or a solution by conventional means for use in Step F. For example, the aged reaction mixture can be filtered and the filtered solution concentrated to precipitate Compound VI which can be recovered by filtration or the filtered solution can be solvent switched to provide a solution for use in Step F.

The present invention also includes a process for preparing a compound of Formula VIII or a sulfonate salt of Compound IX or a sulfate salt of Compound IX which comprises Process P or Process Q or Process R or Process S as described above, Step E as described above, and which further comprises:

(D) contacting a compound of Formula IV :

with a source of hydrogen in the presence of a hydrogenoly sis catalyst to obtain the compound of Formula V; wherein PGI is a hydroxy protective group capable of being cleaved by hydrogenolysis.

Step D is directed to the removal of the hydroxy protective group pGl from Compound IV to provide Compound V containing the hydroxymethyl group. It is understood that Embodiments El to E16 directed to LG₅ PG2_; Rl₅ R3_; R4_? R5_f R6 and R7 and variables incorporated therein (e.g., R^, RA₅ RB_? RC_? etc.) also apply to the process comprising Steps D, E and F₅ the process composing Steps D, E, F and G₅ the process comprising Steps D, E, F, H-I and H-2, and the process comprising Steps D, E, F and K. It is also understood that Step D is conducted prior to Step E.

Hydroxy protective groups capable of being cleaved by hydrogenolysis are well known in the art and include, for example, those described in Greene and Wuts, Protective Groups in Organic Synthesis, 3d edition, (Wiley-Interscience_? 1999), pp. 10-86 (herein incorporated by reference in its entirety); and in McOmie, Protective Groups in Organic Synthesis (Plenum, 1973), pp. 95-120 (herein incorporated by reference in its entirety). The hydroxy protective group PGI can be, for example, (i) phenyl, (ii) benzyl, (iii) diphenylmethyl, (iv) triphenylmethyl, or (v) THP₅ wherein each of the one or more phenyl groups in (i), (ii), (iii) and (iv) is optionally and independently substituted with one or more substituents (e.g., from 1 to 3 substituents, or from 1 to 2 substituents) each of which is independently halogen, nitro, Ci -6 alkyl, or O-Cμ6 alkyl. In one aspect, the hydroxy protective group is phenyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, phenyl, or THP. In another aspect, the hydroxy protective group is benzyl, ρ-nitrobenzyl_? or p-methoxybenzyl. In a feature of this aspect, the hydroxy protective group is benzyl. Step D is conducted in organic solvent D. Solvent D can be, for example, a carboxylic ester, an alcohol, an alcohol- water mixture, or an alcohol-water-carboxylic ester mixture. A class of suitable solvents consists of C 1-4 alkyl esters of C1-C4 alkylcarboxylic acids, C i_4 alkyl alcohols, mixtures of a C 1.4 alkyl alcohol with water, and mixtures of a C 1-4 alkyl alcohol and a Cl -4 alkyl Cl -4 alkylcarboxylate and water. In one aspect, the solvent employed in Step D is ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, n-propaxtol, isobutanol, methanol-water, ethanol- water, methanol-ethyϊ acetate- water, or methanol-isopropyl acetate-water. In a feature of this aspect, the solvent is ethanol, ethyl acetate, or isopropyl acetate. In another feature of this aspect, the solvent is ethanol. The hydrogenolysis of Compound IV in Step D can be conducted at any temperature at which the reaction (deprotection of the hydroxy group) forming Compound V can detectably proceed. The reaction can suitably be conducted at a temperature in a range of from about 0⁰C to about 6O⁰C and is typically conducted at a temperature in a range of from about 10⁰C to about 30⁰C. In one aspect, the hydrogenolysis is conducted at a temperature in a range of from about 15°C to about 25⁰C.

The hydrogen source is typically hydrogen gas, optionally in admixture with a carrier gas that is chemically inert under the reaction conditions employed in Step D (e.g., nitrogen or a noble gas such as helium or argon). The pressure is not a critical aspect in Step D, although atmospheric and superatmospheric pressures tend to be expedient. The pressure ■ typically is at least about 2 psig (about 115 kPa). In one aspect of Step D, the pressure is in a range of from about 2 psig to about 40 psig (about 115 kPa to about 377 kPa). In another aspect, the presuure is in a range of from about 10 psig to about 30 psig (about 170 kPa to about 308 kPa).

The hydrogen source can alternatively be a hydrogen-transfer molecule such as ammonium formate, cyclohexene, or cyclohexadiene.

The uptake of hydrogen is not a critical process parameter, although at least a stoichiometric amount of hydrogen gas or other hydrogen source is typically employed.

The hydrogenolysis catalyst comprises a supported or unsupported Group 8 metal or a supported or unsupported compound, salt or complex of a Group 8 metal. The catalyst typically employed in Step D is supported or unsupported Pd metal or a supported or unsupported Pd compound, salt or complex. Suitable catalyst supports include carbon, silica, alumina, silicon carbide, aluminum fluoride, and calcium fluoride. In an aspect of Step D, the catalyst is Pd black (i.e., fine metallic palladium particles), Pd(OH)2, or Pd/C (i.e., palladium on a carbon support). In another aspect, the catalyst is Pd/C. The hydrogenolysis catalyst can be employed in any amount that allows the reaction to proceed under less extreme conditions and/or in a shorter time compared to the reaction conditions and/or reaction time in the absence of the catalyst. The hydrogenolysis catalyst can suitably be employed in Step D in an amount of at least about 0.01 wt.% relative to the weight of Compound IV, is typically employed in an amount in a range of from about 0.01 wt.% to about 100 wt. % relative to the weight of Compound IV. In one aspect of Step D, the catalyst is employed in an amount in a range of from about 0.2 wt.% to about 5 wt.%. In another aspect of Step D, the catalyst is employed in an amount in a range of from about 1 wt.% to about 3 wt.%.

The hydrogenation can be carried out in batches or continuously in various types of reactors such as a fixed bed reactor or an agitated slurry reactor in which the slurry of gas, solvent, Compound IV, and catalyst is continuously agitated by mechanical or gas means. A suitable reaction vessel for relatively small scale, batch- wise hydrogenations is an autoclave equipped with a stirrer or rocker to agitate the reaction mixture. In a batch process, the order of addition of Compound IV, catalyst, and solvent to the reaction vessel is not critical. As an example, Compound IV pre-mixed with solvent can be charged to the reaction vessel followed by the addition of catalyst. The hydrogenolysis can then be conducted by charging hydrogen gas, optionally in admixture with one or more inert gases, to the vessel and then agitating the mixture under reaction conditions until the desired degree of conversion is achieved.

The present invention also includes a process for preparing a compound of Formula VΪII or a sulfonate salt of Compound IX or a sulfate salt of Compound IX which comprises Process P or Process Q or Process R or Process S as described above, Steps D and E as described above, and which further comprises: (C) contacting a compound of Formula III:

with a pG2-producing agent to obtain the compound of Formula IV.

Step C is directed to protecting the pyrazolyl nitrogen in Compound III to provide Compound IV. It is understood that Embodiments El to E16 directed to LG₅ pG2_f Rl_; R3_; R4_? R.5, Ho and R7 and variables incorporated therein (e.g., R2, RA₅ RB₅ RC_; etc.) also apply to the process comprising Steps C, D, E and F, the process comprising Steps C, D, E, F and G, the process comprising Steps C, D, E, F, H-I and H-2, and the process comprising Steps C, D, E, F and K. It is also understood that Step C is conducted prior to Step D.

Step C is conducted in organic solvent C which is an aprotic solvent. Solvents suitable for use as solvent C include those described above as being suitable for use as organic solvent E in Step E. In other words, it is understood that solvent C independently has a general description, classes, aspects and features corresponding to those set forth above for Solvent E and that solvent C can independently be selected from among the solvents described above as suitable for use as Solvent E. In a separate aspect, the solvent C is 2-methyl-THF, DME, IPAc, chlorobenzene, xylenes (individual isomers or mixtures thereof), or toluene. In a feature of this aspect, solvent C is toluene.

The pG2-producing agent can be any agent which under the conditions of Step C will result in the attachment of the group PG2 to the pyrazolyl nitrogen. Suitable pG2.^.producing agents include dialkyl carbonates; alkyloxycarbonyl halides; alkoxycarbonyloxyiraino-substituted nitriles; dihydropyrans; dihydrofurans; ketals; alkoxyalkenes; and alkoxy substituted cycloalkenes, oxacycloalkenes, thiacycloalkenes, and azacycloalkenes. A class of suitable pG2-p_roducing agents consists of:

( 1 ) C 1-6 alkyl-O-C(O)-Q, wherein Q is halogen, OC(OP-C i -6 alkyl, or

(2) 3,4-dihydro-2H-pyran,

(3) 2,3-dihydrofuran, R^CO^ .OR^C

(4) R R _? wherein RA, RB and RC are as previously defined,

OR^C

(5) ^ , wherein (i) RA and RC are each independently a C \ .4 alkyl, and R.B' is H or C 1 -3 alkyl, or (ii) alternatively RC is C ] -.4 alkyl and

RA and RB¹ together with the carbon atoms to which each is attached form C5-6 cycloaJkenyl, C4.5 oxacycloalkenyl, C4-.5 thiacycloalkenyl, or C4-5 azacycloalkenyl in which the aza nitrogen is substituted with Ci .4 alkyl, and

(6)

wherein RJ, RK and RL are as previously defined, and RM is C 1-4 alkyl.

pG2.producirig agents of group (5) form PG2 groups of formula R ^*X R^ORC in which RB is restricted to CH2-RB', or alternatively they form ring-containing pG2 groups such as those of

formula

wherein W is CH2, O, S, or N-C1.4 alkyl. pG2.p_roducing agents of group

(6) form PG2 groups of formula ^{R R}

Another class of suitable pG2^.p_roducing agents consists of:

( 1 ) t-butyloxycarbonyl halide,

(2) di-t-butyl carbonate,

(3) Boc-ON (4) 3 ,4-dihydro-2H-pyran,

(5) 2,3-dihydrofuran,

H₃CO OCH₃ /N

H3C CH3

(6)

Stiϊl another class of suitable PG2_p_roducing agents consists of di-t-butyl carbonate; t-butyloxycarbonyl halide (e.g., chloride); Boc-ON; 3,4-dihydro-2H-pyran; and 2,3-dihydrofuran. In one aspect, the pG2-producing agent is di-t-butyl carbonate; t-butyloxycarbonyl chloride; Boc-ON; 3,4-dihydro-2H-pyran; or 2,3-dihydrofuran. In another aspect, the pG2_p_roducing agent is 3,4-dihydro-2H-pyran.

When the pG2-producing agent is a dihydropyran, dihydrofuran, ketal, alkoxyalkene, or an alkoxy substituted cycloalkene or heterocycloalkene, Compound III is typically contacted with the pG2_p_rocj_ucmg agent in the presence of an acid (referred to herein as acid C). Acid C can be an organic sulfonic acid, which is optionally in the form of a pyridiniυm salt_f or an inorganic acid. The organic sulfonic acid can be, for example, a Ci -6 alkanesulfonic acid, a Ci -6 haloalkanesulfonic acid, or a benzenesulfonic acid in which the benzene is optionally substituted with one of more substituents (e.g., from 1 to 3 substituents) each of which is independently C 1-6 alkyl, O-Cμg alkyl, or halogen. The inorganic acid can be, for example, sulfuric acid or hydrochloric acid. In one class, acid C is methanesulfonic acid; ethanesulfonic acid; propanesulfonic acid; trifluoromethanesulfonic acid; 1,1,2,2-tetrafluoroethanesulfonic acid; benzenesulfonic acid; p-toluenesulfonic acid; p-chlorobenzenesulfonϊc acid; or p-methoxybenzenesulfonic acid; or is a pyridinium salt of any of the foregoing acids. In another class, acid C is methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-tolueπesulfonic acid, sulfuric acid, and hydrochloric acid, wherein each of the sulfonic acids is optionally in the form of a pyridinium salt. In an aspect, acid C is methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridinium methanesulfonate, pyridinium trifluoromethanesulfonate, pyridinium benzenesulfonate, or pyridinium p-toluenesulfonate. In another aspect, acid C is benzenesulfonic acid, pyridinium benzenesulfonate,, p-toluenesulfonic acid, or pyridinium p-toluenesulfonate. In a feature of this aspect, acid C is pyridinium p-toluenesulfonate.

When the pG2_producing agent is an alkyloxycarbonyl halide, a dialkylcarbonate, or an alkoxycarbonyloxyiinino-substituted nltrile (e.g., Boc-ON), Compound III is typically contacted with the pG2.p_roducing agent in the presence of a base (referred to herein as base C). Base C can be, for example, a tertiary amine, a metal carbonate, pyridine, or DMAP. Suitable bases include TEA, DIPEA, Na carbonate, K carbonate, and Cs carbonate.

