Ezetimibe monohydrate

Ezetimibe monohydrate or 1-(4-fluoro­phenyl)-3(R)-[3-(4-fluoro­phenyl)-3(S)-hydroxy­propyl]-4(S)-(4-hydroxy­phenyl)azetidin-2-one monohydrate, C₂₄H₂₁F₂NO₃·H₂O, belongs to a class of agents that inhibit cholesterol absorption in the intestine. The solvent water mol­ecule present in the structure is involved in several hydrogen bonds.

Key indicators

• Single-crystal X-ray study
• T = 273 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.041
• wR factor = 0.090
• Data-to-parameter ratio = 7.5

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT089_ALERT_3_C Poor Data / Parameter Ratio (Zmax .LT. 18) .....       7.48
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for        C16
PLAT417_ALERT_2_C Short Inter D-H..H-D       H1W    ..  H2O     ..       2.11 Ang.
PLAT480_ALERT_4_C Long H...A H-Bond Reported H23    ..  CG2     ..       2.95 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           25.00
           From the CIF: _reflns_number_total               2215
           Count of symmetry unique reflns         2215
           Completeness (_total/calc)            100.00%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no

   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

   0 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
   2 ALERT type 4 Improvement, methodology, query or suggestion

---

Computing details

Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC (Sheldrick, 1990); software used to prepare material for publication: SHELXL97.

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

Crystal data

C24H21F2NO3·H2O	F(000) = 896
Mr = 427.43	Dx = 1.317 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 4486 reflections
a = 6.2396 (4) Å	θ = 2.3–21.9°
b = 15.4657 (10) Å	µ = 0.10 mm^−1
c = 22.3320 (14) Å	T = 273 K
V = 2155.0 (2) Å^3	Needle, colourless
Z = 4	0.25 × 0.11 × 0.08 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer	2036 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.032
Graphite monochromator	θmax = 25.0°, θmin = 1.6°
ω scans	h = −7→7
15753 measured reflections	k = −18→18
2215 independent reflections	l = −26→26

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.041	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.090	H atoms treated by a mixture of independent and constrained refinement
S = 1.17	w = 1/[σ^2(Fo^2) + (0.0342P)^2 + 0.4556P] where P = (Fo^2 + 2Fc^2)/3
2215 reflections	(Δ/σ)max < 0.001
296 parameters	Δρmax = 0.13 e Å^−3
0 restraints	Δρmin = −0.14 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

