4-Methyl-2-n-propyl-1H-benzimidazole-6-carboxylic acid

Xu, B.; Yong, L.; Wang, D.; Zhang, R.; Li, X.

doi:10.1107/S1600536808043420

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 65| Part 2| February 2009| Page o226

doi:10.1107/S1600536808043420

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4-Methyl-2-n-propyl-1H-benzimidazole-6-carboxylic acid

Bing Xu,^a Ling Yong,^b Dan Wang,^c Ren Zhang ^c and Xiang Li ^d ^*

^aDepartment of Biological & Food Engineering, Changshu Institute of Technology, Changshu 215500, People's Republic of China, ^bCenter of Drug Discovery, China Pharmaceutical University, Nanjing 210009, People's Republic of China, ^cBioengineering Department, Xuzhou Higher Vocational College of Bioengineering, Mine West Road, Xuzhou, Xuzhou 221006, People's Republic of China, and ^dResearch & Development, Xuzhou Nhwa Pharma Corporation, Zhongshan North Road Xuzhou, Xuzhou 221007, People's Republic of China
^*Correspondence e-mail: lxwd521@tom.com

(Received 8 December 2008; accepted 20 December 2008; online 8 January 2009)

In the title compound, C₁₂H₁₄N₂O₂, the benzene ring and imidazole ring are almost coplanar, making a dihedral angle of 2.47 (14)°. Intermolecular O—H⋯N, N—H⋯O and C—H⋯O hydrogen bonds stabilize the crystal structure.

Related literature

For the use of the title compound as an intermediate in the preparation of telmisartan, see: Ries et al. (1993 ). For the biological activity of telmisartan, see: Engeli et al. (2000 ); Goossens et al. (2003 ). For reference structural data, see: Allen et al. (1987 ). For related literature, see: Kintscher et al. (2004 ).

Experimental

Crystal data

C₁₂H₁₄N₂O₂
M_r = 218.25
Tetragonal, I 4₁ /a
a = 12.0548 (17) Å
c = 31.899 (6) Å
V = 4635.5 (13) Å³
Z = 16
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 293 (2) K
0.30 × 0.30 × 0.10 mm

Data collection

Enraf–Nonuis CAD-4 diffractometer
Absorption correction: ψ scan (North et al., 1968 ) T_min = 0.975, T_max = 0.991
4426 measured reflections
2105 independent reflections
1304 reflections with I > 2σ(I)
R_int = 0.042
3 standard reflections every 200 reflections intensity decay: none

Refinement

R[F² > 2σ(F²)] = 0.072
wR(F²) = 0.195
S = 1.00
2105 reflections
133 parameters
2 restraints
H-atom parameters constrained
Δρ_max = 0.62 e Å⁻³
Δρ_min = −0.39 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C3—H3B⋯O2ⁱ	0.97	2.56	3.399 (4)	144
C11—H11A⋯O2ⁱⁱ	0.96	2.66	3.587 (4)	163
O2—H2C⋯N1ⁱⁱⁱ	0.82	1.80	2.562 (3)	153
N2—H2D⋯O1^iv	0.86	1.83	2.673 (3)	165
Symmetry codes: (i) $[y+{\script{3\over 4}}, -x+{\script{3\over 4}}, z-{\script{1\over 4}}]$ ; (ii) $[-y+{\script{5\over 4}}, x-{\script{1\over 4}}, z-{\script{1\over 4}}]$ ; (iii) $[y+{\script{1\over 4}}, -x+{\script{5\over 4}}, z+{\script{1\over 4}}]$ ; (iv) $[x, y-{\script{1\over 2}}, -z]$ .

