Sodium mycophenolate

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.

S1. Comment

Mycophenolic acid (MPA) is the pharmacologically active agent of the recently introduced immunosuppressive drug mycophenolate mofetil (MMF, CellCept^TM) (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 T_max, 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—O2^v 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/Na24^iv/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···Na24^iv distance across the inversion centre is 3.410 (2) Å.

S2. Experimental

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.

S3. Refinement

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.

Computing details

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).

Figures

	Fig. 1. An ORTEPII (Johnson, 1976) plot of the asymmetric unit of (I), showing 50% probability ellipsoids.
	Fig. 2. Packing diagram for (I) showing the Na—O network (broken lines indicate hydrogen bonds); symmetry codes are as in Table 1.

sodium 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)- 4-methylhex-4-enoate

Crystal data

[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) Å^3	Prism, colourless
Z = 4	0.41 × 0.20 × 0.15 mm
F(000) = 720

Data collection

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

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.121	H-atom parameters constrained
S = 0.86	Calculated w = 1/[σ^2(Fo^2) + (0.1P)^2] where P = (Fo^2 + 2Fc^2)/3
2913 reflections	(Δ/σ)max = −0.008
217 parameters	Δρmax = 0.31 e Å^−3
0 restraints	Δρmin = −0.29 e Å^−3

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 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 (Ų)

	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 (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

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—Na24^i	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—Na24^ii	2.259 (2)	C17—C18	1.527 (3)
O5—Na24^iii	2.361 (2)	C18—C19	1.517 (3)
O6—C11	1.383 (3)	C19—C20	1.501 (3)
O6—C21	1.429 (3)	Na24—O5^iv	2.259 (2)
C7—C8	1.450 (3)	Na24—O5^v	2.361 (2)
C8—C9	1.408 (3)	Na24—O2^vi	2.699 (3)
C8—C13	1.389 (3)	Na24—Na24^vii	3.410 (2)
C9—C10	1.420 (3)	Na24—Na24^viii	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—Na24^i	103.4 (2)	C12—C13—C14	129.5 (2)
Na24—O2—Na24^i	121.77 (9)	C8—C13—C14	107.3 (2)
C9—O3—Na24	128.81 (13)	O1—C14—C13	105.4 (2)
C20—O5—Na24^ii	136.0 (2)	C10—C15—C16	111.7 (2)
C20—O5—Na24^iii	128.0 (2)	C17—C16—C15	126.5 (2)
Na24^ii—O5—Na24^iii	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—O5^iv	166.76 (8)
O3—C9—C10	123.5 (2)	O3—Na24—O5^v	83.55 (7)
C8—C9—C10	115.8 (2)	O5^iv—Na24—O5^v	84.88 (7)
C11—C10—C9	119.5 (2)	O3—Na24—O2	81.55 (7)
C11—C10—C15	121.6 (2)	O5^iv—Na24—O2	106.36 (8)
C9—C10—C15	118.9 (2)	O5^v—Na24—O2	152.69 (10)
O6—C11—C10	118.3 (2)	O3—Na24—O2^vi	88.86 (8)
O6—C11—C12	117.4 (2)	O5^iv—Na24—O2^vi	95.58 (9)
C10—C11—C12	124.3 (2)	O5^v—Na24—O2^vi	80.53 (9)
C13—C12—C11	114.9 (2)	O2—Na24—O2^vi	121.77 (9)
C13—C12—C22	122.6 (2)
Na24—O2—C7—O1	−156.5 (2)	C11—C12—C13—C14	−176.1 (2)
Na24^i—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)
Na24^i—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)	Na24^ii—O5—C20—O4	172.4 (2)
O3—C9—C10—C15	4.9 (3)	Na24^iii—O5—C20—O4	5.9 (4)
C8—C9—C10—C15	−176.1 (2)	Na24^ii—O5—C20—C19	−5.5 (4)
C21—O6—C11—C10	87.7 (3)	Na24^iii—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—O5^iv	159.3 (4)
C9—C10—C11—C12	−1.3 (3)	C9—O3—Na24—O5^v	−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—O2^vi	−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—O5^iv	159.5 (2)
C10—C11—C12—C22	178.8 (2)	C7—O2—Na24—O5^v	−89.0 (3)
C11—C12—C13—C8	1.7 (3)	C7—O2—Na24—O2^vi	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)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O4^v	0.88	1.73	2.464 (3)	139

Symmetry code: (v) −x+1, y−1/2, −z+3/2.