EP1196413A2

EP1196413A2 - Preparation of 7-substituted benzothiophenes

Info

Publication number: EP1196413A2
Application number: EP00944592A
Authority: EP
Inventors: Eric David Moher; John Cunningham O'toole; John Robert Rizzo; Jeffrey Thomas Vicenzi; Tony Yantao Zhang
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1999-06-29
Filing date: 2000-06-21
Publication date: 2002-04-17
Also published as: WO2001000620A3; WO2001000620A2; AU5866500A

Abstract

The present provides a novel process for the preparation of 7-substituted benzothiophene derivatives useful as intermediates in the preparation of pharmaceuticals.

Description

PREPARATION OF 7-SUBSTITUTED BENZOTHIOPHENES

The present invention provides a novel process for the preparation of 7- substituted benzothiophene derivatives useful as intermediates in the preparation of pharmaceuticals.

The chemistry surrounding the benzo[b]thiophenes continues to evolve, due in large part to the increasing interest of the medicinal chemist in such heterocyclic functional groups. More specifically, preparation of 7-substituted benzo[b]thiophenes are of particular interest as building blocks of pharmaceutically active compounds.

Various synthetic schemes have been developed recently for preparing certain 7-substituted benzo[b]thiophenes. For example, Katritzky, et al., J. Chem. Soc, Perkin Trans. 1 , 1059 (1998) disclose the preparation of polysubstituted benzothiophenes via cyclization of an aryl thioketone. Terpstra and Van Leusen, J. Org. Chem., 5J_, 230 (1986) disclose preparation of certain 5, 6 and 7-substituted benzothiophenes following a tandem Michael addition- aldol condensation of 2,3-disubstituted thiophenes. In addition, Iwasaki, et al., J. Org. Chem., 56, 1922 (1991 ) and Tetrahedron Lett, 30, 95 (1989) disclose a palladium-catalyzed carbonylative annulation of a 3-substituted allylic acetate thiophene to provide a 7-0-acetyl-benzo[b]thiophene. Furthermore, Sibi, et al., J. Org. Chem., 51, 272 (1986) reveal a 5-step synthesis to provide 7- hydroxybenzothiophene via directed metallation of thiophene, followed by transmetallation, allylation, metallation and cyclization.

The present invention provides a process for the preparation of a compound of formula I:

formula

wherein E represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-Cβ)cycloalkyl group or an unsubstituted or substituted C1-C20 alkyl group; R^1a, R^1b, and R^1c are each independently H, F, Cl, C C₆ alkyl, d-Cβ alkoxy, halo(CrC₆ )alkyl, phenyl, N0₂, NH₂, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, C₁-C-₆ alkyl, Cι-C₆ alkoxy, halo(CrC-₆)alkyl, phenyl, N0₂, and NH₂; or

R^1a and R^1b together form a C₄-C₇ saturated or unsaturated carbocyclic ring, and R^1c is H, F, Cl, CrC₆ alkyl,Cι-C₆ alkoxy, halo(C₁-C₆ )alkyl, phenyl, N0₂, NH₂, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Ci-Ce alkyl, C-ι-C₆ alkoxy, halo(CrC₆)alkyl, phenyl, N0₂, and NH₂; or

R^1b and R^1c together form a C₄-C₇ saturated or unsaturated carbocyclic ring, and R^1a is H, F, Cl, Br, I, C C₆ alkyl, C C₆ alkoxy, halo(C C₆)alkyl, phenyl, N0₂, NH₂, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, Cι-C₆ alkyl, CrC₆ alkoxy, halo(CrC₆)alkyl, phenyl, N0₂, and NH₂;

R² is H, C1-C₂₀ alkyl, OH, C-ι-C₆ alkoxy, an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group;

R³ is H, C-ι-C-₂₀ alkyl, an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group; or

R² and R³ are connected by a C-2-C₄ alkylene; or a pharmaceutically acceptable salt thereof; comprising, treating a compound of formula II; formula II wherein substituents R^1a, R^1b, and R^1c are defined as above, with a suitable base, a suitable electrophile, and a compound of formula III;

formula

wherein R² and R³ are defined as above, and X is a suitable leaving group;

Y is OR⁴; and

Z is OR⁵ wherein R⁴ and R⁵ are each independently C Cι₀ alkyl; or

Y and Z together represent a carbonyl; or

Y and Z are both oxygen and are connected by a C2-C4 alkylene; followed by addition of a suitable acid catalyst.

In addition, the present invention provides a compound of the formula:

which is N-benzyl-4-(benzo[b]thiophene-7-yl)-1 ,2,3,6-tetrahydropyridine hydrochloride.

As used herein, the terms "Halo", "Halide" or "Hal" refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.

As used herein, the term "Me" refers to a methyl group, the term "Et" refers to an ethyl group, the term "Pr" refers to a propyl group, the term "iPr" refers to an isopropyl group, the term "Bu" refers to a butyl group, and the term "Ph" refers to a phenyl group.

As used herein the term "CrC₄ alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. As used herein the term "Ci-Cβ alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. The term "CrCβ alkyl" includes within its scope "CrC₄ alkyl".

As used herein the term "C Cιo alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2- methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like. The term "C1-C10 alkyl" includes within its scope "d-C-₆ alkyl" and "CrC₄ alkyl".

