CHROMANE DERIVATIVES, SYNTHESIS THEREOF, AND INTERMEDIATES

THERETO

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States provisional patent application serial number 60/854,382, filed October 25, 2006, and United States provisional patent application serial number 60/982,091, filed October 23, 2007, the entirety of each of which is hereby incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to 5-HT _2C receptor agonists or partial agonists, processes for their preparation, and uses thereof.

BACKGROUND OF THE INVENTION

[0003] Schizophrenia affects approximately 5 million people. The most prevalent treatments for schizophrenia are currently the 'atypical' antipsychotics, which combine dopamine (D ₂ ) and serotonin (5-HT _2A ) receptor antagonism. Despite the reported improvements in efficacy and side-effect liability of atypical antipsychotics relative to typical antipsychotics, these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic side effects, such as weight gain (Allison, D. B., et. al, Am. J. Psychiatry, 156: 1686-1696, 1999; Masand, P. S., Exp. Opin. Pharmacother. I: 377-389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2:1-9, 2000).

[0004] Atypical antipsychotics also bind with high affinity to 5-HT ₂ c receptors and function as 5-HT ₂ c receptor antagonists or inverse agonists. Weight gain is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been suggested that 5-HT ₂ c antagonism is responsible for the increased weight gain. Conversely, stimulation of the 5-HT ₂ c receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., Human Psychopharmacology Jj): 385-391, 1995; Rosenzweig-Lipson, S., et. al., ASPET abstract, 2000).

[0005] Several lines of evidence support a role for 5-HT ₂ c receptor agonism or partial agonism as a treatment for schizophrenia. Studies suggest that 5-HT ₂ c antagonists increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease

Page 1 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

(Di Matteo, V., et. al, Neuropharmacology 37: 265-272, 1998; Fox, S. H., et. al, Experimental Neurology 151 : 35-49, 1998). Since the positive symptoms of schizophrenia are associated with increased levels of dopamine, compounds with actions opposite to those of 5-HT _2C antagonists, such as 5-HT ₂ c agonists and partial agonists, should reduce levels of synaptic dopamine. Recent studies have demonstrated that 5-HT ₂ c agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37: 953-955, 1998; Di Matteo, V., et. al., Neuropharmacology 3£: 1195-1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine. However, 5-HT ₂ c agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, a recent study demonstrates that 5- HT ₂ c agonists decrease firing in the ventral tegmental area (VTA), but not in the substantia nigra. The differential effects of 5-HT ₂ c agonists in the mesolimbic pathway relative to the nigrostriatal pathway suggest that 5-HT ₂ c agonists have limbic selectivity, and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.

SUMMARY OF THE INVENTION

[0006] As described herein, the present invention provides methods for preparing compounds having activity as 5HT ₂ c agonists or partial agonists. These compounds are useful for treating schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOP A-induced psychosis, psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's disease, psychosis associated with Lewy body disease, dementia, memory deficit, intellectual deficit associated with Alzheimer's disease, bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, eating disorders, epilepsy, sleep disorders, migraines, sexual dysfunction, gastrointestinal disorders, obesity and its comorbidities, or a central nervous system deficiency associated with trauma, stroke, or spinal cord injury. Such compounds include those of formula I:

I or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2;

Page 2 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

n is 0 or 1 ;

== designates a single or double bond;

Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more

R ^* groups; each R is independently -Ph, halogen, -CN, -R or -OR; each R is independently hydrogen, Ci_6 aliphatic or Ci_6 haloaliphatic; x is 0 to 3; each R ¹ is independently -R, -CN, halogen or -OR; R ² is hydrogen, Ci_3 alkyl, or -O(Ci_3 alkyl); and each of R ³ and R ⁴ is independently hydrogen, Ci_6 aliphatic or Ci_6 fluoroaliphatic. [0007] The present invention also provides synthetic intermediates useful for preparing such compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 depicts an XRD pattern for Form A of Compound II- 1 (HCl).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0009] The methods and intermediates of the present invention are useful for preparing compounds as described in United States patent application serial number 11/409,467, filed April 21, 2006, the entirety of which is hereby incorporated herein by reference. In certain embodiments, the present compounds are generally prepared according to Schemes I, II and III as set forth below, wherein each of R ¹ , R ² , R, R ^a , R ^b , CG ¹ , CG ² , x, and y, is as defined below and in classes and subclasses as described herein.

[0010] In one aspect, the present invention provides methods for preparing chiral 2,8- disubstituted chromane compounds of formulae A, B, II, and ILHX in enantiomerically enriched form according to the steps as depicted in Schemes I, II, and III. [0011] One of ordinary skill in the art will appreciate that a wide variety of reaction conditions may be employed to promote each of the synthetic transformations as depicted in Schemes I, II, and III, steps S-I to S-10; therefore, a wide variety of reaction conditions are envisioned (see generally, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5 ^th Edition, John Wiley & Sons, 2001 and Comprehensive Organic Transformaions, R. C. Larock, 2 ^nd Edition, John Wiley & Sons, 1999).

Page 3 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

Scheme I

II H HX

[0012] In step S-I, a compound of formula K with coupling group CG ¹ is reacted with a compound of formula L with coupling group CG ² via a C _sp 2-C _3p 2 coupling reaction between the carbon centers bearing complementary coupling groups (i.e., CG ¹ and CG ² ) to provide a compound of formula J. Suitable coupling reactions are well known to one of ordinary skill in the art and typically involve one of CG ¹ or CG ² being an electron-withdrawing group (e.g., Cl, Br, I, OTf, OTs, OMs etc.), such that the resulting polar carbon-CG bond is susceptible to oxidative addition by an electron-rich metal (e.g., a low-valent palladium or nickel species), and the complementary coupling group being an electropositive group (e.g., boronic acids, boronic esters, boranes, stannanes, silyl species, zinc species, aluminum species, magnesium species, zirconium species, etc.), such that the carbon which bears the electropositive coupling group is susceptible to transfer to other electropositive species (e.g., a Pd ^IWV species or a Ni ^IWV species). Suzuki coupling of boronic acids with different aryl halides is typically conducted using palladium catalysts tetrakis(triphenylphosphine) palladium (O) or another

Page 4 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

suitable source such as trα/?5-dichlorobis(tri-o-tolylphosphine)palladium (II), Pd(II)Cl ₂ (PPh ₃ ) ₂ , Pd(II)Cl ₂ (dppb) ₂ , Pd(II)(OAc) ₂ + PPh ₃ , Pd(II)(OAc) ₂ + tri(o- tolyl)phosphine (palladacycle), or Pd/C under basic conditions. Typically, the reaction base is sodium or potassium or barium hydroxide, sodium or potassium bicarbonate, sodium, potassium, cesium or thallium carbonate, cesium or potassium fluoride sodium or potssium tert-butoxide, potassium phosphate or triethylamine and the solvent includes DMF, ethanol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water, toluene/benzene and mixtures thereof and with phase transfer reagents, such as Bu ₄ NCl or 18-crown-6. Exemplary reactions include those described in Metal-Catalyzed Cross-Coupling Reactions, A. de Meijere and F. Diederich, Eds., 2 ^nd Edition, John Wiley & Sons, 2004; and Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E., de Meijere, A. Editors, Wiley: New York, NY, 2002.

[0013] In certain embodiments, CG ¹ in a compound of formula K is a boronic acid, a boronic ester, or a borane. In other embodiments, CG ¹ in a compound of formula K is a boronic ester. According to one aspect of the present invention, CG ¹ in a compound of formula K is a boronic acid.

[0014] In certain embodiments, CG ² in a compound of formula L is Br, I, OTf, OMs or

OTs. According to one aspect of the present invention, CG ² in a compound of formula L is Br.

[0015] In step S-2, the compound of formula J is deprotected by removal of group R ^a to afford a compound of formula H, wherein R ^a is a hydroxyl protecting group. Hydroxyl protecting groups, and their subsequent removal, are well known in the art and include those described in detail in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Examples of suitably protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formate, benzoyl formate, acetate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p- chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate. Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl carbonate. Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-

Page 5 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, trityl, t-butyl, and allyl ether, or derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4- dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p- cyanobenzyl, 2- and 4-picolyl ethers. In certain embodiments the R ^a group is Ci_ ₆ alkyl. In yet other embodiments the R ^a group is methyl.

[0016] The removal the R ^a group can be promoted by, for example, reaction with base

(e.g., sodium hydroxide, tetrabutylammonium hydroxide, or the like) or an acid (e.g., hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, acetic acid, camphorsulfonic acid, TFA, /?-toluenesulfonic acid, or a Lewis acid (e.g., BBr ₃ , BCl ₃ , AICI3) or the like), with a fluoride source (e.g., tetrabutylammonium fluoride, potassium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium triphenyldifluorosilicate, or the like), or by hydrogenation. In certain embodiments, the removal of the R ^a group is promoted by reaction with BBr ₃ , BCl ₃ , or AlCl ₃ . In certain embodiments, the deprotection reaction is conducted in a suitable medium. In certain embodiments, this transformation is conducted with acetic acid, diphenyl ether, dioxane, anisole, acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol, toluene, benzene, DMSO, water, diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, acetonitrile, N- methylpyrrolidine, or mixtures thereof. In certain embodiments, the removal of the R ^a group is promoted by reaction with BBr ₃ in toluene or hydrobromic acid in acetic acid. In certain embodiments, the reaction is conducted at a temperature between about 0 ⁰ C and about 100 ⁰ C.

[0017] In step S-3, a compound of formula H is reacted, via conjugate addition, with a compound of formula G to provide a compound of formula F. In certain embodiments, the above reaction step may be performed in the presence or absence of a base, and with or without heating. In certain embodiments, the conjugate addition reaction is performed in the presence of potassium carbonate, potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, triethylbenzylammonium hydroxide, 1,1,3,3-tetramethylguanidine, 1,8- diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, diisopropylethylamine,

Page 6 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

tetramethylethylenediamine, pyridine, or triethylamine. In certain embodiments, the conjugate addition reaction is performed in the presence of triethylamine. [0018] In certain embodiments, the conjugate addition reaction is carried out in a suitable medium. A suitable medium is a solvent or a solvent mixture that, in combination with the combined reacting partners and reagents, facilitates the progress of the reaction therebetween. In certain embodiments the present transformation is run in diphenyl ether, dioxane, anisole, acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol, toluene, water, diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, acetonitrile, N-methylpyrrolidine, or mixtures thereof. In certain embodiments, the reaction is performed in ethyl acetate. In other embodiments, no additional solvent is added. In still other embodiments, excess of the phenol (corresponding to the compound of formula H) is employed to serve as a solvent. In other embodiments the reaction is conducted at temperatures between about 25 ⁰ C and about 110 ⁰ C. In yet other embodiments, the reaction is conducted at about 50 ⁰ C. In other embodiments, the conjugate addition is carried out in a manner substantially similar to the procedures outlined in Ruhemann, S. J. Chem. Soc. 1900, 77, 1121, Gudi, M. N. et al. Indian J. Chem. 1969, 7, 971, Cairns, H. et al. J. Med. Chem. 1972, 15, 583, Stoermer, M. J. and Fairlie, D. P. Aust. J. Chem. 1995, 48, 677, and British Patent No. GB1262078.

