Crystal structure of binimetinib (Form A), C17H15BrF2N4O3, from synchrotron X-ray powder diffraction data and density functional theory

Ducreux, J. guillaume; Kaduk, J.A.; Dosen, A.; Blanton, T.N.

doi:10.1107/S2056989026004718

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 82| Part 6| June 2026| Pages 639-644

https://doi.org/10.1107/S2056989026004718

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Crystal structure of binimetinib (Form A), C₁₇H₁₅BrF₂N₄O₃, from synchrotron X-ray powder diffraction data and density functional theory

Jean guillaume Ducreux,^a James A. Kaduk,^a ^* Anja Dosen ^b and Thomas N. Blanton ^b

^aDepartment of Chemistry, North Central College, 131 S. Loomis, St., Naperville IL, 60540, USA, and ^bICDD, 12 Campus Blvd., Newtown Square PA, 19073, USA
^*Correspondence e-mail: [email protected]

Edited by W. T. A. Harrison, University of Aberdeen, United Kingdom (Received 23 March 2026; accepted 6 May 2026; online 15 May 2026)

The crystal structure of binimetinib Form A [systematic name: 6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide], C₁₇H₁₅BrF₂N₄O₃, has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. It crystallizes in space group P2₁2₁2₁ with one molecule in the asymmetric unit at 298 K. The crystal structure consists of layers of molecules lying parallel to the bc plane. Hydrogen bonds (O/N—H⋯N/O) link the layers via sheets in the ac plane. The commercial sample contains minor impurities of KH₂(PO₄) and Fe_0.33Zr₂(PO₄)₃.

Keywords: powder diffraction; binimetinib; Mektovi; Rietveld refinement; density functional theory.

CCDC references: 2552042; 2552043; 2552044; 2552045

1. Chemical context

Binimetinib, C₁₇H₁₅BrF₂N₄O₃, sold under the brand name Mektovi, is an anti-cancer medication (Tran & Cohen, 2020 ). Administered orally, binimetinib is combined with encorafenib for the treatment of melanoma. Its systematic name (CAS Registry Number 606143-89-9) is 6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide.

This work was carried out as part of a project (Kaduk et al., 2014 ) to determine the crystal structures of large-volume commercial pharmaceuticals, and include high-quality powder diffraction data for them in the Powder Diffraction File (Kabekkodu et al., 2024 ).

2. Structural commentary

The powder pattern obtained in this study is similar enough to the one reported for binimetinib Form A by Chen et al. (2016 ) to conclude that they are the same material (Fig. 1). There are extra peaks in the synchrotron pattern indicating the presence of at least two crystalline impurities, which we have identified as 2.6% KH₂(PO₄) and approximately 0.3% Fe_0.33Zr₂(PO₄)₃. It would be interesting to understand how these phases came to be present in this commercial sample.

Figure 1
Comparison of the background-subtracted synchrotron pattern of binimetinib (black) to those for Form A (green) and Form B (red) reported by Chen et al. (2016

). The patent patterns (measured using Cu Kα radiation) were digitized using UN-SCAN-IT (Silk Scientific, 2013

) and converted to the synchrotron wavelength of 0.819325 (2) Å using JADE Pro (MDI, 2025

). Image generated using JADE Pro (MDI, 2025

The root-mean-square difference of the non-H atoms in the Rietveld-refined and VASP-optimized structures of binimetinib, calculated using the Mercury CSD-Materials/Search/Crystal Packing similarity tool (Macrae et al., 2020 ) is 0.549 Å (Fig. 2). The root-mean-square Cartesian displacement of the non-H atoms in the refined and optimized structures, calculated using the Mercury Calculate/Molecule overlay tool, is 0.392 Å (Fig. 3). The largest differences are in the side chains. The agreements are just outside the normal range for correct structures (van de Streek & Neumann, 2014 ). Since the specimen was almost certainly changing due to exposure to the synchrotron beam, the accuracy of this structure might be lower than usual. The asymmetric unit is illustrated in Fig. 4. The remaining discussion will emphasize the VASP-optimized structure.

