Patent Description:
Substituted heterocycle fused gamma-carbolines are known to be agonists or antagonists of <NUM>-HT<NUM> receptors, particularly <NUM>-HT2A receptors, in treating central nervous system disorders. These compounds have been disclosed in <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>, and <CIT>, as novel compounds useful for the treatment of disorders associated with <NUM>-HT2A receptor modulation such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders migraine, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility, and obesity. <CIT>, and <CIT>, also disclose methods of making substituted heterocycle fused gamma-carbolines and uses of these gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders.

In addition, <CIT> discloses use of particular substituted heterocycle fused gamma-carbolines for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and/or mood disorders in patients with psychosis or Parkinson's disease. In addition to disorders associated with psychosis and/or depression, this patent application discloses and claims use of these compounds at a low dose to selectively antagonize <NUM>-HT2A receptors without affecting or minimally affecting dopamine D<NUM> receptors, thereby useful for the treatment of sleep disorders without the side effects associated with high occupancy of the dopamine D<NUM> pathways or side effects of other pathways (e.g., GABAA receptors) associated with conventional sedative-hypnotic agents (e.g., benzodiazepines) including, but not limited to, the development of drug dependency, muscle hypotonia, weakness, headache, blurred vision, vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pain, and chest pain. <CIT> also discloses methods of preparing toluenesulfonic acid addition salt crystals of these substituted heterocycle fused gamma-carbolines.

In addition, recent evidence shows that the aforementioned substituted fused heterocycle gamma carbolines may operate, in part, through NMDA receptor antagonism via mTOR1 signaling, in a manner similar to that of ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine acts through a system that is unrelated to the common psychogenic monoamines (serotonin, norepinephrine and dopamine), and this is a major reason for its much more rapid effects. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also indirectly results in activation of AMPA-type glutamate receptors. The downstream effects involve the brain-derived neurotrophic factor (BDNF) and mTORC1 kinase pathways. Similar to ketamine, recent evidence suggests that compounds related to those of the present disclosure enhance both NMDA and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons via activation of D1 receptors, and that this is associated with increased mTORC1 signaling. <CIT> discloses such effects for certain substituted fused heterocycle gamma-carbolines, and useful therapeutic indications related thereto.

The <CIT> discloses additional substituted fused gamma carbolines. These newer compounds retain much of the unique pharmacologic activity of the previously disclosed compounds, including serotonin receptor inhibition, SERT inhibition, and dopamine receptor modulation. However, these compounds were found to unexpectedly also show significant activity at mu-opiate receptors. Analogs of these novel compounds have also been disclosed, for example, in <CIT> and <CIT>.

For example, the Compound of Formula A, shown below, is a potent serotonin <NUM>-HT2A receptor antagonist and mu-opiate receptor partial agonist or biased agonist. This compound also interacts with dopamine receptors, in particular the dopamine D1 receptors. <CHM>
It is also believed that the Compound of Formula A, via its D1 receptor activity, may also enhance NMDA and AMPA mediated signaling through the mTOR pathway. The Compound of Formula A is thus useful for the treatment or prophylaxis of central nervous system disorders, but there is a need in the art additional compounds having this unique biochemical and pharmacological profile, especially those which may have subtly altered pharmacologic or pharmacokinetic profiles compared to the Compound of Formula A.

The preparation of substituted heterocycle fused gamma-carbolines in free or pharmaceutically acceptable salt forms, intermediates used in their preparation, for example enantiomerically pure <NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole type intermediates, and methods for producing said intermediates and said substituted heterocycle fused gamma-carbolines are disclosed in <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>, and also in <CIT>, and <NPL>.

The present disclosure provides methods of preparing particular fused gamma-carbolines in high purity, yield and economic efficiency.

The present invention provides improved methods for the preparation of substituted heterocycle fused gamma-carbolines in free or pharmaceutically acceptable salt forms, intermediates used in their preparation, for example enantiomerically pure <NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole type intermediates, and methods for producing said intermediates and said substituted heterocycle fused gamma-carbolines are disclosed in the present invention.

Substituted heterocycle fused gamma-carbolines and their pharmaceutically acceptable salts produced by the present invention are represented by the core structures shown in Formula 1J:
<CHM>
wherein R is H, and Q is and <NUM>-(<NUM>-fluorophenoxy)propyl. It is understood that in the compound of Formula 1J (and like Formula <NUM>'s herein throughout) the stereochemistry shown is relative stereochemistry for the two adjacent stereocenters. Thus, for example, in the compound of Formula 1J shown above, the formula represents both compounds having the 6bR, 4aS configuration and compounds having the 6bS, 4aR configuration, or combinations thereof.

In some embodiments, the present disclosure pertains to compounds of Formula 1I, as shown below, in free or salt form, which are useful, e.g., as intermediates for the production of compounds of Formula 1J:
Compounds of Formula 1I:
<CHM>
wherein:
R is H;
in free or salt form, e.g., in acid addition salt form, optionally in solid form.

In some embodiments, the disclosure further pertains to compounds of the following formulae:.

The present disclosure further provides the following compounds that are not part of the invention, which may be formed as impurities in the processes for making the compounds of Formula 1J:
<CHM>
<CHM>
wherein, in each of said compounds <NUM> and <NUM>, the group R is H, and the group Q is selected from -O- and -(C=O)-.

In some embodiments, the present invention pertains to a method for preparing the compound of Formula 1J, as shown in the following scheme:
<CHM>
wherein for each of compounds 1A through 1J, independently:.

wherein each of compounds 1A, 1B, 1C, 1D, 1E', 1F, 1I and 1J are independently in free base or salt form (e.g., acid addition salt form). It is understood that the compound 1B is substantially, essentially, or completely the racemic cis isomers, i.e., containing approximately equal amounts of the two cis enantiomers to the substantial or complete exclusion of any trans isomers. It is further understood that the compound 1C is substantially, essentially, or completely a single cis enantiomer, specifically the 4aS, 9bR enantiomer (as drawn above), to the substantial or complete exclusion of the opposite cis enantiomer or any trans stereoisomer.

In some embodiments, the present invention pertains to methods for preparing the compound of Formula 1J, as shown above, in free or salt form, as follows:.

In a first aspect, the invention provides a method (Method 1J) for preparing a compound of Formula 1J, or any of <NUM>-<NUM>, in free or salt form, comprising the steps of (a) reacting a compound of Formula 1E', in free or salt form, with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), to form an intermediate of Formula 1F, in free or salt form; (b) deprotecting the piperidine nitrogen of the compound of Formula 1F to yield the compound of Formula 1I (or any of <NUM>-<NUM>), in free or salt form; and (c) alkylating the piperidine nitrogen of the compound of Formula 1I with a suitable alkylating agent to yield the compound of Formula 1J (or any of <NUM>-<NUM>) in free or salt form; and optionally (d) converting the compound of Formula 1J in free form to a compound of Formula 1J (or any of <NUM>-<NUM>) in salt form, e.g., acid addition salt form (e.g., tosylate salt form). In some embodiments, the method further comprises the step converting a compound of Formula 1D to the compound of Formula 1E'.

In a second aspect, the invention provides a method (Method <NUM>) for preparing a compound of Formula 1I, or any of <NUM>-<NUM>, in free or salt form, comprising the steps of (a) reacting a compound of Formula 1E', in free or salt form, with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), to form an intermediate of Formula 1F, in free or salt form; and (b) deprotecting the piperidine nitrogen of the compound of Formula 1F to yield the compound of Formula 1I (or any of <NUM>-<NUM>), in free or salt form. In some embodiments, the method further comprises the step of converting a compound of Formula 1D to the compound of Formula 1E'.

In a third aspect that is not part of the invention, the disclosure provides a method (Method 1F) for preparing a compound of Formula 1F, in free or salt form, comprising the steps of (a) reacting a compound of Formula 1D, in free or salt form, with (i) benzophenone imine, (ii) a transition metal catalyst, (iii) a base, and optionally (iv) a monodentate or bidentate ligand, to form the compound of Formula 1E', in free or salt form; and (b) reacting the compound of Formula 1E', in free or salt form, with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) optionally an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), to form the compound of Formula 1F, in free or salt form.

In another aspect, the present disclosure provides for the use of the Compound of Formula 1I, or any of <NUM> et seq. , and/or the Compound of Formula 1F, and/or the Compound of 1E', in a process for the manufacture of a compound of Formula 1J, or any of <NUM>-<NUM>.

