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The structure of the metastable form I polymorph of the macrolide anti­biotic clarithromycin, C38H69NO13, was determined by a powder diffraction method using synchrotron radiation. The space group of form I is P21212. The initial model was determined by a mol­ecular replacement method using the structure of clarithromycin form 0 as a search model, and the final structure was obtained through Rietveld refinements. In the form I crystal structure, the clarithromycin mol­ecules are aligned parallel along the a axis in a head-to-tail manner with inter­molecular hydrogen bonds between the hy­droxy O atoms. The dimethyl­amine groups of the clari­thro­mycin mol­ecule inter­digitate between neighbouring head-to-tail clarithromycin alignments. The novel crystal packing found in form I provides a mechanism that describes the transformation of form 0 to form I.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270111054230/cu3008sup1.cif
Contains datablocks global, I

rtv

Rietveld powder data file (CIF format) https://doi.org/10.1107/S0108270111054230/cu3008Isup2.rtv
Contains datablock I

CCDC reference: 867011

Comment top

Clarithromycin (CAM) is a 14-membered semisynthetic macrolide antibiotic widely used for the treatment of infections with various bacteria, including chlamydia, mycoplasma and Helicobacter pylori. CAM exists in eight different crystal forms designated form 0 (ethanol solvate; Spanton et al., 1999), form I (Liu et al., 1999), form II (Liu & Riley, 1998), form III (acetonitrile solvate; Liu et al., 2003), form IV (water solvate; Avrutov et al., 2003), form V (Gruss, 2008), the hydrochloride salt (Parvez et al., 2000) and the methanol solvate (Iwasaki et al., 1993). Tablet and dry-syrup formulations using form II crystals are in clinical use (Yajima et al., 1999, 2002). CAM tablets are stable in an acidic solution such as gastric fluid, despite the observation that CAM molecules decompose rapidly under low pH conditions (Nakagawa et al., 1992). This is because, in acidic solution, a gel of CAM is formed on the surface of the tablets and this gel prevents the acidic solution from permeating into the tablets (Fujiki et al., 2011). Thus, tablets of acid-labile CAM can be orally administered without an enteric coating. Single-crystal structures of forms 0 (Jin et al., 2009), II (Stephenson et al., 1997) and III (Liang & Yao, 2008), the hydrochloride salt and the methanol solvate have been reported. However, the crystal structure of form I remains unknown because of the difficulties associated with the preparation of single crystals suitable for X-ray analysis. Form I, a metastable form, is prepared by drying form 0 in a vacuum at 273–323 K or by exposing form 0 to air at room temperature (Liu et al., 1999). Form I shows an endothermic peak at around 413 K, as determined by differential thermal analysis, and transforms to form II (Tozuka et al., 2002). Form I has an intrinsic rate of dissolution about three times that of form II (Liu et al., 1999) and this higher dissolution rate suggests the potential application of form I in a new drug formulation. We report here the crystal structure of CAM form I determined by the X-ray powder diffraction method using synchrotron radiation.

The structure determination of CAM form I by direct methods was initially attempted but was unsuccessful. This is probably because the qualities of the extracted diffraction intensities at the higher 2θ angles were not sufficiently high for structure determination by the direct method, owing to the severe overlap of the diffraction peaks caused by the longer cell parameters of form I, even though highly parallel synchrotron X-ray radiation was used. The reported crystal structures of CAM share a common overall conformation, suggesting that the CAM molecule is rather rigid. Therefore, structure determination by the molecular replacement method was performed, which gave a clear solution and resulted in the determination of the CAM form I crystal structure refined by the Rietveld method (Fig. 1). The molecular replacement method has been used primarily for the structure determination of single crystals of biomacromolecules such as proteins that contain a very large number of non-H atoms, because the method can considerably reduce the calculation time for structure determination (Rossmann, 2001). The structure determination of CAM form I demonstrates that the molecular replacement method is a suitable alternative for the determination of an initial structure for Rietveld refinement, especially when the asymmetric unit of the crystal structure contains a large number of non-H atoms.

In the crystal structure of form I, a void space is found near the crystallographic twofold axis. The fractional coordinates of its centre of gravity are (0.000, 0.093, 0.548) and its volume is 36 (2) Å3, as calculated by PLATON (Spek, 2009). The void space is surrounded by five methyl groups of the desosamine (C2 and C8), the cladinose (C34 and C35) and the aglycone rings (C23), indicating that the space is hydrophobic. The volume of the space is too small to accommodate an ethanol molecule, and the difference Fourier maps show no positive density features in this space. These observations indicate the absence of a solvent molecule in the crystal structure. This is consistent with the results of the thermogravimetric analysis, which showed that the powder of CAM form I crystals lost 0.3% of its weight, which is negligible compared with the weight of an ethanol molecule (6.0%). The hydrophobic void space in form I contrasts with the void space observed in form II, which is able to accommodate a water molecule via a hydrogen bond (Tian et al., 2009).

