Preparation of the precursor alcohol (XI) is outlined in Scheme 1. Reduction of 2-bromo-5-methoxybenzoic acid (I) with borane-dimethylsulfide complex gave benzylic alcohol (II). After conversion of (II) to the corresponding mesylate, treatment with NaBr provided bromide (III). (1R,2S)-Aminoindanol (IV) was acylated with propionyl chloride to afford amide (V), which was converted to acetonide (VII) with 2-methoxypropene (VI) using pyridinium tosylate as the acid catalyst. Acetonide (VII) was then alkylated with bromide (III) in the presence of lithium hexamethyldisilazide at -35 C to give the chiral intermediate (VIII). Hydrolysis of acetonide at 10 C, followed by amide hydrolysis under reflux furnished a mixture of acid (IX) and methyl ester (X). This mixture was then reduced with LiAlH4 to provide the chiral alcohol (XI).

Pyridone (XII) was converted to its dianion with LDA and then alkylated with propyl bromide to give the butyl pyridone (XIII). This was converted into bromopyridine (XIV) by subsequent treatment with PBr3. The nitrile group of (XIV) was then reduced to aldehyde (XV) using diisobutylaluminum hydride. The aldehye (XV) underwent a Heck reaction with tert-butyl acrylate (XVI) using tri-o-tolylphosphine and a palladium catalyst to provide unsaturated ester (XVII). Further condensation of the aldehyde group of (XVII) with (S,S)-pseudoephedrine (XVIII) produced the chiral oxazolidine (XIX). Alcohol (XI) was then protected as the silyl ether (XXI) using tert-butyldimethylsilyl chloride. After its conversion to the organolithium reagent with tert-butyllithium, addition to pyridyl acrylate (XIX) gave intermediate (XXII), and further acidic work-up removed the chiral auxiliary to afford aldehyde (XXIII).

Addition of Grignard reagent (XXIV) to this aldehyde (XXIII) at -78 C produced the diastereomeric mixture of alcohols (XXV), which was oxidized to ketone (XXVI) with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide. The tert-butyl ester group of (XXVI) was then transesterified with n-butanol and Ti(OBu)4 to ester (XXVII). Cyclization of ketoester (XXVII) was performed in the presence of lithium hexamethyldisilazide to produce the cyclopentapyridine system (XXVIII). This mixture of tertiary alcohols was deoxygenated with triethylsilane and a Lewis acid to yield (XXIX) as the major diastereoisomer.

Oxidation of the side-chain hydroxyl group of (XXIX) to the carboxylic acid (XXXI) was effected in a two-step procedure involving SO3-pyridine complex oxidation to aldehyde (XXX), followed by oxidation to carboxylic acid (XXXI) with sodium chlorite. Finally, basic hydrolysis of the butyl ester of (XXXI) provided the target compound.

In a related procedure, chiral oxazoline (XXXV) was prepared by condensation of ethyl acetimidate (XXXIII) with (S,S)-thiomicamine (XXXII), followed by O-methylation with MeI and sodium tert-pentoxide. Condensation of the lithium salt of (XXXV) with diethylchlorophosphate at -78 C provided phosphonate (XXXVI), which was submitted to a Horner-Emmons reaction with pyridine aldehyde (XV) to yield the vinyl oxazoline (XXXVII). Conjugate addition of the organolithium reagent (XXXVIII) to (XXXVII) then produced adduct (XXXIX) as the major diastereoisomer. Hydrolysis of the oxazoline of (XXXIX) upon refluxing in isopropyl alcohol with H2SO4 yielded isopropyl ester (XL). Pyridine carboxylate (XLI) was further obtained by carbonylation of (XL) under atmosphere of CO in the presence of bis(diphenylphosphino)ferrocene and palladium diacetate in MeOH.

Intermediate alcohol (XI) was then protected as the benzyl ether (XLII). After its conversion to the corresponding organolithium reagent, addition to pyridine ester (XLI) produced ketone (XLIII). Finally, the title compound was obtained by a similar sequence to that from above, involving cyclization of (XLIII) to (XLIV) with sodium tert-pentoxide, deoxygenation with SmI2, hydrogenolysis of benzyl ether to give (XLV), and then oxidation of (XLV) to acid followed by isopropyl ester hydrolysis.

