The title compound, sodium 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methylhex-4-enoate, Na+·C17H19O6-, is the sodium salt of the natural immunosuppressant compound mycophenolic acid. It consists of a phthalide moiety carrying four different substituents on the aromatic ring. The anion has no intramolecular hydrogen bonds, but a very strong intermolecular hydrogen bond links the phenolic hydroxy group to the carboxyl group of a neighbouring anion found in the same layer. Within a distance of 2.71 Å, the Na+ ion is surrounded by five O atoms from four different anions, forming a distorted square pyramid. This Na-O network forms an infinite two-dimensional system running parallel to the bc plane.
Supporting information
CCDC reference: 144618
Compound (I) was obtained upon treatment of a methanolic solution of
commercially available mycophenolic acid with one equivalent of sodium
methanolate. After stirring for 1 h at room temperature, the solvent was
evaporated to dryness in vacuo to afford the desired compound (m.p. 463 K). Single crystals were grown by evaporation and cooling of a water/ethyl
acetate solution from about 323 K to room temperature.
All H atoms could be localized from a difference Fourier map. The parameters of
the H atom attached to O3 were kept fixed and the other H atoms were treated
as riding.
Data collection: CAD-4 EXPRESS (Enraf-Nonius, 1994); cell refinement: CAD-4 EXPRESS; program(s) used to solve structure: SHELXS86 (Sheldrick, 1990); program(s) used to refine structure: SHELXL93 (Sheldrick, 1993); molecular graphics: ORTEPII (Johnson, 1976) and SCHAKAL97 (Keller, 1997).
sodium 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-
4-methylhex-4-enoate
top
Crystal data top
[NaC17H19O6] | Dx = 1.397 Mg m−3 |
Mr = 342.31 | Melting point: 463 K |
Monoclinic, P21/c | Cu Kα radiation, λ = 1.54178 Å |
a = 16.544 (4) Å | Cell parameters from 25 reflections |
b = 4.477 (1) Å | θ = 15–26° |
c = 21.993 (3) Å | µ = 1.11 mm−1 |
β = 92.14 (1)° | T = 293 K |
V = 1627.8 (6) Å3 | Prism, colourless |
Z = 4 | 0.41 × 0.20 × 0.15 mm |
F(000) = 720 | |
Data collection top
Enraf-Nonius CAD4 diffractometer | Rint = 0.058 |
Radiation source: fine-focus sealed tube | θmax = 74.2°, θmin = 4.0° |
Graphite monochromator | h = −20→20 |
ω/2θ scans | k = 0→5 |
3432 measured reflections | l = 0→27 |
3334 independent reflections | 3 standard reflections every 120 min |
2058 reflections with I > 2σ(I) | intensity decay: 2% |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.048 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.121 | H-atom parameters constrained |