Fig. 2 shows the superimposed CAM structures. The positional r.m.s. differences of all non-H atoms between CAM forms I and 0, forms I and II, forms I and III, form I and the hydrochloride salt, and form I and the methanol solvate are 0.22, 0.60, 0.49, 0.29 and 0.67 Å, respectively. The largest deviations are observed at the cladinose and desosamine rings. The distance between the two rings, represented by the distance between atoms C6 and C37, is narrowest in form I at 3.69 (5) Å, and those in forms 0 and III and the hydrochloride salt are comparable or marginally wider [3.813 (4), 3.833 (4) and 3.753 (6) Å, respectively]. In contrast with these observations, the distances in form II and the methanol solvate are wider by approximately 0.5 Å [4.226 (4) and 4.280 (5) Å, respectively].

Intermolecular hydrogen bonds are formed between atom O6 of the aglycone ring and atom O12 of the cladinose ring in the crystal structure of form I, with a distance of 2.67 (4) Å, as shown in Fig. 3(a). The CAM molecules are aligned in a head-to-tail manner parallel to the a axis via these intermolecular hydrogen bonds. The dimethylamine groups of the desosamine rings interdigitate between neighbouring head-to-tail CAM alignments. The methyl groups (C2) of the dimethylamine groups, related by a crystallographic twofold axis, are in van der Waals contact with a distance of 3.34 (4) Å. This novel molecular packing of CAM found in form I provides insights into a mechanism that describes the easy transformation from form 0 to form I. In form 0, the head-to-tail arrangement of the CAM molecules with hydrogen bonds between atoms O6 and O12 is also parallel along the a axis, as shown in Fig. 3(b). The large channels parallel to the c axis are located near the dimethylamine groups and the channels are filled with ethanol solvent molecules. When form 0 crystals are dried under a vacuum, the ethanol molecules evaporate and the channels become vacant. To fill the vacant channels with dimethylamine groups, the head-to-tail CAM alignments shift by approximately a/2, 2 Å and c/2 along the a, b and c axes, respectively, resulting in the transformation of form 0 to form I with a decrease in the cell volume of 11%, although the small void space remains near the dimethylamine groups, as described above.

Intermolecular hydrogen bonds between atoms O6 and O12 are also formed in form II. However, the CAM molecules are arranged not linearly, as in the case of forms I and 0, but in a zigzag arrangement (Tian et al., 2009). The differences in the CAM molecular arrangements in these crystals indicate that a larger rearrangement of the CAM molecules needs to occur in the transformation from form I to form II. This may explain why the transformation from form I to form II proceeds at an elevated temperature of 413 K, whereas the transformation from form 0 to form I proceeds at ambient temperature.

Related literature top

For related literature, see: Altomare, Camalli, Cuocci, Giacovazzo, Moliterni & Rizzi (2009); Altomare, Campi, Cuocci, Eriksson, Giacovazzo, Moliterni, Rizzi & Werner (2009); Avrutov et al. (2003); Dollase (1986); Fujiki et al. (2011); Gruss (2008); Hanson (2010); Iwasaki et al. (1993); Izumi & Momma (2007); Jin et al. (2009); Liang & Yao (2008); Liu & Riley (1998); Liu et al. (1999, 2003); Murshudov et al. (1997); Nakagawa et al. (1992); Osaka et al. (2010); Parvez et al. (2000); Rossmann (2001); Spanton et al. (1999); Spek (2009); Stephenson et al. (1997); Takata et al. (2002); Tian et al. (2009, 2011); Tozuka et al. (2002); Yajima et al. (1999, 2002).

Experimental top

Bulk CAM (purity >99%) was purchased from Shiono Chemical Co. Ltd (Tokyo, Japan). CAM (1.8 g) was mixed with ethanol (60 ml) and completely dissolved by warming to 343 K. The CAM solution was cooled rapidly to room temperature with vigorous stirring in an ice-cold water bath and was continuously stirred for 3 h at room temperature. The fine powder of CAM form 0 crystals thus obtained was collected by filtration and completely dried for 24 h in a vacuum at room temperature in order to transform the crystals into form I. To quantify the volatiles in the crystal, thermogravimetric analysis was performed over the range 303–503 K using a TG/DTA320 instrument (SEIKO Instruments Inc., Tokyo, Japan) at a heating rate of 5 K min-1 and an air flow rate of 100 ml min-1.

