PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of actaeInternational Union of Crystallographysearchopen accessarticle submissionjournal home pagethis article
 
Acta Crystallogr Sect E Struct Rep Online. 2008 October 1; 64(Pt 10): o1874–o1875.
Published online 2008 September 6. doi:  10.1107/S160053680802285X
PMCID: PMC2959469

Methyl [hydr­oxy(phen­yl)phosphono­meth­yl]phospho­nate methanol solvate

Abstract

The title compound, C8H12O7P2·CH4O, is a monoesterified bis­phospho­nate (or 1-hydroxy­methyl­ene-1,1-bis­phospho­nic acid). These synthetic compounds are widely used in medicine to inhibit bone resorption in diseases like osteoporosis, and are characterized by a stable P—C—P group and are thus analogs of inorganic pyrophosphate. By masking one or several ionizable groups, introduced as phosphono­ester, it was anti­cipated the formation of prodrugs with higher lipophilicity that could facilitate the drug delivery and metabolization. Mol­ecules are paired by inter­molecular hydrogen bonds involving the phospho­nic groups. In addition, dimers are connected side-by-side, building infinite ribbons along the a-axis direction; these ribbons are cross-linked perpendicularly along the b-axis direction via a methanol solvent mol­ecule (disordered over two sites with occupancy factors ca 0.6 and 0.4), forming an extended inter­molecular hydrogen-bonded network. The H atoms of the methyl group in the main molecule are disordered equally over two positions.

Related literature

For related literature, see: Barbey et al. (2003 [triangle]), Migianu et al. (2005 [triangle]), Fleisch (1998 [triangle], 2002 [triangle]); Clezardin et al. (2003 [triangle]); Green & Clezardin (2002 [triangle]); Lecouvey et al. (2003a [triangle],b [triangle]); Vepsalainen (2002 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-o1874-scheme1.jpg

Experimental

Crystal data

  • C8H12O7P2·CH4O
  • M r = 314.16
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-o1874-efi1.jpg
  • a = 6.3085 (5) Å
  • b = 6.9871 (6) Å
  • c = 28.147 (2) Å
  • β = 92.654 (3)°
  • V = 1239.34 (17) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.39 mm−1
  • T = 293 (2) K
  • 0.30 × 0.20 × 0.20 mm

Data collection

  • Nonius KappaCCD diffractometer
  • Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997 [triangle]) T min = 0.847, T max = 0.929
  • 3837 measured reflections
  • 2375 independent reflections
  • 1943 reflections with I > 2σ(I)
  • R int = 0.033

Refinement

  • R[F 2 > 2σ(F 2)] = 0.057
  • wR(F 2) = 0.141
  • S = 1.08
  • 2375 reflections
  • 191 parameters
  • 32 restraints
  • H-atom parameters constrained
  • Δρmax = 0.56 e Å−3
  • Δρmin = −0.44 e Å−3

Data collection: COLLECT (Hooft, 1998 [triangle]); cell refinement: HKL (Otwinowski & Minor, 1997 [triangle]); data reduction: COLLECT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]) and PLATON (Spek (2003 [triangle]); software used to prepare material for publication: WinGX (Farrugia, 1999 [triangle]) and CrystalBuilder (Welter, 2006 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680802285X/pk2106sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S160053680802285X/pk2106Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Comment

The title compound, C8H12O7P2, is a potential prodrug of the corresponding 1-hydroxymethylene-1,1-bisphosphonate (HMBP). This family of molecules has recently become very interesting owing to their biological properties and medical applications. Indeed, they are used in nuclear medicine, in treatment of bone diseases (Paget's disease, osteoporosis) and as adjuvant in the treatment of some cancers (e.g. breast, prostate) due to their antiproliferative properties (Fleisch, 2002; Green & Clezardin, 2002; Clezardin et al., 2003). However, HMBPs show a low intestinal absorption because of their high hydrophilicity and complexing power towards divalent cations of the organism. Moreover, they induce some secondary effects such as gastric and intestinal problems and osteonecrosis of the jaw-bone. To circumvent to these drawbacks, a prodrug strategy was considered that would deliver bisphosphonates with an improved gastrointestinal absorption (Vepsalainen, 2002). The approach in our laboratory consists of modifying the phosphonic acid functionality itself, by introducing an ester group (Lecouvey et al., 2003a,b). Thus, by masking the negative charges of HMBPs with suitable bioreversible substituents, the lipophilicity of bisphosphonates could be enhanced and the complexation with divalent cations decreased. Bisphosphonate prodrugs should then release bisphosphonic acids via enzymatic and/or chemical hydrolysis. Among these synthesized prodrugs, the title compound is a monoesterified version for which we report herein the crystal structure determination (Fig. 1). The crystal structure consists of layers of hydrophobic regions that enclose the phenyl rings and polar regions where bisphosphonate groups are linked as pairs and a disordered methanol molecule takes part in the crystal cohesion (Fig. 2).