S = 0.86 | Calculated w = 1/[σ2(Fo2) + (0.1P)2] where P = (Fo2 + 2Fc2)/3 |
2913 reflections | (Δ/σ)max = −0.008 |
217 parameters | Δρmax = 0.31 e Å−3 |
0 restraints | Δρmin = −0.29 e Å−3 |
Crystal data top
[NaC17H19O6] | V = 1627.8 (6) Å3 |
Mr = 342.31 | Z = 4 |
Monoclinic, P21/c | Cu Kα radiation |
a = 16.544 (4) Å | µ = 1.11 mm−1 |
b = 4.477 (1) Å | T = 293 K |
c = 21.993 (3) Å | 0.41 × 0.20 × 0.15 mm |
β = 92.14 (1)° | |
Data collection top
Enraf-Nonius CAD4 diffractometer | Rint = 0.058 |
3432 measured reflections | 3 standard reflections every 120 min |
3334 independent reflections | intensity decay: 2% |
2058 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.048 | 0 restraints |
wR(F2) = 0.121 | H-atom parameters constrained |
S = 0.86 | Δρmax = 0.31 e Å−3 |
2913 reflections | Δρmin = −0.29 e Å−3 |
217 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 on F2 for ALL reflections except for 554 with very negative
F2 or flagged by the user for potential systematic errors. Weighted
R-factors wR and all goodnesses of fit S are based on
F2, conventional R-factors R are based on F,
with F set to zero for negative F2. The observed criterion of
F2 > σ(F2) is used only for calculating R-factor_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 | Uiso*/Ueq | |
O1 | 0.21916 (12) | 0.8631 (4) | 0.46991 (7) | 0.0603 (5) | |
O2 | 0.33964 (11) | 0.6413 (5) | 0.47912 (7) | 0.0616 (5) | |
O3 | 0.33548 (9) | 0.2105 (4) | 0.58662 (6) | 0.0480 (4) | |
H3 | 0.3800 | 0.1787 | 0.6090 | 0.050* | |
O4 | 0.57408 (10) | 0.3899 (5) | 0.85041 (7) | 0.0625 (5) | |
O5 | 0.50673 (10) | 0.3708 (6) | 0.93454 (8) | 0.0739 (7) | |
O6 | 0.08499 (9) | 0.2922 (4) | 0.68673 (8) | 0.0539 (4) | |
C7 | 0.2719 (2) | 0.6691 (6) | 0.49813 (10) | 0.0509 (6) | |
C8 | 0.23299 (13) | 0.5343 (6) | 0.54933 (9) | 0.0440 (5) | |
C9 | 0.26431 (12) | 0.3281 (5) | 0.59243 (9) | 0.0387 (5) | |
C10 | 0.21308 (12) | 0.2572 (5) | 0.64075 (9) | 0.0388 (5) | |
C11 | 0.13509 (13) | 0.3767 (5) | 0.64081 (10) | 0.0448 (5) | |
C12 | 0.10292 (13) | 0.5718 (5) | 0.59604 (11) | 0.0475 (6) | |
C13 | 0.15491 (14) | 0.6469 (5) | 0.55156 (10) | 0.0462 (5) | |
C14 | 0.14325 (15) | 0.8592 (6) | 0.49962 (11) | 0.0540 (6) | |
H14A | 0.10011 | 0.7914 | 0.47189 | 0.065* | |
H14B | 0.12988 | 1.0570 | 0.51420 | 0.065* | |
C15 | 0.24461 (13) | 0.0530 (5) | 0.69097 (9) | 0.0417 (5) | |
H15A | 0.26931 | −0.1212 | 0.67314 | 0.050* | |
H15B | 0.19977 | −0.0146 | 0.71461 | 0.050* | |
C16 | 0.30611 (13) | 0.2083 (5) | 0.73255 (10) | 0.0416 (5) | |
H16 | 0.34513 | 0.3226 | 0.71401 | 0.050* | |
