Apilimod

Morris, P.J.; Moore, C.; Thomas, C.J.

doi:10.1107/S2414314617006939

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 2| Part 5| May 2017| x170693

https://doi.org/10.1107/S2414314617006939

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access

Apilimod

Patrick J. Morris,^a ^* Curtis Moore ^b and Craig J. Thomas ^a

^aDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA, and ^bUCSD Crystallography Facility, University of California, San Diego, La Jolla, California 92093, USA
^*Correspondence e-mail: patrick.morris@mail.nih.gov

Edited by M. Zeller, Purdue University, USA (Received 21 April 2017; accepted 9 May 2017; online 23 May 2017)

Apilimod {systematic name: N-[(E)-(3-methylbenzylidene)amino]-6-(morpholin-4-yl)-2-[2-(pyridin-2-yl)ethoxy]pyrimidin-4-amine}, C₂₃H₂₆N₆O₂, a molecule of interest for its antiviral properties, was acquired from several different commercial vendors. Analysis of several commercial batches had led to some ambiguity over the exact structure. In order to remove any ambiguity, the structure was confirmed by X-ray crystallography. In addition, the NMR spectra are provided as reference material for future investigations.

Keywords: crystal structure; hydrogen bonding; structural confirmation; NMR; antiviral.

CCDC reference: 1526003

Structure description

Apilimod is an inhibitor of IL12/23 production, originally developed for the treatment of rheumatoid arthritis by Synta pharmaceuticals (Ono et al., 2003 ). More recently, it was disclosed that apilimod acts as an inhibitor of PIKFyve, a key enzyme which phosphorylates phosphatidylinositol 3-phosphate to phosphatidylinositol 3,5-diphosphate (Cai et al., 2013 ). Currently, apilimod is under investigation for its antiviral activity, and recent work has shown that it has pronounced activity against the ebola virus (Cunningham, 2016 ; Lichenstein et al. 2016 ). However, significantly different antiviral activity was noted between different commercial batches of apilimod, which led us to a more thorough chemical characterization of the pharmaceutical. Upon further examination, it was found that there were several commercial batches where the ethoxypyridyl substituent and the morpholine substituent on the core pyrimidine ring were switched, which led to sharply diminished antiviral activity. In order to confirm the correct structure, and ensure the most active batch of apilimod was actually apilimod, single-crystal X-ray crystallography on the most biologically active commercial batch of apilimod was utilized in order to obtain an unambiguous structure.

Structural analysis shows the presence of two crystallographically independent molecules, whose connectivity matches that of the published structure (Fig. 1). Notably, the presence of intermolecular hydrogen bonding between the NH of the hydrazine functionality and the pyrimidine nitrogen atom is present, with a hydrogen-bond length of 3.0626 (16) Å apparent (Table 1). The structures of the two molecules differ slightly in several ways, with the most distinct point of deviation being the O1—C17—C18 angle, which measures 106.76 (10)°, while the corresponding O1′—C17′—C18′ angle is 111.53 (11)°. As expected, in both structures the imine bond maintains an (E) geometry.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯N2′	0.91 (1)	2.16 (1)	3.0626 (16)	169 (1)
N1′—H1′⋯N2	0.92 (1)	2.10 (1)	3.0129 (16)	178 (2)

Figure 1
The molecular structure of the title compound, showing 50% probability displacement ellipsoids

Synthesis and crystallization

Apilimod was provided by Axon Medchem (Reston, VA) and synthesized via the route outlined in the original patent (Ono et al., 2003). The compound was crystallized as colorless blocks by dissolving a sample of approximately 1 mg in 0.35 ml dichloromethane and vapor diffusing the sample with pentane over two days. In addition to X-ray crystallography, the compound was characterized by ¹H NMR and ¹³C NMR. For reference, those values and spectra are reproduced here (Figs. 2 and 3). Notably, apilimod shows the morpholine peaks as two distinct peaks at 3.78 and 3.64 p.p.m. This is a key difference, as the incorrect regioisomeric structure shows a single morpholine peak.

Figure 2
The ¹H NMR spectrum of the title compound in deuterated chloroform. Note the clear splitting of the morphiline peaks at 3.78 and 3.64 p.p.m..

Figure 3
¹³C NMR spectrum of the title compound in deuterated chloroform

¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 8.54 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.74 (s, 1H), 7.60 (td, J = 7.7, 1.9 Hz, 1H), 7.54–7.39 (m, 2H), 7.32–7.23 (m, 1H), 7.20–7.08 (m, 2H), 6.08 (s, 1H), 4.65 (t, J = 6.9 Hz, 2H), 3.78 (dd, J = 5.7, 4.0 Hz, 4H), 3.64 (dd, J = 5.7, 4.1 Hz, 4H), 3.26 (t, J = 6.9 Hz, 2H), 2.38 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 164.7, 163.9, 162.7, 158.7, 149.4, 142.0, 138.5, 136.7, 134.3, 130.5, 128.7, 127.4, 124.2, 124.0, 121.7, 76.5, 66.8, 66.2, 44.8, 37.9, 21.5.