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

	x	y	z	Uiso*/Ueq
F1	0.4154 (4)	0.93015 (14)	0.41498 (9)	0.0946 (7)
F2	−0.3406 (5)	0.28513 (15)	−0.08429 (11)	0.1171 (10)
O1	0.6896 (3)	0.69887 (13)	0.17754 (9)	0.0554 (5)
O2	−0.0850 (4)	0.34138 (14)	0.34856 (12)	0.0696 (7)
H2O	0.007 (6)	0.324 (2)	0.3750 (15)	0.079 (13)*
O3	0.0161 (4)	0.64921 (13)	−0.00824 (9)	0.0562 (6)
H30	0.095 (6)	0.680 (2)	−0.0300 (15)	0.073 (12)*
N1	0.3861 (4)	0.68370 (13)	0.23856 (10)	0.0425 (5)
C1	0.5156 (5)	0.66898 (17)	0.19139 (12)	0.0432 (7)
C2	0.2085 (4)	0.62854 (16)	0.21589 (12)	0.0438 (6)
H2	0.0872	0.6636	0.2022	0.053*
C3	0.3939 (5)	0.74578 (16)	0.28494 (12)	0.0420 (6)
C4	0.2209 (5)	0.75773 (18)	0.32182 (13)	0.0530 (7)
H4	0.0988	0.7239	0.3172	0.064*
C5	0.2285 (6)	0.82017 (19)	0.36581 (14)	0.0609 (8)
H5	0.1118	0.8291	0.3910	0.073*
C6	0.4087 (6)	0.86832 (19)	0.37184 (14)	0.0611 (8)
C7	0.5830 (6)	0.85733 (19)	0.33626 (14)	0.0582 (8)
H7	0.7045	0.8913	0.3417	0.070*
C8	0.5776 (5)	0.79499 (18)	0.29187 (13)	0.0503 (7)
H8	0.6954	0.7863	0.2671	0.060*
C9	0.3627 (5)	0.60588 (16)	0.16307 (11)	0.0452 (7)
H9	0.4163	0.5466	0.1670	0.054*
C10	0.3010 (5)	0.62497 (18)	0.09876 (12)	0.0514 (7)
H10A	0.4291	0.6238	0.0742	0.062*
H10B	0.2417	0.6829	0.0966	0.062*
C11	0.1390 (5)	0.56160 (17)	0.07324 (12)	0.0490 (7)
H11A	0.1826	0.5032	0.0834	0.059*
H11B	0.0006	0.5721	0.0916	0.059*
C12	0.1163 (5)	0.56862 (17)	0.00581 (11)	0.0456 (7)
H12	0.2602	0.5686	−0.0118	0.055*
C13	−0.0074 (5)	0.49389 (18)	−0.02054 (12)	0.0461 (7)
C14	0.0739 (6)	0.4115 (2)	−0.01589 (15)	0.0654 (9)
H14	0.2064	0.4033	0.0023	0.078*
C15	−0.0360 (7)	0.3409 (2)	−0.03753 (17)	0.0802 (11)
H15	0.0202	0.2854	−0.0341	0.096*
C16	−0.2290 (7)	0.3547 (2)	−0.06402 (16)	0.0736 (11)
C17	−0.3139 (7)	0.4343 (3)	−0.07041 (17)	0.0803 (11)
H17	−0.4455	0.4418	−0.0893	0.096*
C18	−0.2023 (6)	0.5044 (2)	−0.04850 (14)	0.0645 (9)
H18	−0.2595	0.5596	−0.0527	0.077*
C19	0.1356 (4)	0.55548 (16)	0.25502 (12)	0.0430 (6)
C20	0.2629 (5)	0.51770 (18)	0.29791 (12)	0.0503 (7)
H20	0.3974	0.5410	0.3058	0.060*
C21	0.1954 (5)	0.44592 (18)	0.32949 (13)	0.0526 (7)
H21	0.2849	0.4210	0.3580	0.063*
C22	−0.0051 (5)	0.41093 (17)	0.31885 (13)	0.0505 (7)
C23	−0.1333 (5)	0.44836 (18)	0.27613 (14)	0.0580 (8)
H23	−0.2680	0.4253	0.2682	0.070*
C24	−0.0639 (5)	0.51994 (18)	0.24486 (14)	0.0525 (8)
H24	−0.1533	0.5448	0.2163	0.063*
O1W	0.1865 (5)	0.25888 (15)	0.43051 (12)	0.0637 (6)
H1W	0.233 (6)	0.231 (2)	0.4024 (15)	0.064 (11)*
