(3β,18β,20β)-N-Eth­oxy­carbonyl­methyl-3-nitrato-11-oxoolean-12-ene-29-carboxamide methanol monosolvate

Laszlo Czollner; Ulrich Jordis; Kurt Mereiter

doi:10.1107/S1600536812012561

. 2012 Mar 31;68(Pt 4):o1229–o1230. doi: 10.1107/S1600536812012561

(3β,18β,20β)-N-Ethoxycarbonylmethyl-3-nitrato-11-oxoolean-12-ene-29-carboxamide methanol monosolvate

Laszlo Czollner ^a, Ulrich Jordis ^a, Kurt Mereiter ^b,^*

PMCID: PMC3344161 PMID: 22606164

Abstract

The title compound, C₃₄H₅₂N₂O₇·CH₄O, is the methanol solvate of a difunctionalized derivative of the therapeutic agent 18β-glycyrrhetinic acid, a pentacyclic triterpene. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring in a half-chair conformation. This moiety is substituted by a nitrate ester group and an O-ethylglycine group. In the crystal, the nonsolvent molecules are packed parallel to (010) in a herringbone fashion with the nitrato, ethylglycine and methanol-O atom being proximate. The methanol solvent molecule is anchored via a donated O—H⋯O_acyl and an accepted N—H⋯O hydrogen bond, giving rise to infinite zigzag chains of hydrogen bonds parallel to [100]. Two weak intermolecular C—H⋯O interactions to the methanol and to an acyl oxygen establish links along [100] and [010], respectively.

Related literature

For overviews on the therapeutic aspects of glycyrrhetinic acid, see: Baran et al. (1974 ▶); Asl & Hosseinzadeh (2008 ▶). For the synthesis of new derivatives of 18β-glycyrrhetinic acid and their effect on 11β-hydroxysteroid dehydrogenase, see: Su et al. (2004 ▶); Beseda et al. (2010 ▶); Amer et al. (2010 ▶). For the crystal structure of 18β-glycyrrhetinic acid, see: Campsteyn et al. (1977 ▶); Alvarez-Larena et al. (2007 ▶). For the crystal structures of derivatives of 18β-glycyrrhetinic acid, see: Beseda et al. (2010 ▶); Amer et al. (2010 ▶); Czollner et al. (2011 ▶).

Experimental

Crystal data

C₃₄H₅₂N₂O₇·CH₄O
M _r = 632.82
Orthorhombic,
a = 10.1598 (8) Å
b = 11.1275 (9) Å
c = 30.387 (2) Å
V = 3435.3 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 100 K
0.55 × 0.53 × 0.15 mm

Data collection

Bruker Kappa APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.88, T _max = 1.00
49017 measured reflections
5565 independent reflections
5044 reflections with I > 2σ(I)
R _int = 0.036

Refinement

R[F ² > 2σ(F ²)] = 0.044
wR(F ²) = 0.122
S = 1.10
5565 reflections
416 parameters
H-atom parameters constrained
Δρ_max = 0.68 e Å⁻³
Δρ_min = −0.38 e Å⁻³

Data collection: APEX2 (Bruker, 2008 ▶); cell refinement: SAINT (Bruker, 2008 ▶); data reduction: SAINT, SADABS and XPREP (Bruker, 2008 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: PLATON (Spek, 2009 ▶) and publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812012561/xu5490sup1.cif

e-68-o1229-sup1.cif^{(44.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812012561/xu5490Isup2.hkl

e-68-o1229-Isup2.hkl^{(272.5KB, hkl)}

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—H2N⋯O8ⁱ	0.88	2.04	2.806 (3)	144
O8—H8⋯O5	0.84	1.89	2.728 (2)	177
C1—H1A⋯O4	0.99	2.34	2.968 (2)	120
C19—H19B⋯O8ⁱ	0.99	2.40	3.359 (3)	163
C25—H25A⋯O4	0.98	2.41	3.058 (3)	123
C34—H34B⋯O5ⁱⁱ	0.98	2.58	3.515 (4)	160

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

Acknowledgments

The work was supported by the ZIT Zentrum für Innovation und Technologie GmbH (Vienna Spot of Excellence, 182081).

supplementary crystallographic information

Comment

The title compound, (I), was synthesized within a research program (Beseda et al., 2010; Amer et al., 2010) designed to create new therapeutically useful derivatives of 18β-glycyrrhetinic acid (GA), an agent for the treatment of metabolic deseases (Baran et al., 1974; Asl & Hosseinzadeh, 2008). For new therapeutic applications, GA is typically modified on ring A (C1 - C5 and C10), on ring C (C8 - C15), and/or on the terminal carboxyl group of C29 (Su et al., 2004; Beseda et al., 2010; Czollner et al., 2011). In the title compound these modifications comprised the introduction of an O-ethylglycine group N-bonded to the COOH group of GA, and, as an uncommon feature, a nitrate ester group replacing the 3-hydroxy group of GA. The compound was then crystallized from methanol to give the stoichiometric crystalline methanol solvate (I). A view of the asymmetric unit is shown in Fig. 1. The GA fragment (C1 through C30, O1, O4, O5) features usual bond lengths, bond angles, and conformation (Campsteyn et al., 1977; Alvarez-Larena et al., 2007; Beseda et al., 2010; Czollner et al., 2011). There are four six-membered saturated carbocycles (A, B, D, and E) in chair and the unsaturated ring C in half-chair conformation (Fig. 2). The carboxamide group O5═C29—N2 is endo-oriented with respect to the amide nitrogen N2 (C19—C20—C29—N2 = -28.1 (3)°), in contrast to a propargyl amide derivative of GA, where it is exo-oriented (Czollner et al., 2011; corresponding torsion angle 162.3°). In the crystal lattice of (I) the non-solvent molecules are arranged in undulating layers parallel to (010) and adopt a typical herring-bone pattern within these layers (Fig. 3). These layers repeat by 2₁ axes parallel to [010]. The oxygen and nitrogen bearing ends of the GA molecules and the methanol solvent molecules are accumulated in reagions near z≈ 0, 1/2, and 1, and are crosslinked by O—H···O, N—H···O and C—H···O interactions (Table 1). The most prominent of them are the hydrogen bonds O8—H8···O5 and N2—H2n···O8ⁱ, which are donated and accepted by the methanol molecule. The methanol molecule and the carboxamide moiety O5═C29—N2 thereby build up an infinite zigzag hydrogen bond chain parallel to [100], as shown in Fig. 3. The nitrato group (N1, O1, O2, O3) is stereochemically inactive by showing no C,N,O—H···O interactions within the usual geometrical limits (Table 1; cut-off values are H···O ≤ 2.60 Å, X—H···O ≥ 120°).

Experimental

To a stirred solution of acetic anhydride (5 ml) and concentrated nitric acid (2 ml) was added N-(ethoxycarbonyl-methyl)-3-hydroxy-11-oxo-olean-12-ene-29-carboxamide (555 mg, 1.0 mmol; compound 26f of Beseda et al., 2010) at 273 K. After 30 min the reaction mixture was dropped to 200 ml of ice water. The solid product obtained was filtered, dried and recrystallized from 3 ml of dichloromethane and 5 ml of n-hexane to yield 400 mg (66.6%) of the desired product as colourless powder. An analytical sample of (I) was then obtained by recrystallization from methanol.