WO2020086765A1

WO2020086765A1 - Processes for preparing a vmat2 inhibitor

Info

Publication number: WO2020086765A1
Application number: PCT/US2019/057729
Authority: WO
Inventors: Jeffrey C. Culhane; David Kucera
Original assignee: Neurocrine Biosciences, Inc.
Priority date: 2018-10-24
Filing date: 2019-10-23
Publication date: 2020-04-30
Also published as: TW202033521A

Abstract

The present invention relates to processes and intermediates for preparing (3R,11bS)-9,10-dimethoxy-2-methyl-3-neopentyl-1,3,4,6,7,11b-hexahydro-2H-pyrazino[2,1-a]isoquinoline, and salts thereof, which is an inhibitor of the vesicular monoamine transporter 2 (VMAT2). The compounds and salts, solvates, and hydrates thereof as described herein are useful in the treatment of neurological and psychiatric diseases and disorders.

Description

PROCESSES FOR PREPARING A VMAT2 INHIBITOR

FIELD OF THE INVENTION

The present invention relates to processes and intermediates for preparing (3R,l lbS)- 9,l0-dimethoxy-2-methyl-3-neopentyl-l,3,4,6,7,l lb-hexahydro-2H-pyrazino[2,l-a]isoquinoline, and salts thereof, which is an inhibitor of the vesicular monoamine transporter 2 (VMAT2). The compounds and salts, solvates, and hydrates thereof as described herein are useful in the treatment of neurological and psychiatric diseases and disorders.

BACKGROUND OF THE INVENTION

Dysregulation of dopaminergic systems is integral to several central nervous system (CNS) disorders, including neurological and psychiatric diseases and disorders. These neurological and psychiatric diseases and disorders include hyperkinetic movement disorders, and conditions such as schizophrenia and mood disorders. The transporter protein vesicular monoamine transporter-2 (VMAT2) plays an important role in presynaptic dopamine release and regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.

VMAT2 inhibitors, including the compound (3R,l lbS)-9,lO-dimethoxy-2-methyl-3- neopentyl-l,3,4,6,7,l lb-hexahydro-2H-pyrazino[2,l-a]isoquinoline (Compound 1; alternatively named (3R,l lbS)-3-(2,2-dimethylpropyl)-9,l0-dimethoxy-2-methyl-lH,2H,3H,4H,6H,7H,l lbH- piperazino[2,l-a]isoquinoline) (see PCT App. No. PCT/US2018/028031 filed April 17, 2018), are being developed for the treatment of a variety of neurological and psychiatric disorders.

There is a need for improved methods of preparing VMAT2 inhibitors like Compound 1 in order, for example, to increase purity, improve reproducibility, improve efficiency, reduce costs, and allow for scale up. The present disclosure helps fulfill these and other needs, as evident in reference to the following disclosure.

SUMMARY OF THE INVENTION

Provided herein are processes for preparing (3R,l lbS)-9,lO-dimethoxy-2-methyl-3- neopentyl-l,3,4,6,7,l lb-hexahydro-2H-pyrazino[2,l-a]isoquinoline and salts thereof.

The processes for preparing Compound 1, or a salt thereof, can comprise: a) coupling 2-(3 ,4-dimethoxyphenyl)ethan- 1 -amine with (f?)-2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentanoic acid, in the presence of Bl, wherein Bl is a base, and CA1, wherein CA1 is a peptide coupling agent, to provide Compound 7 having the formula:

Compound 7;

b) deprotecting Compound 7 with A7, wherein A7 is an acid, to provide Compound 6

having the formula:

Compound 6,

or a salt thereof;

c) reacting Compound 6 with 2,2,-dimethoxyacetaldehyde in the presence of A6, wherein A6 is an acid, and RA3, wherein RA3 is a hydride reducing agent, to provide Compound 5 having the formula:

Compound 5;

d) reacting Compound 5 with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a hydride reducing agent, to provide Compound 4 having the formula:

Compound 4, or a salt thereof;

e) reacting Compound 4, or a salt thereof, with A2, wherein A2 is an acid, to provide

Compound 3 having the formula:

Compound 3,

or a salt thereof;

f) reducing Compound 3, or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Compound 2 having the formula:

Compound 2; g) treating Compound 2 with Al, wherein Al is an acid, to provide Compound 1, or a salt thereof.

Provided herein are also intermediates useful for the preparation of.

DETAILED DESCRIPTION

This disclosure provides processes and intermediates for preparing a VMAT2 inhibitor. VMAT2 inhibitors are described in PCT App. No. PCT/US2018/028031, filed April 17, 2018, which is incorporated herein by reference in its entirety, including (3R,l lbS)-9,lO-dimethoxy-2- methyl-3-neopentyl-l,3,4,6,7,l lb-hexahydro-2H-pyrazino[2,l-a]isoquinoline, which is depicted below as Compound 1.

Compound 1 Provided herein are processes for preparing Compound 1 or a salt thereof. The processes for preparing Compound 1 or a salt thereof provided herein have certain advantages over the processes currently disclosed in the art. For example, the processes described herein demonstrate good scalability and yields. In particular, the reactions are easily handled because the reaction solutions and mixtures are not too viscous or too dilute. In addition, each step of the process provides a filterable crystalline solid.

