HK1209753B - Process for the preparation of heterocyclic ester derivatives - Google Patents

Description

Method for preparing heterocyclic ester derivatives

Related patent applications

This application claims the benefit of U.S. Provisional Patent Application No. 61/680,412, filed August 7, 2012, which is hereby incorporated by reference in its entirety.

Technical Field

The present invention relates to a process for preparing heterocyclic ester derivatives useful as intermediates in the synthesis of derivatives useful as protein tyrosine kinase inhibitors, more particularly c-fms kinase inhibitors.

Background Art

Illig, C. et al. disclosed in U.S. Patent Publication No. US20090105296 A1 published on April 23, 2009, c-FMS kinase inhibitors, pharmaceutically acceptable salts thereof, and methods for preparing the same, wherein the kinase inhibitors are derivatives of the following structural formula:

Illig, C. et al. proposed the preparation of the derivatives of the above structural formula in Scheme 1, comprising the steps of:

Reaction with "a heterocyclic acid P ¹ -WCOOH (or its corresponding salt P ¹ -WCOOM ² , wherein M ² is Li, Na or K), wherein P ¹ is an optional protecting group (e.g., such as 2-(trimethylsilyl)ethoxymethyl (SEM) when W is imidazole, triazole, pyrrole or benzimidazole), or wherein P ¹ is absent, such as when W is furan. The coupling can be carried out according to standard procedures for amide bond formation (see, for example, M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY (1984)) or by reaction with an acyl chloride P ¹ -WCOCl or an activated ester P ¹ -WCO ₂ R ^q (wherein R ^q is a leaving group, such as pentafluorophenyl or N-succinimide)".

Illig, C. et al. further proposed in Scheme 9 a method for preparing protected carboxylic acids of the formula ^P1 -WCOOH or corresponding salts of the formula ^P1 - ^WCOOM2 , more specifically compounds wherein W is an imidazolyl group. In the method proposed by Illig, C. et al., the optionally substituted imidazolyl group is protected at the nitrogen position 1 using an appropriately selected protecting group such as MOM or SEM according to known methods.

The protected imidazole is then halogenated with a suitable reagent such as N-bromosuccinimide or N-iodosuccinimide under electrophilic conditions in a solvent such as DCM or CH ₃ CN, or under free radical conditions in the presence of an initiator such as azobis(isobutyronitrile) (AIBN) in a solvent such as CCl ₄ to produce the corresponding compound, wherein the 2-position on the imidazole is substituted with the corresponding halogen atom. A halogen-magnesium exchange on the compound produces the corresponding organomagnesium species, which then reacts with a suitable electrophile to produce the corresponding protected ester. Alternatively, the protected imidazole is deprotonated with a suitable base such as an alkyl lithium followed by reaction with an electrophile to similarly produce the corresponding protected carboxylic acid of the formula ester.

The protected ester can then be "hydrolyzed" to the corresponding "carboxylic acid" of formula ^P1 -WCOOH or "carboxylate" of formula ^P1 - ^WCOOM2 (wherein ^M2 is Li, Na, or K) using aqueous metal hydroxide (MOH) solution in a suitable solvent.

WALL., MJ et al. in "Cyano-Substituted 2-Carboxyimidazoles: Synthesis of4-Cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylatePotassium Salt" Synthesis , 2008, pp 3377-3379, No. 21 ("Cyano-substituted 2-carboxyimidazoles: Synthesis of 4-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate potassium salt," Synthesis, 2008, pp. 3377-3379, No. 21) describes the synthesis of 4-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate potassium salt, wherein the carboxylate group is introduced via bromine-magnesium exchange on a SEM-protected cyanoimidazole followed by reaction with ethyl cyanoformate. The synthesis involves equilibrating a regioisomeric mixture of SEM-protected imidazoles to produce a single product. The method described by Wall et al. utilizes low temperatures and expensive reagents, which are not preferred for large-scale processing.

BARNARD, CFJ describes the carbonylation of aryl halides in "Carbonylation of Aryl Halides: Extending the Scope of the Reaction", Org . Proc. Res. Dev., 2008, pp. 566-574, Vol. 12. Barnard et al. describe carbonylation conditions using an inorganic base and a temperature greater than 100° C., which are not preferred for large-scale production.

ALBANEZE-WALKER, J. et al., "Improved Carbonylation of Heterocyclic Chlorides and Electronically Challenging Aryl Bromides", Org . Lett. 2004, pp2097-2100, Vol. 6, No. 13, describe the carbonylation of heterocyclic halides. The method described by Albenese-Walker et al. also uses a reaction temperature of 100° C., which is not preferred for large-scale production.

However, there remains a need for methods for preparing compounds of formula (I) as described herein; wherein the methods are suitable for large-scale manufacturing.

Summary of the Invention

The present invention relates to a method for preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof.

in

^A1 is selected from _C1-3 alkyl;

Among them are selected

wherein each R ⁴ is independently selected from H, F, Cl, Br, I, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -SC _(1-4) alkyl, -SOC _(1-4) alkyl, -SO ₂ C _(1-4) alkyl, -C _(1-3) alkyl, -CO ₂ R ^d , -CONR ^e R ^f , -CCR ^g , and -CN;

and wherein R ^d is selected from hydrogen and -C _(1-3) alkyl; R ^e is selected from H and -C _(1-3) alkyl; R ^f is selected from H and -C _(1-3) alkyl; and R ^g is selected from H, -CH ₂ OH, and -CH ₂ CH ₂ OH;

The method comprises:

The compound of formula (VIII) or a mixture of its corresponding SEM-protected regioisomers is reacted with carbon monoxide gas or a carbon monoxide source in the presence of a ^tertiary organic base, in the presence of a coupling system, in an alcohol of formula A 1 OH, at a temperature ranging from about 60° C. to about 120° C. to produce the corresponding compound of formula (I).