Compound III, pG2_p_roducing agent and, depending on the choice of pG2.p_roducing agent, acid C or base C can be employed in any amounts which result in the formation of at least some of Compound IV. Optimal conversion of Compound III and optimal formation of Compound IV are normally desired in Step C, and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed. pG2.p_roducing agent can suitably be employed in an amount of at least about 0.5 equivalent (e.g., at least about 0.95 equivalent, or at least about 1 equivalent) per equivalent of the compound of Formula III, is typically employed in an amount in a range of from about 0.5 to about 10 equivalents per equivalent of Compound IH₅ and is more typically employed in an amount in a range of from about 2 to about 10 equivalents per equivalent of Compound HI. In one aspect, pG2-producing agent is employed in an amount in a range of from about 3 to about 8 equivalents (e.g., about 5 equivalents) per equivalent of Compound HI. When acid C is employed, it is typically used in a catalytic amount, which means any amount that allows the reaction to proceed under less extreme conditions and/or in a shorter time compared to the reaction conditions and/or reaction time in the absence of acid C. Acid C can be employed, for example, in Step C in an amount in a range of from about 0.01 equivalent to about 1 equivalent per equivalent of Compound III. In one aspect of Step C, the catalyst is employed in an amount in a range of from about 0.02 to about 0.1 equivalent (e.g., about 0.05 equivalent) per equivalent of Compound III.

When base C is employed, it is suitably employed in Step C in an amount in a range of from about 0.9 equivalent to about 3 equivalents per equivalent of Compound III. In one aspect of Step C, the base is employed in an amount in a range of from about 1 to about 1.5 equivalents (e.g., about 1.2 equivalents) per equivalent of Compound III.

Step C can be conducted at any temperature at which the reaction forming Compound IV can detectably proceed. The reaction can suitably be conducted at a temperature in a range of from about 40⁰C to about 11O⁰C (e.g., from about 7O⁰C to about 110⁰C) and is typically conducted at a temperature in a range of from about 75⁰C to about 95°C. In one aspect, the reaction is conducted at a temperature in a range of from about 8O⁰C to about 85⁰C.

The reaction time for Step C can vary widely depending upon (i) the choice and relative proportions of Compound III, pG2-ρroducing agent, and acid C or base C, (ii) the choice of solvent, (iii) the choice of reaction temperature, (iv) the scale of the reaction, (v) the level of conversion desired, and so forth. Nonetheless, the reaction can usually be completed (i.e., 100% conversion) in about 36 hours or less (e.g., about 24 hours or less), and is typically complete in about 12 to about 24 hours.

The order of addition of the reactants and reagents to the reaction vessel in Step C is not critical. Step C can be conducted, for example, in the following manner: Compound III in solvent C₅ then pG2_p_roducing agent and then (depending on the choice of pG2-p_roducϊng agent) acid C or base C are sequentially charged to the reaction vessel and the resulting mixture is brought (e.g., heated) to reaction temperature and maintained at that temperature until the desired degree of conversion is achieved. Complete conversion of Compound III is typically desired. The Step C reaction mixture is optionally but typically agitated (e.g.₅ stirred) during addition of the reactants and reagents to the reaction vessel and during the subsequent reaction. Compound IV formed in Step C can be recovered as a solid or a solution by conventional means for use in Step D. For example, the reaction mixture can be cooled and washed, and the washed organic layer concentrated using heat and/or vacuum. Compound IV can be precipitated from the concentrated solution, or the solution can be solvent switched and precipitated/crystallized from the switched solution.

The present invention also includes a process for preparing a compound of Formula VIII or a sulfonate salt of Compound IX or a sulfate salt of Compound ΪX which comprises Process P or Process Q or Process R or Process S as described above, Steps C, D and E as described above, and which further comprises:

(A) contacting a compound of Formula I:

with an amine of Formula RΪ-NH2 to obtain a compound of Formula II:

(B) contacting the compound of Formula II with a source of hydrazine to obtain the compound of Formula III.

Steps A and B are directed to the animation of a difluoropyridine and treating the aminated fluoropyridine with hydrazine to form bicyclic Compound III. It is understood that Embodiments El to E16 directed to LG pG2₅ Rl, R3_} R4, R5, R6 and R? and variables incorporated therein (e.g., R^₅ RA₁ RB_; RC_{5 e}tc.) also apply to the process comprising Steps A, B, C, D, E and F, the process comprising Steps A, B, C, D, E, F and G, the process comprising Steps A₅ B₅ C₅ D, E, F, H-I and H-2, and the process comprising Steps A, B, C₅ D. E, F and K.

A suitable route for the preparation of compounds of Formula I from 2,6- difluoropyridine is shown in Examples 1 and 2 below. 2,6-Difluoropyridine is available commercially or it can be prepared by methods known in the art, such as those described in US 4031100; US 4071521; Hamer et al., Recueil des Travaux Chim. des Pays-Base 1962, 8j_: 1058-60; Boudakian et al., J. Het Chetn. 1968, 5: 683-4; and Lui et al., Spectrochimica Acta, 34A: 583-87.

Steps A and B are respectively conducted in organic solvent A and organic solvent B. Organic solvents A and B are both polar solvents, and they can be the same solvent or different solvents. Solvents suitable for use as solvent A or solvent B include those described above as being suitable for use as organic solvent F in Step F. In other words, it is understood that solvent A and solvent B each independently has a general description, classes, aspects and features corresponding to those set forth above for Solvent F and that solvent A and solvent B can each independently be selected from among the solvents described above as suitable for use as Solvent F. In a separate aspect, solvent A and solvent B are the same and are both NMP, DMAc, DMF₅ DMSO, acetonltrile, isopropanol, methanol, or ethanol. In a feature of this aspect, solvent A and solvent B are both NMP, DMAc, DMF, or DMSO. In another feature of this aspect, solvent A and solvent B are both NMP. The source of hydrazine employed in Step B can suitably be hydrazine hydrate or a hydrazinium salt. Hydrazine hydrate is typically employed as the hydrazine source in Step B.

The reactants and reagents respectively employed in Steps A and B can be employed in any amounts which result in the formation of at least some of Compound III. Optimal conversion of Compounds I and II and optimal formation of Compound III are normally desired in Steps A and B, and thus the relative proportions of reactants and reagents suitable for this purpose are typically employed In Step A, amine R1-NH2 can suitably be employed in an amount of at least about 0.5 equivalent (e.g., at least about 0.95 equivalent, or at least about 1 equivalent) per equivalent of the compound of Formula I, is typically employed in an amount in a range of from about 0.5 to about 20 equivalents per equivalent of Compound I, and is more typically employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound I. In one aspect, amine R.I-NH2 is employed in an amount in a range of from about 3 to about 5 equivalents per equivalent of Compound I.

In Step B, the hydrazine source can suitably be employed in an amount of at least about 0.9 equivalent (e.g., at least about 0.95 equivalent, or at least about 1 equivalent) per equivalent of the compound of Formula II, is typically employed in an amount in a range of from about 1 to about IO equivalents per equivalent of Compound II, and is more typically employed in an amount in a range of from about 2 to about 5 equivalents per equivalent of Compound II.

Steps A and B can each be conducted at any temperature at which their respective reactions can detectably proceed. The reaction in Step A can suitably be conducted at a temperature in a range of from about -3O⁰C to about 50⁰C and is typically conducted at a temperature in a range of from about -15⁰C to about 5°C. The reaction in Step B can suitably be conducted at a temperature in a range of from about -10⁰C to about 100⁰C and is typically conducted at a temperature in a range of from about 0°C to about 3O⁰C. In one aspect, the reaction temperature employed in Step B is initially in a range of from about O⁰C to about 1O⁰C and then is raised to a range of from about 20⁰C to about 3O⁰C.

The reaction times for Steps A and B can vary widely depending upon (i) the choice and relative proportions of the reactants and reagents, (ii) the choice of solvent, (iii) the choice of reaction temperature, (iv) the scale of the reaction, (v) the level of conversion desired, and so forth. Nonetheless, Step A is typically completed in less than about 10 hours (e.g., in about 4 to 8 hours), and Step B in less than about 24 hours (e.g., in about 6 to about 18 hours).

The order of addition of the reactants and reagents to the reaction vessel in Steps A and B respectively is not critical, hi one embodiment, Steps A and B are conducted in the same reaction vessel (i.e., a one-pot synthesis of Compound III). The one-pot synthesis can be conducted in the folio-wing manner: Amine RI-NH2 and solvent A are charged to a reaction vessel and brought (e.g., cooled) to reaction temperature (e.g., from about 0⁰C to about 5⁰C). Compound I dissolved in solvent A is then slowly added (the addition is often exothermic), all the while maintaining the mixture at reaction temperature. Upon completion of the addition, the mixture is aged at the reaction temperature until the desired degree of conversion (i.e., usually complete conversion) is achieved. A source of hydrazine is then slowly added (often exothermic) to the reaction vessel containing the Step A reaction mixture while maintaining the mixture at an initial, relatively cool reaction temperature (e.g., from about O⁰C to about 10⁰C). After addition, the reaction mixture is aged at the initial reaction temperature for a time and then aged at a second, higher reaction temperature (e.g., from about 20⁰C to about 30°C) until the desired degree of conversion (usually 100%) is achieved. Steps A and B are optionally but typically conducted with agitation (e.g., stirring) of the mixtures. Compound III can be recovered using conventional techniques such as solvent extraction. Compound III per se can be recovered or it can be recovered as a solution in organic solvent for use in Step C. When Steps A, B, C, D and E are included in Process Q, the process of the invention involves fewer steps from readily available starting materials than does Process A set forth above in the Background of the Invention. The amino group is introduced in Step A of the process of the invention, whereas the amino group is introduced with low yield in the penultimate step of Process A. When applied to the preparation of Compound A in the form of a sulfonate salt, Process Q starting with Step A has an overall yield of about 37%, whereas Process A's yield is about 0.1% or less.

When applied to the preparation of Compound A in the form of a sulfate salt, Process R starting with Step A has an overall yield of about 45-50%, whereas Process A's yield is about 0.1% or less. When applied to the preparation of Compound A in the form of a sulfate salt,

Process S starting with Step A has an overall yield of about 37%, whereas Process A's yield is about 0.1% or less.

The present invention also includes a process for preparing a compound of Formula VIII' (hereinafter alternatively referred to as Process P'):

which comprises:

(F') contacting a compound of Formula VT or VI":

with biaryl ether 7:

in the presence of KI aad a base F selected from alkali metal carbonates, alkali metal bicarbonates and CsF to obtain the compound of Formula VIIF; wherein:

Rl is a branched C3.8 alkyl; and

R2 is CH3, CF3, or phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, OCH3, CF3, or OCF3.

Aspects of Process P' include the process as originally described incorporating one or more of features (fl ) to (fS) as follows:

(fl-a) Rl is a branched C3_g alkyl;

(fl-b) R-I is isopropyl, t-butyl, isobutyl, sec-butyl, isopentyl, neopentyl, or 1,1-dϊmethylpropyl ;

(fl-c) Rl is t-butyl; (f2-a) R² is CH3, CF3, phenyl, p-methylphenyl, or p-methoxyphenyl;

(f2-b) R2 is CH3; (β-a) Step F is conducted in organic solvent F;

(f3-b) organic solvent F is a polar aprotic solvent;

(D ~c) organic solvent F is NMP or DMAc;

(D-d) organic solvent F is DMAc; (β-e) organic solvent F is acetonitrile;

(G -f) organic solvent F is a combination of acetonitrile and 2-methyl THF;

(f4-a) base F is cesium carbonate, Na carbonate, K carbonate, or CsF;

(f4-b) base F is K carbonate or CsF;

(f4-c) base F is CsF; (f4-d) base F is K2CO3;

(f5-a) base F is employed in an amount of at least about 0.9 equivalent per equivalent of Compound Vf or Compound Vl";

(f5-b) base F is employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound VI' or Compound VI"; (f6-a) when Compound VT is employed, KI is employed in an amount of at least about 0.9 equivalent per equivalent of Compound VI';

(f6-b) when Compound VI is employed, KI is employed in an amount in a range of from about 1 to about 3 equivalents per equivalent of Compound VI';

(f6-c) when Compound VI" is employed, KI is employed in an amount of at least 0.05 equivalent per equivalent of Compound VI";

(f6-d) when Compound VI" is employed, KI is employed in an amount in a range of from about 0.1 to about 0.9 equivalent per equivalent of Compound VI";

(f6-e) when Compound VI" is employed, KI is employed in an amount in a range of from about 0.1 to about 0.5 equivalent per equivalent of Compound VI"; (f6-f) when Compound VI" is employed, KI is employed in an amount in a range of from about 0.1 to about 0.3 equivalent per equivalent of Compound VI";

(f7-a) biaryl ether 7 is employed in an amount of at least about 0.8 equivalent per equivalent of Compound VI' or Compound VI";

(f7-b) biaryl ether 7 is employed in an amount in a range of from about 0.8 to about 1.5 equivalents per equivalent of Compound VI' or Compound VI".

(fS-a) when Compound VT is employed, Step F' is conducted at a temperature in a range of from about 0⁰C to about 50⁰C;

(f8-b) when Compound VF is employed, Step F is conducted at a temperature in a range of from about 1O⁰C to about 40⁰C; (fS-c) when Compound VI" is employed, Step F' is conducted at a temperature in a range of from about 3O⁰C to about 8O⁰C;

(f8-d) when Compound VI" is employed, Step F' is conducted at a temperature in a range of from about 40⁰C to about 70⁰C. It is understood that each of the features (fl) to (fB) can be incorporated singly or multiply in any combination into Process P' as originally described and that the process resulting from each such incorporation is an aspect of Process P¹. It is also understood, however, that certain features cannot be used in combination; e.g., feature (f6~a) relating to Compound VI' is not to be combined with feature (f8-c) relating to Compound VI".)