The processes for preparing Compound 1, or a salt thereof, can comprise:

a) coupling 2-(3 ,4-dimethoxyphenyl)ethan- 1 -amine with (f?)-2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentanoic acid, in the presence of Bl, wherein Bl is a base, and CA1, wherein CA1 is a peptide coupling agent, to provide Compound 7 having the formula:

Compound 7

having the formula:

Compound 6,

or a salt thereof;

Compound 5; d) reacting Compound 5 with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a hydride reducing agent, to provide Compound 4 having the formula:

Compound 4,

or a salt thereof;

Compound 3 having the formula:

Compound 3,

or a salt thereof;

Compound 1 or a salt thereof can be prepared by a process that includes treating Compound 2 with Al, wherein Al is an acid. In some embodiments, Al is phosphoric acid. The salt of Compound 1 can be a phosphoric acid salt, e.g., a di-phosphoric acid salt. In some embodiments, the treating of Compound 2 with Al is performed in the presence of Sl, wherein Sl is a protic solvent. In some embodiments, Sl is an alcohol. For example, Sl can be methanol. In some embodiments, the treating of Compound 2 with Al comprises using about 1 to about 5 molar equivalents of Al relative to Compound 2. In some embodiments, the treating of

Compound 2 with Al comprises using about 1 to about 3 molar equivalents of Al relative to Compound 2. In some embodiments, the treating of Compound 2 with Al comprises using about 2 molar equivalents of Al relative to Compound 2. The treating of Compound 2 with Al can be performed at a temperature between about 55 °C and about 65 °C, e.g., about 60 °C.

Compound 2 or a salt thereof can be prepared by a process that includes reducing

Compound 3, or salt thereof, with RA1, wherein RA1 is a reducing agent. In some embodiments, the salt of Compound 3 is the oxalic acid salt. In some embodiments, the salt of Compound 3 is the hydrochloric acid salt. In some embodiments, RA1 is a hydride reducing agent. In some embodiments, RA1 is lithium aluminum hydride. The reducing of compound 3 can be performed in the presence of S2, wherein S2 is an ether solvent. For example, S2 can be tetrahydrofuran. In some embodiments, the reducing of Compound 3 with RA1 comprises using about 2 to about 4 molar equivalents of RA1 relative to Compound 3. In some embodiments, the reducing of

Compound 3 with RA1 comprises using about 3 molar equivalents of RA1 relative to Compound 3.

Compound 3, or a salt thereof, can be produced by a process that includes reacting Compound 4, or a salt thereof, with A2, wherein A2 is an acid. In some embodiments, the salt of Compound 4 is the di-p-toluoyl-D-tartaric acid salt. In some embodiments, the salt of Compound 4 has the following formula:

In some embodiments, A2 is sulfuric acid. In some embodiments, the reacting of Compound 4, or a salt thereof, with A2 is performed in the presence of S3, wherein S3 is a halogenated solvent. For example, S3 can be dichloromethane. The reacting of Compound 4, or a salt thereof, with A2 can be performed in the presence of water. In some embodiments, the reacting of Compound 4, or a salt thereof, with A2 comprises using about 5 to about 15 molar equivalents of A2 relative to Compound 4. In some embodiments, the reacting of Compound 4, or a salt thereof, with A2 comprises using about 10 molar equivalents of A2 relative to Compound 4. In some embodiments, the reacting of Compound 4, or a salt thereof, with A2 comprises using about 5 to about 10 molar equivalents of water relative to Compound 4. In some embodiments, the reacting of Compound 4, or a salt thereof, with A2 comprises using about 7.5 molar equivalents of water relative to Compound 4. In some embodiments, the process further comprises treating

Compound 3 with A3, wherein A3 is an acid. For example, A3 can be oxalic acid or

hydrochloric acid. In some embodiments, the salt of Compound 3 is the oxalic acid salt of Compound 3. In some embodiments, the salt of Compound 3 is the hydrochloric acid salt of Compound 3. In some embodiments, the process further includes precipitating the oxalic acid salt of Compound 3 from a solution comprising the oxalic acid salt of Compound 3 and S4, wherein S4 is a solvent. In other embodiments, the process further includes precipitating the hydrochloric acid salt of Compound 3 from a solution comprising the hydrochloric acid salt of Compound 3 and S4, wherein S4 is a solvent. In some embodiments, S4 is a protic solvent. For example, S4 can be an alcohol, e.g., isopropanol. In some embodiments, S4 is an ether solvent. For example, S4 can be cyclopentyl methyl ether. In some embodiments, S4 is cyclopentyl methyl ether or methyl tert-butyl ether. In some embodiments, S4 is methyl tert-butyl ether.

Compound 4, or a salt thereof, can be produced by a process that includes reacting Compound 5 with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a reducing agent. In some embodiments, A4 is an organic acid. For example, A4 can be acetic acid. In some embodiments, RA2 is a hydride reducing agent. For example, RA2 can be sodium triacetoxyborohydride. The reacting of Compound 5 with formalin in the presence of A4 and RA2 can be performed in the presence of S5, wherein S5 is a protic solvent. In some

embodiments, S5 is an alcohol. For example, S5 can be ethanol. In some embodiments, the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 1 to about 3 molar equivalents of formalin to Compound 5. In some embodiments, the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 2 molar equivalents of formalin to Compound 5. In some embodiments, the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 1 to about 3 molar equivalents of A4 relative to Compound 5. In some embodiments, the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 2 molar equivalents of A4 relative to Compound 5. In some embodiments, the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 1 to about 3 molar equivalents of RA2 relative to

Compound 5. In some embodiments, the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 2 molar equivalents of RA2 relative to Compound 5. The reacting of Compound 5 with formalin in the presence of A4 and RA2 can be performed at room temperature. In some embodiments, the process further includes treating Compound 4 with A5, wherein A5 is an acid. In some embodiments, A5 is an organic acid. For example, A5 can be di- / ol uoy 1 -D-tartari c acid. In some embodiments, the process further includes precipitating the di- p-toluoyl-D-tartaric acid salt of Compound 4 from a solution comprising the di-p-toluoyl-D- tartaric acid salt of Compound 4 and S6, wherein S6 is a polar aprotic solvent. For example, S6 can be isopropyl acetate.

