3α-Hydroxy-N-(3-hydroxypropyl)-5β-cholan-24-amide

The title compound, C27H47NO3, is a (3-hydroxypropyl)amide derivative of naturally occurring enantiopure lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid). The molecule contains four fused rings: three six-membered rings in chair conformations and one five-membered ring in a half-chair form. The two terminal six-membered rings are cis-fused, while other rings are trans-fused. The structure contains an intramolecular O—H⋯O hydrogen bond and a similar hydrogen-bond framework to the corresponding deoxycholic and chenodeoxycholic acid derivatives. Intermolecular O—H⋯O and N—H⋯O interactions are also present in the crystal. This compound seems to have at least two polymorphic forms from a comparison of the X-ray powder pattern simulated from the present structure of the title compound and that previously obtained for the powder sample.

The title compound, C 27 H 47 NO 3 , is a (3-hydroxypropyl)amide derivative of naturally occurring enantiopure lithocholic acid (3-hydroxy-5-cholan-24-oic acid). The molecule contains four fused rings: three six-membered rings in chair conformations and one five-membered ring in a half-chair form. The two terminal six-membered rings are cis-fused, while other rings are trans-fused. The structure contains an intramolecular O-HÁ Á ÁO hydrogen bond and a similar hydrogen-bond framework to the corresponding deoxycholic and chenodeoxycholic acid derivatives. Intermolecular O-HÁ Á ÁO and N-HÁ Á ÁO interactions are also present in the crystal. This compound seems to have at least two polymorphic forms from a comparison of the X-ray powder pattern simulated from the present structure of the title compound and that previously obtained for the powder sample.
BSc student Mirka Kaariste is gratefully acknowledged for her help with the synthesis of the title compound. AV is grateful to Academy Professor Kari Rissanen and the Academy of Finland for funding.

Comment
The title compound is a lithocholic acid (LCA) derivative which was supposed to be a potential organogelating agent (Valkonen et al., 2004). However, in gelation studies these properties were found to be too weak for utilization in any purposes. Although single crystals of analogous deoxycholic (DCA, 3α,12α-dihydroxy-5β-cholan-24-oic acid) and chenodeoxycholic (CDCA, 3α,7α-dihydroxy-5β-cholan-24-oic acid) acid amide derivatives were easily obtained during gelation tests (Valkonen et al., 2004;Valkonen et al., 2007;, the crystals of the title compound were very thin needles and far too small for crystallographic data collection. Methanol, which is unacceptably good solvent for the title compound and analogues in gel formation (Valkonen et al., 2004), showed to be a good solvent for growing of reasonable size crystals of the title compound for X-ray diffraction studies. The molecular structure of the title compound is shown in Fig. 1.
The simulated powder diffraction pattern by Mercury (Macrae et al., 2006) from the single crystals of title compound in Fig. 2 is not congruent with the powdery sample pattern previously investigated (Valkonen et al., 2004), indicating the title compound to have more than one polymorphic form. However, the single-crystal structure of title compound is isostructural to analogous DCA and CDCA derivatives, N-(3-hydroxypropyl) 3α,12α-dihydroxy-5β-cholan-24-amide and N-(3-hydroxypropyl) 3α,7α-dihydroxy-5β-cholan-24-amide, as also seen from the simulated powder diffraction patterns in Fig. 2. These compounds have also similar unit-cell parameters, an intramolecular O-H···O hydrogen bond between hydroxyl group (O27-H27o) at the end of the side chain and amide carbonyl (O24) ( Fig. 1 and Table 1) as well as similar ttti side chain overall conformation . The intermolecular H-bond frameworks are also identical, which is possible due to the lack of the acceptors for the extra O-H donors in structures of DCA and CDCA derivatives.

Experimental
The first step was a preparation of methyl lithocholate from lithocholic acid according to literature method (Tamminen et al., 2000). In the second step methyl lithocholate (1.69 g, 4.33 mmol) and 3-amino-1-propanol (3.25 g, 43.3 mmol) were dissolved in 20 ml of methanol. The resulting mixture was heated with an oil bath and stirred at 70-80 °C for 2 days. Cooled solution was poured into 50 ml of water, the precipitate was filtered and washed twice with water. The obtained product was dried and recrystallized from acetonitrile. Yield was 1.48 g (79%).
Suitable single crystals for X-ray diffraction were obtained by very slow evaporation of analytical sample from NMRtube, where methanol-d 4 was used as a solvent. The melting point of these single crystals (186-188 °C) was found to be in agreement with the one for powdery product (184-185 °C, Valkonen et al., 2004).

sup-2 Refinement
In the absence of significant anomalous scattering effects Friedel pairs have been merged. The meaningless Flack parameter is not reported. All H atoms were visible in electron density maps, but those bonded to C were placed at idealized positions and allowed to ride on their parent atoms at C-H distances of 0.98 Å (methyl), 0.99 Å (methylene), and 1.00 Å (methine), with U iso (H) of 1.2 times U eq (C) (or 1.5 times U eq (C) for methyls). The N-H proton was found in the electron density map and it was fixed in place by DFIX restraint at distance of 0.91 (2) Å from N atom, and U iso (H) value of 1.2 times U eq (N) was used. The O-H protons were also found in the electron density map, restrained by DFIX [0.84 (2)      Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.