Figure 2
Comparison of the Rietveld-refined (colored by atom type) and VASP-optimized (light green) structures of binimetinib using the Mercury CSD-Materials/Search/Crystal Packing Similarity tool. The root-mean-square Cartesian displacement is 0.549 Å. Image generated using Mercury (Macrae et al., 2020

Figure 3
Comparison of the refined structure of binimetinib (red) to the VASP-optimized structure (blue). The comparison was generated using the Mercury Calculate/Molecule Overlay tool; the r.m.s. difference is 0.392 Å. Image generated using Mercury (Macrae et al., 2020

Figure 4
The asymmetric unit of binimetinib, with the atom numbering. The atoms are represented by 50% probability spheroids. Image generated using Mercury (Macrae et al., 2020

All of the bond distances, and most of the bond angles and torsion angles fall within the normal ranges indicated by a Mercury Mogul geometry check (Macrae et al., 2020). The C21—C20—N8 bond angle [126.1°; average = 118.9 (22)°; Z-score = 3.2] is flagged as unusual. Torsion angles involving rotation about the N8—C20 bond are flagged as unusual. They lie on long tails of the distributions of similar torsion angles, so are unusual but not unprecedented. The O4—C26—C27—O5 torsion angle of −62.9° indicates a gauche conformation for the hydroxyethyl side chain and the dihedral angle between the benzimidazole and phenyl ring mean planes is 57.0°.

Quantum chemical geometry optimization of the isolated binimetinib molecule (DFT/B3LYP/6-31G*/water) using Spartan '24 (Wavefunction, 2025 ) indicated that the observed conformation is 6.2 kcal mol⁻¹ higher in energy than the local minimum. The root-mean-square difference is 0.410 Å, and the maximum differences are in the amide group. The global minimum-energy conformation has a similar energy, but is much more compact (severely folded on itself). The molecule is apparently flexible, and intermolecular interactions are important in determining the solid-state conformation.

3. Supramolecular features

The extended structure (Fig. 5) consists of layers lying parallel to the bc plane. Hydrogen bonds (O/N—H⋯N/O) link the layers via sheets in the ac plane. Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2024 ) indicated that the intramolecular energy is dominated by angle distortion terms. The intermolecular energy is dominated by van der Waals attractions, which in this force field based analysis include hydrogen bonds. The hydrogen bonds are better discussed using the results of the DFT calculation.

Figure 5
Crystal structure of binimetinib, viewed down the c axis. Image generated using Mercury (Macrae et al., 2020

Hydrogen bonds (Table 1) are prominent in the structure. The O6—H42⋯N9, N10—H35⋯O5, and N8—H29⋯O5 hydrogen bonds link the molecules into sheets lying parallel to the ac plane. The energies of the N—H⋯O bonds were calculated using the correlation of Wheatley & Kaduk (2019 ). The O6—H42⋯N9 bond generates a graph-set descriptor (Etter, 1990 ; Bernstein et al., 1995 ; Motherwell et al., 2000 ) C₁¹(12) and the N10—H35⋯O5 bond corresponds to graph set C₁¹(4). Several C—H⋯O hydrogen bonds also contribute to the cohesion of the structure. By the Mulliken overlap population criterion, the C17—H30⋯O6 bond is exceptionally strong.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N8—H29⋯O5	1.02	1.90	2.727	136
N10—H35⋯O5ⁱ	1.04	1.67	2.675	161
O6—H42⋯N9ⁱⁱ	1.00	1.81	2.806	176
C17—H30⋯O6ⁱⁱⁱ	1.09	2.18	3.221	158
C18—H32⋯O5ⁱⁱⁱ	1.10	2.53	3.288	125
C26—H38⋯Br1^iv	1.10	2.92	3.841	142
C26—H39⋯Br1ⁱⁱⁱ	1.10	2.78	3.486	122
Symmetry codes: (i) ; (ii) $[x-{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+1]$ ; (iii) $[-x, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ ; (iv) $[-x, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

The volume enclosed by the Hirshfeld surface of binimetinib (Fig. 6; Hirshfeld, 1977 ; Spackman et al., 2021 ) is 443.0 Å³ or 98.1% of 1/4 of the unit-cell volume. The only significant close contacts (red in Fig. 6) involve the hydrogen bonds. The volume/non-hydrogen atom is smaller than usual, at 16.7 Å³, so the packing seems relatively dense.