In one embodiment, the present invention relates to a process for preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof,

in

^A1 is selected from _C1-3 alkyl;

Among them are selected

wherein each R ⁴ is independently selected from H, F, Cl, Br, I, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -SC _(1-4) alkyl, -SOC _(1-4) alkyl, -SO ₂ C _(1-4) alkyl, -C _(1-3) alkyl, -CO ₂ R ^d , -CONR ^e R ^f , _-CCR ^g , and -CN;

and wherein R ^d is selected from hydrogen and -C _(1-3) alkyl; R ^e is selected from H and -C _(1-3) alkyl; R ^f is selected from H and -C _(1-3) alkyl; and R ^g is selected from H, -CH ₂ OH, and -CH ₂ CH ₂ OH;

The method comprises:

In the presence of an organic base or an inorganic base; in an organic solvent; reacting a compound of formula (V) with SEMCl to produce a mixture of the corresponding compound of formula (VI) or its corresponding SEM-protected regioisomers;

in an organic solvent; reacting a compound of formula (VI) or a mixture of its corresponding SEM-protected regioisomers with a bromine source to produce a corresponding compound of formula (VIII) or a mixture of its corresponding SEM-protected regioisomers;

The compound of formula (VIII) or its corresponding SEM-protected regioisomer mixture is reacted with carbon monoxide gas or a carbon monoxide source in the presence of a tertiary organic base, in the presence of a coupling system, in an alcohol of formula A ¹ OH, at a temperature ranging from about 60° C. to about 120° C. to produce the corresponding compound of formula (I).

In one embodiment, the present invention relates to a method for preparing a compound of formula (I-S) and a pharmaceutically acceptable salt thereof,

^A1 is selected from _C1-3 alkyl;

The method comprises:

The compound of formula (VIII-S) is reacted with carbon monoxide gas or a carbon monoxide source in the presence of a tertiary organic base and a coupling system in an alcohol of formula A ¹ OH at a temperature ranging from about 60° C. to about 120° C. to produce the corresponding compound of formula (IS).

In another embodiment, the present invention relates to a process for preparing a compound of formula (I-S) and pharmaceutically acceptable salts thereof,

^A1 is selected from _C1-3 alkyl;

The method comprises:

In the presence of an organic base or an inorganic base; in an organic solvent; reacting a compound of formula (V-S) with SEMCl to generate a mixture of a corresponding compound of formula (VI-S) and a corresponding compound of formula (VII-S);

in an organic solvent; reacting a mixture of a compound of formula (VI-S) and a compound of formula (VII-S) with a bromine source to produce the corresponding compound of formula (VIII-S);

The compound of formula (VIII-S) is reacted with carbon monoxide gas or a carbon monoxide source in the presence of a tertiary organic base and a coupling system in an alcohol of formula A ¹ OH at a temperature ranging from about 60° C. to about 120° C. to produce the corresponding compound of formula (IS).

The present invention also relates to a product prepared according to any of the methods described herein.

DETAILED DESCRIPTION

The present invention relates to a process for preparing a compound of formula (I),

wherein A ¹ and A 1 are as defined herein. The compounds of formula (I) are useful as intermediates in the synthesis of inhibitors of c-fms kinases of the following structural formula

As disclosed by ILLIG, C. et al. in U.S. Patent Publication No. 2009/0105296 Al published on April 23, 2009.

In one embodiment, the present invention relates to a process for preparing a compound of formula (I), wherein ^A is selected from methyl, ethyl, and isopropyl. In another embodiment, the present invention relates to a process for preparing a compound of formula (I), wherein ^A is selected from methyl and ethyl. In another embodiment, the present invention relates to a process for preparing a compound of formula (I), wherein ^A is methyl. In another embodiment, the present invention relates to a process for preparing a compound of formula (I), wherein ^A is ethyl.

In one embodiment, the present invention relates to a process for preparing a compound of formula (I) and a mixture of its corresponding SEM-protected regioisomers, wherein the compound selected from

In another embodiment, the present invention is a process for preparing a compound of formula (I) and a mixture of its corresponding SEM-protected regioisomers, wherein the compound selected from

In another embodiment, the present invention is a process for preparing a compound of formula (I) and a mixture of its corresponding SEM-protected regioisomers, wherein the compound selected from

In another embodiment, the present invention is a process for preparing a compound of formula (I) or a mixture of its corresponding SEM-protected regioisomers, wherein

In another embodiment, the present invention is a process for preparing a compound of formula (I) or a mixture of its corresponding SEM-protected regioisomers, wherein

As used herein, unless otherwise indicated, the term "alkyl" refers to straight and branched chain groups of up to 12 carbon atoms, preferably up to 6 carbon atoms, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

As used herein, unless otherwise indicated, the term "a mixture of its corresponding SEM-protected regioisomers" shall mean a mixture comprising two or more structural isomers; wherein each individual structural isomer is defined by the bonding of a SEM-protected group to one of the nitrogen atoms of the ^W ring structure. For example, for compound of formula (VIII)

When , the corresponding mixture of SEM-protected regioisomers shall refer to any mixture of the following two structural isomers:

As used herein, the designation "*" shall denote the presence of a stereocenter.

Where the compounds according to the present invention have at least one chiral centre, they may therefore exist as enantiomers. Where the compounds have two or more chiral centres, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, where the compounds exist as enantiomers, the enantiomers are present in an enantiomeric excess of greater than or equal to about 80%, more preferably in an enantiomeric excess of greater than or equal to about 90%, even more preferably in an enantiomeric excess of greater than or equal to about 95%, even more preferably in an enantiomeric excess of greater than or equal to about 98%, and most preferably in an enantiomeric excess of greater than or equal to about 99%. Similarly, where the compound exists as a diastereomer, the diastereomer is present in a diastereomeric excess of greater than or equal to about 80%, more preferably in a diastereomeric excess of greater than or equal to about 90%, still more preferably in a diastereomeric excess of greater than or equal to about 95%, still more preferably in a diastereomeric excess of greater than or equal to about 98%, and most preferably in a diastereomeric excess of greater than or equal to about 99%.

In addition, some of the crystalline forms of the compounds of this invention may exist as polymorphs and are also intended to be included in the present invention. In addition, some of the compounds of this invention may form solvates (i.e., hydrates) with water or with common organic solvents, and such solvates are also intended to be encompassed within the scope of the present invention.