Refinement

Crystal data, data collection and structural refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₂₃H₂₆N₆O₂
M_r	418.50
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	100
a, b, c (Å)	14.9353 (5), 15.0367 (5), 19.4231 (7)
β (°)	98.130 (2)
V (Å³)	4318.2 (3)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	0.69
Crystal size (mm)	0.25 × 0.21 × 0.19

Data collection
Diffractometer	Bruker X8 APEXII
Absorption correction	Multi-scan (SADABS; Bruker, 2014 )
T_min, T_max	0.228, 0.320
No. of measured, independent and observed [I > 2σ(I)] reflections	50098, 7881, 6816
R_int	0.038
(sin θ/λ)_max (Å⁻¹)	0.604

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.103, 1.04
No. of reflections	7881
No. of parameters	569
No. of restraints	2
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.29, −0.22
Computer programs: APEX2 and SAINT (Bruker, 2013 ), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ) and OLEX2 (Dolomanov et al., 2009 ).

Structural data

CCDC reference: 1526003

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314617006939/zl4016sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314617006939/zl4016Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314617006939/zl4016Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2014); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

N-[(E)-(3-Methylbenzylidene)amino]-6-(morpholin-4-yl)-2-[2-(pyridin-2-yl)ethoxy]pyrimidin-4-amine top

Crystal data top

C₂₃H₂₆N₆O₂	F(000) = 1776
M_r = 418.50	D_x = 1.287 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54178 Å
a = 14.9353 (5) Å	Cell parameters from 9651 reflections
b = 15.0367 (5) Å	θ = 4.2–68.5°
c = 19.4231 (7) Å	µ = 0.69 mm⁻¹
β = 98.130 (2)°	T = 100 K
V = 4318.2 (3) Å³	Block, colourless
Z = 8	0.25 × 0.21 × 0.19 mm

Data collection top

Bruker X8 APEXII diffractometer	7881 independent reflections
Radiation source: Micro Focus Rotating Anode, Bruker Microstar FR-592	6816 reflections with I > 2σ(I)
Double Bounce Multilayer Mirrors monochromator	R_int = 0.038
Detector resolution: 7.9 pixels mm^-1	θ_max = 68.5°, θ_min = 3.0°
ω and φ scans	h = −17→18
Absorption correction: multi-scan (SADABS; Bruker, 2014)	k = −18→17
T_min = 0.228, T_max = 0.320	l = −23→22
50098 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.038	Hydrogen site location: mixed
wR(F²) = 0.103	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ²(F_o²) + (0.0527P)² + 1.2958P] where P = (F_o² + 2F_c²)/3
7881 reflections	(Δ/σ)_max = 0.001
569 parameters	Δρ_max = 0.29 e Å⁻³
2 restraints	Δρ_min = −0.22 e Å⁻³

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.

Refinement. All nonhydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL2014). All carbon bonded hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL2014. All other hydrogen atoms (H-bonding) were located in difference mapa. Their relative positions were restrained using DFIX commands and their thermal parameters freely refined.

