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

Gehringer, M.; Pfaffenrot, E.; Keck, P.R.W.E.F.; Schollmeyer, D.; Laufer, S.A.

doi:10.1107/S1600536814004449

organic compounds

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ISSN: 2056-9890

Volume 70| Part 4| April 2014| Pages o382-o383

doi:10.1107/S1600536814004449

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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 and Stefan A. Laufer ^a ^*

^aEberhard-Karls-University Tuebingen, Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Auf der Morgenstelle 8, 72076 Tuebingen, Germany, and ^bUniversity Mainz, Institut of Organic Chemistry, Duesbergweg 10-14, 55099 Mainz, Germany
^*Correspondence e-mail: stefan.laufer@uni-tuebingen.de

(Received 24 February 2014; accepted 26 February 2014; online 5 March 2014)

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.

CCDC reference: 988870

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, P 2₁ 2₁ 2₁
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[F² > 2σ(F²)] = 0.062
wR(F²) = 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

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
Symmetry codes: (i) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]$ ; (ii) $[-x+{\script{1\over 2}}, -y+1, z+{\script{1\over 2}}]$ .

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.

Supporting information

CCDC reference: 988870

Crystal structure: contains datablocks I, Global. DOI: 10.1107/S1600536814004449/bt6965sup1.cif

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

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

checkCIF report

Comment top

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.

Related literature top

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 top

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.

Computing details top

Data collection: X-AREA (Stoe & Cie, 2010); cell refinement: X-AREA (Stoe & Cie, 2010); 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 (Spek, 2009).

Figures top

Fig. 1. Crystal structure of the title compound with labeling and displacement ellipsoids drawn at the 50% probability level. Water molecules are disorderd with s.o.f. 0.52/0.48.

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 top

Crystal data top

C₁₈H₂₄N₆O·H₂O	F(000) = 768
M_r = 358.45	D_x = 1.324 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 6886 reflections
a = 6.6088 (6) Å	θ = 2.5–27.8°
b = 10.1483 (8) Å	µ = 0.09 mm⁻¹
c = 26.813 (2) Å	T = 193 K
V = 1798.3 (3) Å³	Plate, colourless
Z = 4	0.29 × 0.27 × 0.06 mm

Data collection top

Stoe IPDS 2T diffractometer	1716 reflections with I > 2σ(I)
Radiation source: sealed Tube	R_int = 0.079
Graphite monochromator	θ_max = 28.0°, θ_min = 3.2°
Detector resolution: 6.67 pixels mm^-1	h = −7→8
rotation method scans	k = −11→13
6672 measured reflections	l = −29→35
4184 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.062	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.150	H-atom parameters constrained
S = 0.90	w = 1/[σ²(F_o²) + (0.0523P)²] where P = (F_o² + 2F_c²)/3
4184 reflections	(Δ/σ)_max < 0.001
246 parameters	Δρ_max = 0.19 e Å⁻³
0 restraints	Δρ_min = −0.22 e Å⁻³

Crystal data top

C₁₈H₂₄N₆O·H₂O	V = 1798.3 (3) Å³
M_r = 358.45	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 6.6088 (6) Å	µ = 0.09 mm⁻¹
b = 10.1483 (8) Å	T = 193 K
c = 26.813 (2) Å	0.29 × 0.27 × 0.06 mm

Data collection top

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

Refinement top

R[F² > 2σ(F²)] = 0.062	0 restraints
wR(F²) = 0.150	H-atom parameters constrained
S = 0.90	Δρ_max = 0.19 e Å⁻³
4184 reflections	Δρ_min = −0.22 e Å⁻³
246 parameters

