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

Anne Ertan; Parhalad Sharma; Dokka Nagaraju; K Deepthi; Sulur G Manjunatha

doi:10.1107/S1600536811048306

. 2011 Nov 19;67(Pt 12):o3386–o3387. doi: 10.1107/S1600536811048306

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

Anne Ertan ^a,^*, Parhalad Sharma ^b, Dokka Nagaraju ^b, K Deepthi ^b, Sulur G Manjunatha ^b

PMCID: PMC3239028 PMID: 22199876

Abstract

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.

Related literature

For the use of piperazine and substituted piperazines as good linkers to pharmacophores in attempts to obtain compounds with desired pharmacokinetic and pharmacological properties, see: Cho et al. (2010 ▶); Wang et al. (2009 ▶). For packing coefficients, see: Kitaigorodskij (1973 ▶).

Experimental

Crystal data

C₂₀H₂₃N₂O₂ ⁺·Cl⁻
M _r = 358.85
Monoclinic,
a = 8.3492 (3) Å
b = 7.4954 (2) Å
c = 14.9246 (3) Å
β = 90.6740 (18)°
V = 933.93 (5) Å³
Z = 2
Mo Kα radiation
μ = 0.22 mm⁻¹
T = 293 K
0.28 × 0.20 × 0.08 mm

Data collection

Nonius KappaCCD diffractometer
4227 measured reflections
4221 independent reflections
3684 reflections with I > 2σ(I)
R _int = 0.022

Refinement

R[F ² > 2σ(F ²)] = 0.036
wR(F ²) = 0.086
S = 1.03
4221 reflections
227 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.16 e Å⁻³
Δρ_min = −0.15 e Å⁻³
Absolute structure: Flack (1983 ▶), 1922 Friedel pairs
Flack parameter: −0.04 (5)

Data collection: COLLECT (Nonius, 1998 ▶); cell refinement: SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO (Otwinowski & Minor, 1997 ▶) and SCALEPACK; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: initial refinement: maXus (MacKay et al., 2000 ▶); final refinement: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶) and ORTEPII (Johnson, 1976 ▶); software used to prepare material for publication: PLATON and ACD/Labs (ACD, 2011 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811048306/kp2361sup1.cif

e-67-o3386-sup1.cif^{(25KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811048306/kp2361Isup2.hkl

e-67-o3386-Isup2.hkl^{(206.8KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811048306/kp2361Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯Cl1ⁱ	1.06	2.08	3.117 (2)	165
N1—H1B⋯Cl1ⁱⁱ	0.88	2.26	3.135 (2)	171
C2—H2B⋯O8ⁱⁱⁱ	0.96	2.41	3.316 (2)	157
C21—H21⋯O8^iv	0.98	2.54	3.469 (2)	158
C22—H22⋯Cl1	0.96	2.72	3.622 (2)	157

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

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.

supplementary crystallographic information

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 microscope. A large block-shaped crystal of compound I, grown from methanol/heptane, was used for single-crystal X-ray diffraction experiment.