According to standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenyl C ₁ -C ₆ alkylaminocarbonyl C ₁ -C ₆ alkyl" substituent refers to a radical of the formula

The abbreviations used in this specification, especially in the "Schemes" and "Examples", are as follows:

AIBN = Azobisisobutyronitrile

BINPA = 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl

DCE = dichloroethane

DIPEA or DIEA = diisopropylethylamine

DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide

GC = Gas Chromatography

MEK = Methyl Ethyl Ketone

Mesyl = Methanesulfonyl

MTBE = Methyl tert-butyl ether

NBS = N-bromosuccinimide

NORIT A-SUPRA = Available from NORIT America

Inc.) powdered activated carbon

Pd(OAc) ₂ = Palladium(II) acetate

(Ph ₃ P)PdCl ₂ or = Bis(triphenylphosphine)palladium(II) chloride

Pd(PPh ₃ ) ₂ Cl ₂

Ph = phenyl

SEM = 2-(trimethylsilyl)ethoxymethyl

SEMCl or SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride

TEA = triethylamine

THF = Tetrahydrofuran

Tosyl = p-toluenesulfonyl

XantPhos = 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene

As used herein, unless otherwise indicated, the term "isolated form" shall mean that the compound is present in a form separated from any solid mixture, solvent system, or biological environment formed with another compound. In one embodiment, the present invention relates to a method for preparing a compound of formula (I), wherein the compound of formula (I) is prepared in isolated form. In another embodiment, the present invention relates to a method for preparing a compound of formula (I-S), wherein the compound of formula (I-S) is prepared in isolated form. In another embodiment, the present invention relates to a product prepared according to any method as described herein, wherein the product is prepared in isolated form.

As used herein, unless otherwise indicated, the term "substantially pure form" shall mean that the molar percentage of impurities in the isolated compound is less than about 5.0 mole%, preferably less than about 2.0 mole%, more preferably less than about 0.5 mole%, and most preferably less than about 0.1 mole%. In one embodiment, the present invention relates to a method for preparing a compound of formula (I), wherein the compound of formula (I) is prepared in a substantially pure form. In another embodiment, the present invention relates to a method for preparing a compound of formula (I-S), wherein the compound of formula (I-S) is prepared in a substantially pure form. In another embodiment, the present invention relates to a product prepared according to any method as described herein, wherein the product is prepared in a substantially pure form.

As used herein, unless otherwise indicated, the term "substantially free of corresponding salt forms" when used to describe a compound of formula (I) shall mean that the molar percentage of the corresponding salt form in the isolated base of formula (I) is less than about 5.0 mole%, preferably less than about 2.0 mole%, more preferably less than about 0.5 mole%, and most preferably less than about 0.1 mole%. In one embodiment, the present invention relates to a method for preparing a compound of formula (I), wherein the compound of formula (I) is prepared in the form of substantially free of corresponding salt forms. In one embodiment, the present invention relates to a method for preparing a compound of formula (I-S), wherein the compound of formula (I-S) is prepared in the form of substantially free of corresponding salt forms. In another embodiment, the present invention relates to a product prepared according to any method as described herein, wherein the product is prepared in the form of substantially free of corresponding salt forms.

As used herein, unless otherwise indicated, the terms "treating," "treatment," and the like shall include the administration and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise indicated, the term "preventing" shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delaying or preventing the development of additional symptoms; and/or (d) delaying or preventing the development of a disorder or condition.

Those skilled in the art will recognize that in the case where the present invention relates to a method of prevention, a subject in need thereof (i.e., a subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease, or condition to be prevented. In addition, a subject in need thereof may also be a subject (preferably a mammal, more preferably a human) who does not exhibit any symptoms of the disorder, disease, or condition to be prevented, but has been deemed by a physician, clinician, or other medical professional to be at risk of developing the disorder, disease, or condition. For example, due to the subject's medical history, including but not limited to family history, a predisposing constitution, coexisting disorders or conditions (concurrent morbidities), genetic testing, etc., the subject may be deemed to be at risk of developing the disorder, disease, or condition (and therefore in need of prevention or preventative treatment).

As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.

As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that will elicit in a tissue system, animal or human the biological or medicinal response that is being sought by the researcher, veterinarian, medical doctor or other clinician, including the alleviation of symptoms of the disease or condition being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

As provided more generally in this written specification, terms such as "reaction" and "reacted" as used herein refer to chemical entities in either: (a) the actual recited form of such chemical entity, and (b) any form of such chemical entity in the medium in which the compound is contemplated to be when it is named.

Those skilled in the art will recognize that, unless otherwise indicated, the reaction steps are carried out according to known methods under appropriate conditions to provide the desired product. Those skilled in the art will also recognize that in the description and claims presented herein, if a reagent or class of reagents (such as a base, solvent, etc.) is mentioned in more than one step of a method, each reagent should be selected independently for use in each reaction step, and each reagent can be the same or different from each other. For example, if two steps of a method recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step can be the same as or different from the organic or inorganic base selected for the second step. In addition, those skilled in the art will recognize that if the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, the reaction steps can also be carried out in a mixture of suitable solvents or solvent systems. Those skilled in the art will also recognize that if two consecutive reactions or process steps are carried out without separating the intermediate product (i.e., the product of the first of the two consecutive reactions or process steps), the first and second reactions or process steps can be carried out in the same solvent or solvent system; or alternatively, they can be carried out in different solvents or solvent systems after a solvent exchange (which can be accomplished according to known methods).

In order to provide a more concise description, some quantitative expressions given herein are not modified with the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each quantity given herein refers to the actual given value and also refers to the approximate value of such given value that can be reasonably inferred based on ordinary skill in the art, including but not limited to the approximate value caused by the experimental and/or measurement conditions of such given value.

To provide a more concise description, some quantitative expressions herein are described as a range from about X amount to about Y amount. It should be understood that when a range is described, the range is not limited to the upper and lower limits recited, but should include the entire range from about X amount to about Y amount or any amount therebetween.