Special details top

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

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	U_iso*/U_eq	Occ. (<1)
N1	0.1280 (5)	0.1062 (4)	0.42472 (12)	0.0485 (10)
H1	0.1160	0.1276	0.4564	0.058*
C2	0.2919 (7)	0.0433 (4)	0.40332 (16)	0.0485 (12)
H2	0.4106	0.0163	0.4205	0.058*
C3	0.2563 (7)	0.0264 (4)	0.35393 (15)	0.0439 (11)
H3	0.3446	−0.0139	0.3305	0.053*
C4	0.0579 (7)	0.0814 (4)	0.34361 (15)	0.0423 (11)
C5	−0.0680 (7)	0.1060 (4)	0.30217 (14)	0.0391 (10)
N6	−0.2486 (6)	0.1667 (4)	0.30983 (12)	0.0449 (9)
C7	−0.2941 (7)	0.2044 (4)	0.35573 (15)	0.0476 (11)
H7	−0.4211	0.2473	0.3591	0.057*
N8	−0.1909 (6)	0.1916 (4)	0.39726 (12)	0.0470 (9)
C9	−0.0105 (7)	0.1291 (4)	0.38869 (14)	0.0413 (10)
N10	−0.0216 (5)	0.0778 (3)	0.25423 (11)	0.0396 (8)
C11	0.1748 (6)	0.0150 (4)	0.24320 (14)	0.0451 (11)
H11A	0.1885	0.0029	0.2071	0.068*
H11B	0.1815	−0.0709	0.2598	0.068*
H11C	0.2847	0.0712	0.2554	0.068*
C12	−0.1610 (7)	0.1075 (4)	0.21317 (14)	0.0415 (10)
H12	−0.2699	0.1634	0.2281	0.050*
C13	−0.0683 (7)	0.1906 (4)	0.17183 (13)	0.0419 (11)
H13A	−0.1782	0.2339	0.1528	0.050*
H13B	0.0160	0.2606	0.1870	0.050*
N14	0.0562 (5)	0.1135 (3)	0.13743 (11)	0.0401 (9)
C15	−0.0684 (7)	0.0153 (4)	0.11233 (14)	0.0437 (11)
H15A	0.0130	−0.0318	0.0870	0.052*
H15B	−0.1832	0.0588	0.0953	0.052*
C16	−0.1472 (7)	−0.0818 (4)	0.15091 (15)	0.0474 (11)
H16A	−0.0314	−0.1284	0.1663	0.057*
H16B	−0.2331	−0.1483	0.1341	0.057*
C17	−0.2698 (7)	−0.0137 (4)	0.19154 (14)	0.0424 (11)
H17	−0.3970	0.0189	0.1755	0.051*
C18	−0.3324 (7)	−0.1107 (5)	0.23178 (15)	0.0506 (11)
H18A	−0.4324	−0.1724	0.2182	0.076*
H18B	−0.3920	−0.0627	0.2599	0.076*
H18C	−0.2135	−0.1598	0.2432	0.076*
C19	0.1743 (7)	0.1946 (4)	0.10400 (14)	0.0421 (10)
C20	0.3401 (7)	0.2731 (5)	0.12998 (15)	0.0528 (13)
H20A	0.3255	0.3696	0.1259	0.063*
H20B	0.3571	0.2497	0.1656	0.063*
O21	0.4946 (5)	0.2159 (3)	0.09772 (13)	0.0672 (10)
C22	0.3494 (7)	0.1203 (5)	0.07878 (17)	0.0539 (12)
H22A	0.3701	0.0303	0.0920	0.065*
H22B	0.3400	0.1190	0.0419	0.065*
C23	0.0478 (7)	0.2774 (5)	0.06772 (15)	0.0472 (12)
H23A	−0.0318	0.2179	0.0460	0.057*
H23B	−0.0486	0.3322	0.0869	0.057*
C24	0.1729 (8)	0.3629 (5)	0.03667 (16)	0.0484 (12)
N25	0.2739 (7)	0.4295 (4)	0.01284 (15)	0.0658 (12)
O1L	0.0901 (13)	0.1801 (9)	0.5242 (3)	0.077 (2)	0.48
H1L1	0.1783	0.2403	0.5036	0.115*	0.48
H1L2	0.1406	0.1662	0.5525	0.115*	0.48
O2L	0.1719 (14)	0.2748 (9)	0.5074 (2)	0.085 (2)	0.52
H2L1	0.0459	0.2619	0.5042	0.128*	0.52
H2L2	0.1751	0.3371	0.5283	0.128*	0.52