In one aspect, the invention provides a method (Method 1I) for preparing a compound of Formula 1I, or any of <NUM>-<NUM>, in free or salt form, comprising the steps of (a) reacting a compound of Formula 1E', in free or salt form, with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), to form an intermediate of Formula 1F, in free or salt form; and (b) deprotecting the piperidine nitrogen of the compound of Formula 1F to yield the compound of Formula 1I (or any of <NUM>-<NUM>), in free or salt form. In some embodiments, the method further comprises the step of converting a compound of Formula 1D to the compound of Formula 1E'.

Optionally, steps (a) and (b) take place without isolation or without purification of the intermediate of the Formulas 1F. In some embodiments, the steps (a) and (b) take place sequentially in a single reaction vessel or a set of connected reaction vessels.

The base useful for step (a) of Method 1I may be a Bronsted base or a Lewis base, including by way of example only, amine bases (e.g. triethylamine, trimethylamine, N,N'-diisopropylethylamine, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU) or <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]octane (DABCO)), hydrides (e.g. sodium, lithium or potassium hydride), alkoxides (e.g. sodium or potassium tert-butoxide), carbonates (e.g. sodium carbonate or bicarbonate, potassium or cesium carbonate) or phosphates (e.g. potassium phosphate). In a preferred embodiment, the base is a carbonate of an alkali or alkali earth metal (e.g., sodium, potassium, cesium, barium, etc.). In an especially preferred embodiment, said base is potassium carbonate.

The conditions for the deprotection step (b) of Method 1I necessarily varies with the choice of the protecting group B and may involve, for example, acid or base catalysis or catalytic hydrogenation. Thus, for example, wherein the protecting agent is an acyl group such as an alkanoyl or alkoxycarbonyl group (e.g., ethoxycarbonyl) or an aroyl group, deprotection may be accomplished, for example, by hydrolysis with a base such as an alkali metal hydroxide, for example lithium, potassium or sodium hydroxide. Alternatively, an acyl protecting agent such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid. An arylmethoxycarbonyl protecting agent such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as platinum or palladium-on-carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). For further examples of reagents useful for said deprotection step, see "<NPL>).

In a preferred embodiment, the protecting group B is a carbamate protecting group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, or t-butoxycarbonyl. In said embodiment, step (b) of Method 1I may preferably be carried out using an acidic aqueous solution, such as aqueous hydrochloric acid or aqueous hydrobromic acid, or using a non-aqueous acidic medium, such as hydrogen chloride or hydrogen bromide in an organic solvent (e.g., methanol, THF, dioxane, diethyl ether, acetic acid, or a mixture thereof) or using a strong organic acid (e.g., neat trifluoroacetic acid (TFA), or TFA in a suitable organic solvent, e.g. dioxane). In a preferred embodiment, the non-aqueous acidic medium is hydrobromic acid dissolved in an organic solvent (e.g., in acetic acid).

In some embodiments, step (b) of Method 1I is carried out under acidic conditions and the compound of Formula 1I is obtained in the form of an acid addition salt. For example, the reaction can be carried out using hydrochloric acid or hydrobromic acid, resulting in the compound of Formula 1I as a hydrochloride or hydrobromide salt. In other embodiments, step (b) of Method 1I is carried out under acidic conditions and the reaction mixture is subjected to neutralization or basification with a suitable base in order to obtain the compound of Formula 1I in free base form. Suitable bases for carrying out said neutralization or basification include inorganic bases such as hydroxides, oxides, carbonates and bicarbonates (e.g., ammonium, alkali metal or alkaline earth metal bases, including NaOH, KOH, LiOH, NH<NUM>OH, Ca(OH)<NUM>, CaO, MgO, Na<NUM>CO<NUM>, K<NUM>CO<NUM>, Li<NUM>CO<NUM>, NaHCO<NUM>, KHCO<NUM>, LiHCO<NUM>, CaCO<NUM>, MgCO<NUM>, (NH<NUM>)<NUM>CO<NUM>, and the like), optionally in aqueous solution (such as aqueous sodium hydroxide, aqueous sodium carbonate, or aqueous ammonia).

In some embodiments, Method 1I provides the compounds of Formula 1I, respectively, as a crystalline free base or as a crystalline acid-addition salt, e.g., as a hydrochloride or hydrobromide salt. The inventors have unexpectedly found that use of the Method 1I, or one or more of Methods <NUM>-<NUM>, results in the production of compounds of Formula 1I with much lower levels of contamination by transition metal impurities (e.g., copper) compared to prior art methods of making these compounds. For example, use of the present methods can result in the production of compounds of Formula 1I containing less than about <NUM> ppm of copper, or less than about <NUM> ppm of copper, or less than about <NUM> ppm of copper, or about <NUM> ppm of copper.

In specific embodiments of the first aspect, the present disclosure provides:.

In another aspect, the invention provides a method (Method 1J) for preparing a compound of Formula 1J, or any of <NUM>-<NUM>, in free or salt form, comprising the steps of (a) reacting a compound of Formula 1E', in free or salt form, with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), to form an intermediate of Formula 1F, in free or salt form; (c) deprotecting the piperidine nitrogen of the compound of Formula 1F to yield the compound of Formula 1I (or any of <NUM>-<NUM>), in free or salt form; and (c) alkylating the piperidine nitrogen of the compound of Formula 1I with a suitable alkylating agent to yield the compound of Formula 1J (or any of <NUM>-<NUM>) in free or salt form; and optionally (d) converting the compound of Formula 1J in free form to a compound of Formula 1J (or any of <NUM>-<NUM>) in salt form, e.g., pharmaceutically acceptable salt form, such as acid addition salt form (e.g., tosylate salt form). In some embodiments, the method further comprises the step of converting a compound of Formula 1D to the compound of Formula 1E'.

In all respects, steps (a) and (b) of Method 1J may be carried according to the description above for Method 1I, respectively, including any of Methods <NUM>-<NUM>.

Alkylating agents suitable for step (c) of Method 1J include compounds of the general formula Q-X, wherein Q is <NUM>-(<NUM>-fluorophenoxy)propyl, and wherein X is any suitable leaving group. Leaving groups are entities known in the art to be amenable to nucleophilic substitution reactions. In some embodiments, X is selected from chloro, bromo, iodo, C<NUM>-<NUM>alkylsulfonyloxy (e.g. methanesulfonyloxy) and optionally substituted arylsulfonyloxy (e.g., benzenesulfonyloxy, <NUM>-nitrobenzenesulfonyloxy, <NUM>-halosulfonyloxy, and the like).

In some embodiments, step (c) of Method 1J, may further comprise a suitable base. Suitable bases include, but are not limited to, organic bases such as amine bases (e.g., ammonia, triethylamine, N,N'-diisopropylethylamine or <NUM>-(dimethylamino)pyridine (DMAP), <NUM>,<NUM>-diazabicycl[<NUM>. <NUM>]-non-<NUM>-ene (DBN), <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU)); or inorganic bases such as hydrides (e.g. sodium, lithium or potassium hydride), alkoxides (e.g. sodium, potassium or lithium t-butoxide), aryloxides (e.g., lithium, sodium or potassium phenoxide), or carbonates, bicarbonates, phosphates or hydroxides of alkali or alkaline earth metals (e.g. sodium, magnesium, calcium, potassium, cesium or barium carbonate, bicarbonate, hydroxide or phosphate). Optionally, step (c) may further comprise an inorganic iodide salt, such as potassium iodide or sodium iodide, preferably potassium iodide. Suitable solvents include polar protic and/or polar aprotic solvents, such as, acetonitrile, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methanol, ethanol, isopropanol, and mixtures thereof. In a preferred embodiment, step (c) comprises reaction of the compound of Formula 1I with the alkylating agent <NUM>-chloro-<NUM>-(<NUM>-fluorophenoxy)propane, and a base selected from triethylamine, diisopropylethylamine, potassium carbonate and sodium carbonate. Where a base is used, the amount of base can be any amount from a catalytic amount (e.g., <NUM> equivalents) to an excess amount (e.g., <NUM> or more equivalents). In some embodiments, the reaction is performed with from <NUM> to <NUM> equivalents of base, e.g., <NUM> to <NUM> or <NUM> to <NUM> equivalents of base.