Figure 6
The Hirshfeld surface of binimetinib. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white. Image generated using CrystalExplorer (Spackman et al., 2021

The Bravais–Friedel–Donnay–Harker (Bravais, 1866 ; Friedel, 1907 ; Donnay & Harker, 1937 ) algorithm suggests that we might expect needle morphology for binimetinib, with [001] as the long axis, as expected from the anisotropy of the lattice parameters. A photomicrograph (Fig. 7) indicates needle morphology. A 2nd-order spherical harmonic model was included for preferred orientation. The texture index was 1.048 (3), indicating that preferred orientation was significant in this rotated capillary specimen.

Figure 7
Optical micrograph of binimetinib. Original magnification = 40×.

4. Database survey

Powder patterns for crystalline Forms A and B of binimetinib are reported in International Patent Application WO 2016/131406 A1 (Chen et al., 2016; Crystal Pharmatech Co. Ltd.), but no crystal structures were reported. The crystal structure of a DMSO adduct of binimetinib has been determined (Buist et al., 2021 ; Johnson Matthey Public Limited Company), and X-ray powder diffraction data are reported. Powder data are also reported for a citric acid adduct. A Raman spectrum for binimetinib free base is reported, but no diffraction data. Amorphous binimetinib is claimed in International Patent Application WO 2021/116901 A1 (Palle et al., 2021 ; Biocon Ltd.). A reduced-cell search in the Cambridge Structural Database ( CSD Conquest Build 2026.1.0; Groom et al., 2016 ) yielded 15 hits for unrelated structures, but no structures for binimetinib or its derivatives.

5. Synthesis and crystallization

Binimetinib is a commercial reagent, purchased from TargetMol (Batch #146079), and was used as-received.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The white powder was packed into a 0.5 mm diameter Kapton capillary, and rotated during the measurement at ∼2 Hz. The powder pattern was measured at 298 (1) K at the Wiggler Low Energy Beamline (Leontowich et al., 2021 ) of the Brockhouse X-ray Diffraction and Scattering Sector of the Canadian Light Source using a wavelength of 0.819325 (2) Å (15.1 keV) from 1.6–75.0° 2θ with a step size of 0.0025° and a collection time of 3 minutes. The high-resolution powder diffraction data were collected using eight Dectris Mythen2 X series 1K linear strip detectors. NIST SRM 660b LaB₆ was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₇H₁₅BrF₂N₄O₃
M_r	441.23
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	298
a, b, c (Å)	23.1607 (11), 16.0073 (11), 4.86578 (17)
V (Å³)	1803.9 (2)
Z	4
Radiation type	Synchrotron, λ = 0.81933 Å
Specimen shape, size (mm)	Cylinder, 0.45 × 0.15

Data collection
Diffractometer	Wiggler Low Energy Beamline, Brockhouse X-ray Diffraction and Scattering Sector, Canadian Light Source
Specimen mounting	Kapton capillary
Data collection mode	Transmission
Scan method	Step
2θ values (°)	2θ_min = −9.008, 2θ_max = 75.047, 2θ_step = 0.003

Refinement
R factors and goodness of fit	R_p = 0.011, R_wp = 0.018, R_exp = 0.001, χ² = 347.375
No. of parameters	113
No. of restraints	72
(Δ/σ)_max	3.163
Computer programs: GSAS-II (Toby & Von Dreele, 2013).

Illuminating a Br-containing specimen with 15 keV X-rays results in severe fluorescent background (and thus eventually low residuals). It would be very surprising if this sample did not exhibit beam damage, as C—Br bonds are known to be prone to photolysis.

The pattern was difficult to index. Visual examination of the raw data indicated several very sharp peaks at high angles, probably indicating an inorganic impurity. Initial indexing using N-TREOR (Altomare et al., 2013 ) yielded a P2₁/c cell with a = 5.36109, b = 23.26552, c = 16.20200 Å, β = 95.864°, V = 2010.3 Å³, and Z = 4. Although the structure could be solved and refined using this cell, the structure was unsatisfactory - both for the residuals (R_wp = 0.0267) and the agreement of observed and calculated peak positions, even considering potential beam damage.

Indexing with DICVOL14 (Louër & Boultif, 2014 ), permitting up to three unindexed peaks, yielded a primitive monoclinic cell with a = 23.2656, b = 16.0153, c = 4.8916 Å, β = 90.420°, V = 1822.57 Å³, and Z = 4. The β angle being close to 90° suggested that we consider the possibility that the cell was orthorhombic. The space-group-interpretation routine of EXPO2014 (Altomare et al., 2013) suggested space group P2₁2₁2₁, which was confirmed by successful solution and refinement of the structure.

