Nirmatrelvir methyl tert-butyl ether solvate

Smit, J.P.; Purcell, D.K.; Engers, D.A.; Smith, P.A.; Bauser, H.C.; Radocea, A.

doi:10.1107/S2056989026003816

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 82| Part 5| May 2026| Pages 477-479

https://doi.org/10.1107/S2056989026003816

Open

access

Nirmatrelvir methyl tert-butyl ether solvate

Jared P. Smit,^a ^* Dale K. Purcell,^a David A. Engers,^a Pamela A. Smith,^a Haley C. Bauser ^b and Adrian Radocea ^b

^aImproved Pharma, LLC, 1281 Win Hentschel Blvd., West Lafayette, IN 47906, USA, and ^bVarda Space Industries, 225 S. Aviation Blvd., El Segundo, CA 90245, USA
^*Correspondence e-mail: [email protected]

Edited by J. Reibenspies, Texas A & M University, USA (Received 2 April 2026; accepted 10 April 2026; online 14 April 2026)

The structure of nirmatrelvir MTBE solvate, C₂₃H₃₂F₃N₅O₄·C₅H₁₂O, at 150 K has monoclinic (P2₁) symmetry. The asymmetric unit contains one nirmatrelvir molecule and one methyl tert-butyl ether solvent molecule. The extended structure consists of N—H⋯O hydrogen bonds that create create [010] chains. Crystals of the title compound were grown from various methyl tert-butyl ether–methanol solvent mixtures, with crystal morphology dependent upon the mixture ratio.

Keywords: crystal structure; pharmaceutical; nirmatrelvir.

CCDC reference: 2545296

1. Chemical context

Nirmatrelvir (NTV) is an antiviral protease inhibitor developed by Pfizer, currently used in tandem with ritonavir and marketed as Paxlovid^® for the treatment of Covid-19 (Halford, 2022 ; Lamb, 2022 ). Two enantiotropically related anhydrous polymorphs (designated Forms 1 and 4) of NTV have been well characterized, and the higher temperature stable form, Form 1, was selected for use in the drug product (Sadeghi et al., 2024 ). A crystalline X-ray powder diffraction (XRPD) pattern for Form 2, a methyl tert-butyl ether (MTBE) solvate, was published in a US patent although the Form 2 crystal structure was not disclosed (Owens et al., 2022 ). Form 2 is of interest as a key intermediate isolated in the purification process, enabling the subsequent generation of the stable, non-solvated Form 1 through recrystallization. The crystal structure of NTV Form 2, a mono-MTBE solvate, is reported in this work.

2. Structural commentary

The molecular structure of NTV is shown in Fig. 1. Nirmatrelvir Form 2 is a mono-MTBE solvate, crystallizing in space group P2₁, with an asymmetric unit consisting of one NTV molecule and one MTBE solvent molecule. The MTBE solvent molecule is disordered over two conformations that are approximate mirror images of each other, refining to 69% in the predominant orientation. The absolute structure was determined from the data and the NTV molecule was found to bond in the S, S, R, S, S, and S configuration at C3, C10, C14, C15, C17, and C20 respectively.

Figure 1
The title molecule with displacement ellipsoids drawn at the 50% probability level. Solvent disorder is not shown for clarity.

3. Supramolecular features

Nirmatrelvir contains three secondary amide moieties that are available for hydrogen-bond donation. The pyrrolidone amide forms a hydrogen bond to the pyrrolidine amide carbonyl and accepts a hydrogen bond from the trifluoroacetyl amide from an adjacent molecule, creating hydrogen bonded chains propagating along the b-axis direction, shown in Fig. 2. The pyrimidine NH grouping forms a hydrogen bond to the oxygen atom of the MTBE, but this supramolecular feature does not contribute to the dimensionality. Geometric details of hydrogen bonds are given in Table 1.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O4ⁱ	0.80 (3)	2.06 (3)	2.837 (2)	165 (4)
N3—H3⋯O5	0.87 (3)	1.99 (3)	2.848 (4)	170 (2)
N3—H3⋯O5A	0.87 (3)	1.95 (3)	2.795 (10)	163 (3)
N5—H5⋯O2ⁱⁱ	0.85 (3)	2.00 (3)	2.845 (2)	176 (3)
Symmetry codes: (i) $[-x+1, y+{\script{1\over 2}}, -z+1]$ ; (ii) $[-x+1, y-{\script{1\over 2}}, -z+1]$ .