Refinement top

The powder of the form I crystals was enclosed in a 0.3 mm Lindemann glass capillary. The X-ray powder diffraction data were collected at SPring-8 BL19B2 (Osaka et al., 2010), which is equipped with a high-resolution type Debye–Scherrer camera and a curved imaging-plate detector [Make and model of each?] (Takata et al., 2002). The wavelength was set to 1.3000 (1) Å. During data collection, the sample was kept at 300 K and rotated at 1 r min-1 to reduce possible preferential orientation.

Processing the powder data of CAM form I crystals with N-TREOR09 (Altomare, Campi et al., 2009) implemented in EXPO2009 (Altomare, Camalli et al., 2009) suggested a primitive orthorhombic crystal system with the lattice parameters a = 14.452, b = 34.689 and c = 8.712 Å. Although a (001) reflection was observed clearly, it was unclear whether (h00) and (0k0) reflections violated the extinction rule or not, because of the overlaps of the reflection peaks. The intensities of the reflections were extracted from the powder diffraction data assuming a primitive orthorhombic crystal system using EXPO2009.

Structure determination by the molecular replacement method was performed using reflections between 17.3–3.0 Å spacings using MOLREP implemented in CCP4 (Collaborative Computational Project, Number 4, 1994). The search model was the single-crystal structure of CAM form 0, which was refined at high resolution (1.49 < θ < 27.12°, Mo Kα; Tian et al., 2011). The overall isotropic atomic displacement parameter was fixed at 5.0 Å2 and the H atoms were excluded. A clear solution without any inappropriate intermolecular atomic contacts in the crystal structure was found only when the space group was assumed to be P21212. Structure determination by the direct space technique using simulated annealing gave the same solution in the case of space group P21212, and no plausible solution was obtained when assuming other primitive orthorhombic space groups. The bond lengths and angles were restrained to those of the CAM form 0 crystal structure and the positional parameters of the atoms were refined by REFMAC (Murshudov et al., 1997). The crystallographic R factor converged to 0.187 for reflections between 17.3 and 2.3 Å spacings. The partially refined structure was the starting model for Rietveld refinement using RIETAN-FP (Izumi & Momma, 2007). The split pseudo-Voigt function was used to fit the peaks in the powder diffraction, and the background was modelled by Legendre polynomials. The geometry of the CAM molecule was restrained as described above. The overall atomic displacement parameter was refined isotropically, and the March–Dollase function (Dollase, 1986) was used for the correction of the preferred orientation in plane (010). Before the final refinement, H atoms were generated at their theoretical positions using EXPO2009 and Jmol (Hanson, 2010), and were refined as riding, with C—H = 0.96 Å and O—H = 0.82 Å. [Please check added text] At the end of the refinement, the r.m.s. differences of the bond lengths and angles from their target values were 0.022 Å and 2.51°, respectively. Fig. 3 shows the observed, calculated and difference patterns after the Rietveld refinement. A small unassigned peak was observed at 2θ = 3.89°. This peak is thought to be derived from a trace quantity of form 0 crystals that remain in the CAM form I sample, because the 2θ value is identical to that of the form 0 (020) peak; its diffraction intensity is one of the strongest in the form 0 crystal structure.