The molecular structure of binimetinib was downloaded from PubChem (Kim et al., 2023 ) as Conformer3D_COMPOUND_CID_10288191.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., 2020), and to a Fenske–Hall Z-matrix using OpenBabel (O'Boyle et al., 2011 ). The crystal structure was solved by Monte Carlo simulated annealing techniques as implemented in EXPO2014 (Altomare et al., 2013) using the binimetinib molecule as the fragment, including a bump penalty on the non-H atoms and (001) preferred orientation. For the structure solution, a constant 49,000 counts were subtracted from the raw data, to minimize the effect of the high background. The structure was also solved using parallel tempering techniques as implemented in FOX (Favre-Nicolin & Černý, 2002 ), including (001) preferred orientation. Essentially the same structure was obtained from the two programs, and the FOX solution was adopted for refinement.

Indexing the sharp high-angle peaks using DICVOL14 yielded a primitive tetragonal cell with a = 7.4557, c = 6.9776 Å, and V = 387.87 Å³. A reduced cell search in the Powder Diffraction File yielded several metallic phases, as well as (orthorhombic) KH₂PO₄ (PDF entry 04-016-0040; Baur, 1973 ). Including this phase in the refinement revealed the presence of additional peaks, which are best accounted for by a zirconium phosphate phase such as Fe_0.33Zr₂(PO₄)₃ (PDF entry 04-015-1781; Gobechiya et al., 2004 ), which was included as a third phase.

Rietveld refinement was carried out with GSAS-II (Toby & Von Dreele, 2013 ). Only the 3.3–35.0° portion of the pattern was included in the refinements (d_min = 1.362 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury Mogul Geometry Check (Sykes et al., 2011 ; Bruno et al., 2004 ). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The aromatic rings were restrained to be planar. The restraints contributed 7.5% to the overall χ². The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2024). The U_iso were grouped by chemical similarity. An attempt to refine the Br atom anisotropically yielded a non-positive-definite ellipsoid, and so was abandoned. The peak profiles were described using the generalized microstrain model (Stephens, 1999 ). The background was modeled using a six-term shifted Chebyshev polynomial, with a peak at 11.21° to model the scattering from the Kapton capillary and any amorphous component of the sample.

The final refinement of 113 variables using 12,681 observations and 72 restraints yielded the residual R_wp = 0.01891. The largest peak (1.62 Å from F2) and hole (1.92 Å from O6) in the difference-Fourier map are 0.33 (9) and −0.31 (9) e Å⁻³, respectively. The final Rietveld plot is shown in Fig. 8. The largest features in the normalized error plot are in the positions of some of the strong low-angle peaks, and probably indicate beam damage.

Figure 8
The Rietveld plot for binimetinib. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The vertical scale is logarithmic.

The crystal structure of binimetinib was optimized (fixed experimental unit cell) with density functional theory techniques using VASP (Kresse & Furthmüller, 1996 ) through the MedeA graphical interface (Materials Design, 2024 ). The calculation was carried out on 32 cores of a 144-core (768 Gb memory) HPE Superdome Flex 280 Linux server at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å⁻¹ leading to a 3 × 3 × 1 mesh, and took ∼7.4 h. Single-point density functional theory calculations and population analysis were carried out using CRYSTAL23 (Erba et al., 2023 ) (fixed experimental cell) and population analysis was carried out using CRYSTAL17 (Dovesi et al., 2018 ), using a fixed experimental cell. The basis sets for the H, C, N and O atoms in the calculation were those of Gatti et al. (1994 ), and those for Br and F were from Peintinger et al. (2013 ). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ∼2.1 hr

Supporting information

CCDC references: 2552042; 2552043; 2552044; 2552045

Crystal structure: contains datablocks binimetinib_3_publ, binimetinib_3_overall, binimetinib_3_phase_2, binimetinib_3_phase_1, binimetinib_3_phase_0, binimetinib_3_pwd_0, binimetinib_VASP. DOI: https://doi.org/10.1107/S2056989026004718/hb8206sup1.cif

checkCIF report

Computing details top

(binimetinib_3_phase_2) top

Crystal data top

FeO₂₂P₃Zr₈	β = 125.16°
M_r = 1230.51	V = 980.73 Å³
Monoclinic, P2₁/c	Z = 4
a = 8.8395 Å	D_x = 8.334 Mg m⁻³
b = 8.9359 Å	T = 298 K
c = 15.1869 Å

