合成路线: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.
合成路线: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.
参考文献标题:A potent,orally active,most balanced ETA/ETB dual endothelin receptor antagonist.Discovery of J-104132
文献作者:Niiyama,K.; et al.
参考来源:15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998,Edinburgh) 1998,Abst P.297
合成路线: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).
合成路线: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.
合成路线: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).
合成路线: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.
参考文献标题:Practical asymetric synthesis of an endothelin receptor antagonist
文献作者:Song,Z.J.; et al.
参考来源:J Org Chem 1999,64(26),9658
合成路线: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.
参考文献标题:Radiosynthesis of a potent endothelin receptor antagonist: [11C] L-753,037
文献作者:Ravert,H.T.; et al.
参考来源:J Label Compd Radiopharm 2000,43(12),1205
产品链接: CAS No. 198279-45-7››