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

	x	y	z	U_iso*/U_eq
O1	0.34895 (6)	0.49264 (6)	0.73640 (4)	0.0263 (2)
O2	0.79885 (6)	0.64234 (7)	0.75289 (5)	0.0313 (2)
N1	0.35964 (8)	0.58848 (8)	0.51765 (6)	0.0277 (2)
H1	0.2990 (9)	0.5779 (11)	0.5100 (8)	0.031 (4)*
N2	0.35530 (7)	0.54354 (7)	0.62910 (5)	0.0247 (2)
N3	0.48892 (7)	0.53447 (7)	0.71298 (5)	0.0240 (2)
N4	0.62723 (8)	0.58340 (8)	0.68986 (6)	0.0301 (3)
N5	0.40438 (7)	0.62175 (7)	0.46652 (5)	0.0255 (2)
N6	0.41499 (8)	0.34602 (8)	0.92805 (6)	0.0325 (3)
C1	0.40704 (9)	0.57268 (9)	0.58201 (6)	0.0242 (3)
C2	0.49980 (9)	0.58574 (9)	0.59747 (7)	0.0263 (3)
H2	0.5349	0.6060	0.5634	0.032*
C3	0.53853 (9)	0.56760 (9)	0.66551 (7)	0.0245 (3)
C4	0.40211 (9)	0.52482 (8)	0.69093 (6)	0.0232 (3)
C5	0.35753 (9)	0.63339 (9)	0.40663 (7)	0.0256 (3)
H5	0.2947	0.6200	0.4001	0.031*
C6	0.39974 (9)	0.66702 (9)	0.34817 (6)	0.0241 (3)
C7	0.34625 (9)	0.67965 (9)	0.28399 (7)	0.0250 (3)
H7	0.2829	0.6698	0.2802	0.030*
C8	0.38319 (9)	0.70632 (9)	0.22533 (7)	0.0262 (3)
C9	0.47498 (9)	0.72490 (9)	0.23255 (7)	0.0286 (3)
H9	0.5014	0.7447	0.1935	0.034*
C10	0.52836 (9)	0.71475 (10)	0.29639 (7)	0.0297 (3)
H10	0.5909	0.7290	0.3008	0.036*
C11	0.49266 (9)	0.68427 (9)	0.35387 (7)	0.0262 (3)
H11	0.5307	0.6751	0.3968	0.031*
C12	0.32505 (10)	0.71098 (10)	0.15531 (7)	0.0342 (3)
H12A	0.3463	0.6672	0.1239	0.051*
H12B	0.3289	0.7707	0.1358	0.051*
H12C	0.2621	0.6981	0.1607	0.051*
C13	0.68901 (9)	0.62522 (10)	0.64810 (7)	0.0313 (3)
H13A	0.6545	0.6593	0.6096	0.038*
H13B	0.7249	0.5792	0.6278	0.038*
C14	0.75126 (10)	0.68681 (10)	0.69423 (7)	0.0327 (3)
H14A	0.7954	0.7134	0.6667	0.039*
H14B	0.7152	0.7358	0.7105	0.039*
C15	0.67356 (9)	0.53962 (9)	0.75186 (7)	0.0286 (3)
H15A	0.7084	0.4882	0.7381	0.034*
H15B	0.6285	0.5172	0.7804	0.034*
C16	0.73665 (9)	0.60377 (10)	0.79406 (7)	0.0301 (3)
H16A	0.7009	0.6515	0.8124	0.036*
H16B	0.7707	0.5721	0.8342	0.036*
C17	0.39265 (9)	0.47784 (9)	0.80631 (6)	0.0267 (3)
H17A	0.4170	0.5344	0.8274	0.032*
H17B	0.4432	0.4352	0.8065	0.032*
C18	0.32146 (9)	0.44048 (9)	0.84671 (7)	0.0276 (3)
H18A	0.2722	0.4844	0.8474	0.033*
H18B	0.2952	0.3857	0.8238	0.033*
C19	0.36342 (9)	0.41962 (9)	0.91997 (7)	0.0275 (3)
C20	0.35200 (12)	0.47483 (10)	0.97472 (8)	0.0402 (4)
H20	0.3147	0.5261	0.9673	0.048*
C21	0.39550 (14)	0.45474 (12)	1.04074 (8)	0.0497 (4)
H21	0.3889	0.4922	1.0791	0.060*
C22	0.44831 (12)	0.37974 (11)	1.04972 (8)	0.0435 (4)
H22	0.4786	0.3641	1.0944	0.052*
C23	0.45640 (10)	0.32763 (11)	0.99250 (8)	0.0378 (3)
H23	0.4932	0.2759	0.9990	0.045*
O1'	0.14106 (6)	0.53264 (6)	0.39198 (4)	0.0257 (2)
O2'	−0.28751 (7)	0.71945 (7)	0.41569 (5)	0.0376 (2)
N1'	0.16456 (8)	0.61288 (8)	0.61828 (5)	0.0257 (2)
H1'	0.2222 (10)	0.5909 (12)	0.6227 (9)	0.039 (5)*
N2'	0.15315 (7)	0.57612 (7)	0.50314 (5)	0.0231 (2)
N3'	0.01224 (7)	0.58701 (7)	0.42790 (5)	0.0227 (2)
N4'	−0.11443 (7)	0.64966 (8)	0.46210 (6)	0.0266 (2)
N5'	0.12430 (8)	0.63141 (7)	0.67570 (5)	0.0257 (2)
N6'	0.09634 (8)	0.58164 (9)	0.16839 (6)	0.0349 (3)
C1'	0.11114 (9)	0.60824 (8)	0.55523 (6)	0.0229 (3)
C2'	0.02131 (9)	0.63494 (9)	0.54633 (7)	0.0240 (3)
H2'	−0.0058	0.6597	0.5834	0.029*
C3'	−0.02685 (9)	0.62349 (8)	0.48016 (6)	0.0226 (3)