C17 | 0.30996 (13) | 0.1976 (5) | 0.79310 (10) | 0.0436 (5) | |
C18 | 0.38014 (15) | 0.3551 (6) | 0.82678 (11) | 0.0551 (6) | |
H18A | 0.36009 | 0.4529 | 0.86258 | 0.066* | |
H18B | 0.40145 | 0.5083 | 0.80062 | 0.066* | |
C19 | 0.44807 (14) | 0.1440 (6) | 0.84615 (11) | 0.0521 (6) | |
H19A | 0.42708 | −0.0128 | 0.87160 | 0.063* | |
H19B | 0.47006 | 0.0514 | 0.81047 | 0.063* | |
C20 | 0.51375 (13) | 0.3107 (6) | 0.88070 (10) | 0.0478 (6) | |
C21 | 0.0935 (2) | 0.4746 (7) | 0.73990 (12) | 0.0628 (7) | |
H21A | 0.0575 | 0.4047 | 0.77003 | 0.094* | |
H21B | 0.0806 | 0.6778 | 0.72957 | 0.094* | |
H21C | 0.1483 | 0.4639 | 0.75583 | 0.094* | |
C22 | 0.01747 (15) | 0.6913 (7) | 0.59727 (15) | 0.0689 (8) | |
H22A | −0.00882 | 0.6113 | 0.63188 | 0.103* | |
H22B | −0.01191 | 0.6333 | 0.56069 | 0.103* | |
H22C | 0.01890 | 0.9053 | 0.60003 | 0.103* | |
C23 | 0.2522 (2) | 0.0369 (7) | 0.83216 (11) | 0.0616 (7) | |
H23A | 0.2685 | 0.0632 | 0.87419 | 0.092* | |
H23B | 0.2523 | −0.1720 | 0.82232 | 0.092* | |
H23C | 0.1988 | 0.1163 | 0.82509 | 0.092* | |
Na24 | 0.40891 (7) | 0.1766 (4) | 0.50290 (5) | 0.0845 (5) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0795 (12) | 0.0566 (11) | 0.0437 (9) | 0.0125 (9) | −0.0099 (8) | 0.0070 (8) |
O2 | 0.0661 (11) | 0.0756 (13) | 0.0432 (9) | 0.0077 (10) | 0.0040 (8) | 0.0063 (9) |
O3 | 0.0440 (8) | 0.0626 (11) | 0.0371 (8) | 0.0154 (8) | −0.0022 (6) | 0.0072 (7) |
O4 | 0.0597 (10) | 0.0864 (14) | 0.0416 (8) | −0.0234 (10) | 0.0052 (7) | −0.0134 (9) |
O5 | 0.0506 (10) | 0.124 (2) | 0.0479 (9) | −0.0300 (11) | 0.0078 (7) | −0.0281 (11) |
O6 | 0.0432 (8) | 0.0578 (11) | 0.0610 (10) | −0.0060 (8) | 0.0060 (7) | −0.0100 (8) |
C7 | 0.0634 (15) | 0.0542 (15) | 0.0347 (10) | 0.0051 (12) | −0.0063 (10) | −0.0044 (10) |
C8 | 0.0486 (12) | 0.0476 (13) | 0.0349 (10) | 0.0044 (11) | −0.0105 (8) | −0.0044 (10) |
C9 | 0.0383 (10) | 0.0430 (12) | 0.0339 (9) | 0.0036 (9) | −0.0100 (8) | −0.0043 (9) |
C10 | 0.0423 (10) | 0.0397 (12) | 0.0338 (10) | −0.0019 (9) | −0.0081 (8) | −0.0038 (9) |
C11 | 0.0408 (11) | 0.0459 (13) | 0.0472 (12) | −0.0033 (10) | −0.0064 (9) | −0.0065 (10) |
C12 | 0.0382 (11) | 0.0430 (13) | 0.0603 (14) | 0.0032 (10) | −0.0123 (10) | −0.0096 (11) |
C13 | 0.0509 (12) | 0.0401 (12) | 0.0462 (12) | 0.0091 (10) | −0.0150 (10) | −0.0087 (10) |
C14 | 0.0599 (14) | 0.0500 (14) | 0.0503 (13) | 0.0085 (12) | −0.0202 (11) | −0.0042 (11) |
C15 | 0.0419 (10) | 0.0477 (13) | 0.0353 (10) | −0.0056 (10) | −0.0010 (8) | −0.0006 (10) |
C16 | 0.0400 (10) | 0.0434 (12) | 0.0410 (11) | −0.0025 (10) | −0.0039 (8) | −0.0017 (10) |
