(+)-1-[(R)-3,3,3-Trifluoro-2-meth­oxy-2-phenyl­propion­yl]-4-(4-{[(2R,4S)-2-(2,4-dichloro­phen­yl)-2-(1H-imidazol-1-ylmeth­yl)-1,3-dioxolan-4-yl]meth­oxy}phen­yl)piperazine methanol solvate

Peeters, O.M.; Polavarapu, P.L.; Zhang, P.; Gera, L.; Gal, J.

doi:10.1107/S1600536805041048

(+)-1-[(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionyl]-4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine methanol solvate

O. M. Peeters, P. L. Polavarapu, P. Zhang, L. Gera and J. Gal

The crystal structure and absolute configuration of the title compound, C₃₄H₃₃Cl₂F₃N₄O₅·CH₄O, were determined to examine the validity of van 't Hoff's principle of additivity of optical rotations. The conformation of the dioxolane ring is halfway between an envelope, with the flap at the unsubstituted C atom, and a form twisted about C_methylene-O. The methanol molecule is hydrogen bonded via the OH group to the unsubstituted N atom of the imidazole group.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536805041048/cv6612sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S1600536805041048/cv6612Isup2.hkl Contains datablock I

CCDC reference: 296547

checkCIF report

Key indicators

Single-crystal X-ray study
T = 293 K
Mean (C-C) = 0.009 Å
R factor = 0.061
wR factor = 0.186
Data-to-parameter ratio = 12.9

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT199_ALERT_1_C Check the Reported _cell_measurement_temperature        293 K
PLAT340_ALERT_3_C Low Bond Precision on C-C bonds (x 1000) Ang ...          9
PLAT410_ALERT_2_C Short Intra H...H Contact  H24    ..  H29B    ..       1.95 Ang.
PLAT410_ALERT_2_C Short Intra H...H Contact  H26    ..  H33A    ..       1.94 Ang.

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           68.92
           From the CIF: _reflns_number_total               5861
           Count of symmetry unique reflns         3404
           Completeness (_total/calc)            172.18%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured      2457
           Fraction of Friedel pairs measured     0.722
           Are heavy atom types Z>Si present        yes

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   1 ALERT level G = General alerts; check

   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   2 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion

Comment top

Recently we have initiated studies to examine the validity of van 't Hoff's principle of the additivity of optical rotations (van 't Hoff, 1875, 1908). For this purpose we have synthesized the title compound, (I), its epimer and their component halves, namely (2R,4S)-(+)-ketoconazole, (II), (R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-piperidin-1-yl-propan-1-one and its enantiomer to determine whether the optical rotations of (I) and its epimer can be accounted for as the sum of the individual rotations. In this report we provide the determination of the absolute configuration of (I) needed for the above-described studies on van 't Hoff's principle.

A perspective view of (I) is given in Fig. 1. The bond lengths and angles do not show outstanding features. The molecule contains six rings of which the imidazole and the phenyl rings are essentially planar, with a maximum deviation of 0.014 (8) Å. The conformation of the dioxolane ring is halfway between an envelope with the flap at the unsubstituted C atom and a form twisted about C10—O11. The piperazine ring has a chair conformation, somewhat flattened at N31 due to the sp² hybridization of that atom. The conformation of (I) (Table 1) is similar to the conformation of (II) in the crystal structure (Peeters et al., 2004). The methanol molecule is hydrogen bonded via the OH group to the unsubstituted N atom of the imidazole group (Table 2). There are no intermolecular contacts that are significantly shorter than the sum of the corresponding van der Waals radii.

Experimental top

The synthesis of (I) was accomplished by first resolving racemic ketoconazole according to a literature method (Redenti et al., 1999) to obtain (+)-ketoconazole, followed by removal of the N-acetyl group of the latter using alkaline hydrolysis according to a published procedure (Chapman et al., 1990). The deacetylated compound was then acetylated with (S)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride as described (Hoye & Renner, 1996) to obtain (I). Single crystals were grown by slow evaporation of a methanol solution.

Computing details top

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: DIAMOND (Bergerhoff, 1996); software used to prepare material for publication: PARST (Nardelli, 1983).

Figures top

Fig. 1. View of (I), with the atomic numbering scheme and displacement ellipsoids at the 50% probability level.

(+)-1-[(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionyl]- 4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)- 1,3-dioxolan-4-yl]methoxy}phenyl)piperazine methanol solvate top

Crystal data top

C₃₄H₃₃Cl₂F₃N₄O₅·CH₄O	F(000) = 768
M_r = 737.59	D_x = 1.391 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2yb	Cell parameters from 28 reflections
a = 8.389 (1) Å	θ = 6.0–27.6°
b = 14.755 (1) Å	µ = 2.23 mm⁻¹
c = 14.473 (2) Å	T = 293 K
β = 100.47 (1)°	Needle, colourless
V = 1761.6 (3) Å³	0.44 × 0.08 × 0.06 mm
Z = 2

Data collection top

Siemens P4 four-circle diffractometer	R_int = 0.038
ω/2θ scans	θ_max = 68.9°
Absorption correction: ψ scan XEMP (Siemens, 1989)	h = −9→10
T_min = 0.560, T_max = 0.875	k = −17→17
6518 measured reflections	l = −17→17
5861 independent reflections	3 standard reflections every 100 reflections
3978 reflections with F² > 2σ(F²)	intensity decay: none