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.062 (3)	0.052 (3)	0.0307 (18)	−0.009 (2)	−0.0069 (18)	0.0009 (18)
C2	0.048 (3)	0.051 (3)	0.047 (3)	0.001 (2)	0.002 (2)	−0.001 (2)
C3	0.049 (3)	0.044 (3)	0.038 (2)	−0.002 (2)	−0.001 (2)	0.002 (2)
C4	0.049 (3)	0.041 (3)	0.037 (2)	−0.006 (2)	−0.002 (2)	0.0023 (19)
C5	0.053 (3)	0.033 (2)	0.032 (2)	−0.003 (2)	0.0015 (19)	−0.0006 (19)
N6	0.046 (2)	0.052 (2)	0.0373 (19)	0.0060 (19)	0.0052 (17)	−0.0011 (17)
C7	0.056 (3)	0.050 (3)	0.037 (2)	0.002 (2)	0.005 (2)	−0.000 (2)
N8	0.059 (3)	0.048 (2)	0.0340 (18)	−0.004 (2)	0.0029 (19)	−0.0006 (16)
C9	0.052 (3)	0.039 (3)	0.032 (2)	−0.004 (2)	0.001 (2)	0.0042 (19)
N10	0.041 (2)	0.047 (2)	0.0304 (17)	0.0066 (18)	0.0005 (15)	−0.0002 (16)
C11	0.046 (3)	0.051 (3)	0.038 (2)	0.006 (2)	0.003 (2)	0.001 (2)
C12	0.044 (3)	0.043 (3)	0.037 (2)	0.005 (2)	−0.003 (2)	0.001 (2)
C13	0.048 (3)	0.047 (3)	0.031 (2)	0.008 (2)	−0.0015 (19)	−0.001 (2)
N14	0.050 (2)	0.037 (2)	0.0333 (17)	0.0038 (19)	−0.0005 (16)	−0.0040 (16)
C15	0.055 (3)	0.038 (3)	0.039 (2)	−0.000 (2)	−0.003 (2)	−0.005 (2)
C16	0.059 (3)	0.042 (3)	0.041 (2)	−0.001 (2)	−0.002 (2)	0.002 (2)
C17	0.046 (3)	0.042 (3)	0.040 (2)	0.002 (2)	−0.001 (2)	0.001 (2)
C18	0.053 (3)	0.055 (3)	0.044 (2)	0.001 (3)	−0.007 (2)	0.006 (2)
C19	0.044 (3)	0.047 (3)	0.035 (2)	−0.005 (2)	−0.002 (2)	0.003 (2)
C20	0.050 (3)	0.061 (3)	0.048 (3)	−0.004 (3)	−0.000 (2)	−0.002 (2)
O21	0.045 (2)	0.081 (3)	0.076 (2)	−0.002 (2)	0.0006 (18)	−0.005 (2)
C22	0.054 (3)	0.055 (3)	0.052 (3)	0.010 (3)	0.009 (2)	0.002 (2)
C23	0.051 (3)	0.051 (3)	0.040 (2)	−0.001 (2)	−0.001 (2)	0.012 (2)
C24	0.060 (3)	0.048 (3)	0.037 (2)	0.013 (3)	0.002 (2)	−0.004 (2)
N25	0.084 (3)	0.059 (3)	0.054 (2)	−0.003 (2)	0.014 (2)	0.006 (2)
O1L	0.113 (7)	0.072 (6)	0.045 (4)	0.005 (5)	−0.013 (4)	0.001 (4)
O2L	0.130 (7)	0.078 (6)	0.049 (4)	0.010 (5)	−0.020 (5)	−0.024 (4)

Geometric parameters (Å, º) top

N1—C9	1.351 (5)	C15—H15A	0.9900
N1—C2	1.381 (5)	C15—H15B	0.9900
N1—H1	0.8800	C16—C17	1.524 (6)
C2—C3	1.356 (6)	C16—H16A	0.9900
C2—H2	0.9500	C16—H16B	0.9900
C3—C4	1.452 (6)	C17—C18	1.519 (6)
C3—H3	0.9500	C17—H17	1.0000
C4—C9	1.378 (5)	C18—H18A	0.9800
C4—C5	1.410 (6)	C18—H18B	0.9800
C5—N10	1.352 (5)	C18—H18C	0.9800
C5—N6	1.359 (5)	C19—C20	1.523 (6)
N6—C7	1.323 (5)	C19—C23	1.534 (6)
C7—N8	1.312 (5)	C19—C22	1.538 (6)
C7—H7	0.9500	C20—O21	1.458 (5)
N8—C9	1.369 (6)	C20—H20A	0.9900
N10—C12	1.467 (5)	C20—H20B	0.9900
N10—C11	1.476 (5)	O21—C22	1.456 (6)
C11—H11A	0.9800	C22—H22A	0.9900
C11—H11B	0.9800	C22—H22B	0.9900
C11—H11C	0.9800	C23—C24	1.459 (7)
C12—C13	1.521 (6)	C23—H23A	0.9900
C12—C17	1.538 (6)	C23—H23B	0.9900
C12—H12	1.0000	C24—N25	1.145 (6)
C13—N14	1.463 (5)	O1L—H1L1	1.0100
C13—H13A	0.9900	O1L—H1L2	0.8390
C13—H13B	0.9900	O1L—H2L1	1.0319
N14—C19	1.445 (5)	O2L—H1L1	0.3669
N14—C15	1.458 (5)	O2L—H2L1	0.8478
C15—C16	1.520 (6)	O2L—H2L2	0.8441

