organic compounds
Dichlorophosphinic bis(2-chloroethyl)amide
aKey Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chong Qing 400716, People's Republic of China
*Correspondence e-mail: ysong@swu.edu.cn
In the title compound, C4H8Cl4NOP, the two chloroethyl groups are not related by The difference in the conformation of the two groups is shown by their N—C—C—Cl torsion angles of 64.57 (15) and 175.62 (10)°.
Related literature
The title compound is a precursor used in the synthesis of the antitumor drug cyclophosphamide and its analogues. For information on organophosphorus et al. (2009); Srinivasulu et al. (2008); Krishna et al. (2006). For the crystal structures of cyclophosphamide analogues, see: Camerman & Camerman (1973); Jones et al. (1996); Himes et al. (1982); Camerman et al. (1983); Perales & García-Blanco (1977a,b); Gałdecki & Głowka (1981); Boyd et al. (1980); Shih et al. (1986). For the pharmacological activity of cyclophosphamide analogues, see: Lin et al. (1980); Borch & Canute (1991).
see: Surendra BabuExperimental
Crystal data
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Data collection: APEX2 (Bruker, 2009); cell SAINT (Bruker, 2009); data reduction: SAINT; 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: SHELXTL and local procedures.
Supporting information
https://doi.org/10.1107/S1600536812049586/fy2076sup1.cif
contains datablocks I, global. DOI:Supporting information file. DOI: https://doi.org/10.1107/S1600536812049586/fy2076Isup2.cdx
Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536812049586/fy2076Isup3.hkl
Supporting information file. DOI: https://doi.org/10.1107/S1600536812049586/fy2076Isup4.cml
Bis(2-chloroethyl)amine hydrochloride (20.0 g, 0.112 mol) was added dropwise into a 250 ml round bottom bottle containing POCl3 (52 ml, 0.6 mol). Then the mixture was refluxed for 20 h at 110 °C. The disappearance of solid bis(2-chloroethyl)amine hydrochloride indicated completion of the reaction. To remove excess POCl3, reduced vacuum was used. The crude were dissolved into ethyl acetate and the precipitate was filtered off. The filtrate was concentrated in vacuo and the resulting residue was recrystallized with acetone and hexane (v/v = 1:5), giving white crystals (18.0 g) in a yield of 61%. Single crystals for X-ray diffraction were grown at room temperature by slow evaporation from the solution of the title compound in ethanol.
The H-atoms bonded to C-atoms were positioned geometrically and refined using a riding model, with C—H = 0.93 Å, and with Uiso(H) = 1.2 Ueq(C).
Cyclophosphamide, a nitrogen mustard alkylating agent, is widely used as an anti-cancer agent. It is converted in the liver to its active form, which is dependent on
metabolism for its therapeutic effectiveness. During the process of metabolism, a toxic byproduct, acrolein is generated and induces hemorrhagic cystitis. Many cyclophosphamide analogues were developed to reduce this side effect and to find more potent anti-cancer drugs. The title compound is used as an important precursor for the synthesis of cyclophosphamide and its analogues.In the title molecule (I) (Fig. 1), all bond lengths and angles are within normal ranges and correspond to those observed in related compounds. Atoms C3, N1, P1 and O1 are nearly coplanar, with a dihedral angel of 175.23 (10)° between the C3—N1—P1 and N1—P1—O1 planes. Angles for C3—N—P, P—N—C1 and C1—N—C3 are 120.57 (9)°, 121.02 (9)° and 118.04 (11)°, respectively. It is interesting to notice that two 2-chloroethyls are not symmetry-related, the torsion angle of N1—C1—C2—Cl3is 64.57 (15)°, but the torsion angle of N1—C3—C4—Cl4 is 175.62 (10)°. Although the current compound is conformationally flexible, twist conformation isomers form on closing the phospho-heterocycle, as, for example, in cyclophosphamide (Borch et al., 1991).
