EMD-57439((-)-enantiomer), EMD-53998(racemate), EMD-57033

合成路线:Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III),which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV).Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI),which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)].Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of (?-EMD-53998 (EMD-57439) and the camphanoyl amide (X),which are separated by chromatography.Finally,the (+)-enantiomer,EMD-57033,is isolated by further treatment of amide (X) with morpholine in methylene chloride.

参考文献标题:Preparation of the enantiomers of the novel Ca-sensitizer EMD 53 998
文献作者:Klockow,M.; Lues,I.; Jonas,R.
参考来源:Bioorg Med Chem Lett 1992,2(6),589


合成路线:Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III),which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV).Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI),which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)].Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of (?-EMD-53998 (EMD-57439) and the camphanoyl amide (X),which are separated by chromatography.Finally,the (+)-enantiomer,EMD-57033,is isolated by further treatment of amide (X) with morpholine in methylene chloride.

参考文献标题:EMD-57033
文献作者:Castar,J.; Doggrell,S.A.; Brown,L.
参考来源:Drugs Fut 2002,27(1),14


合成路线:Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III),which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV).Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI),which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)].Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of (?-EMD-53998 (EMD-57439) and the camphanoyl amide (X),which are separated by chromatography.Finally,the (+)-enantiomer,EMD-57033,is isolated by further treatment of amide (X) with morpholine in methylene chloride.
参考文献标题:Design,optimization,and operation of SMB chromatography in the production of enantiomerically pure pharmaceuticals
文献作者:Strube,J.; Jupke,A.; Schmidt-Traub,H.; Schulte,M.; Epping,A.; Devant,R.
参考来源:Chirality 1999,11440