Methyl 3-amino-4-butanamido-5-methyl­benzoate

The title compound, C₁₃H₁₈N₂O₃, is an inter­mediate in the synthesis of compounds with medicinial applications. The crystal structure is stabilized by inter­molecular N—H...O, C—H...N and C—H...O hydrogen bonds.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.005 Å
• R factor = 0.075
• wR factor = 0.175
• Data-to-parameter ratio = 15.2

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for         C4
PLAT340_ALERT_3_C Low Bond Precision on C-C Bonds (x 1000) Ang ...          5
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical .          ?
PLAT152_ALERT_1_C Supplied and Calc Volume s.u. Inconsistent .....          ?

Alert level G
PLAT199_ALERT_1_G Check the Reported _cell_measurement_temperature        293 K
PLAT200_ALERT_1_G Check the Reported _diffrn_ambient_temperature .        293 K

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   2 ALERT level G = General alerts; check

   4 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   0 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

---

S1. Comment

3-Amino-4-butyrylamino-5-methyl-benzoic acid methyl ester is important as an intermediate in the synthesis of telmisartan, an angiotensin II receptor blocker, and in the development of obesity and related metabolic disorders in diet-induced obese mice (Ries et al., 1993). Telmisartan can be used as a therapeutic tool for metabolic syndrome, including visceral obesity (Engeli et al., 2000; Kintscher et al., 2004; Goossens et al., 2003; Kurtz et al., 2004). As part of our studies in this area, we report herein the synthesis and crystal structure of the title compound, (I).

In the molecule of (I) (Fig. 1), bond lengths and angles are within normal ranges (Allen et al., 1987). The aromatic ring (C3—C8) is, of course, planar.

The crystal structure is stabilized by intermolecular N—H···O, C—H···N and C—H···O hydrogen bonds (Table 1, Fig. 2).

Related literature

For bond-length data, see: Allen et al. (1987). For related literature, see: Engeli et al. (2000); Goossens et al. (2003); Kintscher et al. (2004); Kurtz & Pravenec (2004); Ries et al. (1993).

S2. Experimental

4-Amino-3-methyl-benzoic acid methyl ester (8.25 g 50 mmol) was acylated with butyryl chloride (5.3 ml 50 mmol) in chlorobenzene at 373 K. The resulting amide was reacted with fuming nitric acid in sulfuric acid (60%) at 273 K. The resulting 4-(butyrylamino)-3-methyl -5-nitrobenzoic acid methyl ester was reduced with hydrogen (5 bar) and palladium (10% on charcoal) in methanol. Then palladium was filtered by suction. The produce separates as a colourless flocculent solid.

Crystals of (I) suitable for X-ray diffraction were obstained by slow evaporation of an ethanolic solution.

S3. Refinement

H atoms were positioned geometrically, with N—H = 0.86 Å (for NH) and C—H = 0.93, 0.98 and 0.96 Å for aromatic, methene and methyl H, and constrained to ride on their parent atoms, with U_iso(H) = xU_eq(C,N), where x = 1.5 for methyl H, and x = 1.2 for all other H atoms.

Computing details

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: SHELXS97 (Sheldrick, 2008).

Figures

	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. A packing diagram for (I). Hydrogen bonds are shown as dashed lines.

Methyl 3-amino-4-butanamido-5-methylbenzoate

Crystal data

C13H18N2O3	F(000) = 536
Mr = 250.29	Dx = 1.238 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 25 reflections
a = 10.547 (2) Å	θ = 10–13°
b = 16.258 (3) Å	µ = 0.09 mm^−1
c = 8.430 (2) Å	T = 293 K
β = 111.69 (3)°	Block, colourless
V = 1343.2 (5) Å^3	0.40 × 0.20 × 0.10 mm
Z = 4

Data collection

Enraf–Nonius CAD-4 diffractometer	1511 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.028
Graphite monochromator	θmax = 25.2°, θmin = 2.1°
ω/2θ scans	h = −12→11
Absorption correction: ψ scan (North et al., 1968)	k = 0→19
Tmin = 0.965, Tmax = 0.991	l = 0→10
2579 measured reflections	3 standard reflections every 200 reflections
2404 independent reflections	intensity decay: none