[0019] In step S-A and step S-5, as depicted in Scheme I (above) and Scheme II

(below), reduction of a compound of formula F (step S-4) followed by deprotection (step S- 4) provides a compound of formula E, which then is cyclized (step S-5) to form a compound of formula D. One of ordinary skill in the art, however, will appreciate that there are alternative ways of making a compound of formula D from a compound of formula F, and such ways are contemplated in the present invention. For instance, a compound of formula F may be deprotected first, then reduced, and then cyclized to form a compound of formula D. Alternatively, a compound of formula D may be deprotected, then cyclized, and then reduced to form a compound of formula D.

Page 7 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[0020] It will be appreciated that any intermediate depicted Schemes I or II may be isolated and/or purified prior to each subsequent step. Alternatively, any intermediate depicted in Schemes I or II may be utilized in subsequent steps without isolation and/or purification. Such telescoping of steps is contemplated in the present invention. In certain embodiments, the conjugate addition step S-3, followed by the reduction and deprotection step S-4 to form a compound of formula E, are conducted without isolation and/or purification of the intermediate compounds.

[0021] In certain embodiments, the reduction reaction is a hydrogenation reaction conducted in the presence of hydrogen gas and a metal catalyst. In certain embodiments, the metal catalyst is palladium on carbon or with ZnBr ₂ , Pt/C, Ru/C, Rh/C, PtO ₂ . In yet other embodiments, the palladium catalyst is palladium (II) hydroxide. In still other embodiments, the hydrogenation reaction can be run in methanol, ethanol, ethyl acetate, or acetic acid, THF, isopropanol. In yet other embodiments, the hydrogenation is conducted in the presence of sulfuric acid, acetic acid, or both. In still other embodiments, the hydrogenation is conducted as described in Witiak, D. T. et al. J. Med. Chem. 1975, 18, 934. In still other embodiments, the hydrogenation reaction, described above and herein, is conducted at pressures at about 50 psi (H ₂ ) or above, and in certain embodiments, the hydrogenations are conducted with heating of the reaction mixture. In other embodiments, the hydrogenations are conducted at temperatures between about 30 ⁰ C and about 50 ⁰ C. In other embodiments, the reduction reaction is a chemical reduction conducted in the presence of zinc powder in acetic acid.

Page 8 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[0022] It was surprisingly found that performing the reduction step S-4 by hydrogenation in acidic medium resulted in a more efficient reaction and a reduction of undesired dehalogenated compounds of formula E. Thus, according to another embodiment, the present invention provides a method for the synthesis of compounds of formula E, as depicted in Scheme I and II, and E-I, as depicted in Scheme III below, by reaction of a compound of formula H or H-I with a compound of formula G, followed by hydrogenation in acidic media, to provide a compound of formula E or E-I. In certain embodiments, the acidic medium can include acetic acid, sulfuric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, phosphoric acid, or a mixture thereof. In certain embodiments, the acidic medium is a sulfuric acid/acetic acid mixture. Scheme III

S-3a S-4a

H-I F-4 E-I

[0023] Each R ^b group of a compound of formulae G and F, and of the intermediate compounds shown in Scheme II and III, is a suitable carboxylic acid protecting group, and is selected from, but is not limited to, alkyl, alkenyl, phenyl, benzyl, or trialkylsilyl. In certain embodiments, each R ^b group is independently selected from methyl, ethyl, t-butyl, allyl, benzyl, phenyl, trimethylsilyl, or tert-butyl dimethyl silyl. In other embodiments, each R ^b is ethyl. The removal the R ^b group can be promoted by, for example, reaction with base (e.g., sodium hydroxide, tetrabutylammonium hydroxide, or the like) or acid (e.g., hydrochloric acid, acetic acid, sulfuric acid, acetic acid, camphorsulfonic acid, /?-toluenesulfonic acid, or the like), with a fluoride source (e.g., tetrabutylammonium fluoride, potassium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium triphenyldifluorosilicate, or the like), by hydrogenation, and optionally with heating of the reaction mixture. In certain embodiments, the removal of the R ^b group is promoted by reaction with sodium hydroxide. In other embodiments, the reaction is promoted by reaction with hydrochloric acid. In yet other embodiments, the reaction is promoted by reaction with HCl/AcOH. In certain embodiments, the deprotection reaction is conducted in a suitable medium. In certain embodiments, this transformation is conducted with ethanol, methanol, isopropanol, acetic acid, or tetrahydrofuran as solvent, or with mixtures of the aforementioned solvents and/or water. In certain embodiments, the reaction is conducted at a temperature between about 40 ⁰ C and about 100 ⁰ C.

Page 9 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[0024] In step S-5, a compound of formula E is cyclized to afford a compound of formula D. In certain embodiments, the cyclization is promoted by treating a compound of fomula E with a suitable Brønsted acid. Exemplary acids include hydrochloric, sulfuric, phosphoric, polyphosphoric, methanesulfonic, Eaton's reagent (P ₂ O ₅ ZMeSO ₃ H), chlorosulfonic, camphorsulfonic, and /?-toluenesulfonic. In other embodiments, additional reagents are employed, including, for example, phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, acetyl chloride, or acetic anhydride. One of ordinary skill in the art will recognize that some of the conditions described will promote formation of an intermediate acylchloride prior to undergoing Friedel-Crafts cyclization mediated by a Lewis acid such as AlCl ₃ . In yet another embodiment, the reaction is conducted with acetyl chloride or water as solvent. In still other embodiments, the cyclization is conducted as described in Ruhemann, S. J. Chem. Soc. 1900, 77, 1121, Gudi, M. N. et al. Indian J. Chem. 1969, 7, 971, Cairns, H. et al. J. Med. Chem. 1972, 15, 583, Stoermer, M. J. and Fairlie, D. P. Aust. J. Chem. 1995, 48, 677, and British Patent No. GB1262078.

[0025] In step S-6, the ketone functional group of a compound of formula D is reduced to a methylene group to provide a compound of formula C. One of ordinary skill in the art will appreciate that a wide variety of reaction conditions may be employed to promote this reduction; therefore, a wide variety of reaction conditions are envisioned (see generally, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5 ^th Edition, John Wiley & Sons, 2001 and Comprehensive Organic Transformaions, R. C. Larock, 2 ^nd Edition, John Wiley & Sons, 1999). In step S-6, the reaction is performed using a suitable reducing agent. Suitable reducing agents include, but are not limited to, H ₂ (g) with palladium or platinum catalysts, cyclohexene with Pd/C (catalytic transfer hydrogenation), Zn/HCl, Li/NH ₃ , Raney Ni, trialkylsilyl hydride (e.g., Et ₃ SiH), sodium borohydride, or lithium aluminum hydride, or the like. In certain embodiments, the reaction is performed in trifluoracetic acid, acetic acid, ethyl acetate, tetrahydrofuran, dioxane, or diethylether. In other embodiments, the reaction is performed at a temperature between about -25 ⁰ C to 80 ⁰ C.

[0026] In step S-7, a carboxylic acid of formula C is subjected to resolution using a suitable chiral species to provide an enantiomerically enriched compound of formula B. In certain embodiments, the suitable chiral species is a chiral amine. In certain embodiments, the chiral amine is (R)-I -phenyl-propylamine, (-)-cinchonidine, R-(-)-epinephrine, (+)-

Page 10 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

cinchonine, (-)-strychnine, or -(-)-l-(l-naphthyl)-ethylamine. In yet other embodiments, the chiral amine is (-)-cinchonidine.

[0027] According to one aspect of the present invention, a mixture of enantiomers of formula C is allowed to react with an enantiomerically enriched chiral amine, and the diastereomeric excess of the resulting salts is increased by selective crystallization of one of the diastereomers over the others. According to yet another aspect of the present invention, the chiral amine employed in the aforementioned crystallizations is (-)-cinchonidine. In certain embodiments, the diastereomeric salts are formed by combining enantiomers of formula B with enantioenriched chiral amine in methanol, ethanol, isopropanol, dichloromethane, acetonitrile, ethyl acetate, dimethylformamide, isopropyl acetate, hexanes, heptane, tetrahydrofuran, cyclohexane, benzene, toluene, xylenes, diethyl ether, tert-butyl methyl ether, water, or a mixture thereof, followed by optional heating to temperatures as high as the reflux temperature of the solvent used. In other embodiments, the aforementioned diastereomeric salts are formed in refluxing acetonitrile and water. In certain embodiments, the crystallization of diastereomeric salts of compounds of formula B is from a solution in methanol, ethanol, isopropanol, dichloromethane, acetonitrile, ethyl acetate, dimethylformamide, isopropyl acetate, hexanes, heptane, tetrahydrofuran, cyclohexane, benzene, toluene, xylenes, diethyl ether, tert-butyl methyl ether, water, or a mixture thereof. In other embodiments, said crystallization is from a solution in acetonitrile and water. In yet other embodiments, the crystallization occurs on cooling of a heated solution of the salt. In certain embodiments, the solution is heated as high as the reflux temperature of the solvent and cooled to as low as 10 ⁰ C. Compounds of formula B can be obtained from the diastereomeric salts by treatment with a suitable acid in a suitable solvent. One of ordinary skill in the art will appreciate that a wide variety of acids and solvents are appropriate for this purpose, thus a large variety thereof is envisioned. In certain embodiments, the suitable acid is hydrochloric acid and the suitable solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, water, or a mixture thereof. According to another aspect of the present invention, the above- mentioned selective crystallization procedures are optionally repeated to further increase the enantiomeric or diastereomeric excesses of the compounds that are being crystallized. [0028] It will be appreciated that enantioenrichment of a compound of formula B also results in enrichment of the opposite enantiomer (i.e., ent-ε>). Accordingly, it is contemplated that both enantiomers may be obtained in enriched form. Accordingly, in another aspect of the present invention, a mixture of enantiomers of formula C is dissolved in a suitable solvent

Page 11 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

and the opposite enantiomer of B (ent-B) is crystallized therefrom to afford a crystalline product that is further enriched in a single enantiomer and a mother liquor enriched in the enantiomer B. Alternatively, in another aspect of the present invention, a mixture of enantiomers of formula C is dissolved in a suitable solvent and the enantiomer B is crystallized therefrom to afford a crystalline product B that is further enriched in a single enantiomer and a mother liquor enriched in the opposite enantiomer ent-B. In certain embodiments, the suitable solvent is selected from methanol, ethanol, isopropanol, dichloromethane, acetonitrile, ethyl acetate, isopropyl acetate, hexanes, heptane, tetrahydrofuran, cyclohexane, benzene, toluene, xylenes, diethyl ether, tert-butyl methyl ether, water, or a mixture thereof. In other embodiments, the mixture of enantiomers of formula C is dissolved in a suitable solvent at a temperature between about 70 ⁰ C and about 90 ⁰ C. In certain embodiments, the crystallization occurs on cooling of a heated solution of enantiomers of formula C and the mother liquor is collected to obtain the enantiomer B in enriched form. Alternatively, in certain embodiments, the crystallization occurs on cooling of a heated solution of enantiomers of formula C and the solid is collected to obtain the enantiomer B in enriched form.