The compound of Formula 1J, which results from step (c) of Method 1J, may be obtained as a free base or as a salt. Suitable salt forms include acid addition salts, such as phosphates, sulfates, hydrohalides (e.g., hydrochloride), and carboxylates (e.g., acetate or formate). Either the free base form or a salt form of the compound of Formula 1J may be obtained, e.g., isolated or purified, by any suitable method. In some embodiments, the reaction of step (c) is performed in the presence of an excess of base, and this may permit the isolation of the free base for of the compound of Formula 1J from the reaction mixture (e.g., by aqueous/organic extraction, and/or by chromatography, and/or by precipitation from a suitable solvent, and/or by evaporation of the reaction solvent). In some embodiments, the reaction of step (c) is performed in the absence of base or in the presence of less than one equivalent of base (e.g., <NUM> equivalent or less, or a catalytic amount). Particularly when performed in the absence of base, step (c) may yield an acid addition salt of the compound of Formula 1J, wherein the acid component of the salt is derived from the alkylating agent. For example, if the compound of Formula 1I is treated with an alkylating agent Q-X, as defined above, and in the absence of an added base, the resulting compound of Formula 1J may be obtained as the acid addition salt corresponding to the group X (e.g., if X is chloro, then the compound of Formula 1J may be obtained in the form of a hydrochloride acid addition salt). In some embodiments, an equimolar or only moderate excess of base is used during the reaction of step (c), but prior to or during purification, an excess of acid (e.g., hydrochloric acid) is added, resulting in obtainment of the compound of Formula 1J as an acid addition salt (e.g. hydrochloride).

In some embodiments, step (c) of Method 1J yields the compound of Formula 1J in free form (i.e., free base form), and this form is isolated and/or purified, and then, optionally, step (d) is performed to convert the free base form of said compound of Formula 1J into a salt form of said compound of Formula 1J, for example, a pharmaceutically acceptable salt form (e.g., an acid addition salt). In some embodiments, this acid addition salt form of said compound of Formula 1J is further isolated and/or purified. Without being bound by theory, it is believed that the initial isolation of the compound of Formula 1J in free form, followed by subsequent conversion of this compound into salt form (e.g., acid addition salt form) results in a final product (compound of Formula 1J) of higher purity and/or workability.

Step (d) of Method 1J may be carried out by reacting the free base form of the compound of Formula 1J with an appropriate acid, in water or in an organic solvent, or in a mixture of the two, to give, for example, a pharmaceutically acceptable acid addition salt of Formula 1J of the present invention. Appropriate acids are generally known in the art, and may include, for example, hydrochloric acid or toluenesulfonic acid. When a monovalent acid is used (e.g., hydrochloric acid or toluenesulfonic acid), step (d) may result in a mono-addition salt or a di-addition salt, depending on the molar equivalent of acid to free base used (e.g., from <NUM>:<NUM> free base to acid to <NUM>:<NUM> free base to acid).

In specific embodiments of this aspect, the present disclosure provides:.

In another aspect, the invention provides a method (Method 1F) for preparing a compound of Formula 1F which is not part of the invention, in free or salt form, comprising the steps of (a) reacting a compound of Formula 1D, in free or salt form, with (i) benzophenone imine, (ii) a transition metal catalyst, (iii) a base, and optionally (iv) a monodentate or bidentate ligand, to form the compound of Formula 1E', in free or salt form; and (b) reacting the compound of Formula 1E', in free or salt form, with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) optionally an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), to form the compound of Formula 1F, in free or salt form.

Prior art methods for the synthesis of compounds such as those of Formula 1F from the compounds of Formula 1D involved a two-step process in which the first step was an alkylation of the indole nitrogen with an alpha-haloacetamide, and the second step was an intramolecular ring closure using a copper catalyst. However, these prior art methods did suffer from one or more of (<NUM>) long reaction times, (<NUM>) the formation of undesirable impurities, and/or (<NUM>) loss of product to decomposition during evaporation of reaction solvent. Applicant has unexpectedly found that present method provides improved yields, purities and/or efficiencies, compared to prior art methods. In particular, the present method avoids the use of a copper catalyst, thus eliminating any possibility of the presence of copper impurities in the final product.

In particular embodiments of Methods 1F which are all not part of the invention, the present disclosure further provides:.

In some embodiments, any of Methods 1F, 1I, 1J, or <NUM>-<NUM> or <NUM>-<NUM>, or <NUM>-<NUM>, may further comprise the step of preparing a compound of Formula 1C:
<CHM>
in free or salt form, comprising the sub-steps of:.

The reduction of Compounds of Formula 1A to Compounds of Formula 1B may be accomplished through the use of a reducing agent including, but not limited to: silanes in the presence of an acid (e.g., acetic, methanesulfonic acid or trifluoroacetic acid); metal (e.g., zinc) and mineral acid (e.g. hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or through the use of borane-amine complexes (e.g. borane-triethylamine in tetrahydrofuran); sodium triacetoxyborohydride; or sodium cyanoborohydride. The conversion of the Compound of Formula 1A to a Compound of Formula 1B may also be accomplished through catalytic hydrogenation, in which the Compound of Formula 1A is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium on carbon or platinum oxide (See<NPL>). In an especially preferred embodiment for the reduction of Compounds of Formula 1A, the reduction is accomplished through the use of triethylsilane in the presence of trifluoroacetic acid, or triethylsilane in the presence of methanesulfonic acid. In particular, it was unexpectedly found that substituting methanesulfonic acid for trifluoroacetic acid significantly improves yield, reaction time and cost efficiency. For example, using <NUM> volumes of methanesulfonic acid instead of <NUM> volumes of trifluoroacetic acid permits a significant reduction in need for the costly triethylsilane reagent (From <NUM> volumes to <NUM> volumes) and reduces reaction time from <NUM> hours to <NUM>-<NUM> hours, while increasing yield for the step.

In some embodiments, enantiomeric enrichment (or separation) of the isomers of the Compounds of Formula 1B to produce the Compounds of Formula 1C may be achieved by chiral salt resolution, in which chiral acids such as chiral sulfonic acids or mono- or di-carboxylic acids or derivatives thereof are used. Examples of such acids include, but are not limited to, (+/-)/(R/S) tartaric acid, (+/-)/ (R/S) (mono- or diacetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (monoor di-pivaloyl)tartaric acid, (+/-)/(R/S) mandelic acid, (+/-)/ (R/S) acetoxyphenyl acetic acid, (+/-)/(R/S) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/)/(R/S) halomandelic acid (e.g. <NUM>-fluoromandelic acid), (+/-)/(R/S) lactic acid, and (+/)/(R/S) camphor sulfonic acid. Preferably, resolution of compounds of Formula 1B is accomplished by using mandelic acid. In an especially preferred embodiment, said acid is (S)-(+)-mandelic acid. Resolution may be optimized where undesired enantiomer is removed first. Therefore, in another preferred embodiment, resolution is accomplished by adding (R)-(-)-mandelic acid to remove the undesired enantiomer first, followed by the addition of (S)-(+)-mandelic acid to obtain the desired product. In some embodiments, only a single resolution is performed using only (S)-(+)-mandelic acid. Preferred solvents for the resolution include methanol, ethanol, methyl tert-butyl ether (MTBE), and combinations thereof.

In another embodiment, enantiomeric enrichment (or separation) of the stereoisomers of the Compounds of Formula 1B may be achieved by using chiral chromatography, for example using amylose tris(<NUM>,<NUM>-dimethylphenylcarbamate) column sold under the tradename "CHIRALPAK® AD®". The isomers of Formula 1B may be separated and eluted with a mobile phase such as ethanol at a flow rate of <NUM>-<NUM>/min. In yet another embodiment, the isomers of Formula 1B may be separated and eluted with mobile phase such as methanol or isopropyl alcohol. The fractions for the desired compounds, preferably, Compounds of Formula 1C, may be collected and isolated. In one embodiment, chiral chromatography comprises the use of CHIRALPAK® AD®, <NUM>, <NUM> ID x <NUM> L column and <NUM>% ethanol mobile phase at a flow rate of <NUM>/min. In another embodiment, chiral chromatography comprises the use of CHIRALPAK® AD®, <NUM>, <NUM> ID x <NUM> L column and <NUM>% ethanol mobile phase at a flow rate of <NUM>/min.