H2W	0.134 (8)	0.221 (3)	0.4566 (19)	0.113 (17)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.1166 (18)	0.0840 (13)	0.0831 (14)	−0.0314 (14)	0.0207 (14)	−0.0432 (11)
F2	0.136 (2)	0.0943 (16)	0.1207 (19)	−0.0486 (17)	−0.0271 (19)	−0.0296 (15)
O1	0.0445 (12)	0.0679 (13)	0.0537 (12)	−0.0073 (11)	0.0014 (10)	−0.0009 (10)
O2	0.0737 (16)	0.0503 (13)	0.0847 (17)	−0.0069 (13)	0.0024 (15)	0.0179 (12)
O3	0.0701 (15)	0.0476 (12)	0.0509 (11)	−0.0013 (12)	−0.0001 (12)	0.0103 (10)
N1	0.0421 (12)	0.0377 (11)	0.0476 (12)	−0.0044 (11)	−0.0003 (11)	−0.0040 (10)
C1	0.0431 (16)	0.0411 (15)	0.0454 (15)	0.0039 (13)	−0.0066 (14)	0.0040 (12)
C2	0.0425 (15)	0.0366 (14)	0.0522 (15)	−0.0010 (13)	−0.0115 (14)	−0.0008 (12)
C3	0.0486 (15)	0.0326 (13)	0.0447 (14)	−0.0036 (13)	−0.0045 (14)	0.0039 (11)
C4	0.0550 (18)	0.0468 (16)	0.0573 (17)	−0.0141 (15)	0.0084 (16)	−0.0021 (14)
C5	0.072 (2)	0.0542 (17)	0.0569 (17)	−0.0104 (17)	0.0199 (18)	−0.0096 (15)
C6	0.084 (2)	0.0466 (16)	0.0530 (17)	−0.0124 (18)	0.0051 (19)	−0.0097 (14)
C7	0.061 (2)	0.0502 (17)	0.0634 (19)	−0.0165 (16)	−0.0056 (18)	−0.0096 (15)
C8	0.0467 (17)	0.0481 (16)	0.0560 (17)	−0.0062 (14)	0.0013 (15)	−0.0014 (14)
C9	0.0520 (17)	0.0365 (13)	0.0471 (14)	0.0038 (13)	−0.0065 (14)	−0.0022 (12)
C10	0.0578 (18)	0.0442 (15)	0.0524 (16)	−0.0039 (15)	−0.0081 (15)	−0.0005 (13)
C11	0.0587 (19)	0.0408 (14)	0.0473 (15)	−0.0040 (15)	−0.0081 (14)	0.0022 (12)
C12	0.0492 (16)	0.0425 (14)	0.0450 (15)	−0.0021 (14)	−0.0003 (13)	0.0022 (12)
C13	0.0531 (17)	0.0493 (16)	0.0360 (13)	−0.0037 (15)	0.0001 (14)	0.0005 (12)
C14	0.063 (2)	0.059 (2)	0.074 (2)	0.0039 (18)	−0.0133 (19)	−0.0154 (17)
C15	0.095 (3)	0.056 (2)	0.090 (3)	0.001 (2)	−0.012 (2)	−0.021 (2)
C16	0.089 (3)	0.068 (2)	0.064 (2)	−0.027 (2)	−0.010 (2)	−0.0152 (18)
C17	0.072 (2)	0.089 (3)	0.079 (2)	−0.023 (2)	−0.030 (2)	0.005 (2)
C18	0.067 (2)	0.0620 (19)	0.065 (2)	−0.0032 (19)	−0.0192 (18)	0.0085 (16)
C19	0.0448 (16)	0.0364 (14)	0.0478 (15)	0.0018 (13)	−0.0030 (13)	−0.0061 (12)
C20	0.0436 (16)	0.0519 (17)	0.0555 (17)	−0.0055 (14)	−0.0090 (14)	−0.0035 (14)
C21	0.0581 (18)	0.0497 (16)	0.0500 (16)	0.0032 (15)	−0.0084 (15)	0.0070 (14)
C22	0.0582 (19)	0.0340 (14)	0.0595 (17)	0.0001 (14)	0.0053 (16)	−0.0025 (13)
C23	0.0453 (17)	0.0468 (16)	0.082 (2)	−0.0087 (15)	−0.0091 (17)	0.0004 (16)
C24	0.0475 (17)	0.0426 (15)	0.0675 (19)	−0.0032 (14)	−0.0170 (15)	0.0070 (14)
O1W	0.0799 (17)	0.0572 (14)	0.0542 (13)	−0.0110 (13)	0.0054 (13)	−0.0108 (12)