As used herein the term "C₁-C₂0 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n- heptadecyl, n-nonadecyl, n-eicosyl and the like. The term "C1-C-2₀ alkyl" includes within its scope "d-do alkyl", "C C₆ alkyl" and "C C₄ alkyl".

As used herein the term "C -C₄ alkylene" refers to a straight or branched, divalent, unsaturated aliphatic chain having from two to four carbon atoms, such as — CH CH2-, -CH2CH2CH2- or — CH2CH2CH2CH2-.

As used herein the term "CrC₆ alkoxy" refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical d-C₆ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term "d-C₆ alkoxy" includes within its definition the term "C1-C4 alkoxy".

As used herein the term "(C₃-C₈)cycloalkyl" refers to nonaromatic monocyclic and polycyclic groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycio[2.2.2]octane. The term "(C₃- C₈)cycloalkyl" includes within its definition the term "(C₄-C₆)cycloalkyl".

As used herein the term "halo(CrC₆)alkyl" refers to a straight or branched alkyl chain having from one to six carbon atoms with 1 , 2 or 3 halogen atoms attached to it. Typical halo(Cι-C₆)alkyl groups include chloromethyl, 2- bromoethyl, 1 -chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term "halo(d-C₆)alkyl" includes within its definition the term "halo(CrC₄)alkyl".

As used herein the term "aromatic group" means the same as aryl, and refers to a monovalent carbocyclic group containing one or more fused or non- fused phenyl rings and includes, for example, phenyl, 1 - or 2-naphthyl, 1 ,2- dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, and the like.

As used herein the terms "heterocyclic group", "heterocyclic" or "heterocycle" refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non- adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; two sulfur atoms in non-adjacent positions; two sulfur atoms in adjacent positions and one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quatemized. The sulfur heteroatoms may optionally be oxidized. The terms "heterocyclic group", "heterocyclic" or "heterocycle" also include bicyclic groups in which any of the above heterocyclic rings are fused to a benzene ring or a cyciohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like). Heterocyclic groups include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.

The term "substituted" as used in the term "substituted aromatic", "substituted heterocyclic" or substituted (C₃-C₈)cycloalkyl" signifies that one or more (for example one or two) substituents may be present. Examples of substituents which may be present are H, F, Cl, Br, I, d-C₆ alkyl,

CrC₆ alkoxy, halo(CrC₆)alkyl, phenyl, N0₂, NH₂, CN, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, d-C₆ alkyl, Cι-C₆ alkoxy, halo(C C₆)alkyl, phenyl, N0₂, NH₂, and CN.

This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2- sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.

It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.

Compounds of formula I can be prepared by following the procedures as set forth in Scheme I. This scheme is not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.

Scheme I

formula II (A) ln Scheme I, step A, the compound of formula II is converted to the compound of structure (A) under the following conditions. A compound of formula II, such as thiophenol is added to about 2 equivalents of a suitable base in a suitable organic solvent at such a rate that the temperature of the stirring solution is maintained at about 0°C to about 90°C. The preferred temperature range is about 25°C to about 50°C. Examples of a suitable base include, n- butyllithium, sec-butyllithium, tert-butyllithium, potassium tert-butoxide, sodium hydride, sodium amide, potassium amide, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium dicyclohexylamide, 2,2,6,6- tetramethylpiperidin-1 -yllithium, lithium hexamethyldisilazane or potassium hexamethyldisilazane, and the like. The preferred suitable base is n-butyllithium. Examples of a suitable organic solvent include cyciohexane, heptane, hexanes, or other hydrocarbon mixtures, methyl tert-butyl ether, diethyl ether, tetrahydrofuran, or mixtures thereof. The preferred suitable organic solvents are cyciohexane, heptane, or hexanes. In addition, it is preferred that a suitable ligand such as N,N,N',N'-tetramethylethylenediamine (TMEDA) be added to help lithiation. The compound of formula II may optionally be dissolved in the suitable organic solvent prior to addition to the strong base. It is preferred that the atmosphere above the reaction mixture be inert, such as a nitrogen or argon atmosphere. After addition of compound of formula II is complete, the reaction mixture is stirred at about 20°C to about 50°C with ambient temperature being preferred, for about 18 hours to about 48 hours, with about 20 hours being preferred.

The reaction mixture is then cooled to about -10°C to about -78°C, with about -60°C being preferred and is diluted with a suitable organic solvent.

Examples of a suitable organic solvent are those that will promote solubilization of the dianion and include tetrahydrofuran or methyl tert-butyl ether.. Tetrahydrofuran is the preferred suitable organic solvent. One equivalent of a suitable electrophile is added dropwise to the stirring reaction mixture maintaining the temperature below about -60°C, preferably below -50°C.