Experimental

Synthesis of the α-ketophosphonate dimethyl ester (I): benzoyl chloride (5.8 ml, 50 mmol) was added dropwise at -10°C under argon to trimethylphosphite (5.9 ml, 50 mmol). The reaction mixture was then stirred at room temperature for 2 h (the end of the reaction was monitored by 31P {1H} NMR or IR spectroscopy). The crude product was purified by distillation under reduced pressure to furnish the desired α-ketophosphonate dimethyl ester with 74% yield (Migianu et al., 2005, compound 2 d).

Synthesis of [hydroxy-(hydroxy-methoxy-phosphoryl)-phenyl-methyl]-phosphonic acid (II): To the α-ketophosphonate dimethyl ester (1.07 g, 5 mmol) in 4 ml of distilled THF at 0°C under argon was added dropwise trimethylsilyl bromide (1.65 ml, 12.5 mmol). The reaction was exothermic and the temperature had to be maintained below 10°C during the addition. The reaction mixture was stirred at room temperature for 5 h (the end of the reaction was monitored by 31P {1H} NMR) and evaporation of volatile fractions (0.01 Torr) at 50°C gave bis(silylated) α-ketophosphonate. Methyl bis(trimethylsilyl) phosphite (1.2 g, 5 mmol) was then added dropwise at 0°C under argon. The reaction mixture was stirred overnight at room temperature and methanolysis for two hours led to the expected 1-hydroxymethylene-1,1- bisphosphonate monomethyl ester. After reduced pressure evaporation of volatile fractions, the crude compound was purified by precipitation in methanol and obtained with 88% yield (Scheme 2, Migianu et al., 2005).

Crystallization of monomethylester II was by slow evaporation at room temperature from a concentrated methanol/ water (9/1) solution to give colorless crystals with max. size 0.3 mm, suitable for diffraction.

Refinement

All H atoms attached to C or O atoms were fixed geometrically and treated as riding with C—H = 0.93 Å (aromatic) or 0.96 Å (methylene) and O—H = 0.82 Å (hydroxyl) with Uiso(H) = 1.2Ueq(C) (aromatic) or 1.5Ueq(C) and 1.5Ueq(O) for others. The methyl group was refined as idealized disordered one with two positions rotated from each other by 60 degrees. Each of the P2—O21 and P2—O22 bonds seems to be a mixture of single and double bonds, so the disordered hydroxyl group bound to P2 was modeled as constrained hydrogen with a site occupation factors of 0.5 on each site. The solvent molecule is a disordered one with two alternative conformations on a single site. H atoms of this disordered methanol molecule are intentionaly not included because they are very difficult to position accurately.

Figures

Fig. 1.
Molecular view of the title compound. Displacement ellipsoids are drawn at the 40 % probability level.
Fig. 2.
Partial packing view, projected along the b axis, showing the formation of the bisphosphonate dimers and the two dimensional network. H-bonds are represented as dashed lines. (PLUTO diagram from PLATON (Spek, 2003))
Fig. 3.
Scheme 2. Chemical pathway of the formation of title compound (II)

Crystal data

C8H12O7P2·CH4OZ = 4
Mr = 314.16F(000) = 656
Monoclinic, P21/cDx = 1.684 Mg m3
Hall symbol: -P 2ybcMo Kα radiation, λ = 0.71073 Å
a = 6.3085 (5) Åθ = 0.4–26.0°
b = 6.9871 (6) ŵ = 0.39 mm1
c = 28.147 (2) ÅT = 293 K
β = 92.654 (3)°Parallelepiped, colourless
V = 1239.34 (17) Å30.30 × 0.20 × 0.20 mm