Refinement top

Refinement on F²	w = 1/[σ²(F_o²) + (0.09P)² + 0.9675P] where P = (F_o² + 2F_c²)/3
Least-squares matrix: full	(Δ/σ)_max = 0.001
R[F² > 2σ(F²)] = 0.061	Δρ_max = 0.28 e Å⁻³
wR(F²) = 0.186	Δρ_min = −0.31 e Å⁻³
S = 1.07	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc²λ³/sin((2θ)]^-1/4
5861 reflections	Extinction coefficient: 0.0119 (9)
455 parameters	Absolute structure: Flack (1983), 2616 Friedel pairs
H-atom parameters constrained	Absolute structure parameter: −0.01 (2)

Crystal data top

C₃₄H₃₃Cl₂F₃N₄O₅·CH₄O	V = 1761.6 (3) Å³
M_r = 737.59	Z = 2
Monoclinic, P2₁	Cu Kα radiation
a = 8.389 (1) Å	µ = 2.23 mm⁻¹
b = 14.755 (1) Å	T = 293 K
c = 14.473 (2) Å	0.44 × 0.08 × 0.06 mm
β = 100.47 (1)°

Data collection top

Siemens P4 four-circle diffractometer	3978 reflections with F² > 2σ(F²)
Absorption correction: ψ scan XEMP (Siemens, 1989)	R_int = 0.038
T_min = 0.560, T_max = 0.875	3 standard reflections every 100 reflections
6518 measured reflections	intensity decay: none
5861 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.061	H-atom parameters constrained
wR(F²) = 0.186	Δρ_max = 0.28 e Å⁻³
S = 1.07	Δρ_min = −0.31 e Å⁻³
5861 reflections	Absolute structure: Flack (1983), 2616 Friedel pairs
455 parameters	Absolute structure parameter: −0.01 (2)