As used herein the term "suitable electrophile" refers to a compound which is an electron pair acceptor which seeks the electron rich center of an organic compound. Suitable electrophiles include alkylating or hydroxylating agents, silylating agents, trialkyl borates and Micheal acceptors. Particular examples of suitable electrophiles include n-alkyl halides, such as n-alkyl bromides and iodides, such as, for example, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, pentyl bromide, hexyl bromide, heptyl bromide, octyl bromide or nonyl bromide or methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentyl iodide, hexyl iodide, heptyl iodide, octyl iodide, nonyl iodide, and the like; n-alkanals such as acetaldehyde, propionaldehyde, butyraldehyde, pentanal, hexanal, heptanal, octanal, nonanal, and the like; substituted and unsubstituted cyclohexanones; substituted and unsubstituted cyclopentanones; substituted and unsubstituted piperidones; oxiranes, such as, for example, oxirane, 2-methyloxirane, 2-ethyloxirane, 2-propyloxirane, 2-butyloxirane, 2- pentyloxirane, 2-hexyloxirane, 2-heptyloxirane, and the like;, silylating agents such as trialkylsilyl halides; ketones of the formula:

The suitable electrophile may optionally be dissolved in the suitable organic solvent prior to addition to the reaction mixture. After addition is complete, the reaction mixture is allowed to warm to ambient temperature. Then about one equivalent of a compound of formula III

formula III

wherein

R² is H, C1-C₂₀ alkyl, OH, C C₆ alkoxy, an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group;

R³ is H, C1-C₂₀ alkyl, an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group; or R² and R³ are connected by a C₂-C alkylene; X is a suitable leaving group; Y is OR⁴; and

Z is OR⁵ wherein R⁴ and R⁵ are each independently C₁-C1₀ alkyl; or

Y and Z together represent a carbonyl; or

Y and Z are both oxygen and are connected by a C₂-C₄ alkylene; is added to the reaction mixture. Examples of suitable leaving groups, X, include chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, and the like. More specifically, examples of compounds of formula III include diethyl bromoacetal, dimethyl bromoacetal, diethyl chloroacetal, and the like.

The reaction mixture is then heated slowly at about 22°C to about 100°C, preferably about 70°C to about 100°C, for about 2 hours to about 24 hours, preferably for about 4 hours to about 6 hours. During this heating period about 20% to about 80% of the reaction mixture solvent is distilled off. The compound of structure (A) is then isolated and optionally purified using techniques and procedures well known to one of ordinary skill in the art. For example, the reaction mixture is cooled to ambient temperature and diluted with a suitable organic solvent, such as toluene. To this mixture is added water with mixing. The layers are separated and the aqueous layer is extracted with toluene. The organic phase and organic extracts are combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of structure (A). This material can then be purified by standard techniques, such as chromatography or recrystallization. In Scheme I, step B, the compound of structure (A) is cyclized using a suitable acid catalyst to provide the compound of formula (I). For example, compound (A) is dissolved in a suitable organic solvent, such as toluene and is combined with a suitable acid catalyst. Examples of suitable acid catalysts include aqueous HCl, methanesulfonic acid, p-toluenesulfonic acid, polymeric sulfonic acid, acidic clays, acidic zeolites, and the like. The reaction is heated at a temperature of about 25°C to about 110°C, preferably about 50°C to about 90°C with 50°C being most preferred, for about 1 hours to about 24 hours with about 2 hours being preferred. The reaction mixture is then cooled and the product is isolated and purified using techniques and procedures well known in the art, such as extraction techniques, filtration, chromatography, recrystallization techniques, and the like.

More specifically, compounds of formula la and formula lb can be prepared as disclosed in Scheme II. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.

Scheme II

formula lb In Scheme II, step A the compound of structure A' is prepared in a manner analogous to the procedure described in Scheme I, step A wherein the suitable electrophile is of the formula IV formula IV

wherein R⁶ and R⁷ are each independently H or Cι-C₆ alkyl; m is the integer 0, 1 or 2; n is the integer 0, 1 or 2; and Pg is a suitable nitrogen protecting group.

Examples of a suitable nitrogen protecting group as used herein refers to those groups intended to protect the nitrogen group against undesirable reactions during synthetic procedures. Choice of the suitable nitrogen protecting group used will depend upon the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art. Commonly used nitrogen protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)). Suitable nitrogen protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,

.alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p- biphenylyl)-1-methylethoxycarbonyl, .alpha.,.alpha.-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, allyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred suitable nitrogen protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, alpha- methylbenzyl (including either chiral form thereof), allyl, methoxycarbonyl, t- butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

In Scheme II, step B' the compound of structure A' is cyclized to the compound of formula la in a manner analogous to the procedure described in Scheme I, step B, with a suitable acid catalyst, such as methanesulfonic acid. R⁸ represents H or a suitable nitrogen protecting group. It is understood that under certain conditions, the suitable acid catalyst may also subsequently effect dehydration of the to provide the compound of formula lb, for example when structure A' is benzyl protected.

In Scheme II, Step C the compound of formula la is then dehydrated to provide the compound of formula lb. For example, the compound of formula la is dissolved in a suitable organic solvent, such as isopropyl alcohol The reaction is heated at a temperature of about 60°C. It is then treated with a suitable dehydrating agent, such as aqueous HCl, and the like. The reaction mixture is stirred for about 0.5 hours to about 20 hours. The compound of formula lb is then isolated and purified using standard techniques, such as filtration and recrystallization. For example, the reaction mixture is cooled to about 0°C for at least one hour and then filtered. The solid is washed with cold isopropyl alcohol and dried under vacuum at 50°C to provide the compound of formula lb. In Scheme II, step B" the compound of structure A' is cyclized and dehydrated to provide the compound of formula lb in a manner analogous to the procedure described in Scheme I, step B, with a suitable acid catalyst which produces cyclization and dehydration of the piperidine ring, in any order. Examples of suitable acid catalysts to effect this reaction are aqueous HCl, methanesulfonic acid, and the like. Aqueous HCl and methanesulfonic acid are the preferred suitable acid catalysts. R⁸ represents H or a suitable nitrogen protecting group.

