supplementary materials


ff2042 scheme

Acta Cryst. (2012). E68, o115    [ doi:10.1107/S1600536811052421 ]

Methyl 2-[2-(tert-butoxycarbonylamino)-1,3-benzothiazole-6-carboxamido]acetate

D. Gao, X. Fang, H.-Y. Yu and J.-D. Wang

Abstract top

In the title compound, C16H19N3O5S, the dihedral angle between the benzene ring and the carbonylamino group is 18.18 (2)°. In the crystal, molecules form centrosymmetric dimers via pairs of N-H...N hydrogen bonds. The dimers are connected via N-H...O hydrogen bonds into a three-dimensional network..

Comment top

Benzothiazole is a heterocyclic compound, which contains a benzene ring and a thiazole ring, and is a component of a lot of natural products, biological pesticides, drugs, spices and so on. The benzothiazole derivatives have broad biological activities that make them play an important role in drug research and development. For example, they showed anti-tumor (Brantley et al., 2004; Mortimer et al., 2006;Ćaleta et al., 2009) and anti-microbial activities (Palmer et al., 1971). During our development of 2-aminobenzothiazole-based Urokinase-Type Plasminogen Activator (uPA) inhibitors, we synthesized the title compound (I) as an intermediate. The compound (I) has certain biological activity, and its IC50 is 780 µM as uPA inhibitor itself.

The molecule structure of the title compound (I) is shown in Fig. 1. The molecular skeleton is slightly distorted from a planar conformation with the angle between benzene and thiazole rings of 1.46 (1)°. And for the substituents, the dihedral angles between the thiazole ring and tert-butyl carbamate is 9.15 (6)°, the dihedral angles between benzene ring and carbonylamino group is 18.18 (2)°, and the dihedral angles between carbonylamino group and methyl acetate is 79.24 (3)°.

In the crystal, there are intermolecular hydrogen bonds of N1—H1···N2 and N3—H3···O3. Where, two molecules form a pair with inversion symmetry via N—H···N hydrogen bonds, and the pairs form a three dimensional network via N—H···O hydrogen bonds. No ππ interactions are found in this structure.

Related literature top

For benzothiazole derivatives with anti-tumor activity, see: Brantley et al. (2004); Ćaleta et al. (2009); Mortimer et al. (2006) and for benzothiazolines with anti-tuberculous properties, see: Palmer et al. (1971). For related benzothiazole structures, see: Lynch et al. (2002); Matković-Čalogović et al. (2003); Lei et al. (2010).

Experimental top

In a 250 ml round bottom flask, the pale yellow solid of ethyl 2-(tert-butoxycarbonylamino) benzothiazole-6-carboxylate, N-Boc ester (3.22 g, 10 mmol) in a mixed solution of EtOH (100 ml) and 2 N aq NaOH (80 ml) were refluxed for 5 h. Then the solution was cooled with an ice bath and acidified with 1 N aq HCl, when pH<2, white floc generated and put it aside for 2 h. Then the mixture was filtered and the filter mass was washed to neutral by water and dried to afford white solid of 2-(tert-butoxycarbonylamino)benzothiazole-6-carboxylic acid, N-Boc acid (2.59 g, yield: 88%).

In a 100 ml round bottom flask, the mixture of N-Boc acid (705 mg, 2.4 mmol), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 759 mg, 2 mmol), N, N-Diisopropylethylamine (DIEA, 310 mg, 2.4 mmol), and glycine methyl ester hydrochloride (251 mg, 2 mmol) in 20 ml dry DMF were stirred at room temperature for 20 h. Then the reaction solution was pured into 200 mL of 10% Na2CO3 solution and stirred for 1 h. The precipitate was filtered, washed with water, and dried to give the white solid of title compound (I) (591 mg, yield: 81%).

The solid was dissolved by DMF and filtered. The DMF was evaporated slowly at room temperature for 15–20 days, and colorless sheetlike crystals suitable for X-ray structure analysis were separated from the solution.