C4'	0.09872 (9)	0.56733 (8)	0.44311 (6)	0.0223 (3)
C5'	0.17579 (9)	0.63390 (9)	0.73411 (7)	0.0270 (3)
H5'	0.2391	0.6254	0.7358	0.032*
C6'	0.13749 (10)	0.64987 (9)	0.79854 (7)	0.0277 (3)
C7'	0.19622 (10)	0.66530 (9)	0.85979 (7)	0.0300 (3)
H7'	0.2597	0.6643	0.8590	0.036*
C8'	0.16319 (11)	0.68225 (9)	0.92267 (7)	0.0326 (3)
C9'	0.07049 (11)	0.68297 (10)	0.92257 (7)	0.0347 (3)
H9'	0.0470	0.6949	0.9646	0.042*
C10'	0.01152 (11)	0.66672 (10)	0.86247 (8)	0.0345 (3)
H10'	−0.0518	0.6670	0.8637	0.041*
C11'	0.04427 (10)	0.65000 (9)	0.80046 (7)	0.0304 (3)
H11'	0.0034	0.6387	0.7593	0.037*
C12'	0.22766 (12)	0.69882 (11)	0.98798 (8)	0.0401 (4)
H12D	0.2258	0.6485	1.0198	0.060*
H12E	0.2102	0.7534	1.0103	0.060*
H12F	0.2891	0.7054	0.9765	0.060*
C13'	−0.16680 (10)	0.69041 (11)	0.51118 (7)	0.0329 (3)
H13C	−0.1259	0.7202	0.5487	0.040*
H13D	−0.2015	0.6443	0.5324	0.040*
C14'	−0.23092 (10)	0.75771 (11)	0.47298 (8)	0.0366 (3)
H14C	−0.2691	0.7834	0.5057	0.044*
H14D	−0.1954	0.8066	0.4561	0.044*
C15'	−0.17133 (9)	0.61136 (9)	0.40220 (7)	0.0283 (3)
H15C	−0.2069	0.5613	0.4174	0.034*
H15D	−0.1330	0.5881	0.3687	0.034*
C16'	−0.23406 (10)	0.68121 (10)	0.36784 (7)	0.0337 (3)
H16C	−0.1983	0.7285	0.3490	0.040*
H16D	−0.2744	0.6544	0.3285	0.040*
C17'	0.08812 (9)	0.52409 (9)	0.32382 (6)	0.0252 (3)
H17C	0.0283	0.4984	0.3287	0.030*
H17D	0.1191	0.4829	0.2952	0.030*
C18'	0.07489 (10)	0.61360 (9)	0.28716 (7)	0.0291 (3)
H18C	0.0332	0.6506	0.3103	0.035*
H18D	0.1337	0.6449	0.2907	0.035*
C19'	0.03685 (9)	0.60182 (9)	0.21177 (7)	0.0275 (3)
C20'	−0.05490 (10)	0.60954 (11)	0.18879 (8)	0.0372 (3)
H20'	−0.0956	0.6231	0.2207	0.045*
C21'	−0.08694 (11)	0.59735 (12)	0.11920 (8)	0.0428 (4)
H21'	−0.1497	0.6025	0.1026	0.051*
C22'	−0.02636 (12)	0.57763 (12)	0.07445 (8)	0.0411 (4)
H22'	−0.0460	0.5694	0.0262	0.049*
C23'	0.06354 (11)	0.57011 (12)	0.10134 (8)	0.0413 (4)
H23'	0.1051	0.5558	0.0702	0.050*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0243 (5)	0.0343 (5)	0.0202 (4)	−0.0029 (4)	0.0029 (3)	0.0037 (4)
O2	0.0267 (5)	0.0350 (5)	0.0321 (5)	−0.0038 (4)	0.0037 (4)	−0.0031 (4)
N1	0.0222 (6)	0.0399 (7)	0.0209 (5)	−0.0032 (5)	0.0028 (4)	0.0033 (5)
N2	0.0239 (5)	0.0290 (6)	0.0211 (5)	−0.0002 (4)	0.0032 (4)	0.0015 (4)
N3	0.0234 (5)	0.0251 (6)	0.0232 (5)	−0.0010 (4)	0.0020 (4)	0.0013 (4)
N4	0.0224 (6)	0.0394 (7)	0.0279 (6)	−0.0029 (5)	0.0013 (5)	0.0089 (5)
N5	0.0267 (6)	0.0297 (6)	0.0207 (5)	−0.0007 (5)	0.0055 (4)	0.0010 (4)
N6	0.0327 (6)	0.0346 (7)	0.0309 (6)	0.0007 (5)	0.0071 (5)	0.0060 (5)
C1	0.0262 (7)	0.0251 (6)	0.0214 (6)	0.0011 (5)	0.0035 (5)	−0.0006 (5)
C2	0.0247 (7)	0.0311 (7)	0.0237 (6)	−0.0001 (5)	0.0056 (5)	0.0024 (5)
C3	0.0245 (6)	0.0238 (6)	0.0252 (6)	0.0007 (5)	0.0034 (5)	0.0008 (5)
C4	0.0249 (6)	0.0231 (6)	0.0220 (6)	−0.0014 (5)	0.0044 (5)	−0.0008 (5)
C5	0.0240 (6)	0.0293 (7)	0.0236 (6)	−0.0013 (5)	0.0038 (5)	−0.0009 (5)
C6	0.0264 (7)	0.0239 (6)	0.0221 (6)	−0.0008 (5)	0.0038 (5)	−0.0019 (5)
C7	0.0239 (6)	0.0249 (7)	0.0259 (6)	−0.0006 (5)	0.0024 (5)	0.0001 (5)
C8	0.0321 (7)	0.0226 (6)	0.0234 (6)	0.0023 (5)	0.0023 (5)	0.0006 (5)
C9	0.0331 (7)	0.0285 (7)	0.0256 (7)	−0.0010 (6)	0.0086 (5)	0.0030 (5)
C10	0.0242 (7)	0.0339 (7)	0.0314 (7)	−0.0026 (5)	0.0055 (5)	0.0004 (6)
