3,3′-[(tert-Butoxy­carbon­yl)aza­nedi­yl]dipropanoic acid

Tao, Y.; Liang, Y.-F.; Guo, X.-Q.; Mao, Z.-H.; Qi, Q.-R.

doi:10.1107/S1600536809018911

organic compounds

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ISSN: 2056-9890

Volume 65| Part 6| June 2009| Page o1408

doi:10.1107/S1600536809018911

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3,3′-[(tert-Butoxycarbonyl)azanediyl]dipropanoic acid

Yuan Tao,^a Yu-Feng Liang,^a Xiao-Qiang Guo,^b Zhi-Hua Mao ^c and Qing-Rong Qi ^a ^*

^aDepartment of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China, ^bFaculty of Biotechnology Industry, Chengdu University, Chengdu 610106, People's Republic of China, and ^cThe Center for Testing and Analysis, Sichuan University, Chengdu 610064, People's Republic of China
^*Correspondence e-mail: qiqingronghh@yahoo.com.cn

(Received 7 May 2009; accepted 19 May 2009; online 29 May 2009)

The title compound, C₁₁H₁₉NO₆, is an important intermediate for the synthesis of cephalosporin derivatives. The N atom is in a planar configuration. In the crystal, molecules are linked into zigzag layers parallel to (100) by O—H⋯O hydrogen bonds.

Related literature

The condensation of the title compound with cephalosporin may improve the pharmacokinetics, see: Sakagami et al. (1990 , 1991 ); Uhrich & Frechet (1992 ).

Experimental

Crystal data

C₁₁H₁₉NO₆
M_r = 261.27
Orthorhombic, P b c a
a = 10.632 (2) Å
b = 14.559 (3) Å
c = 18.257 (4) Å
V = 2826.1 (11) Å³
Z = 8
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 292 K
0.60 × 0.50 × 0.44 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
Absorption correction: none
2979 measured reflections
2601 independent reflections
1050 reflections with I > 2σ(I)
R_int = 0.008
3 standard reflections every 200 reflections intensity decay: 1.3%

Refinement

R[F² > 2σ(F²)] = 0.054
wR(F²) = 0.171
S = 1.09
2601 reflections
175 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3O⋯O4ⁱ	0.98 (5)	1.68 (5)	2.653 (4)	174 (4)
O5—H5O⋯O2ⁱⁱ	0.94 (5)	1.70 (5)	2.628 (3)	168 (4)
Symmetry codes: (i) -x, -y, -z; (ii) $[-x, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

Data collection: DIFRAC (Gabe & White, 1993 ); cell refinement: DIFRAC; data reduction: NRCVAX (Gabe et al., 1989 ); 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, 1997 ); software used to prepare material for publication: SHELXL97.

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809018911/ci2799sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536809018911/ci2799Isup2.hkl

checkCIF report

Comment top

The title compound is an important intermediate for the synthesis of a new type of cephalosporin. The condensation of the title compound with cephalosporin may improve the pharmacokinetics of the cephalosporin (Sakagami et al., 1990). It has two carboxylic acid functionalities that are available for the condensation with the amino group of cephalosporin, while the protected amine can be easily activated by deprotection, so that it can be condensed with the carboxyl of cephalosporin. The condensation with cephalosporin may increase the drug concentration, control the release of drug and reduce the drug toxicity (Uhrich & Frechet, 1992; Sakagami et al., 1991).

The N atom has a trigonal planar configuration, with sum of bond angles around N1 being 359.8 °. The molecules are linked into zigzag layers parallel to the (100) by O—H···O hydrogen bonds.

Related literature top

The condensation of the title compound with cephalosporin may

improve the pharmacokinetics, see: Sakagami et al. (1990, 1991); Uhrich & Frechet (1992).

Experimental top

Dimethyl 3,3'-azanediyldipropanoate (5.67g, 30 mol) was treated with NaOH solution (4.0g NaOH in 20 ml H₂O) and stirred at room temperature for 2 h. Then a solution of (Boc)₂O (7.0g, 32mmol) (Boc is tert-butoxycarbonyl) in tertiary butyl alcohol (10 ml) was added dropwise at 283 K. The contents were stirred for 30 min at room temperature. The reaction mixture was washed with n-pentane (10 ml × 3) and the aqueous layer was adjusted to a pH of 1.0 with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (MgSO₄) and evaporated in vacuo and recrystallized in cyclohexane-ethyl acetate to get colourless crystals.

Computing details top

Data collection: DIFRAC (Gabe & White, 1993); cell refinement: DIFRAC (Gabe & White, 1993); data reduction: NRCVAX (Gabe et al., 1989); 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, 1997); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures top

	Fig. 1. The molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level.
	Fig. 2. A packing diagram of the title compound. Hydrogen bonds are shown as dashed lines.