Data collection: CAD-4 Software (Enraf–Nonius,1989 ); cell refinement: CAD-4 Software; data reduction: XCAD4 (Harms & Wocadlo,1995 ); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808043420/sj2567sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536808043420/sj2567Isup2.hkl

checkCIF report

Comment top

The title compound (I), Fig. 1, 4-methyl-2-n-propyl-1H-benzimidazole-6-carboxylic acid is an important intermediate in the preparation of the angiotensin II receptor blocker telmisartan (Ries et al.,1993). Telmisartan is used as a therapeutic tool for metabolic problems, including visceral obesity (Engeli et al., 2000; Goossens et al., 2003). Bond lengths in the compound are within normal ranges (Allen et al., 1987) and the benzene and imidazole rings are coplanar with a dihedral angle of 2.47 (14)° between them.

In the crystal structure, intermolecular O—H···N, N—H···O and C—H···O hydrogen bonds, Table 1, link the molecules, Fig. 2, and stabilise the crystal packing.

Related literature top

For the use of the title compound as an intermediate in the preparation of telmisartan, see: Ries et al. (1993). For the biological activity of telmisartan, see: Engeli et al. (2000); Goossens et al. (2003). For reference structural data, see: Allen et al. (1987). For related literature, see: Kintscher et al. (2004).

Experimental top

The title compound was prepared from methyl 4-(butyrylamino)-5-methyl -3-aminobenzoate (13 g 52 mmol) in xylene (60 mL) and hydrochloric acid (130 mL). The mixture was refluxed for 3 h at 423 K, concentrated under reduced pressure then 80mL of methanol and 110 mL 15% sodium hydroxide were added. This solution was further , refluxed for 5 h at 383 K. The pH was adjusted to below 7 and the product filtered. Recrystallization of product from a mixture of ethanol/water (5:1) afforded the white powder. Crystals were obtained by dissolving the product (1.0 g) in acetone (10 ml) and evaporating slowly at room temperature for about 30 d.

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius,1989); cell refinement: CAD-4 Software (Enraf–Nonius,1989); data reduction: XCAD4 (Harms & Wocadlo,1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

	Fig. 1. The molecular structure of the title molecule, with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. Crystal packing of the title compound with hydrogen bonds drawn as dashed lines.

4-Methyl-2-n-propyl-1H-benzimidazole-6-carboxylic acid top

Crystal data top

C₁₂H₁₄N₂O₂	D_x = 1.251 Mg m⁻³
M_r = 218.25	Mo Kα radiation, λ = 0.71073 Å
Tetragonal, I4₁/a	Cell parameters from 25 reflections
Hall symbol: -I 4ad	θ = 10–13°
a = 12.0548 (17) Å	µ = 0.09 mm⁻¹
c = 31.899 (6) Å	T = 293 K
V = 4635.5 (13) Å³	Block, colorless
Z = 16	0.30 × 0.30 × 0.10 mm
F(000) = 1856

Data collection top

Enraf–Nonuis CAD-4 diffractometer	1304 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.042
Graphite monochromator	θ_max = 25.2°, θ_min = 1.8°
ω/2θ scans	h = −9→10
Absorption correction: ψ scan (North et al., 1968)	k = 0→14
T_min = 0.975, T_max = 0.991	l = 0→38
4426 measured reflections	3 standard reflections every 200 reflections
2105 independent reflections	intensity decay: none

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.072	H-atom parameters constrained
wR(F²) = 0.195	w = 1/[σ²(F_o²) + (0.1P)² + 5P] where P = (F_o² + 2F_c²)/3
S = 1.00	(Δ/σ)_max < 0.001
2105 reflections	Δρ_max = 0.62 e Å⁻³
133 parameters	Δρ_min = −0.39 e Å⁻³
2 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008)
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.039 (3)

Crystal data top

C₁₂H₁₄N₂O₂	Z = 16
M_r = 218.25	Mo Kα radiation
Tetragonal, I4₁/a	µ = 0.09 mm⁻¹
a = 12.0548 (17) Å	T = 293 K
c = 31.899 (6) Å	0.30 × 0.30 × 0.10 mm
V = 4635.5 (13) Å³