Refinement top

Weighting scheme based on measured s.u.'s

Preferred orientation correction: March-Dollase correction coef. = 1.000 axis = [0, 0, 1]

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

	x	y	z	U_iso*/U_eq
Fe1	0.54200	0.20100	−0.17100	0.0139*
Zr2	0.13090	0.02910	−0.11940	0.0101*
Zr3	0.35780	0.03930	−0.39020	0.0127*
P4	−0.03800	0.25400	−0.50400	0.0127*
P5	0.24800	0.38200	−0.14700	0.0114*
P6	0.53100	0.39800	−0.35400	0.0127*
O7	−0.01200	0.32800	−0.58200	0.0165*
O8	−0.22200	0.17400	−0.57300	0.0165*
O9	−0.04000	0.35500	−0.42700	0.0139*
O10	0.12300	0.14400	−0.43200	0.0139*
O11	0.20400	0.22000	−0.17000	0.0215*
O12	0.30100	0.42400	−0.03500	0.0203*
O13	0.40100	0.40900	−0.16100	0.0177*
O14	0.08900	0.48300	−0.22700	0.0152*
O15	0.49900	0.24300	−0.32900	0.0165*
O16	0.69700	0.38900	−0.36000	0.0152*
O17	0.35600	0.45100	−0.46100	0.0152*
O18	0.56500	0.51900	−0.26800	0.0139*

(binimetinib_3_phase_1) top

Crystal data top

H₂KO₄P	c = 6.9755 (3) Å
M_r = 136.08	V = 387.75 (4) Å³
Orthorhombic, P2₁2₁2₁	Z = 4
a = 7.4487 (5) Å	D_x = 2.331 Mg m⁻³
b = 7.4626 (5) Å	T = 298 K

Refinement top

Weighting scheme based on measured s.u.'s

Preferred orientation correction: March-Dollase correction coef. = 1.000 axis = [0, 0, 1]

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

	x	y	z	U_iso*/U_eq
P1	0.00000	0.25000	0.37500	0.0100*
K2	0.00000	0.25000	0.87500	0.0100*
O3	0.08970	0.40150	0.50060	0.0100*
O4	0.15570	1.16810	1.24930	0.0100*
O5	0.92620	1.10680	0.50530	0.0100*
O6	0.86180	0.33310	1.24490	0.0100*
H7	0.23200	0.39600	0.50300	0.0100*
H8	0.14600	1.02600	1.25700	0.0100*

6-(4-Bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide (binimetinib_3_phase_0) top

Crystal data top

C₁₇H₁₅BrF₂N₄O₃	V = 1803.9 (2) Å³
M_r = 441.23	Z = 4
Orthorhombic, P2₁2₁2₁	D_x = 1.625 Mg m⁻³
a = 23.1607 (11) Å	Synchrotron radiation
b = 16.0073 (11) Å	T = 298 K
c = 4.86578 (17) Å	cylinder, 0.45 × 0.15 mm

Data collection top

Wiggler Low Energy Beamline, Brockhouse X-ray Diffraction and Scattering Sector, Canadian Light Source diffractometer	Data collection mode: transmission
Specimen mounting: Kapton capillary	Scan method: step

Refinement top

Weighting scheme based on measured s.u.'s

Preferred orientation correction: Simple spherical harmonic correction Order = 2 Coefficients: 0:0:C(2,0) = -0.416(16); 0:0:C(2,2) = -0.373(18)