Computing details top

Data collection: local software (Takata et al., 2002); cell refinement: EXPO2009 (Altomare, Camalli et al., 2009) and RIETAN-FP (Izumi & Momma, 2007); data reduction: local software (Takata et al., 2002); program(s) used to solve structure: CCP4 (Collaborative Computational Project, Number 4, 1994); program(s) used to refine structure: RIETAN-FP (Izumi & Momma, 2007); molecular graphics: CCP4MG (McNicholas et al., 2011); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures top
[Figure 1] Fig. 1. The molecular structure of the CAM form I. H atoms have been omitted for clarity.
[Figure 2] Fig. 2. Superposition of the CAM structures of forms I (red in the electronic version of the paper), 0 (cyan), II (blue) and III (purple), the hydrochloride salt (coral) and the methanol solvate (green).
[Figure 3] Fig. 3. The crystal packing of (a) CAM form I (this study) and (b) CAM form 0 (Tian et al., 2011; space group P212121, a = 14.5980, b = 38.368 and c = 8.7685 Å). (In the electronic version of the paper, the N and O atoms are shown in blue and red, respectively, the C atoms of CAM in forms I and 0 are shown in green and cyan, respectively, and the C atoms of the ethanol solvent molecules in form 0 are shown in yellow.) Hydrogen bonds are drawn as dotted lines. The unit cell is drawn with thick grey lines. The figures were drawn using CCP4MG (McNicholas et al., 2011).
[Figure 4] Fig. 4. The final Rietveld plot of CAM form I. The experimental diffraction profile is indicated by crosses (red in the electronic version of the paper) and the calculated diffraction profile is shown as a solid line (green). The difference profile is shown below (blue). The vertical bars (green) correspond to the positions of the Bragg peaks.
(3R,4S,5S,6R,7R,9R,11S, 12R,13S,14S)-6-{[(2S,3R,4S,6R)- 4-dimethylamino-3-hydroxy-6-methyloxan-2-yl]oxy}-14-ethyl-12,13-dihydroxy- 4-{[(2R,4S,5S,6S)-5-hydroxy-4-methoxy-4,6- dimethyloxan-2-yl]oxy}-7-methoxy-3,5,7,9,11,13-hexamethyl-1- oxacyclotetradecane-2,10-dione top
Crystal data top
C38H69NO13Dx = 1.138 Mg m3
Mr = 748.0Synchrotron radiation, λ = 1.3000 Å
Orthorhombic, P21212µ = 0.42 mm1
a = 14.4531 (4) ÅT = 300 K
b = 34.6885 (8) ÅParticle morphology: powder
c = 8.7114 (2) Åwhite
V = 4367.52 (19) Å3cylinder, 3.0 × 0.3 mm
Z = 4Specimen preparation: Prepared at 298 K and 101 kPa
Data collection top
Debye-Scherrer camera
diffractometer
Data collection mode: transmission
Radiation source: synchrotron radiation, SPring-8 BL19B2Scan method: Stationary detector
Si(111) monochromator2θfixed = 65
Specimen mounting: capillary
Refinement top
Least-squares matrix: selected elements onlyProfile function: split psudo-Voigt function
Rp = 0.038185 parameters
Rwp = 0.05796 restraints
Rexp = 0.0150 constraints
RBragg = 0.047H-atom parameters constrained
R(F) = 0.042Weighting scheme based on measured s.u.'s 1/[Yi]
R(F2) = 0.04212(Δ/σ)max = 0.018
χ2 = 13.712Background function: Legendre polynomial
6201 data pointsPreferred orientation correction: March-Dollase preferential orientation correction plane (0 1 0) G factor 1.185(2)
Crystal data top
C38H69NO13V = 4367.52 (19) Å3
Mr = 748.0Z = 4
Orthorhombic, P21212Synchrotron radiation, λ = 1.3000 Å
a = 14.4531 (4) ŵ = 0.42 mm1
b = 34.6885 (8) ÅT = 300 K
c = 8.7114 (2) Åcylinder, 3.0 × 0.3 mm
Data collection top
Debye-Scherrer camera
diffractometer
Scan method: Stationary detector
Specimen mounting: capillary2θfixed = 65
Data collection mode: transmission
Refinement top
Rp = 0.038χ2 = 13.712
Rwp = 0.0576201 data points
