5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine Dihydrochloride Dihydrate

Abstract

The dihydrochloride salt of pexidartinib was synthesized and the crystal structure of its dihydrate was determined from single crystal data. The asymmetric unit consists of one formula unit. In the pexidartinib molecule, the N atom of the central pyridine ring and the pyridine-N atom of the pyrrolopyridine group are both protonated. The pexidartinib molecule forms N–H···O and N–H···Cl interactions with neighboring water molecules and chloride ions, respectively. Water/chloride (O–H···Cl) and water/water (O–H···O) interactions are also observed. Collectively, these intermolecular interactions result in a complex H-bonded framework structure.

1. Introduction

Pexidartinib (I), Scheme 1, is a kinase inhibitor drug used for the treatment of symptomatic tenosynovial giant cell tumor (TGCT), a rare type of joint tumor. It acts by inhibiting multiple receptor tyrosine kinases including colony-stimulating factor-1 receptor (CSF-1R), c-Kit proto-oncogene proteins (c-Kit) and fms-like tyrosine kinase-3 (Flt-3) [1,2]. FDA approval of this drug was granted in 2019 [3,4] and its monohydrochloride is being sold under the brand name Turalio.

The existence of solid forms of pexidartinib and of its monohydrochloride and dihydrochloride salts has been disclosed in the patent literature [5,6]. Herein we report the crystal structure of a dihydrate of pexidartinib dihydrochloride, (II)·2H₂O (Scheme 1), which was produced in the course of a study aimed at optimizing synthetic procedures. Given the great therapeutic importance of pexidartinib, knowledge of the structure of (II)·2H₂O and the analysis of its intermolecular interactions provide valuable information for further studies, e.g., the investigation of biological and physicochemical properties.

2. Results

Crystal data and structure refinement parameters are collected

Table 1. Crystal data and structure refinement.

Compound	(II)·2H2O
Moiety formula	(C20H17ClF3N5)2+ · 2Cl− · 2H2O
Empirical formula	C20H21Cl3F3N5O2
Formula weight	526.77
Temperature (K)	183(2)
Wavelength (Å)	0.71073
Crystal system	Monoclinic
Space group	P21/c
a (Å)	5.4641(3)
b (Å)	16.2163(10)
c (Å)	26.3877(17)
β (°)	93.0718(18)
Unit cell volume (Å3)	2334.8(2)
Z/Z’	4/1
Reflections collected/Rint	34,479/0.0479
Data/restraints/parameters	4145/8/331
Goodness-of-fit on F2	1.044
R1 [I > 2 σ(I)]	0.0365
wR2 (all data)	0.0879
Largest diff. peak and hole (e · Å−3)	0.444 and −0.368
CCDC no.	2265163

. The asymmetric unit of (II)·2H₂O contains one formula unit consisting of one pexidartinib molecule, two chloride ions and two water molecules (Figure 1). The N atom of the central pyridine ring and that of the pyridine ring of the pyrrolopyridine group are both protonated. The molecular conformation is defined by the relative orientation of three nearly planar fragments. The central N,5-methylpyridin-2-amine group (C8 > C14, N3, N4) forms nearly orthogonal arrangements with both the pyrrolopyridine (C1 > C8, N1, N2) plane and with the 3-methylpyridine (C14 > C19, N5) unit as evidenced by angles of 84.69(4)° and 82.75(2)° between the respective mean planes. In addition, the C13–N4–C14–C15 bridge between the pyridine rings (C9 > C13, N3) and (C15 > C19, N5) displays a torsion angle of 89.9(3)°.

Both pyridinium NH groups form hydrogen bonds to water molecules, N2—H2N···O1 and N3—H3N···O2(−x + 1, −y + 1, −z + 1), whilst the other two NH functions are connected to chloride ions, N1—H1N···Cl2 and N4—H4N···Cl3 (

Table 2. Hydrogen bonds (Å and °).

D—H···A	dD—H	dH···A	dD···A	<(DHA)
N1—H1N···Cl2	0.878(16)	2.242(17)	3.1109(19)	171(2)
N2—H2N···O1	0.869(16)	1.895(17)	2.762(2)	175(2)
N3—H3N···O2 i	0.891(16)	1.895(17)	2.774(3)	168(2)
N4—H4N···Cl3	0.871(16)	2.267(17)	3.138(2)	178(2)
O1—H1OA···Cl2	0.836(17)	2.182(19)	3.0014(18)	167(3)
O1—H1OB···Cl3 ii	0.828(18)	2.304(19)	3.1217(18)	169(3)
O2—H2OA···O1	0.854(18)	1.902(19)	2.754(2)	176(3)
O2—H2OB···Cl3 iii	0.851(18)	2.35(2)	3.1561(19)	158(3)

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

, Figure 2). The first water molecule (O1) serves as a bridge between two chloride units via Cl2···H1OA—O1—H1OB···Cl3(x, −y + 1/2, z − 1/2). It also accepts a hydrogen bond from the other water molecule, O2—H2OA···O1. The latter is additionally H-bonded to a chloride ion, O2—H2OB···Cl3(x + 1, −y + 1/2, z − 1/2). Collectively, these classical H-bond interactions define a 3-dimensional framework in which the pexidartinib (Pdt) molecule serves as a four-connected node (connections: 2 × Cl⁻ and 2 × H₂O). The first water molecule (O1) is also four-connected (1 × Pdt, 2 × Cl⁻, 1 × H₂O). By contrast, the second water molecule (O2) is a three-connected node (1 × Pdt, 1 × Cl⁻, 1 × H₂O), and the chloride ions are two- and three-connected (1 × Pdt, 1 × H₂O and 1 × Pdt, 2 × H₂O). An essential fragment of the H-bonded framework structure is shown in Figure 2.

3. Materials and Methods

5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine dihydrochloride (II) was prepared by following a published procedure [6,7] and as illustrated in Scheme 1.

NMR spectra were recorded on a Bruker UltraShield^TM 300 MHz spectrometer. ¹H NMR (300 MHz, DMSO-d6) δ = 11.77 (d, J = 2.5 Hz, 1H), 9.12 (s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 12.3, 2.3 Hz, 2H), 7.97–7.81 (m, 3H), 7.48 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 4.78 (s, 2H), 3.96 (s, 2H). The obtained NMR data were found to be in agreement with previously published data for (II) [6,7] (see Supplementary Materials).

HPLC measurements were carried out with a Shimadzu Nexera-i LC-2040C 3D system with DAD detector; Gemini-NX 3 µ C18 (4.6 × 50 mm) column; mobile phase A: water with 0.1% formic acid, B: acetonitrile with 0.1% formic acid, using a gradient (80:20 to 5:95); flow 0.5 mL/min. LC/Mass spectra were recorded using a Shimadzu LSMS-2020 system with a Single Quadrupole MS detector.

Single crystals suitable for X-ray structure determination were grown from a saturated solution of (II) in dioxane. Intensity data for the single crystal structure determination were recorded with a Bruker D8 Quest Photon 100 diffractometer using MoKα radiation (λ = 0.71073 Å). The crystal structure was solved by Direct Methods with SHELXT [8] and refined with least-squares techniques using SHELXL [9]. H atoms were identified in difference-Fourier maps and those bonded to carbon atoms were refined using a riding model with U_iso parameters set to 1.2U_eq(C). The H atom positions at N and O atoms were refined with distance restraints, N–H = 0.89(2) Å and O–H = 0.83(2) Å, and their U_iso parameters were refined freely.