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

	x	y	z	U_iso*/U_eq
Br1	0.2140 (2)	1.1878 (4)	0.6685 (13)	0.102 (4)*
F2	0.1638 (7)	0.7558 (12)	0.763 (4)	0.162 (7)*
F3	0.1628 (6)	0.8853 (7)	0.467 (3)	0.097 (8)*
O4	−0.1140 (6)	0.9111 (10)	0.360 (4)	0.271 (10)*
O5	−0.0394 (9)	0.8638 (15)	0.772 (3)	0.271 (10)*
O6	−0.2407 (14)	0.9150 (17)	0.579 (6)	0.271 (10)*
N7	0.0781 (5)	0.6083 (9)	0.073 (3)	0.162 (7)*
N8	0.0739 (7)	0.8714 (7)	0.828 (3)	0.097 (8)*
N9	0.1533 (6)	0.6159 (12)	0.362 (4)	0.162 (7)*
N10	−0.0612 (7)	0.8681 (15)	0.320 (3)	0.271 (10)*
C11	0.0672 (5)	0.6757 (12)	0.243 (4)	0.162 (7)*
C12	0.1152 (5)	0.6812 (9)	0.415 (3)	0.162 (7)*
C13	0.0721 (5)	0.8048 (8)	0.629 (4)	0.162 (7)*
C14	0.0224 (5)	0.7937 (9)	0.465 (4)	0.162 (7)*
C15	0.0191 (6)	0.7269 (11)	0.278 (5)	0.162 (7)*
C16	0.1161 (8)	0.7456 (16)	0.607 (6)	0.162 (7)*
C17	0.1321 (6)	0.5817 (14)	0.138 (5)	0.162 (7)*
C18	0.0347 (7)	0.5616 (15)	−0.082 (5)	0.162 (7)*
C19	−0.0326 (6)	0.8372 (8)	0.537 (3)	0.271 (10)*
C20	0.1037 (9)	0.9484 (8)	0.791 (5)	0.097 (8)*
C21	0.1489 (5)	0.9534 (6)	0.606 (3)	0.097 (8)*
C22	0.0928 (12)	1.0187 (11)	0.955 (7)	0.097 (8)*
C23	0.1845 (9)	1.0204 (8)	0.584 (6)	0.097 (8)*
C24	0.1232 (13)	1.0924 (10)	0.906 (7)	0.097 (8)*
C25	0.1697 (10)	1.0907 (8)	0.726 (6)	0.097 (8)*
C26	−0.1620 (8)	0.8543 (15)	0.313 (9)	0.271 (10)*
C27	−0.2166 (9)	0.9025 (19)	0.313 (5)	0.271 (10)*
H28	−0.02487	0.71766	0.16889	0.2456*
H29	0.05232	0.86998	1.03075	0.1171*
H30	0.15757	0.54516	−0.01714	0.2456*
H31	−0.01029	0.58209	−0.01501	0.2456*
H32	0.03773	0.49577	−0.02975	0.2456*
H33	0.03549	0.57555	−0.30781	0.2456*
H34	0.05590	1.02227	1.10109	0.1171*
H35	−0.04360	0.86005	0.10945	0.3252*
H36	0.22406	1.02131	0.43551	0.1171*
H37	0.11483	1.15369	1.03039	0.1171*
H38	−0.16330	0.80548	0.48347	0.3252*
H39	−0.15623	0.82195	0.10608	0.3252*
H40	−0.20864	0.96693	0.22067	0.3252*
H41	−0.24952	0.86822	0.18029	0.3252*
H42	0.22400	0.59610	0.45600	0.3252*

