Ethyl 3-[3-amino-4-methyl­amino-N-(pyridin-2-yl)benzamido]­propano­ate

Wen, G.-J.; Wang, M.-X.; Gu, L.-S.

doi:10.1107/S2414314616019416

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 2| Part 2| February 2017| x161941

https://doi.org/10.1107/S2414314616019416

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Ethyl 3-[3-amino-4-methylamino-N-(pyridin-2-yl)benzamido]propanoate

Gao-Ju Wen,^a ^* Ming-Xin Wang ^a and Lian-Shuai Gu ^a

^aCollege of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, People's Republic of China
^*Correspondence e-mail: wgjzt@sina.com

Edited by D.-J. Xu, Zhejiang University (Yuquan Campus), China (Received 25 September 2016; accepted 4 December 2016; online 3 February 2017)

In the title compound, C₁₈H₂₂N₄O₃, the benzene ring is twisted by 63.29 (15)° with respect to the pyridine ring. In the crystal, molecules are linked by N—H⋯O hydrogen bonds and C—H⋯π interactions, forming slabs parallel to the ac plane.

Keywords: crystal structure; dabigatran etexilate; hydrogen bonding; oral anticoagulant.

CCDC reference: 1520636

Structure description

The title compound (Fig. 1), an important intermediate of dabigatran etexilate, has attracted much attention due to its oral anticoagulant properties (Chen et al., 2013 ).

Figure 1
The molecular structure of the title compound, showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

The benzene ring forms a dihedral angles of 63.29 (15)° with the pyridine ring. The mean plane through the C15/C14/N3 fragment makes dihedral angles of 83.5 (3) and 56.0 (3)° with the pyridine and benzene rings, respectively. The N2—C5 bond [1.386 (3) Å] is slightly shorter than the N1—C4 bond [1.412 (4) Å], which implies that the –NH–CH₃ group is a stronger electron-donating group compared to the NH₂ group, thus resulting in a slightly shorter bond length.

In the crystal, molecules are linked by N—H⋯O hydrogen bonds (Table 1). The N1—H1B⋯O2ⁱⁱ hydrogen bond leads to the formation of chains along [101], while the N1—H1A⋯O1ⁱ hydrogen bond and C—H⋯π interaction link the molecules to form slabs parallel to the ac plane (Table 1 and Fig. 2).

Table 1
Hydrogen-bond geometry (Å, °)

Cg2 is the centroid of the C2–C7 benzene ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯O1ⁱ	0.86	2.31	3.035 (3)	142
N1—H1B⋯O2ⁱⁱ	0.86	2.41	3.018 (4)	128
C12—H12A⋯Cg2ⁱⁱⁱ	0.93	2.79	3.566 (4)	142
Symmetry codes: (i) -x, -y, -z+1; (ii) x-1, y, z-1; (iii) x+1, y, z.

Figure 2
A view along the c axis of the crystal packing, with hydrogen bonds shown as dashed lines (see Table 1

Synthesis and crystallization

The title compound was synthesized by the procedures reported by Chen et al. (2013). Single crystals were obtained from methanol solution.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₈H₂₂N₄O₃
M_r	342.39
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	293
a, b, c (Å)	8.3380 (17), 10.435 (2), 10.885 (2)
α, β, γ (°)	102.95 (3), 97.94 (3), 97.51 (3)
V (Å³)	901.2 (3)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.09
Crystal size (mm)	0.20 × 0.10 × 0.10

Data collection
Diffractometer	Enraf–Nonius CAD-4
No. of measured, independent and observed [I > 2σ(I)] reflections	3550, 3305, 1996
R_int	0.025
(sin θ/λ)_max (Å⁻¹)	0.603

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.063, 0.192, 1.01
No. of reflections	3305
No. of parameters	226
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.35, −0.25
Computer programs: CrystalClear (Rigaku, 2005 ), SHELXS97 and SHELXL97 (Sheldrick, 2008 ) and ORTEP-3 for Windows (Farrugia, 2012 ).