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
N1	0.5288 (6)	0.1683 (3)	0.4720 (3)	0.065 (2)*
C2	0.6916 (9)	0.1631 (4)	0.4910 (5)	0.078 (3)*
N3	0.7561 (8)	0.1541 (4)	0.4164 (5)	0.086 (2)*
C4	0.627 (1)	0.1525 (5)	0.3442 (6)	0.083 (3)*
C5	0.4852 (9)	0.1619 (5)	0.3751 (5)	0.078 (3)*
C6	0.4205 (8)	0.1821 (4)	0.5375 (5)	0.069 (2)*
C7	0.3907 (6)	0.2815 (4)	0.5580 (4)	0.056 (2)*
O8	0.5387 (5)	0.3293 (3)	0.5833 (3)	0.059 (1)*
C9	0.5370 (7)	0.4074 (4)	0.5228 (4)	0.063 (2)*
C10	0.3625 (8)	0.4156 (4)	0.4772 (5)	0.071 (3)*
O11	0.3095 (5)	0.3227 (3)	0.4734 (3)	0.068 (1)*
C12	0.2893 (6)	0.2867 (4)	0.6351 (4)	0.054 (2)*
C13	0.3545 (6)	0.2719 (4)	0.7293 (4)	0.054 (2)*
C14	0.2588 (7)	0.2721 (4)	0.7981 (4)	0.066 (2)*
C15	0.0923 (7)	0.2859 (4)	0.7717 (4)	0.067 (2)*
C16	0.0245 (8)	0.2985 (5)	0.6788 (5)	0.073 (2)*
C17	0.1240 (7)	0.2990 (5)	0.6113 (5)	0.070 (2)*
Cl18	0.5589 (2)	0.2521 (1)	0.7685 (1)	0.0699 (5)*
Cl19	−0.0261 (2)	0.2848 (2)	0.8569 (1)	0.0973 (8)*
C20	0.6491 (8)	0.3862 (4)	0.4563 (4)	0.065 (2)*
O21	0.6875 (5)	0.4669 (3)	0.4108 (3)	0.066 (1)*
C22	0.8161 (7)	0.4592 (4)	0.3628 (4)	0.058 (2)*
C23	0.8715 (8)	0.3777 (4)	0.3344 (5)	0.079 (3)*
C24	0.9997 (8)	0.3747 (4)	0.2879 (5)	0.075 (3)*
C25	1.0821 (7)	0.4527 (4)	0.2697 (4)	0.058 (2)*
C26	1.0245 (7)	0.5344 (4)	0.2986 (4)	0.062 (2)*
C27	0.8934 (8)	0.5373 (4)	0.3446 (4)	0.065 (2)*
N28	1.2261 (5)	0.4496 (3)	0.2308 (3)	0.059 (2)*
C29	1.2513 (8)	0.3665 (4)	0.1793 (5)	0.074 (2)*
C30	1.4221 (9)	0.3619 (5)	0.1597 (5)	0.081 (3)*
N31	1.4614 (6)	0.4443 (3)	0.1116 (3)	0.064 (2)*
C32	1.4380 (8)	0.5256 (4)	0.1641 (5)	0.067 (2)*
C33	1.2667 (7)	0.5305 (4)	0.1823 (4)	0.063 (2)*
C34	1.4918 (7)	0.4385 (4)	0.0235 (4)	0.060 (2)*
O35	1.4900 (6)	0.3657 (3)	−0.0187 (3)	0.079 (2)*
C36	1.5215 (6)	0.5263 (4)	−0.0275 (4)	0.054 (2)*
O37	1.6344 (5)	0.5857 (3)	0.0274 (3)	0.066 (2)*
C38	1.7827 (8)	0.5468 (6)	0.0752 (5)	0.084 (3)*
C39	1.3608 (7)	0.5772 (4)	−0.0542 (4)	0.057 (2)*
C40	1.2192 (7)	0.5300 (4)	−0.0892 (5)	0.069 (2)*
C41	1.0737 (8)	0.5745 (6)	−0.1123 (5)	0.086 (3)*
C42	1.066 (1)	0.6661 (6)	−0.0973 (7)	0.101 (3)*
C43	1.204 (1)	0.7135 (5)	−0.0631 (6)	0.095 (4)*
C44	1.3516 (8)	0.6704 (4)	−0.0414 (5)	0.069 (2)*
C45	1.5843 (8)	0.5056 (4)	−0.1180 (5)	0.066 (2)*
F46	1.4769 (5)	0.4670 (3)	−0.1853 (3)	0.082 (2)*
F47	1.6305 (5)	0.5830 (3)	−0.1554 (3)	0.089 (2)*
F48	1.7179 (4)	0.4527 (3)	−0.1049 (3)	0.089 (2)*
C49	1.056 (1)	0.0309 (7)	0.3656 (7)	0.126 (4)*
O50	1.0745 (7)	0.1233 (4)	0.3839 (6)	0.124 (3)*
H2	0.7519	0.1657	0.5516	0.097*
H4	0.6359	0.1457	0.2814	0.104*
H5	0.3813	0.1636	0.3393	0.097*
H6A	0.4652	0.1521	0.5961	0.086*
H6B	0.3174	0.1537	0.5127	0.086*
H9	0.5730	0.4617	0.5597	0.079*
H10A	0.3025	0.4522	0.5148	0.089*
H10B	0.3513	0.4416	0.4148	0.089*
H14	0.3050	0.2632	0.8608	0.082*
H16	−0.0868	0.3067	0.6610	0.092*
H17	0.0775	0.3079	0.5486	0.088*
H20A	0.7477	0.3591	0.4904	0.082*
H20B	0.5981	0.3429	0.4096	0.082*
H23	0.8212	0.3241	0.3470	0.099*
H24	1.0326	0.3190	0.2679	0.094*
H26	1.0750	0.5882	0.2868	0.078*
H27	0.8575	0.5929	0.3634	0.081*
H29A	1.1747	0.3649	0.1204	0.093*
H29B	1.2312	0.3140	0.2160	0.093*
H30A	1.4979	0.3550	0.2184	0.101*
H30B	1.4326	0.3094	0.1208	0.101*
H32A	1.4603	0.5785	0.1288	0.084*
H32B	1.5134	0.5255	0.2234	0.084*
H33A	1.2554	0.5835	0.2202	0.079*
H33B	1.1920	0.5367	0.1231	0.079*
H38A	1.7593	0.4940	0.1091	0.126*
H38B	1.8397	0.5903	0.1183	0.126*
H38C	1.8486	0.5300	0.0302	0.126*
H40	1.2232	0.4675	−0.0971	0.086*
H41	0.9805	0.5426	−0.1381	0.108*
H42	0.9668	0.6959	−0.1103	0.126*
