(S)-(+)-cis-4′-Benzyloxypraziquantel

The asymmetric unit of the title compound, C26H30N2O3 {systematic name (S)-(+)-2-[cis-4-(benzyloxy)cyclohexanecarbonyl]-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one}, consists of two independent molecules in which the O= Camide group is syn to the N—C(C=Olactam) moiety, making dihedral angles of 2.0 (8) and 3.7 (8)°. The conformation of the 1,4-disubstituted cyclohexane ring is cis in each independent molecule, with the carbonyl group occupying an equatorial position and the benzyloxy group an axial position. In one molecule, two C and one O atom of the benzyloxy group are disordered over two sets of sites, with a refined occupancy ratio of 0.772 (8):0.228 (8). In the crystal, molecules are linked by C—H⋯O interactions, forming ribbons parallel to the b-axis direction.


Comment
The importance of pyrazinoisoquinolone derivatives as anthelmintics is well established (Jung et al., 2008;Thétiot-Laurent et al., 2013). Extensive number of derivatives has been synthesized, nevertheless at the date there are none with an activity comparable to that of praziquantel (Duan et al., 2012;Patra et al., 2013;Wang et al., 2013). Such compounds usually have an asymmetric carbon atom and only one of the enantiomers presents anthelmintic activity, often the enantiomer with (R)-(-)-configuration (Staudt et al., 1992). Herein, we report the synthesis and crystal structure of the title compound, (S)-(+)-cis-4 -benzyloxypraziquantel ( Fig. 1), as a key intermediate for the synthesis of (S)-(+)-cis-4 -hydroxypraziquantel, one of the main metabolites of praziquantel (Meier & Blaschke, 2001).
The most stable conformation for (S)-(+)-cis-4′-benzyloxypraziquantel is observed where the O═ C amide group is syn to the N-C(C═O lactam ) moiety with a dihedral angle of 2.0 (8) and 3.7 (8)° for the two independent molecules per asymmetric unit. Furthermore, the conformation of the 1,4-disubstituted cyclohexane is cis, where the carbonyl moiety occupies an equatorial position and the benzyloxy moiety occupies an axial position. In the crystal (Fig. 2), molecules are linked by intermolecular C-H···O hydrogen interactions (Table 1) to form ribbons parallel to the b axis.

Refinement
All H atoms were geometrically positioned and refined using a riding model, with C-H = 0.95 Å for aromatic CH, 0.99 Å for secondary CH 2 , 1.00 Å for tertiary CH, respectively, and with U iso (H) = 1.2U eq (C). The absolute configuration was not established by anomalous dispersion effects, nevertheless the absolute configuration could be assigned from the known configuration of the chiral centers. In one molecule the C20A, C21A and O3A atoms of the benzyloxy group are disordered over two sets of sites with refined site occupancies of 0.772 (8):0.228 (8). During the refinement, the C21B-C26A, C21B-C22A and C21B-C20B bond lengths were constrained to be 1.38 (1), 1.38 (2) and 1.50 (1) Å, respectively.
In the last cycles of refinement, 14 outliers were omitted.

Figure 1
The asymmetric unit of the title compound with displacement ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Only the major component of the disordered atoms is shown.

Figure 2
Intermolecular C-H···O interactions (dotted lines) forming ribbons parallel to the b axis in the title compound. Only the major components of the disordered atoms are shown. T min = 0.937, T max = 0.979 8420 measured reflections 5852 independent reflections 3845 reflections with I > 2σ(I)  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 > 2σ(F 2 ) is used only for calculating R-factors(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.