Refinement top

All hydrogen atoms were positioned geometrically and refined in a riding model approximation with Uiso (H) = 1.2 or 1.5 Ueq (C).

Computing details top

Data collection: CrystalClear (Rigaku, 2007); cell refinement: CrystalClear (Rigaku, 2007); data reduction: CrystalClear (Rigaku, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEX (McArdle, 1995); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. A view of the molecular structure of (I), with displacement ellipsoids drawn at the 50% probability level for non-H atoms.
Methyl 2-[2-(tert-butoxycarbonylamino)-1,3-benzothiazole-6-carboxamido]acetate top
Crystal data top
C16H19N3O5SF(000) = 768.0
Mr = 365.41Dx = 1.335 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 5508 reflections
a = 16.861 (3) Åθ = 3.0–27.5°
b = 11.317 (2) ŵ = 0.21 mm1
c = 9.6484 (19) ÅT = 293 K
β = 98.94 (3)°Prism, colourless
V = 1818.7 (6) Å30.54 × 0.33 × 0.12 mm
Z = 4
Data collection top
Rigaku Saturn 724 CCD area-detector
diffractometer
4176 independent reflections
Radiation source: fine-focus sealed tube3718 reflections with I > 2σ(I)
graphiteRint = 0.054
Detector resolution: 28.5714 pixels mm-1θmax = 27.5°, θmin = 3.0°
dtprofit.ref scansh = 2021
Absorption correction: numerical
(NUMABS; Higashi, 2000)
k = 1414
Tmin = 0.921, Tmax = 0.975l = 1212
14817 measured reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.083Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.180H-atom parameters constrained
S = 1.26 w = 1/[σ2(Fo2) + (0.0486P)2 + 1.240P]
where P = (Fo2 + 2Fc2)/3
4176 reflections(Δ/σ)max < 0.001
230 parametersΔρmax = 0.34 e Å3
0 restraintsΔρmin = 0.23 e Å3
Crystal data top
C16H19N3O5SV = 1818.7 (6) Å3
Mr = 365.41Z = 4
Monoclinic, P21/cMo Kα radiation
a = 16.861 (3) ŵ = 0.21 mm1
b = 11.317 (2) ÅT = 293 K
c = 9.6484 (19) Å0.54 × 0.33 × 0.12 mm
β = 98.94 (3)°
Data collection top
Rigaku Saturn 724 CCD area-detector
diffractometer
4176 independent reflections
Absorption correction: numerical
(NUMABS; Higashi, 2000)
3718 reflections with I > 2σ(I)
Tmin = 0.921, Tmax = 0.975Rint = 0.054
14817 measured reflectionsθmax = 27.5°
Refinement top
R[F2 > 2σ(F2)] = 0.083H-atom parameters constrained
wR(F2) = 0.180Δρmax = 0.34 e Å3
S = 1.26Δρmin = 0.23 e Å3
4176 reflectionsAbsolute structure: ?