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.075	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.174	H-atom parameters constrained
S = 1.02	w = 1/[σ^2(Fo^2) + (0.05P)^2 + 1.5P] where P = (Fo^2 + 2Fc^2)/3
2404 reflections	(Δ/σ)max = 0.002
158 parameters	Δρmax = 0.50 e Å^−3
0 restraints	Δρmin = −0.40 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
N1	0.7939 (3)	0.28652 (17)	0.4910 (3)	0.0609 (8)
H1A	0.7889	0.2893	0.3870	0.073*
O1	0.9151 (2)	0.31431 (18)	0.7622 (3)	0.0722 (8)
C1	1.2201 (4)	0.4441 (3)	0.6344 (6)	0.1018 (16)
H1B	1.2826	0.4734	0.7305	0.153*
H1C	1.1791	0.4818	0.5418	0.153*
H1D	1.2685	0.4023	0.5994	0.153*
O2	0.3477 (2)	0.05447 (17)	0.6104 (4)	0.0760 (8)
N2	0.7806 (3)	0.11598 (19)	0.5029 (4)	0.0669 (8)
H2A	0.7778	0.0632	0.5085	0.080*
H2B	0.8469	0.1395	0.4845	0.080*
C2	1.1113 (4)	0.4052 (3)	0.6834 (5)	0.084
H2C	1.1555	0.3715	0.7836	0.100*
H2D	1.0630	0.4487	0.7163	0.100*
O3	0.2717 (2)	0.17791 (16)	0.6464 (3)	0.0690 (7)
C3	1.0098 (4)	0.3540 (2)	0.5540 (4)	0.0620 (9)
H3A	1.0570	0.3098	0.5213	0.074*
H3B	0.9645	0.3872	0.4533	0.074*
C4	0.9036 (3)	0.31730 (19)	0.6119 (4)	0.0483 (8)
C5	0.6835 (3)	0.2489 (2)	0.5237 (4)	0.0522 (8)
C6	0.5855 (3)	0.2967 (2)	0.5521 (4)	0.0543 (8)
C7	0.4796 (3)	0.2576 (2)	0.5839 (4)	0.0537 (8)
H7A	0.4141	0.2888	0.6061	0.064*
C8	0.4715 (3)	0.1723 (2)	0.5825 (3)	0.0479 (8)
C9	0.5702 (3)	0.1258 (2)	0.5536 (4)	0.0511 (8)
H9A	0.5644	0.0687	0.5541	0.061*
C10	0.6789 (3)	0.1628 (2)	0.5235 (4)	0.0515 (8)
C11	0.5897 (4)	0.3891 (2)	0.5480 (5)	0.0723 (11)
H11A	0.6766	0.4066	0.5478	0.108*
H11B	0.5768	0.4109	0.6468	0.108*
H11C	0.5185	0.4088	0.4467	0.108*
C12	0.3588 (3)	0.1281 (2)	0.6125 (4)	0.0540 (8)
C13	0.1601 (4)	0.1399 (3)	0.6781 (5)	0.0876 (13)
H13A	0.1050	0.1817	0.7013	0.131*
H13B	0.1953	0.1038	0.7746	0.131*
H13C	0.1056	0.1090	0.5794	0.131*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0727 (19)	0.078 (2)	0.0357 (14)	−0.0270 (16)	0.0244 (14)	−0.0037 (14)
O1	0.0547 (14)	0.120 (2)	0.0446 (13)	−0.0178 (14)	0.0212 (11)	−0.0041 (13)
C1	0.088 (3)	0.127 (4)	0.099 (3)	−0.049 (3)	0.044 (3)	−0.021 (3)
O2	0.0629 (16)	0.0679 (18)	0.106 (2)	−0.0081 (13)	0.0415 (15)	0.0052 (15)
N2	0.0536 (17)	0.074 (2)	0.082 (2)	−0.0098 (15)	0.0355 (16)	−0.0048 (17)
C2	0.084	0.084	0.084	0.000	0.031	0.000
O3	0.0547 (14)	0.0824 (18)	0.0749 (17)	−0.0004 (13)	0.0296 (13)	0.0048 (13)
C3	0.063 (2)	0.072 (2)	0.059 (2)	−0.0144 (19)	0.0328 (18)	−0.0081 (18)
C4	0.0546 (19)	0.0550 (19)	0.0413 (17)	0.0012 (16)	0.0248 (15)	−0.0036 (15)
C5	0.056 (2)	0.069 (2)	0.0284 (15)	−0.0165 (17)	0.0127 (14)	−0.0038 (15)
C6	0.060 (2)	0.060 (2)	0.0363 (16)	−0.0098 (17)	0.0099 (15)	0.0002 (15)
C7	0.0500 (19)	0.061 (2)	0.0455 (18)	−0.0014 (16)	0.0124 (15)	0.0019 (16)
C8	0.0437 (17)	0.061 (2)	0.0325 (15)	−0.0059 (15)	0.0059 (13)	0.0010 (14)
C9	0.0435 (18)	0.0570 (19)	0.0483 (18)	−0.0042 (15)	0.0118 (15)	0.0038 (15)
C10	0.0456 (18)	0.066 (2)	0.0382 (16)	−0.0081 (16)	0.0102 (14)	−0.0020 (15)
C11	0.082 (3)	0.067 (2)	0.066 (2)	−0.010 (2)	0.025 (2)	0.0051 (19)
C12	0.0473 (19)	0.069 (2)	0.0418 (17)	0.0004 (18)	0.0121 (15)	0.0052 (17)
C13	0.063 (2)	0.123 (4)	0.093 (3)	0.004 (2)	0.048 (2)	0.020 (3)

Geometric parameters (Å, º)