The present invention also includes a process (hereinafter alternatively referred to as Process Q') for preparing Compound A in the form of a sulfonate salt:

Compound A,

which comprises conducting Step F' as described above in Process P' to obtain a compound of Formula VIII' and then:

(G') treating the compound of Formula VIII' with phosphoric acid or a carboxylic acid selected from the group consisting of oxalic acid, acetic acid and haloacetic acids and with an organic sulfonic acid to obtain the sulfonate salt of Compound A.

Features of Step G¹ include the following: (gl-a) Step G' is conducted in organic solvent G

(gl-b) organic solvent G is a polar aprotic solvent; (gl-c) organic solvent G is acetonitrile, proprionitrile, MTBE, or anisole; (gl-d) organic solvent G is acetonitrile;

(g2-a) the acid used with the organic sulfonic acid is a carboxylic acid; (g2-b) the acid used with the organic sulfonic acid is a haloacetic acid;

(g2-c) the acid used with the organic sulfonic acid is trifluoroacetic acid, trichloroacetic acid, dichloroacetlc acid, or difluoroacetic acid;

(g2-d) the acid used with the organic sulfonic acid is trifluoroacetic acid or dichloroacetic acid; (g2-e) the acid used with the organic sulfonic acid is trifluoroacetic acid;

(g2-f) the acid used with the organic sulfonic acid is oxalic acid; (g2-g) the acid used with the organic sulfonic acid is phosphoric acid; (g3-a) the organic sulfonic acid is methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, trifluoromethanesulfonic acid, 1,1,2,2-tetrafluoroethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, or p-methoxybenzenesulfonic acid;

(g3-b) the organic sulfonic acid is benzenesulfonic acid or p-toluenesulfonic acid; (g3-c) the organic sulfonic acid is benzenesulfonic acid; (g4-a) the carboxylic acid (or phosphoric acid) is employed in an amount of at least 0.9 equivalent per equivalent of Compound VIIF;

(g4-b) the carboxylic acid (or phosphoric acid) is employed in an amount in a range of from about 10 to about 20 equivalents per equivalent of Compound Vffl'; (g5-a) the organic sulfonic acid is employed in an amount of at least about 0.9 equivalent per equivalent of Compound VIII';

(g5-b) the organic sulfonic acid is employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound VIIF;

(g6-a) Step G' is conducted at a temperature in a range of from about 20⁰C to about 80⁰C;

(gό-b) Step G¹ is conducted at a temperature in a range of from about 60⁰C to about 8O⁰C;

(g6-c) Step G' is conducted at a temperature in a range of from about 65⁰C to about 7S°C. Aspects of Process Q' include the process as originally described above, incorporating one or more of features (fl) to (f8) and (gl) to (g6). It is understood that each of these features can be incorporated singly or multiply in any combination into Process Q¹ as originally described and that the process resulting from each such incorporation is an aspect of Process Q'. The present invention also includes a process (hereinafter alternatively referred to as Process R¹) for preparing Compound A in the form of a sulfate salt, which comprises conducting Step P as described above in Process P' to obtain the compound of Formula VIIF; and

(H¹- 1) treating the compound of Formula VIII' with sulfuric acid in the presence of a Cg-i 2 alkanethiol to obtain a sulfate salt of a compound of Formula VIII-A':

(H'-2) treating the compound of Formula VIII-A' with sulfuric acid to obtain the sulfate salt of Compound A.

Features of Steps Ff-I and H'-2 include the following: (hl~la) Step H'-l is conducted in organic solvent Hl; (hi -Ib) organic solvent Hl is a polar aprotic solvent;

(hi -Ic) organic solvent Hl is acetonitrile, proprionitrile, MTBE, or anisole;

(hi -Id) organic solvent Hl is acetonitrile; (hi -2a) the alkanethiol is octanethiol or dodecanethiol;

(h 1 -2b) the alkanethiol is octanethiol ;

(hi -3 a) sulfuric acid is employed in H'-l in an amount of at least 0.9 equivalent per equivalent of Compound VIII¹; (hi -3b) sulfuric acid is employed in H'-l in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound VIII';

(hi -3 c) sulfuric acid is employed in H'-l in an amount in a range of from about 1.5 to about 3 equivalents per equivalent of Compound VIII';

(hi -4a) the alkanethiol is employed in H'-l in an amount which is at least equivalent to the amount of sulfuric acid;

(h 1 -4b) the ratio of equivalents of alkanethiol to equivalents of sulfuric acid is in a range of from about 0.9:1 to about 1.1 :1;

(hi -5 a) Step H'-l is conducted at a temperature in a range of from about

10⁰C to about 40⁰C; (hi -5b) Step H'-l is conducted at a temperature in a range of from about

15°C to about 3O⁰C;

(h 1 -5c) Step H'-l is conducted at a temperature in a range of from about

15°C to about 25°C;

(h2- 1 a) Step H'-2 is conducted in organic solvent H2 ; (h2-lb) organic solvent H2 is a polar aprotic solvent, which is the same or different as solvent Hl;

(h2-l c) organic solvent H2 is acetonitrile or proprionitrile;

(h2- 1 d) organic solvent H2 is acetonitrile;

(h2-2a) Step H'-2 is conducted in the presence of water; (h2-2b) Step H'-2 is conducted in the presence of water wherein the amount of water employed is less than about 10% by volume based on the total volumes of water and solvent H2 being employed;

(h2-2c) Step H'-2 is conducted using acetonitrile and water;

(h2-2d) Step H'-2 is conducted using acetonitirle and water, wherein the water is employed in an amount from about 2 to about 6 vol.%;

(h2-3a) sulfuric acid is employed in H'-2 in an amount of at least 0.9 equivalent per equivalent of Compound VIFf-A;

(h2-3b) sulfuric acid is employed in H'-2 in an amount in a range of from about 2 to about 20 equivalents per equivalent of Compound VIIF-A; (h2-3c) sulfuric acid is employed in H'-2 in an amount in a range of from about 5 to about 10 equivalents per equivalent of Compound VIIF-A;

(h2-4a) Step H'-2 is conducted at a temperature in a range of from about

2O⁰C to about 9O⁰C; (h2-4b) Step H'-2 is conducted at a temperature in a range of from about

50⁰C to about 80⁰C;

(h2-4c) Step H'-2 is conducted at a temperature in a range of from about

65^CC to about 75°C. Aspects of Process R' include the process as originally described above, incorporating one or more of features (fl) to (£8), (hl-1) to (hl-5), and (h2-l) to (h2-4). It is understood that each of these features can be incorporated singly or multiply in any combination into Process R' as originally described and that the process resulting from each such incorporation is an aspect of Process R¹. The present invention also includes a process (hereinafter alternatively referred to as Process S') for preparing Compound A in the form of a sulfate salt, which comprises conducting Step F' as described above in Process P¹ to obtain the compound of Formula VBT; and

(K¹) treating the compound of Formula VIII' with sulfuric acid to obtain a sulfate salt of Compound A. Features of Step K' include the following:

(kl-a) Step K' is conducted in organic solvent K;

(kl-b) organic solvent K is a polar aprotic solvent, which is the same or different as solvent H2;

(kl-c) organic solvent K is acetonitrile or proprionitrile; (kl-d) organic solvent K is acetonitrile;

(k2-a) Step K¹ is conducted in the presence of water;

(k2~b) Step K' is conducted in the presence of water wherein the amount of water employed is less than about 10% by volume based on the total volumes of water and solvent H2 being employed; (k2-c) Step K' is conducted using acetonitrile and water;

(k2-d) Step K' is conducted using acetonitirle and water, wherein the water is employed in an amount from about 2 to about 6 vol.%;

(k3-a) sulfuric acid is employed in K' in an amount of at least 0.9 equivalent per equivalent of Compound VIIF; (k3-b) sulfuric acid is employed in K'-2 in an amount in a range of from about 2 to about 20 equivalents per equivalent of Compound VIIF;

(k3-c) sulfuric acid is employed in K' in an amount in a range of from about 5 to about 10 equivalents per equivalent of Compound VIH';

(k4-a) Step K' is conducted at a temperature in a range of from about 20⁰C to about 90⁰C;

(k4-b) Step K' is conducted at a temperature in a range of from about 50⁰C to about 8O⁰C; (k4-c) Step K' is conducted at a temperature in a range of from about

65°C to about 75°C.

Aspects of Process K¹ include the process as originally described above, incorporating one or more of features (fl) to (f8) and (kl) to (k4). It is understood that each of these features can be incorporated singly or multiply in any combination into Process S' as originally described and that the process resulting from each such incorporation is an aspect of Process S'.

A first embodiment of Process P¹ (Embodiment P'-El) or Process Q' (Embodiment Q'-El) or Process R' (Embodiment R'-El) or Process S' (Embodiment S'-El) comprises Process P' or Process Q¹ or Process R' or Process S¹ as originally described, and further comprises:

(E') contacting a compound of Formula V:

with R2-S(O)2"Z, wherein Z is halogen, and in the presence of abase E selected from tertiary amines, alkali metal hydroxides, and alkali metal carbonates to obtain a compound of Formula VI' or, with the proviso that Z is chloride, Formula VI" .

Features of Step E' include the following:

(el -a) Step E' is conducted in organic solvent E;

(el-b) organic solvent E is an aprotic solvent;

(el-c) organic solvent E is methylene chloride, acetonitrile, DMF, THF, 2-methyl-THF, MTBE, NMP, EtOAc₅ IPAc, or toluene;

(el-d) organic solvent E is 2-methyl-THF;

(e2-a) base E is NMM, NEM₅ TEA, DIPEA, DABCO, Na carbonate, or K carbonate;

(e2-b) base E is DIPEA; (e3-a) R2-S(O)2-Z is methanesulfonyl chloride;

(e4-a) R2-S(O)2-Z is employed in an amount of at least about 0.9 equivalent per equivalent of Compound V;

(e4-b) R2-S(O)2-Z is employed in an amount in a range of from about 1 to about

5 equivalents per equivalent of Compound V; (e5-a) base E is employed in an amount of at least about 0.9 equivalent per equivalent of Compound V; (eS-b) base E is employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound V;

(e6-a) Step E' is conducted at a temperature in a range of from about -20⁰C to about 40⁰C to obtain Compound VI'; (e6-b) Step E' is conducted at a temperature in a range of from about -5°C to about 10⁰C to obtain Compound VI';

(e6-c) Step E' is initially conducted at a temperature in a range of from about 15⁰C to about 30⁰C and then conducted at a temperature in a range of from about 4O⁰C to about 70^GC to obtain Compound VF. Aspects of Embodiment P'-El or Q'-El or R'-El or S'-El include the process embodiment as originally described above, incorporating one or more of features (el) to (e6), (fl) to (f8), (gl) to (g6), (hi -I) to (hl-5), (h2-l) to (h2-4), and (kl) to (ic4)_? as set forth above. It is understood that each of these features can be incorporated singly or multiply in any combination into the process of Embodiment P'-El or Q'-El or R'-El or S'~E1 as originally described and that the process resulting from each such incorporation is an aspect of

Embodiment P'-El or Q'-El or R'-El or S'-El. It is also understood that certain of these features are not applicable to all of the embodiments of interest; e.g., Process Q' does not include Steps H'-l or H'-2 and thus features (hl-1) to (hl-5) and (h2-l) to (h.2-4) cannot be incorporated therein. A second embodiment of Process P' (Embodiment P'-E2) or Process Q'

(Embodiment Q'-E2) or Process R' (Embodiment R'-E2) or Process S' (Embodiment S'-E2) comprises Process P' or Process Q' or Process R' or Process S' as originally described and Step F, and further comprises:

(D') contacting a compound of Formula IV:

with a source of hydrogen in the presence of a hydrogenolysis catalyst to obtain the compound of Formula V; wherein the hydrogenolysis catalyst comprises supported or unsupported Pd or a supported or unsupported Pd compound, salt or complex, and PGI is a hydroxy protective group capable of being cleaved by hydrogenolysis that is selected from the group consisting of benzyl, p-nitrobenzyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, phenyl, or THP. Features of Step D' include the following: (dl-a) Step D^! is conducted in organic solvent D;

(dl-b) organic solvent D is ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, n-propanol, isobutanol, methanol-water, ethanol-water, methanol-ethyl acetate-water, or raethanol-isopropyl acetate-water; (dl -c) organic solvent D is ethanol, ethyl acetate, or isopropyl acetate;

(dϊ-d) organic solvent D is ethanol;

(d2-a) PGI is benzyl, p-nitrobenzyl, or p-methoxybenzyl;

(d2-b) PGI is benzyl;

(d3-a) the hydrogen source is hydrogen gas optionally in admixture with a chemically inert carrier gas or a hydrogen transfer molecule selected from ammonium formate, cyclohexene, or cyclohexadiene;

(d3-b) the hydrogen source is hydrogen gas optionally in admixture with a chemically inert carrier gas;

(d4-a) the hydro genolysis catalyst is is Pd black, Pd(OH)2, or Pd/C; (d4-b) the hydrogenolysis catalyst is Pd/C;

(d5-a) the hydrogenolysis catalyst is employed in an amount in a range of from about 0.01 wt.% to about 100 wt.% relative to the weight of Compound IV;

(d5-b) the hydrogenolysis catalyst is employed in an amount in a range of from about 0.2 wt.% to about 5 wt.%; (d6-a) Step D' is conducted at a temperature in a range of from about 0⁰C to about 6O⁰C;

(d6-b) Step D' is conducted at a temperature in a range of from about 10⁰C to about 30⁰C.