[0029] One skilled in the art will appreciate that said mother liquor enriched in opposite enantiomer ent-B may be recycled by methods that racemize the stereocenter, thereby forming a racemic mixture that can once again be resolved as described in step S-7. In certain embodiments, this recycling method is carried out in a manner described in example 8 (infra). Such recycling methods are advantageous in that they improve atom economy and cost-effectiveness of the overall synthetic process. Thus, in certain embodiments, the present invention provides a method for preparing compound of formula B from a compound of formula ent-B comprising the step of racemizing the stereocenter to form a compound of formula C-I and isolating a compound of formula B as described herein. [0030] One skilled in the art will appreciate that enantiomeric enrichment of a compound of formula C may be accomplished using a variety of methods, including the aforementioned technique of resolution. Exemplary methods include (a) the separation of

Page 12 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

enantiomers by chiral chromatographic methods, (b) selective crystallization of one enantiomer over the other, optionally by seeding a solution of the mixture of enantiomers with a crystal enriched in the desired enantiomer, (c) selective reaction of one enantiomer over the other with an enantioenriched chiral reaction partner, and (d) selective reaction of one enantiomer over the other through chiral catalyst-promoted transformations (including enzymatic transformations: Pseudomonas fluorencens (aka: Amano Lipase AK)). For the above methods, see generally, Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Silen, 1994; Enantiomers, Racemates and Resolutions, Jacques, et al. Wiley Interscience, New York, 1981; Wilen, S. H. et al, Tetrahedron 1977, 33, 2725; Tables of Resolving Agents and Optical Resolutions, Wilen, S. H. (E. L. Eliel, Ed.), Univ. of Notre Dame Press, Notre Dame, IN 1972. One of ordinary skill in the art will recognize that for those methods in which both enantiomers of the compound of interest are converted by chemical means to a different chemical entity, a subsequent step (or subsequent steps) will be necessary to reacquire the initial compounds.

[0031] As used herein, the term "enantiomerically enriched" or "enantiopure" denotes that one enantiomer makes up at least 75% of the preparation. In certain embodiments, the terms denote that one enantiomer makes up at least 80% of the preparation. In other embodiments, the terms denote that at least 90% of the preparation is one of the enantiomers. In other embodiments, the terms denote that at least 95% of the preparation is one of the enantiomers. In still other embodiments, the terms denote that at least 97.5% of the preparation is one of the enantiomers. In yet another embodiment, the terms denote that the preparation consists of a single enantiomer to the limits of detection (also referred to as "enantiopure"). As used herein, when "enantioenriched" or "enantiomerically enriched" are used to describe a singular noun (e.g., "an enantioenriched compound of formula B"), it should be understood that the "compound" or "acid" may be enantiopure, or may in fact be an enantioenriched mixture of enantiomers. Similarly, when "racemic" is used to describe a singular noun (e.g., "a racemic compound of formula C"), it should be understood that the term is in fact describing a 1 :1 mixture of enantiomers.

[0032] One of ordinary skill in the art will also recognize that compounds of formulae

E, D, C, B, A, II, and ILHX contain a stereogenic carbon. Accordingly, this invention encompasses each individual enantiomer of compounds of formulae E, D, C, B, A, II, and ILHX as well as mixtures thereof. While a single stereochemical isomer is depicted for formulae B, A, II, and ILHX in Scheme I, it will be appreciated that the present invention

Page 13 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

encompasses mixtures of enantiomers of these formulae that are enriched in either enantiomer via methods of the present invention.

[0033] In step S-8, a carboxylic acid of formula B is amidated to provide a compound of formula A. In certain embodiments, the amidation is conducted by first reacting the carboxylic acid with an appropriate reagent (e.g., by reaction with thionyl chloride, oxalyl chloride, or the like) to form an activated carbonyl, and subsequently treating the activated species with a source of ammonia. In certain embodiments, the source of ammonia is ammonia gas or solution of ammonia in a suitable solvent. Suitable solvents include tetrahydrofuran toluene, heptane, tert-butyl methyl ether, diethyl ether, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, or water (e.g., NH ₄ OH). [0034] In other embodiments, this reaction is conducted by first activating the carboxylic acid to facilitate acylation by reaction with oxalyl chloride and subsequently treating the activated species with NH ₄ OH. In still other embodiments, the reaction is performed in toluene, benzene, ethyl acetate, dichloromethane, chloroform, dichloroethane, combinations thereof. In other embodiments, the reaction is performed at a temperature between about -10 ⁰ C and 150 ⁰ C. In still other embodiments, the reaction is performed at a temperature between about 0 ⁰ C and about 50 ⁰ C. In yet other embodiments, the reaction is conducted in a manner substantially similar to that described in Zhang et al., Tetrahedron Lett. 45:5229 (2004); Benz, "Synthesis of Amides and Related Compound" in Comprehensive Organic Synthesis, Trost, B. M., Editor, Pergamon Press: New York, NY, Vol. 6; Bailey et al., "Amides" in Comprehensive Organic Functional Group Transformation, Katritzky, et. al. Editors, Pergamon: New York, NY, Vol. 5; and PCT Publication No. WO05037817.

[0035] In step S-9, an amide of formula A is reduced to form an amine of formula II.

In certain embodiments, the reduction step is performed by treating a compound of formula A with Red-Al [sodium bis(2-methoxyethoxy)aluminumhydride], BH3-THF, diborane, or lithium aluminum hydride. In other embodiments, the reduction step is run in toluene, benzene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, or a mixture thereof. In certain embodiments, the reduction step is run at a temperature between about -40 ⁰ C and about 100 ⁰ C. In other embodiments, the reduction step is run at a temperature between about 0 ⁰ C and 40 ⁰ C. In still other embodiments the reduction is conducted in a manner substantially similar to that described in Gross, Tetrahetron Lett. 44:8563 (2003); WO05037817; WO03040382; WO02020507; or DE10120619. In certain embodiments, the reduction of amide to amine can be accomplished using borane amines such as triethylamine

Page 14 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

borane, trimethylamine borane, t-butylamine borane, diisopropylethylamine borane, diethylaniline borane (DEANB), pyridine borane, and morpholine borane. Other suitable amine boranes are well known in the art. In certain embodiments, the amine borane is DEANB or triethylamine borane. In certain embodiments, the reaction can be performed neat in the amine borane or in an organic solvent such as acetonitrile, tetrahydrofuran or 2- methyl tetrahydrofuran. In certain embodiments, the temperature of the reaction can range from 20 ⁰ C to 100 ⁰ C. In certain embodiments, the temperature is > 60 ⁰ C. The reaction is generally completed in > 20 hr. A typical procedure is to add the amine borane to the amide starting material with or without solvent. The mixture is heated to 60 ⁰ C or above until reaction completion. Additional amine borane can be added to drive the reduction to completion. In certain embodiments, upon completion of the reaction, the free base is not isolated but directly converted to its hydrochloride salt as previously described. [0036] Each R ¹ group of formulae K, J, H, F, E, D, C, B, A, II, and ILHX is independently halogen, -CN, -R, or -OR, wherein each R is independently hydrogen, Ci_6 aliphatic or Ci_6 haloaliphatic, and x is 0 to 3. Examples of suitable R ¹ groups include hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro. In certain embodiments, R ¹ is hydrogen.

[0037] Each R ² group of formulae J, H, F, E, D, C, B, A, II, and II-HX is independently Ph, halogen, -CN,-R, or -OR, wherein each R is independently hydrogen, Ci_ ₆ aliphatic or Ci_6 haloaliphatic, and y is 0 to 5. Examples of suitable R ² groups include methyl, ethyl, isopropyl, chloro, fluoro, methoxy, trifluoromethyl, phenyl, cyano, ethoxy, trifluoromethoxy, and isopropyloxy. According to one aspect of the present invention, R ² is chloro.

[0038] According to another aspect of the present invention, at least one R ² in Ring B of compounds of formulae J, H, F, E, D, C, B, A, II, and ILHX, is located at one of the two ortho ring positions. According to yet another aspect of the present invention, an R ² group is located at each of the two ortho ring positions. In certain embodiments, Ring B is selected from those moieties depicted in Table 1, below, wherein the «>, represents the point of attachment of Ring B to Ring A.

[0039] It is further recognized that atropisomers of the present compounds may exit.

The present invention thus encompasses atropisomeric forms of compounds of formulae II and ILHX as defined above and in Table 1, and in classes and subclasses described above and herein.

Page 15 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

Table 1

Vl VII VIII IX

XII XIII XIV XV

XVII XVIII XIX XX

Page 16 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[0040] One of ordinary skill in the art will appreciate that a compound of formula II, as prepared by the methods of the present invention, may be treated with a suitable Brønsted acid, HX, as depicted in step S-IO, to form a salt thereof (represented by formula II-HX), wherein X is the conjugate base of the acid. Exemplary acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid. According to one aspect of the present invention, a compound of formula II is treated with HCl to form a compound of formula ILHX wherein X is the chorine anion. In certain embodiments, where the acid is HCl, it is introduced to a compound of formula II in gaseous form. In other embodiments, the acid is introduced into a solution comprising a compound of formula II. Suitable solutions include, but are not limited to, methanol, ethanol, isopropanol, water, or a mixture thereof. In yet another embodiment, the acid is introduced into a solution comprising the compound of formula II and isopropanol.

[0041] As used herein, the term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" or "cycloaliphatic"), that has a single point of attachment to the rest of the molecule. In certain embodiments, aliphatic groups contain 1-6 carbon atoms, and in yet other embodiments, aliphatic groups contain 1-3 carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

Page 17 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

Such groups include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0042] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0043] The term "alkyl," as used herein, refers to a hydrocarbon chain having up to 6 carbon atoms, e.g., 1 to 6. The term "alkyl" includes, but is not limited to, straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, iso-pentyl, 1 -methyl-butyl, 2-methyl-butyl, n-hexyl, 1-methyl-pentyl, 2- methyl-pentyl, 3-methyl-pentyl, or 4-methyl-pentyl.

[0044] The terms "halogen" or "halo," as used herein, refer to a chloro (-Cl), bromo (-

Br), fluoro (-F) or iodo (-1) atom.

[0045] The term "haloaliphatic," as used herein, refers to an aliphatic group, as defined herein, that has one or more halogen substituents. In certain embodiment, every hydrogen atom on said aliphatic group is replaced by a halogen atom. Such haloaliphatic groups include -CF ₃ .

[0046] The term "fluoroaliphatic, "as used herein, an aliphatic group, as defined herein, that has one or more fluorine substituents. In a certain embodiment, a fluoroaliphatic group is a fluoroalkyl group.

[0047] The term "fluoroalkyl," as used herein, refers to an alkyl group, as defined herein, that has one or more fluorine substituents. In certain embodiment, every hydrogen atom on said alkyl group is replaced by a fluorine atom.

[0048] The term "Ph," as used herein, refers to a phenyl group.

[0049] The term "alkenyl," as used herein refers to an aliphatic straight or branched hydrocarbon chain having 2 to 8 carbon atoms that may contain 1 to 3 double bonds.