Examples of suitable solvents, bases, reaction temperatures and other reaction parameters and components are given in the detailed description herein below. Those skilled in the art will recognize that the listing of such examples is not intended to, and should not be construed as, limiting in any way the invention set forth in the claims appended hereto. Those skilled in the art will also recognize that if the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, the reaction steps may also be carried out in a mixture of suitable solvents or solvent systems.

As used herein, unless otherwise indicated, the term "aprotic solvent" shall refer to any solvent that does not generate protons. Suitable examples include, but are not limited to, DMF, 1,4-dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, and the like.

As used herein, unless otherwise indicated, the term "leaving group" shall mean a charged or uncharged atom or group that leaves during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any method for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any related molecules. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry , edited by JFW McOmie, Plenum Press, 1973; and TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis . John Wiley & Sons, 1991. Protective groups can be removed at a convenient subsequent stage using methods known in the art.

As used herein, unless otherwise indicated, the term "nitrogen protecting group" shall mean a group that can be attached to a nitrogen atom to protect the nitrogen atom from participating in a reaction and that can be readily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, carbamates - groups of the formula -C(O)OR, where R is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH ₂ ═CH—CH ₂ —, and the like; amides - groups of the formula -C(O)—R′, where R′ is, for example, methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SO ₂ —R″, where R″ is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups can be found in the literature, for example , in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis , John Wiley & Sons, 1991.

In the process of preparing a mixture of stereoisomers produced by the compound according to the present invention, these isomers can be separated by conventional techniques (such as preparative chromatography).Compound can be prepared in racemic form, or a single enantiomer can be synthesized or prepared by splitting by enantiospecificity.For example, by the technology of standard, such as by forming a diastereomeric pair with an optically active acid (such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid), then fractional crystallization and regeneration of free alkali split the compound into their component enantiomers.Also, by forming diastereomeric esters or amides, then chromatographic separation and removal of chiral auxiliary and splitting compound.Alternatively, chiral HPLC column splitting compound can be used.

Alternatively, chiral HPLC can be used to determine the enantiomeric excess (%ee) by comparison with a standard. Enantiomeric excess can be calculated as follows:

[(R mole - S mole)/(R mole + S mole)] × 100%

Wherein R mol and S mol are the mole fractions of R and S in the mixture such that R mol + S mol = 1. Alternatively, the enantiomeric excess can be calculated from the specific rotation of the desired enantiomer and the prepared mixture as follows:

ee=([α-obs]/[α-max])×100.

The present invention includes prodrugs of the compounds of the present invention within its scope. Generally speaking, such prodrugs will be functional group derivatives of the compound that can be easily converted into the desired compound in vivo. Therefore, in the therapeutic methods of the present invention, the term "administering" should cover the use of a specifically disclosed compound or a compound that may not be specifically disclosed (but the unspecified compound is converted into a specifically disclosed compound in vivo after administration to the patient) to treat the various conditions described. For example, conventional procedures for selecting and preparing suitable prodrug derivatives are described in Design of Prodrugs , ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may also be used in the preparation of the compounds according to the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, where the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, edetate calcium salt, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, propionate lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl p-aminophenylarsonic acid salt, hexylresorcinol salt, hydrazine salt, hydrobromide, hydrochloride, hydroxynaphthoic acid Salt, iodide, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (pamoate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, toluenesulfonate, triethyl iodide, and valerate.

Representative acids that can be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acetic acid, 2,2-dichloroacetic acid, acetylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid , L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.

Representative bases that can be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: ammonia, L-arginine, phenethylbenzylamine, benzathine, calcium hydroxide, choline, denanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrazine salt, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

Method of the present invention

The present invention relates to a process for preparing a compound of formula (I) selected from the group consisting of as outlined in Scheme 1 below.

Solution 1

Therefore, in the presence of an appropriately selected organic base or inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ , TEA, pyridine, etc., preferably K ₂ CO ₃ ; wherein the preferred amount of the inorganic base is in the range of about 1.0 to about 3.0 molar equivalents (relative to the moles of the compound of formula (V)), more preferably in the range of about 1.5 to about 2.5 molar equivalents, and more preferably in the amount of about 2.0 molar equivalents;

In an appropriately selected organic solvent, such as acetone, 2-butanone, DCE, etc., preferably acetone; at a temperature in the range of about room temperature to about 60°C, more preferably about 45°C;

An appropriately substituted compound of formula (V) (a known compound or a compound prepared by a known method) is reacted with SEMCl (a known compound) to produce the corresponding compound of formula (VI) or a mixture of SEM-protected regioisomers of the corresponding compound of formula (VI); wherein the SEMCl is preferably present in an amount ranging from about 0.75 to about 2.0 molar equivalents (relative to the moles of the compound of formula (V)), more preferably in an amount ranging from about 1.01 to about 1.5 molar equivalents, more preferably in an amount greater than 1.0 molar equivalent; preferably, the mixture of SEM-protected regioisomers of formula (VI) is not separated.

Those skilled in the art will recognize that when , then reacting a compound of formula (V) with SEMCl as described above will produce the corresponding SEM-protected compound of formula (VI-R1)

Those skilled in the art will also recognize that, when selected from, then reacting a compound of formula (V) with SEMCl as described above will produce a mixture comprising two or three corresponding SEM-protected regioisomers as defined herein. More specifically,

The reaction of a compound of formula (V) with SEMCl can produce a mixture comprising the following two SEM-protected regioisomers:

The reaction of a compound of formula (V) with SEMCl can produce a mixture comprising the following two SEM-protected regioisomers:

The reaction of a compound of formula (V) with SEMCl can produce a mixture comprising the following two SEM-protected regioisomers:

And wherein the reaction of the compound of formula (V) with SEMCl can produce a mixture comprising any two or three of the following SEM-protected regioisomers:

Optionally in the presence of a suitably selected initiator such as AIBN, etc.; wherein the initiator is preferably present in a catalytic amount, for example, in an amount of about 1.0 mol % (ie, 0.01 molar equivalent);

in an appropriately selected organic solvent, such as DCE, CCl ₄ , etc., preferably DCE; preferably at a temperature in the range of about 45° C. to about 100° C., more preferably at a temperature in the range of about 55° C. to about 80° C., more preferably at a temperature of about 60° C.;

