(R)-(+)-2-{[(3-Methyl-4-nitro­pyridin-2-yl)meth­yl]sulfin­yl}-1H-benzimidazole

Manne Naga Raju; Neelam Uday Kumar; Naveenkumar Kolla; Rakeshwar Bandichhor; Peddy Vishweshwar

doi:10.1107/S1600536811029990

. 2011 Jul 30;67(Pt 8):o2190. doi: 10.1107/S1600536811029990

(R)-(+)-2-{[(3-Methyl-4-nitropyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole¹

Manne Naga Raju ^a, Neelam Uday Kumar ^a, Naveenkumar Kolla ^a, Rakeshwar Bandichhor ^a, Peddy Vishweshwar ^b,^*

PMCID: PMC3213621 PMID: 22091198

Abstract

The title compound, C₁₄H₁₂N₄O₃S, is an intermediate of Dexlansoprazole, a proton pump inhibitor (PPI) mainly developed for anti-ulcer activity. The absolute configuration of the title compound was determined as R. The crystal structure reveals that the molecules form chains along the b axis through N—H⋯N and C—H⋯O hydrogen-bonded dimers. These chains are connected via weak C—H⋯O hydrogen bonds.

Related literature

For the synthesis of the title compound, see: Kumar et al. (2009 ▶). For background to this class of anti-ulcer drugs, see: Arimori et al. (1998 ▶); Masa et al. (2001 ▶). For a related structure, see: Fujishima et al. (2002 ▶).

Experimental

Crystal data

C₁₄H₁₂N₄O₃S
M _r = 316.33
Monoclinic,
a = 7.7422 (13) Å
b = 11.0505 (15) Å
c = 8.2318 (13) Å
β = 103.697 (7)°
V = 684.24 (18) Å³
Z = 2
Mo Kα radiation
μ = 0.26 mm⁻¹
T = 298 K
0.22 × 0.20 × 0.18 mm

Data collection

Rigaku Mercury diffractometer
Absorption correction: multi-scan (REQAB; Jacobson, 1998 ▶) T _min = 0.942, T _max = 0.950
7636 measured reflections
2752 independent reflections
2601 reflections with F ² > 2σ(F ²)
R _int = 0.025

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.038
S = 1.25
2752 reflections
215 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.48 e Å⁻³
Δρ_min = −0.37 e Å⁻³
Absolute structure: Flack (1983 ▶), with 1292 Friedel pairs
Flack parameter: −0.02 (4)

Data collection: CrystalClear (Rigaku, 2005 ▶); cell refinement: CrystalClear; data reduction: CrystalStructure (Molecular Structure Corporation & Rigaku, 2006 ▶); program(s) used to solve structure: SIR2004 (Burla et al. 2005 ▶); program(s) used to refine structure: CRYSTALS (Betteridge et al. 2003 ▶); molecular graphics: X-SEED (Barbour, 2001 ▶); software used to prepare material for publication: CrystalStructure.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811029990/gw2104sup1.cif

e-67-o2190-sup1.cif^{(18.4KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811029990/gw2104Isup3.hkl

e-67-o2190-Isup3.hkl^{(150.6KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811029990/gw2104Isup3.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—H1⋯N2ⁱ	0.881 (17)	2.553 (18)	3.425 (2)	170.5 (13)
C2—H2⋯O1ⁱⁱ	0.95	2.33	3.251 (2)	164
C12—H12⋯O2ⁱⁱⁱ	0.95	2.55	3.164 (2)	122

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

Acknowledgments

The authors are grateful to the management of IPDO-API and Dr Reddy’s Laboratories Ltd for encouragement. Many thanks to our colleagues Srinivas Gangula, Naredla Anitha and Baddam Sudhakar Reddy for their support in the overall process development.

supplementary crystallographic information

Comment

Dexlansoprazole II ((R)-(+)) (Fig. 1), (R)-enantiomer of Lansoprazole, is a proton pump inhibitor (PPI) mainly developed for anti-ulcer activity by TAP Pharmaceuticals Ltd., employing new modified-release technology (Arimori et al. 1998; Masa et al. 2001). Dexlansoprazole II ((R)-(+)) was first approved by United States Food and Drug Administration (US-FDA) in the form of 30 and 60 mg capsules for the management of patients with erosive oesophagitis and non-erosive reflux disease (GERD or GORD), under the brand name of DEXILANT.

An alternative and large-scale synthetic method for II ((R)-(+)) was developed in our laboratory by employing asymmetric oxidation conditions on prochiral nitrosulfide intermediate to yield enantiomerically enriched nitro sulphoxide derivative of the title compound I ((R)-(+)) as first stage intermediate (>90% ee) (Kumar et al. 2009). Titanium derived chiral complex (2.2:1.1:0.6 ratio of Titanium (IV)-i-propoxide:(+)-Diethyl L-tartrate:Water) was used in the reaction to induce the chirality. The enantiomerically enriched title compound I ((R)-(+)) as a resultant was subjected to acetone mediated crystallization to yield enantiopure I ((R)-(+)) (>97% ee) which on treatment with potassium salt of 2,2,2-triflouroethanol in dimethylformamide (DMF) yielded Dexlansoprazole II ((R)-(+)) with ICH quality having >99.8% ee.

The structure and stereochemistry of Dexlansoprazole II ((R)-(+)) was well established in the literature with various spectroscopic and single-crystal X-ray diffraction (Fujishima et al. 2002). Herein we have determined the absolute configuration of the title compound I as `R' by anomalous dispersion (Fig. 2). The Flack parameter value, -0.02 (4) for the assigned absolute configuration, suggest that it is correct with high accuracy. The title compound is enantipure sulphoxide containing substituents of benzimidazole and 2-(3-methyl-4-nitro-pyridin-2-yl) methane moieties with dextro (d)- optical configuration. The crystal structure reveals that title molecules are forming chains along the b axis through N₁—H···N₂ and C₂—H···O₁ hydrogen-bonded dimers. Such chains are connected via weak C₁₂—H···O₂ hydrogen bonds (Fig. 3).

Experimental

A mixture of enantiomerically enriched title compound I ((R)-(+)) (12 g, 0.038 mol) and acetone (264 ml) were heated to 45–50 °C until clear solution obtained. The resulting clear solution was cooled to -5 to 0 °C and stirred for 1.0–1.5 h. The precipitated I (RS)-(±) was filtered and the filtrate was evaporated under vacuum at below 45 °C to obtain thick residue of the title compound I ((R)-(+)). The resulting thick residue of the title compound I ((R)-(+)) was dissolved in dichloromethane and kept for slow solvent evaporation to grow single crystals.