tert-Butyl 6-amino-5-cyano-2-(2-meth­oxy­eth­yl)nicotinate

Chen, Y.-N.; Zhao, X.-D.; Deng, J.; Li, Q.-G.

doi:10.1107/S1600536812014328

organic compounds

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ISSN: 2056-9890

Volume 68| Part 5| May 2012| Page o1375

doi:10.1107/S1600536812014328

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tert-Butyl 6-amino-5-cyano-2-(2-methoxyethyl)nicotinate

Yi-Ning Chen,^a Xing-Dong Zhao,^b Jie Deng ^c and Qin-Geng Li ^a ^*

^aLaboratory of Pharmaceutical Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing 400016, People's Republic of China, ^bFochon Pharma Inc., 1933 Davis Street, Suite 207, San Leandro, CA 94577, USA, and ^cChongqing Pharmaceutical Research Institute Co. Ltd, Chongqing 400016, People's Republic of China
^*Correspondence e-mail: sntmilk@yahoo.com.cn

(Received 21 March 2012; accepted 2 April 2012; online 13 April 2012)

The title compound, C₁₄H₁₉N₃O₃, was synthesized by the reaction of 3-methoxypropionitrile, tert-butyl bromoacetate and ethoxymethylenemalononitrile. In the crystal, N—H⋯O hydrogen bonds link the molecules into chains propagating along the b axis.

Related literature

For a related structure, see: Wang et al. (2007 ). For applications of pyridines, see: Spurr (1995 ). For background to the synthesis of highly substituted pyridines, see: Chun et al. (2009 , 2011 ).

Experimental

Crystal data

C₁₄H₁₉N₃O₃
M_r = 277.32
Monoclinic, C 2/c
a = 10.1155 (4) Å
b = 15.2482 (5) Å
c = 19.4882 (6) Å
β = 99.853 (3)°
V = 2961.59 (18) Å³
Z = 8
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 130 K
0.35 × 0.30 × 0.30 mm

Data collection

Agilent Xcalibur Eos diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2010 ) T_min = 0.902, T_max = 1.000
5419 measured reflections
2608 independent reflections
2094 reflections with I > 2σ(I)
R_int = 0.020

Refinement

R[F² > 2σ(F²)] = 0.040
wR(F²) = 0.100
S = 1.05
2608 reflections
191 parameters
4 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.16 e Å⁻³
Δρ_min = −0.22 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2A⋯O3ⁱ	0.88 (1)	2.25 (1)	3.0186 (18)	146 (2)
N2—H2B⋯O1ⁱ	0.88 (1)	2.00 (1)	2.8427 (18)	159 (2)
Symmetry code: (i) $[-x+{\script{1\over 2}}, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

Data collection: CrysAlis PRO (Agilent, 2010); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009 ); software used to prepare material for publication: OLEX2.

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536812014328/cv5269sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536812014328/cv5269Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536812014328/cv5269Isup3.cml

checkCIF report

Comment top

Pyridines can be found in many natural products and biologically active compounds (Spurr, 1995). Thus, the synthesis of highly substituted pyridines has attracted much attention (Chun et al. 2009, 2011). We synthesized the title compound (I). Herein we present its crystal structure.

In (I) (Fig. 1), all bond lengths and angles are normal and comparable with those observed in the related compound methyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-methylpyridine-3-carboxylate (Wang et al., 2007).

In the crystal structure of (I), intermolecular N—H···O hydrogen bonds (Table 1) link the molecules into chains propagated along the b axis.

Related literature top

For a related structure, see: Wang et al. (2007). For applications of pyridines, see: Spurr (1995). For background to the synthesis of highly substituted pyridines, see: Chun et al. (2009, 2011).

Experimental top

A mixture of zinc powder (0.65 g) and 3-methoxypropionitrile (0.85 g) in tetrahydrofuran (10 ml) was refluxed, then tert-Butyl bromoacetate (1.95 g) was added dropwise. Keep stirring under reflux for 1 h. Ethoxymethylenemalononitrile (1.22 g) was added, the reaction mixture was stirred under reflux for 2 h to afford the title compound (I) (Chun et al. 2009, 2011). Single crystals were grown by slow evaporation of a solution of Pet: EtOAc=5:1 at room temperature.