Compound 5 can be produced by a process that includes reacting Compound 6, or a salt thereof, with 2,2-dimethoxyacetaldehyde in the presence of A6, wherein A6 is an acid, and RA3, wherein RA3 is a reducing agent. In some embodiments, A6 is an organic acid. For example, A6 can be acetic acid. In some embodiments, RA3 is a hydride reducing agent. For example, RA3 can be sodium borohydride. In some embodiments, the reacting of Compound 6 with 2,2- dimethoxyacetaldehyde in the presence of A6 and RA3 comprises using about 3 to about 10 molar equivalents of A6 relative to Compound 6. In some embodiments, the reacting of

Compound 6 with 2,2-dimethoxyacetaldehyde in the presence of A6 and RA3 comprises using about 5 molar equivalents of A6 relative to Compound 6. In some embodiments, the reacting of Compound 6 with 2,2-dimethoxyacetaldehyde in the presence of A6 and RA3 comprises using about 1 to about 3 molar equivalents of RA3 relative to Compound 6. In some embodiments, the reacting of Compound 6 with 2,2-dimethoxyacetaldehyde in the presence of A6 and RA3 comprises using about 1 to about 2 molar equivalents of RA3 relative to Compound 6. The reacting of Compound 6 with 2,2-dimethoxyacetaldehyde in the presence of A6 and RA3 can be performed in the presence of S7, wherein S7 is an ether solvent. For example, S7 can be methyl tert-butyl ether. The reacting of Compound 6 with 2,2-dimethoxyacetaldehyde in the presence of A6 and RA3 can be performed at about room temperature.

Compound 6 can be produced by a process that includes deprotecting Compound 7 with A7, wherein A7 is an acid. A7 can be a mineral acid. For example, A7 can be hydrochloric acid. In some embodiments, the deprotecting of Compound 7 with A7 is performed in the presence of S8, wherein S8 is an ether solvent. For example, S8 can be cyclopentyl methyl ether. In some embodiments, S8 is cyclopentyl methyl ether or methyl tert-butyl ether. In some embodiments,

S8 is methyl tert-butyl ether. The deprotecting of Compound 7 with A7 can be performed at room temperature.

Compound 7, or a salt thereof, can be produced by a process that includes coupling 2- (3,4-dimethoxyphenyl)ethan-l -amine with (f?)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanoic acid, in the presence of Bl, wherein Bl is a base, and CA1, wherein CA1 is a peptide coupling agent. In some embodiments, Bl is an amine base. For example, Bl can be dimethylaminopyridine. In some embodiments, CA1 is a diimide peptide coupling reagent. For example, CA1 can be 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide. In some embodiments, the coupling comprises using about 1 to about 2 equivalents of (f?)-2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentanoic acid relative to 2-(3,4-dimethoxyphenyl)ethan-l- amine. In some embodiments, the coupling comprises using about 1 equivalent of (f?)-2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentanoic acid relative to 2-(3,4-dimethoxyphenyl)ethan-l- amine. In some embodiments, the coupling comprises using about 0.05 to about 0.2 molar equivalents of Bl relative to 2-(3,4-dimethoxyphenyl)ethan-l -amine. In some embodiments, the coupling comprises using about 0.1 molar equivalents of Bl relative to 2-(3,4- dimethoxyphenyl)ethan-l -amine. In some embodiments, the coupling comprises using about 1 to about 2 molar equivalents of CA1 relative to 2-(3,4-dimethoxyphenyl)ethan-l -amine. In some embodiments, the coupling comprises using about 1 molar equivalent of CA1 relative to 2-(3,4- dimethoxyphenyl)ethan-l -amine. In other embodiments, the coupling comprises using about 1.1 molar equivalents of CA1 relative to 2-(3,4-dimethoxyphenyl)ethan-l -amine. The coupling can be performed in the presence of S9, wherein S9 is a halogenated solvent. For example, S9 can be dichloromethane. The coupling can be performed at about room temperature.

A process for preparing Compound 1, or a salt thereof, can comprise:

a) reacting Compound 6 with 2,2,-dimethoxyacetaldehyde in the presence of A6, wherein A6 is an acid, and RA3, wherein RA3 is a hydride reducing agent, to provide Compound 5 having the formula:

Compound 5;

b) reacting Compound 5 with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a hydride reducing agent, to provide Compound 4 having the formula:

Compound 4,

or a salt thereof;

c) reacting Compound 4, or a salt thereof, with A2, wherein A2 is an acid, to provide Compound 3 having the formula:

Compound 3,

or a salt thereof;

d) reducing Compound 3, or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Compound 2 having the formula:

Compound 2; e) treating Compound 2 with Al, wherein Al is an acid, to provide Compound 1, or a salt thereof. A process for preparing Compound 3, or a salt thereof, can comprise:

Compound 7

having the formula:

Compound 6,

or a salt thereof;

Compound 5;

Compound 4,

or a salt thereof;

Compound 3 having the formula:

Compound 3,

or a salt thereof.

