Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir

Wang, X.; Xu, H.-J.; Jia, X.-D.; Yang, Y.-T.; Zhang, X.-J.

doi:10.1107/S2053229618002528

Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir

X. Wang, H.-J. Xu, X.-D. Jia, Y.-T. Yang and X.-J. Zhang

The nucleoside analogue entecavir {systematic name: 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one}, C₁₂H₁₅N₅O₃, is an antihepatitis B virus drug that has been approved in the US, EU and several countries worldwide. We report here the single-crystal structure of the anhydrous form and compare it with that of the previously reported monohydrate form [Jiang & Liu (2009). Acta Cryst. E65, o2232]. Hirshfeld surface analysis has been employed to understand and visualize the subtle packing differences between the two crystalline forms. The results show that, compared to the previously reported hydrated form, the anhydrous crystal has significantly different intermolecular interactions and packing patterns.

Keywords: entecavir; antihepatitis B drug; crystal structure; anhydrous; Hirshfeld surface analysis; nucleoside analogue; purinone.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229618002528/sk3678sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229618002528/sk3678Isup2.hkl Contains datablock I

CCDC reference: 1811499

Computing details top

Cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one top

Crystal data top

C₁₂H₁₅N₅O₃	D_x = 1.462 Mg m⁻³
M_r = 277.29	Mo Kα radiation, λ = 0.71073 Å
Tetragonal, P4₃2₁2	Cell parameters from 3656 reflections
a = 7.559 (2) Å	θ = 2.7–25.6°
c = 44.103 (12) Å	µ = 0.11 mm⁻¹
V = 2520.0 (15) Å³	T = 173 K
Z = 8	Block, colourless
F(000) = 1168	0.19 × 0.12 × 0.11 mm

Data collection top

Bruker APEXII CCD diffractometer	2251 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.034
Absorption correction: multi-scan (SADABS; Bruker, 2013)	θ_max = 27.5°, θ_min = 2.7°
T_min = 0.620, T_max = 0.746	h = −9→5
9930 measured reflections	k = −9→7
2865 independent reflections	l = −57→25

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.053	w = 1/[σ²(F_o²) + (0.065P)² + 1.049P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.140	(Δ/σ)_max < 0.001
S = 1.09	Δρ_max = 0.25 e Å⁻³
2865 reflections	Δρ_min = −0.28 e Å⁻³
182 parameters	Absolute structure: Refined as an inversion twin.
0 restraints	Absolute structure parameter: 0 (3)
Primary atom site location: dual