H43	1.1983	0.7758	−0.0543	0.119*
H44	1.4447	0.7034	−0.0183	0.086*
H49A	1.1366	0.0110	0.3310	0.189*
H49B	0.9499	0.0197	0.3294	0.189*
H49C	1.0677	−0.0017	0.4239	0.189*
H50	0.9950	0.1426	0.4035	0.155*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.069 (3)	0.060 (3)	0.072 (3)	−0.002 (2)	0.025 (3)	−0.005 (2)
C2	0.076 (5)	0.066 (4)	0.092 (5)	0.011 (3)	0.021 (4)	0.002 (3)
N3	0.078 (4)	0.082 (4)	0.104 (4)	−0.003 (3)	0.031 (4)	−0.020 (3)
C4	0.094 (6)	0.071 (4)	0.090 (5)	−0.005 (4)	0.031 (5)	−0.016 (4)
C5	0.082 (5)	0.081 (4)	0.071 (4)	−0.009 (4)	0.016 (3)	−0.015 (3)
C6	0.083 (4)	0.057 (3)	0.073 (4)	−0.003 (3)	0.033 (3)	−0.004 (3)
C7	0.050 (3)	0.053 (3)	0.064 (3)	−0.005 (3)	0.013 (3)	0.002 (3)
O8	0.053 (2)	0.061 (2)	0.064 (2)	−0.009 (2)	0.012 (2)	0.006 (2)
C9	0.070 (4)	0.056 (3)	0.068 (3)	−0.002 (3)	0.025 (3)	0.011 (3)
C10	0.070 (4)	0.065 (4)	0.081 (4)	−0.001 (3)	0.016 (3)	0.015 (3)
O11	0.068 (3)	0.070 (2)	0.064 (2)	−0.008 (2)	0.008 (2)	0.009 (2)
C12	0.045 (3)	0.055 (3)	0.064 (3)	−0.001 (2)	0.011 (3)	0.006 (3)
C13	0.045 (3)	0.055 (3)	0.061 (3)	0.000 (2)	0.013 (2)	0.000 (2)
C14	0.060 (4)	0.074 (4)	0.065 (3)	0.003 (3)	0.012 (3)	0.002 (3)
C15	0.051 (3)	0.074 (4)	0.079 (4)	0.003 (3)	0.019 (3)	−0.010 (3)
C16	0.051 (3)	0.077 (4)	0.092 (5)	0.001 (3)	0.014 (3)	0.003 (4)
C17	0.058 (4)	0.079 (4)	0.073 (4)	0.001 (3)	0.010 (3)	0.005 (3)
Cl18	0.0557 (8)	0.0805 (9)	0.0734 (8)	0.0098 (7)	0.0118 (7)	0.0081 (7)
Cl19	0.074 (1)	0.128 (2)	0.099 (1)	0.002 (1)	0.0408 (9)	−0.008 (1)
C20	0.069 (4)	0.061 (3)	0.073 (4)	−0.005 (3)	0.028 (3)	0.011 (3)
O21	0.060 (2)	0.061 (2)	0.083 (3)	−0.002 (2)	0.033 (2)	0.009 (2)
C22	0.055 (3)	0.057 (3)	0.065 (3)	−0.002 (3)	0.019 (3)	0.002 (3)
C23	0.079 (5)	0.058 (3)	0.110 (5)	−0.015 (3)	0.047 (4)	−0.007 (3)
C24	0.079 (4)	0.056 (3)	0.101 (5)	−0.014 (3)	0.044 (4)	−0.011 (3)
C25	0.056 (3)	0.058 (3)	0.062 (3)	−0.002 (3)	0.014 (3)	−0.002 (3)
C26	0.056 (4)	0.055 (3)	0.079 (4)	−0.001 (3)	0.022 (3)	0.000 (3)
C27	0.070 (4)	0.053 (3)	0.079 (4)	−0.004 (3)	0.030 (3)	0.001 (3)
N28	0.056 (3)	0.056 (3)	0.067 (3)	0.000 (2)	0.021 (2)	0.002 (2)
C29	0.084 (5)	0.053 (3)	0.095 (5)	0.002 (3)	0.043 (4)	0.000 (3)
C30	0.096 (5)	0.066 (4)	0.092 (5)	0.019 (4)	0.046 (4)	0.022 (3)
N31	0.068 (3)	0.057 (3)	0.073 (3)	0.007 (2)	0.024 (3)	0.006 (2)
C32	0.064 (4)	0.069 (4)	0.073 (4)	−0.003 (3)	0.025 (3)	−0.013 (3)
C33	0.068 (4)	0.050 (3)	0.077 (4)	−0.006 (3)	0.027 (3)	−0.001 (3)
C34	0.060 (4)	0.058 (3)	0.065 (3)	0.001 (3)	0.020 (3)	−0.001 (3)
O35	0.098 (3)	0.056 (2)	0.086 (3)	0.010 (2)	0.026 (3)	−0.001 (2)
C36	0.045 (3)	0.060 (3)	0.058 (3)	−0.004 (3)	0.010 (3)	0.003 (3)
O37	0.051 (2)	0.069 (3)	0.075 (2)	−0.005 (2)	0.006 (2)	−0.002 (2)
C38	0.046 (4)	0.116 (6)	0.086 (4)	0.007 (4)	−0.001 (3)	0.003 (4)
C39	0.050 (3)	0.055 (3)	0.068 (3)	0.003 (3)	0.014 (3)	0.002 (3)
C40	0.058 (4)	0.059 (3)	0.086 (4)	−0.010 (3)	0.005 (3)	−0.002 (3)
C41	0.047 (4)	0.098 (5)	0.109 (5)	0.011 (4)	0.002 (4)	0.013 (4)
C42	0.080 (6)	0.090 (5)	0.134 (7)	0.029 (5)	0.022 (5)	0.023 (5)
C43	0.085 (6)	0.066 (4)	0.136 (7)	0.017 (4)	0.024 (5)	0.010 (4)
C44	0.066 (4)	0.052 (3)	0.090 (4)	−0.002 (3)	0.017 (3)	0.000 (3)
C45	0.060 (4)	0.069 (4)	0.073 (4)	−0.005 (3)	0.022 (3)	0.002 (3)
F46	0.089 (3)	0.087 (3)	0.072 (2)	0.001 (2)	0.018 (2)	−0.012 (2)
F47	0.101 (3)	0.090 (3)	0.083 (2)	−0.015 (2)	0.038 (2)	0.009 (2)
F48	0.067 (2)	0.104 (3)	0.099 (3)	0.020 (2)	0.028 (2)	−0.009 (2)
C49	0.117 (8)	0.111 (7)	0.139 (8)	0.032 (6)	−0.005 (6)	−0.024 (6)
O50	0.073 (4)	0.110 (5)	0.189 (7)	−0.009 (3)	0.025 (4)	−0.028 (5)