Examples of alkenyl groups include vinyl, prop-1-enyl, allyl, methallyl, but-1-enyl, but-2- enyl, but-3-enyl, or 3,3-dimethylbut-l-enyl. In some embodiments, the alkenyl is preferably a branched alkenyl of 3 to 8 carbon atoms.

[0050] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes acid addition salts, that is salts derived from treating a compound of formula II with an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, or similarly known acceptable acids. Where a compound

Page 18 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

of formula I contains a substituent with acidic properties, the term also includes salts derived from bases, for example, sodium salts. In certain embodiments, the present invention provides the hydrochloride salt of a compound of formula II.

[0051] According to another aspect, the present invention provides a method for preparing a compound of formula ILHX:

wherein: x is 0 to 3; y is 0 to 5; each R ¹ is independently -R, -CN, halogen or -OR; each R ² is independently -Ph, halogen, -CN, -R or -OR; each R is independently hydrogen, Ci_6 aliphatic or Ci_6 haloaliphatic; and X is the conjugate base of a suitable acid, comprising the steps of: (a) providing a compound of formula II:

wherein: x is 0 to 3; y is 0 to 5; each R ¹ is independently -R, -CN, halogen or -OR; each R ² is independently -Ph, halogen, -CN, -R or -OR; and each R is independently hydrogen, Ci_6 aliphatic or Ci_6 haloaliphatic; and

(b) contacting said compound of formula II with said suitable acid of formula HX to form a compound of formula ILHX.

[0052] As defined above, in compounds of formulae II and ILHX, x is 0 to 3, y is 0 to 5, each R ¹ is independently halogen, -CN, -R, -OR; each R is independently hydrogen, Ci_6 aliphatic or Ci_6 haloaliphatic; and each R ² is independently -Ph, halogen, -CN, -R or -OR.

Page 19 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

In certain embodiments, x is 0 to 2. In other embodiments, x is 0. In certain embodiments, y is 2 to 3. In other embodiments, y is 2. In certain embodiments, R ¹ is fluoro or chloro. In other embodiments, R ¹ is fluoro. In some embodiments, R ¹ is hydrogen. In certain embodiments, R ² is fluoro, chloro, or Ci ₃ aliphatic. In other embodiments, R ² is chloro. [0053] As defined above, in compounds of formulae II and ILHX, Ring A is substituted with an R ¹ group at the open meta position relative to the carbon bearing Ring B. In other embodiments, Ring B is substituted with at least one R ² group at a position ortho to the carbon bearing Ring A. In yet other embodiments, Ring B is substituted at each position ortho to the carbon bearing Ring A with an R ² group. In yet other embodiments, Ring B is selected from those moieties depicted in Table 1 (above) wherein the «» represents the point of attachment of Ring B to Ring A.

[0054] HX in the reaction step above is a suitable Brønsted acid, and X is the conjugate base of the acid. Exemplary Brønsted acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid.

[0055] In certain embodiments, X is the conjugate base of the following suitable

Brønsted acids: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, or benzoic acid. In other embodiments, X is chloro. [0056] According to one aspect of the present invention, a compound of formula II is

0 treated with HCl to form a compound of formula ILHX wherein X is Cl. In certain embodiments, where the suitable acid is HCl, the acid is introduced into the medium containing the compound of formula II in gaseous form. In other embodiments, the acid is introduced into the medium containing the compound of formula II as a solution comprising methanol, ethanol, isopropanol, or water, or a mixture thereof. In yet other embodiments, the acid is introduced into the medium comprising the compound of formula II and isopropanol. [0057] In certain embodiments, the compound of formula H-HX is selected from the group of compounds formed by combining those compounds of formula II depicted in Table 2 with a suitable Brønsted acid. In other embodiments, the compound of formula ILHX is selected from those salts formed by combining compound II— 1 with a suitable Brønsted acid. In yet another embodiment, the compound of formula H-HX is the HCl salt of compound II- 1 (e.g., compound H-I(HCl). [0058] In certain embodiments, the compound of formula ILHX is isolated by crystallization. One of ordinary skill in the art will appreciate that a compound of formula II

Page 20 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

or formula ILHX can be purified by crystallization from a standard organic mediums such as, for example, methanol, ethanol, isopropanol, dichloromethane, acetonitrile, ethyl acetate, hexanes, heptane, tetrahydrofuran, cyclohexane, benzene, toluene, xylenes, diethyl ether, tert-butyl methyl ether, water, or a mixture thereof. One of ordinary skill in the art will also appreciate that varying crystallization conditions can provide a compound of formula II or formula ILHX with differing levels of purity, for example, higher or lower enantiomeric or isomeric purity as determined by analytical methods (e.g., NMR, LCMS, or HPLC), compared to the level of purity of a compound of formula II or formula H-HX before the crystallization. Therefore, in other embodiments, the crystallization is optionally repeated until the compound of formula H-HX is of desired purity. In yet another embodiment, crystallization increases the enantiomeric excess of the crystalline product, and is optionally conducted by seeding the solution of the enantiomers of formula H-HX with one or more crystals of the same that is enriched in the desired enantiomeric form. In yet another embodiment, this crystallization step serves as the only isolation or purification step for compounds of this formula.

[0059] Exemplary compounds of formula II are set forth in Table 2 (below).

Table 2

11-11 π-12 π-13 π-14 π-15

Page 21 of 58

Attorney Docket No 2004658-1130 (AM102450) 426261 Iv2

Page 22 of 58

Attorney Docket No 2004658-1130 (AM102450) 426261 Iv2

Page 23 of 58

Attorney Docket No 2004658-1130 (AM102450) 426261 Iv2

[0060] In certain embodiments, a compound of formula II is selected from compounds

II— 1, II-8, and 11-47. In yet other embodiments, a compound of formula II is compound II- 1.

[0061] According to another embodiment, the present invention provides a method for preparing a compound of formula II:

wherein x, y, R, R ¹ and R ² are as defined herein; comprising the steps of:

(a) providing a corresponding compound of formula A:

and

(b) reducing said compound of formula A to afford said compound of formula II. [0062] For compounds of formula A, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX. [0063] In the above reaction step, the amide moiety in a compound of formula A is reduced to an amine. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed to reduce an amide, therefore, a wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999).

Page 24 of 58

Attorney Docket No 2004658-1130 (AM102450) 426261 Iv2

Suitable reducing agents include, but are not limited to, Red-Al [sodium bis(2- methoxyethoxy)aluminumhydride], BH3-THF, diborane, and lithium aluminum hydride. In other embodiments, the reduction step is run in toluene, benzene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, or a mixture thereof. In certain embodiments, the reduction step is run at a temperature between about -40 ⁰ C and about 100 ⁰ C. In other embodiments, the reduction step is run at a temperature between about 0 ⁰ C and about 80 ⁰ C. In still other embodiments the reduction is conducted in a manner substantially similar to that described in Gross, J. L. Tetrahetron Lett. 2003, 44, 8563; Mayweg, A. et al, U.S. patent application publication number US 05250769 (2005); Devant, R. et al, International patent application publication number WO 05037817 (2005); Mitsuda, M. et al, International patent application publication number WO 03040382 (2003); Bokel, H. et al, International patent application publication number WO 02020507 (2002); or Bokel, H. et al,, German patent application publication number DE 10120619 (2002). In certain embodiments, the reduction of amide to amine can be accomplished using borane amines such as triethylamine borane, trimethylamine borane, t-butylamine borane, diisopropylethylamine borane, diethylaniline borane (DEANB), pyridine borane, and morpholine borane. Other suitable amine boranes are well known in the art. In certain embodiments, the amine borane is DEANB or triethylamine borane. In certain embodiments, the reaction can be performed neat in the amine borane or in an organic solvent such as acetonitrile, tetrahydrofuran or 2-methyl tetrahydrofuran. In certain embodiments, the temperature of the reaction can range from 20 ⁰ C to 100 ⁰ C. In certain embodiments, the temperature is > 60 ⁰ C. The reaction is generally completed in > 20 hr. A typical procedure is to add the amine borane to the amide starting material with or without solvent. The mixture is heated to 60 ⁰ C or above until reaction completion. Additional amine borane can be added to drive the reduction to completion. In certain embodiments, upon completion of the reaction, the free base is not isolated but directly converted to its hydrochloride salt as previously described.

[0064] According to another embodiment, the present invention provides a method for preparing a compound of formula A:

wherein x, y, R, R ¹ and R ² are as defined herein;

Page 25 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

comprising the steps of:

(a) providing a corresponding compound of formula B:

and

(b) amidating said compound of formula B to afford said compound of formula A. [0065] For compounds of formula A and B, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX. [0066] In the above reaction step, a compound of formula B is amidated to afford a compound of formula A. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed to amidate compounds of formula G, therefore, a wide variety of conditions are envisioned; see generally, March (2001); Larock (1999); Benz, G. "Synthesis of Amides and Related Compounds." in Comprehensive Organic Synthesis, Trost, B. M., Editor, Pergamon Press: New York, NY, Vol. 6; and Bailey, P. D. et al. "Amides" in Comprehensive Organic Functional Group Transformation, Katritzky, et. al. Editors, Pergamon: New York, NY, Vol. 5. In certain embodiments, the amidation is conducted by first reacting the carboxylic acid with an appropriate reagent (e.g., by reaction with thionyl chloride, oxalyl chloride, or the like) to form an activated carbonyl, and subsequently treating the activated species with a source of ammonia. In certain embodiments, the source of ammonia is ammonia gas or solution of ammonia in a suitable solvent. Suitable solvents include tetrahydrofuran toluene, heptane, tert-hvXy\ methyl ether, diethyl ether, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, dichloroethane, or water (e.g., NH ₄ OH).

[0067] In other embodiments, this reaction is conducted by first activating the carboxylic acid to facilitate acylation by reaction with SOCl ₂ and subsequently treating the activated species with NH ₄ OH. In still other embodiments, the reaction is performed in toluene, benzene, ethyl acetate, dichloromethane, chloroform, dichloroethane, combinations thereof. In other embodiments, the reaction is performed at a temperature between about -10 ⁰ C and 150 ⁰ C. In still other embodiments, the reaction is performed at a temperature between about 50 ⁰ C and about 100 ⁰ C. In yet other embodiments, the reaction is conducted in a manner substantially similar to that described in Zhang et al., Tetrahedron Lett. 45:5229

Page 26 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

(2004); Benz, "Synthesis of Amides and Related Compound" in Comprehensive Organic Synthesis, Trost, B. M., Editor, Pergamon Press: New York, NY, Vol. 6; Bailey et al., "Amides" in Comprehensive Organic Functional Group Transformation, Katritzky, et. al. Editors, Pergamon: New York, NY, Vol. 5; and PCT Publication No. WO05037817. [0068] According to another embodiment, the present invention provides a method for preparing a compound of formula B:

wherein x, y, R, R ¹ and R ² are as defined herein; comprising the steps of:

(a) providing a corresponding compound of formula C-I:

(b) treating the compound of formula C-I with a non-racemic chiral amine to afford a mixture of diastereomeric salts;

(c) selectively crystallizing one of the diastereomeric salts to afford a diastereomerically enriched mixture of salts; and

(d) recovering the compound of formula B in enantioenriched form from the diastereomerically enriched salt thereof.