C11	0.0258 (7)	0.0289 (7)	0.0235 (6)	−0.0007 (5)	0.0018 (5)	−0.0013 (5)
C12	0.0379 (8)	0.0400 (8)	0.0235 (7)	0.0014 (6)	0.0000 (6)	0.0045 (6)
C13	0.0246 (7)	0.0401 (8)	0.0294 (7)	−0.0021 (6)	0.0046 (5)	0.0053 (6)
C14	0.0313 (7)	0.0322 (8)	0.0356 (8)	−0.0016 (6)	0.0086 (6)	0.0018 (6)
C15	0.0262 (7)	0.0297 (7)	0.0286 (7)	0.0003 (5)	−0.0006 (5)	0.0041 (5)
C16	0.0299 (7)	0.0314 (7)	0.0290 (7)	−0.0005 (6)	0.0038 (6)	−0.0009 (6)
C17	0.0278 (7)	0.0321 (7)	0.0198 (6)	−0.0021 (5)	0.0015 (5)	0.0031 (5)
C18	0.0292 (7)	0.0288 (7)	0.0252 (7)	−0.0014 (5)	0.0053 (5)	0.0028 (5)
C19	0.0301 (7)	0.0270 (7)	0.0261 (7)	−0.0042 (5)	0.0068 (5)	0.0046 (5)
C20	0.0618 (10)	0.0292 (8)	0.0303 (8)	0.0036 (7)	0.0090 (7)	0.0023 (6)
C21	0.0840 (13)	0.0380 (9)	0.0266 (8)	−0.0095 (9)	0.0064 (8)	−0.0022 (7)
C22	0.0544 (10)	0.0415 (9)	0.0308 (8)	−0.0155 (8)	−0.0066 (7)	0.0106 (7)
C23	0.0334 (8)	0.0400 (8)	0.0392 (8)	−0.0015 (6)	0.0019 (6)	0.0129 (7)
O1'	0.0230 (4)	0.0346 (5)	0.0192 (4)	0.0046 (4)	0.0018 (3)	−0.0038 (4)
O2'	0.0268 (5)	0.0451 (6)	0.0387 (6)	0.0091 (4)	−0.0036 (4)	−0.0094 (5)
N1'	0.0241 (6)	0.0339 (6)	0.0190 (5)	0.0018 (5)	0.0030 (4)	−0.0023 (4)
N2'	0.0233 (5)	0.0268 (6)	0.0192 (5)	0.0002 (4)	0.0025 (4)	−0.0007 (4)
N3'	0.0223 (5)	0.0244 (5)	0.0212 (5)	0.0009 (4)	0.0028 (4)	−0.0004 (4)
N4'	0.0226 (6)	0.0355 (6)	0.0217 (5)	0.0044 (5)	0.0026 (4)	−0.0027 (5)
N5'	0.0302 (6)	0.0274 (6)	0.0199 (5)	0.0002 (5)	0.0050 (4)	−0.0014 (4)
N6'	0.0321 (6)	0.0459 (7)	0.0277 (6)	0.0008 (5)	0.0071 (5)	0.0016 (5)
C1'	0.0257 (6)	0.0224 (6)	0.0204 (6)	−0.0021 (5)	0.0027 (5)	0.0010 (5)
C2'	0.0258 (6)	0.0254 (6)	0.0214 (6)	0.0015 (5)	0.0052 (5)	−0.0001 (5)
C3'	0.0225 (6)	0.0221 (6)	0.0234 (6)	0.0001 (5)	0.0045 (5)	0.0023 (5)
C4'	0.0233 (6)	0.0228 (6)	0.0209 (6)	−0.0002 (5)	0.0039 (5)	0.0002 (5)
C5'	0.0303 (7)	0.0274 (7)	0.0232 (6)	0.0012 (5)	0.0028 (5)	−0.0008 (5)
C6'	0.0388 (8)	0.0223 (6)	0.0213 (6)	0.0010 (5)	0.0021 (5)	−0.0005 (5)
C7'	0.0378 (8)	0.0260 (7)	0.0255 (7)	0.0011 (6)	0.0017 (6)	0.0001 (5)
C8'	0.0527 (9)	0.0219 (7)	0.0218 (7)	0.0025 (6)	−0.0002 (6)	−0.0001 (5)
C9'	0.0498 (9)	0.0288 (7)	0.0276 (7)	0.0044 (6)	0.0126 (6)	0.0011 (6)
C10'	0.0399 (8)	0.0319 (8)	0.0333 (8)	0.0011 (6)	0.0108 (6)	0.0001 (6)
C11'	0.0366 (8)	0.0275 (7)	0.0276 (7)	−0.0010 (6)	0.0060 (6)	−0.0010 (5)
C12'	0.0543 (10)	0.0376 (8)	0.0264 (7)	0.0030 (7)	−0.0016 (7)	−0.0041 (6)
C13'	0.0284 (7)	0.0446 (8)	0.0266 (7)	0.0059 (6)	0.0066 (6)	−0.0031 (6)
C14'	0.0304 (7)	0.0437 (9)	0.0340 (8)	0.0086 (6)	−0.0008 (6)	−0.0090 (6)
C15'	0.0251 (7)	0.0308 (7)	0.0280 (7)	0.0002 (5)	0.0006 (5)	−0.0021 (5)
C16'	0.0336 (8)	0.0361 (8)	0.0295 (7)	0.0056 (6)	−0.0024 (6)	−0.0037 (6)
C17'	0.0254 (6)	0.0305 (7)	0.0191 (6)	0.0015 (5)	0.0012 (5)	−0.0044 (5)
C18'	0.0315 (7)	0.0309 (7)	0.0248 (7)	−0.0020 (6)	0.0034 (5)	−0.0014 (5)
C19'	0.0302 (7)	0.0277 (7)	0.0250 (7)	−0.0009 (5)	0.0055 (5)	0.0022 (5)
C20'	0.0297 (7)	0.0537 (10)	0.0290 (7)	0.0014 (7)	0.0069 (6)	0.0074 (7)
C21'	0.0316 (8)	0.0612 (11)	0.0335 (8)	−0.0050 (7)	−0.0020 (6)	0.0124 (7)
C22'	0.0485 (9)	0.0504 (10)	0.0227 (7)	−0.0061 (7)	−0.0009 (6)	0.0052 (6)
C23'	0.0451 (9)	0.0549 (10)	0.0257 (7)	0.0013 (7)	0.0115 (6)	−0.0005 (7)