C17 | 0.0453 (11) | 0.0438 (13) | 0.0408 (11) | 0.0014 (10) | −0.0093 (9) | −0.0016 (10) |
C18 | 0.0590 (14) | 0.056 (2) | 0.0486 (12) | −0.0011 (13) | −0.0138 (11) | −0.0069 (12) |
C19 | 0.0480 (12) | 0.059 (2) | 0.0492 (12) | −0.0070 (12) | −0.0048 (10) | −0.0126 (11) |
C20 | 0.0411 (11) | 0.062 (2) | 0.0396 (11) | 0.0002 (11) | −0.0015 (9) | −0.0044 (11) |
C21 | 0.0532 (14) | 0.070 (2) | 0.067 (2) | −0.0093 (14) | 0.0155 (12) | −0.0148 (15) |
C22 | 0.0432 (13) | 0.073 (2) | 0.090 (2) | 0.0106 (14) | −0.0115 (13) | −0.011 (2) |
C23 | 0.0614 (15) | 0.076 (2) | 0.0466 (13) | −0.0089 (14) | −0.0041 (11) | 0.0007 (13) |
Na24 | 0.0686 (7) | 0.1311 (12) | 0.0552 (6) | 0.0425 (7) | 0.0200 (5) | 0.0353 (7) |
Geometric parameters (Å, º) top
O1—C7 | 1.364 (3) | C10—C11 | 1.397 (3) |
O1—C14 | 1.437 (3) | C10—C15 | 1.512 (3) |
O2—C7 | 1.217 (3) | C11—C12 | 1.406 (3) |
O2—Na24 | 2.423 (2) | C12—C13 | 1.369 (3) |
O2—Na24i | 2.699 (3) | C12—C22 | 1.513 (3) |
O3—C9 | 1.300 (2) | C13—C14 | 1.493 (3) |
O3—Na24 | 2.249 (2) | C15—C16 | 1.512 (3) |
O4—C20 | 1.271 (3) | C16—C17 | 1.332 (3) |
O5—C20 | 1.224 (3) | C17—C23 | 1.493 (3) |
O5—Na24ii | 2.259 (2) | C17—C18 | 1.527 (3) |
O5—Na24iii | 2.361 (2) | C18—C19 | 1.517 (3) |
O6—C11 | 1.383 (3) | C19—C20 | 1.501 (3) |
O6—C21 | 1.429 (3) | Na24—O5iv | 2.259 (2) |
C7—C8 | 1.450 (3) | Na24—O5v | 2.361 (2) |
C8—C9 | 1.408 (3) | Na24—O2vi | 2.699 (3) |
C8—C13 | 1.389 (3) | Na24—Na24vii | 3.410 (2) |
C9—C10 | 1.420 (3) | Na24—Na24viii | 4.185 (3) |
| | | |
C7—O1—C14 | 109.9 (2) | C11—C12—C22 | 122.5 (2) |
C7—O2—Na24 | 116.6 (2) | C12—C13—C8 | 123.1 (2) |
C7—O2—Na24i | 103.4 (2) | C12—C13—C14 | 129.5 (2) |
Na24—O2—Na24i | 121.77 (9) | C8—C13—C14 | 107.3 (2) |
C9—O3—Na24 | 128.81 (13) | O1—C14—C13 | 105.4 (2) |
C20—O5—Na24ii | 136.0 (2) | C10—C15—C16 | 111.7 (2) |
C20—O5—Na24iii | 128.0 (2) | C17—C16—C15 | 126.5 (2) |
Na24ii—O5—Na24iii | 95.12 (7) | C16—C17—C23 | 125.8 (2) |
C11—O6—C21 | 113.4 (2) | C16—C17—C18 | 118.4 (2) |
O2—C7—O1 | 119.4 (2) | C23—C17—C18 | 115.8 (2) |
O2—C7—C8 | 131.7 (2) | C17—C18—C19 | 113.0 (2) |
O1—C7—C8 | 108.9 (2) | C20—C19—C18 | 110.3 (2) |
C9—C8—C13 | 122.2 (2) | O5—C20—O4 | 123.4 (2) |
C9—C8—C7 | 129.3 (2) | O5—C20—C19 | 120.4 (2) |
C13—C8—C7 | 108.5 (2) | O4—C20—C19 | 116.2 (2) |
O3—C9—C8 | 120.7 (2) | O3—Na24—O5iv | 166.76 (8) |
O3—C9—C10 | 123.5 (2) | O3—Na24—O5v | 83.55 (7) |
C8—C9—C10 | 115.8 (2) | O5iv—Na24—O5v | 84.88 (7) |
C11—C10—C9 | 119.5 (2) | O3—Na24—O2 | 81.55 (7) |
C11—C10—C15 | 121.6 (2) | O5iv—Na24—O2 | 106.36 (8) |
C9—C10—C15 | 118.9 (2) | O5v—Na24—O2 | 152.69 (10) |