3,3'-[(tert-Butoxycarbonyl)azanediyl]dipropanoic acid top

Crystal data top

C₁₁H₁₉NO₆	F(000) = 1120
M_r = 261.27	D_x = 1.228 Mg m⁻³
Orthorhombic, Pbca	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2ab	Cell parameters from 20 reflections
a = 10.632 (2) Å	θ = 5.7–6.8°
b = 14.559 (3) Å	µ = 0.10 mm⁻¹
c = 18.257 (4) Å	T = 292 K
V = 2826.1 (11) Å³	Block, colourless
Z = 8	0.60 × 0.50 × 0.44 mm

Data collection top

Enraf–Nonius CAD-4 diffractometer	R_int = 0.008
Radiation source: fine-focus sealed tube	θ_max = 25.5°, θ_min = 2.2°
Graphite monochromator	h = −1→12
ω/2–θ scans	k = −3→17
2979 measured reflections	l = −10→22
2601 independent reflections	3 standard reflections every 200 reflections
1050 reflections with I > 2σ(I)	intensity decay: 1.3%

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)] = 0.054	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.171	w = 1/[σ²(F_o²) + (0.0701P)²] where P = (F_o² + 2F_c²)/3
S = 1.09	(Δ/σ)_max = 0.001
2601 reflections	Δρ_max = 0.22 e Å⁻³
175 parameters	Δρ_min = −0.25 e Å⁻³
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0127 (17)

Crystal data top

C₁₁H₁₉NO₆	V = 2826.1 (11) Å³
M_r = 261.27	Z = 8
Orthorhombic, Pbca	Mo Kα radiation
a = 10.632 (2) Å	µ = 0.10 mm⁻¹
b = 14.559 (3) Å	T = 292 K
c = 18.257 (4) Å	0.60 × 0.50 × 0.44 mm

Data collection top

Enraf–Nonius CAD-4 diffractometer	R_int = 0.008
2979 measured reflections	3 standard reflections every 200 reflections
2601 independent reflections	intensity decay: 1.3%
1050 reflections with I > 2σ(I)