Geometric parameters (Å, º) top

Br1—C25	1.883 (3)	C19—O5	1.231 (4)
F2—C16	1.347 (4)	C19—N10	1.343 (3)
F3—C21	1.322 (5)	C19—C14	1.492 (4)
O4—N10	1.417 (4)	C20—N8	1.422 (5)
O4—C26	1.454 (6)	C20—C21	1.386 (2)
O5—C19	1.231 (4)	C20—C22	1.403 (5)
O6—C27	1.421 (10)	C21—F3	1.322 (5)
O6—H42ⁱ	0.85 (3)	C21—C20	1.386 (2)
N7—C11	1.380 (3)	C21—C23	1.357 (3)
N7—C17	1.359 (4)	C22—C20	1.403 (5)
N7—C18	1.462 (3)	C22—C24	1.394 (7)
N8—C13	1.439 (5)	C22—H34	1.113 (7)
N8—C20	1.422 (5)	C23—C21	1.357 (3)
N8—H29	1.107 (11)	C23—C25	1.366 (4)
N9—C12	1.392 (3)	C23—H36	1.167 (7)
N9—C17	1.317 (3)	C24—C22	1.394 (7)
N10—O4	1.417 (4)	C24—C25	1.385 (4)
N10—C19	1.343 (3)	C24—H37	1.170 (9)
N10—H35	1.110 (15)	C25—Br1	1.883 (3)
C11—N7	1.380 (3)	C25—C23	1.366 (4)
C11—C12	1.395 (3)	C25—C24	1.385 (4)
C11—C15	1.395 (4)	C26—O4	1.454 (6)
C12—N9	1.392 (3)	C26—C27	1.481 (9)
C12—C11	1.395 (3)	C26—H38	1.14 (4)
C12—C16	1.393 (2)	C26—H39	1.14 (3)
C13—N8	1.439 (5)	C27—O6	1.421 (10)
C13—C14	1.413 (3)	C27—C26	1.481 (9)
C13—C16	1.397 (3)	C27—H40	1.14 (3)
C14—C13	1.413 (3)	C27—H41	1.14 (3)
C14—C15	1.405 (3)	H28—C15	1.159 (10)
C14—C19	1.492 (4)	H29—N8	1.107 (11)
C15—C11	1.395 (4)	H30—C17	1.121 (13)
C15—C14	1.405 (3)	H31—C18	1.232 (16)
C15—H28	1.159 (10)	H32—C18	1.09 (3)
C16—F2	1.347 (4)	H33—C18	1.12 (3)
C16—C12	1.393 (2)	H34—C22	1.113 (7)
C16—C13	1.397 (3)	H35—N10	1.301 (15)
C17—N7	1.359 (4)	H36—C23	1.167 (7)
C17—N9	1.317 (3)	H37—C24	1.170 (9)
C17—H30	1.121 (13)	H38—C26	1.14 (4)
C18—N7	1.462 (3)	H39—C26	1.14 (3)
C18—H31	1.232 (16)	H40—C27	1.14 (3)
C18—H32	1.09 (3)	H41—C27	1.14 (3)
C18—H33	1.12 (3)	H42—O6ⁱⁱ	0.85 (3)

N10—O4—C26	109.6 (3)	N7—C18—H33	113.1 (19)
C27—O6—H42ⁱ	100 (3)	H31—C18—H33	104.3 (16)
C11—N7—C17	105.96 (9)	H32—C18—H33	114.8 (12)
C11—N7—C18	125.63 (16)	O5—C19—N10	122.8 (3)
C17—N7—C18	126.3 (3)	O5—C19—C14	119.2 (3)
C13—N8—C20	125.0 (4)	N10—C19—C14	114.1 (4)
C13—N8—H29	124.7 (9)	N8—C20—C21	119.9 (3)
C20—N8—H29	110.4 (9)	N8—C20—C22	122.5 (4)
C12—N9—C17	103.2 (2)	C21—C20—C22	117.4 (2)
O4—N10—C19	119.8 (3)	F3—C21—C20	118.0 (2)
O4—N10—H35	120.0 (10)	F3—C21—C23	117.6 (3)
C19—N10—H35	114.3 (9)	C20—C21—C23	123.8 (2)
N7—C11—C12	105.26 (15)	C20—C22—C24	119.3 (6)
N7—C11—C15	132.8 (2)	C20—C22—H34	122.8 (8)
C12—C11—C15	121.7 (3)	C24—C22—H34	117.1 (8)
N9—C12—C11	110.31 (13)	C21—C23—C25	117.3 (4)
N9—C12—C16	132.0 (3)	C21—C23—H36	122.4 (5)
C11—C12—C16	117.59 (18)	C25—C23—H36	120.1 (4)
N8—C13—C14	119.8 (3)	C22—C24—C25	119.0 (5)
N8—C13—C16	122.2 (3)	C22—C24—H37	122.4 (6)
C14—C13—C16	117.8 (2)	C25—C24—H37	118.1 (5)
C13—C14—C15	120.4 (3)	Br1—C25—C23	117.8 (2)
C13—C14—C19	120.22 (19)	Br1—C25—C24	120.1 (3)
C15—C14—C19	117.4 (5)	C23—C25—C24	122.07 (18)
C11—C15—C14	119.0 (3)	O4—C26—C27	109.1 (9)
C11—C15—H28	124.7 (7)	O4—C26—H38	110 (3)
C14—C15—H28	116.2 (7)	C27—C26—H38	110 (2)
F2—C16—C12	118.6 (2)	O4—C26—H39	109 (3)
F2—C16—C13	118.3 (4)	C27—C26—H39	110 (3)
C12—C16—C13	122.8 (2)	H38—C26—H39	109.5 (17)
N7—C17—N9	113.8 (2)	O6—C27—C26	114.1 (11)
N7—C17—H30	119.5 (10)	O6—C27—H40	107 (3)
N9—C17—H30	125.4 (9)	C26—C27—H40	109.4 (19)
N7—C18—H31	107.9 (7)	O6—C27—H41	109 (2)
N7—C18—H32	109.4 (14)	C26—C27—H41	109 (2)
H31—C18—H32	107 (2)	H40—C27—H41	108.6 (15)