N1—C4	1.325 (4)	C3—H3A	0.9700
N1—C5	1.430 (4)	C3—H3B	0.9700
N1—H1A	0.8600	C5—C6	1.384 (5)
O1—C4	1.229 (3)	C5—C10	1.400 (5)
C1—C2	1.496 (5)	C6—C7	1.394 (4)
C1—H1B	0.9600	C6—C11	1.503 (5)
C1—H1C	0.9600	C7—C8	1.391 (4)
C1—H1D	0.9600	C7—H7A	0.9300
O2—C12	1.202 (4)	C8—C9	1.379 (4)
N2—C10	1.378 (4)	C8—C12	1.488 (4)
N2—H2A	0.8600	C9—C10	1.399 (4)
N2—H2B	0.8600	C9—H9A	0.9300
C2—C3	1.472 (5)	C11—H11A	0.9600
C2—H2C	0.9700	C11—H11B	0.9600
C2—H2D	0.9700	C11—H11C	0.9600
O3—C12	1.333 (4)	C13—H13A	0.9600
O3—C13	1.439 (4)	C13—H13B	0.9600
C3—C4	1.500 (4)	C13—H13C	0.9600
C4—N1—C5	123.7 (2)	C5—C6—C7	118.6 (3)
C4—N1—H1A	118.1	C5—C6—C11	121.8 (3)
C5—N1—H1A	118.1	C7—C6—C11	119.5 (3)
C2—C1—H1B	109.5	C8—C7—C6	120.3 (3)
C2—C1—H1C	109.5	C8—C7—H7A	119.8
H1B—C1—H1C	109.5	C6—C7—H7A	119.8
C2—C1—H1D	109.5	C9—C8—C7	120.0 (3)
H1B—C1—H1D	109.5	C9—C8—C12	117.9 (3)
H1C—C1—H1D	109.5	C7—C8—C12	122.1 (3)
C10—N2—H2A	120.0	C8—C9—C10	121.3 (3)
C10—N2—H2B	120.0	C8—C9—H9A	119.4
H2A—N2—H2B	120.0	C10—C9—H9A	119.4
C3—C2—C1	117.2 (3)	N2—C10—C9	120.9 (3)
C3—C2—H2C	108.0	N2—C10—C5	121.7 (3)
C1—C2—H2C	108.0	C9—C10—C5	117.4 (3)
C3—C2—H2D	108.0	C6—C11—H11A	109.5
C1—C2—H2D	108.0	C6—C11—H11B	109.5
H2C—C2—H2D	107.2	H11A—C11—H11B	109.5
C12—O3—C13	117.1 (3)	C6—C11—H11C	109.5
C2—C3—C4	114.2 (3)	H11A—C11—H11C	109.5
C2—C3—H3A	108.7	H11B—C11—H11C	109.5
C4—C3—H3A	108.7	O2—C12—O3	122.5 (3)
C2—C3—H3B	108.7	O2—C12—C8	123.9 (3)
C4—C3—H3B	108.7	O3—C12—C8	113.6 (3)
H3A—C3—H3B	107.6	O3—C13—H13A	109.5
O1—C4—N1	120.2 (3)	O3—C13—H13B	109.5
O1—C4—C3	123.4 (3)	H13A—C13—H13B	109.5
N1—C4—C3	116.4 (3)	O3—C13—H13C	109.5
C6—C5—C10	122.3 (3)	H13A—C13—H13C	109.5
C6—C5—N1	120.4 (3)	H13B—C13—H13C	109.5
C10—C5—N1	117.2 (3)
C1—C2—C3—C4	−179.7 (4)	C7—C8—C9—C10	−0.7 (4)
C5—N1—C4—O1	0.2 (5)	C12—C8—C9—C10	179.7 (3)
C5—N1—C4—C3	179.6 (3)	C8—C9—C10—N2	176.8 (3)
C2—C3—C4—O1	−15.3 (5)	C8—C9—C10—C5	0.0 (4)
C2—C3—C4—N1	165.4 (3)	C6—C5—C10—N2	−176.9 (3)
C4—N1—C5—C6	79.5 (4)	N1—C5—C10—N2	3.8 (4)
C4—N1—C5—C10	−101.3 (4)	C6—C5—C10—C9	−0.1 (5)
C10—C5—C6—C7	0.9 (5)	N1—C5—C10—C9	−179.3 (2)
N1—C5—C6—C7	−179.9 (3)	C13—O3—C12—O2	−1.1 (5)
C10—C5—C6—C11	−178.5 (3)	C13—O3—C12—C8	−179.6 (3)
N1—C5—C6—C11	0.7 (5)	C9—C8—C12—O2	−1.2 (5)
C5—C6—C7—C8	−1.6 (5)	C7—C8—C12—O2	179.2 (3)
C11—C6—C7—C8	177.8 (3)	C9—C8—C12—O3	177.3 (3)
C6—C7—C8—C9	1.6 (5)	C7—C8—C12—O3	−2.4 (4)
C6—C7—C8—C12	−178.8 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1^i	0.86	2.60	3.141 (4)	122
N2—H2A···O2^ii	0.86	2.33	3.077 (4)	145
N2—H2B···N1	0.86	2.46	2.780 (4)	103
N2—H2B···O1^i	0.86	2.36	3.089 (4)	142
C11—H11A···N1	0.96	2.45	2.901 (5)	108

Symmetry codes: (i) x, −y+1/2, z−1/2; (ii) −x+1, −y, −z+1.