Geometric parameters (Å, º) top

O1—C4	1.3575 (15)	O1'—C4'	1.3549 (15)
O1—C17	1.4381 (15)	O1'—C17'	1.4486 (15)
O2—C14	1.4217 (17)	O2'—C14'	1.4204 (17)
O2—C16	1.4313 (17)	O2'—C16'	1.4289 (17)
N1—H1	0.911 (13)	N1'—H1'	0.915 (14)
N1—N5	1.3678 (15)	N1'—N5'	1.3684 (15)
N1—C1	1.3673 (17)	N1'—C1'	1.3656 (16)
N2—C1	1.3513 (17)	N2'—C1'	1.3527 (16)
N2—C4	1.3314 (17)	N2'—C4'	1.3303 (16)
N3—C3	1.3566 (17)	N3'—C3'	1.3564 (16)
N3—C4	1.3147 (17)	N3'—C4'	1.3172 (17)
N4—C3	1.3631 (18)	N4'—C3'	1.3635 (17)
N4—C13	1.4548 (17)	N4'—C13'	1.4515 (17)
N4—C15	1.4583 (17)	N4'—C15'	1.4587 (17)
N5—C5	1.2819 (17)	N5'—C5'	1.2781 (17)
N6—C19	1.3448 (19)	N6'—C19'	1.3429 (18)
N6—C23	1.3443 (19)	N6'—C23'	1.3363 (19)
C1—C2	1.3893 (19)	C1'—C2'	1.3877 (18)
C2—H2	0.9500	C2'—H2'	0.9500
C2—C3	1.3925 (18)	C2'—C3'	1.3918 (18)
C5—H5	0.9500	C5'—H5'	0.9500
C5—C6	1.4645 (18)	C5'—C6'	1.4675 (18)
C6—C7	1.3952 (18)	C6'—C7'	1.3940 (19)
C6—C11	1.4008 (19)	C6'—C11'	1.398 (2)
C7—H7	0.9500	C7'—H7'	0.9500
C7—C8	1.3932 (18)	C7'—C8'	1.404 (2)
C8—C9	1.387 (2)	C8'—C9'	1.384 (2)
C8—C12	1.5083 (18)	C8'—C12'	1.501 (2)
C9—H9	0.9500	C9'—H9'	0.9500
C9—C10	1.3843 (19)	C9'—C10'	1.381 (2)
C10—H10	0.9500	C10'—H10'	0.9500
C10—C11	1.3818 (19)	C10'—C11'	1.386 (2)
C11—H11	0.9500	C11'—H11'	0.9500
C12—H12A	0.9800	C12'—H12D	0.9800
C12—H12B	0.9800	C12'—H12E	0.9800
C12—H12C	0.9800	C12'—H12F	0.9800
C13—H13A	0.9900	C13'—H13C	0.9900
C13—H13B	0.9900	C13'—H13D	0.9900
C13—C14	1.513 (2)	C13'—C14'	1.513 (2)
C14—H14A	0.9900	C14'—H14C	0.9900
C14—H14B	0.9900	C14'—H14D	0.9900
C15—H15A	0.9900	C15'—H15C	0.9900
C15—H15B	0.9900	C15'—H15D	0.9900
C15—C16	1.5071 (19)	C15'—C16'	1.500 (2)
C16—H16A	0.9900	C16'—H16C	0.9900
C16—H16B	0.9900	C16'—H16D	0.9900
C17—H17A	0.9900	C17'—H17C	0.9900
C17—H17B	0.9900	C17'—H17D	0.9900
C17—C18	1.5159 (18)	C17'—C18'	1.5225 (19)
C18—H18A	0.9900	C18'—H18C	0.9900
C18—H18B	0.9900	C18'—H18D	0.9900
C18—C19	1.5045 (18)	C18'—C19'	1.5044 (18)
C19—C20	1.379 (2)	C19'—C20'	1.385 (2)
C20—H20	0.9500	C20'—H20'	0.9500
C20—C21	1.386 (2)	C20'—C21'	1.381 (2)
C21—H21	0.9500	C21'—H21'	0.9500
C21—C22	1.373 (3)	C21'—C22'	1.373 (2)
C22—H22	0.9500	C22'—H22'	0.9500
C22—C23	1.379 (2)	C22'—C23'	1.375 (2)
C23—H23	0.9500	C23'—H23'	0.9500