Aspects of Embodiment P'-E2 or Q'-E2 or R'-E2 or S'-E2 include the process embodiment as originally described above, incorporating one or more of features (dl) to (d6), (el) to (e6), (fl) to (f8), (gl) to (g6), (hl-1) to (hl-5), (h2-l) to (h2-4), and (kl) to (k4), as set forth above. It is understood that, to the extent they are applicable, each of these features can be incorporated singly or multiply in any combination into the process of Embodiment P'-E2 or Q'-E2 or R'-2 or S'-E2 as originally described and that the process resulting from each such incorporation is an aspect of Embodiment P'-E2 or Q'-E2 or R'-E2 or S'-E2.

A third embodiment of Process P' (Embodiment F-E3) or Process Q' (Embodimeαt Q'-E3) or Process R' (Embodiment R'-E3) or Process S' (Embodiment S'-E3) comprises Process P' or Process Q' or Process R' or Process S' as originally described, Step E¹ and Step D'; and further comprises: (C) contacting a compound of Formula III:

with 3,4-dihydro-2H-pyran and in the presence of an acid C to obtain the compound of Formula IV'; wherein the acid C is an organic sulfonic acid which is optionally in the form of a pyridinium salt. Features of Step C include the following:

(cl-a) Step C is conducted in organic solvent C;

(cl-b) organic solvent C is an aprotic solvent;

(cl-c) organic solvent C is 2-methyl-THF, DME, IPAc, chlorobenzene, xylenes (individual isomers or mixtures thereof),, or toluene; (cl-d) organic solvent C is toluene;

(c2-a) acid C is an organic sulfonic acid which is rnethanesulfonic acid, trifhioromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridinium methanesulfonate, pyridinium trifluoromethanesulfonate, pyridinium benzenesulfonate, or pyridinium p-toluenesulfonate; (c2-b) acid C is an organic sulfonic acid which is benzenesulfonic acid, pyridinium benzenesulfonate, p-toluenesulfonic acid, or pyridinium p-toluenesulfonate;

(c2-c) acid C is pyridinium p-toluenesulfonate;

(c3-a) 3,4-dihydro-2H-pyran is employed in an amount of at least about 0.5 equivalent per equivalent of Compound III; (c3-b) 3,4-dihydro-2H~pyran is employed in an amount in a range of from about

0.5 to about 10 equivalents per equivalent of Compound III;

(c3-c) 3,4-dihydro-2H-pyran is employed in an amount in a range of from about 2 to about 10 equivalents per equivalent of Compound III;

(c4-a) acid C is employed in a catalytic amount; (c4-b) acid C is employed in an amount in a range of from about 0.01 equivalent to about 1 equivalent per equivalent of Compound III;

(c4-c) acid C is employed in an amount in a range of from about 0.02 to about 0.1 equivalent per equivalent of Compound III;

(c5-a) Step C is conducted at a temperature in a range of from about 70⁰C to about HO⁰C;

(c5-b) Step C is conducted at a temperature in a range of from about 75°C to about 95°C.

Aspects of Embodiment P'-E3 or Q'-E3 or R'-E3 or S'-E3 include the process embodiment as originally described above, incorporating one or more of features (cl) to (c5), (dl)to (d6), (el) to (e6), (fl) to (fS), (gl) to (g6), (hl-1) to (hl-5), (h2-l) to (h2-4), and (kl) to (k4) as set forth above. It is understood that, to the extent they are applicable, each of these features can be incorporated singly or multiply in any combination into the process of Embodiment P'-E3 or Q'-E3 or R'-E3 or S'-E3 as originally described and that the process resulting from each such incorporation is an aspect of Embodiment P'-E3 or Q'-E3 or R'-E3 or S'-E3.

A fourth embodiment of Process P¹ (Embodiment P'-E4) or Process Q¹ (Embodiment Q'-E4) or Process R' (Embodiment R'-E4) or Process S' (Embodiment S^r-E4) comprises Process P' or Process Q¹ as originally described, Step E', Step D' and Step C; and further comprises :

(A') contacting a compound of Formula I:

with an amine of Formula R1-NH2 to obtain a compound of Formula II:

(B') contacting the compound of Formula II with a source of hydrazine to obtain the compound of Formula III.

Features of Steps A' and B' include the following:

(al-a) Step A' is conducted in organic solvent A;

(al-b) organic solvent A is a polar solvent; (al-c) organic solvent A is NMP, DMAc, DMF, DMSO, acetonitrile, isopropanol, methanol, or ethanol;

(al-d) organic solvent A is NMP, DMAc, DMF, or DMSO;

(al-e) organic solvent A is NMP;

(a2-a) amine RI-NH2 (e.g., t-butylamine) is employed in an amount of at least about 0.5 equivalent per equivalent of Compound I;

(a2-b) amine RΪ -NH2 is employed in a range of from about 0.5 to about 20 equivalents per equivalent of Compound I;

(a2-c) amine RI-NH2 is employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound I; (a3-a) Step A¹ is conducted at a temperature in a range of from about -30⁰C to about 5O⁰C;

(a3-b) Step A' is conducted at a temperature in a range of from about - 15°C to about 5⁰C; (bl-a) Step B' is conducted in organic solvent B;

(bl-b) organic solvent B is a polar solvent;

(bl-c) organic solvent B is NMP, DMAc, DMF, DMSO, acetonitrile, methanol, or ethanol;

(bl -d) organic solvent B is NMP, DMAc, DMF₅ or DMSO; (b 1 -e) organic solvent B is NMP ;

(b2-a) the source of hydrazine is hydrazine hydrate or a hydrazinium salt;

(b2-b) the source of hydrazine is hydrazine hydrate;

(b3~a) the hydrazine source is employed in an amount of at least about 0.9 equivalent per equivalent of the Compound II; (b3-b) the hydrazine source is employed in an amount in a range of from about 1 to about 10 equivalents per equivalent of Compound II;

(b4-a) Step B' is conducted a temperature in a range of from about -10⁰C to about 100⁰C;

(b4~b) Step B' is conducted at a temperature in a range of from about 0⁰C to about 3O⁰C;

(b4-c) Step B' is initially conducted at a temperature in a range of from about 0⁰C to about 10⁰C and then the temperature is raised to a range of from about 20⁰C to about 30⁰C;

(abl) organic solvent A and organic solvent B are the same solvent;

(ab2) organic solvent A and organic solvent B are the same solvent, and Steps A' and B' are conducted in the same reaction pot.

Aspects of Embodiment F-E4 or Q'-E4 or R'-E4 or S'-E4 include the process embodiment as originally described above, incorporating one or more of features (al) to (a3), (abl) to (ab2), (bi) to (b4), (cl) to (c5), (dl) to (d6), (el) to (e6), (fl) to (f8), (gl) to (g6), ChI-I) to (hl-5), (h2-l) to (h2-4), and (kl) to (k4) as set forth above. It is understood that, to the extent they are applicable, each of these features can be incorporated singly or multiply in any combination into the process of Embodiment P'-E4 or Q'-E4 or R'-E4 or S'-E4 as originally described and that the process resulting from each such incorporation is an aspect of Embodiment P'-E4 or Q'-E4 or R'-E4 or S'-E4.

The present invention also includes a compound selected from the group consisting of: a compound of Formula I:

a compound of Formula II:

a compound of Formula IV:

a compound of Formula V:

a compound of Formula VI:

a compound of Formula VIII:

and salts thereof; wherein:

wherein LG, PG2_? Rl ₅ R3_f R4₅ R5₅ R6 and R? are as originally defined in the Summary of the Invention and pGl is a hydroxy protective group capable of being cleaved by hydrogenolysis. Aspects of the invention include any one or more of Compounds I, II, IV, V, VI and VIII incorporating any one or more of the preceding applicable embodiments of L^₅ pGl, PG2₅ Rl, R3, R4_S R5_? R6 and R^ and embodiments defining variables incorporated therein. It is understood that the incorporation of any of the preceding applicable embodiments individually or in combination in any one of Compounds I, II, IV, V, VI and VIII is an aspect of the invention.

The present invention also includes a compound selected from the group consisting of: a compound of Formula I:

a compound of Formula II :

of a compound of Formula IV:

a compound of Formula V:

a compound of Formula VI¹:

a compound of Formula VI" :

a compound of Formula VIII¹:

and salts thereof; wherein: pGl is a hydroxy protective group capable of being cleaved by hydrogenolysis that is selected from the group consisting of: (1) phenyl, (2) benzyl,, (3) diphenylmethyl, (4) triphenylmethyl, or (5) THP; wherein each of the one or more phenyl groups in (1), (2), (3) or (4) is optionally and independently substituted with one or more substituents each of which is independently halogen, nitro, C I _6 alkyl, or O-C I -6 alkyl;

Rl is branched C3.8 alkyl; and

R2 is CH3, CF3, or phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, OCH3, CF3, or OCF3.

The present invention also includes a compound selected from the group consisting of:

and salts thereof.

The present invention also includes a crystalline HCl salt of Compound A having the XRPD pattern shown in Figure 1. This salt is alternatively referred to herein as Form I. This salt can be prepared in the manner described in Part A or Part B in Example 4. In one embodiment, the crystalline Compound A HCl salt is characterized by an X-ray powder diffraction pattern obtained using copper K<χ radiation (i.e., the radiation source is a combination of Cu K_dI ^and K(χ2 radiation) which comprises 2Θ values (i.e., reflections at 2Θ values) in degrees of about 13.5, 19.1 and 24.9. In this embodiment, and any analogous embodiments which follow, the term "about" is understood to modify each of the 2Θ values. In another embodiment, the crystalline Compound A HCl salt is characterized by an X-ray powder diffraction pattern obtained using copper K_α radiation which comprises 2Θ values in degrees of about 13.5, 16.2, 18.0, 19.1, 20.4, 21.5, 24.9, 26.4 and 27.1.

In still another embodiment, the Form I crystalline HCl salt of Compound A is characterized by the PDF trace derived from its X-ray diffraction pattern shown in Figure 1. The PDF trace provides a fingerprint of the inter-atomic distances that define Form I. A PDF trace can be obtained in the manner described in WO 2005/082050. In one aspect of this embodiment, the Form I salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 13.5, 19.1 and 24.9 in the XRPD. In another aspect of this embodiment, the Form I salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 13.5, 16.2, 18.0, 19.1, 20.4, 21.5, 24.9, 26.4 and 27.1 in the XRPD.

The present invention also includes a crystalline HCl salt of Compound A having the XRPD pattern shown in Figure 2. This salt is alternatively referred to herein as Form II. Form II can be prepared as described in Part C of Example 4. In one embodiment, the crystalline Compound A HCl salt is characterized by an X-ray powder diffraction pattern obtained using copper K^ radiation which comprises 2Θ values in degrees of about 13.5, 23.3, 25.7. In another embodiment, the crystalline Compound A HCl salt is characterized by an X-ray powder diffraction pattern obtained using copper K_α radiation which comprises 2Θ values in degrees of about 12.2, 12.8, 13.5, 17.9, 21.3, 23.3, 24.1, 25.7 and 27.1. hi still another embodiment, the Form II crystalline HCl salt of Compound A is characterized by the PDF trace derived from its X-ray diffraction pattern shown in Figure 2. In one aspect of this embodiment, the Form II salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 13.5, 23.3, 25.7 in the XRPD. In another aspect of this embodiment, the Form I salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 12.2, 12.8, 13.5, 17.9, 21.3, 23.3, 24.1, 25.7 and 27.1 in the XRPD.

Form II is a metastable salt form which has the risk of converting to a different form during processing, storage and dosing. Form I is more stable than Form II, and is the preferred form. The present invention also includes a crystalline sulfate salt of Compound P-A (i.e., the bis-sulfate salt of the des-THP penultimate prepared in Step h-1 of Example 5, also identified as bis-sulfate 10), which has the XRPD pattern shown in Figure 3. In one embodiment, the crystalline Compound P-A sulfate salt is characterized by an X-ray powder diffraction pattern obtained using copper K_α radiation (i.e., the radiation source is a combination of Cu K<χl and Kα2 radiation) which comprises 2Θ values (i.e., reflections at 2Θ values) in degrees of about 5.3, 12.4 and 23.6. In another embodiment, the crystalline sulfate salt is characterized by an XRPD pattern obtained using copper K_α radiation which comprises 2Θ values in degrees of about 5.3, 9.4, 11.0, 12.4, 16.3, 16.7, 17.1, 19.2, 19.7, 23.1 and 23.6. In still another embodiment, the crystalline Compound P-A sulfate salt is characterized by the PDF trace derived from its X-ray diffraction pattern shown in Figure 3. In one aspect of this embodiment, the crystalline sulfate salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 5.3, 12.4 and 23.6 in the XRPD. In another aspect of this embodiment, the crystalline salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 5.3, 9.4, 11.0, 12.4, 16.3, 16.7, 17.1, 19.2, 19.7, 23.1 and 23.6 in the XRPD.

