Ezetimibe anhydrate, determined from laboratory powder diffraction data

Ezetimibe {systematic name: (3R,4S)-1-(4-fluoro­phen­yl)-3-[(3S)-3-(4-fluoro­phen­yl)-3-hy­droxy­prop­yl]-4-(4-hy­droxy­phen­yl)azetidin-2-one}, C₂₄H₂₁F₂NO₃, is used to lower cholesterol levels by inhibiting cholesterol resorption in the human intestine. The crystal structure of ezetimibe anhydrate was solved from laboratory powder diffraction data by means of real-space methods using the program DASH [David et al. (2006). J. Appl. Cryst. 39, 910-915]. Subsequent Rietveld refinement with TOPAS Academic [Coelho (2007). TOPAS Academic User Manual. Version 4.1. Coelho Software, Brisbane, Australia] led to a final R_wp value of 8.19% at 1.75 Å resolution. The compound crystallizes in the space group P2₁2₁2₁ with one mol­ecule in the asymmetric unit. The mol­ecules are closely packed and two inter­molecular hydrogen bonds form an extended hydrogen-bond architecture.

Computing details

Data collection: Stoe WINXPOW (Stoe & Cie, 1988); cell refinement: TOPAS Academic (Coelho, 2007); data reduction: DASH (David et al., 2006); program(s) used to solve structure: DASH (David et al., 2006); program(s) used to refine structure: TOPAS Academic (Coelho, 2007); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)- 3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one

Crystal data

C24H21F2NO3	F(000) = 856
Mr = 409.42	Dx = 1.347 Mg m^−3
Orthorhombic, P212121	Cu Kα1 radiation, λ = 1.5406 Å
Hall symbol: P 2ac 2ab	µ = 0.84 mm^−1
a = 5.94606 (19) Å	T = 293 K
b = 15.8898 (5) Å	Particle morphology: no specific habit
c = 21.3765 (6) Å	white
V = 2019.69 (11) Å^3	cylinder, 10 × 0.7 mm
Z = 4	Specimen preparation: Prepared at 293 K

Data collection

Stoe Stadi-P diffractometer with linear position-sensitive detector	Data collection mode: transmission
Radiation source: sealed X-ray tube	Scan method: step
Primary focussing, Ge 111 monochromator	2θmin = 3°, 2θmax = 69.99°, 2θstep = 0.01°
Specimen mounting: glass capillary

Refinement

Refinement on Inet	196 parameters
Least-squares matrix: full with fixed elements per cycle	208 restraints
Rp = 0.079	0 constraints
Rwp = 0.082	All H-atom parameters refined
Rexp = 0.071	Weighting scheme based on measured s.u.'s w = 1/σ[Yobs)^2
RBragg = 1.094	(Δ/σ)max = 0.001
6700 data points	Background function: Bayesian high-pass filter with 20 terms
Excluded region(s): none	Preferred orientation correction: none
Profile function: modified Thompson-Cox-Hastings pseudo-Voigt (Young, 1993)

