PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of actaeInternational Union of Crystallographysearchopen accessarticle submissionjournal home pagethis article
 
Acta Crystallogr Sect E Struct Rep Online. 2010 February 1; 66(Pt 2): o274.
Published online 2010 January 9. doi:  10.1107/S1600536809054555
PMCID: PMC2979877

6-Fluoro-4-oxochroman-2-carboxylic acid

Abstract

The title compound, C10H7FO4, is an inter­mediate in the synthesis of the drug Fidarestat, (2S,4S)-2-aminoformyl-6-fluoro-spiro[chroman-4,4′-imidazolidine]-2′,5′-dione. The di­hydro­pyran­one ring adopts an envelope conformation with the asymmetric C atom in the flap position. In the crystal, the mol­ecules are linked into zigzag chains along [100] by O—H(...)O hydrogen bonds and C—H(...)π inter­actions involving the benzene ring.

Related literature

Fidarestat, which shows strong inhibition to aldose reducta­ses, is used to treat complications of diabetes, see: Mealy (1996 [triangle]); Mitsuru et al. (2000 [triangle]). For related structures, see: Kurono et al. (1989 [triangle]); Yamaguchi et al. (1994 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-0o274-scheme1.jpg

Experimental

Crystal data

  • C10H7FO4
  • M r = 210.16
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-66-0o274-efi1.jpg
  • a = 5.3472 (11) Å
  • b = 12.748 (3) Å
  • c = 12.785 (3) Å
  • V = 871.5 (3) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.14 mm−1
  • T = 113 K
  • 0.28 × 0.23 × 0.22 mm

Data collection

  • Rigaku Saturn CCD area-detector diffractometer
  • Absorption correction: multi-scan (ABSCOR; Higashi, 1995 [triangle]) T min = 0.962, T max = 0.970
  • 8640 measured reflections
  • 1212 independent reflections
  • 1049 reflections with I > 2σ(I)
  • R int = 0.045

Refinement

  • R[F 2 > 2σ(F 2)] = 0.027
  • wR(F 2) = 0.073
  • S = 1.12
  • 1212 reflections
  • 137 parameters
  • H-atom parameters constrained
  • Δρmax = 0.17 e Å−3
  • Δρmin = −0.15 e Å−3

Data collection: CrystalClear (Rigaku/MSC, 2005 [triangle]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 (Farrugia, 1997 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809054555/ci2987sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809054555/ci2987Isup2.hkl

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

supplementary crystallographic information

Comment

The optically active (S)-6-fluoro-4-oxochroman-2-carboxylic acid is a key intermediate for synthesizing Fidarestat which shows strong inhibition to aldose reductases to cure incurable complications of diabetes (Mitsuru et al., 2000; Mealy, 1996). Our interests in synthesizing Fidarestat prompted us to develop an efficient methodology for synthesizing (S)-6-fluoro-4-oxochroman-2-carboxylic acid. In our synthetic work, we obtained the title compound, which is similar to those reported in the literature (Kurono et al., 1989; Yamaguchi et al., 1994). Its crystal structure is reported here.

The dihydropyranone ring adopts an envelope conformation with the asymmetric C atom in the flap position (Fig. 1). The molecules are linked into zigzag chains along the [100] by O—H···O hydrogen bonds and C—H···π interactions (Table 1) involving the benzene ring.

Experimental

To a stirred solution of (2S,4R)-2-(1',2'-Dihydroxyethyl)-6-fluoro-chroman-4-one (10.7 g, 0.05 mol) in 300 ml of anhydrous benzene at room temperature was added lead tetraacetate (22.2 g, 0.05 mol). After 30 min, the solution was filtered and the filtrate was evaporated in vacuum to the residue. To the solution of 2% aqueous silver nitrate (651 ml, 0.07 mol) was added 5% aqueous sodium hydroxide (120 ml, 0.16 mol), and then generated the black precipitate immediately. To this stirred solution at room temperature was added, dropwise over 5 min, 4% ammonia water (520 ml, 0.16 mol). The black precipitate disappeared. The residue described above was dissolved in small amounts of THF and then added in this stirred solution at 323–333 K. After 10 min, the solution was filtered, and the precipitate was washed with water. The filtrate was acidified to pH 1 with 6 N aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extracts were dried (MgSO4) and then concentrated under reduced pressure. The residue was mixed with a mixture of ethanol and water, and left to crystallize 8.7 g (83%) of 6-Fluoro- 4-oxochroman-2-carboxylic acid. Colourless crystals suitable for X-ray analysis were obtained by slow evaporation in ethanol at room temperature.

