SB-269652
Chemical Name: trans-N-[4-[2-(7-Cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide
CAS No. 215802-15-6
项目整合开发状态: Preclinical
项目研究机构: GlaxoSmithKline (Originator)
合成路线:Esterification of trans-4-aminocyclohexylacetic acid (I),followed by protection of the resulting amino ester (II) with di-tert-butyl dicarbonate,afforded carbamate (III).Ester (III) reduction using DIBAL then gave aldehyde (IV) (1,2).6-Cyano-1,2,3,4-tetrahydroisoquinoline (VII) was prepared by acylation of 6-bromotetrahydroisoquinoline (V) with trifluoroacetic anhydride to give amide (VI).Bromide displacement in (VI) with CuCN in NMP,followed by hydrolysis of the trifluoroacetamido group,furnished (VII) (1).Reductive condensation between amine (VII) and aldehyde (IV) in the presence of NaBH(OAc)3 gave adduct (VIII).The Boc protecting group of (VIII) was then removed by treatment with trifluoroacetic acid,yielding amine (IX).This was finally coupled with 4-quinolinecarboxylic acid (X) by means of EDC and HOBt.
合成路线:Tetrahydroisoquinoline (II) was prepared by intramolecular cyclization of N-trifluoroacetyl 4-bromophenethylamine (I) with paraformaldehyde in acetic/ sulfuric acid.Displacement of the bromine atom of (II) with CuCN in boiling N-methyl-2-pyrrolidinone produced nitrile (III).The trifluoroacetyl group og (III) was then removed by means of K2CO3 in aqueous methanol,yielding the intermediate isoquinoline (IV).
合成路线:Swern oxidation of hydroxy ketal (V) led to aldehyde (VI),which was reductively condensed with tetrahydroquinoline (IV) in the presence of sodium triacetoxyborohydride to produce the N-alkylated quinoline (VII).Acid hydrolysis of the ethylene ketal of (VII) afforded the corresponding ketone (VIII).Subsequent reductive amination of (VIII) with ammonium acetate in the presence of sodium borohydride furnished the primary amine (IXa-b) as a mixture of cis and trans isomers.Coupling of (IXa-b) with indole-2-carboxylic acid (X) employing EDC and HOBt yielded the corresponding amide as a mixture of geometric isomers.The target trans isomer was finally isolated by chromatography on silica gel.
📌 参考资料/链接：
参考文献标题:Tetrahydroisoquinoline derivs.as modulators of dopamine D3 receptors
文献作者:Branch,C.L.; Stemp,G.; Johnson,C.N.(SmithKline Beecham plc)
参考来源:EP 0983244; WO 9850364
📄 详细内容
合成路线:Tetrahydroisoquinoline (II) was prepared by intramolecular cyclization of N-trifluoroacetyl 4-bromophenethylamine (I) with paraformaldehyde in acetic/ sulfuric acid.Displacement of the bromine atom of (II) with CuCN in boiling N-methyl-2-pyrrolidinone produced nitrile (III).The trifluoroacetyl group og (III) was then removed by means of K2CO3 in aqueous methanol,yielding the intermediate isoquinoline (IV).
合成路线:An alternative procedure started from trans-4-aminocyclohexylacetic acid hydrogen sulfate (XI),which was esterified with methanol and sulfuric acid to give aminoester (XII).Protection of the amino group of (XII) as the tert-butyl carbamate (XIII),followed by ester reduction with DIBAL gave rise to aldehyde (XIV).Reductive condensation of (XIV) with tetrahydroisoquinoline (IV) provided (XV).The Boc group of (XV) was then cleaved with trifluoroacetic acid to furnish the trans amine (XVI).This was finally converted to the target compound by coupling with indole-2-carboxylic acid (X) as above.
参考文献标题:Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - an intramolecular cyclization complementary to the Pictet-Spengler reaction
文献作者:Stokker,G.E.
参考来源:Tetrahedron Lett 1996,37(31),5453
产品链接: CAS No. 215802-15-6››