Geometric parameters (Å, º) top

N1—C2	1.345 (9)	C26—C27	1.386 (9)
N1—C5	1.387 (8)	C27—H27	0.930
N1—C6	1.441 (9)	N28—C29	1.470 (8)
C2—H2	0.930	N28—C33	1.457 (8)
C2—N3	1.30 (1)	C29—H29A	0.970
N3—C4	1.36 (1)	C29—H29B	0.970
C4—H4	0.930	C29—C30	1.51 (1)
C4—C5	1.36 (1)	C30—H30A	0.970
C5—H5	0.930	C30—H30B	0.970
C6—H6A	0.970	C30—N31	1.468 (9)
C6—H6B	0.970	N31—C32	1.451 (8)
C6—C7	1.526 (8)	N31—C34	1.349 (8)
C7—O8	1.416 (6)	C32—H32A	0.970
C7—O11	1.425 (6)	C32—H32B	0.970
C7—C12	1.523 (8)	C32—C33	1.509 (9)
O8—C9	1.446 (7)	C33—H33A	0.970
C9—H9	0.980	C33—H33B	0.970
C9—C10	1.497 (8)	C34—O35	1.234 (7)
C9—C20	1.50 (1)	C34—C36	1.534 (8)
C10—H10A	0.970	C36—O37	1.423 (6)
C10—H10B	0.970	C36—C39	1.530 (8)
C10—O11	1.439 (8)	C36—C45	1.529 (9)
C12—C13	1.391 (7)	O37—C38	1.429 (7)
C12—C17	1.379 (8)	C38—H38A	0.960
C13—C14	1.388 (9)	C38—H38B	0.960
C13—Cl18	1.730 (5)	C38—H38C	0.960
C14—H14	0.930	C39—C40	1.391 (8)
C14—C15	1.394 (8)	C39—C44	1.391 (8)
C15—C16	1.375 (9)	C40—H40	0.930
C15—Cl19	1.717 (7)	C40—C41	1.373 (9)
C16—H16	0.930	C41—H41	0.930
C16—C17	1.40 (1)	C41—C42	1.37 (1)
C17—H17	0.930	C42—H42	0.930
C20—H20A	0.970	C42—C43	1.37 (1)
C20—H20B	0.970	C43—H43	0.930
C20—O21	1.426 (7)	C43—C44	1.38 (1)
O21—C22	1.389 (7)	C44—H44	0.930
C22—C23	1.378 (9)	C45—F46	1.329 (7)
C22—C27	1.372 (8)	C45—F47	1.350 (8)
C23—H23	0.930	C45—F48	1.351 (7)
C23—C24	1.37 (1)	C49—H49A	0.960
C24—H24	0.930	C49—H49B	0.960
C24—C25	1.392 (9)	C49—H49C	0.960
C25—C26	1.391 (8)	C49—O50	1.39 (1)
C25—N28	1.424 (8)	O50—H50	0.820
C26—H26	0.930

C2—N1—C5	105.9 (6)	C22—C27—H27	119.7
C2—N1—C6	127.6 (6)	C26—C27—H27	119.7
C5—N1—C6	126.4 (5)	C25—N28—C29	116.0 (5)
N1—C2—H2	123.3	C25—N28—C33	117.0 (4)
N1—C2—N3	113.4 (6)	C29—N28—C33	111.8 (4)
H2—C2—N3	123.3	N28—C29—H29A	109.4
C2—N3—C4	104.3 (7)	N28—C29—H29B	109.4
N3—C4—H4	124.2	N28—C29—C30	111.2 (5)
N3—C4—C5	111.6 (7)	H29A—C29—H29B	108.0
H4—C4—C5	124.2	H29A—C29—C30	109.4
N1—C5—C4	104.8 (6)	H29B—C29—C30	109.4
N1—C5—H5	127.6	C29—C30—H30A	109.5
C4—C5—H5	127.6	C29—C30—H30B	109.5
N1—C6—H6A	108.7	C29—C30—N31	110.8 (6)
N1—C6—H6B	108.7	H30A—C30—H30B	108.1
N1—C6—C7	114.1 (5)	H30A—C30—N31	109.5
H6A—C6—H6B	107.7	H30B—C30—N31	109.5
H6A—C6—C7	108.7	C30—N31—C32	111.9 (5)
H6B—C6—C7	108.7	C30—N31—C34	119.6 (5)
C6—C7—O8	111.2 (4)	C32—N31—C34	127.9 (5)
C6—C7—O11	108.3 (4)	N31—C32—H32A	109.5
C6—C7—C12	108.8 (5)	N31—C32—H32B	109.5
O8—C7—O11	105.7 (4)	N31—C32—C33	110.8 (5)
O8—C7—C12	111.4 (4)	H32A—C32—H32B	108.1
O11—C7—C12	111.4 (4)	H32A—C32—C33	109.5
C7—O8—C9	109.1 (4)	H32B—C32—C33	109.5
O8—C9—H9	110.7	N28—C33—C32	111.0 (5)
O8—C9—C10	103.5 (5)	N28—C33—H33A	109.4
O8—C9—C20	106.6 (5)	N28—C33—H33B	109.4
H9—C9—C10	110.7	C32—C33—H33A	109.4
H9—C9—C20	110.7	C32—C33—H33B	109.4
C10—C9—C20	114.3 (5)	H33A—C33—H33B	108.0
C9—C10—H10A	111.3	N31—C34—O35	122.4 (5)
C9—C10—H10B	111.3	N31—C34—C36	118.5 (5)
C9—C10—O11	102.2 (5)	O35—C34—C36	119.1 (5)
H10A—C10—H10B	109.2	C34—C36—O37	113.7 (4)
H10A—C10—O11	111.3	C34—C36—C39	108.8 (4)
H10B—C10—O11	111.3	C34—C36—C45	110.8 (5)
C7—O11—C10	106.1 (4)	O37—C36—C39	107.8 (4)
C7—C12—C13	122.5 (5)	O37—C36—C45	107.7 (4)
C7—C12—C17	119.6 (5)	C39—C36—C45	107.9 (5)
C13—C12—C17	117.6 (5)	C36—O37—C38	117.1 (4)
C12—C13—C14	121.8 (5)	O37—C38—H38A	109.5
C12—C13—Cl18	122.6 (4)	O37—C38—H38B	109.5
C14—C13—Cl18	115.6 (4)	O37—C38—H38C	109.5
C13—C14—H14	120.5	H38A—C38—H38B	109.5
C13—C14—C15	119.0 (5)	H38A—C38—H38C	109.5
H14—C14—C15	120.5	H38B—C38—H38C	109.5
C14—C15—C16	120.2 (6)	C36—C39—C40	120.1 (5)
C14—C15—Cl19	118.9 (5)	C36—C39—C44	121.3 (5)
C16—C15—Cl19	120.8 (5)	C40—C39—C44	118.6 (5)
C15—C16—H16	120.3	C39—C40—H40	119.6
C15—C16—C17	119.5 (6)	C39—C40—C41	120.8 (6)
H16—C16—C17	120.3	H40—C40—C41	119.6
C12—C17—C16	121.8 (6)	C40—C41—H41	120.1
C12—C17—H17	119.1	C40—C41—C42	119.8 (7)
C16—C17—H17	119.1	H41—C41—C42	120.1
C9—C20—H20A	109.6	C41—C42—H42	120.0
C9—C20—H20B	109.6	C41—C42—C43	120.0 (8)
C9—C20—O21	110.1 (5)	H42—C42—C43	120.0
H20A—C20—H20B	108.2	C42—C43—H43	119.6
H20A—C20—O21	109.6	C42—C43—C44	120.9 (8)
H20B—C20—O21	109.6	H43—C43—C44	119.6
C20—O21—C22	115.0 (4)	C39—C44—C43	119.8 (6)
O21—C22—C23	123.8 (5)	C39—C44—H44	120.1
O21—C22—C27	117.6 (5)	C43—C44—H44	120.1
C23—C22—C27	118.6 (5)	C36—C45—F46	114.8 (5)
C22—C23—H23	119.6	C36—C45—F47	110.1 (5)
C22—C23—C24	120.8 (6)	C36—C45—F48	113.6 (5)
H23—C23—C24	119.6	F46—C45—F47	106.0 (5)
C23—C24—H24	119.1	F46—C45—F48	106.9 (5)
C23—C24—C25	121.9 (6)	F47—C45—F48	104.7 (5)
H24—C24—C25	119.1	H49A—C49—H49B	109.5
C24—C25—C26	116.6 (5)	H49A—C49—H49C	109.5
C24—C25—N28	122.3 (5)	H49A—C49—O50	109.5
C26—C25—N28	120.9 (5)	H49B—C49—H49C	109.5
C25—C26—H26	119.3	H49B—C49—O50	109.5
C25—C26—C27	121.4 (5)	H49C—C49—O50	109.5
H26—C26—C27	119.3	C49—O50—H50	109.5
C22—C27—C26	120.7 (6)