O6—C11—C10 | 118.3 (2) | O3—Na24—O2vi | 88.86 (8) |
O6—C11—C12 | 117.4 (2) | O5iv—Na24—O2vi | 95.58 (9) |
C10—C11—C12 | 124.3 (2) | O5v—Na24—O2vi | 80.53 (9) |
C13—C12—C11 | 114.9 (2) | O2—Na24—O2vi | 121.77 (9) |
C13—C12—C22 | 122.6 (2) | | |
| | | |
Na24—O2—C7—O1 | −156.5 (2) | C11—C12—C13—C14 | −176.1 (2) |
Na24i—O2—C7—O1 | 67.0 (2) | C22—C12—C13—C14 | 3.4 (4) |
Na24—O2—C7—C8 | 25.3 (4) | C9—C8—C13—C12 | 1.2 (4) |
Na24i—O2—C7—C8 | −111.2 (3) | C7—C8—C13—C12 | −177.7 (2) |
C14—O1—C7—O2 | 179.8 (2) | C9—C8—C13—C14 | 179.4 (2) |
C14—O1—C7—C8 | −1.6 (3) | C7—C8—C13—C14 | 0.5 (3) |
O2—C7—C8—C9 | 0.2 (5) | C7—O1—C14—C13 | 1.9 (3) |
O1—C7—C8—C9 | −178.1 (2) | C12—C13—C14—O1 | 176.6 (2) |
O2—C7—C8—C13 | 179.0 (3) | C8—C13—C14—O1 | −1.4 (2) |
O1—C7—C8—C13 | 0.7 (3) | C11—C10—C15—C16 | −106.9 (2) |
Na24—O3—C9—C8 | −19.7 (3) | C9—C10—C15—C16 | 73.2 (2) |
Na24—O3—C9—C10 | 159.3 (2) | C10—C15—C16—C17 | 135.7 (2) |
C13—C8—C9—O3 | 175.0 (2) | C15—C16—C17—C23 | −2.1 (4) |
C7—C8—C9—O3 | −6.3 (4) | C15—C16—C17—C18 | 176.2 (2) |
C13—C8—C9—C10 | −4.1 (3) | C16—C17—C18—C19 | −98.9 (3) |
C7—C8—C9—C10 | 174.6 (2) | C23—C17—C18—C19 | 79.7 (3) |
O3—C9—C10—C11 | −175.1 (2) | C17—C18—C19—C20 | −178.2 (2) |
C8—C9—C10—C11 | 4.0 (3) | Na24ii—O5—C20—O4 | 172.4 (2) |
O3—C9—C10—C15 | 4.9 (3) | Na24iii—O5—C20—O4 | 5.9 (4) |
C8—C9—C10—C15 | −176.1 (2) | Na24ii—O5—C20—C19 | −5.5 (4) |
C21—O6—C11—C10 | 87.7 (3) | Na24iii—O5—C20—C19 | −171.9 (2) |
C21—O6—C11—C12 | −94.1 (3) | C18—C19—C20—O5 | 80.3 (3) |
C9—C10—C11—O6 | 176.8 (2) | C18—C19—C20—O4 | −97.8 (3) |
C15—C10—C11—O6 | −3.2 (3) | C9—O3—Na24—O5iv | 159.3 (4) |
C9—C10—C11—C12 | −1.3 (3) | C9—O3—Na24—O5v | −171.4 (2) |
C15—C10—C11—C12 | 178.8 (2) | C9—O3—Na24—O2 | 31.5 (2) |
O6—C11—C12—C13 | −179.7 (2) | C9—O3—Na24—O2vi | −90.8 (2) |
C10—C11—C12—C13 | −1.7 (3) | C7—O2—Na24—O3 | −31.4 (2) |
O6—C11—C12—C22 | 0.8 (3) | C7—O2—Na24—O5iv | 159.5 (2) |
C10—C11—C12—C22 | 178.8 (2) | C7—O2—Na24—O5v | −89.0 (3) |
C11—C12—C13—C8 | 1.7 (3) | C7—O2—Na24—O2vi | 52.0 (2) |
C22—C12—C13—C8 | −178.8 (2) | | |
Symmetry codes: (i) x, y+1, z; (ii) x, −y+1/2, z+1/2; (iii) −x+1, y+1/2, −z+3/2; (iv) x, −y+1/2, z−1/2; (v) −x+1, y−1/2, −z+3/2; (vi) x, y−1, z; (vii) −x+1, −y, −z+1; (viii) −x+1, −y+1, −z+1. |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O3—H3···O4v | 0.88 | 1.73 | 2.464 (3) | 139 |
Symmetry code: (v) −x+1, y−1/2, −z+3/2. |
Experimental details
Crystal data |
Chemical formula | [NaC17H19O6] |
Mr | 342.31 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 293 |
a, b, c (Å) | 16.544 (4), 4.477 (1), 21.993 (3) |