Computing details top

Data collection: CrysAlis PRO (Agilent, 2010); cell refinement: CrysAlis PRO (Agilent, 2010); data reduction: CrysAlis PRO (Agilent, 2010); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures top

Fig. 1. The molecular structure of the title compound. Displacement ellipsoids are drawn at the 50% probability level.

tert-Butyl 6-amino-5-cyano-2-(2-methoxyethyl)nicotinate top

Crystal data top

C₁₄H₁₉N₃O₃	D_x = 1.244 Mg m⁻³
M_r = 277.32	Melting point: 404.16 K
Monoclinic, C2/c	Mo Kα radiation, λ = 0.7107 Å
a = 10.1155 (4) Å	Cell parameters from 2258 reflections
b = 15.2482 (5) Å	θ = 2.9–29.1°
c = 19.4882 (6) Å	µ = 0.09 mm⁻¹
β = 99.853 (3)°	T = 130 K
V = 2961.59 (18) Å³	Block, colourless
Z = 8	0.35 × 0.30 × 0.30 mm
F(000) = 1184

Data collection top

Agilent Xcalibur Eos diffractometer	2608 independent reflections
Radiation source: Enhance (Mo) X-ray Source	2094 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.020
Detector resolution: 16.0874 pixels mm^-1	θ_max = 25.0°, θ_min = 2.9°
ω scans	h = −12→11
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2010)	k = −18→10
T_min = 0.902, T_max = 1.000	l = −15→23
5419 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.040	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.100	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ²(F_o²) + (0.0438P)² + 1.1844P] where P = (F_o² + 2F_c²)/3
2608 reflections	(Δ/σ)_max < 0.001
191 parameters	Δρ_max = 0.16 e Å⁻³
4 restraints	Δρ_min = −0.22 e Å⁻³

Crystal data top

C₁₄H₁₉N₃O₃	V = 2961.59 (18) Å³
M_r = 277.32	Z = 8
Monoclinic, C2/c	Mo Kα radiation
a = 10.1155 (4) Å	µ = 0.09 mm⁻¹
b = 15.2482 (5) Å	T = 130 K
c = 19.4882 (6) Å	0.35 × 0.30 × 0.30 mm
β = 99.853 (3)°