It is understood that upon the separation of the isomers of the Compounds of Formula 1B to yield the Compounds of Formula 1C, the diastereomeric or enantiomeric composition of the Compounds becomes fixed, or substantially fixed, as all further reactions in the sequence arriving at the Compound of Formula 1J does not substantially change the diastereomeric or enantiomeric composition of the Compounds. Thus, in all aspects and embodiments of the present disclosure, each of the intermediates according to Formulas 1D, 1E', 1F, <NUM>, and 1I, may each be substantially, essentially, or completely a single cis enantiomer, to the substantial or complete exclusion of the opposite cis isomer or any trans isomer. Thus, as used herein, each of the intermediates according to Formulas 1D, 1E', 1F, <NUM>, and 1I, may be at least <NUM>%, preferably at least <NUM>%, more preferably at least <NUM>%, most preferably greater than <NUM>%, and up to <NUM>%, cis stereoisomer relative to all other stereoisomers; and/or have an enantiomeric excess (e. ) of at least <NUM>%, preferably at least <NUM>%, more preferably at least <NUM>%, most preferably greater than <NUM>%, or greater than <NUM>%, or greater than <NUM>%, or greater than <NUM>%, or greater than <NUM>%, and up to <NUM>%.

In some embodiments, any of Methods 1F, 1I, 1J, or <NUM>-<NUM> or <NUM>-<NUM>, or <NUM>-<NUM>, may further comprise the step of preparing the compound of Formula 1A, in free or salt form, by reacting <NUM>-bromophenylhydrazine with <NUM>-piperidinone in an acidic solvent (a Fischer Indole reaction). In some embodiments the <NUM>-bromophenylhydrazine and/or the <NUM>-piperidinone is provided as an acid addition salt, for example, a hydrochloride, hydrobromide, acetate or trifluoroacetate salt. In some embodiments, the <NUM>-piperidinone is present as a hydrate, e.g., a monohydrate. In some embodiments, the product is obtained as an acid addition salt, e.g., a hydrochloride, hydrobromide, trifluoroacetate, sulfate, or acetate salt. The reaction may be carried out in any suitable solvent, for example, an aqueous or alcoholic solvent (e.g., water, methanol, ethanol or isopropanol, or any mixture thereof) comprising a dissolved acid (e.g., HCl, HBr, H<NUM>SO<NUM>, acetic acid), or in a neat acidic solvent (e.g., acetic acid, trifluoroacetic acid). In some embodiments, the yield may be improved by using a solvent in which the product is poorly soluble. In some embodiments, the yield is improved by using neat acetic acid as the solvent.

In some embodiments, any of Methods 1F, 1I, 1J, or <NUM>-<NUM> or <NUM>-<NUM>, or <NUM>-<NUM> may further comprise the step of preparing a compound of Formula 1D:
<CHM>
wherein:.

Examples of suitable protecting agent for reaction with the compounds of Formula 1C include, but are not limited to, benzyloxycarbonyl chloride (Cbz-Cl), triphenylmethyl chloride, ethyl chloroformate, t-butoxycarbonyl anhydride (Boc<NUM>O), benzyl N-succinimidyl carbonate, or benzoyl halide (e.g. benzoyl chloride or bromide), (benzyloxycarbonyl)-benzo triazole, benzyl halide (e.g. benzyl chloride or bromide), <NUM>-arene sulfonyl chloride or toluene sulfonyl chloride. Another example of a protecting group of Compounds of Formula 1C is p-methoxybenzyl, which may be prepared using p-methoxybenzyl chloride, p-methoxybenzyl bromide or p-methoxybenzaldehyde. The protective agents disclosed herein are not intended to be exhaustive. For further examples of amine protecting agent, see one of the many general texts on the subject, for example, "<NPL>), the disclosure of which is hereby incorporated by reference. Upon addition of the protecting agent to the compounds of Formula 1C, the substituent B of the resulting compound 1D therefore has the general formula:
<CHM>
wherein:.

The protection step of this embodiment generally requires the addition of a base such as: butyl lithium or metal hydrides (e.g., potassium hydride); bicarbonates, carbonates, or hydroxides of alkali or alkaline earth metals (e.g., potassium or sodium carbonate, sodium bicarbonate, or sodium hydroxide), or organic amines (e.g., triethylamine). Preferably, the protecting agent of compounds of Formula 1D is ethyl chloroformate or BOC anhydride. In an especially preferred embodiment, said protecting agent is ethyl chloroformate and said base is triethylamine or sodium hydroxide.

In some embodiments, the conversion of the compound of Formula 1C to the compound of Formula 1D comprises treatment with ethyl chloroformate and sodium hydroxide in a mixture of water and THF.

In some embodiments, the procedure for protecting the piperidine nitrogen of the compound of Formula 1C will entail first neutralizing a salt of the compound of Formula 1C, for example a mandelic acid salt, with a suitable base, followed by isolation, separation, or purification of the free base of the compound of Formula 1C. The appropriate reagents for the protection of the piperidine nitrogen of the compound of Formula 1C are then added, along with suitable base to yield the compound of Formula 1D. The base used for neutralization may or may not be the base used for the protection reaction. In other embodiments, the salt of the compound of Formula 1C (e.g., the mandelate salt) is reacted with the appropriate protection reagents in the presence of excess base, in order to arrive at the compound of Formula 1D in a single step. Thus, the free base formation and acylation reactions are conducted simultaneously in these embodiments. Preferably the base is sodium hydroxide.

In some embodiments, any of Methods 1I, 1J, or <NUM>-<NUM> or <NUM>-<NUM>, may further comprise the step of reacting a compound of Formula 1D, in free or salt form, with (i) benzophenone imine, (ii) a transition metal catalyst, (iii) a base, and optionally (iv) a monodentate or bidentate ligand, to form the compound of Formula 1E', respectively, in free or salt form.

In some of these embodiments, the transition metal catalyst is a palladium catalyst. For example, the transition metal catalyst may be selected from Pd/C, PdCl<NUM>, Pd(OAc)<NUM>, (CH<NUM>CN)<NUM>PdCl<NUM>, Pd[P(C<NUM>H<NUM>)<NUM>]<NUM>, bis(dibenzylideneacetone)palladium [Pd(dba)<NUM>], and tris(dibenzylideneacetone)dipalladium [Pd<NUM>(dba)<NUM>]. In some embodiments, the catalyst is selected from [Pd(dba)<NUM>] and [Pd<NUM>(dba)<NUM>]. The transition metal catalyst may be present in an amount of <NUM> to <NUM> equivalents, e.g., from <NUM> to <NUM> equivalents, or from <NUM> to <NUM> equivalents, or from <NUM> to <NUM> equivalents, or about <NUM> equivalents. In some embodiments, a base is included in the reaction step, for example, a Bronsted base, e.g., selected from amine bases, alkoxides, carbonates and phosphates, and mixtures thereof. In some embodiments, the base is an alkoxide base (e.g., a C<NUM>-<NUM>alkoxide), for example, an alkali or alkaline earth metal alkoxide, or mixtures thereof (e.g., sodium t-butoxide and/or potassium t-butoxide). The base may be used in an amount of <NUM> to <NUM> equivalents, e.g., <NUM> to <NUM> equivalents, or about <NUM> equivalents. This step may further comprise a monodentate or bidentate ligand, for example, a bidentate phosphine ligand. In some embodiments, the ligand is a bis(tri-arylphosphino) ligand, such as <NUM>,<NUM>'-bis(diphenylphosphino)-<NUM>,<NUM>'-binapthyl (BINAP). The ligand may be used in an amount of <NUM> to <NUM> equivalents, e.g., from <NUM> to <NUM> equivalents, or from <NUM> to <NUM> equivalents, or from <NUM> to <NUM> equivalents, or about <NUM> equivalents.

Unless the terms are specifically defined for an embodiment, the terms used herein are generally defined as follows.

The phrase "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid; and the salts prepared from organic acids such as toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media are preferred. Compounds of the present disclosure, have more than one basic nitrogen atom. For example, compounds of Formula 1J have two basic nitrogen atoms (one N-aryl piperazine nitrogen, and one aliphatic piperidine nitrogen). It is understood that the piperidine nitrogen is more basic than the piperazine nitrogen. It is also understood that any one or both of these nitrogen atoms can form an acid addition salt with an acidic hydrogen of a monoprotic, diprotic or triprotic Bronsted acid, depending on the molar ratio of free base to acid provided in a reaction. As a result, when terms such as "acid addition salt" are used in this disclosure, such term refers to any such salts that are possible, as well as combinations thereof.