Rexp = 0.015185 parameters
RBragg = 0.04796 restraints
R(F) = 0.042H-atom parameters constrained
R(F2) = 0.04212
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.2462 (14)0.0595 (8)0.0226 (13)0.059 (4)*
C10.202 (3)0.0467 (6)0.254 (5)0.059 (4)*
O20.3983 (18)0.0688 (5)0.035 (3)0.059 (4)*
C20.113 (3)0.0099 (13)0.432 (5)0.059 (4)*
O30.3761 (14)0.0277 (10)0.307 (3)0.059 (4)*
C30.2071 (15)0.0233 (6)0.250 (3)0.059 (4)*
O40.5846 (19)0.2272 (11)0.002 (4)0.059 (4)*
C40.3066 (16)0.0275 (8)0.1867 (16)0.059 (4)*
O50.675 (2)0.1918 (9)0.164 (3)0.059 (4)*
C50.3091 (19)0.0638 (8)0.100 (2)0.059 (4)*
O60.888 (2)0.1759 (8)0.051 (3)0.059 (4)*
C60.1515 (14)0.0597 (8)0.0134 (18)0.059 (4)*
O70.760 (2)0.1859 (10)0.249 (3)0.059 (4)*
C70.1340 (16)0.0260 (10)0.117 (3)0.059 (4)*
O80.6673 (17)0.1308 (9)0.441 (3)0.059 (4)*
C80.1060 (18)0.0552 (18)0.137 (3)0.059 (4)*
O90.5058 (16)0.1435 (6)0.203 (4)0.059 (4)*
C90.4180 (12)0.1088 (7)0.007 (2)0.059 (4)*
C100.4788 (10)0.1281 (7)0.121 (3)0.059 (4)*
C110.478 (2)0.1090 (10)0.277 (4)0.059 (4)*
C120.443 (2)0.1704 (7)0.137 (3)0.059 (4)*
C130.521 (2)0.1950 (9)0.217 (3)0.059 (4)*
C140.487 (3)0.2336 (12)0.275 (5)0.059 (4)*
C150.5957 (16)0.2045 (14)0.108 (4)0.059 (4)*
C160.7586 (15)0.2015 (8)0.075 (3)0.059 (4)*
C170.8306 (16)0.2192 (13)0.185 (5)0.059 (4)*
C180.794 (2)0.2466 (14)0.303 (5)0.059 (4)*
C190.7944 (15)0.1653 (7)0.0020 (18)0.059 (4)*
C200.799 (3)0.1330 (8)0.119 (4)0.059 (4)*
C210.732 (2)0.1569 (10)0.144 (3)0.059 (4)*
C220.742 (3)0.1162 (11)0.207 (4)0.059 (4)*
C230.841 (4)0.1039 (16)0.259 (6)0.059 (4)*
C240.6717 (18)0.1083 (7)0.331 (3)0.059 (4)*
C250.6054 (12)0.0732 (6)0.307 (2)0.059 (4)*
C260.660 (3)0.0340 (7)0.291 (3)0.059 (4)*
C270.540 (3)0.0760 (10)0.168 (3)0.059 (4)*
C280.4621 (13)0.1065 (7)0.172 (2)0.059 (4)*
C290.390 (2)0.0938 (14)0.294 (5)0.059 (4)*
N10.200 (2)0.0108 (7)0.347 (2)0.059 (4)*
C300.465 (3)0.1720 (10)0.299 (5)0.059 (4)*
C310.292 (2)0.2007 (11)0.168 (4)0.059 (4)*
C320.216 (3)0.2054 (9)0.282 (5)0.059 (4)*
C330.1336 (16)0.1766 (10)0.277 (4)0.059 (4)*
C340.059 (2)0.1870 (16)0.393 (4)0.059 (4)*
C350.214 (3)0.1339 (13)0.447 (6)0.059 (4)*
C360.0998 (16)0.1741 (11)0.113 (3)0.059 (4)*
C370.182 (2)0.1653 (6)0.012 (2)0.059 (4)*
C380.153 (3)0.1688 (15)0.152 (3)0.059 (4)*
O100.353 (2)0.1721 (8)0.218 (4)0.059 (4)*
O110.165 (2)0.1383 (7)0.306 (3)0.059 (4)*
O120.034 (2)0.1445 (9)0.090 (4)0.059 (4)*
O130.2550 (17)0.1929 (10)0.023 (2)0.059 (4)*
H10.875110.232790.123290.059 (4)*
H20.860510.198400.237520.059 (4)*
H30.576970.081350.078980.059 (4)*
H40.510480.051310.155890.059 (4)*
H50.484050.168160.402940.059 (4)*
H60.483500.197160.264950.059 (4)*
H70.398460.169970.292620.059 (4)*
H80.190550.230770.267590.059 (4)*
H90.242990.203590.382050.059 (4)*
H100.279040.138150.429000.059 (4)*
H110.205150.108280.485590.059 (4)*
H120.191930.152300.520150.059 (4)*
H650.229090.067080.313170.059 (4)*
H660.237320.042460.162900.059 (4)*
H670.139560.053590.227070.059 (4)*
H680.063170.017240.365170.059 (4)*
H690.102120.015680.470100.059 (4)*
H700.116100.027620.516590.059 (4)*
H710.192350.044600.315690.059 (4)*
H720.321250.005680.123290.059 (4)*
H730.294330.085360.164160.059 (4)*
H740.129520.082360.064980.059 (4)*
H750.073550.028660.161630.059 (4)*
H760.136580.002770.057510.059 (4)*
H770.094930.080110.181380.059 (4)*
H780.048230.041950.124210.059 (4)*
H790.145300.040530.204340.059 (4)*
H800.364840.125290.013090.059 (4)*
H810.542030.125980.088740.059 (4)*
H820.416660.110120.319250.059 (4)*
H830.520170.122150.344050.059 (4)*
H840.496580.082560.266560.059 (4)*
H850.431540.181240.037770.059 (4)*