Special details top

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

Refinement. Refined as a 2-component inversion twin

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

	x	y	z	U_iso*/U_eq
O3	0.6682 (4)	0.0682 (3)	−0.10690 (5)	0.0464 (7)
O2	0.5702 (5)	0.1161 (4)	0.09913 (5)	0.0618 (10)
H2	0.6193	0.0520	0.1122	0.093*
O1	0.9663 (5)	0.0859 (4)	0.11947 (6)	0.0776 (13)
H1	0.9867	0.1734	0.1307	0.116*
N4	0.6897 (4)	0.4481 (4)	−0.03853 (5)	0.0297 (6)
N5	0.6731 (4)	0.3531 (4)	−0.08987 (5)	0.0339 (7)
H5	0.6659	0.3887	−0.1088	0.041*
N3	0.6610 (4)	0.6510 (4)	−0.07758 (6)	0.0350 (7)
H3A	0.7126	0.7215	−0.0650	0.042*
H3B	0.7099	0.6617	−0.0951	0.042*
N1	0.7015 (4)	0.1937 (4)	−0.00497 (5)	0.0331 (7)
N2	0.7037 (4)	−0.0291 (4)	−0.03865 (6)	0.0358 (7)
C10	0.6766 (4)	0.4833 (4)	−0.06778 (6)	0.0279 (7)
C8	0.6967 (5)	0.2714 (4)	−0.03304 (6)	0.0269 (7)
C9	0.6965 (5)	0.1324 (4)	−0.05355 (6)	0.0309 (7)
C11	0.6795 (5)	0.1715 (4)	−0.08496 (6)	0.0313 (7)
C4	0.7045 (5)	0.2843 (5)	0.02461 (6)	0.0347 (8)
H4	0.6810	0.4104	0.0214	0.042*
C7	0.7070 (6)	0.0138 (5)	−0.00984 (7)	0.0383 (9)
H7	0.7124	−0.0690	0.0057	0.046*
C3	0.8827 (5)	0.2642 (4)	0.04055 (6)	0.0344 (8)
C2	0.8488 (6)	0.2251 (5)	0.07373 (6)	0.0390 (9)
H2A	0.8267	0.3369	0.0844	0.047*
C6	0.6760 (6)	0.1202 (5)	0.07222 (7)	0.0426 (10)
H6	0.7022	−0.0014	0.0660	0.051*
C5	0.5680 (6)	0.2107 (6)	0.04740 (7)	0.0431 (9)
H5A	0.4972	0.3057	0.0558	0.052*
H5B	0.4900	0.1266	0.0376	0.052*
C1	1.0019 (6)	0.1316 (6)	0.08886 (8)	0.0530 (11)
H1A	1.0293	0.0249	0.0776	0.064*
H1B	1.1052	0.2077	0.0882	0.064*
C12	1.0345 (6)	0.2676 (7)	0.02672 (9)	0.0579 (12)
H12A	1.1379	0.2444	0.0374	0.070*
H12B	1.0398	0.2933	0.0061	0.070*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O3	0.068 (2)	0.0436 (15)	0.0271 (11)	0.0115 (14)	−0.0107 (12)	−0.0147 (10)
O2	0.094 (3)	0.059 (2)	0.0331 (12)	0.0131 (17)	0.0254 (15)	0.0143 (13)
O1	0.142 (4)	0.059 (2)	0.0323 (13)	−0.026 (2)	−0.0291 (18)	0.0172 (13)
N4	0.0369 (17)	0.0286 (15)	0.0237 (11)	0.0030 (12)	−0.0011 (11)	−0.0010 (10)
N5	0.053 (2)	0.0299 (16)	0.0188 (10)	0.0030 (14)	−0.0012 (12)	−0.0017 (11)
N3	0.0483 (19)	0.0333 (17)	0.0235 (11)	−0.0010 (14)	−0.0035 (12)	0.0033 (11)
N1	0.0516 (18)	0.0282 (14)	0.0194 (11)	0.0073 (13)	−0.0014 (12)	−0.0032 (11)
N2	0.0523 (19)	0.0266 (15)	0.0285 (12)	0.0038 (14)	−0.0014 (13)	−0.0018 (11)
C10	0.0306 (18)	0.0272 (17)	0.0258 (13)	0.0022 (14)	−0.0019 (13)	−0.0035 (12)
C8	0.0346 (18)	0.0269 (17)	0.0191 (12)	0.0036 (14)	−0.0014 (12)	−0.0026 (12)
C9	0.0382 (19)	0.0295 (17)	0.0251 (13)	0.0042 (16)	0.0002 (14)	−0.0038 (13)
C11	0.039 (2)	0.0313 (18)	0.0232 (13)	0.0078 (15)	−0.0026 (13)	−0.0035 (13)
C4	0.053 (2)	0.0333 (18)	0.0179 (12)	0.0045 (17)	−0.0011 (14)	−0.0012 (13)
C7	0.059 (2)	0.0287 (18)	0.0273 (14)	0.0071 (17)	−0.0019 (16)	0.0018 (13)
C3	0.054 (2)	0.0262 (18)	0.0233 (13)	−0.0034 (16)	−0.0016 (15)	0.0002 (12)
C2	0.067 (3)	0.0292 (19)	0.0209 (13)	0.0047 (18)	−0.0040 (15)	−0.0017 (13)
C6	0.069 (3)	0.0326 (19)	0.0260 (14)	0.0018 (19)	0.0121 (17)	0.0022 (14)
C5	0.052 (2)	0.050 (2)	0.0268 (14)	−0.0003 (19)	0.0053 (15)	−0.0061 (16)
C1	0.075 (3)	0.050 (3)	0.0341 (17)	0.001 (2)	−0.0216 (19)	0.0057 (17)
C12	0.055 (3)	0.077 (3)	0.0419 (19)	0.003 (2)	0.002 (2)	0.010 (2)

Geometric parameters (Å, º) top

O3—C11	1.246 (4)	C9—C11	1.422 (4)
O2—H2	0.8379	C4—H4	0.9800
O2—C6	1.431 (4)	C4—C3	1.527 (5)
O1—H1	0.8399	C4—C5	1.544 (5)
O1—C1	1.419 (4)	C7—H7	0.9300
N4—C10	1.321 (4)	C3—C2	1.515 (4)
N4—C8	1.359 (4)	C3—C12	1.300 (6)
N5—H5	0.8802	C2—H2A	0.9800
N5—C10	1.385 (4)	C2—C6	1.529 (6)
N5—C11	1.391 (4)	C2—C1	1.512 (6)
N3—H3A	0.8623	C6—H6	0.9800
N3—H3B	0.8615	C6—C5	1.527 (5)
N3—C10	1.345 (4)	C5—H5A	0.9700
N1—C8	1.371 (4)	C5—H5B	0.9700
N1—C4	1.474 (4)	C1—H1A	0.9700
N1—C7	1.377 (4)	C1—H1B	0.9700
N2—C9	1.387 (4)	C12—H12A	0.9300
N2—C7	1.312 (4)	C12—H12B	0.9300
C8—C9	1.386 (4)