A process for preparing Compound 4, or a salt thereof, can comprise:

Compound 7

having the formula:

Compound 6,

or a salt thereof; c) reacting Compound 6 with 2,2,-dimethoxyacetaldehyde in the presence of A6, wherein A6 is an acid, and RA3, wherein RA3 is a hydride reducing agent, to provide Compound 5 having the formula:

Compound 5;

Compound 4,

or a salt thereof.

The processes for preparing Compound 1, or a salt thereof, can comprise:

Compound 7; b) deprotecting Compound 7 with A7, wherein A7 is an acid, to provide Compound 6 having the formula:

Compound 6,

or a salt thereof;

Compound 5;

Compound 4;

e) treating Compound 4 with A5, wherein A5 is di -/Mol uoy 1 -D-tartari c acid, to provide the di- -toluoyl-D-tartaric acid salt of Compound 4;

f) reacting the di -p-tol uoy 1 -D-tartari c acid salt of Compound 4, with A2, wherein A2 is an acid, to provide Compound 3 having the formula:

Compound 3,

or a salt thereof; g) reducing Compound 3, or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Compound 2 having the formula:

Compound 2; h) treating Compound 2 with Al, wherein Al is an acid, to provide Compound 1, or a salt thereof.

A process for preparing Compound 3 or salt thereof can include reacting the di-p-toluoyl-D- tartaric acid salt of Compound 4 having the formula:

with A2, wherein A2 is an acid.

A process for preparing the di-p-toluoyl-D-tartaric acid salt of Compound 4 can include: a) treating Compound 4 with A5, wherein A5 is di-p-toluoyl-D-tartaric acid; and b) precipitating the di-p-toluoyl-D-tartaric acid salt of Compound 4 from a solution

comprising the di-p-toluoyl-D-tartaric acid salt of Compound 4 and S6, wherein S6 is a polar aprotic solvent.

A process for preparing Compound 4 can include: reacting Compound 5 having the formula:

Compound 5,

with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a hydride reducing agent. A process for preparing Compound 5 can include: reacting Compound 6 having the formula:

Compound 6

or a salt thereof,

with 2,2,-dimethoxyacetaldehyde in the presence of A6, wherein A6 is an acid, and RA3, wherein RA3 is sodium borohydride.

In some embodiments, provided herein is a compound having the formula:

Compound 3;

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

Compound 4;

or a salt thereof. In some embodiments, provided herein is a compound having the formula:

Compound 5;

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

Compound 6;

or a salt thereof.

In some embodiments, provided herein is a compound having the formula:

Compound 7;

or a salt thereof.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

As used herein, the term“reacting,”“contacting” or“treating” when describing a certain process is used as known in the art and generally refers to the bringing together of chemical reagents in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reacting involves two reagents, wherein one or more equivalents of second reagent are used with respect to the first reagent. The reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product.

The terms“protecting” and“deprotecting” as used herein in a chemical reaction refer to inclusion of a chemical group in a process and such group is removed in a later step in the process. The term preparation of Compound 1 and its salts can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g ., in Kocienski, Protecting Groups , (Thieme, 2007); Robertson, Protecting Group Chemistry , (Oxford University Press, 2000); Smith el al ., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 6^th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 77(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis , 4th Ed., (Wiley, 2006). Examples of protecting groups include amino protecting groups. As used herein,“amino protecting group” refers to any protecting group for the protection of amines. Example amino protecting groups include, but are not limited to, phenylsulfonyl, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4- trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxy carbonyl (BOC), 1- adamantyloxy carbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3- yloxy carbonyl (Doc), cyclohexyloxy carbonyl (Hoc), 1,1 -dimethyl-2, 2, 2-trichloroethoxy carbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4- nitrobenzyl, diphenyl-4-pyridylmethyl, N’,N’-dimethylhydrazinyl, methoxymethyl, t- butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), tri(Ci-4 alkyl)silyl (e.g., tri(isopropyl)silyl), l, l-diethoxymethyl, or N-pivaloyloxymethyl (POM).

The term“amine base” refers to a base that has an amine group. The amine can be a primary, secondary, or tertiary amine. Examples of an amine base include methylamine, dimethylamine, diphenylamine, trimethylamine, triethylamine, l,8-diazabicyclo[5.4.0]undec-7- ene, and the like.

The term“mineral acid” refers to an acid that is formed from inorganic compound and can form hydrogen ions and conjugate base ions in an aqueous solution. Mineral acids can be a strong acid or a weak acid. Examples of mineral acids include but not limited to hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.

The term“organic acid” refers to an acid with an organic moiety. Examples of organic acid include but not limited to acetic acid, trifluoroacetic acid, formic acid, benzoic acid, toluenesulfonic acid, triflic acid, and the like.

The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane (methylene chloride), tetrachloroethylene, trichloroethylene, l,l, l-trichloroethane, l, l,2-trichloroethane, l, l-dichloroethane, 2- chloropropane, a,a,a-trifluorotoluene, l,2-dichloroethane, l,2-dibromoethane,

hexafluorobenzene, 1,2, 4-trichlorobenzene, 1 ,2-di chlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof and the like.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, cyclopentyl methyl ether, l,3-dioxane, l,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl /c/T-butyl ether, mixtures thereof and the like.

Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1- propanol, 2-propanol, 2-m ethoxy ethanol, 1 -butanol, 2-butanol, Ao-butyl alcohol, tert- butyl alcohol, 2-ethoxy ethanol, di ethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, Ar/-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. The polar protic solvent can be an alcohol such as methanol, ethanol, 1 -propanol, 2-propanol, and the like.

Suitable aprotic solvents can include, by way of example and without limitation, 2- butanone, acetonitrile, dichloromethane, N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), 1,3- dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N- methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene,

hexamethylphosphoramide, and the like.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

The term“reducing agent” as used herein refers to a compound that donates an electron to another compound in a redox reaction. The reducing agent would be oxidized after it loses its electrons. Examples of reducing agents include, but not limited to, borohydride,

triacetoxyborohydride, sodium borohydride, lithium aluminium hydride, hydrogen on palladium, and the like. The reducing agent can be a hydride reducing agent. Hydride reducing agents are reducing agents that contain one or more hydrogen centers having reducing properties. Example hydride reducing agents include, but are not limited to, lithium alumin hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.

The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 'H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., ETV-visible), or mass spectrometry; or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. The compounds obtained by the reactions can be purified by any suitable method known in the art. For example, chromatography (medium pressure) on a suitable adsorbent (e.g., silica gel, alumina and the like), HPLC, or preparative thin layer chromatography; distillation; sublimation, trituration, or recrystallization. The purity of the compounds, in general, are determined by physical methods such as measuring the melting point (in case of a solid), obtaining a NMR spectrum, or performing a HPLC separation. If the melting point decreases, if unwanted signals in the NMR spectrum are decreased, or if extraneous peaks in an HPLC trace are removed, the compound can be said to have been purified. In some embodiments, the compounds are substantially purified.

The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a

temperature from about 20 °C to about 30 °C.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results.

EXAMPLES

The following abbreviations may be used herein: aq. (aqueous); atm. (atmosphere(s)); br (broad); Cbz (carboxybenzyl); calc (calculated); d (doublet); dd (doublet of doublets); DCM (dichlorom ethane); Et (ethyl); EtOAc (ethyl acetate); FCC (flash column chromatography); g (gram(s)); h (hour(s)); HC1 (hydrochloric acid); HPLC (high performance liquid

chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography - mass spectrometry); m (multiplet); M (molar); MS (Mass spectrometry); Me (methyl); MeOH

(methanol); mg (milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N

(normal); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC (reverse phase high performance liquid chromatography); r.t. (room temperature), s (singlet); t (triplet or tertiary); THF (tetrahydrofuran); pg

(microgram(s)); pL (microliter(s)); pM (micromolar); wt % (weight percent). Analytical Method - Ultra-High Performance Liquid Chromatography (TJPLC-MS)

Platform: Agilent 1260 series UPLC: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), column thermostat, a MS detector (electrospray);

Column: Waters XBridge BEH C18 XP, 2.5 micron, 3 x 50 mm;

Mobile phase: A=water, 0.025 % TFA; B=acetonitrile, 0.025% TFA;

Flow rate: 1.5 mL/min;

Gradient: 10% B/90% A to 90% B/l0% A over 1.5 min, then hold 0.3 min, return to initial conditions for 0.5min; total run time 2.5min; Example 1: Synthesis of (3R,llbS)-9,10-dimethoxy-2-methyl-3-neopentyl-l,3,4,6,7,llb- hexahydro-2H-pyrazino[2,l-a]isoquinoline

2-(3,4-Dimethoxyphenyl)ethan-l -amine (77.6 g, 428 mmol) was dissolved in DCM (776 mL). The solution was cooled and ( /^)-2-((tert-butoxycarbonyl )amino)-4, 4-dim ethyl pentanoic acid (115.6 g, 471 mmol, 1.1 eq.) was charged. DMAP (5.23 g, 42.8 mmol, 0.1 eq.) was charged, followed by ED AC (90.3 g, 471 mmol, 1.1 eq.) in portions, producing a heterogeneous mixture. The mixture was warmed to room temperature and stirred until completion. Upon completion the reaction was quenched with citric acid. The phases were separated. The organic phase was washed with water and concentrated by rotary evaporation.

The solution of intermediate tert-butyl (f?)-(l-((3,4-dimethoxyphenethyl)amino)-4,4- dimethyl-l-oxopentan-2-yl)carbamate was cooled prior to the addition of 3 M HC1 in

cyclopentyl methyl ether (875 mL). The reaction was warmed to room temperature and stirred until completion. Vacuum distillation of solvent at elevated temperature lead to crystallization. Upon cooling, the slurry was filtered and the cake was washed with cyclopentyl methyl ether. The wet cake was dried in a vacuum oven to provide (i?)-2-amino-/V-(3,4-dimethoxyphenethyl)- 4,4-dimethylpentanamide hydrochloride.