Figure 2
One-dimensional hydrogen-bonded chain of nirmatrelvir molecules (left) and NTV hydrogen bonded to MTBE (right).

4. Database survey

Two anhydrous polymorphs are in the Cambridge Structural Database (CSD, version 6.01, update 1, February 2026; Groom et al., 2016 ), refcodes ZIVMEA through ZIVMEA10 (Sadeghi et al., 2024; Jiang et al., 2023 ).. The two forms are enantiotropic polymorphs, both crystallizing in space group P2₁2₁2₁, and the molecular packing is similar enough that the two forms can undergo a first order solid-state single crystal-to-single crystal phase transition (Shi et al., 2025 ). The pyrrolidone amide forms and accepts hydrogen bonds to and from the same amide oxygen moiety on two different adjacent molecules rather than the hydrogen bonding to the pyrrolidine amide and from the trifluoroacetyl amide on one adjacent molecule in the framework of the title solvate.

Isostructural ethanol and isopropanol solvates (refcodes AMEPOB and AMESOE) have also been reported (Li et al., 2026 ). These solvates have three NTV molecules in the asymmetric unit, each forming different hydrogen bonds. The pyrrolidone amide moiety on one of the three unique molecules forms the same hydrogen bonds as in the structure of the MTBE solvate.

5. Synthesis and crystallization

Nirmatrelvir was obtained from ChemShuttle and used without purification. Single crystals were obtained from MTBE and from solutions of 94 to 99% (v/v) MTBE in methanol. The solid (0.02 g) was dissolved in each MTBE solution. After standing at room temperature overnight, a solid precipitate was observed. Solubilities of NTV in each solution were determined gravimetrically from supernatant filtered through a 0.2 mm PTFE membrane into clean pre-tared vials. The measured solubilities ranged from 0.7 mg ml⁻¹ in MTBE to 6.5mg ml⁻¹ in 94% (v/v) MTBE–methanol solution. After standing at room temperature for an extended time (18 months), crystals suitable for single crystal X-ray diffraction (SCXRD) were discovered and isolated. The apparent morphology of the crystals varied with solution composition, with finer blades and needle-shaped crystals obtained at 99% (v/v) MTBE and larger block-shaped and prismatic crystals obtained as methanol concentration increased, 95–96% (v/v) MTBE, shown in polarized light microscopy images (Fig. 3).

Figure 3
Morphology of NTV MTBE solvate crystals at MTBE:methanol ratios of 99:1, 96:4, and 95:5 (left to right)

Polarized light microscopy was conducted using an Olympus Series BX51TRF (Olympus America Inc., Melville, NY) equipped with 12 V/100 W transmission and reflection illumination, an achromat 0.9 NA polarized light condenser, Olympus Series MPlanFL N objectives: 50X/0.75 NA BDP, 20X/0.40 NA BDP, 10X/0.25 NA BDP, 5X/0.15 NA BDP, an intermediate tube with variable position analyzer and compensator, a trinocular viewing head with a Lumenera Series Infinity 3-3URC (Teledyne Lumenera, Ottawa, Ontario, Canada) digital camera. Image capture and image processing using Image-Pro® version 10.0.11 Build 7240 (Date: 01-April-2020).

A small portion of the sample was pipetted into the well of a scrupulously cleaned depression microscope slide and a No. 1 ½ cover glass was placed over the sample, which was sealed using grease to prevent fast of the volatile solvent.

The relatively larger amount of the more polar methanol in MTBE increased the solubility and therefore decreased the nucleation rate, leading to fewer, but larger, crystals. Face indexing using CrysAlis PRO (Rigaku OD, 2026 ) indicates that the needles are growing faster along the [010] direction, consistent with the direction of hydrogen bonding and therefore the presence of the hydrogen-bond donating methanol slows that process (McArdle & Erxleben, 2024 ). Crystals from each solution were indexed with unit-cell parameters matching the crystal structure of the MTBE solvate. The XRPD pattern calculated from the crystal structure is consistent with the powder pattern previously published (Owens et al., 2022).

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms residing on nitrogen were refined independently. Hydrogen atoms residing on carbon were included in the refinement using the appropriate riding models. The MTBE molecule is disordered over two orientations that are related through a pseudo-inversion, refining to 69% in the predominant orientation, and modeled using restraints to the anisotropic displacement parameters (SIMU/DELU).