C9—N1—C2	108.3 (3)	H15A—C15—H15B	108.3
C9—N1—H1	125.8	C15—C16—C17	112.0 (4)
C2—N1—H1	125.8	C15—C16—H16A	109.2
C3—C2—N1	109.2 (4)	C17—C16—H16A	109.2
C3—C2—H2	125.4	C15—C16—H16B	109.2
N1—C2—H2	125.4	C17—C16—H16B	109.2
C2—C3—C4	107.1 (4)	H16A—C16—H16B	107.9
C2—C3—H3	126.4	C18—C17—C16	111.0 (4)
C4—C3—H3	126.4	C18—C17—C12	112.2 (3)
C9—C4—C5	115.8 (4)	C16—C17—C12	112.6 (4)
C9—C4—C3	105.3 (4)	C18—C17—H17	106.9
C5—C4—C3	138.7 (4)	C16—C17—H17	106.9
N10—C5—N6	116.0 (4)	C12—C17—H17	106.9
N10—C5—C4	125.3 (4)	C17—C18—H18A	109.5
N6—C5—C4	118.6 (4)	C17—C18—H18B	109.5
C7—N6—C5	118.1 (4)	H18A—C18—H18B	109.5
N8—C7—N6	130.0 (4)	C17—C18—H18C	109.5
N8—C7—H7	115.0	H18A—C18—H18C	109.5
N6—C7—H7	115.0	H18B—C18—H18C	109.5
C7—N8—C9	110.8 (4)	N14—C19—C20	113.7 (3)
N1—C9—N8	123.3 (4)	N14—C19—C23	114.2 (4)
N1—C9—C4	110.1 (4)	C20—C19—C23	113.3 (4)
N8—C9—C4	126.5 (4)	N14—C19—C22	113.6 (4)
C5—N10—C12	121.8 (3)	C20—C19—C22	85.2 (3)
C5—N10—C11	118.8 (3)	C23—C19—C22	113.6 (3)
C12—N10—C11	119.4 (3)	O21—C20—C19	91.4 (3)
N10—C11—H11A	109.5	O21—C20—H20A	113.4
N10—C11—H11B	109.5	C19—C20—H20A	113.4
H11A—C11—H11B	109.5	O21—C20—H20B	113.4
N10—C11—H11C	109.5	C19—C20—H20B	113.4
H11A—C11—H11C	109.5	H20A—C20—H20B	110.7
H11B—C11—H11C	109.5	C22—O21—C20	90.6 (3)
N10—C12—C13	114.1 (3)	O21—C22—C19	90.9 (3)
N10—C12—C17	114.3 (3)	O21—C22—H22A	113.5
C13—C12—C17	110.9 (3)	C19—C22—H22A	113.5
N10—C12—H12	105.5	O21—C22—H22B	113.5
C13—C12—H12	105.5	C19—C22—H22B	113.5
C17—C12—H12	105.5	H22A—C22—H22B	110.8
N14—C13—C12	112.9 (4)	C24—C23—C19	112.2 (4)
N14—C13—H13A	109.0	C24—C23—H23A	109.2
C12—C13—H13A	109.0	C19—C23—H23A	109.2
N14—C13—H13B	109.0	C24—C23—H23B	109.2
C12—C13—H13B	109.0	C19—C23—H23B	109.2
H13A—C13—H13B	107.8	H23A—C23—H23B	107.9
C19—N14—C15	114.1 (3)	N25—C24—C23	178.8 (5)
C19—N14—C13	113.0 (3)	H1L1—O1L—H1L2	111.5
C15—N14—C13	109.8 (3)	H1L1—O1L—H2L1	52.4
N14—C15—C16	108.8 (3)	H1L2—O1L—H2L1	135.9
N14—C15—H15A	109.9	H1L1—O2L—H2L1	86.4
C16—C15—H15A	109.9	H1L1—O2L—H2L2	153.9
N14—C15—H15B	109.9	H2L1—O2L—H2L2	102.0
C16—C15—H15B	109.9