It is understood by one of ordinary skill in the art that when R⁸ represents a nitrogen protecting group in formula la or formula lb, the protecting group can be readily removed under conditions well known in the art, for example, as disclosed by Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)). In addition, see A. Delgado, et al., Syn. Comm., 18(16&17), 2017 (1988), and Baldwin and Li, J. Chem. Soc, Chem. Comm., 261 (1988).

The following examples represent by way of example the process of the present invention as described generally above in Schemes I and II. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "μL" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "mm Hg" refers to millimeters of mercury; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "R_f" refers to retention factor; "R " refers to retention time; "δ'ϊefers to part per million down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N- dimethylformamide; "DMSO" refers to methyl sulfoxide; "LDA" refers to lithium diisopropylamide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether; "TMEDA" refers to N,N,N',N'- tetramethylethylenediamine, and "RT" refers to room temperature.

Example 1 Preparation of 1 -N-Benzyl-4-hvdroxy-4-(2'-(2".2"-0-diethoxy)ethylthio- phenvDpiperidine.

Scheme I or Scheme II, step A: A 3 L flask containing 238 mL TMEDA

(183.8g, 1.575 mmol) was purged with nitrogen at 5°C for 10 minutes and n-BuLi (2M in cyciohexane, 786.5 mL, 1.537 mole) was added via addition funnel. A mild exotherm and some yellowish precipitate were observed. The addition funnel was rinsed clean with 125 mL of cyciohexane (dried over 4A molecular sieves and purged with nitrogen). Thiophenol (750 mmol, 82.7g, 77.30 mL) in 45 mL of cyciohexane was added at such a rate so as to keep the temperature below 22°C, with the aid of an ice bath and vigorous stirring. The reaction mixture turned clear after 10 mL of the thiophenol solution was added, and remained so during the course of the addition which lasted 50 minutes. The solution was stirred at room temperature (22°C) and turned cloudy after 2 h. After stirring for another 20 h at ambient temperature, the off-white suspension was cooled to -5°C, mixed with 500 mL of THF (sieve dried, nitrogen purged), stirred at -5°C for 20 minutes, and then cooled to -60°C. N-benzyl-4-piperidone (distilled, 139.86 g, 740 mmol) in 250 mL of THF was added dropwise within 50 minutes, while keeping the reaction temperature below -50°C. The resulting yellow suspension was stirred at -60°C for 20 minutes, then allowed to warm to ambient temperature within 2 h to give a clear solution. Diethyl bromoacetal (149.7g, 760 mmol) was added, and the resulting solution was heated to reflux at 76°C for 3 h. Then with continuous heating, 1300 mL of solvents were distilled off, while the temperature reached 100°C. After heating at 100°C for another 2 h, the solution was cooled to 22°C, mixed with 700 mL of toluene and an equal volume of water (exotherming to 35°C). The aqueous layer was extracted with toluene (300 mL x 3, and the combined organic layers were washed with water (300 mL x 4) and brine (300 mL x 2) to give a toluene solution of title compound and by-product and residual solvent. The wet toluene solution was dried over anhydrous MgS0₄, vacuum filtered, and concentrated to afford 345.0 g of crude title compound as an amber oil. The oil was seeded with crystals from previously made title compound, and the flask was cooled in an ice bath. Recrystallization was slow so leaving the mixture standing overnight was necessary. The title compound crystallized into a solid mass. Heptane (308 mL) was added to the mixture and the solid was broken up with a spatula. The mixture slurry was cooled in an ice bath with stirring for 3 h, vacuum filtered, washed with 100 mL of cold (about -22°C) heptane, and air dried to afford 173.93 g (56%) of title compound as a beige solid. The filtrate was concentrated to afford 134.31 g of oil containing title compound and the following by-product:

Alternatively, the crude title compound can be easily be purified by gel filtration using Silica Gel 60 by washing the filter plug first with 9:1 hexane EtOAc to remove the above by-product, and then washing it with EtOAc to obtain the title compound as an oil and recrystallize the material according to the procedure above.

¹H NMR (d⁶-DMSO): δ 7.49-7.51 (m, 1 H, thiophenol Ar-CH), 7.41-7.42 (m, 1 H, thiophenol Ar-CH), 7.28-7.31 (m, 1 H, benzyl Ar-CH), 7.21-7.24 (m, 1 H, benzyl p- Ar-CH), 7.16-7.19 (m, 1 H, thiophenol Ar-CH), 7.10-7.13 (m, 1 H, thiophenol Ar- CH), 4.83 (br s, 1 H, -OH), 4.54 (t, J = 5.5 Hz, 1 H, -CH(OEt)₂), 3.53-3.59 (m, 2H, - OCH₂CH₃), 3.48 (s, 2H, -NCH h), 3.39-3.45 (m, 2H, -OCH₂CH₃), 3.08 (d, J = 5.5 Hz, 2H, -SCH₂CH(OEt)₂), 2.58-2.60 (m, 2H, piperidine CJi), 2.42-2.46 (m, 2H, piperidine CH₂), 2.27-2.33 (m, 2H, piperidine CH₂), 1.78-1.81 (m, 2H, piperidine CH₂), 1.06 (t, J = 7.0 Hz, 6H, -OCH₂CH₃). ¹³C NMR (d⁶-DMSO): δ 147.62, 138.83, 134.84 (aromatic C); 129.76 (aromatic

CH); 128.72, 128.01 (2C, benzyl aromatic CH); 127.04, 126.66, 125.79, 125.15

(aromatic CH); 100.66 (-CH(OEt)₂); 70.98 (-COH); 62.29 (-SCH₂-); 61.16 (2C, -

OCH2CH3); 48.93 (2C, piperidine CH₂); 37.64 (-NCH₂Ph); 35.02 (2C, piperidine

CH₂); 15.11 (2C, -OCH₂CH₃). m/z+ = 416.3 [M+1 ], 417.3 [M+2]; MW = 415.59.