C4—O1—C17	116.13 (10)	C4'—O1'—C17'	116.94 (10)
C14—O2—C16	110.36 (10)	C14'—O2'—C16'	110.32 (11)
N5—N1—H1	121.4 (10)	N5'—N1'—H1'	120.9 (11)
C1—N1—H1	119.6 (10)	C1'—N1'—H1'	119.2 (11)
C1—N1—N5	118.97 (11)	C1'—N1'—N5'	118.22 (11)
C4—N2—C1	113.68 (11)	C4'—N2'—C1'	113.60 (11)
C4—N3—C3	115.31 (11)	C4'—N3'—C3'	115.79 (11)
C3—N4—C13	122.94 (11)	C3'—N4'—C13'	122.64 (11)
C3—N4—C15	122.16 (11)	C3'—N4'—C15'	121.38 (11)
C13—N4—C15	113.03 (11)	C13'—N4'—C15'	112.53 (11)
C5—N5—N1	116.67 (11)	C5'—N5'—N1'	116.79 (11)
C23—N6—C19	117.29 (13)	C23'—N6'—C19'	117.19 (13)
N1—C1—C2	123.00 (12)	N1'—C1'—C2'	121.93 (11)
N2—C1—N1	113.80 (11)	N2'—C1'—N1'	114.52 (11)
N2—C1—C2	123.20 (12)	N2'—C1'—C2'	123.54 (11)
C1—C2—H2	121.8	C1'—C2'—H2'	121.8
C1—C2—C3	116.44 (12)	C1'—C2'—C3'	116.33 (11)
C3—C2—H2	121.8	C3'—C2'—H2'	121.8
N3—C3—N4	115.19 (11)	N3'—C3'—N4'	115.02 (11)
N3—C3—C2	121.56 (12)	N3'—C3'—C2'	121.34 (11)
N4—C3—C2	123.24 (12)	N4'—C3'—C2'	123.61 (12)
N2—C4—O1	112.42 (11)	N2'—C4'—O1'	112.95 (11)
N3—C4—O1	117.91 (11)	N3'—C4'—O1'	117.81 (11)
N3—C4—N2	129.66 (12)	N3'—C4'—N2'	129.24 (11)
N5—C5—H5	119.6	N5'—C5'—H5'	119.9
N5—C5—C6	120.74 (12)	N5'—C5'—C6'	120.24 (13)
C6—C5—H5	119.6	C6'—C5'—H5'	119.9
C7—C6—C5	119.00 (12)	C7'—C6'—C5'	118.75 (13)
C7—C6—C11	118.76 (12)	C7'—C6'—C11'	119.07 (12)
C11—C6—C5	122.21 (12)	C11'—C6'—C5'	122.18 (12)
C6—C7—H7	119.1	C6'—C7'—H7'	119.4
C8—C7—C6	121.80 (12)	C6'—C7'—C8'	121.10 (14)
C8—C7—H7	119.1	C8'—C7'—H7'	119.4
C7—C8—C12	120.45 (12)	C7'—C8'—C12'	120.20 (14)
C9—C8—C7	118.39 (12)	C9'—C8'—C7'	118.34 (13)
C9—C8—C12	121.11 (12)	C9'—C8'—C12'	121.46 (13)
C8—C9—H9	119.9	C8'—C9'—H9'	119.4
C10—C9—C8	120.28 (12)	C10'—C9'—C8'	121.20 (13)
C10—C9—H9	119.9	C10'—C9'—H9'	119.4
C9—C10—H10	119.3	C9'—C10'—H10'	119.8
C11—C10—C9	121.41 (12)	C9'—C10'—C11'	120.37 (14)
C11—C10—H10	119.3	C11'—C10'—H10'	119.8
C6—C11—H11	120.4	C6'—C11'—H11'	120.0
C10—C11—C6	119.26 (12)	C10'—C11'—C6'	119.91 (13)
C10—C11—H11	120.4	C10'—C11'—H11'	120.0
C8—C12—H12A	109.5	C8'—C12'—H12D	109.5
C8—C12—H12B	109.5	C8'—C12'—H12E	109.5
C8—C12—H12C	109.5	C8'—C12'—H12F	109.5
H12A—C12—H12B	109.5	H12D—C12'—H12E	109.5
H12A—C12—H12C	109.5	H12D—C12'—H12F	109.5
H12B—C12—H12C	109.5	H12E—C12'—H12F	109.5
N4—C13—H13A	110.0	N4'—C13'—H13C	109.9
N4—C13—H13B	110.0	N4'—C13'—H13D	109.9
N4—C13—C14	108.63 (11)	N4'—C13'—C14'	108.83 (11)
H13A—C13—H13B	108.3	H13C—C13'—H13D	108.3
C14—C13—H13A	110.0	C14'—C13'—H13C	109.9
C14—C13—H13B	110.0	C14'—C13'—H13D	109.9
O2—C14—C13	112.48 (12)	O2'—C14'—C13'	112.23 (13)
O2—C14—H14A	109.1	O2'—C14'—H14C	109.2
O2—C14—H14B	109.1	O2'—C14'—H14D	109.2
C13—C14—H14A	109.1	C13'—C14'—H14C	109.2
C13—C14—H14B	109.1	C13'—C14'—H14D	109.2
H14A—C14—H14B	107.8	H14C—C14'—H14D	107.9
N4—C15—H15A	109.6	N4'—C15'—H15C	109.8
N4—C15—H15B	109.6	N4'—C15'—H15D	109.8
