Syntheses, Crystal Structures, and Biological Activities of Two Enantiomeric 2-Trifluoromethylthieno[2,3-d]pyrimidin-4-amine Derivatives

GAO Hui ^a,b ,
FU Ju ^b ,
ZHAO Ming-Juan ^b ,
SONG Xin-Jian ^a,b ,
YANG Ping ^b ,
ZHENG Yin ^b

a.
a. Key Laboratory of Biologic Resources Protection and Utilization of Hubei Province, Hubei University for Nationalities, Enshi 445000, China;
b.
b. School of Chemical and Environmental Engineering, Hubei University for Nationalities, Enshi 445000, China

Received Date: 8 May 2015
Available Online: 15 June 2015
Fund Project: Supported by the National Natural Science Foundation of China (No. 21262012) (No. 21262012) the Natural Science Foundation of Hubei Province (No. 2014CFB621) (No. 2014CFB621) the Project of New Strategic Industries for Fostering Talents in Applied Chemistry of Higher Education of Hubei Province, the Open Fund of Key Laboratory of Biologic Resources Protection & Utilization of Hubei Province (No. PKLHB1506) (No. MY2014T004) and the First-class Discipline of Forestry in Hubei University for Nationalities (No. PKLHB1506)

Two enantiomeric 2-trifluoromethyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d] pyrimidin-4-amine derivatives were synthesized by nucleophilic substitution of two chiral amines with 4-chloro-2-trifluoromethyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine, which started from 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile, trifluoroacetic acid (TFA) and phosphoryl trichloride via one-pot procedure. Their structures were determined by single-crystal X-ray diffraction. Enantiomer (R)-3,(R)-N-(1-phenylethyl)-2-trifluoromethyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-amine crystallizes in the tetragonal system, space group P4₃ with a=8.6847(6), b=8.6847(6), c=22.419(2)Å, V=1690.9(3)Å³, Z=4, D_c=1.428 g/cm³, μ=0.228 mm^-1, F(000)=752, the final R=0.0463 and wR=0.1257 for 3442 observed reflections with I>2σ(I). Enantiomer (S)-3,(S)-N-(1-phenylethyl)-2-trifluoromethyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-amine crystallizes in the tetragonal system, space group P4₁ with a=8.688, b=8.688, c=22.421Å, V=1692.4Å³, Z=4, D_c=1.426 g/cm³, μ=0.227 mm^-1, F(000)=752, the final R=0.0682 and wR=0.1806 for 3182 observed reflections with I>2σ(I). The preliminary bioassay indicated that the R-enantiomer exhibits higher antitumor activity against MCF-7 than gefitinib.

Syntheses, Crystal Structures, and Biological Activities of Two Enantiomeric 2-Trifluoromethylthieno[2,3-d]pyrimidin-4-amine Derivatives

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