β (°) | 92.14 (1) |
V (Å3) | 1627.8 (6) |
Z | 4 |
Radiation type | Cu Kα |
µ (mm−1) | 1.11 |
Crystal size (mm) | 0.41 × 0.20 × 0.15 |
|
Data collection |
Diffractometer | Enraf-Nonius CAD4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 3432, 3334, 2058 |
Rint | 0.058 |
(sin θ/λ)max (Å−1) | 0.624 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.048, 0.121, 0.86 |
No. of reflections | 2913 |
No. of parameters | 217 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.31, −0.29 |
Selected geometric parameters (Å, º) topO1—C7 | 1.364 (3) | O3—Na24 | 2.249 (2) |
O1—C14 | 1.437 (3) | O4—C20 | 1.271 (3) |
O2—C7 | 1.217 (3) | O5—C20 | 1.224 (3) |
O2—Na24 | 2.423 (2) | Na24—O5ii | 2.259 (2) |
O2—Na24i | 2.699 (3) | Na24—O5iii | 2.361 (2) |
O3—C9 | 1.300 (2) | Na24—Na24iv | 3.410 (2) |
| | | |
O3—Na24—O5ii | 166.76 (8) | O5iii—Na24—O2 | 152.69 (10) |
O3—Na24—O5iii | 83.55 (7) | O3—Na24—O2v | 88.86 (8) |
O5ii—Na24—O5iii | 84.88 (7) | O5ii—Na24—O2v | 95.58 (9) |
O3—Na24—O2 | 81.55 (7) | O5iii—Na24—O2v | 80.53 (9) |
O5ii—Na24—O2 | 106.36 (8) | O2—Na24—O2v | 121.77 (9) |
Symmetry codes: (i) x, y+1, z; (ii) x, −y+1/2, z−1/2; (iii) −x+1, y−1/2, −z+3/2; (iv) −x+1, −y, −z+1; (v) x, y−1, z. |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O3—H3···O4iii | 0.88 | 1.73 | 2.464 (3) | 139 |
Symmetry code: (iii) −x+1, y−1/2, −z+3/2. |
Mycophenolic acid (MPA) is the pharmacologically active agent of the recently introduced immunosuppressive drug mycophenolate mofetil (MMF, CellCeptTM) (Behrend, 1998). In fact, MMF has never been detected systemically due to its fast hydrolysis to MPA, which is responsible for the gastrointestinal side effects and leukocytopenia observed in transplanted patients (Holt et al., 1998). To alleviate the upper gastrointestinal tract problems, an enteric coated formulation of sodium mycophenolate, ERL080, (I), is currently in phase III clinical trials for the prophylaxis of transplant rejection. The phase I results demonstrated that, upon oral dosing, (I) affords equivalent MPA exposure to that of MMF but with a longer mean Tmax, which is indicative of the delivery of the drug in the small intestine (Schmouder et al., 1999). Since the NMR conformation of (I) in water solution has been reported (Makara et al., 1996), as well as that of MPA in the solid state (Harrison et al., 1972), a crystal structure analysis of (I) was performed to determine its packing and to compare the resulting conformation with those in the above-mentioned reports. \scheme