The compound of formula (VI) or the corresponding mixture of regioisomers of the compound of formula (VI) is reacted with an appropriately selected bromine source such as NBS, _Br2 (g), 1,3-dibromo-5,5-dimethyl-hydantoin, and the like, preferably NBS, to produce the corresponding compound of formula (VIII); wherein the bromine source is preferably present in an amount ranging from about 1.0 to about 2.0 molar equivalents, more preferably in an amount ranging from about 1.05 to about 1.5 molar equivalents, and more preferably in an amount ranging from about 1.05 to about 1.2 molar equivalents.

in the presence of a tertiary organic base such as TEA, DIPEA, and the like, preferably TEA; wherein the organic base is preferably present in an amount ranging from about 1.05 to about 15.0 molar equivalents (relative to the moles of the compound of formula (VIII)), more preferably in an amount ranging from about 1.05 to about 5 molar equivalents, more preferably in an amount ranging from about 2.0 to about 4.0 molar equivalents, and more preferably in an amount of about 3.0 molar equivalents; (wherein those skilled in the art will recognize that, although the use of non-tertiary amines can produce the desired product, the use of non-tertiary amines will also cause competition during the reaction and thereby reduce the yield of the desired product);

in the presence of an appropriately selected coupling system such as a pre-prepared catalyst coupling system, such as BINAP-PdCl ₂ , (Ph ₃ P) ₂ PdCl ₂ , etc., or an in situ catalyst coupling system, such as a mixture of an appropriately selected palladium compound such as PdCI ₂ (CH ₃ CN) ₂ , Pd(OAc) ₂ , etc. and an appropriately selected ligand such as BINAP, XantPhos, etc., preferably a mixture of Pd(OAc) ₂ and XantPhos; for example, a 1:1 (molar) mixture of the palladium compound and the ligand, preferably a 1:1 (molar) mixture of Pd(OAc) ₂ and XantPhos;

wherein the components of the coupling system or the in situ catalyst coupling system are preferably present in an amount ranging from about 2.0 mol % to about 6.0 mol % (relative to the moles of the compound of formula (VIII)), more preferably in an amount ranging from about 2.0 mol % to about 3.5 mol %, more preferably in an amount of about 2.5 mol %; (wherein the selection of XantPhos results in, for example, an increase in yield);

(In one example, the coupling system is an in situ mixture of a palladium compound and a ligand, wherein the coupling system is present in an amount of about 5.0 mol %. In another example, the coupling system is an in situ mixture of a palladium compound and a ligand, wherein the palladium compound is present in an amount of about 2.5 mol % and the ligand is present in an amount of about 2.5 mol %.)

In an appropriately selected alcohol (solvent) of the formula A ¹ OH, wherein A ¹ is selected from C _1-3 alkyl, preferably, A ¹ is selected from methyl and ethyl, more preferably, A ¹ is ethyl; wherein the alcohol of the formula A ¹ OH is preferably present in an amount ranging from about 1.5 moles to about 5.0 moles, more preferably in an amount ranging from about 2.0 moles to about 4.0 moles;

Preferably at a temperature in the range of about 60°C to about 120°C, more preferably at a temperature in the range of about 70°C to about 90°C, more preferably at about 80°C; (wherein lower temperatures result in, for example, less formation of SEM-removing by-products)

The compound of formula (VIII) is reacted with carbon monoxide gas or a suitably selected carbon monoxide source such as a suitably selected carbonyl metal such as tungsten hexacarbonyl, molybdenum hexacarbonyl, etc., optionally under a carbon monoxide atmosphere to produce the corresponding compound of formula (I); wherein the compound of formula (VIIII) is preferably reacted with carbon monoxide gas under a carbon monoxide atmosphere, preferably at a pressure in the range of about 40 psi to about 90 psi, more preferably at a pressure of about 60 psi, for example at a pressure in the range of about 3.0 bar to about 4.0 bar.

In one embodiment, the present invention is directed to a process for preparing a compound of formula (I-S), as outlined in Scheme 2 below.

Option 2

therefore,

in the presence of an appropriately selected organic base or inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ , TEA, pyridine, and the like, preferably K ₂ CO ₃ ; wherein the inorganic base is preferably in an amount ranging from about 1.0 to about 3.0 molar equivalents (relative to the moles of the compound of formula (VS)), more preferably in an amount ranging from about 1.5 to about 2.5 molar equivalents, and more preferably in an amount of about 2.0 molar equivalents;

In an appropriately selected organic solvent, such as acetone, 2-butanone, DCE, etc., preferably acetone; at a temperature in the range of about room temperature to about 60°C, more preferably about 45°C;

An appropriately substituted compound of Formula (V-S) (a known compound or a compound prepared by a known method) is reacted with SEMCl (a known compound) to produce a mixture of regioisomers, the corresponding compound of Formula (VI-S), and a compound of Formula (VII-S); wherein SEMCl is preferably present in an amount ranging from about 0.75 to about 2.0 molar equivalents (relative to the moles of the compound of Formula (V-S)), more preferably in an amount ranging from about 1.01 to about 1.5 molar equivalents, and more preferably in an amount greater than 1.0 molar equivalent; preferably, the mixture of regioisomers of Formula (VI-S) and Formula (VII-S) is not separated.

optionally in the presence of a suitably selected initiator such as AIBN or the like; wherein the initiator is preferably present in a catalytic amount, for example, in an amount of about 1.0 mole percent (0.01 molar equivalent);

in an appropriately selected organic solvent, such as DCE, CCl ₄ , etc., preferably DCE; preferably at a temperature in the range of about 45° C. to about 100° C., more preferably at a temperature in the range of about 55° C. to about 80° C., more preferably at a temperature of about 60° C.;

The mixture of regioisomers of Formula (VI-S) and Formula (VII-S) is reacted with an appropriately selected bromine source such as NBS, _Br2 (g), 1,3-dibromo-5,5-dimethyl-hydantoin, and the like, preferably NBS, to produce the corresponding compound of Formula (VIII-S); wherein the bromine source is preferably present in an amount ranging from about 1.0 to about 2.0 molar equivalents, more preferably in an amount ranging from about 1.05 to about 1.2.5 molar equivalents, and more preferably in an amount ranging from about 1.05 to about 1.2 molar equivalents.