The present invention also includes a crystalline sulfate salt of Compound A having the XRPD pattern shown in Figure 4. This salt can be prepared in the manner described in Step h-2 of Example 5. In one embodiment, the crystalline Compound A sulfate salt is characterized by an X-ray powder diffraction pattern obtained using copper K_α radiation (i.e., the radiation source is a combination of Cu K_αi and K_α2 radiation) which comprises 2Θ values (i.e., reflections at 2Θ values) in degrees of about 7.7, 16.8 and 25.5. In another embodiment, the crystalline Compound A sulfate salt is characterized by an XRPD pattern obtained using copper Ka radiation which comprises 2® values in degrees of about 7.7, 12.7, 16.8, 17.8, 18.7, 19.1, 21.8, 23.3, 24.9, 25.5, 26.4 and 27.1.

In still another embodiment, the crystalline sulfate salt of Compound A is characterized by die PDF trace derived from its X-ray diffraction pattern shown in Figure 4. In one aspect of this embodiment, the sulfate salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 7.7, 16.8 and 25.5 in the XRPD. In another aspect of this embodiment, the sulfate salt is characterized by the parts of the PDF trace corresponding to the 2Θ values in degrees of about 7.7, 12.7, 16.8, 17.8, 18.7, 19.1, 21.8, 23.3, 24.9, 25.5, 26.4 and 27.1 in the XRPD.

Additional embodiments of the present invention include individually the Compounds I, II, IV, V, VI, VIII, FV', V¹, VF, VI", VIIF, 1, 2, 4, 5, 6', 6" and 8 and their salts and the Compound A HCl crystalline salts, the crystalline sulfate salt of Compound P-A, and the crystalline Compound A sulfate salt as described in the immediately preceding paragraphs, wherein the compound or salt is in a substantially pure form. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., IOO wt.%) of a product containing a given compound or salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined in a given sample, then the method providing the highest purity level governs. A compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis. With respect to a compound or salt of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer. The progress of any reaction step set forth herein can be followed by monitoring the disappearance of a reactant (e.g., Compound I in Step A) and/or the appearance of the desired product (e.g., Compound II in Step A) using such analytical techniques as TLC, HPLC, IR, NMR, MS, or GC.

The term "organic solvent" in reference to any of the organic solvents employed in a reaction or treatment step set forth herein refers to any organic substance which under the reaction conditions employed in the step of interest is in the liquid phase, is chemically inert, and will dissolve, suspend, and/or disperse the reactants and any reagents so as to bring the reactants and reagents into contact and to permit the reaction to proceed.

The term "ageing" and variants thereof (e.g., "aged") mean allowing the reactants in a given reaction or treatment step to stay in contact for a time and under conditions effective for achieving the desired degree of conversion. The terms "ageing" and variants thereof (e.g., "aged" are used herein interchangeably with the expression "maintaining at reaction temperature until the desired degree of conversion is achieved" and variants thereof (e.g., "maintained ...")

The expression that the order of addition of reactants and reagents to the reaction vessel in a reaction step is "not critical" means that reactants and reagents can be added concurrently, either together or separately, or they can be added sequentially in any order, or some can be added concurrently and others sequentially prior or subsequent to the concurrent addition.

The term "about", when modifying the quantity (e.g., equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and/or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like. In the particular case of the 2Θ values in degrees in an XRPD described herein, the term "about" typically means the value ± 0.1. Abbreviations employed herein include the following: AΪBN =

2,2-azobϊsisobutyronitrile; Boc (or BOC) = t-butyloxycarbonyl; Boc2θ = di-t-butyl carbonate;

Boc-ON = [2-(t-butyloxycarbonyloxyimino)-2~phenylacetonitriie; BsOH = benzenesulfonic acid; Bn= benzyl; n-Bu = n-butyl; t-Bu = tert-butyl; CDI = carbonyldiimidazole; DABCO = l,4-diazabicyclo[2.2.2]octane ; DCAA = dichloroacetic acid; DHP = 3,4-dihydro-2H-pyran; DIPEA = diisopropylethylamine (altenatively referred to as Hunig's base); DCM = dichioromethaae (methylene chloride); DIVIAc = N,N-dimethylacetamide; DMAP = 4-dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMF = N,N~dimethylformamide; DMPU = l,3-dimethyl-3,4,5,6~tetrahydro-2(lH)~pyrimidinone (orN,N'-dimethylpropyleneurea); DMSO = dimethylsulfoxide; Eq(s) or eq(s) = equivalents); ESI = electron spray ionization; EtOAc = ethyl acetate; EtOH = ethanol; GC = gas chromatography; HMPA = hexamethylphosphoramide; HPLC = high-performance liquid chromatography; HRMS = high resolution mass spectroscopy; IPA = isopropyl alcohol; IPAc = isopropyl acetate; KF = Karl Fisher titration for water; LCAP = liquid chromatography area percent; MCPBA = meta-chloroperbenzoic acid; Me = methyl; Ms = methanesulfonyl (mesyl); MTBE = methyl tert-butyl ether; MeCN = acetonitrile; NBS = N-bromosuccinimide; NEM = N-ethylmorpholine; NMM = N-methylmorphoIine; NMP = N-methyl pyrrolidinone; NMR = nuclear magentic resonance; PDF = atomic pair distribution function; PPTS = pyridinium p-toluene sulfonate; TEA = triethylamine; TFA = trifluoroacetic acid; THF - tetrahydrofuran; THP = tetrahydropyran-2-yl; TsOH = p-toluenesulfonic acid; Ts2θ = toluenesulfonic anhydride; XRPD = X-ray powder diffraction.

The following example serves only to illustrate the invention and its practice. The example is not to be construed as a limitation on the scope or spirit of the invention.

EXAMPLE 1 Preparation of 2-Ben2yloxy-N-methoxy-N-methyl-acetamide (Weinreb amide, S2)

Procedure 1

Materials MW Amount Moles Eqfs). benzyloxyacetic acid Sl 166.17 60.0O g 361 mmol 1.00 CDI 162.15 76.0O g 469 mmol 1.30 CH2C12 60O mL

NEt3 101.19 70.5 mL 505 mmol 1.40

(OMe)MeNHHCl 97.54 50.3 g 505 mmol 1.40 2 N HCl 80O mL saturated NaHCθ3 30O mL

To a three liter, three-necked flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple was added benzyloxyacetic acid Sl (60 g) and methylene chloride (600 rnL). The mixture was cooled to < 10⁰C and CDI was added portion wise while keeping the internal temperature <15°C. The mixture was then aged at 15-2O⁰C for ϊ hour and re-cooled to < 10⁰C. To the mixture was added TEA in one portion followed by the portion wise addition of N-methoxy-N-methyl amine hydrochloride while keeping the internal temperature < 25⁰C. The reaction mixture was aged at room temperature for 1 hour and quenched with 800 mL of 2 Ν HCl. The layers were separated and the organic layer was washed with water (200 mL) followed by saturated ΝaHCθ3 (300 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure and flushed with 2-MeTHF (300 mL) and the volume adjusted to 170 mL to give -70 g of the title compound S2 as a 2 M solution in 2-MeTHF which was used without further purification.

HPLC Conditions: Zorbax Eclipse Plus Cl 8 50 x 4.6 mm, 1.8 μm, 1.5 mL/minute, 230 nm, 25⁰C₁ Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes,, 5% A 6 minutes. benzyloxyacetic acid Sl 2,55 minutes Weinreb amide S2 2.89 minutes

Procedure 2

Materials MW Amount Moles Eqfs). benzyloxy acetic acid 166.17 69.8 g 0.420 1.00

DMF 73.09 48.7 mL 0.629 1.50 d = 0.944 phosphorous oxychloride 153.33 50.8 mL 0.545 1.30 d = 1.645

MeKHOMe-HCl 97.54 57.3 g 0.587 1.40

NaH2Pθ4-H2θ 137.99 9.O g 0.065 0.15

K2HPO4 174.18 93.2 g 0.535 1.27

10 M NaOH 37O mL

2-MeTHF 85O mL water I L

MTBE 1.2 L To a two-liter, three-necked round bottom flask equipped with a nitrogen inlet, addition funnel and a temperature probe was added 600 mL of 2-Me-THF followed by DMF (48.7 mL, 629 mmol). The solution was cooled to an internal temperature of 2.7⁰C in an ice bath and phosphorous oxychloride (50.8 mL, 545 mmol, 1.3 eqs.) was added dropwise (addition is exothermic) over 15 minutes. The resulting heterogeneous yellow solution was aged for 20 minutes at 3.3°C, after which the benzyloxy acetic acid Sl (69.8 g, 420 mmol) as a solution in 50 mL 2-Me-THF was added dropwise (addition is exothermic) from the addition funnel over 15 minutes. The yellow solution was aged for 20 minutes at 2.6°C and then transferred to a large addition funnel. In a 5-liter, four-necked round bottom flask equipped with an addition funnel, temperature probe, overhead mechanical stirrer and pH meter, N,6>-dimethylhydroxyIamine hydrochloride (57.3 g, 587 mmol, 1.4 eqs.) was dissolved in 600 mL of a pH 7.3 phosphate buffer (9.0 g ΝaH2Pθ4-H2θ + 93.2 g K2HPO4). The pH of the resulting solution was adjusted to 7.4 by addition of 80 mL 10 M NaOH. The solution of the above acid chloride was added dropwise from an addition funnel while maintaining the internal temperature at circa 20-25⁰C with the aid of an ice bath. Portion-wise addition of 290 mL 10 M NaOH during the addition of the acid chloride solution was required in order to maintain a pH greater than 6.8. The addition, of the acid chloride and the hydroxide was mildly exothermic. Upon completion of the addition, the reaction was aged at room temperature for 1 hour. HPLC analysis showed greater than 98 % conversion to the title compound. To this solution was added 1 L MTBE and the biphasic mixture was filtered to remove precipitated phosphate solids and the solids were washed with 100 mL MTBE. The organic layer was washed with 200 mL water (2X). The resulting organic solution was then concentrated under reduced pressure and flushed twice with 100 mL 2-Me-THF. After concentration, 87.51 g of a yellow oil was obtained (93 LCAP, 82 wt %, 82 % yield) which showed a water content of 146 μg/mL.

HPLC Conditions: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 μm, 1.5 mL/minute, 230 nm, 25 ⁰C, Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes. benzyloxyacetic acid Sl 2.55 minutes

Weinreb amide S2 2.89 minutes

EXAMPLE 2 Preparation of 2-Benzyloxy-l-(2,6-difluoro-ρyridin-3-yl)-ethanone (2,6-difluoroρyridine ketone, 1)

Materials MW Eq(s). Moles _Kg_ L Density

2,6-dmuoropyndine 115.08 1.05 0.439 0.0516

S3 (98 wt%)

2.5 M R-BuLi 64.06 1.10 0.461 0.185

Weinreb amide S2 209.24 1.00 0.418 0.101

(87 wt%)

THF 72.11 1.294 0.889

5 N HCl 36.45 3.50 1.465 0.293

MTBE 88.15 0.516 0.744

NMP 99.13 0.180 1.028

To a two-liter round bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged 2,6-difluoropyridine S3 (0.0516 5 kg), and THF (0.616 L, KF = 238 ppm), and the resulting mixture was cooled to circa -70⁰C. To the mixture was added R-butyllithium (2.5 M in hexane) dropwise through the addition funnel while maintaining the internal temperature <-65°C. After the addition of butyllithium was complete, the resulting mixture was aged at -65°C for 1 hour. In a separate flask was dissolved Weinreb amide S2 (0.101 kg, 87 wt%) in 2-MeTHF (0.175 mL) and this solution was pre-cooled ] 0 to -60 to -55°C. The Weinreb amide-containing solution was rapidly charged to the lithium difluoropyridine solution and the resulting reaction mixture was aged at -65⁰C for 1 hour, and then slowly warmed to -10⁰C over 4 hours. The reaction mixture was inversely quenched into a solution of 5 N HCl (0.293 L) in THF (0.175 L) at -15 to -5°C. The mixture was extracted with MTBE (0.516 L) aad the resulting organic layer was washed with water (2 x 0.258 L), 15 concentrated, azeotropically dried to KF < 250 ppm, and then solvent-switched to NMP for use without further purification. Assay yield of title product 1 was 81 %.

A small amount of crude title product 1 was crystallized from EtO Ac/heptane (1:4) at -10 ⁰C to give pure title product as colorless needles: mp 52.3-52.8 ⁰C; lH NMR (400 MHz, CDCI3) δ 8.54 (dd, J- 16.5, 8.4 Hz, 1 H). 7.52-7.31 (m, 5 H), 6.98 (dd, J= 8.4. 1.9 Hz, 1 20 H), 4.70 (s, 2 H), 4.69 (d, J= 3.0 Hz. 2 H) ppm; 13C NMR (100 MHz₅ CDCI3) δ 192.2 (d, J- 8.0 Hz), 163.7 (dd,J= 254, 16.0 Hz)₉ 160.3 (dd, J- 251, 16.0 Hz), 146.9 (d, J= 9.0 Hz), 137.0, 128.6 (2 C), 128.2, 128.1 (2 C), 115.5 (d₅ J- 33.0 Hz), 107.7 (dd, J= 33.0, 9.0 Hz), 75.3 (d, J= 10.0 Hz), 73.8 ppm. HRMS (ESI) calculated for C14H11F2NO2 (M+H) 264.0836, found 264.0807.

HPLC Conditions: Zorbax Eclipse Plus Cl 8 50 x 4.6 mm, 1.8 μm, 1.5 mL/rninute, 230 nm, 25⁰C, Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes.