Data collection top

Enraf–Nonuis CAD-4 diffractometer	1304 reflections with I > 2σ(I)
Absorption correction: ψ scan (North et al., 1968)	R_int = 0.042
T_min = 0.975, T_max = 0.991	3 standard reflections every 200 reflections
4426 measured reflections	intensity decay: none
2105 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.072	2 restraints
wR(F²) = 0.195	H-atom parameters constrained
S = 1.00	Δρ_max = 0.62 e Å⁻³
2105 reflections	Δρ_min = −0.39 e Å⁻³
133 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
O1	0.7815 (2)	0.4947 (2)	0.07388 (7)	0.0591 (8)
O2	0.7256 (2)	0.32125 (18)	0.07006 (6)	0.0471 (7)
H2C	0.7077	0.3341	0.0944	0.071*
N1	0.8807 (2)	0.3584 (2)	−0.11544 (7)	0.0376 (7)
N2	0.8170 (2)	0.2123 (2)	−0.08282 (7)	0.0420 (7)
H2D	0.7940	0.1458	−0.0785	0.050*
C1	0.6545 (5)	0.2486 (5)	−0.18175 (17)	0.104
H1B	0.5891	0.2171	−0.1941	0.155*
H1C	0.6843	0.3042	−0.2001	0.155*
H1D	0.6358	0.2818	−0.1553	0.155*
C2	0.7407 (4)	0.1577 (5)	−0.17491 (18)	0.100
H2A	0.7097	0.1043	−0.1554	0.120*
H2B	0.7513	0.1195	−0.2014	0.120*
C3	0.8501 (3)	0.1904 (3)	−0.15925 (10)	0.0561 (10)
H3A	0.8860	0.2355	−0.1805	0.067*
H3B	0.8945	0.1239	−0.1557	0.067*
C4	0.8509 (3)	0.2525 (3)	−0.11926 (9)	0.0402 (8)
C5	0.8656 (2)	0.3874 (3)	−0.07355 (9)	0.0324 (7)
C6	0.8820 (2)	0.4885 (2)	−0.05283 (9)	0.0341 (7)
C7	0.8539 (2)	0.4896 (3)	−0.01107 (9)	0.0351 (7)
H7A	0.8653	0.5543	0.0042	0.042*
C8	0.8085 (2)	0.3966 (2)	0.00960 (9)	0.0315 (7)
C9	0.7938 (3)	0.2969 (2)	−0.01128 (9)	0.0353 (8)
H9A	0.7645	0.2350	0.0021	0.042*
C10	0.8246 (3)	0.2941 (2)	−0.05289 (9)	0.0325 (7)
C11	0.9269 (3)	0.5876 (3)	−0.07572 (11)	0.0523 (10)
H11A	0.9410	0.5681	−0.1044	0.078*
H11B	0.9947	0.6112	−0.0627	0.078*
H11C	0.8737	0.6467	−0.0747	0.078*
C12	0.7704 (3)	0.4069 (2)	0.05433 (9)	0.0352 (7)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.097 (2)	0.0411 (14)	0.0391 (14)	−0.0157 (14)	0.0171 (13)	−0.0130 (11)
O2	0.0713 (17)	0.0394 (13)	0.0306 (12)	−0.0073 (12)	0.0238 (11)	−0.0056 (10)
N1	0.0401 (16)	0.0475 (17)	0.0250 (13)	0.0030 (13)	0.0022 (11)	0.0055 (12)
N2	0.0599 (19)	0.0366 (15)	0.0295 (13)	−0.0022 (13)	0.0098 (13)	0.0006 (12)
C1	0.104	0.104	0.104	0.000	0.000	0.000
C2	0.100	0.100	0.100	0.000	0.000	0.000
C3	0.062 (2)	0.079 (3)	0.0275 (18)	0.006 (2)	0.0032 (16)	−0.0106 (17)
C4	0.0392 (19)	0.056 (2)	0.0250 (16)	0.0079 (16)	0.0066 (14)	0.0000 (15)
C5	0.0309 (16)	0.0392 (18)	0.0271 (15)	0.0063 (13)	0.0052 (13)	0.0077 (13)
C6	0.0356 (17)	0.0303 (17)	0.0365 (17)	−0.0015 (13)	0.0005 (14)	0.0093 (13)
C7	0.0379 (18)	0.0330 (17)	0.0345 (16)	−0.0008 (13)	0.0032 (13)	−0.0027 (13)
C8	0.0410 (18)	0.0273 (16)	0.0261 (15)	0.0038 (13)	0.0033 (13)	0.0040 (12)
C9	0.0472 (19)	0.0318 (17)	0.0269 (16)	−0.0020 (14)	0.0091 (13)	0.0032 (13)
C10	0.0454 (19)	0.0293 (16)	0.0229 (14)	0.0015 (13)	0.0046 (13)	0.0015 (12)
C11	0.064 (2)	0.041 (2)	0.052 (2)	−0.0089 (17)	0.0104 (18)	0.0146 (17)
C12	0.0430 (19)	0.0321 (17)	0.0305 (16)	0.0009 (14)	0.0040 (14)	−0.0042 (14)