in the presence of a tertiary organic base such as TEA, DIPEA, and the like, preferably TEA; wherein the organic base is preferably present in an amount ranging from about 1.05 to about 15.0 molar equivalents (relative to the moles of the compound of formula (VIII-S)), more preferably in an amount ranging from about 1.05 to about 5.0 molar equivalents, more preferably in an amount ranging from about 2.0 to about 4.0 molar equivalents, and more preferably in an amount of about 3.0 molar equivalents; (wherein those skilled in the art will recognize that, although the use of non-tertiary amines can produce the desired product, the use of non-tertiary amines will also cause competition during the reaction and thereby reduce the yield of the desired product);

in the presence of an appropriately selected coupling system such as a pre-prepared catalyst coupling system, such as BINAP-PdCl ₂ , (Ph ₃ P) ₂ PdCl ₂ , etc., or an in situ catalyst coupling system, such as a mixture of an appropriately selected palladium compound such as PdCl ₂ (CH ₃ CN) ₂ , Pd(OAc) ₂ , etc. and an appropriately selected ligand such as BINAP, XantPhos, etc., preferably a mixture of Pd(OAc) ₂ and XantPhos; for example, a 1:1 (molar) mixture of the palladium compound and the ligand, preferably a 1:1 (molar) mixture of Pd(OAc) ₂ and XantPhos;

wherein the components of the coupling system or the in situ catalyst coupling system are preferably present in an amount ranging from about 2.0 mol % to about 6.0 mol % (relative to the moles of the compound of formula (VIII)), more preferably in an amount ranging from about 2.0 mol % to about 3.5 mol %, more preferably in an amount of about 2.5 mol %; (wherein the selection of XantPhos results in, for example, an increase in yield);

(In one example, the coupling system is an in situ mixture of a palladium compound and a ligand, wherein the coupling system is present in an amount of about 5.0 mol %. In another example, the coupling system is an in situ mixture of a palladium compound and a ligand, wherein the palladium compound is present in an amount of about 2.5 mol % and the ligand is present in an amount of about 2.5 mol %.)

In an appropriately selected alcohol (solvent) of the formula A ¹ OH, wherein A ¹ is selected from C _1-3 alkyl, preferably, A ¹ is selected from methyl and ethyl, more preferably, A ¹ is ethyl; wherein the alcohol of the formula A ¹ OH is preferably present in an amount of about 1.5 to about 5.0 moles, more preferably in an amount of 2.0 to about 4.0 moles;

preferably at a temperature in the range of about 60°C to about 120°C, more preferably at a temperature in the range of about 70°C to about 90°C, more preferably at about 80°C; (wherein lower temperatures result in, for example, less formation of de-SEM by-products);

The compound of formula (VIII-S) is reacted with carbon monoxide gas (or an appropriately selected carbon monoxide source such as an appropriately selected carbonyl metal such as tungsten hexacarbonyl, molybdenum hexacarbonyl, etc., optionally under a carbon monoxide atmosphere) to produce the corresponding compound of formula (I-S); wherein the compound of formula (VIIII) is preferably reacted with carbon monoxide gas under a carbon monoxide atmosphere, preferably at a pressure in the range of about 40 psi to about 90 psi, more preferably at a pressure of about 60 psi (for example, at a pressure in the range of about 3.0 bar to about 4.0 bar).

Examples

The following examples are given to aid in understanding the present invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims that follow the examples.

In the following examples, some synthetic products that have been isolated as residues are listed. One of ordinary skill in the art will understand that the term "residue" does not limit the physical state of the product when it is isolated and can include, for example, solids, oils, foams, colloids, slurries, etc. One of ordinary skill in the art will also recognize that in the following examples, the term "rag-layer" refers to the emulsion that can form between the organic layer and the aqueous layer during the separation process.

Synthesis Example 1

Ethyl 4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

A 60 mL stainless steel MULTIMAX reactor was charged with 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (2.41 g, 7.97 mmol, 1 equiv), ethanol (32.0 mL, 25.32 g, 549.64 mmol), TEA (3.30 mL, 2.40 g, 23.68 mmol), racemic BINAP (0.12 g, 0.20 mmol) and dichlorobis(acetonitrile)palladium(II) (0.05 g, 0.20 mmol). The reactor was sealed, purged three times with nitrogen, heated to 70° C. and pressurized to an internal pressure of less than 0.5 bar. Carbon monoxide was introduced into the reactor to a pressure of 4 bar and stirred at 400 rpm. The reaction was allowed to proceed while being monitored by GC. After 4 hours at 70° C., the temperature was raised to 80° C. and stirring was increased to 600 rpm while the CO pressure was maintained at 4 bar. The reaction was allowed to proceed for an additional 3 days under these conditions. The resulting mixture was then allowed to cool to room temperature, resulting in a red solution with a black precipitate at the bottom of the reactor. The resulting product mixture was filtered, washed with ethanol, and the reactor was rinsed with ethanol; the total volume was 63 mL.

To a portion of the product mixture (25 mL) was added water (15 mL) and the resulting mixture was extracted with isopropyl acetate (20 mL). Additional water (15 mL) was added to produce a good separation and the organic layer was washed twice more with water (15 mL). The resulting combined organic layers (red solution) were allowed to stand overnight to allow the mixture to solidify.

The remainder of the product mixture (33 mL) was evaporated on a rotary evaporator and the resulting residue was dissolved in isopropyl acetate (20 mL) and water (20 mL). The layers were separated, the organic layer was washed twice with water (20 mL), and the resulting mixture was evaporated on a rotary evaporator to generate a red oily residue.