230 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
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
xyzUiso*/Ueq
S10.36614 (4)0.72248 (7)0.16296 (8)0.0467 (2)
O30.05637 (13)0.7065 (2)0.3160 (2)0.0637 (7)
O40.06380 (16)0.6314 (3)0.0995 (3)0.0789 (8)
O20.49650 (13)0.7178 (2)0.3633 (2)0.0574 (6)
O10.60458 (12)0.59926 (19)0.3591 (2)0.0479 (5)
O50.16027 (18)0.7431 (4)0.2127 (5)0.1271 (15)
N10.50500 (13)0.5954 (2)0.1795 (2)0.0415 (6)
H10.53630.54900.14260.050*
N20.40231 (13)0.5568 (2)0.0059 (2)0.0377 (5)
N30.05095 (15)0.7905 (3)0.1077 (3)0.0524 (7)
H30.07560.80950.02590.063*
C90.21789 (16)0.7285 (3)0.0217 (3)0.0431 (7)
H90.19850.78900.02900.052*
C30.5917 (3)0.5968 (4)0.6084 (4)0.0761 (12)
H3A0.54410.64480.59450.114*
H3B0.61990.60890.70170.114*
H3C0.57700.51510.59620.114*
C150.0922 (2)0.7299 (4)0.1594 (4)0.0696 (11)
C160.1190 (3)0.5336 (5)0.1009 (7)0.133 (2)
H16A0.16400.55740.05780.199*
H16B0.09220.46840.04980.199*
H16C0.13730.51000.19600.199*
C10.7200 (2)0.5557 (4)0.5209 (4)0.0855 (14)
H1A0.70530.47400.50870.128*
H1B0.74970.56730.61320.128*
H1C0.75260.57810.45210.128*
C60.43024 (16)0.6160 (2)0.1075 (3)0.0372 (6)
C70.32479 (16)0.5921 (2)0.0557 (3)0.0363 (6)
C100.17080 (16)0.6823 (3)0.1401 (3)0.0409 (6)
C80.29461 (16)0.6830 (2)0.0201 (3)0.0384 (6)
C120.27640 (17)0.5443 (3)0.1727 (3)0.0427 (7)
H120.29510.48280.22280.051*
C110.20071 (17)0.5895 (3)0.2130 (3)0.0440 (7)
H110.16840.55750.29090.053*
C130.08877 (18)0.7271 (3)0.1946 (3)0.0460 (7)
C50.53326 (17)0.6445 (3)0.3083 (3)0.0419 (6)
C40.64493 (19)0.6309 (3)0.5033 (3)0.0484 (7)
C140.03095 (19)0.8269 (4)0.1511 (4)0.0637 (10)
H14A0.03500.86380.24270.076*
H14B0.04410.88640.08600.076*
C20.6663 (2)0.7601 (3)0.5084 (4)0.0668 (10)
H2A0.69740.77770.43560.100*
H2B0.69720.77850.59800.100*
H2C0.61810.80650.49470.100*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0417 (4)0.0507 (5)0.0453 (4)0.0087 (3)0.0005 (3)0.0150 (3)
O30.0521 (13)0.096 (2)0.0399 (12)0.0100 (13)0.0022 (10)0.0002 (12)
O40.0595 (16)0.095 (2)0.0791 (18)0.0064 (15)0.0023 (14)0.0225 (16)
O20.0514 (13)0.0652 (15)0.0529 (13)0.0140 (11)0.0002 (10)0.0218 (11)
O10.0480 (11)0.0523 (13)0.0397 (11)0.0121 (9)0.0045 (9)0.0131 (9)
O50.0533 (18)0.141 (3)0.172 (4)0.0003 (19)0.029 (2)0.035 (3)
N10.0374 (12)0.0463 (14)0.0399 (12)0.0078 (10)0.0028 (10)0.0081 (10)