H860.540930.179230.301000.059 (4)*
H870.468480.249280.189420.059 (4)*
H880.536080.246220.329580.059 (4)*
H890.435340.229790.342210.059 (4)*
H900.745170.220020.004020.059 (4)*
H910.794850.272310.261970.059 (4)*
H920.832560.245470.392490.059 (4)*
H930.731960.239590.329120.059 (4)*
H940.796720.108420.068880.059 (4)*
H950.746700.135350.187230.059 (4)*
H960.854980.135260.176670.059 (4)*
H970.667400.157840.119850.059 (4)*
H980.730300.100010.119730.059 (4)*
H990.858090.117990.349210.059 (4)*
H1000.841760.076830.280340.059 (4)*
H1010.884450.109490.177940.059 (4)*
H1020.567980.073770.397660.059 (4)*
H1030.668100.022630.390310.059 (4)*
H1040.626380.016660.225920.059 (4)*
H1050.719990.038950.246240.059 (4)*
H1060.330040.103260.265180.059 (4)*
H1070.388500.066160.299050.059 (4)*
H1080.406910.104100.392030.059 (4)*
H1090.326920.224080.158080.059 (4)*
H1100.071890.174300.488460.059 (4)*
H1110.000000.178740.354840.059 (4)*
H1120.058530.214370.408100.059 (4)*
H1130.070710.198200.088850.059 (4)*
H1140.201830.140220.043740.059 (4)*
H1150.131320.144370.188150.059 (4)*
H1160.205630.176750.212260.059 (4)*
H1170.105030.187670.160830.059 (4)*
H1180.355980.016810.384110.059 (4)*
H1190.926520.165480.003900.059 (4)*
H1200.730710.183810.329240.059 (4)*
H1210.044210.126470.147630.059 (4)*
Geometric parameters (Å, º) top
O1—C61.40 (3)C4—H720.96
O1—C51.41 (3)C5—H730.96
C1—N11.48 (4)O6—H1190.82
O2—C51.41 (4)C6—H740.96
O2—C91.46 (3)O7—H1200.82
C2—N11.46 (5)C7—H760.96
O3—C41.45 (3)C7—H750.96
C3—N11.46 (3)C8—H780.96
C3—C41.55 (3)C8—H770.96
C3—C71.57 (3)C8—H790.96
O4—C151.22 (5)C9—H800.96
C4—C51.47 (4)C10—H810.96
O5—C151.32 (4)C11—H830.96
O5—C161.48 (4)C11—H840.96
O6—C191.46 (4)C11—H820.96
C6—C81.48 (3)C12—H850.96
C6—C71.50 (4)C13—H860.96
O7—C211.42 (4)C14—H880.96
O8—C241.24 (4)C14—H890.96
O9—C301.42 (5)C14—H870.96
O9—C281.46 (3)C16—H900.96
C9—C101.57 (3)C17—H20.96
C9—C281.57 (2)C17—H10.96
C10—C111.51 (4)C18—H910.96
C10—C121.56 (3)C18—H920.96
C12—O101.49 (4)C18—H930.96
C12—C131.57 (4)C20—H940.96
C13—C151.48 (4)C20—H950.96
C13—C141.51 (5)C20—H960.96
C16—C191.52 (3)C21—H970.96
C16—C171.54 (4)C22—H980.96
C17—C181.50 (6)C23—H990.96
C19—C201.54 (4)C23—H1000.96
C19—C211.55 (3)C23—H1010.96
C21—C221.52 (5)C25—H1020.96
C22—C241.51 (5)C26—H1040.96
C22—C231.56 (7)C26—H1030.96
C24—C251.57 (3)C26—H1050.96
C25—C271.54 (4)C27—H30.96
C25—C261.58 (4)C27—H40.96
C27—C281.54 (5)C29—H1060.96
C28—C291.55 (4)C29—H1080.96
C31—O131.40 (4)C29—H1070.96
C31—O101.40 (5)C30—H50.96
C31—C321.49 (5)C30—H60.96
C32—C331.55 (5)C30—H70.96
C33—O111.43 (4)C31—H1090.96
C33—C361.51 (4)C32—H80.96
C33—C341.52 (4)C32—H90.96
C35—O111.43 (6)C34—H1110.96
C36—O121.41 (4)C34—H1100.96
C36—C371.51 (4)C34—H1120.96
C37—O131.43 (4)C35—H110.96
C37—C381.49 (3)C35—H100.96
C1—H670.96C35—H120.96
C1—H650.96C36—H1130.96
C1—H660.96C37—H1140.96
C2—H700.96C38—H1170.96
C2—H680.96C38—H1160.96
C2—H690.96C38—H1150.96
O3—H1180.82O12—H1210.82
C3—H710.96
C10—C12—C13108 (2)H113—C36—C33107.3
C10—C9—C28116.3 (15)H113—C36—C37113.0
C11—C10—C12109 (2)H113—C36—O12107.9
C11—C10—C9117 (2)H114—C37—C36104.5
C12—C10—C9106.2 (18)H114—C37—C38115.9
C14—C13—C12113 (3)H114—C37—O13111.2
C15—C13—C12111 (2)H115—C38—C37109.5
C15—C13—C14105 (3)H116—C38—C37109.4
C15—O5—C16116 (3)H116—C38—H115109.5
C16—C19—C20108.4 (19)H117—C38—C37109.5
C16—C19—C21108 (2)H117—C38—H115109.4
C18—C17—C16116 (2)H117—C38—H116109.5
C19—C16—C17112 (2)H118—O3—C4109.9
C2—N1—C1108 (3)H118—O3—H72110.2
C20—C19—C21116 (2)H119—O6—C19110.3
C21—C22—C23117 (4)H12—C35—O11109.5
C22—C21—C19114 (3)H120—O7—C21109.6
C22—C24—C25117 (2)H121—O12—C36110.3
