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The crystal structure of the title compound, C16H16N3O3+·Cl-·CH4O (WHI-P131, an inhibitor of Janus kinase 3), contains four hydrogen bonds. There are two hydrogen bonds within the asymmetric unit, i.e. interactions between WHI-P131 OH and Cl-, and between methanol and Cl-. There is a third interaction between WHI-P131 NH and Cl- (related by a 21 screw) and a fourth between WHI-P131 NH and methanol (related by an n-glide). The hydrogen-bond pattern for these interactions can be described by the first-level hydrogen-bond graph-set notation D11(2)D11(2)D11(2)D11(2). The second-level graph-set notation (for combinations of two hydrogen bonds) was determined to be D12(3)­D12(3)­D22(4)­D22(9)­D22(14)­C12(9).

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270100007496/bk1527sup1.cif
Contains datablocks WHI-P131, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270100007496/bk1527WHI-P131sup2.hkl
Contains datablock WHI-P131

CCDC reference: 152639

Comment top

The title compound, WHI-P131 (Fig. 1), inhibited the kinase activity of Janus kinase 3 (JAK3), with an IC50 of 9.1µM (Sudbeck et al., 1999). Although WHI-P131 inhibited JAK3, it did not inhibit the Janus kinases JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN or the receptor family tyrosine kinase IRK, even at concentrations as high as 350µM. The relatively high potency and selectivity of WHI-P131 for JAK3 makes it a promising candidate for new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer. In addition to its antileukemic properties, WHI-P131 also shows clinical potential for the treatment of mast-cell-mediated immediate hypersensitivity reactions and allergic disorders (Malaviya & Uckun, 1999). \sch

The crystal structure of WHI-P131 contains four different hydrogen bonds: N1—H1···O4, N4—H4···Cl1, O3—H3···Cl1 and O4—H26···Cl1 (Fig. 2 and Table 3). Each of these can be described in graph-set notation (Bernstein et al., 1990, 1995; Etter, 1990, 1991; Etter et al., 1990) as D11(2) (Fig. 2). The second-level motif combining the N1—H1···O4 and N4—H4···Cl1 hydrogen bond is D22(9), the motif combining N4—H4···Cl1 and O3—H3···Cl1 is C12(9), and the motif combining N1—H1···O4 and O3—H3···Cl1 is D22(14). The combination of N1—H1···O4 and O4—H26···Cl1 can be described as a D22(4) pattern, N4—H4···Cl1 plus O4—H26···Cl1 forms a D12(3) pattern, and O3—H3···Cl1 plus O4—H26···Cl1 is D12(3). The complete first-level hydrogen-bond graph-set notation for WHI-P131 is D11(2)D11(2)D11(2)D11(2) and the second-level graph-set notation (for combinations of two hydrogen bonds) is D12(3)D12(3)D22(4)D22(9)D22(14) C12(9).

An alternative way to describe the two-dimensional hydrogen-bonded network in the crystal of WHI-P131 is C21(9)C32(15), which combines the second-level motif for N4—H4···Cl1 and O3—H3···Cl1, C21(9), and the third-level motif for O4—H16···Cl1, O3—H3···Cl1 and N1—H1···O4, C32(15).

Experimental top

Yellow needles of WHI-P131 were grown from methanol/dichloromethane by vapor diffusion at room temperature. The hydrochloride salt crystallized as a methanol solvate.

Refinement top

H atoms were placed at calculated positions, except for H1 and H4, which were located in the electron-density difference map and refined isotropically. The hydroxyl H3 and H26 atoms were not observed in the electron-density map but were included at calculated positions based on an assessment of the best hydrogen-bond interactions to nearby N, O or Cl atoms.