Structural data

CCDC reference: 1520636

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2414314616019416/xu4015sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314616019416/xu4015Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314616019416/xu4015Isup3.cml

checkCIF report

Computing details top

Data collection: CrystalClear (Rigaku, 2005); cell refinement: CrystalClear (Rigaku, 2005); data reduction: CrystalClear (Rigaku, 2005); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Ethyl 3-[3-amino-4-methylamino-N-(pyridin-2-yl)benzamido]propanoate top

Crystal data top

C₁₈H₂₂N₄O₃	Z = 2
M_r = 342.39	F(000) = 364
Triclinic, P1	D_x = 1.262 Mg m⁻³
a = 8.3380 (17) Å	Mo Kα radiation, λ = 0.71073 Å
b = 10.435 (2) Å	Cell parameters from 445 reflections
c = 10.885 (2) Å	θ = 2.4–22.8°
α = 102.95 (3)°	µ = 0.09 mm⁻¹
β = 97.94 (3)°	T = 293 K
γ = 97.51 (3)°	Block, brown
V = 901.2 (3) Å³	0.20 × 0.10 × 0.10 mm

Data collection top

Enraf–Nonius CAD-4 diffractometer	θ_max = 25.4°, θ_min = 2.0°
Radiation source: fine-focus sealed tube	h = 0→10
ω/2θ scans	k = −12→12
3550 measured reflections	l = −13→12
3305 independent reflections	3 standard reflections every 200 reflections
1996 reflections with I > 2σ(I)	intensity decay: 1%
R_int = 0.025

Refinement top

Refinement on F²	1 restraint
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.063	H-atom parameters constrained
wR(F²) = 0.192	w = 1/[σ²(F_o²) + (0.1P)²] where P = (F_o² + 2F_c²)/3
S = 1.01	(Δ/σ)_max < 0.001
3305 reflections	Δρ_max = 0.35 e Å⁻³
226 parameters	Δρ_min = −0.25 e Å⁻³

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.

