(2R)-4-[(9H-Fluoren-9-ylmethoxy)carbonyl]-2-methylpiperazin-1-ium chloride

The synthesis of the title salt, C20H23N2O2 +·Cl−, was carried out with a precursor of known absolute configuration (R) and the X-ray analysis confirmed that the product retained the absolute configuration. In the crystal, the dominant packing motif is a chain running along [010] generated by N—H⋯Cl hydrogen bonding. C—H⋯O and C—H⋯Cl interactions are also observed.

The synthesis of the title salt, C 20 H 23 N 2 O 2 + ÁCl À , was carried out with a precursor of known absolute configuration (R) and the X-ray analysis confirmed that the product retained the absolute configuration. In the crystal, the dominant packing motif is a chain running along [010] generated by N-HÁ Á ÁCl hydrogen bonding. C-HÁ Á ÁO and C-HÁ Á ÁCl interactions are also observed.
Thanks to the Pharmaceutical Development Team in Bangalore for providing the material for single-crystal X-ray investigation. The authors also thank Jaikumar Keshavan and other members of AstraZeneca for all their support. This refers to ATP NO 11/0793.

Comment
Piperazine and substituted piperazines are good linkers to pharmacophores to bring out drug substance with desired pharmacokinetics and pharmacological properties (Cho et al., 2010;Wang et al., 2009). In this context there is a great need in selective mono N-protectected piperazines and efficient synthetic procedures for their preparation. As a part of our research in drug development we were in need of selective mono protection of 2-methylpiperazines. We could develop a simple procedure for the mono N-protection of 2-methylpiperazine with F-moc. The chromatographic and spectroscopic analysis indicated that the process is highly regioselective to give the mono protected product but the same techniques were inadequate to elucidate the structure (Fig. 1, Scheme I & II, ACD/Labs,1994-2011), therefore single-crystal technique was employed. The X-ray investigation of the title compound was undertaken to verify the structure and confirm the absolute stereochemistry of the intermediate made in the course of synthesis (Fig. 2). The absolute configuration around the chiral carbon atom C6 was determined to be 6R, which was expected from the synthesis using a precursor of R-configuration.
The Flack's x parameter (Flack, 1983) was refined to -0.04 (5). The molecule has four hetero-atoms of which only one is protonated, the N1 atom. This potential H-bond donor participates in intermolecular H-bond interaction with the chloride ion (Table 1, Fig. 3), linking the molecules into infinite chain by N-H···Cl (chloride) interactions along the [0 1 0] direction ( Fig. 3). Themolecules are efficiently packed, with no residual void for solvent inclusion (Fig. 4). The packing coefficient of I, calculated by PLATON, is 66.7% (Kitaigorodskij, 1973), reflecting an efficient molecular packing arrangement.

Experimental
The chemicals used for the synthesis are purchased from: (R)-2-methyl piperazine from Manjing Gaungtong Pharmaceutical & Chemical Co. Ltd. and F-moc chloride from Spectrochem India Ltd.
Preparation of (2R)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylpiperazine-1-ium chloride A solution of F-moc chloride (11.6 g, 0.0449 mol) in acetone (100 mL) was added drop wise to a solution of 2(R)-methyl piperazine (5.0 g, 0.0499 mol) in acetone (75 mL) at 2893 K over a period of 1.7 h. The temperature of the reaction mass was raised from 295 to 298 K and was allowed to stir for 1.5 h. The resulting solid was collected by filtration and washed with acetone to give 9.89 g (yield: 55.2% w/w) of the title compound as a white solid in form of hydrochloride salt. HPLC purity >98% and M+1: 323, melting point: 412 K (DSC thermogram).

Crystallization process
The single-crystal of (2R)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylpiperazin-1-ium chloride has been grown using vapour diffusion method: (2R)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylpiperazine-1-ium chloride (0.5 g) is dissolved in methanol (20 mL) in a small vial, which is placed inside a larger vial containing a small volume of a heptane (100 mL) in which the sample is insoluble. The larger vial is then sealed but the smaller one is open for the second solvent to intrude. The unit is kept as such for a period of 72 h. The obtained solid was collected by filtration and examined under supplementary materials sup-2 microscope. A large block-shaped crystal of compound I, grown from methanol/heptane, was used for single-crystal X-ray diffraction experiment.

Refinement
Data collection, structure solution and refinement: Diffraction data for compound 1 was collected at RT using a Nonius Kappa-CCD diffractometer (Nonius, 1998), with graphite-monochromated Mo Kα radiation (0.71073 Å). Details of X-ray experiment are summarized in Supplementary Material. The structure was solved by direct methods (Altomare et al., 1999, SIR97) and refined with F 2 against all reflections. The title compound 1 had one molecule in the asymmetric unit. The absolute configuration at the chiral C6 carbon atom was determined to be R. The number of Friedel pairs measured was 1922. All non-H atoms were anisotropically refined. Although identified in late difference Fourier maps, the aromatic-and methyl-H atoms were calculated due to poor bond angles and constrained to ideal geometry positions with distance 0.96-0.98 Å, from the parent atoms. The H1A and H1B atoms, found from difference Fourier map, were refined a few cycles with isotropic displacement parameters but were constrained in the final cycles of refinement to 1.06 and 0.86 Å from their parent atoms. Due to the fact that both these H-atoms are involved in H-bonds, the refined positions were kept in the final structure model. The H atoms were refined using a riding model, with U iso (H) = 1.2U eq (C). Six low integer reflections shadowed by the beam stop were omitted from the final calculations. The highest residual electron density peak was located close to carbon C11 atom and the deepest hole close to carbon C10 atom. The original structure model was obtained (Altomare, SIR97) and refined initially within maXus software suite (MacKay et al., 2000) but the final refinement of the structure was done with SHELXL97 (Sheldrick, 2008).