[0069] For compounds of formula B and C-I, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX. [0070] In the above reaction step, the carboxylic acid of formula C-I is resolved to provide the enantiomerically enriched compound of formula B. One of ordinary skill in the art will recognize that there are a wide variety of resolution conditions that can be employed, therefore, a wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999). In a certain embodiment, the chiral amine in the above resolution step is (R)-I -phenyl-propylamine, (-)-cinchonidine, R-(-)-epinephrine, (+)-cinchonine, (-)- strychnine, or -(-)-l-(l-naphthyl)-ethylamine. In yet other embodiments, the chiral amine

Page 27 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

is (-)-cinchonidine. In yet other embodiment, the chiral amine is (-)-cinchonidine. In a certain embodiment, the chiral amine can be from 0.3 to 2 molar equivalents to the amount of the racemic acid, preferably, the amount is from 0.5 to 1 equivalents. In certain embodiments, the crystallization in step (c) is conducted in acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, diethyl ether, tert-butyi methyl ether, benzene, toluene, dichloromethane, water or the like, or a mixture thereof. In certain embodiments, the acid is liberated in step (d) by treating the salt with hydrochloric acid or sulfuric acid. In other embodiments, step (d) is conducted in isopropyl acetate, water, or mixtures thereof. In other embodiments, the resolution step is conducted in a manner substantially similar to that described in Wigerinck, P. T. B. P. et ah, International patent application number WO 9929687 Al (1999); Van Lommen, G. R. E. et ah, European patent application publication number EP 145067 A2 (1985); or Schaff, T. K. et al. J. Med. Chem. 1983, 26, 328. In certain embodiments, the present invention provides a method for preparing compound of formula B from a compound of formula ent-B comprising the step of racemizing the stereocenter to form a compound of formula C-I, as described herein.

[0071] According to another embodiment, the present invention provides a method for preparing a compound of formula C-I:

wherein x, y, R, R ¹ and R ² are as defined herein: comprising the steps of:

(a) providing a corresponding compound of formula D:

and

(b) reducing said compound of formula D to afford said compound of formula C-I.

[0072] For compounds of formula C-I (e.g., C) and D, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX.

Page 28 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[0073] In the above reaction step, the ketone moiety in a compound of formula D is reduced to a methylene group. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed to reduce a ketone to a methylene, therefore, a wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999). Suitable reducing agents for the above reaction step include H ₂ (g) with palladium or platinum catalysts, cyclohexene with Pd/C (catalytic transfer hydrogenation), Zn/HCl, Li/NH3, Raney Ni, trialkylsilyl hydride (e.g., Et ₃ SiH), sodium borohydride, or lithium aluminum hydride. In certain embodiments, a suitable solvent for the above reaction step is ethyl acetate, tetrahydrofuran, dioxane, or diethylether. In other embodiments, the reaction is performed at a temperature between about -25 ⁰ C and 80 ⁰ C. [0074] According to another embodiment, the present invention provides a method for preparing a compound of formula D:

wherein x, y, R, R ¹ and R ² are as defined herein; comprising the steps of:

(a) providing a corresponding compound of formula E:

and

(b) cyclizing said compound of formula E to afford said compound of formula D.

[0075] For compounds of formula D and E, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX. [0076] In this cyclization step, a compound of formula E is cyclized to afford a compound of formula D. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed to cyclize compounds of formula E, therefore, a wide variety of conditions are envisioned; see generally, Smith and March, (2001) and Larock (1999). In certain embodiments, the cyclization is promoted by treating a compound of fomula E with a suitable Brønsted acid. Exemplary acids include hydrochloric, sulfuric, phosphoric, polyphosphoric, methanesulfonic, Eaton's reagent (P ₂ Os/MeSθ ₃ H),

Page 29 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

chlorosulfonic, camphorsulfonic, and /?-toluenesulfonic. In other embodiments, additional reagents are employed, including, for example, phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride, acetyl chloride, or acetic anhydride. One of ordinary skill in the art will recognize that some of the conditions described will promote formation of an intermediate acylchloride prior to undergoing cyclization. In yet another embodiment, the reaction is conducted with acetyl chloride or water as solvent. In still other embodiments, the cyclization is conducted in a manner substantially similar to that described in Ruhemann (1900), Gudi (1969), Cairns (1972), Stoermer (1995), or Fitzmaurice, C. et al. British Patent No. 1262078, (filed 24 May, 1968). [0077] Alternatively, according to another embodiment, the present invention provides a method for preparing a compound of formula D:

wherein x, y, R, R ¹ and R ² are as defined herein: comprising the steps of:

(a) providing a corresponding compound of formula F:

wherein R ^b is a suitable carboxylic acid protecting group;

(b) removing said R ^b group from said compound of formula F to afford said corresponding compound of formula F-2:

(c) cyclizing said corresponding compound of formula F-2 to afford a compound of the formula F-3:

Page 30 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

and

(d) reducing said compound of formula F-3 to afford said compound of formula D.

[0078] According to another embodiment, the present invention provides a method for preparing a compound of formula E:

wherein x, y, R, R ¹ and R ² are as defined hereinx; comprising the steps of: (a) providing a corresponding compound of formula F:

wherein

R ^b is a suitable carboxylic acid protecting group;

(b) reducing said compound of formula F to afford a corresponding compound of the formula

F-I:

and

(c) removing said R ^b group from said compound of formula F-I to afford said compound of formula E.

[0079] Alternatively, according to another embodiment, the present invention provides a method for preparing a compound of formula E:

Page 31 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

wherein x, y, R, R ¹ and R ² are as defined herein comprising the steps of:

(a) providing a corresponding compound of formula F:

(b) removing said R ^b group from said compound of formula F to afford said corresponding compound of formula F-2:

and

(c) reducing said compound of formula F-2 to afford a compound of the formula E. [0080] For compounds of formula E, F, F-I, F-2, and F-3, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX. [0081] In the above reaction step, the double bond in a compound of formula F is reduced to afford a compound of formula F-I. Alternatively, the double bond in a compound of formula F-2 is reduced to afford a compound of formula E. Alternatively, the double bond in a compound of formula F-3 is reduced to afford a compound of formula D. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed to reduce a double bond to a single bond, therefore, a wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999). In certain embodiments, a suitable reducing agent for the above reaction step is hydrogen gas with a palladium catalyst. Suitable palladium catalysts include, but are not limited to, is palladium on carbon and palladium (II) hydroxide. In certain embodiments, the hydrogenation reaction can be run in methanol, ethanol, ethyl acetate, or acetic acid. In yet other embodiments, the hydrogenation is conducted in the presence of sulfuric acid, acetic acid, or both. In some embodiments, the hydrogenation is conducted in the presence of sulfuric acid. In still other

Page 32 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

embodiments, the hydrogenation is conducted as described in Witiak, D. T. et al. J. Med. Chem. 1975, 18, 934. In still other embodiments, the hydrogenation reaction, described above and herein, is conducted at pressures at about 50 psi or above, and in certain embodiments, the hydrogenations are conducted with heating of the reaction mixture. In other embodiments, the hydrogenations are conducted at temperatures between about 30 ⁰ C and about 50 ⁰ C.

[0082] In the above reactions, the carboxylic acid protecting group group R ^b in a compound of formula F-I is removed to afford a compound of formula E. Alternatively, the carboxylic acid protecting group group R ^b in a compound of formula F is removed to afford a compound of formula F-2. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed to reduce a double bond to a single bond, therefore, a wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999).

[0083] In certain embodiments, suitable carboxylic acid protecting groups of group R ^b include, but are not limited to, methyl, ethyl, t-butyl, allyl, benzyl, phenyl, trimethylsilyl, or tert-butyl dimethyl silyl. In other embodiments, each R ^b is ethyl. The removal the R ^b group can be promoted by, for example, reaction with base (e.g., sodium hydroxide, tetrabutylammonium hydroxide, or the like) or acid (e.g., hydrochloric acid, acetic acid, sulfuric acid, acetic acid, camphorsulfonic acid, /?-toluenesulfonic acid, or the like), with a fluoride source (e.g., tetrabutylammonium fluoride, potassium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium triphenyldifluorosilicate, or the like), or by hydrogenation. In certain embodiments, the removal of the R ^b group is promoted by reaction with sodium hydroxide. In other embodiments, the reaction is promoted by reaction with hydrochloric acid. In other embodiments, the reaction is promoted by reaction with HCl/ AcOH. In other embodiments, this reaction is conducted at a temperature of between about 40 ⁰ C and about 100 ⁰ C. In certain embodiments, the deprotection reaction is conducted in a suitable medium. In certain embodiments, this transformation is conducted with ethanol, methanol, isopropanol, acetic acid, or tetrahydrofuran as solvent, or with mixtures of the aforementioned solvents and/or water. In certain embodiments, the removal of R ^b and reduction of the olefin occur concomitantly. One of ordinary skill in the art will recognize that certain R ^b protecting groups are removed by hydrogenation conditions. Thus, according to another embodiment, the above methods for preparing a compound of formula E provides that the deprotection step and reduction step are performed in one step under identical conditions.

Page 33 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[0084] According to another embodiment, the present invention provides a method for preparing a compound of formula F:

wherein x, y, R, comprising the steps of:

(a) providing a corresponding compound of formula H:

and

(b) contacting said compound of formula H with a compound of formula G:

to afford said compound of formula F, wherein R ^b is a suitable carboxylic acid protecting group and if desired removing R ^b to give a corresponding carboxylic acid. [0085] In the above reaction step, the compound of formula H is reacted with a compound of formula G via conjugate addition to provide a compound of formula F. One of ordinary skill in the art will recognize that there are a wide variety of reaction conditions that can be employed for a conjugate addition reaction, therefore, a wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999). In certain embodiments, above reaction step may be performed in the presence or absence of a base, and with or without heating. In certain embodiments, the conjugate addition reaction is performed in the presence of potassium carbonate, potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, triethylbenzylammonium hydroxide, 1 , 1 ,3,3-tetramethylguanidine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, diisopropylethylamine, tetramethylethylenediamine, pyridine, or triethylamine. In certain embodiments, the conjugate addition reaction is performed in the presence of triethylamine. [0086] In certain embodiments, the conjugate addition reaction is carried out in a suitable medium. A suitable medium is a solvent or a solvent mixture that, in combination with the combined reacting partners and reagents, facilitates the progress of the reaction therebetween.

Page 34 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

In certain embodiments the present transformation is run in diphenyl ether, dioxane, anisole, acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol, toluene, water, diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, acetonitrile, N-methylpyrrolidine, or mixtures thereof. In certain embodiments, the reaction is performed in ethyl acetate. In other embodiments, no additional solvent is added. In still other embodiments, excess of the phenol (corresponding to the compound of formula H) is employed to serve as a solvent. In other embodiments the reaction is conducted at temperatures between about 25 ⁰ C and about 110 ⁰ C. In yet other embodiments, the reaction is conducted at about 50 ⁰ C. In other embodiments, the conjugate addition is carried out in a manner substantially similar to the procedures outlined in Ruhemann, S. J. Chem. Soc. 1900, 77, 1121, Gudi, M. N. et al. Indian J. Chem. 1969, 7, 971, Cairns, H. et al. J. Med. Chem. 1972, 15, 583, Stoermer, M. J. and Fairlie, D. P. Aust. J. Chem. 1995, 48, 677, and British Patent No. GB1262078.