The term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C<NUM>-C<NUM> alkyl" denotes alkyl having <NUM> to <NUM> carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

"Halo", "halogen" or "halide" as used herein refers to fluoro, chloro, bromo, and iodo. Therefore, "alkyl halide" refers to a halogen group attached to an alkyl group as defined above, such as methyl iodide or iodobutane.

"Alkali metal" refers lithium sodium and potassium. "Ammonium" refers to both the ammonium ion (NH<NUM>+) and tetraalkylammonium ions (NR<NUM>+), wherein R is a C<NUM>-<NUM> alkyl radical. For example, tetraalkylammonium includes tetramethylammonium, tetraethylammonium, tetrapropylammonium and tetrabutylammonium. Thus, the term "alkali metal or ammonium iodide or bromide" includes, but is not limited to, the iodide and bromide salts of sodium, potassium lithium, ammonium and tetraalkylammonium.

"Cycloalkyl" is intended to include monocyclic or polycyclic ring systems comprising at least one aliphatic ring. Therefore, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like. Wherein cycloalkyl is a polycyclic system, such system may contain an aliphatic ring fused to an aromatic, non-aromatic, heteroaromatic or hetero nonaromatic rings. Examples of such include octahydro-<NUM>-indene, <NUM>,<NUM>-dihydro-<NUM>-indene and <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinoline.

The term "heterocycloalkyl" herein refers to a monocyclic or polycyclic system comprising at least one aliphatic ring containing at least one heteroatom selected from a group consisting of O, N and S. Therefore, heterocycloalkyl may refer to piperidinyl, piperazinyl, <NUM>-pyrrolidonyl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinolinyl, <NUM>,<NUM>-<NUM>,<NUM>,<NUM>-dithiazinyl, <NUM>-pyrrolyl or <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>,<NUM>-naphthyridine.

As used herein, the term "aryl" is intended to mean a stable <NUM>- to <NUM>-membered monocyclic or polycyclic or <NUM>- to <NUM>-membered polycyclic ring system which comprises at least one aromatic ring (i.e., planar ring that contains 4n+<NUM> Pi electrons, wherein n is an integer). Therefore, the term "aryl" includes phenyl, naphthyl and their derivatives. The term "aryl" is also intended to include polycyclic ring systems which contain at least one aromatic ring fused to one or more aromatic or non-aromatic or heteroaromatic rings (e.g., <NUM>,<NUM>-dihydro-<NUM>-indene).

As used herein, the term "heterocycle", "heterocyclic ring" or "heteroaryl" is intended to mean a stable <NUM>- to <NUM>-membered monocyclic or polycyclic or <NUM>- to <NUM>-membered polycyclic ring which comprises at least one aromatic ring containing at least one heteroatom independently selected from the group consisting of N, O and S. Therefore, a "heterocycle" or "heterocyclic ring" or "heteroaryl" may include a single heteroaromatic ring or a heteroaromatic ring fused to another heteroaromatic ring or to a non-heteroaromatic or non-aromatic ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of heterocycles or heteroaryl groups include, but are not limited to <NUM>-indazolyl, thiazolyl, furyl, pyridyl, quinolinyl, pyrollyl, indolyl and <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinolinyl.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Therefore, optionally substituted alkyl may refer to an alkyl group as defined above whereby one or more hydrogens are replaced with a selection from the indicated group including, but not limited to, halogen, hydroxy, amino, sulfhydryl, alkyl, alkenyl, alkynyl, haloalkyl (e.g. CH<NUM>Cl, CF<NUM>, CH<NUM>CH<NUM>Br, etc.), amido, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, carboxy, carbonyl, silyl, alkylamino, alkylamido, nitro, cyano, halo, -S(O)-alkyl, - S(O)<NUM>-alkyl, R-cycloalkyl, R-heterocycloalkyl, R-C(O)-, R-C(O)-OR', R-O-, -N(R)(R') wherein R and R' are independently H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl or heterocycloalkyl.

The term "resolution" is a term of art and refers to the separation of a racemic mixture into its enantiomers by any means, including reacting a chiral organic acid or base with the components of the racemic mixture to form diastereomeric salts and separating said salts by, for example, crystallization techniques. The term "chiral salt resolution" refers to the separation of a racemic mixture into its enantiomers through the use of a chiral acid.

The term "chromatography" is well known in the art and refers to a technique of separating the components of a mixture by interacting it with a stationary phase and eluting the components of the mixture with a mobile phase such as ethanol, methanol, acetonitrile, water or mixtures thereof. The term "chiral chromatography" refers to chromatography wherein the stationary phase is chiral.

The term "chiral acid" refers to any optically active acid capable of forming diastereomeric salts with compounds of Formula 1B. The terms "mono or di-carboxylic acid" or "sulfonic acid" herein refers to any compound that contains one or two carboxylic functional groups and a sulfonic acid group respectively. Examples of such acids include but are not limited to (+/-)/(R/S) tartaric acid, (+/-)/ (R/S) (mono- or diacetyl)tartaric acid, (+/-)/(R/S) (mono- or di-benzoyl)tartaric acid, (+/-)/(R/S) (monoor di-pivaloyl)tartaric acid, (+/-)/(R/S) mandelic acid, (+/-)/(R/S) acetoxyphenyl acetic acid, (+/-)/(RlS) methoxyphenyl acetic acid, (+/-)/(R/S) hydroxymandelic acid, (+/)/(R/S) halomandelic acid (e.g. <NUM>-fluoromandelic acid), (+/-) /(R/S) lactic acid, and (+/)/(R/S) camphor sulfonic acid.

The term "protecting agent" refers to any compound that reacts with the atom for which protection is desired so as to block or mask its functionality. It is typically used to temporarily modify a potentially reactive functional group so as to protect it from undesired chemical transformation. A desirable protecting agent is one which is compatible with or stable to the reaction condition and is easily cleaved off at a later point when protection is no longer desired.

The terms "protecting group" and "protective group" refer to removable chemical groups that are used to protect or mask reactive functional moieties during synthetic transformations. The term "protecting agent" refers to a reagent that is used to attach protecting a group to the functional moiety to be protected. For example, the protecting agent ethyl chloroformate is used to attach the protecting group ethoxycarbonyl, and the protecting agent BOC-anhydride is used to attach the protecting group t-butoxycarbonyl. Protecting groups, as defined herein, include groups with the general formula -P-Z, wherein Z is optionally substituted alkyl, aryl, alkylaryl, alkoxycarbonyl, or -OR wherein R is alkyl, aryl, arylalkyl or heteroarylalkyl, and wherein P is -CH<NUM>-, -C(O)-, -C(O)O-, or S(O)<NUM>. Examples of protecting groups include benzyloxycarbonyl (Cbz), triphenylmethyl, alkyloxy and aryloxy carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl), benzyl N-succinimidyl carbonyl, benzoyl, substituted benzoyl, substituted benzyloxycarbonyl, benzyl, substituted benzyl, and alkyl and aryl sulfonyl (e.g., methanesulfonyl, benzenesulfonyl, toluenesulfonyl). Further suitable protecting agents and protecting groups can be found, for example, in "<NPL>).

The term "deprotection" or "deprotect" or "deprotecting" refers to the act of removing or cleaving off a protecting group. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group and may involve acid (e.g., hydrochloric, sulphuric, phosphoric or trifluoroacetic acid or a Lewis acid such as boron tris(trifluoroacetate)) or base (alkali metal hydroxide, e.g., lithium, potassium or sodium hydroxide) catalysis or catalytic hydrogenation condition (e.g., hydrogen and palladium-on-carbon).