Special details

Experimental. specimen was rotated

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N1	0.8376 (7)	0.7622 (3)	0.78693 (17)	0.056 (1)
C11	0.8616 (6)	0.7090 (2)	0.73652 (14)	0.056 (1)
C12	0.6960 (6)	0.7035 (2)	0.69024 (16)	0.056 (1)
H12	0.565 (2)	0.7401 (10)	0.6945 (6)	0.067 (2)
C13	0.7249 (6)	0.6467 (2)	0.63929 (14)	0.056 (1)
H13	0.626 (2)	0.6396 (8)	0.6071 (5)	0.067 (2)
C14	0.9080 (6)	0.6006 (2)	0.63697 (14)	0.056 (1)
F14	0.9388 (7)	0.5468 (2)	0.59029 (19)	0.087 (3)
C15	1.0698 (6)	0.6045 (2)	0.68028 (16)	0.056 (1)
H15	1.197 (2)	0.5687 (9)	0.6750 (6)	0.067 (2)
C16	1.0500 (6)	0.6600 (2)	0.73206 (14)	0.056 (1)
H16	1.154 (2)	0.6641 (10)	0.7616 (6)	0.067 (2)
C2	0.9265 (8)	0.7650 (3)	0.8447 (2)	0.056 (1)
O2	1.0908 (9)	0.7290 (4)	0.8662 (2)	0.056 (1)
C3	0.7580 (7)	0.8320 (3)	0.86934 (17)	0.056 (1)
H3	0.816 (2)	0.8915 (9)	0.8726 (6)	0.067 (2)
C31	0.6498 (6)	0.8061 (2)	0.93088 (18)	0.056 (1)
H31b	0.769 (3)	0.7934 (9)	0.9600 (7)	0.067 (2)
H31a	0.565 (3)	0.7570 (8)	0.9241 (5)	0.067 (2)
C32	0.5114 (6)	0.8750 (2)	0.95722 (17)	0.056 (1)
H32a	0.442 (2)	0.9055 (8)	0.9234 (6)	0.067 (2)
H32b	0.402 (3)	0.8518 (8)	0.9834 (7)	0.067 (2)
C33	0.6517 (6)	0.9325 (2)	0.99593 (16)	0.056 (1)
H33a	0.789 (2)	0.9477 (10)	0.9727 (6)	0.067 (2)
H33b	0.638 (2)	0.8544 (9)	1.0767 (6)	0.067 (2)
C34	0.5467 (6)	1.0118 (2)	1.01939 (15)	0.056 (1)
C35	0.6513 (6)	1.0895 (2)	1.00967 (12)	0.056 (1)
H35	0.793 (2)	1.0912 (9)	0.9856 (6)	0.067 (2)
C36	0.5501 (6)	1.1644 (2)	1.03423 (14)	0.056 (1)
H36	0.613 (3)	1.2194 (8)	1.0287 (6)	0.067 (2)
C37	0.3510 (6)	1.1575 (2)	1.06703 (13)	0.056 (1)
F37	0.2580 (7)	1.2276 (3)	1.09075 (16)	0.087 (3)
C38	0.2490 (5)	1.0826 (2)	1.07628 (15)	0.056 (1)
H38	0.117 (2)	1.0787 (9)	1.0978 (6)	0.067 (2)
C39	0.3468 (6)	1.0104 (2)	1.05259 (14)	0.056 (1)
H39	0.273 (2)	0.9611 (9)	1.0596 (5)	0.067 (2)
O33	0.7337 (7)	0.8871 (3)	1.0496 (2)	0.056 (1)
C4	0.6449 (6)	0.8157 (2)	0.80320 (16)	0.056 (1)
H4	0.508 (2)	0.7833 (9)	0.8087 (6)	0.067 (2)
C41	0.6082 (6)	0.8903 (2)	0.76234 (16)	0.056 (1)
C42	0.4144 (6)	0.9347 (2)	0.76716 (16)	0.056 (1)
H42	0.306 (2)	0.9188 (9)	0.7953 (6)	0.067 (2)
C43	0.3687 (5)	1.0031 (2)	0.73212 (15)	0.056 (1)
H43	0.242 (3)	1.0287 (9)	0.7376 (6)	0.067 (2)
C44	0.5156 (7)	1.0332 (2)	0.68926 (16)	0.056 (1)
H44	0.511 (6)	1.1066 (8)	0.6092 (6)	0.067 (2)
O44	0.4729 (9)	1.1015 (3)	0.65419 (17)	0.056 (1)
H45	0.807 (3)	1.0136 (9)	0.6529 (6)	0.067 (2)
C45	0.7119 (6)	0.9916 (2)	0.68256 (16)	0.056 (1)
C46	0.7626 (6)	0.9189 (2)	0.71895 (15)	0.056 (1)
H46	0.906 (2)	0.8889 (9)	0.7132 (6)	0.067 (2)

Geometric parameters (Å, º)