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

(binimetinib_VASP) top

Crystal data top

C₁₇H₁₅BrF₂N₄O₃	b = 16.01200 Å
M_r = 441.23	c = 4.86608 Å
Orthorhombic, P2₁2₁2₁	V = 1804.71 Å³
a = 23.16240 Å	Z = 4

Data collection top

h = →	l = →
k = →

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

	x	y	z	B_iso*/B_eq
Br1	0.21583	1.19671	0.75423
F2	0.17429	0.77297	0.66775
F3	0.16697	0.90877	0.32040
O4	−0.10831	0.89653	0.26129
O5	−0.04005	0.85262	0.68214
O6	−0.21696	0.91024	0.54783
N7	0.09310	0.60081	0.01736
N8	0.07664	0.87294	0.71560
N9	0.17259	0.63256	0.26145
N10	−0.05892	0.84888	0.22432
C11	0.07868	0.67001	0.17370
C12	0.12943	0.68901	0.32456
C13	0.07819	0.80469	0.53543
C14	0.02728	0.78152	0.38710
C15	0.02719	0.71394	0.20461
C16	0.12781	0.75578	0.50880
C17	0.14903	0.58161	0.07714
C18	0.05533	0.55671	−0.17077
C19	−0.02660	0.82946	0.44334
C20	0.10956	0.94556	0.71049
C21	0.15473	0.96344	0.52698
C22	0.09601	1.00905	0.90051
C23	0.18688	1.03650	0.53834
C24	0.12630	1.08382	0.91226
C25	0.17252	1.09668	0.73321
C26	−0.15852	0.84578	0.19082
C27	−0.21257	0.89367	0.26039
H28	−0.01202	0.69634	0.09477
H29	0.03603	0.88130	0.79338
H30	0.17098	0.52878	−0.01938
H31	0.01541	0.53825	−0.06465
H32	0.07718	0.50010	−0.24257
H33	0.04410	0.59684	−0.34606
H34	0.06091	0.99782	1.04600
H35	−0.04755	0.83869	0.02052
H36	0.22171	1.04588	0.39098
H37	0.11482	1.13114	1.06363
H38	−0.15639	0.78740	0.30960
H39	−0.15748	0.83253	−0.03098
H40	−0.21384	0.95254	0.14206
H41	−0.24900	0.85504	0.18852
H42	−0.25621	0.89297	0.61096

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N8—H29···O5	1.02	1.90	2.727	136
N10—H35···O5ⁱ	1.04	1.67	2.675	161
O6—H42···N9ⁱⁱ	1.00	1.81	2.806	176
C17—H30···O6ⁱⁱⁱ	1.09	2.18	3.221	158
C18—H32···O5ⁱⁱⁱ	1.10	2.53	3.288	125
C26—H38···Br1^iv	1.10	2.92	3.841	142
C26—H39···Br1ⁱⁱⁱ	1.10	2.78	3.486	122

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

Acknowledgements

Part of the research described in this paper was performed at the Canadian Light Source, a national research facility of the University of Saskatchewan, which is supported by the Canada Foundation for Innovation (CFI), the Natural Sciences and Engineering Research Council (NSERC), the Canadian Institute of Health Research (CIHR), the Government of Saskatchewan, and the University of Saskatchewan. We thank Adam Leontowich for his assistance in the data collection. We also thank the ICDD team – Megan Rost, Steve Trimble, and Dave Bohnenberger - for their contribution to research, sample preparation, and in-house XRD data collection and verification.

Funding information

Funding for this research was provided by: International Centre for Diffraction Data (grant No. 09-03).

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