N4—C15—C16	110.33 (12)	N4'—C15'—C16'	109.59 (12)
H15A—C15—H15B	108.1	H15C—C15'—H15D	108.2
C16—C15—H15A	109.6	C16'—C15'—H15C	109.8
C16—C15—H15B	109.6	C16'—C15'—H15D	109.8
O2—C16—C15	111.14 (11)	O2'—C16'—C15'	111.32 (12)
O2—C16—H16A	109.4	O2'—C16'—H16C	109.4
O2—C16—H16B	109.4	O2'—C16'—H16D	109.4
C15—C16—H16A	109.4	C15'—C16'—H16C	109.4
C15—C16—H16B	109.4	C15'—C16'—H16D	109.4
H16A—C16—H16B	108.0	H16C—C16'—H16D	108.0
O1—C17—H17A	110.4	O1'—C17'—H17C	109.3
O1—C17—H17B	110.4	O1'—C17'—H17D	109.3
O1—C17—C18	106.76 (10)	O1'—C17'—C18'	111.53 (11)
H17A—C17—H17B	108.6	H17C—C17'—H17D	108.0
C18—C17—H17A	110.4	C18'—C17'—H17C	109.3
C18—C17—H17B	110.4	C18'—C17'—H17D	109.3
C17—C18—H18A	109.7	C17'—C18'—H18C	109.5
C17—C18—H18B	109.7	C17'—C18'—H18D	109.5
H18A—C18—H18B	108.2	H18C—C18'—H18D	108.0
C19—C18—C17	109.76 (11)	C19'—C18'—C17'	110.93 (11)
C19—C18—H18A	109.7	C19'—C18'—H18C	109.5
C19—C18—H18B	109.7	C19'—C18'—H18D	109.5
N6—C19—C18	115.92 (12)	N6'—C19'—C18'	116.42 (12)
N6—C19—C20	122.47 (13)	N6'—C19'—C20'	121.94 (13)
C20—C19—C18	121.57 (13)	C20'—C19'—C18'	121.62 (12)
C19—C20—H20	120.4	C19'—C20'—H20'	120.2
C19—C20—C21	119.29 (15)	C21'—C20'—C19'	119.64 (14)
C21—C20—H20	120.4	C21'—C20'—H20'	120.2
C20—C21—H21	120.6	C20'—C21'—H21'	120.6
C22—C21—C20	118.82 (15)	C22'—C21'—C20'	118.70 (14)
C22—C21—H21	120.6	C22'—C21'—H21'	120.6
C21—C22—H22	120.7	C21'—C22'—H22'	120.9
C21—C22—C23	118.60 (14)	C21'—C22'—C23'	118.23 (14)
C23—C22—H22	120.7	C23'—C22'—H22'	120.9
N6—C23—C22	123.52 (15)	N6'—C23'—C22'	124.28 (14)
N6—C23—H23	118.2	N6'—C23'—H23'	117.9
C22—C23—H23	118.2	C22'—C23'—H23'	117.9

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N2′	0.91 (1)	2.16 (1)	3.0626 (16)	169 (1)
N1′—H1′···N2	0.92 (1)	2.10 (1)	3.0129 (16)	178 (2)

Acknowledgements

The authors would like to thank Judith M. White, Julie Dyall, Elizabeth A. Nelson, Gene G. Olinger Jr and Lisa Dewald at the University of Virginia and at the National Institute of Allergy and Infectious Diseases for leading the research that led to the discovery of the discrepancy. The authors would also like to thank the intramural research program at the National Center for Advancing Translational Studies for funding and the UCSD crystallography facility for the X-ray data collection.

Funding information

Funding for this research was provided by: The National Institutes of Health, National Center for Advancing Translational Sciences intramural research fund.

References

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Volume 2| Part 5| May 2017| x170693

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organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Apilimod

Structure description

Synthesis and crystallization

Refinement

Structural data

Acknowledgements

Funding information

References

organic compounds