C5—N1—C2—H2	−180.0	C24—C25—C26—H26	−178.9
C5—N1—C2—N3	0.0 (8)	C24—C25—C26—C27	1.1 (9)
C6—N1—C2—H2	2.8	N28—C25—C26—H26	6.2
C6—N1—C2—N3	−177.2 (6)	N28—C25—C26—C27	−173.9 (5)
C2—N1—C5—C4	0.5 (8)	C24—C25—N28—C29	21.7 (8)
C2—N1—C5—H5	−179.5	C24—C25—N28—C33	157.2 (6)
C6—N1—C5—C4	177.8 (6)	C26—C25—N28—C29	−163.6 (5)
C6—N1—C5—H5	−2.2	C26—C25—N28—C33	−28.2 (8)
C2—N1—C6—H6A	−34.6	C25—C26—C27—C22	−0.2 (9)
C2—N1—C6—H6B	−151.5	C25—C26—C27—H27	179.8
C2—N1—C6—C7	87.0 (8)	H26—C26—C27—C22	179.8
C5—N1—C6—H6A	148.7	H26—C26—C27—H27	−0.2
C5—N1—C6—H6B	31.8	C25—N28—C29—H29A	71.4
C5—N1—C6—C7	−89.8 (7)	C25—N28—C29—H29B	−46.7
N1—C2—N3—C4	−0.6 (8)	C25—N28—C29—C30	−167.7 (5)
H2—C2—N3—C4	179.4	C33—N28—C29—H29A	−66.3
C2—N3—C4—H4	−179.1	C33—N28—C29—H29B	175.6
C2—N3—C4—C5	0.9 (9)	C33—N28—C29—C30	54.7 (7)
N3—C4—C5—N1	−0.9 (8)	C25—N28—C33—C32	167.3 (5)
N3—C4—C5—H5	179.1	C25—N28—C33—H33A	46.4
H4—C4—C5—N1	179.1	C25—N28—C33—H33B	−71.8
H4—C4—C5—H5	−0.9	C29—N28—C33—C32	−55.4 (6)
N1—C6—C7—O8	−51.1 (6)	C29—N28—C33—H33A	−176.3
N1—C6—C7—O11	64.5 (6)	C29—N28—C33—H33B	65.5
N1—C6—C7—C12	−174.3 (5)	N28—C29—C30—H30A	66.9
H6A—C6—C7—O8	70.4	N28—C29—C30—H30B	−174.8
H6A—C6—C7—O11	−174.0	N28—C29—C30—N31	−54.0 (7)
H6A—C6—C7—C12	−52.7	H29A—C29—C30—H30A	−172.2
H6B—C6—C7—O8	−172.7	H29A—C29—C30—H30B	−53.9
H6B—C6—C7—O11	−57.0	H29A—C29—C30—N31	67.0
H6B—C6—C7—C12	64.2	H29B—C29—C30—H30A	−54.0
C6—C7—O8—C9	125.7 (5)	H29B—C29—C30—H30B	64.3
O11—C7—O8—C9	8.4 (5)	H29B—C29—C30—N31	−174.9
C12—C7—O8—C9	−112.7 (5)	C29—C30—N31—C32	55.6 (7)
C6—C7—O11—C10	−148.3 (5)	C29—C30—N31—C34	−115.8 (6)
O8—C7—O11—C10	−29.0 (5)	H30A—C30—N31—C32	−65.2
C12—C7—O11—C10	92.1 (5)	H30A—C30—N31—C34	123.4
C6—C7—C12—C13	76.7 (6)	H30B—C30—N31—C32	176.4
C6—C7—C12—C17	−97.8 (6)	H30B—C30—N31—C34	5.0
O8—C7—C12—C13	−46.3 (7)	C30—N31—C32—H32A	−177.4
O8—C7—C12—C17	139.2 (5)	C30—N31—C32—H32B	64.3
O11—C7—C12—C13	−164.0 (5)	C30—N31—C32—C33	−56.5 (7)
O11—C7—C12—C17	21.5 (7)	C34—N31—C32—H32A	−6.9
C7—O8—C9—H9	132.9	C34—N31—C32—H32B	−125.1
C7—O8—C9—C10	14.2 (6)	C34—N31—C32—C33	114.0 (6)
C7—O8—C9—C20	−106.7 (5)	C30—N31—C34—O35	−1.0 (9)
O8—C9—C10—H10A	88.0	C30—N31—C34—C36	176.0 (5)
O8—C9—C10—H10B	−149.9	C32—N31—C34—O35	−170.9 (6)
O8—C9—C10—O11	−31.0 (6)	C32—N31—C34—C36	6.2 (9)
H9—C9—C10—H10A	−30.6	N31—C32—C33—N28	56.1 (6)
H9—C9—C10—H10B	91.5	N31—C32—C33—H33A	177.0
H9—C9—C10—O11	−149.6	N31—C32—C33—H33B	−64.8
C20—C9—C10—H10A	−156.5	H32A—C32—C33—N28	176.9
C20—C9—C10—H10B	−34.4	H32A—C32—C33—H33A	−62.2
C20—C9—C10—O11	84.5 (6)	H32A—C32—C33—H33B	56.0
O8—C9—C20—H20A	−44.2	H32B—C32—C33—N28	−64.8
O8—C9—C20—H20B	74.4	H32B—C32—C33—H33A	56.1