Step 2 : (R)-2-((2,2-dimethoxyethyl)(methyl)amino)-N-(3,4-dimethoxyphenethyl)-4,4- dimethylpentanamide ( 2S, 3S)-2, 3-bis( ( 4-methylbenzoyl)oxy)succinate

(i?)-2-amino-/V-(3,4-dimethoxyphenethyl)-4,4-dimethylpentanamide hydrochloride (50 g, 145 mmo]) was dissolved in H2O (200 mL) and diluted with MTBE (300 mL). Aqueous sodium hydroxide (50% w/w) was charged until a pH of 10-11 was reached. The phases were separated. The organic phase was washed with water. To the organic phase was charged acetic acid (43.5 g, 725 mmol, 5 eq.) and aqueous 2,2-dimethoxyacetaldehyde (60% w/w) (37.7 g, 218 mmol, 1.5 eq.) The slurry was stirred at room temperature, and over time the solids dissipated. Sodium borohydride (9.6 g, 254 mmol, 1.75 eq.) was charged in portions, maintaining room temperature. Upon completion, the reaction was diluted with water and quenched with sodium carbonate to a pH of 11. The phases were separated. The organic phase was washed with water and

concentrated by rotary evaporation to provide a solution of (i?)-2-((2,2-dimethoxyethyl)amino)- A-(3,4-dimethoxyphenethyl)-4,4-di methyl pentanamide j_n MTBE.

The solution of intermediate (i?)-2-((2,2-dimethoxyethyl)amino)-/V-(3,4-dimethoxyphenethyl)- 4,4-dimethylpentanamide was diluted with EtOH (100 mL). Formalin (37% w/w) (17.4 g, 290 mmol, 2 eq.) and acetic acid (23.5 g, 290 mmol, 2 eq.) were charged and stirred at room temperature. Sodium triacetoxyborohydride (61.5 g, 290 mmol, 2 eq.) was charged in portions, maintaining room temperature. Upon completion, the reaction was diluted with water and quenched with sodium carbonate to a pH of 11. The phases were separated. The organic phase was washed with water and concentrated by rotary evaporation to provide (f?)-2-((2,2- di methoxyethyl )(methyl )ami no)-A-(3,4-dimethoxyphenethyl)-4, 4-dim ethyl pentanamide.

The free-base of (f?)-2-((2,2-dimethoxyethyl)(methyl)amino)-/V-(3,4-dimethoxyphenethyl)-4,4- dimethylpentanamide was solvent exchanged into IP Ac (600 mL). As the solution was heated, di-p-toluoyl-D-tartaric acid (56.0 g, 145 mmol, 1.0 eq.) was charged with complete dissolution. Crystallization of the product D-DTTA salt was initiated by charging a small amount of crystalline seed material. After a slow cooling ramp, the slurry was filtered and the cake was washed with IP Ac. The wet cake was dried in a vacuum oven to provide (R)- 2-((2,2- di methoxyethyl ((methyl )amino)-A_'-(3,4-dimethoxyphenethyl)-4, 4-dimethyl pentanamide 2S,3S)-

2,3-bis((4-methylbenzoyl)oxy)succinate.

Step 3 : (3R)-9,10-dimethoxy-2-methyl-3-neopentyl-J2,3, 6, 7, l lb-hexahydro-4H-pyrazino[2, l- a ]isoquinolin-4-one hydrochloride

Concentrated sulfuric acid (12.3 g, 125 mmol, 10 eq.) was dissolved/suspended in DCM (50 mL) and cooled. Water (1.7 g, 94.3 mmol, 7.5 eq.) was slowly charged. R)- 2-((2,2- di methoxyethyl (( ethyl )amino)-A-(3,4-dimethoxyphenethyl)-4, 4-dimethyl pentanamide (2S,3S)- 2,3-bis((4-methylbenzoyl)oxy)succinate (10 g, 12.5 mmol) was dissolved in DCM (20 mL) and charged to the acid solution, maintaining the reduced temperature. Upon completion, the reaction was diluted with water and the phases were separated. The organic phase was concentrated by rotary evaporation and solvent exchanged into cyclopentyl methyl ether. Water was charged followed by aqueous ammonium hydroxide to a pH of 11. The phases were separated. The organic phase was washed with water and concentrated by rotary evaporation to azeotropically dry the product free-base solution. The concemtrated organic layer was diluted in isopropanol. Charging an isopropyl alcohol solution of oxalic acid lead to crystallization of the product oxalic acid salt (providing the desired cis-diastereomer in a 95:5 ratio to the trans-diastereomer). The slurry was filtered and the cake was washed with isopropanol. The wet cake was dried in a vacuum oven to provide (3f?)-9,l0-dimethoxy-2-methyl-3-neopentyl-l,2,3,6,7,l lb-hexahydro- 4i7-pyrazino[2, l-a]isoquinolin-4-one hydrochloride.

Alternatively, the concentrated organic phase 3M HC1 in cyclopentyl methyl ether lead to crystallization of the product HC1 salt (providing the desired cis-diastereomer in a 60:40 ratio to the trans-diastereomer). The slurry was filtered and the cake was washed with cyclopentyl methyl ether. The wet cake was dried in a vacuum oven to provide (3f?)-9,l0-dimethoxy-2- methyl-3-neopentyl-l,2,3,6,7,l lb-hexahydro-4i7-pyrazino[2,l-a]isoquinolin-4-one

hydrochloride.

Step 4: (3R, 1 lbS)-9 ,10-dimethoxy-2-methyl-3-neopentyl-J 3, 4, 6, 7, 1 lb-hexahydro-2H-

(3f?)-9,l0-dimethoxy-2-methyl-3-neopentyl-l,2,3,6,7,l lb-hexahydro-4F/-pyrazino[2, l- a]isoquinolin-4-one hydrochloride (8.45 g, 24.4 mmol) was dissolved in anhydrous THF (101 mL) and cooled. Lithium aluminum hydride, 2M, (36.6 mL, 73.2 mmol, 3 eq.) was added and the reaction was heated. Upon completion, the LAH was quenched in the manner of Feiser. The precipitated aluminum salts were filtered and washed. The filtrate was stripped of THF and replaced with methyl -t-butyl ether. The phases were separated and the aqueous phase was back- extracted with MTBE. The pooled organics were washed with brine and solvent exchanged into MeOH to provide (3R)-3-(2,2-dimethylpropyl)-9,l0-dimethoxy-2-methyl- lH,2H,3H,4H,6H,7H, l lbH-piperazino[2,l-a]isoquinoline as a mixture of diastereomers.