Data collection

Nonius KappaCCD diffractometer2375 independent reflections
Radiation source: fine-focus sealed tube1943 reflections with I > 2σ(I)
graphiteRint = 0.033
Detector resolution: 9 pixels mm-1θmax = 25.9°, θmin = 3.3°
[var phi] and ω scansh = −7→7
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997)k = −7→8
Tmin = 0.847, Tmax = 0.929l = −34→34
3837 measured reflections

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.057Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.142H-atom parameters constrained
S = 1.08w = 1/[σ2(Fo2) + (0.0456P)2 + 3.3095P] where P = (Fo2 + 2Fc2)/3
2375 reflections(Δ/σ)max < 0.001
191 parametersΔρmax = 0.56 e Å3
32 restraintsΔρmin = −0.44 e Å3

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 (Å2)

xyzUiso*/UeqOcc. (<1)
P10.41077 (14)0.23600 (13)0.08924 (3)0.0240 (3)
O110.4358 (4)0.3030 (4)0.03727 (9)0.0317 (6)
H110.37000.23050.01900.047*
O120.2224 (4)0.1143 (4)0.09548 (10)0.0371 (7)
O130.4134 (4)0.4188 (4)0.12031 (9)0.0340 (6)
H130.44280.51160.10400.051*
P20.68094 (15)−0.12727 (14)0.07691 (3)0.0273 (3)
O210.4976 (4)−0.2548 (4)0.08552 (11)0.0410 (7)
H210.3883−0.19120.08510.061*0.50
O220.7272 (5)−0.0849 (4)0.02594 (9)0.0394 (7)
H220.6239−0.03280.01270.059*0.50
O230.8962 (4)−0.2125 (4)0.09820 (10)0.0377 (7)
C230.9189 (8)−0.3297 (7)0.14094 (17)0.0532 (12)
H23A1.0653−0.36390.14660.080*0.50
H23B0.8352−0.44380.13680.080*0.50
H23C0.8711−0.25880.16760.080*0.50
H23D0.7825−0.34710.15410.080*0.50
H23E1.0126−0.26720.16390.080*0.50
H23F0.9766−0.45220.13300.080*0.50
C1A0.5094 (7)−0.0159 (6)0.18502 (14)0.0360 (9)
H1A0.3840−0.04840.16830.043*
C2A0.5336 (8)−0.0566 (7)0.23324 (15)0.0455 (11)
H2A0.4235−0.11460.24870.055*
C3A0.7199 (8)−0.0115 (7)0.25829 (14)0.0464 (11)
H3A0.7371−0.04160.29040.056*
C4A0.8802 (7)0.0784 (7)0.23536 (15)0.0454 (11)
H4A1.00560.10960.25230.054*
C5A0.8572 (6)0.1230 (6)0.18731 (13)0.0341 (9)
H5A0.96570.18610.17240.041*
C6A0.6723 (6)0.0736 (5)0.16151 (12)0.0259 (8)
C70.6573 (5)0.1066 (5)0.10757 (12)0.0223 (7)
O70.8204 (4)0.2294 (4)0.09186 (8)0.0267 (6)
H70.93570.17610.09580.040*
O620.1603 (6)0.8597 (7)0.04096 (16)0.0193 (14)0.559 (10)
C610.159 (5)0.695 (3)0.0135 (8)0.072 (6)0.559 (10)
O720.1408 (11)0.5812 (12)−0.0056 (3)0.037 (2)0.441 (10)
C710.167 (5)0.754 (4)0.0172 (13)0.067 (7)0.441 (10)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
P10.0226 (5)0.0195 (5)0.0300 (5)0.0013 (4)0.0009 (3)0.0004 (4)
O110.0375 (14)0.0296 (14)0.0274 (13)0.0005 (12)−0.0040 (10)−0.0004 (11)
O120.0213 (13)0.0321 (15)0.0580 (18)−0.0016 (12)0.0036 (11)0.0031 (14)
O130.0476 (16)0.0214 (14)0.0335 (14)0.0038 (12)0.0075 (12)−0.0028 (11)
P20.0311 (5)0.0191 (5)0.0314 (5)0.0023 (4)−0.0027 (4)−0.0039 (4)
O210.0399 (16)0.0255 (14)0.0571 (19)−0.0008 (13)−0.0027 (13)−0.0066 (13)
O220.0545 (17)0.0334 (16)0.0300 (14)0.0042 (14)−0.0012 (12)−0.0061 (12)
O230.0381 (15)0.0328 (16)0.0419 (16)0.0107 (13)−0.0008 (12)0.0005 (13)
C230.065 (3)0.042 (3)0.052 (3)0.013 (2)−0.014 (2)0.002 (2)
C1A0.039 (2)0.032 (2)0.037 (2)−0.0049 (19)0.0036 (17)0.0032 (18)
C2A0.060 (3)0.037 (2)0.041 (2)−0.006 (2)0.015 (2)0.006 (2)
C3A0.073 (3)0.043 (3)0.024 (2)0.004 (2)0.002 (2)0.0043 (19)
C4A0.053 (3)0.049 (3)0.033 (2)0.003 (2)−0.0079 (19)−0.002 (2)
C5A0.035 (2)0.033 (2)0.034 (2)−0.0004 (18)0.0001 (16)−0.0016 (17)
C6A0.0329 (19)0.0182 (17)0.0267 (18)0.0032 (15)0.0028 (14)−0.0003 (14)
C70.0192 (16)0.0193 (17)0.0286 (17)−0.0045 (14)0.0022 (13)0.0002 (14)
O70.0219 (12)0.0242 (13)0.0341 (14)−0.0034 (11)0.0015 (10)0.0061 (11)
O620.012 (2)0.016 (3)0.029 (3)−0.0013 (18)−0.0002 (16)−0.0083 (19)
C610.094 (14)0.066 (16)0.057 (10)0.005 (12)0.004 (9)0.026 (10)
O720.035 (4)0.031 (4)0.046 (4)−0.006 (3)−0.003 (3)−0.003 (3)
C710.043 (9)0.054 (15)0.105 (15)−0.015 (10)0.011 (9)−0.003 (13)

