2-(3-{(3R,4R)-4-Methyl-3-[meth­yl(7H-pyrrolo­[2,3-d]pyrimidin-4-yl)amino]­piperidin-1-yl}oxetan-3-yl)aceto­nitrile monohydrate

Matthias Gehringer; Ellen Pfaffenrot; Peter R W E F Keck; Dieter Schollmeyer; Stefan A Laufer

doi:10.1107/S1600536814004449

. 2014 Mar 5;70(Pt 4):o382–o383. doi: 10.1107/S1600536814004449

2-(3-{(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}oxetan-3-yl)acetonitrile monohydrate

Matthias Gehringer ^a, Ellen Pfaffenrot ^a, Peter R W E F Keck ^a, Dieter Schollmeyer ^b, Stefan A Laufer ^a,^*

PMCID: PMC3998552 PMID: 24826108

Abstract

In the title compound, C₁₈H₂₄N₆O·H₂O, the piperidine ring adopts a chair conformation with an N—C—C—C torsion angle of 39.5 (5)° between the cis-related substituents. The pyrrole N—H group forms a water-mediated intermolecular hydrogen bond to one of the N atoms of the annelated pyrimidine ring. The water molecule connects two organic molecules and is disorderd over two positions (occupancies of 0.48 and 0.52). The crystal packing shows zigzag chains of alternating organic and water molecules running parallel to the a axis.

Related literature

For the biological activity and structure–activity relationships of tofacitinib {systematic name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile} derivatives, see: Flanagan et al. (2010 ▶). For a general overview on the JAK–STAT pathway, see: Shuai & Liu (2003 ▶). The use of oxetanes as carbonyl bioisosteres has been reviewed extensively by Wuitschik et al. (2010 ▶). For a recent application of this concept towards tofacitinib-derived JAK3 inhibitors, see: Gehringer et al. (2014 ▶).

Experimental

Crystal data

C₁₈H₂₄N₆O·H₂O
M _r = 358.45
Orthorhombic,
a = 6.6088 (6) Å
b = 10.1483 (8) Å
c = 26.813 (2) Å
V = 1798.3 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 193 K
0.29 × 0.27 × 0.06 mm

Data collection

Stoe IPDS 2T diffractometer
6672 measured reflections
4184 independent reflections
1716 reflections with I > 2σ(I)
R _int = 0.079

Refinement

R[F ² > 2σ(F ²)] = 0.062
wR(F ²) = 0.150
S = 0.90
4184 reflections
246 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.22 e Å⁻³

Data collection: X-AREA (Stoe & Cie, 2010 ▶); cell refinement: X-AREA; data reduction: X-RED (Stoe & Cie, 2010 ▶); program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: PLATON.

Supplementary Material

Crystal structure: contains datablock(s) I, Global. DOI: 10.1107/S1600536814004449/bt6965sup1.cif

e-70-0o382-sup1.cif^{(31.8KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814004449/bt6965Isup2.hkl

e-70-0o382-Isup2.hkl^{(205.1KB, hkl)}

Click here for additional data file.^{(8KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814004449/bt6965Isup3.cml

CCDC reference: 988870

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1L	0.88	1.90	2.783 (8)	178
N1—H1⋯O2L	0.88	2.06	2.816 (7)	144
O1L—H1L2⋯N8ⁱ	0.84	2.27	2.868 (8)	129
O2L—H2L2⋯N8ⁱ	0.84	2.20	2.733 (7)	121
O2L—H2L2⋯N25ⁱⁱ	0.84	2.43	3.026 (10)	129

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

The authors thank Michael Forster for fruitful discussions and suggestions and acknowledge support by the Deutsche Forschungsgemeinschaft and the Open Access Publishing Fund of Tuebingen University.

supplementary crystallographic information

1. Comment

Janus Kinases (JAKs) are non-receptor protein tyrosine kinases mediating signalling through the JAK-STAT (Signal Transducer and Activator of Transcription) pathway. Being crucial signal transducers for a variety of cytokines, growth factors, and interferons, JAKs are involved in numerous pathologies including malignancies, myeloproliferative disorders and autoimmune diseases (Shuai & Liu, 2003). Recently, Tofacitinib (CP690,550; 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile) a small-molecule pan-JAK inhibitor was approved by the US Food and Drug Administration for the treatment of rheumatoid athritis (Flanagan et al., 2010). The compound also shows promising results in late stage clinical trials for psoriasis, transplant rejection, and other disorders of the immune system. In search for novel JAK inhibitors, the title compound was prepared as a Tofacitinib bioisostere with altered physicochemical properties (Wuitschik et al., 2010).

In the crystal structure of the title compound, C₁₈H₂₄N₆O, the exocyclic amino substituent is oriented almost coplanar to the heteroaromatic ring system with a torsion angle of 0.6 (2)° for C11-N10-C5-C4. The piperidine ring adopts a chair conformation with a torsion angle of 39.5 (5) ° between the cis substituents. One of the protons (H23B) of the methylene group between the oxetane ring and the nitrile function is involved in an intermolecular C—H···π interaction while the other methylene proton forms an intermolecular C—H···N interaction with the nitrile group. The oxygen atom of the oxetane ring makes two intermolecular C—H···O contacts with two H atoms (H13A and H15B) of the piperidine ring. The heterocyclic pyrrol N—H forms an intermolecular water mediated hydrogen bond to one of the nitrogen atoms (N8) in the 6-membered pyrmidine heterocycle with a length of 2.78 (2) Å for the N—H···O and 2.86 (8) Å for the O—H···N contact. The water molecule connecting two molecules is disorderd over two positions (s.o.f. 0.48/0.52). The crystal packing is shows N—H···OH···N hydrogen bonds resulting in infinite chains parallel to the a axis.

2. Experimental

In an HPLC-vial, (3R,4R)-N,4-dimethyl-N-{7H-pyrrolo[2,3-d]pyrimidin-4- yl}piperidin-3-amine (50.0 mg, 204 µmol) and (oxetan-3-ylidene)acetonitrile (19.9 mg, 210 µmol) were dissolved in dry ethanol (400 µl) and the mixture stirred at 323 K during 48 h. The solvent was evaporated under reduced pressure and the product purified by column chromatography (SiO₂, ethyl acetate + 2% methanol). The product was obtained as off-white solid (57.0 mg, 82%). Crystals of the title compound were obtained by slow evaporation of a solution in chloroform + 10% methanol at 298 K.