C9—N1—C2—C3	−0.2 (5)	C12—C13—N14—C19	−169.0 (3)
N1—C2—C3—C4	−0.2 (5)	C12—C13—N14—C15	62.3 (4)
C2—C3—C4—C9	0.5 (5)	C19—N14—C15—C16	167.6 (4)
C2—C3—C4—C5	174.8 (5)	C13—N14—C15—C16	−64.4 (4)
C9—C4—C5—N10	174.1 (4)	N14—C15—C16—C17	58.3 (5)
C3—C4—C5—N10	0.2 (8)	C15—C16—C17—C18	−175.4 (4)
C9—C4—C5—N6	−3.7 (6)	C15—C16—C17—C12	−48.6 (5)
C3—C4—C5—N6	−177.5 (5)	N10—C12—C17—C18	39.5 (5)
N10—C5—N6—C7	−175.4 (4)	C13—C12—C17—C18	170.1 (4)
C4—C5—N6—C7	2.6 (6)	N10—C12—C17—C16	−86.7 (4)
C5—N6—C7—N8	−0.7 (7)	C13—C12—C17—C16	44.0 (5)
N6—C7—N8—C9	0.1 (7)	C15—N14—C19—C20	−166.0 (4)
C2—N1—C9—N8	−179.3 (4)	C13—N14—C19—C20	67.7 (5)
C2—N1—C9—C4	0.5 (5)	C15—N14—C19—C23	61.8 (5)
C7—N8—C9—N1	178.2 (4)	C13—N14—C19—C23	−64.6 (5)
C7—N8—C9—C4	−1.5 (6)	C15—N14—C19—C22	−70.7 (5)
C5—C4—C9—N1	−176.4 (4)	C13—N14—C19—C22	162.9 (3)
C3—C4—C9—N1	−0.7 (5)	N14—C19—C20—O21	123.8 (4)
C5—C4—C9—N8	3.3 (6)	C23—C19—C20—O21	−103.5 (4)
C3—C4—C9—N8	179.1 (4)	C22—C19—C20—O21	10.2 (3)
N6—C5—N10—C12	−1.8 (6)	C19—C20—O21—C22	−10.7 (3)
C4—C5—N10—C12	−179.6 (4)	C20—O21—C22—C19	10.6 (3)
N6—C5—N10—C11	178.5 (4)	N14—C19—C22—O21	−124.0 (4)
C4—C5—N10—C11	0.6 (6)	C20—C19—C22—O21	−10.2 (3)
C5—N10—C12—C13	125.6 (4)	C23—C19—C22—O21	103.2 (4)
C11—N10—C12—C13	−54.6 (5)	N14—C19—C23—C24	176.8 (4)
C5—N10—C12—C17	−105.3 (4)	C20—C19—C23—C24	44.4 (5)
C11—N10—C12—C17	74.5 (5)	C22—C19—C23—C24	−50.7 (5)
N10—C12—C13—N14	79.8 (4)	C19—C23—C24—N25	−12 (26)
C17—C12—C13—N14	−51.0 (5)

Hydrogen-bond geometry (Å, º) top

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

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

Hydrogen-bond geometry (Å, º) top

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

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

Acknowledgements

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.

References

Altomare, A., Burla, M. C., Camalli, M., Cascarano, G. L., Giacovazzo, C., Guagliardi, A., Moliterni, A. G. G., Polidori, G. & Spagna, R. (1999). J. Appl. Cryst. 32, 115–119. Web of Science CrossRef CAS IUCr Journals Google Scholar
Flanagan, M. E., Blumenkopf, T. A., Brissette, W. H., Brown, M. F., Casavant, J. M., Shang-Poa, C., Doty, J. L., Elliott, E. A., Fisher, M. B., Hines, M., Kent, C., Kudlacz, E. M., Lillie, B. M., Magnuson, K. S., McCurdy, S. P., Munchhof, M. J., Perry, B. D., Sawyer, P. S., Strelevitz, T. J., Subramanyam, C., Sun, J., Whipple, D. A. & Changelian, P. S. (2010). J. Med. Chem. 53, 8468–8484. Web of Science CrossRef CAS PubMed Google Scholar
Gehringer, M., Pfaffenrot, E., Bauer, S. & Laufer, S. A. (2014). ChemMedChem, 9, 277–281. Web of Science CrossRef CAS PubMed Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Shuai, K. & Liu, B. (2003). Nat. Rev. Immunol. 3, 900–911. Web of Science CrossRef PubMed CAS Google Scholar
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Stoe & Cie (2010). X-RED and X-AREA. Stoe & Cie, Darmstadt, Germany. Google Scholar
Wuitschik, G., Carreira, E. M., Wagner, B., Fischer, H., Parrilla, I., Schuler, F., Rogers-Evans, M. & Mueller, K. J. (2010). J. Med. Chem. 53, 3227–3246. Web of Science CSD CrossRef CAS PubMed Google Scholar

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Volume 70| Part 4| April 2014| Pages o382-o383

doi:10.1107/S1600536814004449

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

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

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Experimental

Crystal data

Data collection

Refinement

Supporting information

Acknowledgements

References

organic compounds

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