N20.0387 (12)0.0367 (12)0.0376 (12)0.0003 (9)0.0053 (10)0.0051 (10)
N30.0409 (14)0.0684 (19)0.0456 (14)0.0096 (12)0.0003 (11)0.0011 (13)
C90.0388 (15)0.0472 (17)0.0439 (15)0.0045 (12)0.0080 (12)0.0043 (13)
C30.103 (3)0.079 (3)0.0425 (19)0.007 (2)0.003 (2)0.0012 (19)
C150.0423 (19)0.099 (3)0.065 (2)0.0063 (19)0.0001 (16)0.007 (2)
C160.097 (4)0.135 (5)0.160 (6)0.038 (4)0.000 (4)0.054 (5)
C10.085 (3)0.092 (3)0.067 (2)0.040 (2)0.029 (2)0.028 (2)
C60.0377 (14)0.0371 (14)0.0367 (14)0.0016 (11)0.0049 (11)0.0013 (11)
C70.0362 (14)0.0352 (14)0.0377 (14)0.0004 (11)0.0064 (11)0.0003 (11)
C100.0381 (14)0.0473 (17)0.0374 (14)0.0010 (12)0.0064 (11)0.0013 (12)
C80.0372 (14)0.0384 (15)0.0392 (14)0.0007 (11)0.0050 (11)0.0016 (12)
C120.0445 (16)0.0406 (16)0.0428 (15)0.0016 (12)0.0059 (12)0.0043 (13)
C110.0441 (16)0.0492 (17)0.0371 (14)0.0039 (13)0.0013 (12)0.0023 (13)
C130.0409 (16)0.0563 (19)0.0400 (15)0.0027 (13)0.0037 (12)0.0069 (14)
C50.0397 (15)0.0447 (16)0.0407 (15)0.0016 (12)0.0048 (12)0.0061 (13)
C40.0539 (18)0.0501 (18)0.0372 (15)0.0083 (14)0.0057 (13)0.0104 (13)
C140.0473 (18)0.074 (3)0.067 (2)0.0189 (17)0.0000 (16)0.0019 (19)
C20.065 (2)0.059 (2)0.071 (2)0.0095 (17)0.0060 (18)0.0116 (19)
Geometric parameters (Å, °) top
S1—C81.742 (3)C3—H3C0.9600
S1—C61.757 (3)C15—C141.501 (6)
O3—C131.235 (4)C16—H16A0.9600
O4—C151.312 (5)C16—H16B0.9600
O4—C161.444 (5)C16—H16C0.9600
O2—C51.207 (3)C1—C41.513 (4)
O1—C51.329 (3)C1—H1A0.9600
O1—C41.494 (3)C1—H1B0.9600
O5—C151.191 (4)C1—H1C0.9600
N1—C61.362 (3)C7—C121.395 (4)
N1—C51.377 (3)C7—C81.403 (4)
N1—H10.8600C10—C111.401 (4)
N2—C61.307 (3)C10—C131.490 (4)
N2—C71.380 (3)C12—C111.373 (4)
N3—C131.338 (4)C12—H120.9300
N3—C141.440 (4)C11—H110.9300
N3—H30.8600C4—C21.505 (5)
C9—C101.389 (4)C14—H14A0.9700
C9—C81.393 (4)C14—H14B0.9700
C9—H90.9300C2—H2A0.9600
C3—C41.506 (5)C2—H2B0.9600
C3—H3A0.9600C2—H2C0.9600
C3—H3B0.9600
C8—S1—C688.06 (13)N2—C7—C8115.6 (2)
C15—O4—C16117.2 (3)C12—C7—C8119.5 (2)
C5—O1—C4120.4 (2)C9—C10—C11119.4 (3)
C6—N1—C5123.7 (2)C9—C10—C13122.9 (3)
C6—N1—H1118.2C11—C10—C13117.7 (3)
C5—N1—H1118.2C9—C8—C7121.1 (3)
C6—N2—C7110.0 (2)C9—C8—S1129.2 (2)
C13—N3—C14120.0 (3)C7—C8—S1109.7 (2)
C13—N3—H3120.0C11—C12—C7119.0 (3)
C14—N3—H3120.0C11—C12—H12120.5
C10—C9—C8119.1 (3)C7—C12—H12120.5
C10—C9—H9120.5C12—C11—C10121.9 (3)
C8—C9—H9120.5C12—C11—H11119.1