Synthesis Example 2

Ethyl 4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

A 500 mL stainless steel MULTIMAX reactor was charged with 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (25.80 g, 75.12 mmol, 1 equiv), ethanol (300.00 mL, 237.39 g, 5152.92 mmol), TEA (32.00 mL, 23.23 g, 229.58 mmol), XantPhos (1.10 g, 1.90 mmol) and Pd(OAc) ₍ 0.41 g, 1.83 mmol). The reactor was sealed, purged twice with carbon monoxide, heated to 80° C. and pressurized to an internal pressure of less than 1.0 bar. Carbon monoxide was introduced into the reactor to a pressure of 4 bar and stirred at 500 rpm. The reaction was allowed to proceed while being monitored by GC. After 2 hours, the stirring speed was increased to 750 rpm and the reaction was allowed to proceed overnight under these conditions. The resulting mixture was cooled to room temperature and the resulting mixture (which contained a yellow residue) was transferred to a pear-shaped flask. The solvent was evaporated to yield a dry residue.

The dry residue was dissolved in toluene (225 mL), water (150 mL) was added, the mixture was stirred for a while, and the heterogeneous layer was removed by filtration. The resulting layers were separated. The organic layer was washed with water (150 mL), the heterogeneous layer and the aqueous layer were discarded, and washed a second time with water (150 mL). The organic layer was then transferred to a 4-necked round-bottom flask, and approximately 50 mL of solvent was removed by distillation. The mixture was then azeotropically dried at 100°C. Some material was observed to precipitate and adhere to the glass walls of the flask.

To the remaining reaction mixture was added silica gel thiol (8 g) and the resulting mixture was stirred at 60° C. for several hours and then allowed to stand overnight without stirring. The resulting mixture was then filtered. To this resulting mixture was again added silica gel thiol (6 g) and the resulting mixture was stirred at 60° C. for 4 hours. The resulting mixture was filtered, the solids washed with toluene and the organic layer evaporated on a rotary evaporator to yield the title compound as a residue.

crystallization

To the remaining residue (17.7 g) was added MTBE (18 mL) and the resulting mixture was heated to reflux. A solution was observed at 40° C., and hexane (85 mL) was added at reflux. The resulting mixture was cooled to 35° C. and seeded, whereupon a precipitate was observed. The resulting mixture was then cooled to room temperature, and the solid was filtered, washed with a 5:1 mixture of hexane:MTBE (60 mL total), and dried at 45° C. for 2 hours to yield the title compound as a solid.

Synthesis Example 3

Ethyl 4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

A 5 L reactor was charged with 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (337.6 g, 1116.96 mmol))ethanol (2.4 L), TEA (472 mL), Pd(OAc) ₂ (6.32 g, 28.21 mmol) and XantPhos (16.24 g, 28.05 mmol). The reactor was set to stirring, purged 10 times with nitrogen, and then purged 3 times with carbon monoxide at a pressure of about 5 bar. The reactor was then charged with 1.0 bar of carbon monoxide and heated to 80° C. The carbon monoxide charge was then increased to about 4 to 5 bar and the reaction mixture was stirred at 900 r/min for 20 hours and then cooled to room temperature.

The solvent was evaporated on a rotary evaporator to produce a red solid residue. To this residue was added toluene (1100 mL) and water (1100 mL) and the mixture was stirred for 20 minutes and then filtered. The solid was washed with toluene (50 mL). The layers of the resulting mixture were separated and the organic layer was washed twice more with water (1000 mL). The combined organic layers were azeotropically dried at about 110° C. and about 100 mL of solvent was removed.

The resulting mixture was cooled to 90°C. 33.4 grams of NORIT A-SUPRA (33.4 g) was added at this temperature and the resulting mixture was stirred at 90°C for another two hours. The resulting mixture was then cooled to room temperature and filtered, and the solid was washed twice with toluene (50 mL). The resulting mixture was transferred to a round-bottom flask and silica gel mercaptan (82 g) was added. The resulting mixture was heated to 90°C and stirred at this temperature for 4 hours. The resulting mixture was then cooled to room temperature, filtered, and the solid was washed twice with toluene (50 mL). The resulting mixture was transferred again to a round-bottom flask and silica gel mercaptan (82 g) was added. The resulting mixture was heated to 90°C and stirred at this temperature for 20 hours. The resulting mixture was then cooled to room temperature, filtered, and the solid was washed twice with toluene (50 mL). The resulting mixture was transferred again to a round-bottom flask and silica gel mercaptan (82 g) was added. The resulting mixture was heated to 90°C and stirred at this temperature for 4 hours. The resulting mixture was then cooled to room temperature, filtered, and the solid was washed twice with toluene (50 mL).

The resulting mixture was then evaporated on a rotary evaporator at 50° C. to produce a yellow solid residue. Ethanol + 2% MEK (880 mL) was then added to the residue and the resulting mixture was heated to 4° C. to produce an orange homogeneous solution. Water (44 mL) was then added. Seed crystals of the desired product were then added and the resulting mixture was stirred at 40° C. for 2 hours. The resulting mixture was allowed to cool to room temperature overnight and then filtered. The solid was washed twice with a mixture of ethanol: water (150 mL: 100 mL, 125 mL) and then dried at 50° C. overnight to produce the title compound as a solid.

While the foregoing description sets forth the principles of the present invention and provides examples for illustrative purposes, it should be understood that the practice of the invention encompasses all common variations, changes and/or modifications that fall within the scope of the following claims and their equivalents.

Claims (32)