Geometric parameters (Å, °)

P1—O121.478 (3)C23—H23F0.9600
P1—O131.548 (3)C1A—C2A1.388 (6)
P1—O111.551 (3)C1A—C6A1.396 (5)
P1—C71.851 (3)C1A—H1A0.9300
O11—H110.8200C2A—C3A1.379 (7)
O13—H130.8200C2A—H2A0.9300
P2—O211.489 (3)C3A—C4A1.376 (6)
P2—O221.507 (3)C3A—H3A0.9300
P2—O231.575 (3)C4A—C5A1.389 (6)
P2—C71.857 (4)C4A—H4A0.9300
O21—H210.8200C5A—C6A1.389 (5)
O22—H220.8200C5A—H5A0.9300
O23—C231.457 (5)C6A—C71.534 (5)
C23—H23A0.9600C7—O71.426 (4)
C23—H23B0.9600O7—H70.8200
C23—H23C0.9600O62—C611.384 (18)
C23—H23D0.9600O72—C711.37 (2)
C23—H23E0.9600
O12—P1—O13113.27 (16)O23—C23—H23F109.5
O12—P1—O11113.79 (16)H23A—C23—H23F56.3
O13—P1—O11106.55 (15)H23B—C23—H23F56.3
O12—P1—C7110.81 (16)H23C—C23—H23F141.1
O13—P1—C7105.00 (15)H23D—C23—H23F109.5
O11—P1—C7106.82 (15)H23E—C23—H23F109.5
P1—O11—H11109.5C2A—C1A—C6A120.4 (4)
P1—O13—H13109.5C2A—C1A—H1A119.8
O21—P2—O22117.32 (17)C6A—C1A—H1A119.8
O21—P2—O23111.97 (16)C3A—C2A—C1A120.4 (4)
O22—P2—O23103.58 (16)C3A—C2A—H2A119.8
O21—P2—C7111.78 (16)C1A—C2A—H2A119.8
O22—P2—C7107.03 (16)C4A—C3A—C2A119.5 (4)
O23—P2—C7104.03 (15)C4A—C3A—H3A120.3
P2—O21—H21109.5C2A—C3A—H3A120.3
P2—O22—H22109.5C3A—C4A—C5A120.9 (4)
C23—O23—P2125.2 (3)C3A—C4A—H4A119.6
O23—C23—H23A109.5C5A—C4A—H4A119.6
O23—C23—H23B109.5C6A—C5A—C4A120.0 (4)
H23A—C23—H23B109.5C6A—C5A—H5A120.0
O23—C23—H23C109.5C4A—C5A—H5A120.0
H23A—C23—H23C109.5C5A—C6A—C1A118.9 (3)
H23B—C23—H23C109.5C5A—C6A—C7119.5 (3)
O23—C23—H23D109.5C1A—C6A—C7121.5 (3)
H23A—C23—H23D141.1O7—C7—C6A112.6 (3)
H23B—C23—H23D56.3O7—C7—P1103.2 (2)
H23C—C23—H23D56.3C6A—C7—P1111.2 (2)
O23—C23—H23E109.5O7—C7—P2108.1 (2)
H23A—C23—H23E56.3C6A—C7—P2109.0 (2)
H23B—C23—H23E141.1P1—C7—P2112.63 (17)
H23C—C23—H23E56.3C7—O7—H7109.5
H23D—C23—H23E109.5
O21—P2—O23—C23−32.5 (4)O13—P1—C7—O7−66.9 (2)
O22—P2—O23—C23−159.8 (3)O11—P1—C7—O746.0 (2)
C7—P2—O23—C2388.4 (3)O12—P1—C7—C6A−68.5 (3)
C6A—C1A—C2A—C3A−0.9 (7)O13—P1—C7—C6A54.1 (3)
C1A—C2A—C3A—C4A1.5 (7)O11—P1—C7—C6A167.0 (2)
C2A—C3A—C4A—C5A−0.4 (7)O12—P1—C7—P254.2 (2)