Computing details top

Data collection: SMART (Bruker, 1998); cell refinement: SMART; data reduction: SHELXTL (Bruker, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures top
[Figure 1] Fig. 1. The X-ray crystal structure of WHI-P131 (30% probability displacement ellipsoids, T = 297 K).
[Figure 2] Fig. 2. Hydrogen-bond patterns observed WHI-P131. Four hydrogen bonds (labeled 1–4) are observed in the crystal structure. The complete first-level hydrogen-bond graph-set pattern is D11(2)D11(2)D11(2)D11(2) and the second-level pattern is D12(3)D12(3)D22(4)D22(9)D22(14) C12(9).
'4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline' top
Crystal data top
C16H16N3O3+·Cl·CH4ODx = 1.374 Mg m3
Mr = 365.81Melting point: 245-248°C K
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
a = 7.4128 (7) ÅCell parameters from 2622 reflections
b = 10.7752 (10) Åθ = 2.6–25.0°
c = 22.337 (2) ŵ = 0.24 mm1
β = 97.538 (2)°T = 297 K
V = 1768.8 (3) Å3Needle, yellow
Z = 40.45 × 0.15 × 0.12 mm
F(000) = 768
Data collection top
CCD area-detector
diffractometer
3117 independent reflections
Radiation source: fine-focus sealed tube2087 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.050
ϕ and ω scansθmax = 25.0°, θmin = 1.8°
Absorption correction: empirical (using intensity measurements)
(SADABS; Sheldrick, 1996)
h = 88
Tmin = 0.90, Tmax = 0.97k = 1212
8982 measured reflectionsl = 2622
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.048Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.12H atoms treated by a mixture of independent and constrained refinement
S = 0.99 w = 1/[σ2(Fo2) + (0.0672P)2]
where P = (Fo2 + 2Fc2)/3
3117 reflections(Δ/σ)max = 0.003
239 parametersΔρmax = 0.33 e Å3
0 restraintsΔρmin = 0.26 e Å3
Crystal data top
C16H16N3O3+·Cl·CH4OV = 1768.8 (3) Å3
Mr = 365.81Z = 4
Monoclinic, P21/nMo Kα radiation
a = 7.4128 (7) ŵ = 0.24 mm1
b = 10.7752 (10) ÅT = 297 K
c = 22.337 (2) Å0.45 × 0.15 × 0.12 mm
β = 97.538 (2)°
Data collection top
CCD area-detector
diffractometer
3117 independent reflections
Absorption correction: empirical (using intensity measurements)
(SADABS; Sheldrick, 1996)
2087 reflections with I > 2σ(I)
Tmin = 0.90, Tmax = 0.97Rint = 0.050
8982 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0480 restraints
wR(F2) = 0.12H atoms treated by a mixture of independent and constrained refinement
S = 0.99Δρmax = 0.33 e Å3
3117 reflectionsΔρmin = 0.26 e Å3
239 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
xyzUiso*/Ueq
Cl10.52383 (11)0.62330 (7)0.19676 (3)0.0574 (3)
O10.0122 (3)0.26977 (16)0.40580 (8)0.0491 (5)
N10.3539 (3)0.03508 (19)0.58342 (10)0.0393 (5)
H10.376 (3)0.011 (2)0.6238 (12)0.047 (8)*
O20.0802 (2)0.35313 (15)0.51354 (8)0.0440 (5)