C6—O2—H2	109.5	N2—C7—N1	113.2 (3)
C1—O1—H1	109.4	N2—C7—H7	123.4
C10—N4—C8	112.0 (3)	C2—C3—C4	108.4 (3)
C10—N5—H5	116.9	C12—C3—C4	124.1 (3)
C10—N5—C11	126.2 (3)	C12—C3—C2	127.3 (4)
C11—N5—H5	116.9	C3—C2—H2A	108.8
H3A—N3—H3B	109.1	C3—C2—C6	101.7 (3)
C10—N3—H3A	109.6	C6—C2—H2A	108.8
C10—N3—H3B	109.8	C1—C2—C3	112.8 (3)
C8—N1—C4	126.9 (3)	C1—C2—H2A	108.8
C8—N1—C7	106.4 (2)	C1—C2—C6	115.5 (3)
C7—N1—C4	126.6 (3)	O2—C6—C2	116.9 (3)
C7—N2—C9	104.0 (3)	O2—C6—H6	109.0
N4—C10—N5	123.0 (3)	O2—C6—C5	107.8 (3)
N4—C10—N3	120.7 (3)	C2—C6—H6	109.0
N3—C10—N5	116.3 (3)	C5—C6—C2	104.8 (3)
N4—C8—N1	125.7 (3)	C5—C6—H6	109.0
N4—C8—C9	129.0 (3)	C4—C5—H5A	110.6
N1—C8—C9	105.3 (3)	C4—C5—H5B	110.6
N2—C9—C11	130.4 (3)	C6—C5—C4	105.7 (3)
C8—C9—N2	111.0 (3)	C6—C5—H5A	110.6
C8—C9—C11	118.6 (3)	C6—C5—H5B	110.6
O3—C11—N5	119.7 (3)	H5A—C5—H5B	108.7
O3—C11—C9	129.2 (3)	O1—C1—C2	112.9 (4)
N5—C11—C9	111.1 (3)	O1—C1—H1A	109.0
N1—C4—H4	108.8	O1—C1—H1B	109.0
N1—C4—C3	112.0 (3)	C2—C1—H1A	109.0
N1—C4—C5	113.5 (3)	C2—C1—H1B	109.0
C3—C4—H4	108.8	H1A—C1—H1B	107.8
C3—C4—C5	104.7 (3)	C3—C12—H12A	120.0
C5—C4—H4	108.8	C3—C12—H12B	120.0
N1—C7—H7	123.4	H12A—C12—H12B	120.0

O2—C6—C5—C4	156.1 (3)	C4—N1—C8—N4	−1.6 (6)
N4—C8—C9—N2	−179.5 (3)	C4—N1—C8—C9	179.7 (3)
N4—C8—C9—C11	−2.9 (6)	C4—N1—C7—N2	−179.6 (3)
N1—C8—C9—N2	−0.9 (4)	C4—C3—C2—C6	32.3 (3)
N1—C8—C9—C11	175.7 (3)	C4—C3—C2—C1	156.6 (3)
N1—C4—C3—C2	−137.1 (3)	C7—N1—C8—N4	179.7 (3)
N1—C4—C3—C12	38.3 (5)	C7—N1—C8—C9	1.0 (4)
N1—C4—C5—C6	111.7 (3)	C7—N1—C4—C3	68.2 (5)
N2—C9—C11—O3	−0.6 (7)	C7—N1—C4—C5	−50.1 (5)
N2—C9—C11—N5	178.4 (3)	C7—N2—C9—C8	0.4 (4)
C10—N4—C8—N1	−176.5 (3)	C7—N2—C9—C11	−175.7 (4)
C10—N4—C8—C9	1.8 (5)	C3—C4—C5—C6	−10.7 (4)
C10—N5—C11—O3	177.2 (3)	C3—C2—C6—O2	−157.7 (3)
C10—N5—C11—C9	−2.0 (5)	C3—C2—C6—C5	−38.5 (3)
C8—N4—C10—N5	−0.8 (5)	C3—C2—C1—O1	−176.6 (3)
C8—N4—C10—N3	177.4 (3)	C2—C6—C5—C4	31.0 (4)
C8—N1—C4—C3	−110.3 (4)	C6—C2—C1—O1	−60.2 (4)
C8—N1—C4—C5	131.4 (4)	C5—C4—C3—C2	−13.6 (4)
C8—N1—C7—N2	−0.8 (5)	C5—C4—C3—C12	161.7 (4)
C8—C9—C11—O3	−176.4 (4)	C1—C2—C6—O2	79.8 (4)
C8—C9—C11—N5	2.6 (5)	C1—C2—C6—C5	−161.0 (3)
C9—N2—C7—N1	0.3 (5)	C12—C3—C2—C6	−142.8 (4)
C11—N5—C10—N4	1.2 (5)	C12—C3—C2—C1	−18.5 (6)
C11—N5—C10—N3	−177.1 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O3ⁱ	0.84	2.19	2.895 (4)	142
N5—H5···O1ⁱⁱ	0.88	2.21	2.789 (4)	123
N5—H5···O3ⁱⁱⁱ	0.86	2.39	3.097 (4)	138
N3—H3B···O3ⁱⁱⁱ	0.86	2.41	3.226 (4)	157
N3—H3A···N2^iv	0.86	2.22	2.983 (4)	148
O1—H1···O2^v	0.84	1.93	2.758 (4)	169