In contrast with MPA, whose solid state conformation was consistent with the solution NMR data for (I) (Makara et al., 1996), the latter adopts a different conformation in the solid state. The discrepancies between MPA and (I) are solely due to changes in the conformation of the hexenoic acid chain. The most relevant differencies in the torsion angles are: C10—C15—C16—C17 135.7 (2) [-120.8 (3) in MPA], C16—C17—C18—C19 - 98.9 (3) [-5.9 (5) in MPA] and C18—C19—C20—O5 80.3 (3)° [-4.8 (5)° in MPA]. The close contact of 3.802 (3) Å between the two methyl groups, C21 and C23, in (I) is remarkable compared with the values of 6.258 (5) Å in MPA and 5.67 Å in solution. For steric reasons, the C15—C16 bond of the alkyl side chain and the methoxy group lie at angles of 72.4 (2) and 87.5 (3)°, respectively, to the phenyl ring plane. The corresponding values in MPA are 82.3 (3)° and 81.8 (3)°, respectively. In MPA and (I), atom C21 and the hexenoic side chain are on the same side of the phthalide ring system. An intramolecular O3—H···O2 hydrogen bond can be observed in MPA but not in (I). In spite of the various deviations, the data on the structure of MPA and (I) demonstrate that the hexenoic acid chain adopts an extended conformation and not the bent conformation seen upon complexation of the molecule with its enzymatic target (Sintchak et al., 1996).
The asymmetric unit with the adopted numbering scheme is shown in Fig. 1. The phthalide ring system is not completely planar, the dihedral angle between the plane of the five-membered ring and that of the aromatic ring being 4.0 (2)°. The Na+ ion coordinated to O2 and O3 lies 0.807 (2) Å from the plane defined by the atoms O2/C7/C8/C9/O3.
The packing is illustrated in Fig. 2. The hydrophilic parts (O2, O3, O4 and O5) of neighbouring anions are directed towards each other and connected via Na+ ions and hydrogen bonds to form an infinite two-dimensional network which runs parallel to the yz plane. This kind of packing is probably the reason why the hexenoic acid chains adopt different conformations in the solid states of MPA and (I).
The environment of the Na+ ion is a distorted square pyramid, with the longest Na—O bond [Na24—O2v 2.699 (3) Å; symmetry code: (v) x, y - 1, z] being in the apical position. The equatorial bond lengths fall into the range 2.249 (2)–2.423 (2) Å. Atoms O5 and O2 serve as bridging atoms between Na+ ions. The four-membered ring [Na24/O5ii/Na24iv/O5iii; symmetry codes (ii) x, 1/2 - y, z - 1/2; (iii) 1 - x, y - 1/2, 3/2 - z; (iv) 1 - x, -y, 1 - z] lies on an inversion centre and is therefore planar. The Na24···Na24iv distance across the inversion centre is 3.410 (2) Å.