Table 2
Experimental details

Crystal data
Chemical formula	C₂₃H₃₂F₃N₅O₄·C₅H₁₂O
M_r	587.68
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	150
a, b, c (Å)	12.7655 (1), 9.2588 (1), 14.3951 (1)
β (°)	103.208 (1)
V (Å³)	1656.40 (3)
Z	2
Radiation type	Cu Kα
μ (mm⁻¹)	0.78
Crystal size (mm)	0.35 × 0.24 × 0.12

Data collection
Diffractometer	XtaLAB Synergy, Single source at home/near, HyPix-Bantam
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2026)
T_min, T_max	0.691, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	31765, 5959, 5890
R_int	0.023
(sin θ/λ)_max (Å⁻¹)	0.604

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.094, 1.03
No. of reflections	5959
No. of parameters	442
No. of restraints	46
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.29, −0.20
Absolute structure	Flack x determined using 2630 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	−0.03 (3)
Computer programs: CrysAlis PRO (Rigaku OD, 2026), SHELXT (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ) and OLEX2 (Dolomanov et al., 2009 ).

Supporting information

CCDC reference: 2545296

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989026003816/jy2071sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989026003816/jy2071Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989026003816/jy2071Isup3.mol

checkCIF report

Computing details top

(1R,2S,5S)-N-[(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclohexane-2-carboxamide methyl <it>tert</it>-butyl ether monosolvate top

Crystal data top

C₂₃H₃₂F₃N₅O₄·C₅H₁₂O	F(000) = 628
M_r = 587.68	D_x = 1.178 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54184 Å
a = 12.7655 (1) Å	Cell parameters from 28535 reflections
b = 9.2588 (1) Å	θ = 3.2–68.6°
c = 14.3951 (1) Å	µ = 0.78 mm⁻¹
β = 103.208 (1)°	T = 150 K
V = 1656.40 (3) Å³	Block, colourless
Z = 2	0.35 × 0.24 × 0.12 mm

Data collection top

XtaLAB Synergy, Single source at home/near, HyPix-Bantam diffractometer	5959 independent reflections
Radiation source: micro-focus sealed X-ray tube, PhotonJet (Cu) X-ray Source	5890 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.023
Detector resolution: 10.0000 pixels mm^-1	θ_max = 68.7°, θ_min = 3.2°
ω scans	h = −15→15
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2026)	k = −11→11
T_min = 0.691, T_max = 1.000	l = −17→17
31765 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.035	w = 1/[σ²(F_o²) + (0.062P)² + 0.2608P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.094	(Δ/σ)_max = 0.001
S = 1.03	Δρ_max = 0.29 e Å⁻³
5959 reflections	Δρ_min = −0.20 e Å⁻³
442 parameters	Absolute structure: Flack x determined using 2630 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
46 restraints	Absolute structure parameter: −0.03 (3)
Primary atom site location: dual