C20.4062 (4)0.1486 (2)0.57080 (12)0.0429 (7)
H20.46270.19590.60270.051*
O30.4681 (3)0.64338 (16)0.32994 (8)0.0616 (6)
H30.47540.63830.29370.074*
N30.3850 (3)0.19951 (19)0.51742 (9)0.0405 (5)
O40.9139 (3)0.5371 (2)0.20208 (9)0.0689 (6)
H260.81010.56080.20480.083*
N40.2750 (3)0.18402 (19)0.41662 (10)0.0395 (5)
H40.211 (4)0.145 (2)0.3866 (12)0.044 (8)*
C40.2978 (3)0.1321 (2)0.47112 (11)0.0347 (6)
C50.1492 (3)0.0703 (2)0.43343 (11)0.0353 (6)
H50.12540.04040.39410.042*
C60.0990 (3)0.1886 (2)0.44617 (11)0.0360 (6)
C70.1341 (3)0.2351 (2)0.50644 (11)0.0343 (6)
C80.2178 (3)0.1611 (2)0.55155 (11)0.0364 (6)
H80.24110.19100.59090.044*
C90.2680 (3)0.0403 (2)0.53817 (10)0.0328 (6)
C100.2371 (3)0.0070 (2)0.47959 (11)0.0321 (6)
C110.3347 (3)0.3031 (2)0.39844 (11)0.0348 (6)
C120.3854 (4)0.3097 (2)0.34094 (11)0.0413 (6)
H120.38840.23790.31800.050*
C130.4315 (4)0.4224 (2)0.31758 (11)0.0429 (7)
H130.46450.42660.27890.052*
C140.4285 (4)0.5286 (2)0.35173 (11)0.0403 (6)
C150.3821 (4)0.5219 (2)0.40931 (12)0.0425 (7)
H150.38290.59360.43250.051*
C160.3346 (4)0.4102 (2)0.43303 (12)0.0409 (6)
H160.30260.40660.47190.049*
C170.0109 (5)0.2350 (3)0.34362 (12)0.0655 (9)
H190.08160.29700.32030.098*
H180.10610.22790.32990.098*
H170.07280.15660.33890.098*
C180.1278 (4)0.4089 (2)0.57202 (12)0.0518 (8)
H220.09170.49460.57040.078*
H210.06640.36610.60120.078*
H200.25690.40340.58350.078*
C200.9658 (8)0.4476 (4)0.24667 (19)0.1060 (15)
H251.09560.43750.25140.23 (3)*
H240.90850.36990.23480.22 (3)*
H230.92890.47400.28430.24 (3)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0729 (6)0.0585 (5)0.0396 (4)0.0129 (4)0.0023 (3)0.0048 (3)
O10.0663 (13)0.0346 (11)0.0434 (11)0.0119 (9)0.0042 (9)0.0042 (8)
N10.0491 (14)0.0325 (13)0.0356 (13)0.0049 (10)0.0031 (10)0.0044 (10)
O20.0541 (12)0.0287 (10)0.0474 (11)0.0091 (8)0.0002 (9)0.0028 (8)
C20.0500 (17)0.0341 (16)0.0439 (16)0.0071 (13)0.0030 (13)0.0107 (12)
O30.1116 (19)0.0324 (11)0.0422 (11)0.0181 (11)0.0155 (11)0.0015 (8)
N30.0469 (14)0.0329 (12)0.0406 (13)0.0083 (10)0.0018 (10)0.0052 (10)
O40.0756 (16)0.0705 (16)0.0584 (13)0.0149 (12)0.0003 (11)0.0030 (11)
N40.0513 (15)0.0276 (12)0.0378 (13)0.0081 (10)0.0006 (11)0.0022 (10)
C40.0336 (14)0.0296 (14)0.0414 (15)0.0003 (11)0.0066 (11)0.0023 (12)
C50.0406 (16)0.0300 (14)0.0344 (14)0.0009 (11)0.0022 (12)0.0011 (11)
C60.0374 (15)0.0295 (14)0.0402 (14)0.0010 (12)0.0012 (11)0.0071 (12)
C70.0319 (14)0.0271 (14)0.0445 (15)0.0012 (11)0.0073 (11)0.0008 (11)
C80.0399 (15)0.0327 (14)0.0369 (14)0.0007 (11)0.0065 (12)0.0016 (11)
C90.0318 (14)0.0314 (14)0.0356 (14)0.0013 (11)0.0062 (11)0.0048 (11)
C100.0309 (13)0.0266 (13)0.0391 (14)0.0002 (11)0.0061 (11)0.0013 (11)
C110.0377 (15)0.0235 (13)0.0426 (15)0.0025 (11)0.0033 (11)0.0003 (11)
