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

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 inter-molecular hydrogen bond to one of the N atoms of the annelated pyrimidine ring. The water mol-ecule connects two organic mol-ecules and is disorderd over two positions (occupancies of 0.48 and 0.52). The crystal packing shows zigzag chains of alternating organic and water mol-ecules 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-oxo­propane­n class="Chemical">nitrile} 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·n class="Chemical">H2O

M = 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

Δρmax = 0.19 e Å−3

Δρmin = −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.

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

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

Click here for additional data file.

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

CCDC reference: 988870

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

C18H24N6O·H2O	F(000) = 768
Mr = 358.45	Dx = 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

Stoe IPDS 2T diffractometer	1716 reflections with I > 2σ(I)
Radiation source: sealed Tube	Rint = 0.079
Graphite monochromator	θmax = 28.0°, θmin = 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 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(Fo2) + (0.0523P)2] where P = (Fo2 + 2Fc2)/3
4184 reflections	(Δ/σ)max < 0.001
246 parameters	Δρmax = 0.19 e Å−3
0 restraints	Δρmin = −0.22 e Å−3

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.

	x	y	z	Uiso*/Ueq	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

	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)

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)

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

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) ; (ii) .