2,6-difluoropyridine S3 2.620 minutes

Weinreb amide S2 2.906 minutes

2,6-difluoropyridine ketone 1 4.118 minutes

EXAMPLE 3

Preparation of the besylate salt of

3 - { 5 -[(6-amino- 1 H-pyrazolo [3 ,4-Z>]pyridin-3 -yl)methoxy] -2-chlorophenoxy} -5- chlorobenzonitrile 9

Steps a & b: Preparation of (3-benzyloxymethyl-l-H-pyrazolo[3,4έ>]pyridine-6-yl)- fert-butylamine (Benzyloxypyrazole 3).

Materials MW Eq(s). Moles Kg L

2,6-difluoropyridine 263.24 1.00 0.337 0.0887 ketone 1 førf-butylamine 73.14 5.00 1.684 0.123 0.179 0.69

hydrazine 50.06 5.00 1.684 0.0860 0.0833 1.032 monohydrate (98%)

NMP 99.13 0.532 1.028

5 N H2SO4 98.08 0.21 MTBE 88.15 1.400 0.744 toluene 92.14 1.500 0.865

Step a - To a one-liter round bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged tert-buiylamins (0.179 L, KF = 130 ppm) and NMP (0.532 L, KF = 130 ppm). To the resulting solution was slowly added via the addition runnel 2,6-difluoropyridine ketone 1 (0.0887 g) in NMP (0.266 L, total volume, KF <150 ppm) while maintaining the internal temperature between 0-5⁰C (exothermic) over 1 hour, and aged at the same temperature for 2-3 hours (100 A% conversion).

Step b - The reaction mixture from Step A containing 2 was degassed by vacuum and then placed under an atmosphere of nitrogen and hydrazine monohydrate (0.0833 L) was slowly added while maintaining the internal temperature between 0-5 ⁰C (exothermic). After complete addition, the reaction mixture was aged at 0-5 ⁰C for 5 hours, and at room temperature for 3-5 hours. The reaction mixture was then cooled to O⁰C, and the pH was adjusted to 5 by the addition of 5 N sulfuric acid keeping the internal temperature < 20 ⁰C. Water (0.70O L) and MTBE (0.800 L) were charged and the layers allowed to separate. After the phase cut, the aqueous layer was back extracted with MTBE (2 x 0.300 L). The combined organic extracts were washed with water (4 x 0.300 L), concentrated under reduced pressure while solvent switching to toluene and azeotropically dried to a final volume of toluene (0.600 L, total volume, KF <150 ppm), which was used in the next step without further purification. Assay of title product 3 was 81% yield from the 2,6-difluoropyridine ketone starting reactant.

A small amount of crude benzyloxypyrazole product 3 was purified by chromatography on silica gel (EtO Ac/heptane = 1 :4) to give pure benzyloxypyrazole as colorless oil: lH NMR (400 MHz, CDCI3) 5 10.24 (br s, 1 H), 7.56 (d, J= 8.9 Hz, 1 H), 7.36-7.27 (m, 5

H), 6.22 (d, J= 8.9 Hz, 1 H)₅ 4.83 (s, 2 H), 4.72 (br s, 1 H), 4.57 (s, 2 H), 1.51 (s, 9 H); 13c NMR (IOO MHz, CDCI3) δ 158.1, 152.8, 143.5, 138.2, 130.4, 128.4 (2 C), 128.0 (2 C), 127.7, 107.4, 105.9, 72.1, 66.1, 51.7, 29.3 (3 C). HRMS (ESI) calculated for C18H22N4O (M+H) 311.1872, found 311.1854.

HPLC Conditions: Zorbax Eclipse Plus Cl 8 50 x 4.6 mm, 1.8 μm, 1.5 mL/minute, 230 nm, 25 ⁰C, Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes. desired regioisomer 2 4.909 minutes undesired regioisomer 2a 5.529 minutes benzyloxypyrazole 3 3.136 minutes.

Reaction step a was conducted in a manner similar to that described above, but on a smaller scale, with a series of different solvents. It was observed that the ratio of desired regioisomer 2 to undesired regioisomer 2a as measured by 1 H-NMR depended significantly on the choice of solvent, wherein the solvents providing the highest ratios were NMP, DMF, DMAc, and DMSO:

Conversion in all runs was 100%. Room temperature = 20-25⁰C.

Step c: Preparation of [β-tert-butylammo- 1 -(tetrahydro-pyran-2-yl)- lH-pyrazolo[3,4-b]pyridine-3-yI]-methylene benzyl ether (THP-pyrazole 4).

Materials MW Eq(s). Moles Kg Liters Density benzyloxy pyrazole 3 310.39 1.00 0.2728 0.08466

PPTS (98%) 172.20 0.0500 0.01364 0.00350

DHP (97%) 84.12 5.00 1.364 0.117 0.126 0.928 toluene 92.14 0.532 1.028

5 wt% NaHCO3 84.01 0.100 cyclohexane 84.16 1.60 heptane 110.20 0.050 To a one-liter round bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged benzyloxypyrazole 3 (0.08466 kg assay) in toluene (0.600 L, total volume, KF < 150 ppm), DHP (0.126 L), and PPTS (0.00350 kg). The resulting mixture was heated at 80-85 ⁰C for 18 hours (100A% conversion). The reaction mixture was cooled to ambient temperature, washed with 5% NaHCθ3 (0.100 L) and water (0.200 L). The organic layer was concentrated under reduced pressure, and solvent- switched to cyclohexane at 50 ⁰C (0.330 L, total volume). The resulting solution was cooled to 30 ⁰C₅ and seeded with pure THP pyrazole 4. (Note: Crystallization would occur without seed, but seeding provides a more consistent product.) The resulting slurry was aged at room temperature for 5 hours, and at 10⁰C for 1 hour. The crystalline solid was filtered, washed with cold cyclohexane (O.080 L)₅ cold cyclohexane/heptane (2:1, 0.150 L) and dried under vacuum/Nf2 sweep to afford THP-pyrazole 4 as off white crystals (105.43 g, 93.8 wt%, 100 LCAP% purity, 93% isolated yield): m.p.69.3-70.2 ⁰C; lH NMR (400 MHz₅ CDCI3) δ 7.72 (d, J - 8.7 Hz, 1 H), 7.35-7.28 (m, 5 H), 6.19 (d, J= 8.7 Hz, 1 H), 5.87 (άd, J= 12.3, 1.9 HZ, 1 H), 4.84 (d, 7 = 12.7 Hz, 1 H), 4.81 (d, J= 12.7 Hz, 1 H), 4.62 (br s, 1 H)₅ 4.57 (d, J= 11.9 Hz, 1 H), 4.54 (d, /= 11.9 Hz, 1 H), 4.14 (m, 1 H)₅ 3.76 (m, 1 H), 2.66 (m, 1 H), 2.12 (m, 1 H)₅ 1.95 (m, 1 H), 1.86-1.73 (in, 2 H), 1.59 (m, 1 H)₅ 1.53 (s, 9 H);13CNMR (1OO MHz, CDCI3) δ 157.8,

151.6, 142.9, 138.4, 130.4, 128.4 (2 C), 128.0 (2 C), 127.6, 107.4, 106.8, 82.6, 72.2, 68.4, 66.5, 51.6, 29.7, 29.3 (3 C), 25.2, 23.5. HRMS (ESI) calculated for C23H30N4O2 (M+H) 395.2447, found 395.2431.

HPLC Conditions: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 μm, 1.5 mL/minute, 230 nm, 25 ⁰C, Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes.

THP-pyrazole 4 5.35 minutes benzyloxypyraole 3 3.14 minutes

DHP 2.86 minutes

Step d: Preparation of [6-fer/-butylamino-l-(tctrahydro-pyran-2-yl)- lH-pyrazolo[3,4-£]pyridin-3-yl]-methanol (pyrazolyl methanol 5)

Procedure 1 : Carbon Treatment Material MW Amount mmol Eq(s)

THP pyrazole 4 394.51 5-OO g 10.9 1.O0 Nuchar RGC carbon 1.5 g MTBE 70 mL

10% PoVC₅ 1.16 g 0.545 0.05

Degussa type ElOl NE/W

EtOH -70 mL

The THP-pyrazole 4 was dissolved in 40 mL of MTBE and 1.5 g of Nuchar RGC activated carbon was added. The slurry was aged at room temperature for 45 minutes and filtered through a small pad of Solka Floe and the pad was rinsed with - 30 mL of MTBE. The solvent was removed under reduced pressure and solvent switched to EtOH and a final volume of - 40 mL. To the solution was added 1.16 g of 10 % Pd/C (~ 50% wet Degussa type ElOl

NE/W). The stirred solution was placed under an atmosphere of hydrogen (20 psig) and aged at room temperature for 18 hours. HPLC analysis confirmed complete consumption of the THP pyrazole. The reaction mixture was filtered through a pad of Solka fioc eluting with - 30 mL of EtOAc. The filtrate was then concentrated under reduced pressure and flushed with EtOH (30 mL) and the final volume adjusted to 20 mL. To the EtOH solution containing the title compound (pyrazolyl methanol) was added dropwise 23 mL of water and the mixture seeded with pure pyrazolyl methanol 5. (Note: Crystallization would occur without seed, but seeding provides a more consistent product.) The slurry was aged at room temperature for 30 minutes and the remaining 20 mL of water was added over 30 minutes. The slurry was cooled to 2-5 ⁰C and was filtered. The wet cake was washed with water (2 X 20 mL) and dried under vacuum/N2 sweep for 12 hours to give the title product 5 (94%) as a white to off-white crystalline solid.

Procedure 2 -from THP pyrazole

Material MW Amount mmol Eq(s)

THP pyrazole 4 394.51 8.50 g 21.55 1.00

10% Pd/C, 3.14 g 1.08 0.08

Degussa type ElOl NE/W EtOH 70 mL

The THP-pyrazole 4 was dissolved in 40 mL of EtOH and 1.96 g of 10 % Pd/C (~ 50% wet Degussa type ElOl NE/W). The stirred solution was placed under an atmosphere of hydrogen (20 psig) and aged at room temperature for 18 hours. HPLC analysis indicated conversion at ~60%. An additional 1.14 g of catalyst was added and the reaction mixture re- subjected to the hydrogenation conditions. After an additional 5 hours, HPLC confirmed complete consumption of THP pyrazole. The reaction mixture was filtered through a pad of Solka floe eluting with ~ 40 mL of EtOAc. The filtrate was then concentrated under reduced pressure and flushed with EtOH (35 rnL) and the final volume adjusted to 30 mL. Using substantially the same procedure as described in Procedure 1, white to off-white crystals of pyrazolyl methanol 5 (93% yield) were obtained by adding water the the EtOH solution, seeding with pure pyrazolyl methanol, ageing the resulting slurry, filtering the slurry, and washing and drying the wet cake.: m.p. = 146-147 ⁰C; *H NMR (CDCI3, 400 MHz) δ 1.51 (s, 9H), 1.59 (m, IH), 1.76 (m, 2H), 1.91 (m, IH), 2.11 (m, IH)₅ 2.20-2.50 (brm, IH), 2.61 (m, IH), 3.73 (t, 1H, J = 10.8 Hz), 4.12 (d, IH, J= 11.4 Hz), 4.66 (br s, IH), 4.87 (s, 2H)₅ 5.83 (d, IH, J- 10.8 Hz), 6.19 (d, IH, J- 8.6 Hz), 7.67 (d, IH, J= 8.6 Hz); 13c NMR (CDCl3_> 100 MHz) δ 23.4, 25.2,

29.3, 29.6, 51.6, 59.1, 68.4, 82.5, 106.0, 107.4, 130.0, 145.1, 151.6, 157.8.

HPLC Conditions: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 μm, 1.5 mL/minute, 230 nm, 25 C, Eluents: Water 0.1% H3PO4 (A)₅ Acetonϊtrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes

THP-pyrazole 4 5.35 minutes pyrazolyl methanol 5 3.56 minutes toluene 4.11 minutes

Steps e, f & g: Preparation of the besylate salt of Compound A (9)

Material MW Amount Mole(s) Eq(s)

Pyrazolyl methanol 5 (95 wt%) 304.39 20.00 g 62.7 mmol 1.00

MsCl 114.55 5.13 mL 65.8 mmol 1.05 d = 1.47

Hunig's base 129.24 12.0I mL 68.9 mmol LlO d - 0.742

2-MeTHF 86.13 16O mL (8 IAg)

Biaryl ether 7 280.11 16.7 g 58.3 mmol 0.93

KI 166.00 17.69 g 107.0 mmol 1.70 K2CO3 151.90 43.3 g 313.0 mmol 5.00

MeCN 41.05 33O mL

BsOH 158.18 49.6 g 940 mmol 5.00

DCAA 128.94 77.0 mL 940 mmol 15 d = 1.57 MeCN 41.05 -10O mL

Step e - In a 500 mL round bottomed flask equipped with a stir bar and thermocouple was added the starting pyrazolyl methanol 5 (20.00 g @ 95 wt%) and 160 mL of 2-MeTHF. The resulting mixture was stirred at room temperature for 15 minutes at which point a homogeneous solution resulted. The solution was cooled in an ice bath to an internal temperature of < 5⁰C and the Hunig's base (DIPEA) was added in one portion. Then MsCl was added dropwise to the solution at such a rate that the internal temperature was maintained < 8⁰C and the mixture aged at this temperature for 45 minutes post addition of MsCL The reaction mixture was then filtered through a pad of Solka Floe eluting with ~ 100 mL of 2-MeTHF. The solvent was removed under reduced pressure and solvent switched to a final volume of ~110 mL of MeCN.