Data collection top

Agilent Xcalibur Eos diffractometer	2608 independent reflections
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2010)	2094 reflections with I > 2σ(I)
T_min = 0.902, T_max = 1.000	R_int = 0.020
5419 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.040	4 restraints
wR(F²) = 0.100	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	Δρ_max = 0.16 e Å⁻³
2608 reflections	Δρ_min = −0.22 e Å⁻³
191 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	0.21160 (13)	0.04640 (8)	0.29380 (6)	0.0402 (3)
O2	0.12016 (10)	0.02438 (7)	0.38946 (5)	0.0280 (3)
O3	0.33430 (10)	−0.04292 (7)	0.12374 (6)	0.0296 (3)
N1	0.17189 (12)	−0.23015 (8)	0.25819 (6)	0.0241 (3)
N2	0.16078 (15)	−0.36625 (9)	0.30598 (8)	0.0322 (4)
H2A	0.1613 (17)	−0.4024 (9)	0.3412 (8)	0.039*
H2B	0.1820 (17)	−0.3884 (10)	0.2674 (7)	0.039*
N3	0.11844 (14)	−0.34153 (10)	0.48130 (7)	0.0367 (4)
C1	0.15937 (14)	−0.27913 (10)	0.31410 (8)	0.0237 (4)
C2	0.14474 (14)	−0.24020 (10)	0.37841 (8)	0.0233 (4)
C3	0.14728 (14)	−0.15014 (10)	0.38336 (8)	0.0230 (4)
H3	0.1386	−0.1227	0.4261	0.028*
C4	0.16250 (13)	−0.09908 (10)	0.32599 (8)	0.0218 (3)
C5	0.17249 (13)	−0.14259 (10)	0.26322 (8)	0.0219 (3)
C6	0.16804 (14)	−0.00242 (11)	0.33331 (8)	0.0250 (4)
C7	0.13015 (15)	−0.29497 (11)	0.43634 (8)	0.0263 (4)
C8	0.11812 (17)	0.11866 (10)	0.40839 (9)	0.0303 (4)
C9	0.0559 (2)	0.11529 (13)	0.47372 (11)	0.0529 (6)
H9A	0.0480	0.1749	0.4913	0.079*
H9B	0.1128	0.0802	0.5092	0.079*
H9C	−0.0334	0.0886	0.4629	0.079*
C10	0.25917 (19)	0.15437 (14)	0.42359 (11)	0.0505 (5)
H10A	0.2974	0.1550	0.3806	0.076*
H10B	0.3143	0.1171	0.4583	0.076*
H10C	0.2575	0.2142	0.4417	0.076*
C11	0.03036 (19)	0.16861 (12)	0.35095 (10)	0.0459 (5)
H11A	0.0773	0.1751	0.3112	0.069*
H11B	0.0104	0.2268	0.3680	0.069*
H11C	−0.0536	0.1364	0.3363	0.069*
C12	0.18509 (14)	−0.09710 (11)	0.19592 (8)	0.0247 (4)
H12A	0.1426	−0.0385	0.1950	0.030*
H12B	0.1367	−0.1315	0.1563	0.030*
C13	0.33020 (14)	−0.08676 (11)	0.18746 (8)	0.0252 (4)
H13A	0.3796	−0.0524	0.2268	0.030*
H13B	0.3732	−0.1451	0.1873	0.030*
C14	0.46425 (17)	−0.04423 (13)	0.10532 (10)	0.0417 (5)
H14A	0.4621	−0.0133	0.0611	0.063*
H14B	0.4923	−0.1051	0.1004	0.063*
H14C	0.5280	−0.0152	0.1418	0.063*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0612 (8)	0.0263 (7)	0.0407 (7)	−0.0069 (6)	0.0305 (6)	−0.0014 (6)
O2	0.0394 (6)	0.0213 (6)	0.0262 (6)	−0.0012 (5)	0.0138 (5)	−0.0030 (5)
O3	0.0326 (6)	0.0331 (7)	0.0258 (6)	−0.0025 (5)	0.0128 (4)	0.0028 (5)
N1	0.0260 (7)	0.0240 (7)	0.0236 (7)	−0.0005 (6)	0.0082 (5)	−0.0018 (6)
N2	0.0477 (9)	0.0228 (8)	0.0300 (8)	0.0015 (7)	0.0177 (7)	−0.0008 (7)
N3	0.0444 (9)	0.0367 (9)	0.0296 (8)	−0.0065 (7)	0.0077 (6)	0.0051 (7)
C1	0.0204 (8)	0.0241 (8)	0.0274 (8)	0.0001 (6)	0.0065 (6)	−0.0001 (7)
C2	0.0225 (8)	0.0249 (8)	0.0235 (8)	0.0001 (6)	0.0066 (6)	0.0007 (7)
C3	0.0207 (8)	0.0274 (8)	0.0216 (8)	0.0005 (6)	0.0060 (6)	−0.0013 (7)
C4	0.0185 (7)	0.0245 (8)	0.0231 (8)	0.0004 (6)	0.0059 (6)	−0.0003 (7)
C5	0.0164 (7)	0.0253 (8)	0.0249 (8)	−0.0001 (6)	0.0062 (6)	0.0010 (7)
C6	0.0241 (8)	0.0274 (9)	0.0248 (8)	−0.0003 (7)	0.0078 (6)	−0.0009 (7)
C7	0.0282 (9)	0.0258 (9)	0.0259 (9)	−0.0014 (7)	0.0071 (7)	−0.0029 (8)
C8	0.0399 (9)	0.0211 (8)	0.0324 (9)	−0.0023 (7)	0.0132 (7)	−0.0071 (8)
C9	0.0851 (15)	0.0328 (11)	0.0507 (13)	−0.0069 (10)	0.0392 (11)	−0.0133 (10)
C10	0.0487 (12)	0.0491 (12)	0.0533 (13)	−0.0149 (10)	0.0076 (9)	−0.0227 (11)
C11	0.0542 (12)	0.0304 (10)	0.0526 (12)	0.0095 (9)	0.0080 (9)	−0.0036 (10)
C12	0.0259 (8)	0.0268 (9)	0.0219 (8)	−0.0008 (7)	0.0052 (6)	−0.0002 (7)
C13	0.0304 (9)	0.0246 (8)	0.0223 (8)	0.0020 (7)	0.0094 (6)	0.0022 (7)
C14	0.0431 (11)	0.0426 (11)	0.0470 (11)	0.0023 (9)	0.0290 (8)	0.0050 (10)