The title compound is a precursor used in the synthesis of the antitumor drug cyclophosphamide and its analogues. For information on organophosphorus
see: Surendra Babu et al. (2009); Srinivasulu et al. (2008); Krishna et al. (2006). For the crystal structures of cyclophosphamide analogues, see: Camerman & Camerman (1973); Jones et al. (1996); Himes et al. (1982); Camerman et al. (1983); Perales & García-Blanco (1977a,b); Gałdecki & Głowka (1981); Boyd et al. (1980); Shih et al. (1986). For the pharmacological activity of cyclophosphamide analogues, see: Lin et al. (1980); Borch & Canute (1991).Data collection: APEX2 (Bruker, 2009); cell
SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); 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: SHELXTL (Sheldrick, 2008) and local procedures.C4H8Cl4NOP | F(000) = 520 |
Mr = 258.88 | Dx = 1.735 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
a = 9.0723 (15) Å | Cell parameters from 4728 reflections |
b = 8.4810 (14) Å | θ = 2.3–31.1° |
c = 13.135 (2) Å | µ = 1.30 mm−1 |
β = 101.221 (2)° | T = 298 K |
V = 991.4 (3) Å3 | Block, colourless |
Z = 4 | 0.16 × 0.12 × 0.10 mm |
Bruker APEXII CCD diffractometer | 3255 independent reflections |
Radiation source: fine-focus sealed tube | 2725 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.020 |
φ and ω scans | θmax = 32.2°, θmin = 2.3° |
Absorption correction: multi-scan (SADABS; Bruker, 2009) | h = −13→13 |
Tmin = 0.819, Tmax = 0.881 | k = −12→12 |
9480 measured reflections | l = −19→13 |
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)] = 0.029 | H-atom parameters constrained |
wR(F2) = 0.090 | w = 1/[σ2(Fo2) + (0.0482P)2 + 0.1876P] where P = (Fo2 + 2Fc2)/3 |
S = 1.05 | (Δ/σ)max = 0.002 |
3255 reflections | Δρmax = 0.57 e Å−3 |
101 parameters | Δρmin = −0.46 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: 0.0064 (13) |
C4H8Cl4NOP | V = 991.4 (3) Å3 |
Mr = 258.88 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 9.0723 (15) Å | µ = 1.30 mm−1 |
b = 8.4810 (14) Å | T = 298 K |
c = 13.135 (2) Å | 0.16 × 0.12 × 0.10 mm |
β = 101.221 (2)° |
Bruker APEXII CCD diffractometer | 3255 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2009) | 2725 reflections with I > 2σ(I) |
Tmin = 0.819, Tmax = 0.881 | Rint = 0.020 |
9480 measured reflections |
R[F2 > 2σ(F2)] = 0.029 | 0 restraints |
wR(F2) = 0.090 | H-atom parameters constrained |
S = 1.05 | Δρmax = 0.57 e Å−3 |
3255 reflections | Δρmin = −0.46 e Å−3 |
101 parameters |
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. |
x | y | z | Uiso*/Ueq | ||
C1 | 0.38633 (16) | 0.82538 (16) | 0.87493 (12) | 0.0381 (3) | |
H1A | 0.4301 | 0.7845 | 0.8186 | 0.046* | |
H1B | 0.4682 | 0.8544 | 0.9310 | 0.046* | |
C2 | 0.2970 (2) | 0.97152 (18) | 0.83776 (13) | 0.0467 (3) | |
H2A | 0.2125 | 0.9432 | 0.7834 | 0.056* | |
H2B | 0.3599 | 1.0447 | 0.8087 | 0.056* | |
