Methyl [hydroxy(phenyl)phosphonomethyl]phosphonate methanol solvate

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.

The title compound, C 8 H 12 O 7 P 2 ÁCH 4 O, 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 aaxis 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.
Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PK2106).

Comment
The title compound, C 8 H 12 O 7 P 2 , is a potential prodrug of the corresponding 1-hydroxymethylene-1,1-bisphosphonate (HM-BP). 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 31 P {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).
The reaction mixture was stirred at room temperature for 5 h (the end of the reaction was monitored by 31 P {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).
supplementary materials sup-2 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 U iso (H) = 1.2U eq (C) (aromatic) or 1.5U eq (C) and 1.5U eq (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.    Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-supplementary materials sup-4 factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 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 (Å 2 )
x y z U iso */U eq Occ. (