Gliclazide impurity F: N-[(perhydro­cyclo­penta­[c]pyrrol-2-yl)amino­carbon­yl]-o-toluene­sulfonamide

Di Wu; Xueyuan Wang; Dongying Pang; Wei Su; Yan Sun

doi:10.1107/S1600536811054985

. 2012 Jan 18;68(Pt 2):o446. doi: 10.1107/S1600536811054985

Gliclazide impurity F: N-[(perhydrocyclopenta[c]pyrrol-2-yl)aminocarbonyl]-o-toluenesulfonamide

Di Wu ^a, Xueyuan Wang ^b, Dongying Pang ^b, Wei Su ^c,^*, Yan Sun ^c

PMCID: PMC3275201 PMID: 22347057

Abstract

The title compound, C₁₅H₂₁N₃O₃S, is known to be an impurity of gliclazide [systematic name: N-(hexahydro-1H-cyclopenta[c]pyrrol-2-ylcarbamoyl)-4-methylbenzenesulfonamide], a sulfonylurea antidiabetic drug. Gliclazide has a p-tolyl group substituting the sulfonamide functionality, while the title molecule contains an o-tolyl group. Both five-membered fused rings adopt envelope conformations. In the crystal, N—H⋯O hydrogen bonds are formed between HN(C=O)NH groups, building centrosymmetric dimers. These dimers are further linked through N—H⋯O(sulfonyl) contacts, forming chains in [100].

Related literature

For general background to gliclazide and the impurities of gliclazide, see: Lebovitz & Feinglos (1983 ▶). For the crystal structure of gliclazide, see: Parvez et al. (1999 ▶); Winters et al. (1994 ▶).

Experimental

Crystal data

C₁₅H₂₁N₃O₃S
M _r = 323.41
Monoclinic,
a = 10.891 (7) Å
b = 11.226 (7) Å
c = 13.477 (9) Å
β = 95.509 (9)°
V = 1640.2 (18) Å³
Z = 4
Mo Kα radiation
μ = 0.21 mm⁻¹
T = 113 K
0.20 × 0.18 × 0.10 mm

Data collection

Rigaku Saturn724 CCD diffractometer
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2002 ▶) T _min = 0.959, T _max = 0.979
16805 measured reflections
3904 independent reflections
3461 reflections with I > 2σ(I)
R _int = 0.070

Refinement

R[F ² > 2σ(F ²)] = 0.044
wR(F ²) = 0.113
S = 1.04
3904 reflections
208 parameters
3 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.30 e Å⁻³
Δρ_min = −0.51 e Å⁻³

Data collection: CrystalClear (Rigaku/MSC, 2002 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: CrystalStructure (Rigaku/MSC, 2006 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811054985/bh2389sup1.cif

e-68-0o446-sup1.cif^{(19.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811054985/bh2389Isup2.hkl

e-68-0o446-Isup2.hkl^{(191.4KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811054985/bh2389Isup3.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
N2—H2⋯O3ⁱ	0.90 (1)	1.92 (1)	2.820 (2)	177 (2)
N1—H1⋯O2ⁱⁱ	0.89 (1)	2.23 (1)	3.077 (2)	158 (2)

Open in a new tab

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

Acknowledgments

This study was supported by the Tianjin Natural Science Foundation (10JCZDJC23900).

supplementary crystallographic information

Comment

Gliclazide Impurity F is one of the gliclazide impurities, as described in the European Pharmacopoeia. Gliclazide is a second-generation sulfonylurea oral hypoglycemic agent, which can reduce blood sugar and improve blood clotting function (Lebovitz & Feinglos, 1983). It not only can improve the metabolism of diabetic patients, but also improve or delay the incidence of vascular complications of diabetes.

The reason for the existence of this impurity is mainly due to the generation of ortho-isomeride during the production process of raw material, 4-methylphenylsulfonylurea or ethyl-[(4-methylphenyl)sulfonyl]carbamate. In the liquid chromatography separation experiments, the ortho gliclazide derivative has frequently been used as working sample. In this paper, we report the crystal structure of this compound.

The molecular structure is shown in Fig. 1. Molecular dimensions are within the normal ranges. The similar corresponding bond distances and angles have been reported in structure of gliclazide (Parvez et al., 1999; Winters et al., 1994). The methyl position of toluenesulfonyl moiety is the important difference between the two structures. The mean bond distances in the o-toluenesulfonyl moiety are C—C_aromatic = 1.507 (2), S=O = 1.4354 (14), Csp²-Csp²=1.394 (3) and S—Csp² = 1.7690 (18) Å, the aromatic ring being essentially planar. The mean values of the bond distances in the perhydrocyclopenta[c]pyrrole moiety in the title compound are Csp³-Csp³ =1.536 (3) and Csp³-N=1.473 (2) Å. The pyrrole (N3, C9, C10, C14, C15) ring and the fused five-membered cyclopentane (C10···C14) adopt N3- and C12- envelope conformations, respectively, with N3 0.624 and C12 0.611Å out of the planes of the remaining atoms of the corresponding rings.

The molecules are linked into dimers by intermolecular hydrogen bonds involving amino H-atoms. Intermolecular contacts between symmetry-related dimers form chains in the [100] direction.

Experimental

A 1000 ml reactor fitted with an electric heater in the bottom, a mechanical stirrer, a thermometer and a condenser was loaded with urea (100 g) and sodium hydroxide (5 g). Slow heating and addition of o-toluenesulfonamide (48 g) after the reactants changed the mixture to the molten state. When the reaction was completed after 6 h, water and hydrochloric acid were added until pH = 7. After filtering, draining and vacuum drying, the o-toluene sulfonylurea was obtained (yield 90%). The o-toluene sulfonylurea was added to the equal amount of azolidine hydrochloride in acetonitrile under reflux for 6 h. Then, the desired products were obtained after cooling down, and filtered (yield 86%). Finally, the products were recrystallized from methanol.