Prasugrel, a new medicine for preventing blockages in the arteries

Prasugrel {systematic name: 5-[(2-cyclopropylcarbonyl)(2-fluorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate}, C20H20FNO3S, is a new third-generation thienopyridine which was recently approved for clinical use as a more potent blocker of the platelet P2Y12 receptor than clopidogrel, which was previously used for this purpose. The molecule features a tetrahydrothienopyridine system with the tetrahydropyridine ring showing a half-chair conformation; the dihedral angle formed by the the planes of the benzene and thiophene rings is 83.17 (3)°.

Prasugrel {systematic name: 5-[(2-cyclopropylcarbonyl)(2fluorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate}, C 20 H 20 FNO 3 S, is a new third-generation thienopyridine which was recently approved for clinical use as a more potent blocker of the platelet P2Y 12 receptor than clopidogrel, which was previously used for this purpose. The molecule features a tetrahydrothienopyridine system with the tetrahydropyridine ring showing a half-chair conformation; the dihedral angle formed by the the planes of the benzene and thiophene rings is 83.17 (3) .

Related literature
For the biological activity of the title compound, see: Farid et al. (2008). For details of the synthesis, see: Sun et al. (2009 (Bruker, 2000); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.
Prasugrel, a new medicine for preventing blockages in the arteries Z.-M. Wang, J. Zhao and G. Xu

Comment
Prasugrel was recently approved for clinical use in combination with aspirin as an option for preventing blockages in the arteries in patients with acute coronary syndromes who are undergoing treatment via percutaneous coronary intervention (Farid et al., 2008). Both enantiomers of prasugrel show similar activity, therefore it was approved for use in its racemic form. The synthesis of prasugrel has been published recently (Sun et al., 2009). Herein we report its crystal structure (Fig. 1).

Experimental
The description of the seven-step synthesis of the title compound is published by Sun et al. (2009). Here we report the details for the two final steps of the synthesis.
Synthesis of prasugrel. 5-(2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-\ c]pyridin-2(4H)-one (3.31 g, 0.01 mol) was dissolved in the mixture of DMF (20 ml) and acetate anhydride (1.13 ml, 0.012 mol). NaH (0.44 g, 0.011 mol) was added at 0°C and stirred for 1 h at room temperature. The reaction solution was poured into iced water (50 ml) and extracted with ethyl acetate (30 ml x 3). The organic phase was separated and washed with saturated NaCl solution (50 ml x 4), then dried with anhydrous Na 2 SO 4 and filtered. The filtrate was distilled in vacuo and the solvent was removed. The residue was washed in 10 ml of ether, and thus prasugrel, in the form of colorless solid, was obtained (2.5 g, 66%). supplementary materials sup-2 Refinement All the H atoms were positioned geometrically and included in the refinement using riding model approximation with C-H = 0.93-0.97 Å and U iso (H) = 1.2U eq (C) [U iso (H) = 1.5U eq (C) for methyl H atoms]. Unfortunately, all crystals, finally formed after the prolonged crystallization, were of limited quality, which is reflected in rather poor accuracy of the structure. Fig. 1. Molecular structure of the title compound with thermal ellipsoids drawn at the 30% probability level.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.