Refinement top

R[F² > 2σ(F²)] = 0.054	0 restraints
wR(F²) = 0.171	H atoms treated by a mixture of independent and constrained refinement
S = 1.09	Δρ_max = 0.22 e Å⁻³
2601 reflections	Δρ_min = −0.25 e Å⁻³
175 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	0.1690 (2)	0.18631 (13)	0.36711 (10)	0.0709 (7)
O2	0.0153 (3)	0.10681 (16)	0.31021 (11)	0.0841 (8)
O3	0.0720 (3)	−0.04162 (19)	0.08342 (15)	0.0995 (10)
H3O	0.031 (4)	−0.058 (3)	0.037 (3)	0.129 (16)*
O4	0.0484 (3)	0.09467 (16)	0.03663 (14)	0.1078 (11)
O5	0.1228 (3)	0.49187 (18)	0.26626 (13)	0.0833 (8)
H5O	0.066 (5)	0.526 (3)	0.238 (2)	0.137 (18)*
O6	0.1031 (3)	0.39281 (16)	0.17583 (15)	0.1142 (11)
N1	0.1433 (3)	0.20065 (16)	0.24663 (13)	0.0669 (8)
C1	0.2392 (4)	0.1974 (2)	0.48679 (17)	0.0898 (12)
H1A	0.3223	0.1849	0.4687	0.135*
H1B	0.2328	0.1772	0.5367	0.135*
H1C	0.2233	0.2622	0.4843	0.135*
C2	0.1697 (4)	0.0451 (2)	0.4391 (2)	0.0981 (14)
H2A	0.1055	0.0146	0.4112	0.147*
H2B	0.1700	0.0217	0.4882	0.147*
H2C	0.2501	0.0342	0.4169	0.147*
C3	0.0128 (4)	0.1701 (3)	0.4649 (2)	0.1067 (14)
H3A	−0.0026	0.2343	0.4571	0.160*
H3B	0.0038	0.1560	0.5160	0.160*
H3C	−0.0467	0.1347	0.4371	0.160*
C4	0.1436 (4)	0.1469 (2)	0.44047 (16)	0.0686 (10)
C5	0.1046 (4)	0.1604 (2)	0.30812 (18)	0.0623 (9)
C6	0.0904 (4)	0.1711 (2)	0.17744 (16)	0.0688 (10)
H6A	0.1042	0.2185	0.1409	0.083*
H6B	0.0003	0.1629	0.1829	0.083*
C7	0.1484 (3)	0.0821 (2)	0.15127 (17)	0.0747 (11)
H7A	0.2365	0.0922	0.1400	0.090*
H7B	0.1437	0.0368	0.1902	0.090*
C8	0.0838 (4)	0.0459 (3)	0.08533 (19)	0.0719 (10)
C9	0.2554 (4)	0.2605 (2)	0.24626 (18)	0.0762 (10)
H9A	0.2844	0.2675	0.1962	0.091*
H9B	0.3220	0.2308	0.2738	0.091*
C10	0.2318 (4)	0.3548 (2)	0.27853 (18)	0.0762 (11)
H10A	0.1970	0.3475	0.3273	0.091*
H10B	0.3116	0.3865	0.2833	0.091*
C11	0.1451 (4)	0.4125 (2)	0.2344 (2)	0.0732 (11)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0897 (19)	0.0642 (13)	0.0588 (12)	−0.0127 (13)	−0.0146 (12)	−0.0004 (10)
O2	0.097 (2)	0.0806 (16)	0.0750 (16)	−0.0276 (16)	−0.0109 (14)	−0.0061 (12)
O3	0.152 (3)	0.0724 (19)	0.0737 (17)	0.0156 (18)	−0.0244 (17)	−0.0096 (14)
O4	0.164 (3)	0.0759 (17)	0.0831 (17)	0.0102 (17)	−0.0439 (18)	−0.0010 (15)
O5	0.094 (2)	0.0750 (17)	0.0803 (16)	0.0181 (15)	−0.0104 (14)	0.0071 (14)
O6	0.153 (3)	0.0836 (18)	0.106 (2)	0.0274 (18)	−0.053 (2)	−0.0026 (16)
N1	0.078 (2)	0.0626 (15)	0.0595 (16)	−0.0032 (16)	−0.0056 (15)	0.0027 (14)
C1	0.094 (3)	0.103 (3)	0.073 (2)	0.004 (2)	−0.017 (2)	−0.012 (2)
C2	0.132 (4)	0.072 (3)	0.090 (3)	0.002 (3)	−0.012 (3)	0.015 (2)
C3	0.091 (4)	0.132 (3)	0.097 (3)	0.009 (3)	0.013 (3)	−0.017 (3)
C4	0.080 (3)	0.069 (2)	0.0572 (18)	0.002 (2)	−0.0009 (18)	−0.0036 (17)
C5	0.066 (3)	0.054 (2)	0.067 (2)	−0.0066 (19)	−0.0100 (19)	−0.0035 (17)
C6	0.080 (3)	0.065 (2)	0.060 (2)	0.011 (2)	−0.0078 (17)	−0.0011 (16)
C7	0.073 (3)	0.082 (2)	0.069 (2)	0.014 (2)	−0.0123 (18)	−0.0100 (18)
C8	0.081 (3)	0.071 (3)	0.064 (2)	0.025 (2)	−0.0029 (19)	−0.009 (2)
C9	0.069 (3)	0.075 (2)	0.084 (2)	0.005 (2)	−0.0019 (19)	0.014 (2)
C10	0.078 (3)	0.064 (2)	0.087 (2)	−0.010 (2)	−0.023 (2)	0.0155 (17)
C11	0.087 (3)	0.062 (2)	0.071 (2)	−0.006 (2)	−0.011 (2)	0.0116 (19)

Geometric parameters (Å, º) top

O1—C5	1.331 (4)	C2—H2B	0.96
O1—C4	1.482 (3)	C2—H2C	0.96
O2—C5	1.229 (4)	C3—C4	1.499 (5)
O3—C8	1.281 (4)	C3—H3A	0.96
O3—H3O	0.98 (5)	C3—H3B	0.96
O4—C8	1.199 (4)	C3—H3C	0.96
O5—C11	1.315 (4)	C6—C7	1.513 (4)
O5—H5O	0.94 (5)	C6—H6A	0.97
O6—C11	1.193 (4)	C6—H6B	0.97
N1—C5	1.331 (4)	C7—C8	1.482 (5)
N1—C6	1.448 (4)	C7—H7A	0.97
N1—C9	1.477 (4)	C7—H7B	0.97
C1—C4	1.514 (5)	C9—C10	1.515 (4)
C1—H1A	0.96	C9—H9A	0.97
C1—H1B	0.96	C9—H9B	0.97
C1—H1C	0.96	C10—C11	1.486 (5)
C2—C4	1.508 (4)	C10—H10A	0.97
C2—H2A	0.96	C10—H10B	0.97