C3 | 0.19521 (15) | 0.60676 (16) | 0.83359 (10) | 0.0353 (3) | |
H3A | 0.1429 | 0.6769 | 0.7802 | 0.042* | |
H3B | 0.1208 | 0.5556 | 0.8662 | 0.042* | |
C4 | 0.27918 (18) | 0.48303 (19) | 0.78420 (13) | 0.0448 (3) | |
H4A | 0.3374 | 0.4169 | 0.8376 | 0.054* | |
H4B | 0.3479 | 0.5337 | 0.7463 | 0.054* | |
Cl1 | 0.31341 (5) | 0.44237 (4) | 1.05878 (3) | 0.05244 (12) | |
Cl3 | 0.22968 (5) | 1.06456 (5) | 0.94101 (4) | 0.05789 (13) | |
Cl2 | 0.08981 (4) | 0.71564 (5) | 1.05773 (3) | 0.05103 (12) | |
Cl4 | 0.14781 (6) | 0.36563 (5) | 0.69800 (4) | 0.06145 (14) | |
N1 | 0.29789 (12) | 0.69934 (13) | 0.91169 (9) | 0.0328 (2) | |
O1 | 0.41231 (13) | 0.76345 (14) | 1.10623 (8) | 0.0474 (3) | |
P1 | 0.29887 (4) | 0.67627 (4) | 1.03420 (3) | 0.03356 (10) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.0403 (6) | 0.0353 (6) | 0.0409 (7) | −0.0035 (5) | 0.0131 (5) | −0.0024 (5) |
C2 | 0.0600 (9) | 0.0347 (6) | 0.0451 (8) | −0.0025 (6) | 0.0094 (7) | 0.0020 (6) |
C3 | 0.0376 (6) | 0.0343 (6) | 0.0330 (6) | 0.0004 (5) | 0.0042 (5) | −0.0035 (5) |
C4 | 0.0481 (8) | 0.0409 (7) | 0.0444 (8) | −0.0001 (6) | 0.0067 (6) | −0.0131 (6) |
Cl1 | 0.0676 (3) | 0.03754 (19) | 0.0523 (2) | 0.00726 (15) | 0.01214 (19) | 0.01047 (15) |
Cl3 | 0.0608 (3) | 0.0414 (2) | 0.0733 (3) | 0.00801 (16) | 0.0174 (2) | −0.01022 (18) |
Cl2 | 0.04327 (19) | 0.0641 (3) | 0.0497 (2) | 0.00731 (16) | 0.01884 (16) | −0.00236 (17) |
Cl4 | 0.0777 (3) | 0.0514 (2) | 0.0521 (3) | −0.0121 (2) | 0.0049 (2) | −0.01980 (19) |
N1 | 0.0376 (5) | 0.0315 (5) | 0.0292 (5) | −0.0022 (4) | 0.0062 (4) | −0.0026 (4) |
O1 | 0.0479 (6) | 0.0540 (6) | 0.0369 (5) | −0.0032 (5) | −0.0006 (4) | −0.0072 (5) |
P1 | 0.03567 (17) | 0.03484 (17) | 0.02971 (16) | 0.00247 (12) | 0.00520 (12) | −0.00150 (12) |
C1—N1 | 1.4732 (18) | C3—H3A | 0.9700 |
C1—C2 | 1.509 (2) | C3—H3B | 0.9700 |
C1—H1A | 0.9700 | C4—Cl4 | 1.7800 (16) |
C1—H1B | 0.9700 | C4—H4A | 0.9700 |
C2—Cl3 | 1.7767 (17) | C4—H4B | 0.9700 |
C2—H2A | 0.9700 | Cl1—P1 | 2.0100 (6) |
C2—H2B | 0.9700 | Cl2—P1 | 2.0081 (6) |
C3—N1 | 1.4713 (16) | N1—P1 | 1.6195 (12) |
C3—C4 | 1.515 (2) | O1—P1 | 1.4567 (11) |
N1—C1—C2 | 114.16 (12) | H3A—C3—H3B | 108.0 |
N1—C1—H1A | 108.7 | C3—C4—Cl4 | 109.25 (11) |
C2—C1—H1A | 108.7 | C3—C4—H4A | 109.8 |
N1—C1—H1B | 108.7 | Cl4—C4—H4A | 109.8 |
C2—C1—H1B | 108.7 | C3—C4—H4B | 109.8 |
H1A—C1—H1B | 107.6 | Cl4—C4—H4B | 109.8 |
C1—C2—Cl3 | 111.13 (11) | H4A—C4—H4B | 108.3 |
C1—C2—H2A | 109.4 | C3—N1—C1 | 118.04 (11) |
Cl3—C2—H2A | 109.4 | C3—N1—P1 | 120.57 (9) |
C1—C2—H2B | 109.4 | C1—N1—P1 | 121.02 (9) |
Cl3—C2—H2B | 109.4 | O1—P1—N1 | 116.78 (7) |
H2A—C2—H2B | 108.0 | O1—P1—Cl2 | 112.63 (5) |
N1—C3—C4 | 111.43 (11) | N1—P1—Cl2 | 108.07 (5) |
N1—C3—H3A | 109.3 | O1—P1—Cl1 | 112.37 (5) |
C4—C3—H3A | 109.3 | N1—P1—Cl1 | 105.45 (4) |
N1—C3—H3B | 109.3 | Cl2—P1—Cl1 | 100.01 (2) |
C4—C3—H3B | 109.3 | ||
N1—C1—C2—Cl3 | 64.57 (15) | C3—N1—P1—O1 | 175.23 (10) |