The term "catalyst" herein refers to any substance or agent capable of affecting, inducing, increasing, influencing or promoting the reactivity of a compound or reaction without itself being consumed. The phrase "transition metal catalyst" refers to any metal having valence electrons in the d-orbitals, e.g. metals selected from one of Groups <NUM>-<NUM> of the periodic table. Such catalysts may include atoms, ions, salts or complexes of transition metals from Groups <NUM>-<NUM> of the Periodic Table. "Group <NUM>-<NUM> of the Periodic Table" refers to the groups of the Periodic Table as numbered according to the IUPAC system. Therefore, transition metals from Group <NUM>-<NUM> which include iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver and gold. Examples of such catalysts include, but are not limited to CuI, CuCl, CuBr, CuBr<NUM>, Cu(II) acetate, Cu<NUM>Cl<NUM>, Cu<NUM>O, CuSO<NUM>, Cu<NUM>SO<NUM>, Cu, Pd/C, PdCl<NUM>, Pd(OAc)<NUM>, (CH<NUM>CN)<NUM>PdCl<NUM>, Pd[P(C<NUM>H<NUM>)<NUM>]<NUM>, bis(dibenzylideneacetone)palladium [Pd(dba)<NUM>], tris(dibenzylideneacetone)dipalladium [Pd<NUM>(dba)<NUM>], Ni(acetylacetonate)<NUM>, NiCl<NUM>[P(C<NUM>H<NUM>)]<NUM> and Ni(<NUM>,<NUM>-cyclooctadiene)<NUM>. Catalysts are typically, but not necessarily used in sub-stoichiometric amount relative to the reactants.

The term "base" herein refers to organic or inorganic bases such as amine bases (e.g., ammonia, triethylamine, N,N'-diisopropylethylamine or <NUM>-(dimethylamino)pyridine (DMAP); <NUM>,<NUM>-diazabicycl[<NUM>. <NUM>]-non-<NUM>-ene (DBN), <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU)); hydrides (e.g. sodium, lithium or potassium hydride); alkoxides, (e.g. sodium, potassium or lithium t-butoxide and K(OAr), Na(OAr)); or carbonates, bicarbonates, phosphates or hydroxides of an alkali or alkaline earth metal (e.g. sodium, magnesium, calcium, potassium, cesium or barium carbonate, bicarbonate, hydroxide or phosphate).

The term "Bronsted base" is art-recognized term and refers to an uncharged or charged atom or molecule, e.g., an oxide, amine, alkoxide, or carbonate, which is a proton acceptor. Examples of Bronsted base include, but are not limited to K<NUM>PO<NUM>, K<NUM>CO<NUM>, Na<NUM>CO<NUM>, Tl<NUM>CO<NUM>, Cs<NUM>CO<NUM>, K(OtBu), Li(OtBu), Na(OtBu), K(OPh), and Na(OPh), or mixtures thereof.

The term "Lewis base" is recognized in the art and refers to a chemical moiety capable of donating a pair of electrons under certain reaction conditions. Examples of Lewis bases include, but are not limited to, uncharged compounds such as alcohols, thiols, olefins, and amines (e.g., ammonia, triethylamine), and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.

The term "acid" herein refers to Lewis or Bronsted acid. Lewis acid is a term of art and refers to a chemical moiety capable of accept a pair of electrons (e.g., boron trifluoride). Bronsted acid refers to any chemical moiety capable of donating a proton (e.g., acetic acid, hydrochloric acid, phosphoric acid as well as other organic acids known in the art).

The term "ligand" refers to any atom, molecule or ion capable of donating or sharing one or more electrons through a coordinate and/or covalent bond with another central atom, typically a metal. "Monodentate ligand" refers to ligands that have one binding site to the central atom (e.g., pyridine or ammonia). "Bidentate ligand" refers to ligands that have two binding sites (e.g., N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine or <NUM>,<NUM>-phenathroline). Examples of useful ligands for group <NUM>-<NUM> transition metals include, but are not limited to, <NUM>-phenylphenol, <NUM>,<NUM>-dimethylphenol, <NUM>-isopropylphenol, <NUM>-naphthol, <NUM>-hydroxyquinoline, <NUM>-aminoquinoline, DBU, DBN, DABCO, <NUM>-(dimethylamino)ethanol, N,N-diethylsalicylamide, <NUM>-(dimethylamino)glycine, N,N,N',N'-tetramethyl-<NUM>,<NUM>-diaminoethane, <NUM>,<NUM>-diphenyl-<NUM>,<NUM>-phenanthroline, <NUM>,<NUM>-dimethyl-<NUM>,<NUM>-phenanthroline, <NUM>-methyl-<NUM>,<NUM>-phenanthroline, <NUM>-chloro-<NUM>,<NUM>-phenanthroline, <NUM>-nitro-<NUM>,<NUM>-phenanthroline, <NUM>-(dimethylamino)pyridine, <NUM>-(aminomethyl)pyridine, (methylimino)diacetic acid, cis-<NUM>,<NUM>-diaminocyclohexane, trans-<NUM>,<NUM>-diaminocyclohexane, a mixture of cis- and trans-<NUM>,<NUM>-diaminocyclohexane, cis-N,N'-dimethyl-<NUM>,<NUM>-diaminocyclohexane, trans-N,N'-dimethyl-<NUM>,<NUM>-diaminocyclohexane, a mixture of cis- and trans-N,N'-dimethyl-<NUM>,<NUM>-diaminocyclohexane, cis-N-tolyl-<NUM>,<NUM>-diaminocyclohexane, trans-N-tolyl-<NUM>,<NUM>-diaminocyclohexane, a mixture of cis- and trans-N-tolyl-<NUM>,<NUM>-diaminocyclohexane, ethanolamine, <NUM>,<NUM>-diaminoethane, N,N'-dimethyl-<NUM>,<NUM>-diaminoethane, N,N-dimethyl-<NUM>-hydroxybenzamide, N,N-diethyl-<NUM>-hydroxybenzamide, fluoro-N,N-diethyl-<NUM>-hydroxybenzamide, chloro-N,N'-diethyl-<NUM>-hydroxybenzamide, (<NUM>-hydroxyphenyl)(pyrrolidin-<NUM>-yl)methanone, biphenyl-<NUM>-ol, <NUM>-pyridylphenol, <NUM>,<NUM>-benezenediamine, ammonia, N,N-dimethylformamide, dimethylsulfoxide, <NUM>-methyl-<NUM>-pyrrolidinone or mixtures thereof as well as the biphenyl and binaphthyl ligands hereinbefore described. In certain embodiments, the amount of ligand used may be a stoichiometric or an excess amount. In other embodiments, the ligand may be used as a solvent for the reaction. Therefore, reagents such as N,N-dimethylformamide, dimethylsulfoxide, <NUM>-methyl-<NUM>-pyrrolidinone or other liquid amines may serve as a solvent as well as ligand for the reaction.

Additional suitable monodentate or bidentate ligands include:.

The term "N,N'-dimethylethylenediamine" is used interchangeably with "N,N'-dimethyl-<NUM>,<NUM>-diaminoethane".

The phrase "nucleophilic alkyl halide" refers to any compound having both an alkyl halide functional group (electrophilic) and a nucleophilic functional group. The term "nucleophilic" or "nucleophile" is well recognized in the art and refers to a chemical moiety having a reactive pair of electrons.

The term "reduction" or "reducing" refers to the conversion of a functional group in a molecule from a higher oxidation state to a lower oxidation state. The term "reducing agent" or "reductive agent" refers to any compound or complex that is known in the field for its effects in converting a functional group in a molecule from a higher oxidation state to a lower oxidation state. Examples of reduction include both the reduction of a carbon-carbon double bond to a carbon-carbon single bond, and reduction of a carbonyl group (C=O) to a methylene (CH<NUM>). The reduction may be achieved via a direct electron, hydride or hydrogen-atom transfer. Typical reducing agents useful for Methods 1C and 2C include metal hydrides (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride) and hydrogen in the presence of a catalyst (e.g., Raney nickel, palladium on charcoal, nickel boride, platinum metal or its oxide, rhodium, ruthenium and zinc oxide, pentacyanocobaltate(II) Co(CN)<NUM><NUM>-). Catalytic hydrogenation is typically carried out at room temperature and at atmospheric pressure, but higher temperature and/or higher pressure may be required for more resistant double bonds. Other reducing agents useful for converting double bonds to single bonds include silane and acid; sodium cyanoborohydride and acid; zinc and acid; sodium and liquid ammonia; sodium in ethanol; and borane-triethylamine.

The term "alkylation" refers to the introduction of an alkyl radical onto an organic compound by substitution or addition. Therefore, the term "N-alkylation" refers to the introduction of an alkyl radical onto the nitrogen atom of the organic compound.

Procedures for the production of compounds described herein and for the carrying out of some of the steps of the methods described herein are known to those skilled in the art, and can be found, for example, in <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>.