C24—C22—C21111 (3)H2—C17—C16107.7
C24—C22—C23111 (3)H2—C17—C18107.7
C24—C25—C26112 (2)H2—C17—H1109.5
C27—C25—C24116 (2)H3—C27—C25107.3
C27—C25—C26107 (2)H3—C27—C28107.3
C27—C28—C29108 (2)H3—C27—H4109.5
C27—C28—C9108.0 (17)H4—C27—C25107.3
C28—C27—C25118 (2)H4—C27—C28107.3
C29—C28—C9111.6 (19)H5—C30—H6109.5
C3—N1—C1111 (2)H5—C30—H7109.5
C3—N1—C2110 (3)H5—C30—O9109.5
C30—O9—C28123 (3)H6—C30—H7109.5
C31—C32—C33118 (3)H6—C30—O9109.5
C31—O10—C12116 (3)H65—C1—H66109.5
C31—O13—C37118 (2)H65—C1—N1109.5
C33—O11—C35114 (3)H66—C1—N1109.4
C34—C33—C32112 (3)H67—C1—H65109.4
C36—C33—C32108 (3)H67—C1—H66109.5
C36—C33—C34114 (2)H67—C1—N1109.5
C37—C36—C33107.9 (19)H68—C2—H69109.4
C38—C37—C36109 (3)H68—C2—N1109.5
C4—C3—C7110.9 (19)H69—C2—N1109.5
C5—C4—C3107 (2)H7—C30—O9109.5
C5—O2—C9113 (2)H70—C2—H68109.4
C6—C7—C3112 (2)H70—C2—H69109.6
C6—O1—C5117.3 (15)H70—C2—N1109.5
C8—C6—C7112 (3)H71—C3—C4110.3
N1—C3—C4110 (2)H71—C3—C7104.2
N1—C3—C7115 (2)H71—C3—N1105.2
O1—C5—C4106 (2)H72—C4—C3109.6
O1—C5—O2107.2 (17)H72—C4—C5111.8
O1—C6—C7107 (2)H72—C4—H118106.6
O1—C6—C8103.6 (15)H72—C4—O3105.6
O10—C12—C10112 (2)H73—C5—C4111.0
O10—C12—C13113 (2)H73—C5—O1112.5
O10—C31—C32110 (3)H73—C5—O2109.9
O11—C33—C32111 (2)H74—C6—C7107.5
O11—C33—C34109 (3)H74—C6—C8110.8
O11—C33—C36103 (3)H74—C6—O1115.6
O12—C36—C33113 (3)H75—C7—C3108.8
O12—C36—C37108 (3)H75—C7—C6108.8
O13—C31—C32110 (3)H76—C7—C3108.8
O13—C31—O10113 (3)H76—C7—C6108.8
O13—C37—C36114 (2)H76—C7—H75109.5
O13—C37—C38103 (2)H77—C8—C6109.5
O2—C5—C4109 (2)H77—C8—H79109.4
O2—C9—C10109.6 (18)H78—C8—C6109.4
O2—C9—C28105.0 (19)H78—C8—H77109.5
O3—C4—C3112.7 (16)H78—C8—H79109.5
O3—C4—C5111 (2)H79—C8—C6109.5
O4—C15—C13122 (3)H8—C32—C31107.2
O4—C15—O5127 (3)H8—C32—C33107.2
O5—C15—C13109 (3)H8—C32—H9109.5
O5—C16—C17109 (2)H80—C9—C10103.4
O5—C16—C19109 (2)H80—C9—C28107.7
O6—C19—C16104 (2)H80—C9—O2115.0
O6—C19—C20110 (2)H81—C10—C11103.8
O6—C19—C21110.5 (18)H81—C10—C12114.4
O7—C21—C19102 (2)H81—C10—C9106.8
O7—C21—C22114 (3)H82—C11—C10109.5
O8—C24—C22118 (3)H83—C11—C10109.4
O8—C24—C25124 (2)H83—C11—H82109.5
O9—C28—C27107 (2)H83—C11—H84109.5
O9—C28—C29115 (2)H84—C11—C10109.4
O9—C28—C9108 (2)H84—C11—H82109.5
C16—C19—H119109.1H85—C12—C10110.1
C28—O9—H5118.7H85—C12—C13108.3
C31—O13—H114104.0H85—C12—O10104.9
C33—O11—H10111.3H86—C13—C12104.2
C37—C36—H121104.8H86—C13—C14110.4
H1—C17—C16107.7H86—C13—C15113.1
H1—C17—C18107.7H87—C14—C13109.5
H10—C35—H12109.4H88—C14—C13109.5
H10—C35—O11109.5H88—C14—H87109.5
H100—C23—C22109.4H88—C14—H89109.5
H100—C23—H101109.6H89—C14—C13109.4
H101—C23—C22109.4H89—C14—H87109.5
H102—C25—C24102.4H9—C32—C31107.2
H102—C25—C26111.9H9—C32—C33107.2
H102—C25—C27107.5H90—C16—C17108.3
H103—C26—C25109.5H90—C16—C19107.9
H103—C26—H105109.4H90—C16—O5111.4
H104—C26—C25109.5H91—C18—C17109.5
H104—C26—H103109.4H91—C18—H92109.5
H104—C26—H105109.5H91—C18—H93109.4
H105—C26—C25109.5H92—C18—C17109.4
H106—C29—C28109.5H92—C18—H93109.5
H106—C29—H107109.5H93—C18—C17109.5
H106—C29—H108109.5H94—C20—C19109.5
H107—C29—C28109.4H94—C20—H95109.5
H108—C29—C28109.5H94—C20—H96109.5
H108—C29—H107109.5H95—C20—C19109.5
H109—C31—C32110.5H95—C20—H96109.4
H109—C31—O10107.3H96—C20—C19109.5
H109—C31—O13106.7H97—C21—C19112.7
H11—C35—H10109.5H97—C21—C22101.7
H11—C35—H12109.5H97—C21—O7113.3
H11—C35—O11109.5H98—C22—C21103.8
H110—C34—C33109.5H98—C22—C23103.6
H110—C34—H112109.5H98—C22—C24109.8
H111—C34—C33109.5H99—C23—C22109.5
H111—C34—H110109.5H99—C23—H100109.4
H111—C34—H112109.5H99—C23—H101109.5
H112—C34—C33109.4
Hydrogen-bond geometry (Å) top
D—H···AD—HH···AD···A
O6—H119···O12i0.821.872.67 (4)
Symmetry code: (i) x+1, y, z.