Special details top

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

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

	x	y	z	U_iso*/U_eq	Occ. (<1)
F3	0.71689 (12)	0.98226 (17)	0.18387 (10)	0.0502 (4)
O2	0.42888 (11)	0.49248 (18)	0.29537 (9)	0.0346 (3)
F2	0.63537 (16)	0.9574 (2)	0.29654 (13)	0.0622 (5)
F1	0.77491 (12)	0.82994 (19)	0.29599 (12)	0.0575 (4)
N2	0.34108 (12)	0.54106 (18)	0.14552 (11)	0.0260 (3)
N1	0.60011 (13)	0.6527 (2)	0.22920 (12)	0.0291 (4)
O3	0.24679 (16)	0.2686 (2)	0.13660 (13)	0.0480 (4)
O4	0.32501 (18)	0.1791 (2)	0.57021 (11)	0.0584 (6)
N3	0.16245 (13)	0.3324 (2)	0.25251 (12)	0.0308 (4)
N5	0.45298 (16)	0.0532 (3)	0.51601 (13)	0.0431 (5)
O1	0.5744 (2)	0.7964 (3)	0.09820 (14)	0.0756 (8)
C1	0.68689 (17)	0.8859 (3)	0.23966 (15)	0.0358 (5)
C8	0.43156 (15)	0.5203 (2)	0.21144 (13)	0.0264 (4)
C15	0.23765 (14)	0.5218 (2)	0.17219 (13)	0.0265 (4)
H15	0.236566	0.576525	0.231853	0.032*
C16	0.21747 (15)	0.3610 (2)	0.18512 (14)	0.0300 (4)
C2	0.61382 (17)	0.7711 (3)	0.18146 (14)	0.0341 (4)
C3	0.53816 (14)	0.5313 (2)	0.18022 (13)	0.0288 (4)
H3A	0.520209	0.554521	0.110540	0.035*
C23	0.36464 (19)	0.1326 (3)	0.50598 (15)	0.0377 (5)
C10	0.21163 (16)	0.6146 (2)	0.00894 (14)	0.0324 (4)
H10	0.174056	0.589426	−0.057936	0.039*
C14	0.15510 (15)	0.5825 (2)	0.08827 (14)	0.0316 (4)
H14	0.082198	0.536855	0.071303	0.038*
C17	0.14115 (18)	0.1852 (3)	0.27582 (15)	0.0363 (5)
H17	0.169676	0.119004	0.232567	0.044*
C11	0.16674 (18)	0.7362 (3)	0.05803 (15)	0.0366 (5)
C9	0.32856 (16)	0.5740 (3)	0.04271 (13)	0.0311 (4)
H9A	0.346067	0.488590	0.007773	0.037*
H9B	0.375806	0.655132	0.033691	0.037*
C20	0.31739 (16)	0.1561 (3)	0.39984 (13)	0.0333 (4)
H20	0.338981	0.253910	0.381412	0.040*
C19	0.19543 (17)	0.1480 (3)	0.37928 (15)	0.0356 (5)
H19A	0.169260	0.215436	0.422334	0.043*
H19B	0.174017	0.049149	0.393515	0.043*
O5	0.1325 (3)	0.5375 (4)	0.3916 (2)	0.0557 (10)	0.687 (8)
C4	0.60242 (17)	0.3874 (3)	0.19259 (15)	0.0355 (5)
C21	0.3745 (2)	0.0415 (3)	0.35336 (15)	0.0457 (6)
H21A	0.386753	0.075998	0.291617	0.055*
H21B	0.332176	−0.049036	0.342658	0.055*
C12	0.2382 (2)	0.8424 (3)	0.12260 (18)	0.0461 (5)
H12A	0.307656	0.796793	0.150239	0.069*
H12B	0.203839	0.871835	0.173883	0.069*
H12C	0.249686	0.927433	0.085634	0.069*
C5	0.6507 (2)	0.3496 (3)	0.29742 (17)	0.0448 (6)
H5A	0.696781	0.429029	0.327825	0.067*
H5B	0.693608	0.261189	0.300766	0.067*
H5C	0.592597	0.334485	0.330615	0.067*
C7	0.5265 (2)	0.2675 (3)	0.14520 (18)	0.0443 (5)
H7A	0.469853	0.253609	0.180198	0.066*
H7B	0.567102	0.177540	0.145900	0.066*
H7C	0.493925	0.294566	0.079088	0.066*
C22	0.4812 (2)	0.0190 (4)	0.42612 (18)	0.0550 (7)
H22A	0.506473	−0.081976	0.425368	0.066*
H22B	0.537516	0.084957	0.413796	0.066*
C13	0.0639 (2)	0.8043 (4)	0.0006 (2)	0.0557 (7)
H13A	0.081874	0.878817	−0.041587	0.084*
H13B	0.024111	0.848199	0.044097	0.084*
H13C	0.019303	0.729924	−0.037838	0.084*