Geometric parameters (Å, º)

F1—C6	1.358 (3)	C10—H10B	0.9700
F2—C16	1.359 (4)	C11—C12	1.516 (4)
O1—C1	1.220 (3)	C11—H11A	0.9700
O2—C22	1.358 (3)	C11—H11B	0.9700
O2—H2O	0.87 (4)	C12—C13	1.509 (4)
O3—C12	1.429 (3)	C12—H12	0.9800
O3—H30	0.84 (4)	C13—C14	1.375 (4)
N1—C1	1.347 (3)	C13—C18	1.377 (4)
N1—C3	1.413 (3)	C14—C15	1.377 (5)
N1—C2	1.487 (3)	C14—H14	0.9300
C1—C9	1.504 (4)	C15—C16	1.358 (6)
C2—C19	1.499 (4)	C15—H15	0.9300
C2—C9	1.562 (4)	C16—C17	1.348 (5)
C2—H2	0.9800	C17—C18	1.379 (5)
C3—C4	1.370 (4)	C17—H17	0.9300
C3—C8	1.385 (4)	C18—H18	0.9300
C4—C5	1.378 (4)	C19—C20	1.375 (4)
C4—H4	0.9300	C19—C24	1.379 (4)
C5—C6	1.355 (5)	C20—C21	1.381 (4)
C5—H5	0.9300	C20—H20	0.9300
C6—C7	1.358 (5)	C21—C22	1.384 (4)
C7—C8	1.383 (4)	C21—H21	0.9300
C7—H7	0.9300	C22—C23	1.373 (4)
C8—H8	0.9300	C23—C24	1.379 (4)
C9—C10	1.516 (4)	C23—H23	0.9300
C9—H9	0.9800	C24—H24	0.9300
C10—C11	1.519 (4)	O1W—H1W	0.82 (3)
C10—H10A	0.9700	O1W—H2W	0.89 (5)
C22—O2—H2O	109 (2)	C12—C11—H11B	109.0
C12—O3—H30	111 (2)	C10—C11—H11B	109.0
C1—N1—C3	131.9 (2)	H11A—C11—H11B	107.8
C1—N1—C2	94.8 (2)	O3—C12—C13	111.0 (2)
C3—N1—C2	131.7 (2)	O3—C12—C11	108.7 (2)
O1—C1—N1	131.9 (3)	C13—C12—C11	112.3 (2)
O1—C1—C9	134.7 (3)	O3—C12—H12	108.2
N1—C1—C9	93.3 (2)	C13—C12—H12	108.2
N1—C2—C19	117.4 (2)	C11—C12—H12	108.2
N1—C2—C9	85.8 (2)	C14—C13—C18	118.0 (3)
C19—C2—C9	117.3 (2)	C14—C13—C12	119.4 (3)
N1—C2—H2	111.4	C18—C13—C12	122.5 (3)
C19—C2—H2	111.4	C13—C14—C15	121.6 (3)
C9—C2—H2	111.4	C13—C14—H14	119.2
C4—C3—C8	120.7 (2)	C15—C14—H14	119.2
C4—C3—N1	120.3 (2)	C16—C15—C14	118.0 (4)
C8—C3—N1	118.9 (3)	C16—C15—H15	121.0
C3—C4—C5	119.7 (3)	C14—C15—H15	121.0
C3—C4—H4	120.1	C17—C16—C15	122.5 (3)
C5—C4—H4	120.1	C17—C16—F2	119.1 (4)
C6—C5—C4	119.0 (3)	C15—C16—F2	118.4 (4)
C6—C5—H5	120.5	C16—C17—C18	118.9 (3)
C4—C5—H5	120.5	C16—C17—H17	120.6
C5—C6—C7	122.5 (3)	C18—C17—H17	120.6
C5—C6—F1	118.9 (3)	C13—C18—C17	120.9 (3)
C7—C6—F1	118.6 (3)	C13—C18—H18	119.5
C6—C7—C8	119.2 (3)	C17—C18—H18	119.5
C6—C7—H7	120.4	C20—C19—C24	117.8 (3)
C8—C7—H7	120.4	C20—C19—C2	123.4 (2)
C7—C8—C3	118.9 (3)	C24—C19—C2	118.6 (2)
C7—C8—H8	120.5	C19—C20—C21	121.4 (3)
C3—C8—H8	120.5	C19—C20—H20	119.3
C1—C9—C10	115.7 (2)	C21—C20—H20	119.3
C1—C9—C2	85.85 (19)	C20—C21—C22	120.2 (3)
C10—C9—C2	121.0 (2)	C20—C21—H21	119.9
C1—C9—H9	110.7	C22—C21—H21	119.9
C10—C9—H9	110.7	O2—C22—C23	117.4 (3)
C2—C9—H9	110.7	O2—C22—C21	123.9 (3)