UV (MeCN): λ = 258.00 (ε = 6409.25).

IR (KBr pellet): 3200-3400 cm ^"1 (br, -OH stretch); 1580 cm ^"1 (aromatic C=C stretch); 1000 cm ^"1, 1020 cm ^"1, 1050 cm ^"1, 1100 cm ^"1, 1120 cm ^"1, 1140 cm ^"

¹(C-0 stretch); 690 cm ^"1, 720 cm ^"1, 750 cm ^"1 (out-of-plane aromatic ring bending).

Calculated: %C = 69.36, %H = 8.00, %N = 3.37, %0 = 11.55; Found: %C = 69.05, %H = 7.89, %N = 3.36, %Q = 11.70. Molecular Formula = C₂₄H₃₃N0₃S.

Example 2 Preparation of N-Benzyl-4-(benzofb1thiophene-7-yl)-1 ,2,3,6-tetrahydropyridine hydrochloride.

Scheme I, Step B or Scheme II, Step B': A solution of 1.00 g (0.00241 mol) of 1 -N-benzyl-4-hydroxy-4-(2'-(2",2"-0-diethoxy)ethylthio-phenyl)piperidine (prepared in example 1) in 20 mL of toluene was added dropwise to 20 mL of 6 N HCl (aq) at reflux. Washings with 20 mL of toluene was added all at once. Water was added after 1 h to replenish the aqueous phase. After heating for 3 h, the mixture was cooled to room temperature and the title compound, as a white solid, was vacuum filtered, washed with 20 mL of THF and air dried to afford 0.18 g (22 %) of title compound as a white solid.

The filtrate was neutralized with 6.00 g of NaHC0₃, 40 mL of 10 % NaHC0₃ (aq) (pH = 8), and extracted with 20 mL of toluene. The organic phase was saved. The aqueous phase was extracted with a solution of 20 mL of THF and 20 mL of toluene, and then with 20 mL of THF. The organic phases were combined, washed with 25 mL of 25 % NaCI (aq), dried over anhydrous MgS0₄, gravity filtered, and concentrated to afford 0.69 g of crude free base of the title compound. The crude free base of the title compound was purified by gel filtration

(silica gel 60; 9:1 hexane: EtOAc) to afford 0.26 g (35 %) of free base of the title compound. Total yield was 57%.

¹H NMR of title compound (d⁶-DMSO): δ 11.3-11.6 (br s, 1 H, R3N⁺-H), 7.84-7.85 (m, 1 H, aromatic CH), 7.79-7.80 (m, 1 H, aromatic CH), 7.56 (m, 2H, aromatic

CH), 7.50-7.51 (m, 4H, aromatic CH), 7.41-7.44 (m, 1 H, aromatic CH), 7.33-7.34 (m, 1 H, aromatic CH), 6.28 (br s, 1 H, C=C-H), 4.40-4.50 (m, 2H, -NCHsPh), 3.80- 3.95 (m, 2H, piperidine CH2), 3.60-3.67 (m, 1 H, piperidine CH₂), 3.20-3.30 (m, 1 H, piperidine CH₂), 2.90-3.00 (m, 1 H, piperidine CH₂), 2.76-2.84 (m, 1 H, piperidine CH₂).

¹³C NMR of title compound (d⁶-DMSO): δ 140.31 (aromatic C); 135.05 (2C, aromatic C); 134.53 (aromatic C); 131.39 (2C, benzyl aromatic CH); 129.85 (C=CH); 129.45 (aromatic CH); 128.75 (2C, benzyl aromatic CH); 127.48, 124.63, 124.45, 123.31 , 122.18 (aromatic CH); 118.97 (C=CH); 57.94 (-CH₂-); 48.66 (-CH2-); 47.72 (-CH₂-); 25.18 (-CH₂-). m/z+ = 306.2 [M+1 , free base]; MW = 341.90 [HCl salt], 305.44 [free base]. UV (MeCN): λ = 274.00 (ε = 5977.46).

IR (KBr pellet): 2928.38 cm ^"1 (NH stretch); 1458.59 cm ^"1 (vinylic CH), 791.23 cm ^"1 (out-of-plane aromatic ring bending), 700.12 cm ^"1 (out-of-plane aromatic ring bending). Calculated: %C = 70.26, %H = 5.90, %CI = 10.37, %N = 4.10, %S = 9.38; Found: %C = 69.27, %H = 5.80, %CI = 11.27, %N = 4.08, %S = 9.42. Molecular Formula = C₂₀H₂oCINS.