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

	x	y	z	U_iso*/U_eq
O1	0.2166 (3)	0.1355 (2)	0.65272 (19)	0.0547 (6)
N1	−0.0262 (3)	−0.0047 (2)	0.1767 (2)	0.0445 (6)
H1A	−0.0624	−0.0731	0.2028	0.053*
H1B	−0.0635	0.0012	0.1008	0.053*
C1	0.3201 (3)	0.1803 (3)	0.5971 (3)	0.0385 (7)
N2	0.0901 (3)	0.2199 (3)	0.0943 (2)	0.0515 (7)
H2A	0.0084	0.1615	0.0497	0.062*
C2	0.2749 (3)	0.1894 (3)	0.4627 (3)	0.0353 (7)
O2	0.6824 (3)	0.0688 (3)	1.0268 (3)	0.0793 (8)
N3	0.4777 (3)	0.2287 (2)	0.6610 (2)	0.0399 (6)
C3	0.1552 (3)	0.0899 (3)	0.3803 (3)	0.0356 (7)
H3A	0.1154	0.0160	0.4084	0.043*
O3	0.6338 (4)	0.2761 (3)	1.0443 (2)	0.0796 (9)
C4	0.0943 (3)	0.0979 (3)	0.2585 (3)	0.0354 (7)
N4	0.7219 (3)	0.3610 (3)	0.6602 (3)	0.0565 (8)
C5	0.1541 (3)	0.2097 (3)	0.2156 (3)	0.0379 (7)
C6	0.2708 (4)	0.3093 (3)	0.2993 (3)	0.0413 (7)
H6A	0.3096	0.3845	0.2728	0.050*
C7	0.3308 (3)	0.2995 (3)	0.4209 (3)	0.0397 (7)
H7A	0.4095	0.3676	0.4750	0.048*
C8	0.1558 (5)	0.3243 (4)	0.0416 (3)	0.0773 (12)
H8A	0.0954	0.3143	−0.0427	0.116*
H8B	0.1472	0.4089	0.0952	0.116*
H8C	0.2692	0.3202	0.0367	0.116*
C9	0.6160 (3)	0.2519 (3)	0.6011 (3)	0.0379 (7)
C10	0.6416 (4)	0.1628 (3)	0.4945 (3)	0.0439 (7)
H10A	0.5646	0.0865	0.4561	0.053*
C11	0.7814 (4)	0.1880 (3)	0.4461 (3)	0.0518 (8)
H11A	0.8008	0.1291	0.3740	0.062*
C12	0.8924 (4)	0.3007 (4)	0.5044 (4)	0.0620 (10)
H12A	0.9888	0.3202	0.4733	0.074*
C13	0.8578 (4)	0.3840 (4)	0.6098 (4)	0.0690 (11)
H13A	0.9330	0.4612	0.6491	0.083*
C14	0.5114 (4)	0.2464 (3)	0.8003 (3)	0.0475 (8)
H14A	0.4104	0.2557	0.8337	0.057*
H14B	0.5888	0.3282	0.8385	0.057*
C15	0.5797 (5)	0.1331 (4)	0.8390 (3)	0.0655 (10)
H15A	0.4958	0.0541	0.8098	0.079*
H15B	0.6709	0.1160	0.7947	0.079*
C16	0.6378 (4)	0.1525 (4)	0.9788 (3)	0.0599 (9)
C17	0.6878 (6)	0.3086 (5)	1.1817 (3)	0.0847 (14)
H17A	0.7971	0.2879	1.2014	0.102*
H17B	0.6137	0.2571	1.2208	0.102*
C18	0.6888 (6)	0.4523 (5)	1.2312 (4)	0.0952 (15)
H18A	0.7242	0.4766	1.3223	0.143*
H18B	0.7628	0.5024	1.1921	0.143*
H18C	0.5801	0.4716	1.2115	0.143*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0435 (13)	0.0743 (16)	0.0496 (13)	−0.0010 (11)	0.0100 (11)	0.0272 (12)
N1	0.0462 (15)	0.0471 (15)	0.0367 (14)	−0.0005 (12)	−0.0029 (11)	0.0137 (11)
C1	0.0357 (16)	0.0398 (16)	0.0391 (16)	0.0055 (13)	0.0030 (13)	0.0108 (13)
N2	0.0542 (17)	0.0577 (17)	0.0418 (15)	0.0017 (13)	−0.0019 (13)	0.0212 (13)
C2	0.0284 (14)	0.0419 (16)	0.0388 (16)	0.0093 (12)	0.0059 (12)	0.0143 (13)
O2	0.0681 (17)	0.094 (2)	0.0817 (19)	0.0158 (15)	−0.0147 (14)	0.0491 (17)
N3	0.0369 (14)	0.0513 (15)	0.0321 (13)	0.0058 (11)	0.0041 (11)	0.0137 (11)
C3	0.0306 (15)	0.0371 (16)	0.0419 (16)	0.0068 (12)	0.0049 (12)	0.0153 (13)
O3	0.103 (2)	0.101 (2)	0.0398 (14)	0.0422 (17)	−0.0046 (14)	0.0235 (14)
C4	0.0308 (15)	0.0403 (16)	0.0347 (15)	0.0096 (12)	0.0026 (12)	0.0081 (13)
N4	0.0394 (15)	0.0587 (18)	0.0618 (18)	−0.0022 (13)	0.0067 (13)	0.0026 (14)
C5	0.0354 (16)	0.0432 (17)	0.0374 (16)	0.0112 (13)	0.0051 (13)	0.0123 (14)
C6	0.0456 (17)	0.0386 (16)	0.0446 (17)	0.0073 (14)	0.0130 (14)	0.0174 (14)
C7	0.0344 (16)	0.0411 (17)	0.0409 (17)	0.0009 (13)	0.0033 (13)	0.0094 (13)
C8	0.105 (3)	0.077 (3)	0.052 (2)	−0.001 (2)	0.005 (2)	0.035 (2)
C9	0.0347 (15)	0.0392 (16)	0.0409 (16)	0.0077 (13)	0.0013 (13)	0.0143 (13)
C10	0.0427 (18)	0.0427 (18)	0.0472 (18)	0.0100 (14)	0.0077 (14)	0.0113 (15)
C11	0.050 (2)	0.055 (2)	0.058 (2)	0.0177 (17)	0.0181 (16)	0.0182 (17)
C12	0.0394 (19)	0.069 (2)	0.086 (3)	0.0152 (18)	0.0211 (19)	0.027 (2)
C13	0.043 (2)	0.059 (2)	0.094 (3)	−0.0072 (17)	0.005 (2)	0.009 (2)
C14	0.0495 (19)	0.058 (2)	0.0350 (17)	0.0111 (15)	0.0008 (14)	0.0157 (15)
C15	0.081 (3)	0.069 (2)	0.051 (2)	0.021 (2)	0.0042 (19)	0.0235 (18)
C16	0.052 (2)	0.079 (3)	0.055 (2)	0.0171 (19)	0.0002 (17)	0.030 (2)
C17	0.091 (3)	0.126 (4)	0.039 (2)	0.043 (3)	−0.001 (2)	0.018 (2)
C18	0.086 (3)	0.126 (4)	0.061 (3)	0.016 (3)	−0.003 (2)	0.008 (3)