Alternatively, pyridine ester (XLI) was condensed with the organolithium reagent derived from the silyl-protected intermediate (XXI) to give the corresponding ketone (XLVI). Subsequent desilylation of (XLVI) with HF to (XLVII), followed by base-catalyzed aldol cyclization afforded (XLVIII). Then, the sequence of oxidation to acid (XLIX) with Jones reagent, followed by deoxygenation with SmI2 and basic hydrolysis provided the title diacid.

In a further procedure, pyridine-2,3-dicarboxylic acid (L) was esterified with MeOH and SOCl2 and then oxidized to the N-oxide (LI), which by treatement with POCl3 gave chloropyridine (LII). Then, substitution of the halogen atom of (LII) for a butyl group using n-BuLi in the presence of ZnCl2 and palladium catalyst provided butylpyridine (LIII). Saponification of the methyl esters, followed by reaction with Ac2O gave cyclic anhydride (LIV). This was condensed with organozinc reagent (LV) to give ketone (LVI). After activation of (LVI) with carbonyl diimidazole, condensation with the lithium enolate of ethyl acetate, followed by cyclization produced cyclopentenone (LVII). This was condensed with Grignard reagent (XXIV) to give (LVIII) and then reduced with Zn and HCl and isomerized in the presence of EtONa to provide (LIX) as a racemic mixture.

Hydrogenolysis of the benzyl ether of (LIX) and subsequent treatment with Tf2O gave aryl triflate (LX). Stille coupling reaction of (LX) with organotin reagent (LXI) produced unsaturated ester (LXII), which was then hydrogenated over Pd/C to give (LXIII). Basic hydrolysis of both ester groups of (LXIII) yielded the racemic diacid, which was finally resolved using quinidine.

The intermediate 3-(6-butyl-3-formylpyridin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) has been obtained as follows: the alhylation of 2-hydroxy-6-methylpyridine-3-carbonitrile (I) with propyl bromide and LDA gives 6-butyl-2-hydroxypyridine-3-carbonitrile (II), which is brominated with tetrabutylammonium bromide and P2O5 yielding the 2-bromo-6-butylpyridine-3-carbonitrile (III). The reduction of (III) with DIBAL affords the corresponding aldehyde (IV), which is finally condensed with tert-butyl acrylate (V) by means of allyl palladium chloride dimer to furnich the target intermediate (VI).

The intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) has been obtained as follows: the reduction of 2-bromo-5-methoxybenzoic acid (VII) with NaBH4/BF3 gives the expected benzyl alcohol (VIII), which by treatment with SOCl2 is converted into the benzyl chloride (IX). The condensation of (IX) with the chiral auxiliary (X) by means of LIHMDS provides the 2(S)-methylpropionic acid derivative (XI). Elimination of the chiral auxiliary with sulfuric acid gives 3-(2-bromo-5-methoxyphenyl)-2(S)-methylpropionic acid (XII), which is reduced with NaBH4/BF3 to the corresponding alcohol (XIII). Finally, this compound is silylated to afford the intermediate (XIV) with TBDMS-Cl and imidazole.

The cyclization of the intermediate 3-(6-butyl-3-formylpyridin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) with the chiral auxiliary (XV) by means of AcOH gives the chiral oxazolidine (XVI), which is enantioselectively condensed with the intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) by means of n-BuLi to yield the adduct (XVII). Elimination of the chiral auxiliary with citric acid affords the aldehyde (XVIII), which is treated with 1,3-benzodioxol-5-ylmagnesium bromide (XIX) to provide the corresponding secondary alcohol (XX). Alternatively, the cyclization of the intermediate 3-(6-butyl-3-formylpyidin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) with the chiral auxiliary (XXI) by means of AcOH gives the chiral oxazolidine (XXII), which is enantioselectively condensed with the intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) by means of n-BuLi to yield the adduct (XXIII). Elimination of the chiral auxiliary with citric acid affords the previously reported aldehyde (XVIII).

The cyclization of (XX) by means of ClPO(OEt)2 and LiHMDS gives the cyclopenta[b]pyridine (XXIV), which is hydrolyzed and desilylated yielding the hydroxyacid (XXV). Finally, the primary alcohol of (XXV) is oxidized with NaClO2, TEMPO and NaClO or with H5IO6/CrO3.

The labeled compound has been obtained by methylation of the phenolic OH of the known compound (L-843974) with 11C-methyl iodide (II) by means of tetrabutylammonium hydroxide in DMF.