Experimental details

Crystal data
Chemical formulaC38H69NO13
Mr748.0
Crystal system, space groupOrthorhombic, P21212
Temperature (K)300
a, b, c (Å)14.4531 (4), 34.6885 (8), 8.7114 (2)
V3)4367.52 (19)
Z4
Radiation typeSynchrotron, λ = 1.3000 Å
µ (mm1)0.42
Specimen shape, size (mm)Cylinder, 3.0 × 0.3
Data collection
DiffractometerDebye-Scherrer camera
diffractometer
Specimen mountingCapillary
Data collection modeTransmission
Scan methodStationary detector
2θ values (°)2θfixed = 65
Refinement
R factors and goodness of fitRp = 0.038, Rwp = 0.057, Rexp = 0.015, RBragg = 0.047, R(F) = 0.042, R(F2) = 0.04212, χ2 = 13.712
No. of data points6201
No. of parameters185
No. of restraints96
H-atom treatmentH-atom parameters constrained

Computer programs: local software (Takata et al., 2002), EXPO2009 (Altomare, Camalli et al., 2009) and RIETAN-FP (Izumi & Momma, 2007), CCP4 (Collaborative Computational Project, Number 4, 1994), RIETAN-FP (Izumi & Momma, 2007), CCP4MG (McNicholas et al., 2011), publCIF (Westrip, 2010).

 

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