Geometric parameters (Å, º) top

O1—C6	1.2072 (18)	C8—C10	1.508 (2)
O2—C6	1.3342 (17)	C8—C11	1.510 (2)
O2—C8	1.4852 (19)	C9—H9A	0.9800
O3—C13	1.4170 (18)	C9—H9B	0.9800
O3—C14	1.4209 (18)	C9—H9C	0.9800
N1—C1	1.3447 (19)	C10—H10A	0.9800
N1—C5	1.339 (2)	C10—H10B	0.9800
N2—H2A	0.880 (12)	C10—H10C	0.9800
N2—H2B	0.883 (12)	C11—H11A	0.9800
N2—C1	1.338 (2)	C11—H11B	0.9800
N3—C7	1.149 (2)	C11—H11C	0.9800
C1—C2	1.417 (2)	C12—H12A	0.9900
C2—C3	1.377 (2)	C12—H12B	0.9900
C2—C7	1.432 (2)	C12—C13	1.513 (2)
C3—H3	0.9500	C13—H13A	0.9900
C3—C4	1.392 (2)	C13—H13B	0.9900
C4—C5	1.410 (2)	C14—H14A	0.9800
C4—C6	1.481 (2)	C14—H14B	0.9800
C5—C12	1.508 (2)	C14—H14C	0.9800
C8—C9	1.515 (2)

C6—O2—C8	121.51 (12)	H9A—C9—H9B	109.5
C13—O3—C14	112.44 (12)	H9A—C9—H9C	109.5
C5—N1—C1	119.64 (13)	H9B—C9—H9C	109.5
H2A—N2—H2B	117.1 (16)	C8—C10—H10A	109.5
C1—N2—H2A	121.9 (11)	C8—C10—H10B	109.5
C1—N2—H2B	119.3 (11)	C8—C10—H10C	109.5
N1—C1—C2	121.50 (14)	H10A—C10—H10B	109.5
N2—C1—N1	116.81 (14)	H10A—C10—H10C	109.5
N2—C1—C2	121.69 (15)	H10B—C10—H10C	109.5
C1—C2—C7	119.56 (14)	C8—C11—H11A	109.5
C3—C2—C1	118.44 (14)	C8—C11—H11B	109.5
C3—C2—C7	121.99 (14)	C8—C11—H11C	109.5
C2—C3—H3	119.8	H11A—C11—H11B	109.5
C2—C3—C4	120.32 (14)	H11A—C11—H11C	109.5
C4—C3—H3	119.8	H11B—C11—H11C	109.5
C3—C4—C5	117.88 (14)	C5—C12—H12A	109.3
C3—C4—C6	119.12 (13)	C5—C12—H12B	109.3
C5—C4—C6	123.00 (14)	C5—C12—C13	111.75 (12)
N1—C5—C4	122.18 (14)	H12A—C12—H12B	107.9
N1—C5—C12	113.27 (13)	C13—C12—H12A	109.3
C4—C5—C12	124.55 (14)	C13—C12—H12B	109.3
O1—C6—O2	123.89 (15)	O3—C13—C12	108.60 (12)
O1—C6—C4	124.35 (14)	O3—C13—H13A	110.0
O2—C6—C4	111.76 (13)	O3—C13—H13B	110.0
N3—C7—C2	177.52 (17)	C12—C13—H13A	110.0
O2—C8—C9	101.62 (13)	C12—C13—H13B	110.0
O2—C8—C10	110.20 (14)	H13A—C13—H13B	108.4
O2—C8—C11	109.60 (13)	O3—C14—H14A	109.5
C10—C8—C9	111.25 (16)	O3—C14—H14B	109.5
C10—C8—C11	112.31 (16)	O3—C14—H14C	109.5
C11—C8—C9	111.34 (16)	H14A—C14—H14B	109.5
C8—C9—H9A	109.5	H14A—C14—H14C	109.5
C8—C9—H9B	109.5	H14B—C14—H14C	109.5
C8—C9—H9C	109.5