[0087] According to another embodiment, the present invention provides a method for preparing a compound of formula H:

wherein x, y, R, R ¹ and R ² are as defined herein; comprising the steps of:

(a) providing a corresponding compound of formula K:

wherein

R ^a is a suitable hydroxyl protecting group; and

CG ¹ is a suitable coupling group that facilitates transition metal-mediated C _sp 2-C _3p 2 coupling between the attached C _sp 2 carbon and a C _sp 2 carbon bearing a CG ² coupling group;

(b) contacting said compound of formula K with a corresponding compound of formula L:

wherein

Page 35 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

CG ² is a coupling group that facilitates transition metal-mediated C _sp 2-C _3p 2 coupling between the attached C _sp 2 carbon and a C _sp 2 carbon bearing a CGi coupling group; and

(c) removing said R ^a group from the product of the reaction between said compound of formula K and said compound of formula L to afford said compound of formula H. [0088] For compounds of formula H, K, and L, each of x, y, R ¹ , and R ² are as defined above in embodiments and subembodiments for compounds of formula II and ILHX. [0089] In certain embodiments, a suitable hydroxyl protecting group R ^a of a compound of formula K includes esters, carbonates, sulfonates allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formate, benzoyl formate, acetate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4- methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate. Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonate. Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and allyl ether, or derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl ethers. In certain embodiments the R ^a group is Ci_6 aliphatic or Ci_6 haloaliphatic. In yet other embodiments the R ^a group is methyl.

[0090] The removal the R ^a group can be promoted by, for example, reaction with base (e.g., sodium hydroxide, tetrabutylammonium hydroxide, or the like) or an acid (e.g., hydrochloric acid, acetic acid, sulfuric acid, acetic acid, camphorsulfonic acid, TFA, p- toluenesulfonic acid, or a Lewis acid (e.g., BBr ₃ , BCl ₃ , AICI3) or the like), with a fluoride source (e.g., tetrabutylammonium fluoride, potassium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium triphenyldifluorosilicate, or the like), or by hydrogenation. In certain embodiments, the deprotection reaction is conducted in a suitable

Page 36 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

medium. In certain embodiments, this transformation is conducted with diphenyl ether, dioxane, anisole, acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol, toluene, benzene, DMSO, water, diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, acetonitrile, N- methylpyrrolidine, or mixtures thereof. In certain embodiments, the removal of the R ^a group is promoted by reaction with BBr ₃ , BCl ₃ , or AlCl ₃ . In certain embodiments, the removal of the R ^a group is promoted by reaction with BBr ₃ in toluene. In certain embodiments, the reaction is conducted at a temperature between about 0 ⁰ C and about 100 ⁰ C. [0091] A suitable coupling group CG ¹ of a compound of formula K is selected from, but not limited to, boronic acids, boronic esters, boranes, stannanes, silyl species, zinc species, aluminum species, magnesium species, or zirconium species. In certain embodiments, CG ¹ in a compound of formula K is a boronic acid, a boronic ester, or a borane. In other embodiments, CG ¹ in a compound of formula K is a boronic ester. According to one aspect of the present invention, CG ¹ in a compound of formula K is a boronic acid.

[0092] A suitable coupling group CG ² of a compound of formula L is selected from, is selected from, but not limited to, -Cl, -Br, -I, and -OTf. In certain embodiments, CG ² in a compound of formula L is -Br, -I, or -OTf. According to one aspect of the present invention, CG ² in a compound of formula L is -Br.

[0093] According to another embodiment, the present invention provides a method for preparing a compound of formula E-I:

E-I wherein x, R and R ¹ are as defined herein; comprising the steps of:

(a) providing a corresponding compound of formula F-4:

F-4 wherein R ^b is a suitable carboxylic acid protecting group;

Page 37 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

(b) reducing said compound of F-4 in an acidic medium to provide said corresponding compound of formula F-5:

F-5 and

(c) deprotecting said compound of formula F-5 to provide said compound of E-I.

[0094] Suitable acidic media includes acetic acid, sulfuric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, phosphoric acid, or a mixture thereof.

EXAMPLES

[0095] NMR spectra were recorded on a Varian Inova 300 at 300 MHz ( ¹ H and ¹³ C) and chemical shifts were identified in ppm relative to TMS internal standard. HPLC conditions for chiral purity of i?-acid: Column: CHIRALCEL OD-H 250 x4.6 mm, #ODH0CE EF033 at 35 ⁰ C. Mobile Phase: hexanes: IPA: TFA = 950: 50 mol: 1. Flow rate: 1.0 niL/min. UV detector: 220 nm. Inj VoI: 10 μL. Instrumentation: Detector: WATERS PDA 996. Pump: Alliance 2690 System G. Isocratic: Time from 0 to 30min. [0096] Mass spectra were recorded on a Finnigan mass spectrometer.

Example 1 Preparation of 2,6-dichloro-2'-methoxybiphenyl (110):

(108) (109) (110)

[0097] To a 100-L reactor were charged 2-methoxybenzeneboronic acid (109) (3.51 kg, 23.1 mol, 1.37eq) and a solution of 2-bromo-l, 3-dichlorobenzene (108) in dimethoxyethane (DME, 7.64 kg, 50 w/w%, 16.9 mol). To this mixture was added dimethoxyethane (DME, 29 kg). The reaction contents were stirred to provide a solution, and the solution was then heated to 50 ⁰ C. To this solution was added a 4.4 M aqueous solution of sodium hydroxide (3.55 kg of NaOH in 19.0 kg of water, 5.0 eq) over a 20 minute period,

Page 38 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

maintaining a temperature of 50 + 5 ⁰ C. The reaction was then heated to 70 ⁰ C over 15 minutes, followed by addition of Pd(PPtLs) ₄ (0.41 kg, 0.35 mol, 2 mol%) in one portion. The mixture was gradually heated to reflux ( to 80 ⁰ C) over a 15 minute period, and was then stirred at 80 + 2 ⁰ C for 18 hours. At that time, the reaction was cooled to room temperature (22 - 25 ⁰ C), the DME/water layers were separated, and the organic layer was concentrated under reduced pressure to obtain a brown oil. To this brown oil was added tert-butyl methyl ether (TBME) (15.0 kg) and water (12.0 kg). The mixture was heated to 33 + 2 ⁰ C, and recirculated with a R53-SP Zeta filter cartridge for 4 h (charcoalization). The amber-colored TBME organic layer was separated. The organic layer was washed with water (2 X 12.0 kg). TBME was removed by atmospheric distillation to obtain 16 ± 2 L. IPA (2 X 8.0 kg) was then added to replace TBME and the IPA solution (8 ± 2 L) was cooled to 0 to 10 ⁰ C to induce crystallization. The crystals were filtered, washed with IPA (2 x 5.0 kg), and dried at 45 ⁰ C for 20 h to obtain 3.4 kg (76%) of compound (110). ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 7.54 (dd, J= 0.9, 7.8 Hz, 2H), 7.46-7.37 (m, 2H), 7.15-7.02 (m, 3H).

Example 2 Preparation of 2',6'-dichloro-biphenyl-2-ol (111):

(110) (111)

[0098] To a 50-L reactor were added 2, 6-dichloro-2'-methoxybiphenyl (110) (3.0 kg,

11.9 mol) and toluene (13.0 kg). The solution was cooled to -5 + 3 ⁰ C and to the solution was added BBr ₃ (3.3 kg, 13.2 mol, 1.1 eq) over 30 minutes, maintaining the temperature at -5 + 3 ⁰ C. The reaction mixture was stirred at -5 + 3 ⁰ C for 30 minutes, and then gradually warmed to 20 ± 2 ⁰ C over a 1 hour period (minimum time period) and stirred for 18 hours. The reaction mixture was cooled to 0-5 ⁰ C, methanol (12.0 kg) was added cautiously over 20 minutes, maintaining the temperature at 5 to 15 ⁰ C, and then the reaction was heated to 40 ± 2 ⁰ C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 5 + 3 L, methanol (10.0 kg) was added, the reaction mixture was re-concentrated, and EtOAc (16.0 kg) and water (15.0 kg) were added. The organic and aqueous layers were separated. The organic layer was washed with 8% NaHCO ₃ (0.40 kg in 5.00 kg of water) and concentrated under reduced pressure to 5 + 3 L followed by azeotroping with heptanes (10.0 kg x 2) under

Page 39 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

reduced pressure to 5 ± 3 L. The resulted suspension was cooled slowly to 0-5 ⁰ C over a minimum of 1 hour and held at that temperature for 1 hour. The solids were filtered, washed with cold heptanes (2 x 3.0 kg), and dried at 45 ⁰ C for 20 h to obtain compound (111) (2.6 kg, 94%). ¹ H NMR (300 MHz, DMSO-J ₆ ) £9.53 (s, IH), 7.54-7.51 (m, 2H), 7.41-7.35 (m, IH), 7.26-7.21 (m, IH), 7.02-6.85 (m, 3H).

Example 3 Preparation of 2-(2',6'-dichloro-biphenyl)-2-(succinic acid) ether (115):

(115) (114)

[0099] To a 12 L multi-necked round-bottom flask were charged 2', 6'- dichlorobiphenyl-2-ol ((111), 103 g, 0.431 mol), triethylamine (72 mL, 0.518 mol, 1.2 eq) and THF (1.0 L). To the mixture was added acetylene methyl diester (112) (80 mL, 0.646 mol, 1.5eq) at 50 ⁰ C over 1 hour. The mixture was stirred overnight (>12 hours) at 50 ⁰ C, and then concentrated to one-fifth of its original volume. To this reaction mixture 800 mL of EtOAc was added. The organic solution was washed with 200 mL of 10% aqueous HCl and 3 x 20OmL of water, dried over anhydrous sodium sulfate and concentrated to give (113) as a brown oil (~1 : 1 mixture of Z- and E-isomers as determined by ¹ H NMR). [00100] Crude compound (113) was dissolved in 1.5 L of EtOAc, and the resulting solution was hydrogenated overnight (>24 h) under 50 psi (H ₂ gas) at 20-25 ⁰ C with Pd(OH) ₂ (32.8g, 20% w/w). The catalyst was filtered, and the filtrate was concentrated to give the crude diester (114) as a brown oil. ¹ H NMR (300 MHz, DMSO-J ₆ ) £ 7.55-7.50 (m, 2H), 7.42-7.36 (m, 2H), 7.12-7.04 (m, 3H), 5.18-5.14 (m, IH), 3.64 (s, 3H), 3.49 (s, 3H), 2.88- 2.56 (m, 2H). MS 383.04 [M], 400.07 [M+NH ₄ ⁺ ], 421.00 [M+K ⁺ ].