<NUM>-(<NUM>-bromophenyl)hydrazine hydrochloride and <NUM>-piperidinone monohydrate hydrochloride are combined in about <NUM>:<NUM> molar ratio, in acetic acid, and the resulting slurry is heated to reflux until less than <NUM>% of the hydrazine starting material remains by HPLC analysis (e.g., for <NUM> hours). The reaction mixture is then cooled to room temperature, filtered, and the cake is washed with acetone and dried to a solid which is used in the next step.

Reduction: To a <NUM> <NUM>-neck RBF with magnetic stirrer, N<NUM> inlet and drying tube is charged methanesulfonic acid (<NUM>). <NUM>-bromo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole hydrochloric acid salt (<NUM>) is charged in portions. The reaction mixture is heated to <NUM> to <NUM>, and then triethylsilane (TES) (<NUM>, <NUM> eq. ) is charged drop wise over <NUM> hour in order to control exotherm. The temperature is kept at <NUM> to <NUM>. Once the addition is complete, the mixture is stirred at <NUM> to <NUM> for <NUM>. Additional TES (<NUM>, <NUM> eq. ) may be added over approximately <NUM> minutes, after which, the mixture is stirred at <NUM> to <NUM> for <NUM>. Additional TES (<NUM>, <NUM> eq. ) may be added over approximately <NUM> minutes, after which the mixture is stirred at room temperature overnight. Additional TES (<NUM>, <NUM> eq. ) may be charged and the mixture stirred at room temperature for <NUM>. After cooling to <<NUM>, the reaction is quenched with water (<NUM>) by adding water drop wise at a rate to maintain <<NUM> (strong exotherm observed). Dichloromethane (<NUM>) is added and the mixture is adjusted to about pH = <NUM> with <NUM>% w/v aqueous NaOH. The mixture is filtered through a layer of Celite. The layers are separated and the aqueous layer is extracted with dichloromethane (<NUM>). The combined organic layer is washed with water (<NUM>), dried over magnesium sulfate (<NUM>), filtered and concentrated under vacuum. The residue is treated with heptanes. After filtration, the obtained solid is dried under vacuum at <NUM> to give <NUM> of product (yield: <NUM>%, HPLC purity: <NUM>%).

Separation: [4aS, 9bR]-<NUM>-bromo-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>H-pyrido[<NUM>,<NUM>-b]indole may be separated by dissolving the racemic cis <NUM>-bromo-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole (<NUM>, <NUM>. 0mmol) in methanol (<NUM>) at <NUM> and adding (S)-(+)-Mandelic acid (<NUM>, <NUM>. 0mmol) in portions. The resulting clear solution is stirred at <NUM> for several minutes and ether (<NUM>) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-Mandelate salt, <NUM>) is filtered off. HPLC analysis shows ><NUM> % e.

(4aS,9bR)-ethyl <NUM>-bromo-<NUM>,<NUM>,4a,<NUM>-tetrahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole-<NUM>(9bH)-carboxylate may be prepared by first obtaining [4aS, 9bR]-<NUM>-bromo-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>H-pyrido[<NUM>,<NUM>-b]indole (<NUM>, <NUM>. 142mol)) as a free base by using <NUM>% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl <NUM>-bromo-<NUM>,<NUM>,4a,<NUM>-tetrahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole-<NUM>(9bH)-carboxylate may then be done by cooling a suspension of [4aS, 9bR]-<NUM>-bromo-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>H-pyrido[<NUM>,<NUM>-b]indole (<NUM>, <NUM>. 142mol)) in THF (<NUM>) and triethylamine (<NUM>) in an ice-water bath. Ethyl chloroformate is added dropwise (<NUM>, <NUM>. 142mol) via a syringe pump over <NUM> hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of Celite and the solvent is evaporated to give (4aS,9bR)-ethyl <NUM>-bromo-<NUM>,<NUM>,4a,<NUM>-tetrahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole-<NUM>(9bH)-carboxylate). <NUM>H NMR (CDCl<NUM>, <NUM>): <NUM>-<NUM> (m,<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (Br, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Alternative to the use of [4aS, 9bR]-<NUM>-bromo-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>H-pyrido[<NUM>,<NUM>-b]indole (Compound of Formula 1C) free base, the reaction may also be carried out by starting with the (S)-mandelate salt of [4aS, 9bR]-<NUM>-bromo-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>H-pyrido[<NUM>,<NUM>-b]indole. A <NUM> round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N<NUM> inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (<NUM>, <NUM> mmol), Na<NUM>CO<NUM> (<NUM>, <NUM> mmol), and <NUM> of THF. To the yellow reaction mixture at <NUM> (heating block temperature) is added a solution of ethyl chloroformate (<NUM>, <NUM> mmol) in <NUM> of THF dropwise over ca <NUM> minutes. The batch is stirred at <NUM> for another <NUM>, and then is checked by HPLC. Less than <NUM>% of the starting material is observed by HPLC, and the desired product is registered at ca. To the batch is added <NUM> of EtOH, and the batch is concentrated under reduced pressure to remove about <NUM> of solvent (mostly THF). To the batch is then added <NUM> of H<NUM>O, and the resultant mixture shows pH ><NUM> by pH paper. The yellow mixture is then stirred at room temperature for about <NUM>, and then is filtered. The solid is rinsed with <NUM> of H<NUM>O. After drying in a vacuum oven at <NUM> for about <NUM>, <NUM> of a yellow solid is obtained (<NUM>% yield). <NUM>H NMR of the solid conformed and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at ><NUM>% purity. LC-MS showed a peak with M/e = <NUM> (M+<NUM>).

((4aS,9bR)-ethyl <NUM>-bromo-<NUM>,<NUM>,4a,<NUM>-tetrahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole-<NUM>(9bH)-carboxylate (<NUM>, 80mmol), benzophenone imine (<NUM>, 88mmol), t-BuONa (<NUM>, 157mmol) and BINAP (<NUM>, <NUM>. 5mmol) are placed in a <NUM> three neck round bottom flask equipped with a condenser and a teflon covered thermocouple. Toluene (<NUM>) is added and nitrogen is bubbled into the suspension through a steel needle through a hole bored in the septum. The temperature is gradually raised to <NUM> via heating mantle. The heating mantle is then removed and the flask is cooled to ambient temperature. Pd<NUM>(dba)<NUM> (<NUM>, <NUM>. 8mmol) is added and the flask is warmed up to <NUM>. Following this the needle was removed and nitrogen is introduced through the top of the condenser. The reaction mixture was heated at <NUM>.

Following the same procedure, a second batch of the reaction with the same conditions is prepared. After both reactions are heated at <NUM> overnight, they are combined and diluted with t-butyl methyl ether (<NUM>). The resulting suspension is passed through a pad of Celite and concentrated to give the title compound as a dark brown foam (<NUM>), which was taken to next step without further purification.

A suspension of ethyl (4aS,9bR)-<NUM>-((diphenylmethylene)amino)-<NUM>,<NUM>,<NUM>,4a,<NUM>,9b-hexahydro-<NUM>-pyrido[<NUM>,<NUM>-b]indole-<NUM>-carboxylate (ca. <NUM>, <NUM> mmol), ethyl bomoacetate (<NUM>, <NUM> mmol), Na<NUM>CO<NUM> (<NUM>, <NUM> mmol) and KI (<NUM>, <NUM> mmol) in acetone (<NUM>) is refluxed for <NUM> hours. The acetone is removed in vacuo and dichloromethane (<NUM>) is added, then washed with water (<NUM>), brine (<NUM>) and dried (Na<NUM>SO<NUM>). Evaporation of the solvent gives an oil, which is then dissolved in THF (<NUM>). 2N HCl (<NUM>) is added in portions at room temperature. HPLC shows that the reaction step is complete at <NUM> hours. The THF is then removed in vacuo and 1N HCl (<NUM>) is added and the mixture is filtered. The brown solid is dissolved in dichloromethane (<NUM>) and washed with brine (<NUM>), dried (Na<NUM>SO<NUM>). Evaporation of the solvent and flash chromatography of the residue over alumina using hexanes/ethyl acetate then DCM/methanol, gives the title compound as solid (<NUM>, <NUM>% from Int-<NUM>). Purity: <NUM>% by HPLC. <NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> (br, <NUM>), <NUM> (br, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM>(m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>); <NUM>C- NMR (CDCl<NUM>, <NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. LC/Ms: <NUM> (M+<NUM>).

