(R)-Baclofen [(R)-4-amino-3-(4-chlorophenyl)butanoic acid]

The first single-crystal XRD-based structure of enantiopure (R)-baclofen, a commonly used spasmolytic drug, without any co-crystallized molecules is reported in this article.


Chemical context
(R)-Baclofen, an unnatural -amino acid and artificial GABA receptor agonist, is a frequently used non-addictive drug to treat muscle spasticity (Dario & Tomei, 2004). Although baclofen is conventionally applied as a racemic mixture, only the (R)-enantiomer actually mediates a therapeutic effect (Olpe et al., 1978). In addition, baclofen has been recently approved in France as an alternative medication to treat alcohol dependence (Reade, 2021). Considering those new developments, the establishment of synthetic routes towards enantiopure (R)-baclofen were discussed recently (Có rdova- Villanueva et al., 2018;Gendron et al., 2019).

Structural commentary
The molecular structure of the title compound is shown in Fig. 1. A partial packing diagram is shown in Fig. 2.
A prediction of crystal forms of the title compound was previously presented by Couvrat et al. (2021), which is based on detailed XRPD-studies and Rietveld refinement. Based on the available XRPD-data, three forms, A, B and C, were observed, of which form C is considered to be the most stable form at higher temperatures. The (R)-baclofen crystal analyzed in this work corresponds to the newly predicted polymorphic form C presented by Couvrat et al. (2021).
The molecules crystallize in a zwitterionic configuration, forming an ammonium and a carboxylate residue. The Nbound hydrogen atoms were located and refined freely. Bond lengths and angles fall into the typically observed ranges for organic molecules without any strain.
The combination of both effects yields the observed structure of form C of (R)-baclofen. In contrast, the cohesion of the apparently less stable form A is ensured byinteractions.
Hydrogen-bond geometry data as well as non-classical C-HÁ Á ÁCl interaction data are summarized in Table 1.

Database survey
Using the CSD database (version 5.42 updates 2 and 3; Groom et al., 2016), a search for the title compound's structure and names used in this article was conducted with CONQUEST (version 2021.2.0; Bruno et al., 2002).
While the crystal structures of (R)-and (S)-baclofenium hydrochloride were reported in the early 1980s (Chang et al., 1981(Chang et al., , 1982refcodes: CRBMZB, CRBMZC10), studies on the phase behavior of pure baclofen have gained attention just recently. This is particularly relevant for the crystal structure of enantiomerically pure (R)-baclofen since X-ray powder diffraction studies were recently described by Couvrat et al. (2021). A total of three polymorphic forms (A, B and C) of (R)-baclofen were analyzed by X-ray powder diffraction, form C being identified as previously unknown. Based on this nomenclature, the crystal structure of form C is reported in this study. For the crystal structure of racemic baclofen, see

Synthesis and crystallization
Crystals of the title compound were grown from a saturated aqueous solution containing enantiopure (R)-baclofen, which was evaporated slowly by a stream of dry argon at 313 K. The purity of the (R)-baclofen was verified via 1 H NMR. Enantiopure (R)-baclofen was purchased from abcr GmbH  Table 1 Hydrogen-bond geometry (Å , ). (2) 3.3192 (14) 105.3 (16)

Figure 1
The molecular structure of (R)-baclofen with displacement ellipsoids shown at the 50% probability level.

Figure 2
Partial packing diagram of (R)-baclofen form C.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The N-bound hydrogen atoms were found in difference syntheses, and refined freely. All Cbound H atoms were positioned geometrically and refined using a riding model, with C-H = 0.99 Å (methylene groups), 1.00 Å (methine groups) or 0.95 Å (aryl CH) and with U iso (H) = 1.2U eq (C) (methylene groups, aryl CH, methine groups). The structure was refined as a two-component inversion twin (BASF 0.04470).