Page 40 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[00101] A mixture of the crude diester (114), 1.0 L of glacial HOAc and 1.0 L cone HCl was gently refluxed (90-95 ⁰ C) for 2 h. After cooling to 0-5 ⁰ C and staying at this temperature for Ih, the precipitates were filtered and washed with 3 x 500 mL of water to obtain compound (115) (118 g, 77%) as off-white solid. ¹ H NMR (300 MHz, DMSO-J ₆ ) £7.54- 7.48 (m, 2H), 7.42-7.36 (m, 2H), 7.12-7.02 (m, 3H), 4.99-4.95 (m, IH), 2.75-2.46 (m, 2H).

Example 4 Preparation of 8-(2,6-dichloro-phenyl)-4-oxo-chroman-2-carboxylic acid (116):

1. (COCl) ₂ (2.11 eq),

(115) (116)

[00102] To a 12-L multi-necked round-bottom flask was charged (115) (867g, 2.44mol, l.Oeq.), DMF (38mL, 0.491mol, 0.2eq) and 5.2 L of methylene chloride. To the mixture was added dropwise oxalyl chloride (450 mL, 5.16 mol, 2.11 eq) at 0-5 ⁰ C over 1 h, the mixture was stirred overnight (>12 hours) at 20 to 25 ⁰ C. The resulting solution was cooled to -15 ⁰ C and AICI3 (667 g, 5.00 mol, 2.05 eq) was added in portions over a 30 minute period, maintaining the reaction temperature between -15 to -10 ⁰ C. The mixture was stirred for 30 minutes at -15 to -10 ⁰ C. 1.7L of a 1.2 N aqueous HCl solution was added dropwise to the reaction mixture, maintaining the temperature below 10 ⁰ C. After complete addition, the organic and aqueous phases were separated, and the organic phase was washed with 3 x 3.5 L of water, dried over anhydrous sodium sulfate and concentrated to give (116) as off-white solid (600 g, 81%). Compound (116) was used directly in next step without further purification. ¹ H NMR (300 MHz, DMSO-J ₆ ) £7.93 (dd, J= 1.8, 7.8 Hz, IH), 7.37-7.25 (m, 3H), 7.15-7.08 (m, 2H), 4.82 (m, IH), 2.91 (s, 2H). MS 334.9 [M-H].

Page 41 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

Example 5 Preparation of (±)-8-(2,6-dichloro-phenyl)-chroman-2-carboxylic acid amide (117):

(116) (117)

[00103] To a 5-L multi-necked round-bottom flask were charged (116) (1.0 kg, 2.97 mol, 1.0 eq) and TFA (5.0 L). To the mixture was added triethylsilane (1.66 L, 10.4 mol, 3.5eq) at 65 ⁰ C over 2.5 hours, maintaining the reaction temperature between 65-7O ⁰ C. The mixture was stirred for 4 h at the same temperature. After being cooled to room temperature (20 to 25 ⁰ C), and stirring overnight (>12 hours), the reaction mixture was filtered, washed with 4 x 1.0 L of heptanes and dried to give (117) (929 g, 97%) as white solid. ¹ H NMR (300 MHz, DMSO-J ₆ ) £ 12.86 (s, IH), 7.54-7.49 (m, 2H), 7.40-7.35 (m, IH), 7.15-7.12 (m, IH), 6.94-6.92 (m, 2H), 4.71-4.68 (m, IH), 2.90-2.67 (m, 2H), 2.12-2.05 (m, 2H). MS 321.0 [M- H].

Example 6 Preparation of (R)-8-(2,6-dichloro-phenyl)-chroman-2-carboxylic acid amide (R)-(118): 5eq) eq)

(117) (R)-(117) (R)-(118)

[00104] To a 12 L multi-necked round-bottom flask were charged racemic (117) (800 g, 2.48 mol), (-)-cinchonidine (729 g, 2.48 mol, 1.0 eq) and acetonitrile/water (9:1, 4.8 L). The mixture was heated to 70-75 ⁰ C for 1 hour. After being cooled to 55 ⁰ C, a suspension of crystals was formed and more acetonitrile/water (9:1, 1.6 L) was added to the suspension. The mixture was further cooled to 20-25 ⁰ C and held for 12 hours at that temperature. The crystals was filtered, washed with acetonitrile/water (9:1, 2 x 2.5 L) and suspended in i- PrOAc (isopropyl acetate, 4 L) followed by the addition of aqueous 10% HCl. The organic layer was separated, washed with a 10 % HCl solution (I L x 2), then washed with water (IL x 3), and concentrated to a low volume (1.6 L) to obtain a suspension. For analysis, an aliquot was sampled and evaporated to give (R)-(117) as white solid (98% e.e.). ¹ H NMR (300 MHz,

Page 42 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

DMSO-J ₆ ) £ 12.84 (s, IH), 7.54-7.49 (m, 2H), 7.40-7.35 (m, IH), 7.15-7.11 (m, IH), 6.94- 6.92 (m, 2H), 4.71-4.68 (m, IH), 2.91-2.67 (m, 2H), 2.12-2.05 (m, 2H). MS 321.0 [M-H]. [00105] To the above suspension of optically enriched (R)-(117) were charged DMF (38 mL, 0.496 mol, 0.2 eq) and cooled to 0-10 ⁰ C. Oxalyl chloride (108 mL, 1.24 mmol, 0.5 eq) was added over 40 minutes, maintaining the temperature below 15 ⁰ C, and then the mixture was stirred for 2 hours. In another 12 L flask was charged ammonium hydroxide (1.72 L, 28%, 12.4 mol, 5.0 eq) and heptanes (2.75 L), which was cooled to 0-5 ⁰ C. The acid chloride solution was added to the ammonium hydroxyide solution, maintaining the reaction temperature below 1O ⁰ C. After complete addition, the reaction was warmed to 20-25 ⁰ C, the pH of the mixture was adjusted to a pH of 9-10, and the mixture was stirred for 30 min. The precipitate was filtered, washed water (0.1 L x 2) and heptanes (0.1 L x 2) to give a crude (R)-(118), which was reslurried in z-PrOAc (2.7 L) at 85 ⁰ C for 2 h to give (R)-(118) as an off-white solid (238 g, 30%, 100% ee). ¹ H NMR (300 MHz, DMSO-J ₆ ) £ 7.60-7.39 (m, 4H), 7.20-7.16 (m, IH), 6.98-6.96 (m, 2H), 6.34 (s, IH), 4.49 (dd, J = 3.6, 8.1 Hz, IH), 2.95-2.69 (m, 2H), 2.19-1.85 (m, 2H). MS 321.8 [M+H].

Example 7 Upgrading enantiomeric excess of (117):

h (R)-(117)

[00106] A method is described to upgrade the enantiomeric excess of (R)-(117) by upgrading the enantiomeric excess of the cinchonidine salt before conversion to the free acid. To ensure compound H-I(HCl) can be manufactured with the enantiomeric excess exceeding 99%, it is desirable to resolve racemic (117) to provide (R)-(117) in > 98% enantiomeric excess. With the enantiomeric excess at < 98%, the enantiomeric excess of the end product, H-I(HCl) will be < 99%. Conversion of (R)-(117) to H-I(HCl) requires an additional 5 steps. However, no upgrade in enantiomeric excess can be achieved during these additional steps. A simple method was developed to produce (R)-(117) in > 98% enantiomeric excess. Resolution of (117) with cinchonidine produced the salt with an enantiomeric excess of

Page 43 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

approximately 95%. The enantiomeric excess can be upgraded to > 98% by reslurrying the salt in 7 parts of 9:1 acetonirile: water. After filtration and drying, the enantiomeric excess was found to be 98.4%.

[00107] A typical procedure is described as follows: 30.0 g of (117) was dissolved in 6 parts of 9:1 acetonitrile: water at 70-75 ⁰ C. 1.0 eq of (-) cinchonidine was added portionwise. The resulting solution was held for 2 hr and then cooled to room temp. The mixture was filtered and washed with 9:1 acetonitrile: water (4 parts). The material was dried at 60 ⁰ C for -4-5 hr. HPLC of this material showed it to be -94.9% ee. 26.50 g of material was obtained. This material was transferred to a 500 ml flask and 7 parts of 9:1 acetonitrile: water was added. The white slurry was heated to 70-75 ⁰ C where it stayed as a slurry. The mixture was held for 20 mins, then cooled to room temp over 30 mins and stirred for additional 15 mins. The mixture was filtered, washed with 4 (2 x 2) parts of 9:1 acetonitrile: water. After drying the filter cake at 60 ⁰ C for -15 hr, the %ee of the solid was -98.4%. The %ee of the combined mother liquors and washes was estimated to be -86.1%. The dried material weighed -23.5 g (82%). Theoretical yield is 28.66 g.

Example 8 Recycling of (±)-8-(2,6-dichloro-phenyl)-chroman-2-carboxylic acid (117):

NaOH

[00108] To a 100-L reactor was charged 8-(2,6-dichlorophenyl)-2-chromanecarboxylic acid (-)-cinchonidine salt mother liquors (46 kg of solution at 21% solid, 15.6 mol). The solution was concentrated under reduce pressure to 16 ± 2 L. Isopropyl acetate (40 kg) and potable water (18.4 kg) were added. To the mixture, hydrochloric acid 20 ⁰ Be (degree Baume, i.e., muriatic acid, 32% HCl in water) was added to adjust the pH to 1 to 2 (3.3 kg).

Page 44 of 58

Attorney Docket No 2004658-1130 (AM102450) 426261 Iv2

The biphasic mixture was stirred at 20 to 30 ⁰ C for 5 minutes. The layers were separated. The organic layer was washed with diluted hydrochloric acid (1 kg of Hydrochloric acid 20 ⁰ Be into 18 kg of potable water) and three times with water (18 kg). The washed organic layer was concentrated under reduce pressure to 12 ± 2 L. Heptanes (9.4 kg) was charged and the suspension is stirred at 19 to 25 ⁰ C for 3 hours. The solids were filtrated, washed with heptanes (5 kg) and dried at 50 ⁰ C for 10 hours to obtain 4.5 kg (89%) of compound (S)- (117).

[00109] To a 100-L reactor were charged 8-(2,6-dichlorophenyl)-2-chromanecarboxylic acid (117) (4.5 kg, 13.9 mol) and methanol (17.1 kg). Sulfuric acid 66 ⁰ Be (77 g, 0.01 mol, 0.07 mol%) was added, heated to reflux and held for 5 hours. The solution was cooled to -15 to -5 ⁰ C and held for 30 minutes. The solids were filtered, washed with cold methanol (3.8 kg) and dried at 55 ⁰ C for 11 hours to obain 3.3 kg (70%) of compound (117a). [00110] To a 100-L reactor, prepare a suspension of sodium hydride 37% dispersion (0.83 kg, 12.8 mol, 1.3 eq) into THF (5.8 kg). A solution of 8-(2,6-dichlorophenyl)-2- chromanecarboxylic acid methyl ester (117a) (3.3 kg, 9.8 mol, 1.0 eq) into THF (8.7 kg) was added to the NaH/THF suspension over 1 hr and the mixture was held for 1 hour at 15 to 25 ⁰ C. Methanol (1.5 kg) was added over 1 hour and solution was held for 150 minutes at 22 to 28 ⁰ C. Sodium hydroxide 30% (5.9kg) was added, the mixture was held 19 to 25 ⁰ C for 30 minutes then potable water (33 kg) was added. The solution was concentrated under reduce pressure to 39 ± 2 L. Heptanes (14 kg) was added and the mixture was acidified to pH 1 to 2 with hydrochloric acid 20° Be (5.8 kg). The suspension was held for 1 hour at 19 to 25 ⁰ C, then the solids were filtered and washed twice with water (5 kg) and once with Heptanes (5 kg). The cake was dried at 60 ⁰ C for 12 hours to obtain 3.4 kg (67% from mother liquors) of compound (117). ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 12.86 (s, IH), 7.54-7.49 (m, 2H), 7.40- 7.35 (m, IH), 7.15-7.12 (m, IH), 6.94-6.92 (m, 2H), 4.71-4.68 (m, IH), 2.90-2.67 (m, 2H), 2.12-2.05 (m, 2H). MS 321.0 [M-H].