(6bR, 10aS)-<NUM>-oxo-<NUM>,<NUM>,6b,<NUM>,<NUM>,10a-hexahydro-<NUM>,<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>] pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxaline-<NUM>-carboxylic acid ethyl ester (<NUM>, <NUM> mmol) is suspended in HBr/acetic acid solution (<NUM>, <NUM>% w/w) at room temperature. The mixture is heated at <NUM> for <NUM> hours. After cooling and treatment with ethyl acetate (<NUM>), the mixture is filtered. The filter cake is washed with ethyl acetate (<NUM>), and then dried under vacuum. The obtained HBr salt is then suspended in methanol (<NUM>), and cooled with dry ice in isopropanol. Under vigorous stirring, ammonia solution (<NUM>, 7N in methanol) is added slowly to the suspension to adjust the pH of the mixture to <NUM>. The obtained mixture is dried under vacuum without further purification to give crude (6bR, 10aS)-<NUM>-oxo-<NUM>,<NUM>,6b,<NUM>,<NUM>,10a-hexahydro-<NUM>,<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxaline (<NUM>), which is used directly in the next step. MS (ESI) m/z <NUM> [M+H]+.

A mixture of (6bR,10aS)-6b,<NUM>,<NUM>,<NUM>,<NUM>,10a-hexahydro-<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>(<NUM>)-one (<NUM>, <NUM> mmol), <NUM>-(<NUM>-chloroproxy)-<NUM>-fluorobenzene (100µL, <NUM> mmol) and KI (<NUM>, <NUM> mmol) in DMF (<NUM>) is degassed with argon for <NUM> minutes and DIPEA (<NUM>µL, <NUM> mmol) is added. The resulting mixture is heated to <NUM> and stirred at this temperature for <NUM>. The mixture is cooled to room temperature and then filtered. The filter cake is purified by silica gel column chromatography using a gradient of <NUM> - <NUM>% ethyl acetate in a mixture of methanol/7N NH<NUM> in methanol (<NUM> : <NUM> v/v) as an eluent to produce partially purified product, which is further purified with a semi-preparative HPLC system using a gradient of <NUM> - <NUM>% acetonitrile in water containing <NUM>% formic acid over <NUM> to obtain the title product as a solid (<NUM>, yield <NUM>%). MS (ESI) m/z <NUM> [M+<NUM>]+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM><NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

In additional experiments, it is found that yield and purity are improved by conducting the reaction in DMSO solvent at <NUM>-<NUM> for <NUM>-<NUM> hours (<NUM>% conversion, <NUM>- <NUM> scale)). The product may be isolated by quenching with an ethyl acetate-water mixture, followed by solvent exchange with n-heptane after phase separation. The crude product may be isolated by crystallization from n-heptane, followed by filtration, washing and drying under vacuum. The crude product may be further purified by slurrying and filtering from acetonitrile. The obtained product conforms to expected <NUM>H-NMR, and HPLC-MS analysis. The following purity profile is obtained (organic impurities are determined by HPLC, except that solvent impurities are determined by HS-GC):.

It was unexpectedly found during scale-up experiments that re-slurrying crude (6bR,10aS)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)propyl)-6b,<NUM>,<NUM>,<NUM>,<NUM>,10a-hexahydro-<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>(<NUM>)-one in either acetonitrile or acetone resulted in overall acceptable HPLC purity for the purified product (<NUM>-<NUM>%), but having an excessive of amount of certain particular impurities, for example, of <NUM>-(<NUM>-chloroproxy)-<NUM>-fluorobenzene, which is present in an amount of <NUM> to <NUM>% w/w. This impurity should be limited to no more than <NUM>% w/w in the final product.

A crystallization study is therefore performed to determine optimum conditions for further purification of the free base product. Initially screened solvents include methanol, ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, <NUM>-methyltetrahydrofuran, ethyl acetate and isopropyl acetate. Based on initial screening results, further studies are limited to methanol, acetone and acetonitrile.

Initial results are shown in the table below:.

When the above noted recrystallized products are each dried at <NUM> and <NUM> mbar vacuum, however, levels of residual solvent exceed ICH limits, as shown in the table below (<NUM> hours drying for acetonitrile, <NUM> hours drying for methanol and acetone):.

This data shows that the product unexpectedly tends to entrap solvents in such a way that makes it very difficult to remove, even after prolonged periods of drying under vacuum. In combination with further studies, it is found that (6bR, 10aS)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)propyl)-6b,<NUM>,<NUM>,<NUM>,<NUM>,10a-hexahydro-<NUM>-pyrido[<NUM>',<NUM>':<NUM>,<NUM>]pyrrolo[<NUM>,<NUM>,<NUM>-de]quinoxalin-<NUM>(<NUM>)-one free base tends to entrap solvents in its crystal structure at about a <NUM> mol % amount.

Further studies show that the rate of cooling during crystallization has an impact on residual solvent levels. It is found that faster cooling (e.g., <NUM>/hr versus <NUM>/hr) helps to produce smaller-sized crystals which entrap less solvent. In contrast, drying the crystals at higher temperatures or lower pressure (higher vacuum) does not significantly influence residual solvent levels.

Further studies are performed to evaluate the role of antisolvents (e.g., n-heptane or MTBE) in the crystallization process. Without being bound by theory, it is suspected that by using a mixture of solvents, each solvent can be reduced to below ICH levels. However, each set of binary solvent mixtures must be analyzed to also ensure that recrystallization from the solvent mixture maintains sufficient overall HPLC purity and satisfactory impurity profile.

Various combinations of recrystallization solvent mixture are studied, including acetone-ethyl acetate and acetone-methanol, at various solvent ratios. It is found that acetone-methanol recrystallization at a <NUM>:<NUM> or <NUM>:<NUM> ratio provides satisfactory results, as shown in the table below:.

All drying conditions for the crystals prepared above is <NUM> hours, <NUM> at <NUM> mbar.

Claim 1:
A method for preparing a compound of Formula 1J,
<CHM>
in free or salt form, wherein R is H, and Q is <NUM>-(<NUM>-fluorophenoxy)propyl; comprising the steps of (a) reacting a compound of Formula 1E',
<CHM>
in free or salt form, wherein
(i) B is a protecting group of the formula P-Z, wherein P is C(O)O, and Z is an optionally substituted alkyl, aryl, or alkylaryl;
with (i) an alkyl haloacetate of the formula XCH<NUM>C(O)OR' wherein X is a halide selected from Cl, Br and I, and R' is C<NUM>-<NUM>alkyl (e.g., ethyl), (ii) a base, and (iii) an alkali metal or ammonium iodide or bromide (e.g. potassium iodide or tetrabutylammonium bromide), in acetone solvent, to form an intermediate of Formula 1F,
<CHM>
in free or salt form, wherein B is a protecting group of the formula P-Z, wherein P is C(O)O, and Z is an optionally substituted alkyl, aryl, or alkylaryl, and R is H; (b) deprotecting the piperidine nitrogen of the compound of Formula 1F to yield the compound of Formula 1I,
<CHM>
in free or salt form, wherein R is H, using hydrobromic acid in acetic acid (e.g., <NUM>% w/w HBr in AcOH); and (c) alkylating the piperidine nitrogen of the compound of Formula 1I with a suitable alkylating agent to yield the compound of Formula 1J in free or salt form, wherein the suitable alkylating agent is <NUM>-chloro-<NUM>-(<NUM>-fluorophenoxy)propane; and optionally (d) converting the compound of Formula 1J in free form to a compound of Formula 1J in salt form, e.g., acid addition salt form (e.g., tosylate salt form); wherein the method further comprises the step of preparing the compound of Formula 1E', in free or salt form, by reacting a compound of Formula 1D, in free or salt form, with (i) benzophenone imine, (ii) a transition metal catalyst, (iii) a base, and (iv) a monodentate or bidentate ligand, to form the compound of Formula 1E', wherein the transition metal catalyst is selected from Pd/C, PdCl<NUM>, Pd(OAc)<NUM>, (CH<NUM>CN)<NUM>PdCl<NUM>, Pd[P(C<NUM>H<NUM>)<NUM>]<NUM>, Pd(dba)<NUM>, and Pd<NUM>(dba)<NUM>, and the base is a C<NUM>-<NUM>alkoxide base, and the monodentate or bidentate ligand is BINAP.