¹H NMR of free base of title compound (d⁶-DMSO): δ 7.73-7.77 (m, 2H, aromatic CH), 7.46-7.47 (m, 1 H, aromatic CH), 7.32-7.38 (m, 5H, aromatic CH), 7.27-7.28 (m, 2H, aromatic CH), 6.24 (br s, 1 H, C=C-H), 3.59-3.62 (m, 2H, -NCHsPh), 3.13 (m, 2H, piperidine CH₂), 2.68 (m, 2H, piperidine CH₂), 2.56 (m, 2H, piperidine Chb).

The above free base, N-benzyl-4-(benzo[b]thiophene-7-yl)-1 ,2,3,6- tetrahydropyridine, decomposes approximately 10-20% at room temperature when exposed to light and air. Surprisingly, it has now been discovered that there is no noticeable decomposition of N-benzyl-4-(benzo[b]thiophene-7-yl)- 1 ,2,3,6-tetrahydropyridine hydrochloride after one month at room temperature when exposed to light and air.

Example 3 Preparation of N-Benzyl-4-hvdroxy-(benzo[b1thiophene-7-yl)-piperidine.

Scheme II, Step B': A 3-neck 500 mL roundbottom flask fitted with a condenser, dropping funnel and nitrogen purge, was charged with toluene (600 mL) and methanesulfonic acid (202 mL, 300 g, 6.5 eq). The mixture was heated to 45-55oC, and 1-N-benzyl-4-hydroxy-4-(2'-(2",2"-0-diethoxy)ethylthio- phenyl)piperidine (200 g, 481.4 mmol, prepared in example 1) dissolved in toluene (1400 mL) was added over approximately 30 minutes maintaining the temperature at 45-50°C. The reaction mixture was stirred for about 1 to 2 hours at 45-55°C and then quenched with a mixture of 2N sodium hydroxide (1685 mL, 7 eq) and isopropyl alcohol (400 mL). The layers were separated and the organic phase was washed with water (1000 mL). Approximately 800 mL of solvent were removed under vacuum (less than 100 mm Hg) and silica G60 (160 g) was added. The mixture was then stirred for at least 30 minutes at room temperature. The mixture was then filtered and the silica G60 was rinsed with toluene (1000 mL). The filtrate was concentrated under vacuum (less than 100 mm Hg) to a final pot volume of about 400 mL. The title compound could then be isolated by complete concentration under vacuum or, alternatively, it is allowed to remain in the toluene and carried on to the dehydration step C.

Example 4 Alternative Preparation of N-Benzyl-4-(benzorblthiophene-7-yl)-1 ,2,3,6- tetrahvdropyridine hydrochloride. Scheme II, Step C: The toluene solution from example 3 containing the compound prepared in example 3 was diluted with isopropyl alcohol (1000 mL) and heated to 60°C. Then 2.5 M HCI/isopropanol (212 mL, 1.1 eq) was added over 30 minutes. The reaction mixture was then cooled in an ice bath and stirred for at least one hour at 0°C. The cooled mixture was then filtered, the solid rinsed with cold isopropyl alcohol and dried under vacuum at 50°C to provide the title compound (55-60%) as the HCl salt .

Example 5 Preparation of 1 -N-Carbethoxy-4-hvdroxy-4-(2'-(2".2"-0-diethoxy)ethylthio- phenvDpiperidine.

Scheme I or Scheme II, step A: A solution of 2.0M of n-BuLi in cyciohexane ( 11.99 mL, 24 mmol) was cooled to 5°C under a nitrogen atmosphere. TMEDA (3.71 mL, 24.6 mmol) was added dropwise keeping the exotherm under 10°C. Thiophenol (1.20 mL, 11.7 mmol) in 2 mL cyciohexane was added dropwise keeping the exotherm under 20°C. The resulting solution was allowed to stir to ambient temperature overnight. The thick white slurry was cooled to -50°C, and diluted with 2 mL of dry THF. A solution of 1 -carbethoxy-4- piperidone (2.0 g, 11.7 mmol) in 1 mL of dry THF was added dropwise keeping the exotherm less than -50°C. The resulting solution was warmed to ambient temperature and stirred for 2 hours. Bromo acetaldehyde diethyl acetal (1.78 mL, 11.82 mmol) was added all at once, and the resulting solution was heated at reflux for 4 hr. The solution was cooled to ambient temperature, quenched with pH=7 buffer (50 mL), and extracted with ethyl acetate (3 X 50 mL). The combined organics were absorbed on silica gel, and purified using silica gel flash chromatography to provide the title compound (3.30 g) as a colorless oil. MS (FD)=397.1 ; ¹H-NMR (CDCI₃): δ 7.6(1 H, m); 7.3(1 H, m); 7.2(2H, m); 4.9(1 H, s); 4.6(1 H, t); 4.2(4H, m); 3.75(2H, t); 3.6(2H, m); 3.5(2H, m); 3.4(2H, m); 3.2(2H, d); 2.5(2H,t); 2.2(2H, m); 1.8(2H, m); 1.2(3H, t); 1.1 (6H, t). Elemental Analysis:

Theory Found C 60.49 60.69 H 7.86 7.83

N 3.52 3.89

Example 6 Preparation of N-Carbethoxy-4-(benzorb1thiophene-7-yl)-1.2.3.6- tetrahvdropyridine.