Step f - In a separate flask was added sequentially the biaryl ether 7, KI, K2CO3 and 190 mL of MeCN. To this slurry was added the above MeCN solution containing the crude mesylate 6* over a 45 minute period. The thick heterogeneous reaction mixture was aged at room temperature for 18-21 hours. The reaction mixture was then diluted with 200 mL of MTBE and 200 mL of water and the layers well mixed for 15 minutes and then allowed to separate. The organic layer was washed with water (2 X 100 mL) and assayed. The solvent was concentrated under reduced pressure and solvent switched to a final volume of 150 mL of MeCN and a KF < 200 ppm.

Step g - BsOH was added directly to the solution obtained from Step F followed by DCAA, and the resulting dark mixture was heated to 65-7O⁰C for 90 minutes at which point HPLC indicated nearly complete formation of product 9 (> 94%). The reaction mixture was cooled to room temperature and water (40 mL) was added over the course of 45 minutes. The resulting slurry was aged at room temperature for 20 hours and filtered. The wet cake was washed with - 150 mL of MeCN and then with 100 mL of MTBE and the solid dried under vacuum/N2 sweep for 5 hours to give 25.0 g (68%, 96 LCAP, 94 wt%) of the besylate salt of 9.

Recrystallization: To the crude besylate salt of 9 (2.5 g) was added 12 mL of DMF and the mixture warmed to 35 ⁰C. To the solution was added 5 mL of water and the mixture was seeded with pure besylate salt of 9 and the slurry was aged at 35⁰C for 1 hour. (Note: Crystallization would occur without seed, but seeding provides a more consistent product.) To the slurry was added dropwise 9.4 mL of water over 30 minutes. The slurry was aged for 1 hour while allowing the slurry to cool to room temperature. The slurry was filtered and the contents of the flask washed into the filter with an additional 3 mL of water. The wet cake was washed with 2 bed volumes of water and then with 2 bed -volumes of MTBE and dried under vacuum/N2 sweep for 8 hours to give 2.37 g (95%, 98 LCAP, 100 wt%) of besylate salt.

HPLC Conditions: Zorbax Eclipse Plus Cl 8 50 x 4.6 mm, 1.8 μm, 1.5 mL/mJnute_} 230 nm, 25°C, Elueπts: Water 0.1% H3PO4 (A)₅ Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes pyrazolyl methanol 5 3.56 minutes biaryl ether 7 4.43 minutes biaryl ether mesylate 6' 4.68 minutes coupled intermediate 8 6.15 minutes

Compound A (as product 9) 3.48 minutes

EXAMPLE 4

Crystalline HCl Salts of Compound A

HCI salt of Compound A

Part A

EtOH (52 L) was charged to a cylindrical vessel and heated to 51⁰C. At this temperature, the free base Compound A (923 g) was added. Heating was continued to a final temperature of 74⁰C at which point the slurry turned into a homogenous solution. The batch was then transferred through an inline filter into a round bottom flask equipped with an overhead stirrer., thermocouple and nitrogen inlet. The temperature was adjusted to 55⁰C and concentrated aqueous HCl (180 mL) was added. After 10 minutes the crystalline HCl salt began to form. The batch was cooled to 24⁰C and the solids were isolated by filtration, washed with EtOH (2 x 4L) and dried with vacuum under nitrogen to afford 804 g of crystalline HCl salt (Form I). Part B

Material MW Amount Mole EqCs) besylate salt 584.43 9.04 g 15.47 mmol 1.00

EtOAc 36O mL

6.5 wt% NaHCO3 58.3O g 45.1 mmol 2.91

0.3N HCl in IPA 45.4 mL water 9O mL

DMSO 26.6 niL

IPA 54 mL Compound A besylate salt was slurried in EtOAc (360 mL) and the slurry was heated to 5O⁰C. To the mixture was added a 6.5 wt% aqueous NaHCO3 solution (58.3 g) and the mixture became homogeneous. The layers were allowed to separate and the bottom aqueous layer was discarded. The organic layer was washed with deionized water (90 mL) at 50 ⁰C, after which the layers were allowed to separate and the bottom aqueous layer was removed. The organic layer was concentrated by removal of ethyl acetate under vacuum (50-100 mm Hg) and dimethyl sulfoxide (15.6 mL) was added to bring the batch concentration to 200 mg free base/g of solution. The resulting concentrate was added simultaneously with 0.3 N HCl in IPA (45.4 mL) to a seedbed of Compound A HCl salt (233 mg out of solution) in 1 :2 DMS(MPA (17 mL) over 8 hrs. The resulting slurry was separated by filtration, washed with 1 :2 DMSO:IPA (16 ml), then IPA (2 x 16 mL) and then vacuum dried at 50 ⁰C to afford 6.30 g of crystalline HCl salt (Form I).

Part C

An X-ray powder diffraction (XRPD) pattern of the Form I Compound A HCl crystalline salt prepared in the manner described in Part B was generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a continuous scan from 2.5 to 40 degrees 2Θ (2 theta). Copper K-Alρha 1 (Ka l) and K-Alpha 2 (K_α2) radiation was used as the source. The experiment was run under ambient conditions. The diffraction peak positions were referenced by silicon which has a 2Θ value of 28.443 degree. The XRPD pattern is shown in Figure 1. 2Θ values and the corresponding d-spacings in the XRPD pattern include the following:

A metastable crystalline form (Form II) of the Compound A HCI has been observed as a by-product when the preparation set forth in Part B is conducted without the use of seed. The XRPD pattern for this form (obtained in the manner described above for Form I) is shown in Figure 2. 2Θ values and the corresponding d-spacings in the XRPD pattern include the following:

Form II has also been prepared from the TFA salt of Compound A (see Example 37 in US 2007/0021442) by adding acetonitrile (1.2 L) to the TFA salt (11.4 g), then adding HCl (7 eqs.) in ether, stirring for 2 hours, removing the solvents with a rotary evaporator, azeotroping with methylene chloride (5x), and then collecting the HCl salt.

EXAMPLE 5

Preparation of the sulfate salt of

3 - { 5 -[(6-amino- 1 H-pyrazolo [3 ,4-b] pyridin-3-yl)methoxy] -2-chIorophenoxy } - 5 - chlorobenzonitrile 11

Steps e and f

Materials MW Amount Molefsϊ Eqfs)

Pyrazole methanol 5 (98 wt%) 304.39 75 g (98 wt%) 241 mm 1.00

MsCl 114.55 29.O g 254 mm 1.05 d -1.47 19.76 raL

Hϋnigs Base 129.24 34.3 g 266 mm 1.10 d =0.742 46.3 mL

Biaryl ether 7 280.11 67.6 g 241 mm 1.00

KJ 166.00 8.0O g 48.2 mm 0.20

K2CO3 138.21 133 g 966 mm 5.00

Step e - In a 1 L round bottomed flask equipped with a mechanical stirrer and thermocouple was added the starting benzyl methanol 5 (75 kg @ 98 wt%) and 300 mL (4 L/kg) of 2-MeTHF. The resulting heterogeneous mixture was cooled to an internal temperature of ~5°C and the Hunig's base was added in one portion. To the slurry was added dropwise MsCl at such a rate that the internal temperature was maintained less than 3O⁰C. The resulting mixture was then heated to an internal temperature of 50-55⁰C and the solution was aged at this temperature for 3 hours. The resulting hot mixture of the chloride 6" was then cooled in an ice bath to 5 ⁰C and aged at this temperature for 30 minutes and then filtered. The flask and filter cake were rinsed with 300 mL of 2-MeTHF. The resulting filtrate was then concentrated to a final volume of ~300 mL and used in the next step.

Step f - In a separate 3 L round bottom flask equipped with a mechanical stirrer and thermocouple was added the biaryl ether 7, KI, K2CO3 and 450 L of MeCN (6 L/kg based on pyrazole alcohol SM). The resulting mixture was then heated to an internal temperature of 55-60⁰C and the crude chloride solution in 2-MeTHF from Step e above was added over 20 minutes. The reaction mixture was then aged at 59⁰C for 5.5 hours and allowed to cool to room temperature and aged overnight at room temperature. The reaction mixture was diluted with IPAc (600 mL, 8 L/kg) and water (600 mL, 8 L/kg) and the layers well mixed for 15 minutes and allowed to separate. The organic layer was washed with water (375 mL) and then brine (375 mL). The solvent was concentrated under reduced pressure flushing first with IPAc to bring the KF down and then MeCN was added to a provide a final volume of 400 mL of MeCN and a KF ~ 200 ppm. The assay yield was 133 g of 8 (97%).

Ste _.p_, h-1

Materials MW Amount Molefs) Eq(S)

Coupled intermediate 8 566.48 35.9 g 63.4 mm 1.00 rt-Octanethiol 146.30 20.4 g 139 mm 2.20 d - 0.843 (24.2 mL) ccoonnee.. HH29SSOO44 9988..1100 1133..6677 g e 113399 m mmm 2.20 d = 1.84 (7.43 mL)

MTBE 13O mL

Heptane 13O mL

In a 1 L flask containing the concentrated coupled intermediate 8 resulting from

Step f (131 mL of a 274 mg/mL solution in MeCN, 35.9 g assay) was added the 1-octanethiol in one portion. The reaction mixture was cooled to 15⁰C and concentrated sulfuric acid was added while maintaining the internal temperature under 25⁰C₅ wherein the addition of the acid is exothermic. The resulting solution was aged for 30 minutes at room temperature. The resulting slurry was aged at room temperature for 30 minutes and then MTBE (130 mL) was added dropwise over 45 minutes at room temperature and the slurry aged at room temperature for an additional 30 minutes. Heptane (65 mL) was then added to the slurry over 45 minutes and the slurry aged for 30 minutes. An additional portion of heptane (65 mL) was then added over 45 minutes and the slurry aged at room temperature for 2-3 hours and filtered. The reaction flask and wet cake were washed with 100-150 mL of MTBE and the solid was dried under vacuum/N2 sweep for 3 hours. The isolated yield of 10 was 40.85 g (95%) as a crystalline bis~sulfate salt. Salt 10 is alternatively referred to herein as Compound P-A. Step h-2

Materials MW Amount MoIeCs) EaIs)

Bis-sulfate 10 678.52 53.9 g 79 mm 1.00 cone. H2SO4 98.10 2.0O g 556 mm 7.00 d = 1.84

96:4 MeCN/water 35O mL

Water 19O mL

The starting des-THP sulfate salt 10 was dissolved in 350 L (6.5 L/kg) of 96:4 MeCN/water (by volume). To the solution was added concentrated sulfuric acid and the reaction mixture was heated to 70 °C for 2 hours. The slurry was cooled to room temperature and diluted with 190 niL of water (3.5 L/kg) and the slurry aged at room temperature for 3 hours. The slurry was filtered and the wet cake washed with 150 mL (2X) of 2:1 MeCN/water and dried under vacuum/N2 sweep until dry. The isolated yield of 11 in the form of a crystalline sulfate salt was 39.8 g @ 96 wt% (92%, 98.3 LCAP).

HPLC Conditions: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 μm, 1.5 mL/minute, 230 nm, 25°C, Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 minutes, 5% A 5 minutes, 5% A 6 minutes pyrazolyl methanol S 3.56 minutes biaryl ether 7 4.43 minutes biaryl ether mesylate 6' 4.68 minutes coupled intermediate 8 6.15 minutes des-THP intermediate 10 5.13 minutes Compound A (as product 11) 3.48 minutes

EXAMPLE 6

Characterization of crystalline salts Part A - Crystalline sulfate salt of Compound P-A (10) An X-ray powder diffraction (XRPD) pattern of the crystalline salt prepared in

Step h-1 of Example 5 was generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a continuous scan from 2.5 to 40 degrees 2Θ (2 theta). Copper K- Alpha 1 (K_αl) and K-Alpha 2 (Kα2) radiation from a PW3373/00 ceramic Cu LEF

X~ray tube was used as the source. The experiment was run under ambient conditions. The diffraction peak positions were referenced by silicon which has a 2Θ value of 28.443 degrees. The XRPD pattern is shown in Figure 3. 2Θ values and the corresponding d~spacings in the XRPD pattern include the following:

Part B - Crystalline sulfate salt of Compound A (11)

An XRPD pattern of the crystalline salt prepared in Step h-2 of Example 5 was generated in the manner described in Part A above. The XRPD pattern is shown in Figure 4. 2Θ values and the corresponding d-s acin s in the XRp attern include the following:

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety into the disclosure.

Claims

WHAT IS CLAIMED IS:

A process for preparing a compound of Formula VIII:

which comprises:

(F) contacting a compound of Formula VI:

with a biaryl ether of Formula VII:

in the presence of an iodide selected from alkali metal iodides and ammonium iodide and a base F to obtain the compound of Formula VIII;

wherein:

Rl is:

(1) Cl-IO alkyl,

(2) phenyl, or

(3) C i_4 alkyl substituted with I₅ 2 or 3 phenyl groups, wherein each phenyl in (2) or (3) is optionally and independently substituted with one or more substituents each of which is independently halogen, NO2, Ci -^ alkyl, O-Ci_6 alkyl, Q-g fluoroalkyl, or O-Ci-g fluoroalkyl;

LG is a leaving group; pG2 is a nitrogen-protective group;

R3 and R.4 are each independently selected from the group consisting of hydrogen, halogen, C\.β alkyl and Ci-6 fluoroalkyl; and

IRS, R6 and R? are each independently selected from the group consisting of hydrogen, halogen, CN, Cl -6 alkyl and Cl _6 fluoroalkyl.