C9—C10—C11	113.5 (2)	C23—C22—C21	118.8 (3)
C9—C10—H10A	108.9	C22—C23—C24	120.5 (3)
C11—C10—H10A	108.9	C22—C23—H23	119.8
C9—C10—H10B	108.9	C24—C23—H23	119.8
C11—C10—H10B	108.9	C23—C24—C19	121.4 (3)
H10A—C10—H10B	107.7	C23—C24—H24	119.3
C12—C11—C10	112.9 (2)	C19—C24—H24	119.3
C12—C11—H11A	109.0	H1W—O1W—H2W	107 (3)
C10—C11—H11A	109.0
C3—N1—C1—O1	8.4 (5)	C9—C10—C11—C12	−167.1 (3)
C2—N1—C1—O1	174.6 (3)	C10—C11—C12—O3	−68.9 (3)
C3—N1—C1—C9	−170.0 (3)	C10—C11—C12—C13	167.8 (2)
C2—N1—C1—C9	−3.7 (2)	O3—C12—C13—C14	174.7 (3)
C1—N1—C2—C19	122.2 (2)	C11—C12—C13—C14	−63.3 (4)
C3—N1—C2—C19	−71.5 (3)	O3—C12—C13—C18	−6.4 (4)
C1—N1—C2—C9	3.6 (2)	C11—C12—C13—C18	115.6 (3)
C3—N1—C2—C9	169.9 (3)	C18—C13—C14—C15	−1.0 (5)
C1—N1—C3—C4	167.8 (3)	C12—C13—C14—C15	177.9 (3)
C2—N1—C3—C4	6.3 (4)	C13—C14—C15—C16	0.1 (6)
C1—N1—C3—C8	−11.2 (4)	C14—C15—C16—C17	0.9 (6)
C2—N1—C3—C8	−172.7 (3)	C14—C15—C16—F2	−178.6 (3)
C8—C3—C4—C5	0.9 (4)	C15—C16—C17—C18	−0.9 (6)
N1—C3—C4—C5	−178.2 (3)	F2—C16—C17—C18	178.5 (3)
C3—C4—C5—C6	−0.4 (5)	C14—C13—C18—C17	0.9 (5)
C4—C5—C6—C7	−0.2 (5)	C12—C13—C18—C17	−178.0 (3)
C4—C5—C6—F1	179.6 (3)	C16—C17—C18—C13	0.0 (6)
C5—C6—C7—C8	0.3 (5)	N1—C2—C19—C20	−23.9 (4)
F1—C6—C7—C8	−179.5 (3)	C9—C2—C19—C20	76.1 (3)
C6—C7—C8—C3	0.2 (5)	N1—C2—C19—C24	160.9 (2)
C4—C3—C8—C7	−0.8 (4)	C9—C2—C19—C24	−99.1 (3)
N1—C3—C8—C7	178.3 (3)	C24—C19—C20—C21	0.7 (4)
O1—C1—C9—C10	−52.2 (4)	C2—C19—C20—C21	−174.5 (3)
N1—C1—C9—C10	126.1 (3)	C19—C20—C21—C22	−0.7 (4)
O1—C1—C9—C2	−174.7 (3)	C20—C21—C22—O2	−178.9 (3)
N1—C1—C9—C2	3.6 (2)	C20—C21—C22—C23	0.6 (4)
N1—C2—C9—C1	−3.22 (18)	O2—C22—C23—C24	179.0 (3)
C19—C2—C9—C1	−122.0 (2)	C21—C22—C23—C24	−0.6 (4)
N1—C2—C9—C10	−120.8 (2)	C22—C23—C24—C19	0.6 (5)
C19—C2—C9—C10	120.4 (3)	C20—C19—C24—C23	−0.6 (4)
C1—C9—C10—C11	−177.5 (2)	C2—C19—C24—C23	174.9 (3)
C2—C9—C10—C11	−76.2 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2O···O1W	0.87 (4)	1.95 (4)	2.801 (4)	166 (3)
O3—H30···O1W^i	0.84 (4)	1.88 (4)	2.708 (3)	169 (3)
O1W—H1W···O1^ii	0.82 (3)	1.91 (3)	2.698 (3)	161 (3)
O1W—H2W···O3^iii	0.89 (5)	1.85 (5)	2.737 (3)	171 (5)
C2—H2···O1^iv	0.98	2.60	3.521 (3)	157
C5—H5···F2^v	0.93	2.51	3.123 (4)	124
C23—H23···Cg2^vi	0.93	2.95	3.613	129

Symmetry codes: (i) −x+1/2, −y+1, z−1/2; (ii) −x+1, y−1/2, −z+1/2; (iii) −x, y−1/2, −z+1/2; (iv) x−1, y, z; (v) −x−1/2, −y+1, z+1/2; (vi) x+5/2, −y−1/2, −z.