C6	0.6935 (2)	0.4043 (3)	0.1404 (2)	0.0514 (6)
H6A	0.662914	0.420029	0.072286	0.077*
H6B	0.737522	0.316514	0.148864	0.077*
H6C	0.738318	0.487166	0.166663	0.077*
C18	0.0234 (2)	0.1619 (3)	0.2606 (2)	0.0582 (8)
N4	−0.0664 (2)	0.1441 (4)	0.2507 (3)	0.0961 (13)
C27	0.0365 (3)	0.6271 (5)	0.3776 (3)	0.0502 (12)	0.687 (8)
C28	0.2129 (10)	0.5420 (14)	0.4736 (7)	0.101 (4)	0.687 (8)
H28A	0.269746	0.473453	0.468243	0.151*	0.687 (8)
H28B	0.243009	0.639743	0.482490	0.151*	0.687 (8)
H28C	0.183275	0.516023	0.528416	0.151*	0.687 (8)
C24	−0.0276 (6)	0.5901 (14)	0.2767 (7)	0.133 (5)	0.687 (8)
H24A	0.017885	0.604487	0.231128	0.199*	0.687 (8)
H24B	−0.050962	0.489079	0.274766	0.199*	0.687 (8)
H24C	−0.090841	0.653078	0.259808	0.199*	0.687 (8)
C26	0.0834 (11)	0.7670 (11)	0.3672 (11)	0.183 (7)	0.687 (8)
H26A	0.120388	0.763557	0.314619	0.275*	0.687 (8)
H26B	0.026426	0.840144	0.353478	0.275*	0.687 (8)
H26C	0.135088	0.792067	0.426510	0.275*	0.687 (8)
C25	−0.0220 (11)	0.6102 (18)	0.4520 (11)	0.231 (10)	0.687 (8)
H25A	−0.049249	0.511175	0.451164	0.347*	0.687 (8)
H25B	0.026171	0.630006	0.514173	0.347*	0.687 (8)
H25C	−0.082490	0.678083	0.441141	0.347*	0.687 (8)
H3	0.147 (2)	0.399 (3)	0.290 (2)	0.037 (7)*
H5	0.491 (2)	0.035 (4)	0.571 (2)	0.048 (8)*
H1	0.625 (3)	0.645 (4)	0.285 (2)	0.050 (8)*
C28A	−0.0441 (7)	0.5301 (14)	0.3463 (16)	0.086 (5)	0.313 (8)
H28D	−0.076611	0.463036	0.295219	0.129*	0.313 (8)
H28E	−0.068231	0.505978	0.404360	0.129*	0.313 (8)
H28F	−0.065948	0.629095	0.326818	0.129*	0.313 (8)
O5A	0.0714 (8)	0.5189 (11)	0.3649 (7)	0.075 (3)	0.313 (8)
C27A	0.1104 (9)	0.6173 (10)	0.4379 (7)	0.061 (3)	0.313 (8)
C25A	0.0502 (12)	0.7738 (16)	0.414 (2)	0.165 (14)	0.313 (8)
H25D	0.078353	0.841867	0.465413	0.248*	0.313 (8)
H25E	0.063707	0.811400	0.353747	0.248*	0.313 (8)
H25F	−0.027408	0.761711	0.407048	0.248*	0.313 (8)
C24A	0.2273 (17)	0.591 (3)	0.465 (2)	0.133 (15)	0.313 (8)
H24D	0.260701	0.656770	0.516101	0.199*	0.313 (8)
H24E	0.240780	0.490800	0.486222	0.199*	0.313 (8)
H24F	0.258158	0.607410	0.409066	0.199*	0.313 (8)
C26A	0.0671 (15)	0.583 (4)	0.5248 (13)	0.184 (15)	0.313 (8)
H26D	0.095278	0.653228	0.575311	0.275*	0.313 (8)
H26E	−0.011687	0.588288	0.507957	0.275*	0.313 (8)
H26F	0.089540	0.485615	0.547460	0.275*	0.313 (8)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F3	0.0568 (8)	0.0476 (9)	0.0466 (7)	−0.0173 (7)	0.0125 (6)	0.0103 (6)
O2	0.0304 (7)	0.0502 (9)	0.0207 (6)	−0.0057 (6)	0.0009 (5)	0.0028 (6)
F2	0.0774 (11)	0.0554 (10)	0.0626 (10)	−0.0134 (8)	0.0344 (9)	−0.0182 (8)
F1	0.0467 (7)	0.0512 (9)	0.0614 (9)	−0.0119 (7)	−0.0154 (7)	0.0109 (7)
N2	0.0268 (7)	0.0292 (9)	0.0209 (7)	−0.0007 (6)	0.0029 (6)	0.0007 (6)
N1	0.0291 (8)	0.0358 (10)	0.0202 (8)	−0.0041 (7)	0.0011 (6)	0.0021 (7)
O3	0.0662 (11)	0.0326 (9)	0.0515 (10)	−0.0062 (8)	0.0268 (8)	−0.0101 (7)
O4	0.0767 (12)	0.0669 (13)	0.0258 (8)	0.0359 (11)	−0.0006 (7)	−0.0044 (8)