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) in ^A1 is selected from _C1-3 alkyl groups; Among them are; The method includes: In the presence of a tertiary organic base; in the presence of a coupling system; in an alcohol of formula ^A1OH ; the compound of formula (VIII) is reacted with carbon monoxide gas or a carbon monoxide source to produce the corresponding compound of formula (I). The carbon monoxide gas is present at a pressure in the range of 40 psi to 60 psi. The compound of formula (VIII) reacts with the carbon monoxide or carbon monoxide source at a temperature in the range of 70°C to 90°C. The coupling system is a mixture of a palladium compound and a ligand, wherein the palladium compound is selected from _PdCl2 ( _CH3CN ) ₂ and Pd(OAc) ₂ , and the ligand is selected from BINAP and XantPhos. 2. The method according to claim 1, wherein ^A1 is selected from methyl and ethyl. 3. The method according to claim 1, wherein the carbon monoxide or carbon monoxide source is a carbonyl metal selected from hexacarbonyltungsten and hexacarbonylmolybdenum. 4. The method according to claim 1, wherein the carbon monoxide or carbon monoxide source is carbon monoxide gas. 5. The method of claim 1, wherein the carbon monoxide gas reacts at a pressure of 60 psi. 6. The method according to claim 1, wherein the tertiary organic base is selected from TEA and DIPEA. 7. The method according to claim 6, wherein the tertiary organic base is TEA. 8. The method of claim 7, wherein the TEA is present in an amount ranging from 1.05 to 5.0 molar equivalents. 9. The method of claim 8, wherein the TEA is present in an amount ranging from 2.0 to 4.0 molar equivalents. 10. The method of claim 9, wherein the TEA is present in an amount of 3.0 molar equivalents. 11. The method according to claim 1, wherein the palladium compound is Pd(OAc) ₂ . 12. The method of claim 11, wherein the Pd(OAc) ₂ is present in an amount ranging from 2.0 mol% to 6.0 mol%. 13. The method of claim 12, wherein the Pd(OAc) ₂ is present in an amount ranging from 2.0 mol% to 3.5 mol%. 14. The method of claim 13, wherein the Pd(OAc) _₂ is present in an amount of 2.5 mol%. 15. The method of claim 1, wherein the ligand is XantPhos. 16. The method of claim 15, wherein the XantPhos is present in an amount ranging from 2.0 mol% to 6.0 mol%. 17. The method of claim 16, wherein the XantPhos is present in an amount ranging from 2.0 mol% to 3.5 mol%. 18. The method of claim 17, wherein the XantPhos is present in an amount of 2.5 mol%. 19. The method of claim 1, wherein the palladium compound is Pd(OAc) ₂ and the ligand is XantPhos. 20. The method of claim 19, wherein the Pd(OAc) ₂ is present in an amount ranging from 2.0 mol% to 3.5 mol%; and wherein the XantPhos is present in an amount ranging from 2.0 mol% to 3.5 mol%. 21. The method of claim 1, wherein the coupling system is a 1:1 mixture of a palladium compound and a ligand; wherein the palladium compound is Pd(OAc) _₂ ; and wherein the ligand is XantPhos; and wherein the coupling system is present in an amount ranging from 2.0 mol% to 6.0 mol%. 22. The method according to claim 1, wherein the coupling system is a mixture of a palladium compound and a ligand; The palladium compound is Pd(OAc) _₂ ; wherein the Pd(OAc) _₂ is present in an amount ranging from 2.0 mol% to 3.5 mol%. The ligand is XantPhos; and the XantPhos is present in an amount ranging from 2.0 mol% to 3.5 mol%. 23. The method of claim 22, wherein the Pd(OAc) _₂ is present in an amount of 2.5 mol% and the XantPhos is present in an amount of 2.5 mol%. 24. The method according to claim 1, wherein the alcohol of formula ^A1OH is ethanol. 25. The method of claim 24, wherein the alcohol of formula ^A1OH is present in an amount ranging from 1.5 mol to 5.0 mol. 26. The method of claim 25, wherein the alcohol of formula ^A1OH is present in an amount ranging from 2.0 mol to 4.0 mol. 27. The method according to claim 1, wherein the compound of formula (VIII) reacts with the carbon monoxide or carbon monoxide source at a temperature of 80°C. 28. The method according to claim 1, further comprising: A compound of formula (VI) or a mixture of its corresponding SEM-protected regioisomers is reacted with a bromine source in an organic solvent to generate the corresponding compound of formula (VIII). 29. The method of claim 27, further comprising: In the presence of an organic or inorganic base; in an organic solvent; the compound of formula (V) is reacted with SEMCl to produce the corresponding compound of formula (VI) or a mixture of its corresponding SEM-protected regioisomers. 30. A method for preparing a compound of the following formula or a pharmaceutically acceptable salt thereof, (I-S) ^A1 is selected from _C1-3 alkyl groups; The method includes: In the presence of a tertiary organic base; in the presence of a coupling system; in an alcohol of formula ^A1OH ; the compound of formula (VIII-S) is reacted with carbon monoxide gas or a carbon monoxide source to produce the corresponding compound of formula (IS). The carbon monoxide gas or carbon monoxide source is carbon monoxide gas; the carbon monoxide gas is present in an amount of 60 psi. The tertiary organic base is TEA; the TEA is present in an amount of 3.0 molar equivalents. The coupling system is a 1:1 mixture of Pd(OAc) _₂ and XantPhos; wherein Pd(OAc) _₂ is present in an amount of 2.5 mol%; wherein XantPhos is present in an amount of 2.5 mol%. The alcohol of formula ^A1OH is selected from methanol and ethanol; Furthermore, the compound of formula (VIII-S) reacts at a temperature of 80°C. 31. A method for preparing a compound of the following formula or a pharmaceutically acceptable salt thereof, (I-S) ^A1 is selected from _C1-3 alkyl groups; The method includes: In the presence of a tertiary organic base; in the presence of a coupling system; in an alcohol of formula ^A1OH ; the compound of formula (VIII-S) is reacted with carbon monoxide gas or a carbon monoxide source to produce the corresponding compound of formula (IS). The carbon monoxide gas is present at a pressure in the range of 40 psi to 60 psi. The compound of formula (VIII-S) reacts with the carbon monoxide or carbon monoxide source at a temperature in the range of 70°C to 90°C, wherein the coupling system is a mixture of a palladium compound and a ligand, wherein the palladium compound is selected from _PdCl₂ ( _CH₃CN ) _₂ and Pd(OAc) _₂ , and wherein the ligand is selected from BINAP and XantPhos. The method also includes A mixture of the compounds of formula (VI-S) and formula (VII-S) is reacted with a bromine source in an organic solvent to generate the corresponding compound of formula (VIII-S). 32. The method according to claim 31, further comprising: In the presence of an organic or inorganic base; in an organic solvent; the compound of formula (V-S) is reacted with SEMCl to produce a mixture of the corresponding compound of formula (VI-S) and the corresponding compound of formula (VII-S).