Geometric parameters (Å, º) top

O1—C12	1.237 (4)	C3—H3A	0.9700
O2—C12	1.268 (3)	C3—H3B	0.9700
O2—H2C	0.8200	C5—C10	1.394 (4)
N1—C4	1.332 (4)	C5—C6	1.400 (4)
N1—C5	1.393 (4)	C6—C7	1.374 (4)
N2—C4	1.324 (4)	C6—C11	1.501 (4)
N2—C10	1.376 (4)	C7—C8	1.411 (4)
N2—H2D	0.8600	C7—H7A	0.9300
C1—C2	1.526 (6)	C8—C9	1.385 (4)
C1—H1B	0.9600	C8—C12	1.504 (4)
C1—H1C	0.9600	C9—C10	1.379 (4)
C1—H1D	0.9600	C9—H9A	0.9300
C2—C3	1.465 (6)	C11—H11A	0.9600
C2—H2A	0.9700	C11—H11B	0.9600
C2—H2B	0.9700	C11—H11C	0.9600
C3—C4	1.479 (4)

C12—O2—H2C	109.5	N1—C5—C6	130.7 (3)
C4—N1—C5	107.0 (2)	C10—C5—C6	121.9 (3)
C4—N2—C10	109.1 (3)	C7—C6—C5	115.5 (3)
C4—N2—H2D	125.5	C7—C6—C11	123.5 (3)
C10—N2—H2D	125.5	C5—C6—C11	120.9 (3)
C2—C1—H1B	109.5	C6—C7—C8	122.7 (3)
C2—C1—H1C	109.5	C6—C7—H7A	118.6
H1B—C1—H1C	109.5	C8—C7—H7A	118.6
C2—C1—H1D	109.5	C9—C8—C7	120.9 (3)
H1B—C1—H1D	109.5	C9—C8—C12	119.2 (3)
H1C—C1—H1D	109.5	C7—C8—C12	119.8 (3)
C3—C2—C1	118.0 (5)	C10—C9—C8	116.7 (3)
C3—C2—H2A	107.8	C10—C9—H9A	121.6
C1—C2—H2A	107.8	C8—C9—H9A	121.6
C3—C2—H2B	107.8	N2—C10—C9	131.9 (3)
C1—C2—H2B	107.8	N2—C10—C5	105.9 (2)
H2A—C2—H2B	107.2	C9—C10—C5	122.1 (3)
C2—C3—C4	115.8 (4)	C6—C11—H11A	109.5
C2—C3—H3A	108.3	C6—C11—H11B	109.5
C4—C3—H3A	108.3	H11A—C11—H11B	109.5
C2—C3—H3B	108.3	C6—C11—H11C	109.5
C4—C3—H3B	108.3	H11A—C11—H11C	109.5
H3A—C3—H3B	107.4	H11B—C11—H11C	109.5
N2—C4—N1	110.7 (3)	O1—C12—O2	122.9 (3)
N2—C4—C3	124.8 (3)	O1—C12—C8	121.1 (3)
N1—C4—C3	124.5 (3)	O2—C12—C8	116.0 (3)
N1—C5—C10	107.3 (3)