N1—C11	1.378 (5)	C33—O33	1.439 (6)
N1—C2	1.343 (6)	H33b—O33	0.97 (1)
N1—C4	1.468 (6)	C34—C35	1.398 (5)
C11—C12	1.399 (5)	C34—C39	1.384 (5)
C11—C16	1.367 (5)	C35—H35	0.99 (1)
C12—H12	0.97 (1)	C35—C36	1.434 (5)
C12—C13	1.425 (5)	C36—H36	0.96 (1)
C13—H13	0.91 (1)	C36—C37	1.380 (5)
C13—C14	1.313 (5)	C37—F37	1.343 (5)
C14—F14	1.327 (5)	C37—C38	1.350 (5)
C14—C15	1.337 (5)	C38—H38	0.91 (1)
C15—H15	0.95 (1)	C38—C39	1.383 (5)
C15—C16	1.420 (5)	C39—H39	0.91 (1)
C16—H16	0.89 (1)	C4—H4	0.97 (1)
C2—O2	1.222 (7)	C4—C41	1.488 (5)
C2—C3	1.554 (6)	C41—C42	1.355 (5)
C3—H3	1.01 (1)	C41—C46	1.382 (5)
C3—C31	1.521 (5)	C42—H42	0.92 (1)
C3—C4	1.587 (5)	C42—C43	1.347 (5)
C31—H31b	0.96 (1)	C43—H43	0.87 (2)
C31—H31a	0.94 (1)	C43—C44	1.354 (5)
C31—C32	1.481 (5)	C44—O44	1.343 (5)
C32—H32a	0.97 (1)	C44—C45	1.349 (5)
C32—H32b	0.93 (1)	H44—O44	0.99 (1)
C32—C33	1.489 (5)	H45—C45	0.92 (1)
C33—H33a	0.99 (1)	C45—C46	1.426 (5)
C33—C34	1.493 (5)	C46—H46	0.98 (1)
C11—N1—C2	134.3 (4)	H33a—C33—O33	104.1 (9)
C11—N1—C4	128.4 (3)	C34—C33—O33	107.3 (3)
C2—N1—C4	94.0 (3)	C33—C34—C35	120.6 (3)
N1—C11—C12	121.2 (3)	C33—C34—C39	121.2 (3)
N1—C11—C16	119.3 (3)	C35—C34—C39	118.2 (3)
C12—C11—C16	119.5 (3)	C34—C35—H35	118.8 (9)
C11—C12—H12	117.2 (9)	C34—C35—C36	119.5 (3)
C11—C12—C13	119.7 (3)	H35—C35—C36	121.7 (9)
H12—C12—C13	123.1 (9)	C35—C36—H36	123.3 (9)
C12—C13—H13	125.1 (8)	C35—C36—C37	118.7 (3)
C12—C13—C14	118.9 (3)	H36—C36—C37	118.0 (9)
H13—C13—C14	116.0 (8)	C36—C37—F37	118.6 (3)
C13—C14—F14	120.2 (3)	C36—C37—C38	122.0 (3)
C13—C14—C15	123.0 (3)	F37—C37—C38	119.4 (3)
F14—C14—C15	116.9 (3)	C37—C38—H38	121.4 (9)
C14—C15—H15	117.3 (9)	C37—C38—C39	119.3 (3)
C14—C15—C16	120.6 (3)	H38—C38—C39	119.4 (9)
H15—C15—C16	122.0 (9)	C34—C39—C38	122.4 (3)
C11—C16—C15	118.4 (3)	C34—C39—H39	120.7 (9)
C11—C16—H16	119 (1)	C38—C39—H39	116.9 (9)
C15—C16—H16	123 (1)	C33—O33—H33b	123.2 (9)
N1—C2—O2	130.2 (5)	N1—C4—C3	88.6 (3)
N1—C2—C3	94.6 (4)	N1—C4—H4	112.1 (8)
O2—C2—C3	135.1 (5)	N1—C4—C41	115.9 (3)
C2—C3—H3	116.4 (8)	C3—C4—H4	109.5 (8)
C2—C3—C31	112.4 (3)	C3—C4—C41	117.1 (3)
C2—C3—C4	81.9 (3)	H4—C4—C41	111.8 (8)
H3—C3—C31	109.8 (8)	C4—C41—C42	119.7 (3)
H3—C3—C4	111.0 (8)	C4—C41—C46	123.9 (3)
C31—C3—C4	123.2 (3)	C42—C41—C46	116.4 (3)
C3—C31—H31b	107.7 (9)	C41—C42—H42	120.3 (9)
C3—C31—H31a	108.6 (9)	C41—C42—C43	123.3 (3)
C3—C31—C32	111.3 (3)	H42—C42—C43	116.4 (9)
H31b—C31—H31a	109 (1)	C42—C43—H43	119 (1)
H31b—C31—C32	108.5 (9)	C42—C43—C44	122.1 (3)
H31a—C31—C32	111.8 (9)	H43—C43—C44	119 (1)
C31—C32—H32a	109.0 (8)	C43—C44—O44	122.8 (4)
C31—C32—H32b	108.9 (9)	C43—C44—C45	117.2 (3)
C31—C32—C33	110.7 (3)	O44—C44—C45	120.0 (4)
H32a—C32—H32b	110 (1)	C44—O44—H44	124 (1)
H32a—C32—C33	110.5 (8)	C44—C45—H45	114.9 (9)
H32b—C32—C33	107.4 (9)	C44—C45—C46	121.5 (3)
C32—C33—H33a	109.5 (9)	H45—C45—C46	123.6 (9)
C32—C33—C34	118.1 (3)	C41—C46—C45	119.5 (3)
C32—C33—O33	108.9 (3)	C41—C46—H46	120.0 (8)
H33a—C33—C34	108.1 (9)	C45—C46—H46	120.5 (8)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O44—H44···O33^i	0.99 (1)	1.99 (3)	2.842 (6)	143 (2)
O33—H33b···O2^ii	0.97 (1)	1.82 (1)	2.715 (7)	152 (1)

Symmetry codes: (i) −x+3/2, −y+2, z−1/2; (ii) x−1/2, −y+3/2, −z+2.