Geometric parameters (Å, º) top

O1—C1	1.223 (3)	C7—H7A	0.9300
N1—C4	1.412 (4)	C8—H8A	0.9600
N1—H1A	0.8600	C8—H8B	0.9600
N1—H1B	0.8600	C8—H8C	0.9600
C1—N3	1.371 (4)	C9—C10	1.375 (4)
C1—C2	1.487 (4)	C10—C11	1.363 (4)
N2—C5	1.386 (3)	C10—H10A	0.9300
N2—C8	1.424 (4)	C11—C12	1.364 (5)
N2—H2A	0.8600	C11—H11A	0.9300
C2—C7	1.377 (4)	C12—C13	1.365 (5)
C2—C3	1.394 (4)	C12—H12A	0.9300
O2—C16	1.187 (4)	C13—H13A	0.9300
N3—C9	1.421 (4)	C14—C15	1.494 (4)
N3—C14	1.469 (3)	C14—H14A	0.9700
C3—C4	1.378 (4)	C14—H14B	0.9700
C3—H3A	0.9300	C15—C16	1.492 (5)
O3—C16	1.333 (4)	C15—H15A	0.9700
O3—C17	1.450 (4)	C15—H15B	0.9700
C4—C5	1.409 (4)	C17—C18	1.474 (6)
N4—C9	1.320 (4)	C17—H17A	0.9700
N4—C13	1.342 (4)	C17—H17B	0.9700
C5—C6	1.387 (4)	C18—H18A	0.9600
C6—C7	1.380 (4)	C18—H18B	0.9600
C6—H6A	0.9300	C18—H18C	0.9600

C4—N1—H1A	120.0	C10—C9—N3	122.2 (3)
C4—N1—H1B	120.0	C11—C10—C9	119.1 (3)
H1A—N1—H1B	120.0	C11—C10—H10A	120.5
O1—C1—N3	119.9 (3)	C9—C10—H10A	120.5
O1—C1—C2	120.6 (2)	C10—C11—C12	119.3 (3)
N3—C1—C2	119.5 (2)	C10—C11—H11A	120.4
C5—N2—C8	121.9 (3)	C12—C11—H11A	120.4
C5—N2—H2A	119.0	C11—C12—C13	118.0 (3)
C8—N2—H2A	119.0	C11—C12—H12A	121.0
C7—C2—C3	118.6 (3)	C13—C12—H12A	121.0
C7—C2—C1	122.7 (3)	N4—C13—C12	124.0 (3)
C3—C2—C1	118.3 (2)	N4—C13—H13A	118.0
C1—N3—C9	124.7 (2)	C12—C13—H13A	118.0
C1—N3—C14	118.6 (2)	N3—C14—C15	113.1 (3)
C9—N3—C14	116.4 (2)	N3—C14—H14A	109.0
C4—C3—C2	121.9 (3)	C15—C14—H14A	109.0
C4—C3—H3A	119.1	N3—C14—H14B	109.0
C2—C3—H3A	119.1	C15—C14—H14B	109.0
C16—O3—C17	117.4 (3)	H14A—C14—H14B	107.8
C3—C4—C5	119.3 (3)	C16—C15—C14	115.9 (3)
C3—C4—N1	120.7 (3)	C16—C15—H15A	108.3
C5—C4—N1	120.0 (2)	C14—C15—H15A	108.3
C9—N4—C13	116.7 (3)	C16—C15—H15B	108.3
N2—C5—C6	122.1 (3)	C14—C15—H15B	108.3
N2—C5—C4	119.5 (3)	H15A—C15—H15B	107.4
C6—C5—C4	118.3 (2)	O2—C16—O3	123.7 (3)
C7—C6—C5	121.6 (3)	O2—C16—C15	124.5 (4)
C7—C6—H6A	119.2	O3—C16—C15	111.7 (3)
C5—C6—H6A	119.2	O3—C17—C18	107.8 (3)
C2—C7—C6	120.3 (3)	O3—C17—H17A	110.2
C2—C7—H7A	119.8	C18—C17—H17A	110.2
C6—C7—H7A	119.8	O3—C17—H17B	110.2
N2—C8—H8A	109.5	C18—C17—H17B	110.2
N2—C8—H8B	109.5	H17A—C17—H17B	108.5
H8A—C8—H8B	109.5	C17—C18—H18A	109.5
N2—C8—H8C	109.5	C17—C18—H18B	109.5
H8A—C8—H8C	109.5	H18A—C18—H18B	109.5
H8B—C8—H8C	109.5	C17—C18—H18C	109.5
N4—C9—C10	123.0 (3)	H18A—C18—H18C	109.5
N4—C9—N3	114.7 (3)	H18B—C18—H18C	109.5