Symmetry codes: (i) y+1/2, −x+1/2, z+1/4; (ii) −y+1/2, x−1/2, z−1/4; (iii) −x+3/2, y+1/2, −z−1/4; (iv) x, y+1, z; (v) x+1/2, −y+1/2, −z+1/4.

Experimental details top

	(I) (this work)	(II) (Jiang & Liu, 2009)
Crystal data
Chemical formula	C₁₂H₁₅N₅O₃	C₁₂H₁₅N₅O₃·H₂O
M_r	277.29	295.31
Crystal system, space group	Tetragonal, P4₃2₁2	Orthorhombic, C222₁
Temperature (K)	173	273
a, b, c (Å)	7.559 (2), 7.559 (2), 44.103 (12)	6.9986 (10), 11.6229 (10), 33.932 (3)
V (Å³)	2520.0 (15)	2760.1 (5)
Z	8	8
Radiation type	Mo Kα	Mo Kα
µ (mm^-1)	0.11	0.11
Crystal size (mm)	0.19 × 0.12 × 0.11	0.12 × 0.10 ×0.08

Data collection
Diffractometer	Bruker APEXII CCD	Bruker APEXII CCD
T_min, T_max	0.620, 0.746	0.987, 0.991
No. of measured, independent and observed [I > 2σ(I)] reflections	9930, 2865, 2251	6725, 1377, 1270
R_int	0.034	0.030
(sin θ/λ)_max (Å^-1)	0.649

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.053, 0.140, 1.09	0.030, 0.079, 1.00
No. of reflections	2865	1377
No. of parameters	182	204
H-atom treatment	H-atom parameters constrained	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å^-3)	0.25, -0.28	0.16, -0.18

Computer programs: SAINT (Bruker, 2013), SHELXT (Sheldrick, 2015a), SHELXL2014 (Sheldrick, 2015b), OLEX2 (Dolomanov et al., 2009) and PLATON (Spek, 2009).

Hydrogen-bond geometry for (I) and (II) (Å, °) top

	D—H···A	D—H	H···A	D···A
(I)
O2—H2···O3ⁱ	0.84	2.19	2.895 (4)	142
N5—H5···O1ⁱⁱ	0.88	2.21	2.789 (4)	123
N5—H5···O3ⁱⁱⁱ	0.86	2.39	3.097 (4)	138
N3—H3B···O3ⁱⁱⁱ	0.86	2.41	3.226 (4)	157
N3—H3A···N2^iv	0.86	2.22	2.983 (4)	148
O1—H1···O2^v	0.84	1.93	2.758 (4)	169

(II)
N3—H3B···O3ⁱ	0.86	2.24	3.039 (3)	154
N5—H5C···N2ⁱ	0.97 (3)	1.86 (3)	2.829 (3)	177 (3)
O2—H2A···O1wⁱⁱ	0.82	1.83	2.639 (3)	169
O1W—H1W···O2ⁱⁱⁱ	0.821 (12)	2.000 (16)	2.783 (3)	159 (4)
O1—H1···N4^iv	0.82	2.04	2.857 (2)	172
O1W—H2W···O1^v	0.821 (19)	2.113 (10)	2.900 (3)	161 (3)

Symmetry codes for (I): (i) y+1/2, -x+1/2, z+1/4; (ii) -y+1/2, x-1/2, z-1/4; (iii) -x+3/2, y+1/2, -z-1/4; (iv) x, y+1, z; (v) x+1/2, -y+1/2, -z+1/4. Symmetry codes for (II): (i) -x+3/2, y+1/2, -z+3/2; (ii) x+1, y, z; (iii) x-1/2, -y+1/2, -z+1; (iv) x-1 /2, y-1/2, z; (v) x, -y, -z+1.

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Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir

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