N3	0.0334 (8)	0.0299 (9)	0.0268 (8)	−0.0039 (7)	0.0023 (7)	0.0018 (7)
N5	0.0417 (10)	0.0575 (13)	0.0252 (9)	0.0101 (9)	−0.0026 (7)	0.0043 (8)
O1	0.1116 (18)	0.0650 (15)	0.0349 (10)	−0.0384 (13)	−0.0147 (10)	0.0176 (9)
C1	0.0381 (11)	0.0349 (12)	0.0335 (10)	−0.0039 (9)	0.0066 (9)	0.0045 (9)
C8	0.0288 (9)	0.0254 (9)	0.0227 (8)	−0.0029 (7)	0.0013 (7)	−0.0021 (7)
C15	0.0264 (8)	0.0279 (10)	0.0238 (8)	−0.0017 (7)	0.0029 (7)	−0.0008 (7)
C16	0.0278 (9)	0.0318 (11)	0.0278 (9)	−0.0034 (8)	0.0007 (7)	−0.0014 (8)
C2	0.0364 (10)	0.0378 (12)	0.0263 (10)	−0.0043 (9)	0.0032 (8)	0.0045 (9)
C3	0.0266 (9)	0.0353 (11)	0.0214 (8)	−0.0001 (8)	−0.0007 (7)	0.0001 (7)
C23	0.0469 (12)	0.0357 (12)	0.0250 (10)	0.0020 (9)	−0.0030 (8)	−0.0007 (8)
C10	0.0328 (10)	0.0368 (11)	0.0242 (9)	0.0046 (8)	−0.0004 (7)	0.0015 (8)
C14	0.0264 (9)	0.0375 (11)	0.0283 (9)	0.0014 (8)	0.0011 (7)	−0.0005 (8)
C17	0.0364 (10)	0.0347 (12)	0.0325 (10)	−0.0079 (9)	−0.0031 (8)	0.0057 (9)
C11	0.0376 (11)	0.0371 (12)	0.0343 (10)	0.0108 (9)	0.0067 (8)	0.0058 (9)
C9	0.0318 (9)	0.0399 (12)	0.0198 (9)	0.0046 (8)	0.0022 (7)	0.0028 (8)
C20	0.0352 (10)	0.0374 (11)	0.0242 (9)	−0.0033 (9)	0.0005 (7)	0.0047 (8)
C19	0.0366 (10)	0.0381 (12)	0.0308 (10)	−0.0027 (9)	0.0050 (8)	0.0089 (9)
O5	0.0424 (18)	0.070 (2)	0.0494 (17)	0.0150 (17)	−0.0005 (14)	−0.0184 (15)
C4	0.0354 (10)	0.0379 (12)	0.0302 (10)	0.0055 (9)	0.0014 (8)	−0.0028 (9)
C21	0.0481 (12)	0.0608 (16)	0.0262 (10)	0.0103 (11)	0.0046 (9)	0.0014 (10)
C12	0.0617 (14)	0.0274 (12)	0.0499 (13)	0.0038 (10)	0.0144 (11)	0.0003 (10)
C5	0.0483 (12)	0.0401 (13)	0.0380 (12)	0.0101 (10)	−0.0064 (10)	0.0011 (10)
C7	0.0486 (13)	0.0352 (12)	0.0434 (13)	0.0050 (10)	−0.0013 (10)	−0.0083 (10)
C22	0.0502 (13)	0.080 (2)	0.0346 (11)	0.0178 (14)	0.0094 (10)	0.0104 (12)
C13	0.0519 (14)	0.0627 (19)	0.0515 (15)	0.0282 (13)	0.0093 (11)	0.0170 (13)
C6	0.0418 (12)	0.0605 (17)	0.0536 (15)	0.0105 (12)	0.0144 (11)	−0.0055 (13)
C18	0.0457 (15)	0.0526 (17)	0.0647 (17)	−0.0178 (12)	−0.0117 (12)	0.0222 (14)
N4	0.0440 (14)	0.094 (3)	0.132 (3)	−0.0278 (15)	−0.0163 (16)	0.043 (2)
C27	0.045 (2)	0.046 (2)	0.064 (3)	0.0086 (17)	0.022 (2)	−0.0032 (18)
C28	0.143 (8)	0.063 (7)	0.066 (4)	0.032 (5)	−0.040 (4)	−0.036 (4)
C24	0.078 (4)	0.185 (11)	0.111 (6)	0.072 (6)	−0.030 (4)	−0.060 (7)
C26	0.220 (13)	0.068 (6)	0.327 (18)	0.028 (7)	0.198 (14)	0.059 (8)
C25	0.205 (13)	0.29 (2)	0.264 (17)	0.148 (14)	0.192 (14)	0.172 (16)
C28A	0.027 (4)	0.057 (7)	0.161 (16)	0.006 (4)	−0.005 (6)	0.013 (8)
O5A	0.056 (5)	0.083 (6)	0.083 (6)	0.017 (5)	0.011 (4)	−0.026 (5)
C27A	0.091 (8)	0.041 (5)	0.060 (6)	−0.005 (5)	0.036 (6)	−0.005 (4)
C25A	0.061 (8)	0.054 (9)	0.34 (3)	0.016 (7)	−0.039 (14)	−0.090 (15)
C24A	0.100 (13)	0.08 (2)	0.16 (2)	0.034 (12)	−0.077 (14)	−0.074 (16)
C26A	0.095 (12)	0.36 (4)	0.116 (14)	−0.01 (2)	0.065 (11)	−0.06 (2)