C5—O1—C4	121.8 (3)	O1—C5—N1	113.5 (3)
C8—O3—H3O	108 (2)	N1—C6—C7	111.8 (3)
C11—O5—H5O	110 (3)	N1—C6—H6A	109.3
C5—N1—C6	119.0 (3)	C7—C6—H6A	109.3
C5—N1—C9	120.9 (3)	N1—C6—H6B	109.3
C6—N1—C9	119.0 (3)	C7—C6—H6B	109.3
C4—C1—H1A	109.5	H6A—C6—H6B	107.9
C4—C1—H1B	109.5	C8—C7—C6	111.8 (3)
H1A—C1—H1B	109.5	C8—C7—H7A	109.2
C4—C1—H1C	109.5	C6—C7—H7A	109.2
H1A—C1—H1C	109.5	C8—C7—H7B	109.2
H1B—C1—H1C	109.5	C6—C7—H7B	109.2
C4—C2—H2A	109.5	H7A—C7—H7B	107.9
C4—C2—H2B	109.5	O4—C8—O3	122.6 (3)
H2A—C2—H2B	109.5	O4—C8—C7	122.5 (4)
C4—C2—H2C	109.5	O3—C8—C7	114.9 (3)
H2A—C2—H2C	109.5	N1—C9—C10	113.5 (3)
H2B—C2—H2C	109.5	N1—C9—H9A	108.9
C4—C3—H3A	109.5	C10—C9—H9A	108.9
C4—C3—H3B	109.5	N1—C9—H9B	108.9
H3A—C3—H3B	109.5	C10—C9—H9B	108.9
C4—C3—H3C	109.5	H9A—C9—H9B	107.7
H3A—C3—H3C	109.5	C11—C10—C9	113.9 (3)
H3B—C3—H3C	109.5	C11—C10—H10A	108.8
O1—C4—C3	110.5 (3)	C9—C10—H10A	108.8
O1—C4—C2	109.4 (3)	C11—C10—H10B	108.8
C3—C4—C2	113.4 (3)	C9—C10—H10B	108.8
O1—C4—C1	101.2 (3)	H10A—C10—H10B	107.7
C3—C4—C1	110.4 (3)	O6—C11—O5	122.7 (3)
C2—C4—C1	111.3 (3)	O6—C11—C10	125.6 (3)
O2—C5—O1	123.5 (3)	O5—C11—C10	111.6 (3)
O2—C5—N1	123.0 (3)

C5—O1—C4—C3	−63.2 (4)	C9—N1—C6—C7	89.6 (3)
C5—O1—C4—C2	62.3 (4)	N1—C6—C7—C8	173.1 (3)
C5—O1—C4—C1	179.9 (3)	C6—C7—C8—O4	39.8 (5)
C4—O1—C5—O2	4.4 (5)	C6—C7—C8—O3	−142.1 (3)
C4—O1—C5—N1	−177.7 (3)	C5—N1—C9—C10	−76.4 (4)
C6—N1—C5—O2	−8.8 (5)	C6—N1—C9—C10	115.9 (3)
C9—N1—C5—O2	−176.5 (3)	N1—C9—C10—C11	−67.1 (4)
C6—N1—C5—O1	173.3 (3)	C9—C10—C11—O6	−5.7 (6)
C9—N1—C5—O1	5.6 (4)	C9—C10—C11—O5	177.0 (3)
C5—N1—C6—C7	−78.3 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3O···O4ⁱ	0.98 (5)	1.68 (5)	2.653 (4)	174 (4)
O5—H5O···O2ⁱⁱ	0.94 (5)	1.70 (5)	2.628 (3)	168 (4)

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

Experimental details

Crystal data
Chemical formula	C₁₁H₁₉NO₆
M_r	261.27
Crystal system, space group	Orthorhombic, Pbca
Temperature (K)	292
a, b, c (Å)	10.632 (2), 14.559 (3), 18.257 (4)
V (Å³)	2826.1 (11)
Z	8
Radiation type	Mo Kα
µ (mm⁻¹)	0.10
Crystal size (mm)	0.60 × 0.50 × 0.44

Data collection
Diffractometer	Enraf–Nonius CAD-4 diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	2979, 2601, 1050
R_int	0.008
(sin θ/λ)_max (Å⁻¹)	0.606

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.054, 0.171, 1.09
No. of reflections	2601
No. of parameters	175
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.22, −0.25

Computer programs: DIFRAC (Gabe & White, 1993), NRCVAX (Gabe et al., 1989), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 1997).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3O···O4ⁱ	0.98 (5)	1.68 (5)	2.653 (4)	174 (4)
O5—H5O···O2ⁱⁱ	0.94 (5)	1.70 (5)	2.628 (3)	168 (4)

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

Acknowledgements

This work was supported by the National 973 Project under grant No. 2004CB518800.

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