Refinement

H atoms were positioned geometrically (O-H = 0.84 and C-H = 0.95–1.00 Å) and refined using a riding model, with Uiso(H) = 1.2Ueq(C) and 1.5Ueq(O). In the absence of significant anomalous scattering, Friedel pairs were merged prior to the final refinement. Nine reflections that were affected by the beamstop were discarded.

Figures

Fig. 1.
The molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level.

Crystal data

C10H7FO4F(000) = 432
Mr = 210.16Dx = 1.602 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 3184 reflections
a = 5.3472 (11) Åθ = 1.6–27.8°
b = 12.748 (3) ŵ = 0.14 mm1
c = 12.785 (3) ÅT = 113 K
V = 871.5 (3) Å3Block, colourless
Z = 40.28 × 0.23 × 0.22 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer1212 independent reflections
Radiation source: rotating anode1049 reflections with I > 2σ(I)
confocalRint = 0.045
Detector resolution: 7.31 pixels mm-1θmax = 27.9°, θmin = 2.3°
ω and [var phi] scansh = −7→6
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)k = −16→16
Tmin = 0.962, Tmax = 0.970l = −16→16
8640 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)] = 0.027Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.073H-atom parameters constrained
S = 1.12w = 1/[σ2(Fo2) + (0.0448P)2] where P = (Fo2 + 2Fc2)/3
1212 reflections(Δ/σ)max = 0.001
137 parametersΔρmax = 0.17 e Å3
0 restraintsΔρmin = −0.15 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*/Ueq
F10.8260 (2)0.32440 (8)0.43315 (9)0.0336 (3)
O10.2480 (2)0.03466 (8)0.23160 (9)0.0189 (3)
O20.1188 (2)0.34646 (9)0.17373 (10)0.0230 (3)
O30.5538 (2)0.03536 (10)0.06321 (10)0.0230 (3)
O40.2609 (3)0.11076 (10)−0.03716 (9)0.0250 (3)
H40.37990.1179−0.07950.037*
C10.6806 (3)0.25426 (12)0.38164 (13)0.0200 (4)
C20.5057 (3)0.29048 (13)0.31336 (12)0.0184 (4)
H20.48620.36360.30150.022*
C30.3547 (3)0.21751 (12)0.26079 (12)0.0152 (3)
C40.1561 (3)0.25266 (12)0.19024 (12)0.0154 (3)
C5−0.0026 (3)0.16808 (13)0.14292 (12)0.0175 (3)
H5A−0.05880.19050.07260.021*
H5B−0.15290.15730.18680.021*
C60.1404 (3)0.06506 (12)0.13377 (12)0.0167 (3)
H60.01820.00950.11300.020*
C70.3894 (3)0.10981 (12)0.27966 (12)0.0155 (4)
C80.5700 (3)0.07625 (13)0.35030 (12)0.0182 (4)
H80.59230.00340.36300.022*
C90.7161 (4)0.14813 (12)0.40169 (12)0.0200 (4)
H90.83960.12570.45020.024*
C100.3450 (3)0.06823 (12)0.05065 (13)0.0174 (3)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
F10.0418 (7)0.0231 (5)0.0358 (6)−0.0017 (5)−0.0248 (5)−0.0041 (5)
O10.0218 (6)0.0139 (5)0.0211 (5)−0.0031 (5)−0.0003 (5)0.0013 (4)
O20.0246 (7)0.0158 (6)0.0287 (6)0.0020 (5)−0.0091 (5)0.0024 (5)
O30.0155 (6)0.0265 (6)0.0270 (6)0.0037 (5)0.0012 (5)−0.0053 (5)
O40.0189 (6)0.0340 (6)0.0221 (6)−0.0007 (6)0.0050 (6)0.0024 (5)
C10.0225 (10)0.0191 (8)0.0184 (7)−0.0018 (7)−0.0048 (7)−0.0029 (7)
C20.0226 (10)0.0146 (7)0.0181 (7)0.0007 (7)−0.0026 (7)−0.0004 (6)
C30.0155 (8)0.0147 (7)0.0155 (7)0.0006 (6)0.0004 (6)0.0009 (6)
C40.0137 (8)0.0165 (8)0.0161 (7)0.0007 (7)0.0018 (6)−0.0007 (6)
C50.0142 (8)0.0182 (8)0.0201 (8)−0.0016 (7)0.0011 (6)−0.0024 (6)
C60.0151 (8)0.0149 (7)0.0201 (8)−0.0027 (7)0.0004 (6)−0.0013 (6)
C70.0170 (9)0.0140 (7)0.0154 (7)−0.0006 (7)0.0045 (7)−0.0012 (6)
C80.0226 (9)0.0137 (7)0.0181 (7)0.0049 (7)0.0033 (7)0.0035 (6)
C90.0217 (9)0.0229 (8)0.0154 (7)0.0042 (7)−0.0006 (7)0.0024 (6)
C100.0174 (9)0.0133 (7)0.0214 (8)−0.0041 (7)0.0010 (7)−0.0048 (7)