C120.0532 (17)0.0290 (14)0.0408 (15)0.0008 (12)0.0031 (12)0.0066 (12)
C130.0598 (19)0.0322 (15)0.0372 (15)0.0063 (13)0.0080 (13)0.0025 (12)
C140.0511 (17)0.0268 (14)0.0418 (15)0.0053 (12)0.0017 (12)0.0003 (11)
C150.0565 (18)0.0257 (14)0.0457 (16)0.0020 (13)0.0082 (13)0.0071 (12)
C160.0479 (16)0.0315 (15)0.0445 (15)0.0006 (12)0.0111 (12)0.0027 (12)
C170.097 (3)0.0485 (19)0.0452 (18)0.0110 (17)0.0114 (16)0.0070 (14)
C180.060 (2)0.0354 (16)0.0578 (18)0.0065 (14)0.0003 (15)0.0131 (13)
C200.148 (5)0.085 (3)0.075 (3)0.043 (3)0.023 (3)0.013 (2)
Geometric parameters (Å, º) top
O1—C61.357 (3)C5—C61.368 (3)
O1—C171.427 (3)C5—C101.416 (3)
N1—C21.324 (3)C6—C71.428 (3)
N1—C91.385 (3)C7—C81.368 (3)
O2—C71.349 (3)C8—C91.397 (3)
O2—C181.439 (3)C9—C101.395 (3)
N3—C21.303 (3)C11—C121.386 (3)
N3—C41.356 (3)C11—C161.389 (3)
O3—C141.375 (3)C12—C131.383 (3)
O4—C201.404 (4)C13—C141.377 (3)
N4—C41.330 (3)C14—C151.376 (4)
N4—C111.433 (3)C15—C161.380 (3)
C4—C101.442 (3)
C6—O1—C17117.6 (2)N1—C9—C10118.3 (2)
C2—N1—C9120.4 (2)N1—C9—C8120.0 (2)
C7—O2—C18117.4 (2)C10—C9—C8121.7 (2)
N3—C2—N1125.5 (2)C9—C10—C5118.2 (2)
C2—N3—C4117.4 (2)C9—C10—C4116.7 (2)
C4—N4—C11129.0 (2)C5—C10—C4125.2 (2)
N4—C4—N3117.6 (2)C12—C11—C16119.5 (2)
N4—C4—C10120.6 (2)C12—C11—N4116.1 (2)
N3—C4—C10121.8 (2)C16—C11—N4124.3 (2)
C6—C5—C10120.5 (2)C13—C12—C11120.3 (2)
O1—C6—C5125.5 (2)C14—C13—C12119.9 (2)
O1—C6—C7114.3 (2)O3—C14—C15118.0 (2)
C5—C6—C7120.1 (2)O3—C14—C13122.1 (2)
O2—C7—C8125.2 (2)C15—C14—C13119.9 (2)
O2—C7—C6114.9 (2)C14—C15—C16120.8 (2)
C8—C7—C6119.9 (2)C15—C16—C11119.5 (2)
C7—C8—C9119.6 (2)
C9—N1—C2—N30.4 (4)N1—C9—C10—C5180.0 (2)
N1—C2—N3—C41.9 (4)C8—C9—C10—C51.2 (3)
C11—N4—C4—N31.9 (4)N1—C9—C10—C40.1 (3)
C11—N4—C4—C10175.9 (2)C8—C9—C10—C4178.9 (2)
C2—N3—C4—N4179.6 (2)C6—C5—C10—C91.0 (3)
C2—N3—C4—C102.5 (3)C6—C5—C10—C4179.2 (2)
C17—O1—C6—C57.6 (4)N4—C4—C10—C9179.5 (2)
C17—O1—C6—C7173.7 (2)N3—C4—C10—C91.7 (3)
C10—C5—C6—O1179.0 (2)N4—C4—C10—C50.7 (4)
C10—C5—C6—C70.3 (4)N3—C4—C10—C5178.4 (2)
C18—O2—C7—C85.4 (3)C4—N4—C11—C12145.5 (3)
C18—O2—C7—C6174.1 (2)C4—N4—C11—C1638.2 (4)
O1—C6—C7—O21.7 (3)C16—C11—C12—C131.5 (4)
C5—C6—C7—O2179.4 (2)N4—C11—C12—C13175.0 (2)
O1—C6—C7—C8178.7 (2)C11—C12—C13—C140.5 (4)
C5—C6—C7—C80.1 (4)C12—C13—C14—O3178.1 (3)
O2—C7—C8—C9179.6 (2)C12—C13—C14—C150.9 (4)
C6—C7—C8—C90.1 (4)O3—C14—C15—C16177.7 (3)
C2—N1—C9—C100.5 (4)C13—C14—C15—C161.4 (4)
C2—N1—C9—C8178.3 (2)C14—C15—C16—C110.4 (4)
C7—C8—C9—N1179.5 (2)C12—C11—C16—C151.0 (4)
C7—C8—C9—C100.8 (4)N4—C11—C16—C15175.1 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O4—H26···Cl1??3.024 (2)?
O3—H3···Cl1??3.064 (2)?
N1—H1···O4i0.93 (3)1.81 (3)2.742 (3)179 (2)
N4—H4···Cl1ii0.88 (3)2.39 (3)3.206 (2)155 (2)
Symmetry codes: (i) x1/2, y+1/2, z+1/2; (ii) x+1/2, y1/2, z+1/2.