N1—C1—C2—C3	−1.8 (2)	C4—C5—C12—C13	93.76 (17)
N1—C1—C2—C7	179.27 (13)	C5—N1—C1—N2	−179.37 (13)
N1—C5—C12—C13	−86.09 (16)	C5—N1—C1—C2	0.9 (2)
N2—C1—C2—C3	178.53 (14)	C5—C4—C6—O1	−18.0 (2)
N2—C1—C2—C7	−0.4 (2)	C5—C4—C6—O2	162.63 (13)
C1—N1—C5—C4	1.0 (2)	C5—C12—C13—O3	−179.41 (12)
C1—N1—C5—C12	−179.11 (12)	C6—O2—C8—C9	179.74 (14)
C1—C2—C3—C4	0.7 (2)	C6—O2—C8—C10	−62.23 (19)
C1—C2—C7—N3	−3 (4)	C6—O2—C8—C11	61.86 (18)
C2—C3—C4—C5	1.2 (2)	C6—C4—C5—N1	177.67 (13)
C2—C3—C4—C6	−178.59 (13)	C6—C4—C5—C12	−2.2 (2)
C3—C2—C7—N3	178 (100)	C7—C2—C3—C4	179.59 (13)
C3—C4—C5—N1	−2.1 (2)	C8—O2—C6—O1	−0.6 (2)
C3—C4—C5—C12	178.08 (12)	C8—O2—C6—C4	178.73 (12)
C3—C4—C6—O1	161.74 (15)	C14—O3—C13—C12	−169.39 (13)
C3—C4—C6—O2	−17.62 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2A···O3ⁱ	0.88 (1)	2.25 (1)	3.0186 (18)	146 (2)
N2—H2B···O1ⁱ	0.88 (1)	2.00 (1)	2.8427 (18)	159 (2)

Symmetry code: (i) −x+1/2, y−1/2, −z+1/2.

Experimental details

Crystal data
Chemical formula	C₁₄H₁₉N₃O₃
M_r	277.32
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	130
a, b, c (Å)	10.1155 (4), 15.2482 (5), 19.4882 (6)
β (°)	99.853 (3)
V (Å³)	2961.59 (18)
Z	8
Radiation type	Mo Kα
µ (mm⁻¹)	0.09
Crystal size (mm)	0.35 × 0.30 × 0.30

Data collection
Diffractometer	Agilent Xcalibur Eos diffractometer
Absorption correction	Multi-scan (CrysAlis PRO; Agilent, 2010)
T_min, T_max	0.902, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	5419, 2608, 2094
R_int	0.020
(sin θ/λ)_max (Å⁻¹)	0.594

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.040, 0.100, 1.05
No. of reflections	2608
No. of parameters	191
No. of restraints	4
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.16, −0.22

Computer programs: CrysAlis PRO (Agilent, 2010), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), OLEX2 (Dolomanov et al., 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2A···O3ⁱ	0.880 (12)	2.247 (13)	3.0186 (18)	146.3 (15)
N2—H2B···O1ⁱ	0.883 (12)	2.003 (13)	2.8427 (18)	158.5 (16)

Symmetry code: (i) −x+1/2, y−1/2, −z+1/2.

Acknowledgements

The authors thank Yin Ping, Fang Bo and Fochon Pharma, Inc.

References

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