Scheme II, step C: A solution of methanesulfonic acid (0.98 mL, 15.11 mmol) in 5 mL toluene was cooled to 0°C. To this solution was added 1-N- carbethoxy-4-hydroxy-4-(2'-(2",2"-0-diethoxy)ethylthio-phenyl)piperidine (1.0 g, 2.52 mmol, prepared in example 5) in 5 mL of toluene dropwise at 0°C. The solution was then stirred at 10°C for 15 minutes, and slowly warmed to ambient temperature. After the starting material disappeared by TLC, the reaction was quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate (3 X 25 mL). The organics were dried over anhydrous magnesium sulfate, filtered and purified over silica gel (ethyl acetate/hexane, 1 :1 ) to provide the title compound (123 mg) as a light yellow oil.

MS (FD)= 287; ¹H-NMR (CDCI₃): δ (1 H, d); 7.4 (1 H, d); 7.3(2H, m); 7.2(1 H, d); 6.2(1 H, m); 4.2(4H, m); 3.7(2H, m); 2.7(2H, m); 1.3(3H, t). Example 7 Preparation of 4-(Benzofblthiophene-7-yl)-1 ,2,3.6-tetrahydropyridine.

Dissolve N-carbethoxy-4-(benzo[b]thiophene-7-yl)-1 ,2,3,6- tetrahydropyridine (105mg, 0.3652mmol, prepared in example 6) in 1 mL ethylene glycol and add potassium hydroxide (102 mg, 1.826 mmol) dissolved in 1 mL of water. The reaction mixture is heated at reflux for 8 hours and then cooled to room temperature. It is then diluted with 5 mL water and extracted with ethyl acetate (3 X 5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The reside is purified over silica gel to provide the title compound as a yellow oil (51 mg), MS(ion spray)=216.3 (M+1); ¹H-NMR (CDCI₃): δ 7.7 (1 H, d); 7.4 (1 H, d); 7.3(2H, m); 7.2(1 H, d); 6.3 (1 H, bs), 3.6(2H, m); 3.2(2H, m); 2.6(2H, m).

Example 8

Preparation of 4-(Benzorblthiophene-7-yl)-1 ,2,3,6-tetrahydropyridine from N- Benzyl-4-(benzo[b1thiophene-7-vπ-1 ,2,3,6-tetrahydropyridine prepared in Example 2.

To a solution of N-benzyl-4-(benzo[b]thiophene-7-yl)-1 , 2,3,6- tetrahydropyridine (101 mg, 0.331 mmol, prepared in example 2) in 1.3 mL of acetonitrile at room temperature with magnetic stirring was added phenyl chloroformate (46 μL, 0.364 mmol). After stirring at room temperature for 15 h the reaction was concentrated to 0.5 mL and purified by flash chromatography (14 g of flash silica gel, 3:1/heptane:ethyl acetate) to yield 100 mg (90%) of N- carbobenzyloxy-4-(benzo[b]thiophene-7-yl)-1 ,2,3,6-tetrahydropyridine as an off- white oil: 500 MHz ¹H NMR (CDCI3) δ 7.75 (d, 1 H, J = 7.5 Hz), 7.46 (d, 1 H, J = 5.5 Hz), 7.41-7.36 (m, 4H), 7.25-7.15 (m, 4H), 6.30 (br s, 1 H), 4.42 (br s, 1 H), 4.30 (br s, 1 H), 3.95 (t, 1 H, J = 5.5 Hz), 3.86 (t, 1 H, J = 5.5 Hz), 2.75 (br s, 2H). To a solution of N-carbobenzyloxy-4-(benzo[b]thiophene-7-yl)-1 ,2,3,6- tetrahydropyridine (346 mg, 1.03 mmol, prepared directly above) in 2 mL of methyl sulfoxide at room temperature was added 5 N aqueous sodium hydroxide (619 μL, 3.09 mmol). The reaction was heated in an oil bath at 50°C, another 0.25 mL of methyl sulfoxide was added to completely clarify the solution. After stirring for 7 h, the thick reaction mixture was cooled to room temperature and diluted with 6 mL of f-butyl methyl ether and 4 mL of water. Once all solids dissolved, the layers were separated and the aqueous layer was washed with t- butyl methyl ether (4 X 6 mL). The combined organics were washed with water (1 X 2 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated in vacuo to a faint brown white oil (229 mg). 500 MHz ¹H NMR analysis (CDCI₃) showed the crude oil to contain 10wt% methyl sulfoxide and some minor impurities (<10%) with the remainder being the title compound (ca. 90% corrected).

Example 9

Alternative preparation of 4-(Benzorb1thiophene-7-yl)-1 ,2.3.6-tetrahvdro From N- Benzyl-4-(benzo[b1thiophene-7-yl)-1 ,2,3,6-tetrahvdropyridine prepared in Example 2.

Combine N-benzyl-4-(benzo[b]thiophene-7-yl)-1 ,2,3,6-tetrahydropyridine (20 g, prepared in example 2) with toluene under an atmosphere of nitrogen.