Geometric parameters (Å, º) top

F3—C1	1.314 (3)	C10—C9	1.508 (3)
O2—C8	1.243 (2)	C14—C11	1.506 (3)
F2—C1	1.337 (3)	C17—C19	1.531 (3)
F1—C1	1.331 (3)	C17—C18	1.484 (3)
N2—C8	1.331 (2)	C11—C12	1.508 (3)
N2—C15	1.468 (2)	C11—C13	1.520 (3)
N2—C9	1.484 (2)	C20—C19	1.519 (3)
N1—C2	1.327 (3)	C20—C21	1.525 (3)
N1—C3	1.460 (3)	O5—C27	1.456 (5)
O3—C16	1.216 (3)	O5—C28	1.376 (10)
O4—C23	1.229 (3)	C4—C5	1.535 (3)
N3—C16	1.348 (3)	C4—C7	1.528 (3)
N3—C17	1.444 (3)	C4—C6	1.529 (3)
N5—C23	1.326 (3)	C21—C22	1.531 (3)
N5—C22	1.455 (3)	C18—N4	1.135 (4)
O1—C2	1.212 (3)	C27—C24	1.534 (8)
C1—C2	1.531 (3)	C27—C26	1.449 (10)
C8—C3	1.531 (3)	C27—C25	1.448 (9)
C15—C16	1.529 (3)	C28A—O5A	1.440 (12)
C15—C14	1.518 (3)	O5A—C27A	1.394 (13)
C3—C4	1.553 (3)	C27A—C25A	1.641 (16)
C23—C20	1.525 (3)	C27A—C24A	1.47 (2)
C10—C14	1.513 (3)	C27A—C26A	1.513 (17)
C10—C11	1.510 (3)