O8—C9—C20—O21	−164.9 (4)	H32B—C32—C33—H33B	174.3
H9—C9—C20—H20A	76.3	N31—C34—C36—O37	48.0 (7)
H9—C9—C20—H20B	−165.2	N31—C34—C36—C39	−72.1 (6)
H9—C9—C20—O21	−44.5	N31—C34—C36—C45	169.4 (5)
C10—C9—C20—H20A	−157.9	O35—C34—C36—O37	−134.9 (5)
C10—C9—C20—H20B	−39.3	O35—C34—C36—C39	105.0 (6)
C10—C9—C20—O21	81.4 (6)	O35—C34—C36—C45	−13.4 (7)
C9—C10—O11—C7	37.2 (6)	C34—C36—O37—C38	47.4 (6)
H10A—C10—O11—C7	−81.7	C39—C36—O37—C38	168.1 (5)
H10B—C10—O11—C7	156.2	C45—C36—O37—C38	−75.8 (6)
C7—C12—C13—C14	−176.6 (5)	C34—C36—C39—C40	−41.6 (7)
C7—C12—C13—Cl18	3.5 (7)	C34—C36—C39—C44	136.4 (6)
C17—C12—C13—C14	−2.0 (8)	O37—C36—C39—C40	−165.4 (5)
C17—C12—C13—Cl18	178.1 (4)	O37—C36—C39—C44	12.6 (7)
C7—C12—C17—C16	175.9 (6)	C45—C36—C39—C40	78.7 (6)
C7—C12—C17—H17	−4.1	C45—C36—C39—C44	−103.3 (6)
C13—C12—C17—C16	1.2 (9)	C34—C36—C45—F46	68.8 (6)
C13—C12—C17—H17	−178.8	C34—C36—C45—F47	−171.8 (5)
C12—C13—C14—H14	−178.8	C34—C36—C45—F48	−54.7 (7)
C12—C13—C14—C15	1.2 (9)	O37—C36—C45—F46	−166.3 (5)
Cl18—C13—C14—H14	1.2	O37—C36—C45—F47	−46.9 (6)
Cl18—C13—C14—C15	−178.8 (5)	O37—C36—C45—F48	70.2 (6)
C13—C14—C15—C16	0.3 (9)	C39—C36—C45—F46	−50.3 (6)
C13—C14—C15—Cl19	179.2 (4)	C39—C36—C45—F47	69.2 (6)
H14—C14—C15—C16	−179.7	C39—C36—C45—F48	−173.7 (5)
H14—C14—C15—Cl19	−0.8	C36—O37—C38—H38A	−49.7
C14—C15—C16—H16	178.9	C36—O37—C38—H38B	−169.6
C14—C15—C16—C17	−1 (1)	C36—O37—C38—H38C	70.4
Cl19—C15—C16—H16	0.1	C36—C39—C40—H40	−0.8
Cl19—C15—C16—C17	−179.9 (5)	C36—C39—C40—C41	179.2 (6)
C15—C16—C17—C12	0 (1)	C44—C39—C40—H40	−178.9
C15—C16—C17—H17	−179.7	C44—C39—C40—C41	1.1 (9)
H16—C16—C17—C12	−179.7	C36—C39—C44—C43	−177.8 (6)
H16—C16—C17—H17	0.3	C36—C39—C44—H44	2.2
C9—C20—O21—C22	167.0 (5)	C40—C39—C44—C43	0.3 (9)
H20A—C20—O21—C22	46.3	C40—C39—C44—H44	−179.7
H20B—C20—O21—C22	−72.3	C39—C40—C41—H41	177.3
C20—O21—C22—C23	19.8 (8)	C39—C40—C41—C42	−2 (1)
C20—O21—C22—C27	−158.9 (5)	H40—C40—C41—H41	−2.7
O21—C22—C23—H23	0.5	H40—C40—C41—C42	177.4
O21—C22—C23—C24	−179.5 (6)	C40—C41—C42—H42	−177.2
C27—C22—C23—H23	179.2	C40—C41—C42—C43	3 (1)
C27—C22—C23—C24	0 (1)	H41—C41—C42—H42	2.8
O21—C22—C27—C26	178.8 (5)	H41—C41—C42—C43	−177.2
O21—C22—C27—H27	−1.2	C41—C42—C43—H43	178.6
C23—C22—C27—C26	0.0 (9)	C41—C42—C43—C44	0 (1)
C23—C22—C27—H27	−180.0	H42—C42—C43—H43	−1.4
C22—C23—C24—H24	−178.1	H42—C42—C43—C44	178.6
C22—C23—C24—C25	2 (1)	C42—C43—C44—C39	0 (1)
H23—C23—C24—H24	1.9	C42—C43—C44—H44	179.9
H23—C23—C24—C25	−178.1	H43—C43—C44—C39	179.9
C23—C24—C25—C26	−1.9 (9)	H43—C43—C44—H44	−0.1
C23—C24—C25—N28	172.9 (6)	H49A—C49—O50—H50	168.2
H24—C24—C25—C26	178.1	H49B—C49—O50—H50	48.2
H24—C24—C25—N28	−7.1	H49C—C49—O50—H50	−71.8