With stirring add phenylchloroformate (11.66 g) with stirring at a temperature of

20-25°C over 5 to 10 minutes followed by addition of diisopropylethylamine (9.61 g) at a temperature of 20-30°C over 30 minutes. The reaction is stirred for at least 15 minutes. It is then quenched with 50% sodium hydroxide (9.17 g) and water (50 mL). The mixture is then filtered over Cuno zetaplus paper or over hyflo and wash residue with 10 mL of toluene. The filtrate layers are separated and the aqueous is discarded. Treat the toluene layer with 40wt% aqueous dimethylamine (16.1 g) and isopropanol (20 mL) and heat the reaction mixture to 75°C with stirring for 1 hour. Allow the reaction mixture to cool, wash with aqueous HCL (50 mL water and 16.9 g concentrated HCl) followed by a water

(50 mL) wash. Concentrate the organic layer under vacuum and dissolve the residue in propylene glycol (100 mL). Add 50% sodium hydroxide (22.9 g) and heat the reaction mixture at 75°C for 3 hours. Then quench the reaction with toluene (100 mL) and water (200 mL). Separate the layers at a temperature of 40 to 50°C and back extract the aqueous layer with toluene (100 mL). Combine the toluene layers and wash with a mixture of water (100 mL) and 50% sodium hydroxide (0.92 g). Concentrate the organic layer under vacuum and dissolve the residue in ethanol. Heat the solution to reflux and add oxalic acid (5.16 g) and ethanol (27 mL) over 30 minutes. Then slowly cool the solution to room temperature and then to 0°C. Collect the title compound by filtration and rinse with cold ethanol (40 mL).

The following substituents are preferred: with respect to substituent E, compounds wherein E is:

wherein R⁶ and R⁷ are each independently H or d-Cβ alkyl; m is the integer 0, 1 or 2; n is the integer 0, 1 or 2; and R⁸ is H or a suitable nitrogen protecting group are preferred;

With respect to substituent E, compounds wherein E is:

are most preferred; with respect to substituents R^1a, R^1b, and R^1c, compounds wherein R^1a, R^1b, and

R^1c are each independently H, F, Cl, Br, I, C C₆ alkyl, d-Cβ alkoxy, CF₃, phenyl, or NO₂, are preferred; with respect to substituent R², compounds wherein R² is H, C₁-C-₂₀ alkyl, OH, or

C C₆ alkoxy are preferred. with respect to substituent R³, compounds wherein R³ is H, or C₁-C₂₀ alkyl are preferred; with respect to R⁸, compounds wherein R⁸ are H, or benzyl are preferred. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood by one of the ordinary skill in the art, that the practice of the invention encompasses all of the usual variations, adaptations, or modifications, as come within the scope of the following claims and its equivalents.

Claims

WHAT IS CLAIMED IS:

1. A process for the preparation of a compound of formula I:

R formula I

wherein

E represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group or an unsubstituted or substituted C₁-C-2₀ alkyl group;

R^1a, R^1b, and R^1c are each independently H, F, Cl, Ci-Ce alkyl, C C₆ alkoxy, halo(Cι-C₆)alkyl, phenyl, N0₂, NH₂, or phenyl substituted with from

1 to 3 substituents selected from the group consisting of F, Cl, d-C₆ alkyl, Ci-Ce alkoxy, halo(Cι-C₆)alkyl, phenyl, N0 , and NH₂; or

R^1a and R^1b together form a C -C saturated or unsaturated carbocyclic ring, and R^1c is H, F, Cl, Ci-Ce alkyl,d-C₆ alkoxy, halo(d-C₆ )alkyl, phenyl, N0₂, NH₂, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, C Ce alkyl, CrC₆ alkoxy, halo(d-C₆)alkyl, phenyl, N0₂, and NH₂; or

R^1b and R^1c together form a C -C₇ saturated or unsaturated carbocyclic ring, and R^1a is H, F, Cl, Br, I, Cι-C₆ alkyl, d-C₆ alkoxy, halo(CrC₆ )alkyl, phenyl, N0₂, NH₂, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CrC₆ alkyl, Cι-C₆ alkoxy, halo(d-C₆)alkyl, phenyl, N0₂, and NH₂;

R² is H, C1-C20 alkyl, OH, d-C₆ alkoxy, an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group; R³ is H, C₁-C₂₀ alkyl, an unsubstituted or substituted aromatic group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted (C₃-C₈)cycloalkyl group; or

R² and R³ are connected by a C₂-C₄ alkylene; or a pharmaceutically acceptable salt thereof; comprising, treating a compound of formula II;

formula II wherein substituents R'^a, R'^D, and R^1c are defined as above, with a suitable base, a suitable electrophile, and a compound of formula III; z .-,2

Y- formula

wherein R² and R³ are defined as above, and X is a suitable leaving group;

Y is OR⁴; and Z is OR⁵ wherein R⁴ and R⁵ are each independently C1-C10 alkyl; or

Y and Z together represent a carbonyl; or

Y and Z are both oxygen and are connected by a C₂-C₄ alkylene; followed by addition of a suitable acid catalyst.

2. The process according to claim 1 wherein E is:

wherein R⁶ and R⁷ are each independently H or C1-C-6 alkyl; m is the integer 0, 1 or 2; n is the integer 0, 1 or 2; and

R⁸ is H or a suitable nitrogen protecting group.

3. The process according to claim 2 wherein R^1a, R^1b, R^1c, R², R³, R⁶, and R⁷ are H.

4. The process according to claim 3 wherein the compound of formula III is diethyl bromoacetal.

5. The process according to claim 4 wherein R⁸ is H.

6. A compound which is N-benzyl-4-(benzo[b]thiophene-7-yl)-

1 ,2,3,6-tetrahydropyridine hydrochloride.