C8—N2—C15	118.82 (16)	N3—C17—C18	110.0 (2)
C8—N2—C9	128.26 (16)	C18—C17—C19	109.19 (19)
C15—N2—C9	112.80 (15)	C10—C11—C13	115.3 (2)
C2—N1—C3	120.48 (17)	C14—C11—C10	60.22 (14)
C16—N3—C17	120.65 (19)	C14—C11—C12	121.58 (19)
C23—N5—C22	113.62 (19)	C14—C11—C13	114.8 (2)
F3—C1—F2	106.9 (2)	C12—C11—C10	122.23 (19)
F3—C1—F1	108.25 (18)	C12—C11—C13	113.0 (2)
F3—C1—C2	111.28 (17)	N2—C9—C10	104.24 (15)
F2—C1—C2	110.81 (19)	C23—C20—C21	102.78 (18)
F1—C1—F2	106.53 (19)	C19—C20—C23	109.96 (17)
F1—C1—C2	112.8 (2)	C19—C20—C21	116.8 (2)
O2—C8—N2	120.71 (17)	C20—C19—C17	113.22 (17)
O2—C8—C3	121.51 (17)	C28—O5—C27	122.8 (6)
N2—C8—C3	117.78 (16)	C5—C4—C3	113.04 (18)
N2—C15—C16	109.67 (15)	C7—C4—C3	107.91 (17)
N2—C15—C14	104.44 (15)	C7—C4—C5	110.2 (2)
C14—C15—C16	110.58 (16)	C7—C4—C6	109.3 (2)
O3—C16—N3	123.7 (2)	C6—C4—C3	107.3 (2)
O3—C16—C15	122.15 (19)	C6—C4—C5	109.06 (19)
N3—C16—C15	114.15 (18)	C20—C21—C22	103.54 (19)
N1—C2—C1	115.23 (17)	N5—C22—C21	102.51 (19)
O1—C2—N1	126.7 (2)	N4—C18—C17	178.8 (4)
O1—C2—C1	118.1 (2)	O5—C27—C24	104.8 (4)
N1—C3—C8	109.22 (16)	C26—C27—O5	99.8 (6)
N1—C3—C4	113.04 (16)	C26—C27—C24	104.2 (9)
C8—C3—C4	113.02 (17)	C25—C27—O5	113.3 (6)
O4—C23—N5	126.7 (2)	C25—C27—C24	115.0 (9)
O4—C23—C20	124.6 (2)	C25—C27—C26	117.9 (10)
N5—C23—C20	108.67 (19)	C27A—O5A—C28A	105.5 (10)
C11—C10—C14	59.74 (14)	O5A—C27A—C25A	110.3 (10)
C9—C10—C14	108.39 (16)	O5A—C27A—C24A	104.7 (12)
C9—C10—C11	119.22 (18)	O5A—C27A—C26A	110.6 (13)
C10—C14—C15	108.01 (15)	C24A—C27A—C25A	126.8 (14)
C11—C14—C15	118.91 (18)	C24A—C27A—C26A	106.8 (18)
C11—C14—C10	60.04 (14)	C26A—C27A—C25A	96.9 (12)
N3—C17—C19	111.78 (18)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O4ⁱ	0.80 (3)	2.06 (3)	2.837 (2)	165 (4)
N3—H3···O5	0.87 (3)	1.99 (3)	2.848 (4)	170 (2)
N3—H3···O5A	0.87 (3)	1.95 (3)	2.795 (10)	163 (3)
N5—H5···O2ⁱⁱ	0.85 (3)	2.00 (3)	2.845 (2)	176 (3)
C5—H5C···O2	0.98	2.51	3.119 (3)	120
C7—H7C···O1ⁱⁱⁱ	0.98	2.50	3.456 (3)	165
C12—H12A···N2	0.98	2.41	3.069 (3)	124
C24—H24C···F1^iv	0.98	2.51	3.418 (11)	154

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

Acknowledgements

The authors declare the following competing financial interest(s): H. C. Bauser and A. Radocea are employees of Varda Space Industries and may own Varda Space Industries stock.

References

Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Halford, B. (2022). ACS Cent. Sci. 8, 405-407. Web of Science CrossRef CAS PubMed Google Scholar
Jiang, B., Li, G., Yu, J., Xu, X., Pan, H., Zhao, C., Zhong, J. & Zhang, F. (2023). React. Chem. Eng. 8, 1747–1759. Web of Science CrossRef CAS Google Scholar
Lamb, Y. N. (2022). Drugs 82, 585–591. Web of Science CrossRef CAS PubMed Google Scholar
Li, G., Sun, W., Yang, J., Shan, H., Pan, H., Zhang, F., Zuo, L. & Zhong, J. (2026). J. Mol. Struct. 1350, 144145. Web of Science CrossRef Google Scholar
McArdle, P. & Erxleben, A. (2024). CrystEngComm 26, 416–430. Web of Science CrossRef CAS Google Scholar
Owens, D. R., Pettersson, M. Y., Reese, M. R., Sammons, M. F., Tuttle, J. B., Verhoest, P. R., Wei, L., Yang, Q. & Yang, X. (2022). US Patent Number 11,351,149 B2, US Patent and Trademark Office. Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Rigaku OD, (2026). CrysAlis PRO Software System. Rigaku Corporation, Wroclaw, Poland Google Scholar
Sadeghi, M. S., Guo, R., Bellucci, M. A., Quino, J., Buckle, E. L., Nisbet, M. L., Yang, Z., Greenwell, C., Gorka, D. E., Pickard Iv, F. C., Wood, G. P. F., Sun, G., Wen, S.-H., Krzyzaniak, J. F., Meenan, P. A., Hancock, B. C. & Yang, X. H. (2024). Mol. Pharm. 21, 3800–3814. Web of Science CrossRef CAS PubMed Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Shi, D., Liu, J., Liu, S., Wang, Y., Yu, K. & Hu, X. (2025). CrystEngComm 27, 6009–6018. Web of Science CrossRef CAS Google Scholar