The mixture of diastereomers (20 g, 60.2 mmol) was dissolved in MeOH (160 mL). The solution was filtered and heated to 50 °C. Phosphoric acid (7.25 g, 1.05 eq.) was added. The solution was heated to 60 °C and a second equivalent of phosphoric acid was added over 1 hour (7.25 g, 1.05 eq.) and stirred at 60 °C for 10 minutes before cooling to 20 °C over 4 hours. The suspension was filtered and the solids were washed with MeOH. Solids were dried in a vacuum oven for 3 days at 50 °C to provide (3R,l lbS)-9,lO-dimethoxy-2-methyl-3-neopentyl- l,3,4,6,7,l lb-hexahydro-2H-pyrazino[2,l-a]isoquinoline as the diphosphate salt. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A process for preparing Compound 1 having the formula:

Compound 1, or a salt thereof, comprising:

a) reacting Compound 5, having the formula:

Compound 5, with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a hydride reducing agent, to provide Compound 4 having the formula:

Compound 4,

or a salt thereof;

b) reacting Compound 4, or a salt thereof, with A2, wherein A2 is an acid, to provide Compound 3 having the formula:

Compound 3,

or a salt thereof; c) reducing Compound 3, or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Compound 2 having the formula:

Compound 2; d) treating Compound 2 with Al, wherein Al is an acid, to provide Compound 1, or a salt thereof.

2. The process of claim 1, wherein Al is phosphoric acid.

3. The process of claim 1 or 2, wherein the salt of Compound 1 is the di-phosphoric acid salt.

4. The process of any one of claims 1-3, wherein the treating of Compound 2 with Al is performed in the presence of Sl, wherein Sl is a protic solvent.

5. The process of claim 4, wherein Sl is methanol.

6. The process of any one of claims 1-5, wherein the treating of Compound 2 with Al comprises using about 1 to about 3 molar equivalents of Al relative to Compound 2.

7. The process of any one of claims 1-6, wherein RA1 is a hydride reducing agent.

8. The process of any one of claims 1-6, wherein RA1 is lithium aluminum hydride.

9. The process of any one of claims 1-8, wherein the reducing of Compound 3 is performed in the presence of S2, wherein S2 is an ether solvent.

10. The process of claim 9, wherein S2 is tetrahydrofuran.

11. The process of any one of claims 1-10, wherein the reducing of Compound 3 with RA1 comprises using about 2 to about 4 molar equivalents of RA1 relative to Compound 3.

12. The process of any one of claims 1-11, wherein the salt of Compound 3 is the oxalate salt.

13. The process of any one of claims 1-12, wherein the salt of Compound 4 is the di-p- toluoyl-D-tartaric acid salt.

14. The process of any one of claims 1-12, wherein the salt of Compound 4 has the formula:

15. The process of any one of claims 1-14, wherein A2 is sulfuric acid.

16. The process of any one of claims 1-15, wherein the reacting of Compound 4, or a salt thereof, with A2 is performed in the presence of S3, wherein S3 is a halogenated solvent.

17. The process of claim 16, wherein S3 is dichloromethane.

18. The process of any one of claims 1-17, wherein the reacting of Compound 4, or a salt thereof, with A2 is performed in the presence of water.

19. The process of any one of claims 1-18, where the reacting of Compound 4, or a salt thereof, with A2 comprises using about 5 to about 15 molar equivalents of A2 relative to

Compound 4.

20. The process of claim 18 or 19, wherein the reacting of Compound 4, or a salt thereof, with A2 comprises using about 5 to about 10 molar equivalents of water relative to Compound 4.

21. The process of any one of claims 1-20, wherein the process further comprises treating Compound 3 with A3, wherein A3 is an acid.

22. The process of claim 21, wherein A3 is oxalic acid.

23. The process of any one of claims 1-22, wherein the salt of Compound 3 is the oxalic acid salt of Compound 3.

24. The process of claim 23, further comprises precipitating the oxalic acid salt of Compound 3 from a solution comprising the oxalic acid salt of Compound 3 and S4, wherein S4 is a protic solvent.

25. The process of claim 24, wherein S4 is isopropanol.

26. The process of any one of claims 1-25, wherein A4 is acetic acid.

27. The process of any one of claims 1-26, wherein RA2 is sodium triacetoxyborohydride.

28. The process of any one of claims 1-27, wherein the reacting of Compound 5 with formalin in the presence of A4 and RA2 is performed in the presence of S5, wherein S5 is a protic solvent.

29. The process of claim 28, wherein S5 is ethanol.

30. The process of any one of claims 1-29, wherein the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 1 to about 3 molar equivalents of formalin to Compound 5.

31. The process of any one of claims 1-30, wherein the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 1 to about 3 molar equivalents of A4 relative to Compound 5.

32. The process of any one of claims 1-31, wherein the reacting of Compound 5 with formalin in the presence of A4 and RA2 comprises using about 1 to about 3 molar equivalents of RA2 relative to Compound 5.