C1—C2—C3—C4	56.3 (6)	C6—C7—C8—C12	−174.6 (3)
C10—N2—C4—N1	−0.2 (4)	C7—C8—C9—C10	−0.6 (5)
C10—N2—C4—C3	−177.3 (3)	C12—C8—C9—C10	176.5 (3)
C5—N1—C4—N2	0.5 (4)	C4—N2—C10—C9	175.5 (3)
C5—N1—C4—C3	177.5 (3)	C4—N2—C10—C5	−0.1 (4)
C2—C3—C4—N2	63.9 (5)	C8—C9—C10—N2	−176.8 (3)
C2—C3—C4—N1	−112.7 (4)	C8—C9—C10—C5	−1.8 (5)
C4—N1—C5—C10	−0.5 (3)	N1—C5—C10—N2	0.4 (3)
C4—N1—C5—C6	−178.6 (3)	C6—C5—C10—N2	178.6 (3)
N1—C5—C6—C7	177.2 (3)	N1—C5—C10—C9	−175.7 (3)
C10—C5—C6—C7	−0.6 (4)	C6—C5—C10—C9	2.5 (5)
N1—C5—C6—C11	−2.5 (5)	C9—C8—C12—O1	−179.5 (3)
C10—C5—C6—C11	179.7 (3)	C7—C8—C12—O1	−2.4 (5)
C5—C6—C7—C8	−1.8 (4)	C9—C8—C12—O2	−0.4 (4)
C11—C6—C7—C8	177.9 (3)	C7—C8—C12—O2	176.7 (3)
C6—C7—C8—C9	2.4 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3B···O2ⁱ	0.97	2.56	3.399 (4)	144
C11—H11A···O2ⁱⁱ	0.96	2.66	3.587 (4)	163
O2—H2C···N1ⁱⁱⁱ	0.82	1.80	2.562 (3)	153
N2—H2D···O1^iv	0.86	1.83	2.673 (3)	165

Symmetry codes: (i) y+3/4, −x+3/4, z−1/4; (ii) −y+5/4, x−1/4, z−1/4; (iii) y+1/4, −x+5/4, z+1/4; (iv) x, y−1/2, −z.

Experimental details

Crystal data
Chemical formula	C₁₂H₁₄N₂O₂
M_r	218.25
Crystal system, space group	Tetragonal, I4₁/a
Temperature (K)	293
a, c (Å)	12.0548 (17), 31.899 (6)
V (Å³)	4635.5 (13)
Z	16
Radiation type	Mo Kα
µ (mm⁻¹)	0.09
Crystal size (mm)	0.30 × 0.30 × 0.10

Data collection
Diffractometer	Enraf–Nonuis CAD-4 diffractometer
Absorption correction	ψ scan (North et al., 1968)
T_min, T_max	0.975, 0.991
No. of measured, independent and observed [I > 2σ(I)] reflections	4426, 2105, 1304
R_int	0.042
(sin θ/λ)_max (Å⁻¹)	0.600

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.072, 0.195, 1.00
No. of reflections	2105
No. of parameters	133
No. of restraints	2
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.62, −0.39

Computer programs: CAD-4 Software (Enraf–Nonius,1989), XCAD4 (Harms & Wocadlo,1995), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3B···O2ⁱ	0.97	2.56	3.399 (4)	144.3
C11—H11A···O2ⁱⁱ	0.96	2.66	3.587 (4)	163.1
O2—H2C···N1ⁱⁱⁱ	0.82	1.80	2.562 (3)	153.1
N2—H2D···O1^iv	0.86	1.83	2.673 (3)	164.9

Symmetry codes: (i) y+3/4, −x+3/4, z−1/4; (ii) −y+5/4, x−1/4, z−1/4; (iii) y+1/4, −x+5/4, z+1/4; (iv) x, y−1/2, −z.

Acknowledgements

The authors thank the Center of Testing and Analysis, Nanjing University, for support.

References

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