Experimental details

Crystal data
Chemical formulaC16H16N3O3+·Cl·CH4O
Mr365.81
Crystal system, space groupMonoclinic, P21/n
Temperature (K)297
a, b, c (Å)7.4128 (7), 10.7752 (10), 22.337 (2)
β (°) 97.538 (2)
V3)1768.8 (3)
Z4
Radiation typeMo Kα
µ (mm1)0.24
Crystal size (mm)0.45 × 0.15 × 0.12
Data collection
DiffractometerCCD area-detector
diffractometer
Absorption correctionEmpirical (using intensity measurements)
(SADABS; Sheldrick, 1996)
Tmin, Tmax0.90, 0.97
No. of measured, independent and
observed [I > 2σ(I)] reflections
8982, 3117, 2087
Rint0.050
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.048, 0.12, 0.99
No. of reflections3117
No. of parameters239
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.33, 0.26

Computer programs: SMART (Bruker, 1998), SMART, SHELXTL (Bruker, 1998), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXTL.

Selected geometric parameters (Å, º) top
N3—C21.303 (3)O4—C201.404 (4)
N3—C41.356 (3)N4—C41.330 (3)
O3—C141.375 (3)N4—C111.433 (3)
C17—O1—C6—C57.6 (4)C4—N4—C11—C1638.2 (4)
C18—O2—C7—C85.4 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O4—H26···Cl1??3.024 (2)?
O3—H3···Cl1??3.064 (2)?
N1—H1···O4i0.93 (3)1.81 (3)2.742 (3)179 (2)
N4—H4···Cl1ii0.88 (3)2.39 (3)3.206 (2)155 (2)
Symmetry codes: (i) x1/2, y+1/2, z+1/2; (ii) x+1/2, y1/2, z+1/2.
First- and second-level graph-set motifs for hydrogen bonds in WHI-P131 top
O4—H26···Cl1O3—H3···Cl1N1—H1···O4N4—H4···Cl1
O4—H26···Cl1D11(2)D21(3)D22(4)D21(3)
O3—H3···Cl1D11(2)D22(14)C12(9)
N1—H1···O4D11(2)D22(9)
N4—H4···Cl1D11(2)
 

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