C3A—C4A—C5A—C6A−1.3 (7)O13—P1—C7—P2176.81 (17)
C4A—C5A—C6A—C1A1.9 (6)O11—P1—C7—P2−70.3 (2)
C4A—C5A—C6A—C7−174.2 (4)O21—P2—C7—O7−171.4 (2)
C2A—C1A—C6A—C5A−0.8 (6)O22—P2—C7—O7−41.7 (3)
C2A—C1A—C6A—C7175.2 (4)O23—P2—C7—O767.6 (2)
C5A—C6A—C7—O7−14.6 (5)O21—P2—C7—C6A65.9 (3)
C1A—C6A—C7—O7169.4 (3)O22—P2—C7—C6A−164.4 (2)
C5A—C6A—C7—P1−129.9 (3)O23—P2—C7—C6A−55.1 (3)
C1A—C6A—C7—P154.1 (4)O21—P2—C7—P1−58.0 (2)
C5A—C6A—C7—P2105.4 (3)O22—P2—C7—P171.7 (2)
C1A—C6A—C7—P2−70.6 (4)O23—P2—C7—P1−179.03 (17)
O12—P1—C7—O7170.5 (2)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O13—H13···O21i0.821.752.548 (4)163.
O11—H11···O22ii0.821.722.525 (4)169.
O21—H21···O62iii0.821.892.548 (5)136.
O7—H7···O12iv0.821.862.658 (3)164.

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PK2106).

References

  • Barbey, C., Lecouvey, M., Mallard, I., Prangé, T., Neuman, A., Lance, M. & Navaza, A. (2003). Z. Kristallogr.218, 445–449.
  • Clezardin, P., Fournier, P., Boissier, S. & Peyruchaud, O. (2003). Curr. Med. Chem.10, 173–180. [PubMed]
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Farrugia, L. J. (1999). J. Appl. Cryst.32, 837–838.
  • Fleisch, H. (1998). Endocr. Rev 19 80–100. [PubMed]
  • Fleisch, H. (2002). Breast Cancer Res.4 30–34. [PMC free article] [PubMed]
  • Green, J. R. & Clezardin, P. (2002). Am. J. Clin. Oncol.25, S3–S9. [PubMed]
  • Hooft, R. W. W. (1998). COLLECT Nonius BV, Delft, The Netherlands.
  • Lecouvey, M., Leroux, Y., Kraemer, M., Crepin, M., El Manouni, D. & Louriki, M. (2003a). World Patent WO 03/008425.
  • Lecouvey, M., Leroux, Y., Kraemer, M., Crepin, M., El Manouni, D. & Louriki, M. (2003b). Chem. Abstr.138, 122736.
  • Migianu, E., Guénin, E. & Lecouvey, M. (2005). Synlett, 3, 425–428.
  • Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Spek, A. L. (2003). J. Appl. Cryst.36, 7–13.
  • Vepsalainen, J. J. (2002). Curr. Med. Chem.62, 1201–1208. [PubMed]
  • Welter, R. (2006). Acta Cryst. A62, s252.

Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography