Crystal structure of (S)-4-carbamoyl-4-(1,3-dioxo-isoindolin-2-yl)butanoic acid.

In the title compound, C13H12N2O5, the phthalimide ring system is essentially planar, with a maximum deviation of 0.0479 (14) Å. In the crystal, each mol-ecule is linked via six neighbouring mol-ecules into a three-dimensional network through N-H⋯O and O-H⋯O hydrogen bonds, which form an R 3 (2)(8) ring motif.

In the title compound, C 13 H 12 N 2 O 5 , the phthalimide ring system is essentially planar, with a maximum deviation of 0.0479 (14) Å . In the crystal, each molecule is linked via six neighbouring molecules into a three-dimensional network through N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds, which form an R 3

Chemical context
The title compound, 5-(aminoxy)-4-(3-oxo-2H-isoindol-2oyl)valeric acid (phthaloylisoglutamine), is one of the firststep hydrolysis products of thalidomide. Thalidomide was first synthesized in 1953 and was marketed as a hypnotic medicine in 1956. After that, the teratogenic side effect of thalidomide was proved and caused serious drug disaster (Lenz, 1961). Blashke et al. (1979) reported that only (S)-thalidomide exhibits teratogenicity while (R)-thalidomide exhibits sedative effects. In other words, the hypnotic and teratogenic mechanisms of thalidomide are different. For a long time, the target protein of thalidomide has not been clarified. However in 2010, the protein cereblon, which is one of the E3 ubiquitin ligase proteins, was identified as the primary target of thalidomide teratogenicity (Ito et al., 2010). Furthermore, the conformation of a Cereblon and thalidomide complex has been reported (Fischer et al., 2014).
Hydrolysis compounds of thalidomide are generated rapidly in vivo (Schumacher et al., 1965;Nishimura et al., 1994) and some of these showed TNF-production-inhibitory activity (Nakamura et al., 2007). Although the crystal structures of racemic and enantiomeric thalidomide were solved and reported earlier (Allen & Trotter, 1971;Suzuki et al., 2010), the crystal structures of hydrolysis compounds of thalidomide have not been reported. Considering that knowing the structure of the molecule enables us to calculate the affinity between ligand and receptor using computer simulation, our report herein will be helpful in clarifying the differences between the biological effects of thalidomide and phthaloylisoglutamine. ISSN 2056-9890

Figure 3
A crystal packing view of the title compound, showing the intermolecular hydrogen bonds. A yellow molecule is linked with two red, two green and two blue molecules. Table 1 Hydrogen-bond geometry (Å , ).

Supramolecular features
In the crystal structure, each molecule has six hydrogen bonds, which are divided into three types (Table 1). The three hydrogen bonds form a hydrogen-bonded ring with an R 2 3 (8) ring motif, which unites three molecules (Fig. 2). Taken together as shown in Fig. 3, one molecule (yellow) is linked to another six molecules (blue, red, and green) by three sets of circular hydrogen bonds.

Database survey
A search of the Cambridge Structural Database (Version 5.35 update in 2014; Groom & Allen, 2014) for the structure of thalidomide gave 11 hits, but there was no hydrolysis compound of thalidomide.

Synthesis and crystallization
The title compound was purchased from WuXi AppTec. The title compound (2 mg) was dissolved in ethanol (500 ml). After a few days of slow evaporation at 278 K, colourless single crystals suitable for X-ray diffraction were obtained.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2 Special details Refinement. Refinement was performed using all reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F 2 . R-factor (gt) are based on F. The threshold expression of F 2 > 2.0 σ(F 2 ) is used only for calculating R-factor (gt).