C4—C3—H3A109.5C10—C11—H11119.1
C4—C3—H3B109.5O3—C13—N3120.8 (3)
H3A—C3—H3B109.5O3—C13—C10121.3 (3)
C4—C3—H3C109.5N3—C13—C10117.9 (3)
H3A—C3—H3C109.5O2—C5—O1126.9 (3)
H3B—C3—H3C109.5O2—C5—N1123.0 (3)
O5—C15—O4123.9 (4)O1—C5—N1110.1 (2)
O5—C15—C14122.7 (4)O1—C4—C2109.6 (3)
O4—C15—C14113.4 (3)O1—C4—C3109.4 (3)
O4—C16—H16A109.5C2—C4—C3113.1 (3)
O4—C16—H16B109.5O1—C4—C1102.8 (2)
H16A—C16—H16B109.5C2—C4—C1110.5 (3)
O4—C16—H16C109.5C3—C4—C1110.9 (3)
H16A—C16—H16C109.5N3—C14—C15115.3 (3)
H16B—C16—H16C109.5N3—C14—H14A108.4
C4—C1—H1A109.5C15—C14—H14A108.4
C4—C1—H1B109.5N3—C14—H14B108.4
H1A—C1—H1B109.5C15—C14—H14B108.4
C4—C1—H1C109.5H14A—C14—H14B107.5
H1A—C1—H1C109.5C4—C2—H2A109.5
H1B—C1—H1C109.5C4—C2—H2B109.5
N2—C6—N1121.6 (2)H2A—C2—H2B109.5
N2—C6—S1116.6 (2)C4—C2—H2C109.5
N1—C6—S1121.8 (2)H2A—C2—H2C109.5
N2—C7—C12124.9 (2)H2B—C2—H2C109.5
C16—O4—C15—O50.7 (7)C8—C7—C12—C111.5 (4)
C16—O4—C15—C14179.2 (4)C7—C12—C11—C100.1 (4)
C7—N2—C6—N1178.2 (2)C9—C10—C11—C121.6 (5)
C7—N2—C6—S11.2 (3)C13—C10—C11—C12178.3 (3)
C5—N1—C6—N2171.5 (3)C14—N3—C13—O35.3 (5)
C5—N1—C6—S17.8 (4)C14—N3—C13—C10174.5 (3)
C8—S1—C6—N20.2 (2)C9—C10—C13—O3161.8 (3)
C8—S1—C6—N1179.1 (3)C11—C10—C13—O318.2 (5)
C6—N2—C7—C12178.0 (3)C9—C10—C13—N318.4 (5)
C6—N2—C7—C81.8 (3)C11—C10—C13—N3161.7 (3)
C8—C9—C10—C111.4 (4)C4—O1—C5—O25.0 (5)
C8—C9—C10—C13178.6 (3)C4—O1—C5—N1174.9 (2)
C10—C9—C8—C70.3 (4)C6—N1—C5—O26.2 (5)
C10—C9—C8—S1179.6 (2)C6—N1—C5—O1173.7 (3)
N2—C7—C8—C9178.4 (3)C5—O1—C4—C265.7 (4)
C12—C7—C8—C91.8 (4)C5—O1—C4—C358.8 (4)
N2—C7—C8—S11.7 (3)C5—O1—C4—C1176.7 (3)
C12—C7—C8—S1178.2 (2)C13—N3—C14—C1571.6 (4)
C6—S1—C8—C9179.3 (3)O5—C15—C14—N3168.8 (4)
C6—S1—C8—C70.8 (2)O4—C15—C14—N312.7 (5)
N2—C7—C12—C11178.6 (3)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N1—H1···N2i0.862.163.005 (3)167.
N3—H3···O3ii0.862.112.802 (3)137.
Symmetry codes: (i) −x+1, −y+1, −z; (ii) x, −y+3/2, z+1/2.
Table 1
Hydrogen-bond geometry (Å, °)
top
D—H···AD—HH···AD···AD—H···A
N1—H1···N2i0.862.163.005 (3)167.
N3—H3···O3ii0.862.112.802 (3)137.
Symmetry codes: (i) −x+1, −y+1, −z; (ii) x, −y+3/2, z+1/2.
Acknowledgements top

The authors gratefully acknowledge financial support from the Foundations of Fuzhou University (Nos. XRC0924, 2010-XQ-06, JA11020).

references
References top

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