33. The process of any one of claims 1-32, further comprising treating Compound 4 with A5, wherein A5 is an acid.

34. The process of claim 33, wherein A5 is di-p-toluoyl-D-tartaric acid.

35. The process of claim 34, further comprising precipitating the di-p-toluoyl-D-tartaric acid salt of Compound 4 from a solution comprising the di-p-toluoyl-D-tartaric acid salt of

Compound 4 and S6, wherein S6 is a polar aprotic solvent.

36. The process of claim 35, wherein S6 is isopropyl acetate.

37. The process of any one of claims 1-36, wherein Compound 5 is produced by a process comprising: reacting Compound 6 having the formula:

Compound 6

or a salt thereof,

with 2,2,-dimethoxyacetaldehyde in the presence of A6, wherein A6 is an acid, and RA3, wherein RA3 is a hydride reducing agent.

38. The process of claim 37, wherein A6 is acetic acid.

39. The process of claim 37 or 38, wherein RA3 is sodium borohydride.

40. The process of any one of claims 37-39, wherein the reacting of Compound 6 with 2,2- dimethoxyacetaldehyde in the presence of A6 and RA3 comprises using about 3 to about 10 molar equivalents of A6 relative to Compound 6.

41. The process of any one of claims 37-40, wherein the reacting of Compound 6 with 2,2- dimethoxyacetaldehyde in the presence of A6 and RA3 comprises using about 1 to about 3 molar equivalents of RA3 relative to Compound 6.

42. The process of any one of claims 37-41, wherein the reacting of Compound 6 with 2,2- dimethoxyacetaldehyde in the presence of A6 and RA3 is performed in the presence of S7, wherein S7 is an ether solvent.

43. The process of claim 42, wherein S7 is methyl tert-butyl ether.

44. The process of any one of claims 37-43, wherein Compound 6, or a salt thereof, is produced by a process comprising: deprotecting Compound 7 having the formula:

Compound 7

with A7, wherein A7 is an acid.

45. The process of claim 44, wherein A7 is hydrochloric acid.

46. The process of claim 44 or 45, wherein the deprotecting of Compound 7 with A7 is performed in the presence of S8, wherein S8 is an ether solvent.

47. The process of claim 46, wherein S8 is cyclopentyl methyl ether.

48. The process of claim 46, wherein S8 is methyl tert-butyl ether.

49. The process of any one of claims 44-48, wherein Compound 7, or a salt thereof, is produced by coupling 2-(3,4-dimethoxyphenyl)ethan-l -amine with (f?)-2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentanoic acid, in the presence of Bl, wherein Bl is a base, and CA1, wherein CA1 is a peptide coupling agent.

50. The process of claim 49, wherein Bl is dimethylaminopyridine.

51. The process of claim 49 or 50, wherein CA1 is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide.

52. The process of any one of claims 49-51, wherein the coupling comprises using about 1 to about 2 equivalents of (f?)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanoic acid relative to 2-(3,4-dimethoxyphenyl)ethan-l -amine.

53. The process of any one of claims 49-52, wherein the coupling comprises using about 0.05 to about 0.2 molar equivalents of Bl relative to 2-(3,4-dimethoxyphenyl)ethan-l -amine.

54. The process of any one of claims 49-53, wherein the coupling comprises using about 1 to about 2 molar equivalents of CA1 relative to 2-(3,4-dimethoxyphenyl)ethan-l -amine.

55. The process of any one of claims 49-54, wherein the coupling is performed in the presence of S9, wherein S9 is a halogenated solvent.

56. The process of claim 55, wherein S9 is dichloromethane.

57. A process for preparing Compound 1 having the formula:

Compound 1, or a salt thereof, comprising:

Compound 7

having the formula:

Compound 6,

or a salt thereof;

Compound 4,

or a salt thereof;

e) reacting Compound 4, or a salt thereof, with A2, wherein A2 is an acid, to provide Compound 3 having the formula:

Compound 3,

or a salt thereof;

58 A process for preparing Compound 1 having the formula:

Compound 1, or a salt thereof, comprising:

Compound 7;

having the formula:

Compound 6,

or a salt thereof;

Compound 4;

Compound 3,

or a salt thereof;

g) reducing Compound 3, or a salt thereof, with RA1, wherein RA1 is a reducing agent, to provide Compound 2 having the formula:

59. A process for preparing Compound 3, having the formula:

Compound 3,

or a salt thereof, comprising reacting the di-p-toluoyl-D-tartaric acid salt of Compound 4 having the formula:

with A2, wherein A2 is an acid.

60. A process for preparing the di-p-toluoyl-D-tartaric acid salt of Compound 4 having the formula:

Compound 4, comprising:

a) treating Compound 4 with A5, wherein A5 is di-p-toluoyl-D-tartaric acid; and b) precipitating the di-p-toluoyl-D-tartaric acid salt of Compound 4 from a solution

61. The process of claim 60, wherein S6 is isopropyl acetate.

62. A process for preparing Compound 4, having the formula:

Compound 4,

comprising: reacting Compound 5 having the formula:

Compound 5,

with formalin in the presence of A4, wherein A4 is an acid, and RA2, wherein RA2 is a hydride reducing agent.

63. A process for preparing Compound 5 having the formula:

Compound 5,

comprising reacting Compound 6 having the formula:

Compound 6

or a salt thereof,