Page 45 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

Example 9

Preparation of (R)-[8-(2,6-dichloro-phenyl)-chroman-2-yl]-methylamine and (R)-[8-(2,6- dichloro-phenyl)-chroman-2-yl]-methylamine hydrochloride (H-I and H-I(HCl)):

[00111] To a 12 L multi-necked round-bottom flask were charged (R)-(118) (300.5 g, 0.93 mol) and THF (1.50 L). The mixture was heated to 65 ⁰ C and borane-THF (1.0 M, 3.26 L, 3.26 mol, 3.5 eq) was added over a minimum of 4 hours, maintaining the temperature between 65 to 68 ⁰ C. The mixture was stirred and held at 65 to 68 ⁰ C for another 3 hours before being cooled to -10 to 0 ⁰ C. cone HCl (0.676 L) and water (1.50 L) were then added to the reaction mixture over 10 minutes. The temperature of the mixture was adjusted to 25 to 28 ⁰ C and held at this temperature for a minimum of 12 hours. THF (3.40 L) was distilled off under reduced pressure and more water (2.0 L) was added to the mixture. The aqueous layer was extracted with te/t-butylmethyl ether (TBME, 2 L X 3) and basifϊed with aq. NaOH (50%, 0.85 kg) to a pH 11. The aqueous layer was then extracted with TBME (2 L X 2). The TBME layers were combined, washed with water (I L X 3), dried over anhydrous Na ₂ SO ₄ (0.10 kg), filtered and the TBME was removed by atmospheric distillation to provide the free amine (315g), compound II- 1.

[00112] To a 5 L multi-necked round-bottom flask were charged the free amine H-I (315 g, 1.02 mol) and TBME (3 78 L). The mixture was heated to 45 to 50 ⁰ C, and to this mixture was added HCl in IPA (11.6% w/w). The resulting suspension was heated to 55-60 ⁰ C and held at this temperature for 1 hour. The crude compound H-I(HCl) (335 g) which crystallized out from this solution was collected and washed with TBME (3 X 150 mL). The crude compound H-I(HCl) was transferred to a 12 L multi-necked flask equipped with a temperature probe, a N ₂ inlet and a condenser. Isopropanol (IPA) (5.33 L) was added. The mixture was heated to 65-70 ⁰ C and clarified through a 0.2 μm cartridge. The clear mixture solution was atmospherically concentrated to a lower volume (1.67 L) cooled to 20 to 25 ⁰ C, and then further cooled to 0 to 5 ⁰ C. Water (66.6 g) was added to the resulting slurry and

Page 46 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

held at this temperature for a minimum of 1 hour. Crystals were collected, washed with cold IPA (300 mL) and dried at 20 to 25 ⁰ C under 25-30 mmHg to obtain compound H-I(HCl) (287.98 g, 68.6%) as monohydrate HCl salt. Purity 99.6%, ee 98.0 %. Water content 5.15%.

HCl content 9.88% (10.0% in theory). M.P. 210 ⁰ C. [α] _D ⁵ = -1.5°. ¹ U NMR (300 MHz,

DMSO-J ₆ ) £ 8.25 (s, 2H), 7.550-7.547 (m, 2H), 7.42-7.40 (m, IH), 7.20-7.17 (m, IH), 6.99-6.94 (m, 2H), 4.31-4.25 (m, IH), 2.99-2.85 (m, 4H), 2.19-2.10 (m, IH), 1.80-1.73 (m, IH). ¹³ C NMR (75 MHZ ₅ DMSO-J ₆ ) £ 151.3, 136.4, 135.2, 135.2, 130.9, 130.6, 129.3, 128.9, 128.8, 125.1, 123.1, 121.0, 73.0, 42.3, 24.6, 23.7.MS 307.9 [M+H].

[00113] X-Ray Diffraction (XRD): XRD analyses were acquired using an X-ray powder diffractometer (Bruker-axs, model D8 advance, Vantec-1 detector) having the following parameters: voltage 40 kV, current 40.0 mA, with a Ni filter. For XRPD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can often affect the 2-theta values. Therefore, the peak assignments of diffraction patterns can vary by plus or minus about 0.3°. Accordingly, the term "about" as used in connection with a given 2-theta value, is intended to mean plus or minus 0.3 °.

[00114] In certain embodiments of the present invention, H-I(HCl) is provided as a hydrochloride monohydrate polymorphic form. It has been found that H-I(HCl) can exist as a hydrochloride monohydrate form, referred to herein as Form A. As used herein, the term "hydrochloride monohydrate form" is interchangeable with the terms "monohydrate", "Form A" and "hydrochloride monohydrate polymorphic form".

[00115] In certain embodiments, the present invention provides Form A of H-I(HCl). In some embodiments, the present invention provides Form A of H-I(HCl) characterized in that it has a peak in its XRD pattern at about 9.7 degrees 2-theta. As used herein, the term "about", when used in reference to any degree 2-theta value recited herein, refers to the stated value ± 0.3 degree 2-theta.

[00116] In certain embodiments, degree 2-theta values, as described herein, are reported with two decimal places. In other embodiments, degree 2-theta values, as described herein, are reported with one decimal place. In still other embodiments, degree 2-theta values, as described herein, are reported with no decimal places. It will be understood that where the term "about" is used in reference to any degree 2-theta value recited herein, this term refers to the stated value ± 0.3 degree 2-theta in accordance with the value's reported decimal place.

Page 47 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[00117] In certain embodiments, the present invention provides Form A of H-I(HCl). In certain embodiments, the present invention provides Form A of H-I(HCl), substantially free of other forms of Compound H-I(HCl). As used herein, the term "substantially free of other forms of Compound H-I(HCl)" means that the solid contains no significant amount of solid form of Compound H-I(HCl) other than Form A. In certain embodiments of the present invention, the term "substantially free of other forms of Compound H-I(HCl)" means that at least about 95% by weight of Compound H-I(HCl) is Form A. In certain embodiments of the invention, the term "substantially free of another form of Compound H-I(HCl)" means that at least about 99% by weight of Compound H-I(HCl) is Form A. [00118] In certain embodiments, Form A is a monohydrate polymorphic form of H-I(HCl). According to one embodiment, Form A is characterized in that it has one or more peaks in its XRD pattern selected from those at about 9.7, 14.0, 18.1, and 19.6 degrees 2- theta. In certain embodiments, Form A is characterized in that it has two or more, or three or more, peaks in its XRD pattern selected from those at about 9.7, 14.0, 18.1, and 19.6 degrees 2-theta.

[00119] In other embodiments, Form A of H-I(HCl) is characterized in that is has substantially all of the peaks in its XRD pattern listed in Table 3 A, below.

Table 3A: XRD Peaks of Form A

[00120] In still other embodiments, Form A of H-I(HCl) is characterized in that is has substantially all of the peaks in its XRD pattern listed in Table 3B, below.

Table 3B: XRD Peaks of Form A

Page 48 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

[00121] According to one aspect, Form A of H-I(HCl) has an XRD pattern containing substantially all of the peaks depicted in Figure 1. As used herein, the phrase "substantially all of the peaks" means that the compound exhibits, in its XRD, at least about 80% of the peaks listed. In other embodiments, the phrase "substantially all of the peaks" means that the compound exhibits, in its XRD, at least about 85, 90, 95, 97, 98, or 99% of the peaks listed. Additionally, one skilled in the art will appreciate throughout, that XRD peak intensities and relative intensities as listed herein may change with varying particle size and other relevant variables.

Example 10 Reduction of amide to amine using borane amines:

(R)-118 11-1 11-1(HCI)

[00122] The reduction of amide to amine can be accomplished using borane amines such as triethylamine borane, trimethylamine borane, t-butylamine borane, diisopropylethylamine borane, diethylaniline borane (DEANB), pyridine borane, and morpholine borane. Other suitable amine boranes are well known in the art. In certain embodiments, the amine borane is DEANB or triethylamine borane. In certain embodiments, the reaction can be performed neat in the amine borane or in an organic solvent such as acetonitrile, tetrahydrofuran or 2- methyl tetrahydrofuran. In certain embodiments, the temperature of the reaction can range

Page 49 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2

from 20 ⁰ C to 100 ⁰ C. In certain embodiments, the temperature is > 60 ⁰ C. The reaction is generally completed in > 20 hr. A typical procedure is to add the amine borane to the amide starting material with or without solvent. The mixture is heated to 60 ⁰ C or above until reaction completion. Additional amine borane can be added to drive the reduction to completion. In certain embodiments, upon completion of the reaction, the free base is not isolated but directly converted to its hydrochloride salt as previously described. [00123] HPLC conditions for chiral purity of (i?)-[8-(2,6-dichloro-phenyl)-chroman-2- yl]-methylamine H-I: (and API): Column: CHIRALCEL OD-RH 150 x4.6 mm, #ODRHCD-DL023 at 30 ⁰ C. Mobile Phase: [9.22g KPF ₆ in IL water pH 3.5]: acetonitrile = 650: 350 mL. Flow rate: 1.0 mL/min. UV detector: 220 nm. Inj VoI: 10 μL. Instrumentation: Detector: WATERS PDA 996. Pump: Alliance 2690 System G. Isocratic: Time from 0 to 30min. HPLC conditions for purity: Column: SYMMETRY SHIELD RP8 3.5μ 150 x 4.6 mm. Mobile Phase: A: water: acetonitrile: IN NH ₄ OAc= 950: 50: 2, B: water: acetonitrile: IN NH ₄ OAc= 50: 950: 2. Flow rate: 1.0 mL/min. UV detector: 220 nm. Inj VoI: 10 μL. Instrumentation: Detector: WATERS PDA 996. Pump: Alliance 2690 System G. Gradient: Time: 0 min, 80% of Mobile Phase A, 20% of Mobile Phase B; Time: 40 min, 10% of Mobile Phase A, 90% of Mobile Phase B; Time: 50 min, 10% of Mobile Phase A, 90% of Mobile Phase B; Time: 52 min, 80% of Mobile Phase A, 20% of Mobile Phase B; Time: 60 min, 80% of Mobile Phase A, 20% of Mobile Phase B.

Page 50 of 58

Attorney Docket No. 2004658-1130 (AM102450) 426261 Iv2