O1—C1—C2—C7	136.9 (3)	C5—C6—C7—C2	−0.3 (4)
N3—C1—C2—C7	−40.0 (4)	C13—N4—C9—C10	1.3 (5)
O1—C1—C2—C3	−34.9 (4)	C13—N4—C9—N3	177.4 (3)
N3—C1—C2—C3	148.3 (3)	C1—N3—C9—N4	140.7 (3)
O1—C1—N3—C9	163.5 (3)	C14—N3—C9—N4	−45.4 (3)
C2—C1—N3—C9	−19.6 (4)	C1—N3—C9—C10	−43.2 (4)
O1—C1—N3—C14	−10.3 (4)	C14—N3—C9—C10	130.7 (3)
C2—C1—N3—C14	166.6 (2)	N4—C9—C10—C11	−0.8 (4)
C7—C2—C3—C4	1.1 (4)	N3—C9—C10—C11	−176.5 (3)
C1—C2—C3—C4	173.2 (2)	C9—C10—C11—C12	0.1 (5)
C2—C3—C4—C5	−0.1 (4)	C10—C11—C12—C13	0.0 (5)
C2—C3—C4—N1	179.6 (2)	C9—N4—C13—C12	−1.3 (5)
C8—N2—C5—C6	8.7 (5)	C11—C12—C13—N4	0.7 (6)
C8—N2—C5—C4	−174.3 (3)	C1—N3—C14—C15	98.0 (3)
C3—C4—C5—N2	−178.3 (2)	C9—N3—C14—C15	−76.3 (3)
N1—C4—C5—N2	2.0 (4)	N3—C14—C15—C16	172.1 (3)
C3—C4—C5—C6	−1.2 (4)	C17—O3—C16—O2	0.1 (6)
N1—C4—C5—C6	179.1 (2)	C17—O3—C16—C15	−179.8 (3)
N2—C5—C6—C7	178.4 (3)	C14—C15—C16—O2	173.4 (4)
C4—C5—C6—C7	1.4 (4)	C14—C15—C16—O3	−6.6 (5)
C3—C2—C7—C6	−0.9 (4)	C16—O3—C17—C18	174.3 (3)
C1—C2—C7—C6	−172.7 (2)

Hydrogen-bond geometry (Å, º) top

Cg2 is the centroid of the C2–C7 benzene ring.

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1ⁱ	0.86	2.31	3.035 (3)	142
N1—H1B···O2ⁱⁱ	0.86	2.41	3.018 (4)	128
C12—H12A···Cg2ⁱⁱⁱ	0.93	2.79	3.566 (4)	142

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

Acknowledgements

We are very grateful for the financial support from the National Natural Science Foundation of China (grant No. 21371031).

References

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