N1—C3—C4—Cl4 | 175.62 (10) | C1—N1—P1—O1 | −11.87 (13) |
C4—C3—N1—C1 | 78.71 (15) | C3—N1—P1—Cl2 | −56.60 (10) |
C4—C3—N1—P1 | −108.18 (13) | C1—N1—P1—Cl2 | 116.30 (10) |
C2—C1—N1—C3 | 75.10 (16) | C3—N1—P1—Cl1 | 49.65 (10) |
C2—C1—N1—P1 | −97.97 (14) | C1—N1—P1—Cl1 | −137.45 (10) |
Experimental details
Crystal data | |
Chemical formula | C4H8Cl4NOP |
Mr | 258.88 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 298 |
a, b, c (Å) | 9.0723 (15), 8.4810 (14), 13.135 (2) |
β (°) | 101.221 (2) |
V (Å3) | 991.4 (3) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 1.30 |
Crystal size (mm) | 0.16 × 0.12 × 0.10 |
Data collection | |
Diffractometer | Bruker APEXII CCD |
Absorption correction | Multi-scan (SADABS; Bruker, 2009) |
Tmin, Tmax | 0.819, 0.881 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 9480, 3255, 2725 |
Rint | 0.020 |
(sin θ/λ)max (Å−1) | 0.749 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.029, 0.090, 1.05 |
No. of reflections | 3255 |
No. of parameters | 101 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.57, −0.46 |
Computer programs: APEX2 (Bruker, 2009), SAINT (Bruker, 2009), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008) and local procedures.
Acknowledgements
This work was supported by the Program for New Century Excellent Talents in Universities (NCET-10–0660), the National Scientific & Technological Special Project – Major Creation of New Drugs (Nos. 2010ZX09401–306-1–4 and 2010ZX09401–306-2–19) and the 211 Project of Southwest University (the Third Term).
References
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Cyclophosphamide, a nitrogen mustard alkylating agent, is widely used as an anti-cancer agent. It is converted in the liver to its active form, which is dependent on cytochrome P450 metabolism for its therapeutic effectiveness. During the process of metabolism, a toxic byproduct, acrolein is generated and induces hemorrhagic cystitis. Many cyclophosphamide analogues were developed to reduce this side effect and to find more potent anti-cancer drugs. The title compound is used as an important precursor for the synthesis of cyclophosphamide and its analogues.
In the title molecule (I) (Fig. 1), all bond lengths and angles are within normal ranges and correspond to those observed in related compounds. Atoms C3, N1, P1 and O1 are nearly coplanar, with a dihedral angel of 175.23 (10)° between the C3—N1—P1 and N1—P1—O1 planes. Angles for C3—N—P, P—N—C1 and C1—N—C3 are 120.57 (9)°, 121.02 (9)° and 118.04 (11)°, respectively. It is interesting to notice that two 2-chloroethyls are not symmetry-related, the torsion angle of N1—C1—C2—Cl3is 64.57 (15)°, but the torsion angle of N1—C3—C4—Cl4 is 175.62 (10)°. Although the current compound is conformationally flexible, twist conformation isomers form on closing the phospho-heterocycle, as, for example, in cyclophosphamide (Borch et al., 1991).