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O50—H50···N3	0.82	2.05	2.832 (9)	158

Experimental details

Crystal data
Chemical formula	C₃₄H₃₃Cl₂F₃N₄O₅·CH₄O
M_r	737.59
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	293
a, b, c (Å)	8.389 (1), 14.755 (1), 14.473 (2)
β (°)	100.47 (1)
V (Å³)	1761.6 (3)
Z	2
Radiation type	Cu Kα
µ (mm⁻¹)	2.23
Crystal size (mm)	0.44 × 0.08 × 0.06

Data collection
Diffractometer	Siemens P4 four-circle diffractometer
Absorption correction	ψ scan XEMP (Siemens, 1989)
T_min, T_max	0.560, 0.875
No. of measured, independent and observed [F² > 2σ(F²)] reflections	6518, 5861, 3978
R_int	0.038
(sin θ/λ)_max (Å⁻¹)	0.605

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.061, 0.186, 1.07
No. of reflections	5861
No. of parameters	455
No. of restraints	?
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.28, −0.31
Absolute structure	Flack (1983), 2616 Friedel pairs
Absolute structure parameter	−0.01 (2)

Computer programs: XSCANS (Siemens, 1996), XSCANS, SIR92 (Altomare et al., 1994), SHELXL97 (Sheldrick, 1997), DIAMOND (Bergerhoff, 1996), PARST (Nardelli, 1983).

Selected torsion angles (º) top

C2—N1—C6—C7	87.0 (8)	C9—C20—O21—C22	167.0 (5)
N1—C6—C7—O8	−51.1 (6)	C20—O21—C22—C23	19.8 (8)
N1—C6—C7—O11	64.5 (6)	C23—C24—C25—N28	172.9 (6)
N1—C6—C7—C12	−174.3 (5)	C24—C25—N28—C29	21.7 (8)
C6—C7—O8—C9	125.7 (5)	C25—N28—C29—C30	−167.7 (5)
O11—C7—O8—C9	8.4 (5)	C29—C30—N31—C34	−115.8 (6)
O8—C7—O11—C10	−29.0 (5)	C30—N31—C34—C36	176.0 (5)
C6—C7—C12—C13	76.7 (6)	N31—C34—C36—O37	48.0 (7)
C7—O8—C9—C10	14.2 (6)	N31—C34—C36—C39	−72.1 (6)
C7—O8—C9—C20	−106.7 (5)	N31—C34—C36—C45	169.4 (5)
O8—C9—C10—O11	−31.0 (6)	O35—C34—C36—O37	−134.9 (5)
O8—C9—C20—O21	−164.9 (4)	C34—C36—C39—C40	−41.6 (7)
C9—C10—O11—C7	37.2 (6)