2. A process for preparing a compound of Formula IX in. the form of a sulfonate salt:

which comprises conducting Step F according to claim 1 to obtain the compound of Formula Vffl; and (G) treating the compound of Formula VIII with (i) phosphoric acid or a carboxylic acid selected from the group consisting of oxalic acid, acetic acid and haloacetic acids and with (ii) an organic sulfonic acid to obtain the sulfonate salt of the compound of Formula IX.

3. A process for preparing a compound of Formula IX in the form of a sulfate salt:

which comprises conducting Step F according to claim 1 to obtain the compound of Formula VIII; and

(H- 1 ) treating the compound of Formula VIII with sulfuric acid in the presence of a C i -i g alkanethiol or benzenethiol to obtain a sulfate salt of a compound of Formula VIII-A:

(H-2) treating the compound of Formula VIII-A with sulfuric acid to obtain the sulfate salt of a compound of Formula IX.

4. A process for preparing a compound of Formula IX in the form of a sulfate salt:

which comprises conducting Step F according to claim 1 to obtain the compound of Formula Viπ; and (K) treating the compound of Formula VIII with sulfuric acid to obtain the sulfate salt of a compound of Formula IX.

5. The process according to any one of claims 1 to 4, which further comprises: (E) contacting a compound of Formula V:

with an LG-producing agent to obtain a compound of Formula VI.

6. The process according to claim 5, which further comprises: (D) contacting a compound of Formula IV:

with a source of hydrogen in the presence of a hydrogenolysis catalyst to obtain the compound of Formula V; wherein pGl is a hydroxy protective group capable of being cleaved by hydrogenolysis.

7. The process according to claim 6, which further comprises: (C) contacting a compound of Foπnula HI :

with a pG2-producing agent to obtain the compound of Formula IV.

8. The process according to claim. 7, which further comprises: (A) contacting a compound of Formula I:

with an amine of Formula R.1-NH2 to obtain a compound of Formula II:

(B) contacting the compound of Formula II with a source of hydrazine to obtain the compound of Formula III.

9. The process according to any one of claims 1 to 4, wherein Rl is: (1) Ci-8 alkyl,

(2) phenyl,

(3) CH2-phenyl,

(4) diphenylmethyl, or (5) trityl wherein the phenyl in (2) or (3) is optionally substituted with one or more substituents each of which is independently Cl, Br, F₅ NO2, C 1.4 alkyl, O-C1.4 alkyl, CF3, CH2CF3, OCF3, or OCH2CF3;

LG is a halide, a sulfonate, a sulfinate, a phosphonate, a phosphinate, or an imidate;

PG2 i_S:

( 1 ) C 1 _6 alkyloxycarbonyl,

(2) tetrahydropyran-2-yl, (3) tetrahydrofuran-2-yl.

V^OR^C

(4) R^A R , wherein RA₅ RB and RC are each independently a Ci^j. alkyl; or alternatively RC is C] -4 alkyl, and R A and RB together with the carbon to which they are both attached form C 5 -6 cycloalkyl, C4-5 oxacycloalkyl, C4.-5 thiacycloalkyl, or C4-5 azacycloalkyl in which the aza nitrogen is substituted with Ci_4 alkyl, or

RL is attached and the O to which RJ is attached form C4-5 oxacycloalkyl;

R? and R4 are each independently selected from the group consisting of H, Cl, Br₅ F, C 1-4 alkyl, CF3 and CH2CF3; and

R5, RO and R? are each independently selected from the group consisting of hydrogen, Cl₅ Br₅ F, CN. C 1-4 alkyl CF3 and CH2CF3.

10. The process according to claim 9, which further comprises:

(E) contacting a compound of Formula V:

with an LG-producing agent to obtain a compound of Formula VI; wherein the LG-producing agent is:

(1 ) a hydrogen halide or a sulfonyl halide when L^ is halogen,

(2) a sulfonyl halide when LG is sulfonate,

(3) a sulfinyl halide when LG is sulfinate,

(4) a phosphonyl halide when LG is phosphonate,

(5) a phosphinyl halide when LG is phosphinate, and

(6) a cyanide when LG is an imidate; and provided that:

(i) when the LG-producing agent is (1), (2), (3), (4), or (5), then Compound V and the LG-producing agent are contacted in the presence of a base E; and

(ii) when the LG-producing agent is (6), then Compound V and the LG-producing agent are contacted in the presence of an acid E.

11. The process according to claim 10, which further comprises: (D) contacting a compound of Formula IV :

with a source of hydrogen in the presence of a hydrogenolysis catalyst to obtain the compound of Formula V; wherein the hydrogenolysis catalyst comprises supported or unsupported Pd or a supported or unsupported Pd compound, salt or complex; and PGl Js a hydroxy protective group capable of being cleaved by hydrogenolysis that is selected from the group consisting of: (1) phenyl, (2) benzyl, (3) diphenylmethyl, (4) triphenylmethyl, or (5) THP; wherein each of the one or more phenyl groups in (1), (2), (3) or (4) is optionally and independently substituted with one or more substituents each of which is independently halogen, nitro, Ci _6 alkyl, or O-Ci _g alkyl.

12. The process according to claim 11, which further comprises: (C) contacting a compound of Formula III:

with a pG2-p_roducing agent to obtain the compound of Formula IV; wherein pG2-p_roducing agent is:

(1) Ci-6 alkyl-O-C(O)-Q, wherein Q is halogen, OC(O)O-Ci_6 alkyl, or

O-N=C(-CN)-phenyl,

(2) 3,4-dihydro-2H-pyran,

(3) 2,3-dihydrofuran, R^CO^ .OR^C

(4) R R _? wherein RA₁, RB and RC are as previously defined, OR^C

R^B' (5) R , wherein (i) RA and RC are each independently a C 1-4 alkyl, and RB' is H or C 1-3 alkyl, or (ii) alternatively RC is Cj -4 alkyl and

RA and RB' together with the carbon atoms to which each is attached form C5-6 cycloalkenyl, C4-.5 oxacycloalkenyl, C4-5 thiacycloalkenyl, or C4-5 azacycloalkenyl in which the aza nitrogen is substituted with C 1.4 alkyl, or

R^MO^ .OR^J κ A. _L (6) R R , wherein RJ, RK and RL are as previously defined, and RM is C 1-4 alkyl. and provided that:

(i) when the PG2.producing agent is (1), then Compound III and the pG2_p_røducing agent are contacted in the presence of a base E; and (ii) when the pG2-p_roducing agent is (2), (3), (4), (5), or (6), then

Compound III and the pG2-producing agent are contacted in the presence of an acid E.

13. The process according to claim 12_f which further comprises: (A) contacting a compound of Formula I:

with an amine of Formula Rl -NH2 to obtain a compound of Formula II:

(B) contacting the compound of Formula II with a source of hydrazine to obtain the compound of Formula III.

14. A process for preparing a compound of Formula VIH¹;

which comprises:

(F¹) contacting a compound of Formula VI' or VI":

with biaryl ether 7:

in the presence of KI and a base F selected from alkali metal carbonates, alkali metal bicarbonates and CsF to obtain the compound of Formula VIII¹; wherein:

Rl is a branched C3.8 alkyl; and R.2 is CH3, CF3, or phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, OCH3, CF3, or OCF3.

15. A process for preparing Compound A in the form of a sulfonate salt:

Compound A,

which comprises conducting Step F' according to claim 14 to obtain the compound of Formula VIII'; and:

(G¹) treating the compound of Formula VIII' with phosphoric acid or a carboxylic acid selected from the group consisting of oxalic acid, acetic acid and haloacetic acids and with an organic sulfonic acid to obtain the sulfonate salt of Compound A.

16. A process for preparing Compound A in the form of a sulfate salt:

Compound A,

which comprises conducting Step F' according to claim 14 to obtain the compound of Formula VHI¹; and

(H¹- 1) treating the compound of Formula VIIF with sulfuric acid in the presence of a Cg.12 alkanethiol to obtain a sulfate salt of a compound of Formula VIII-A':

(H'-2) treating the compound of Formula VIII-A¹ with sulfuric acid to obtain the sulfate salt of Compound A.

17. A process for preparing Compound A in the form of a sulfate salt:

Compound A₅

which comprises conducting Step F according to claim 14 to obtain the compound of Formula VIIF; and

(K¹) treating the compound of Formula VIII' with sulfuric acid to obtain the sulfate salt of Compound A.

18. The process according to any one of claims 14 to 17, wherein Rl is t- butyl.

19. The process according to any one of claims 14 to 17, which further comprises:

(E') contacting a compound of Formula V:

with R2-S(O)2-Z and in the presence of a base E selected from tertiary amines, alkali metal hydroxides, and alkali metal carbonates to obtain a compound of Formula VI'; wherein Z is halogen.

20. The process according to any one of claims 14 to 17, which further comprises:

(E') contacting a compound of Formula V:

with CH3S(O)2CI and in the presence of abase E selected from tertiary amines to obtain a compound of Formula VI".

21. The process according to either claim 19 or claim 2O₅ which further comprises:

(D') contacting a compound of Formula IV:

with a source of hydrogen in the presence of a hydrogenolysis catalyst to obtain the compound of Formula V; wherein the hydrogenolysis catalyst comprises supported or unsupported Pd or a supported or unsupported Pd compound, salt or complex, and pGl is a hydroxy protective group capable of being cleaved by hydrogenolysis that is selected from the group consisting of benzyl, p-nitrobenzyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, phenyl, or THP.

22. The process according to claim 21, wherein PGl is benzyl.

23. The process according to claim 21 , which further comprises: (C) contacting a compound of Formula III:

with 3,4-dihydro-2H-pyran and in the presence of an. acid C to obtain the compound of Formula rV'; wherein the acid C is an organic sulfonic acid which is optionally in the form of a pyridinium salt.

24. The process according to claim 23, wherein the organic sulfonic acid is benzenesulfonic acid, pyridinium benzenesulfonate, p-toluenesulfonic acid, or pyridinium p-toluenesulfonate .

25. The process according to claim 23, which further comprises: (A') contacting a compound of Formula I:

with an amine of Formula R.I-NH2 to obtain a compound of Formula II:

(B¹) contacting the compound of Formula II with a source of hydrazine to obtain the compound of Formula III.

26. The process according to claim 25, wherein Rl is t-butyl, and pGl is benzyl.

27. A compound selected from the group consisting of: a compound of Formula I:

a compound of Formula II:

a compound of Formula IV:

a compound of Formula V:

a compound of Formula VI:

a compound of Formula VHI:

and salts thereof; wherein: lβ is a leaving group; PGI is a hydroxy protective group capable of being cleaved by hydrogenolysis;

pG2 is a nitrogen-protective group; and

Rl is:

(1) Ci-io alkyl,

(2) phenyl, or

(3) C 1-4 alkyl substituted with 1 _s 2 or 3 phenyl groups, wherein the phenyl in (2) or (3) is optionally and independently substituted with one or more substituents each of which is independently halogen, NO2, Ci -6 alkyl, O-Ci-6 alkyl, Ci_6 fluoroalkyl, or O-Ci-6 fluoroalkyl;

R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C J _β fluoroalkyl; and

R5_r R6 and R^ are each independently selected from the group consisting of hydrogen, halogen, CN₅ C 1-6 alkyl and Ci -6 fluoroalkyl.

28. A compound according to claim 27 which is selected from the group consisting of: a compound of Formula I:

a compound of Formula II:

a compound of Formula IV:

a compound of Formula V:

a compound of Formula VI':

a compound of Formula VI":

a compound of Formula VIII':

and salts thereof; wherein:

pGl is a hydroxy protective group capable of being cleaved by hydrogenolysis that is selected from the group consisting of: (1) phenyl, (2) benzyl, (3) diphenylmethyl, (4) triphenylmethyl, or (5) THP; wherein each of the one or more phenyl groups in (1), (2), (3) or (4) Is optionally and independently substituted with one or more substituents each of which is independently halogen, nitro, C 1-6 alkyl, or O-Ci-g alfcyl;

Rl is branched C3.6 alkyl; and

R2 is CH3, CF3, or phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, OCH3, CF3, or OCF3.

29. The compound according to claim 28, which is a compound selected from the group consisting of:

and salts thereof.

30. A crystalline HCl salt of Compound A:

Compound A, which is characterized by an X-ray powder diffraction pattern obtained using copper K_α radiation which comprises 2Θ values in degrees of about 13.5, 19.1 and 24.9.

31. A crystalline HCl salt of Compound A:

Compound A, which is characterized by an X-ray powder diffraction pattern obtained using copper K₀₁ radiation which comprises 2Θ values in degrees of about 13.5, 23.3 and 25.7.

32. A crystalline sulfate salt of Compound P-A:

Compound P-A, which is characterized by an X-ray powder diffraction pattern obtained using copper K_α radiation which comprises 2Θ values in degrees of about 5.3, 12.4 and 23.6.

33. A crystalline sulfate salt of Compound A:

Compound A, which is characterized by an X-ray powder diffraction pattern obtained using copper K<χ radiation which comprises 2Θ values in degrees of about 7.7, 16.8 and 25.5.