Geometric parameters (Å, °)

F1—C11.3557 (18)C3—C41.464 (2)
O1—C71.366 (2)C4—C51.499 (2)
O1—C61.4302 (19)C5—C61.524 (2)
O2—C41.2305 (19)C5—H5A0.99
O3—C101.203 (2)C5—H5B0.99
O4—C101.325 (2)C6—C101.526 (2)
O4—H40.84C6—H61.00
C1—C21.360 (2)C7—C81.390 (2)
C1—C91.390 (2)C8—C91.372 (2)
C2—C31.403 (2)C8—H80.95
C2—H20.95C9—H90.95
C3—C71.406 (2)
C7—O1—C6115.20 (12)H5A—C5—H5B108.0
C10—O4—H4109.5O1—C6—C5111.60 (12)
F1—C1—C2118.84 (14)O1—C6—C10109.14 (14)
F1—C1—C9118.29 (15)C5—C6—C10112.98 (13)
C2—C1—C9122.87 (16)O1—C6—H6107.6
C1—C2—C3118.56 (15)C5—C6—H6107.6
C1—C2—H2120.7C10—C6—H6107.6
C3—C2—H2120.7O1—C7—C8117.44 (14)
C2—C3—C7119.28 (15)O1—C7—C3122.30 (15)
C2—C3—C4120.64 (14)C8—C7—C3120.25 (15)
C7—C3—C4120.03 (14)C9—C8—C7120.09 (15)
O2—C4—C3121.39 (14)C9—C8—H8120.0
O2—C4—C5122.54 (15)C7—C8—H8120.0
C3—C4—C5116.04 (13)C8—C9—C1118.95 (16)
C4—C5—C6111.51 (13)C8—C9—H9120.5
C4—C5—H5A109.3C1—C9—H9120.5
C6—C5—H5A109.3O3—C10—O4124.77 (16)
C4—C5—H5B109.3O3—C10—C6124.27 (15)
C6—C5—H5B109.3O4—C10—C6110.96 (14)
F1—C1—C2—C3−179.60 (15)C6—O1—C7—C324.6 (2)
C9—C1—C2—C3−0.1 (3)C2—C3—C7—O1179.64 (14)
C1—C2—C3—C7−0.4 (2)C4—C3—C7—O12.1 (2)
C1—C2—C3—C4177.15 (14)C2—C3—C7—C80.5 (2)
C2—C3—C4—O21.2 (2)C4—C3—C7—C8−177.00 (14)
C7—C3—C4—O2178.73 (16)O1—C7—C8—C9−179.41 (14)
C2—C3—C4—C5−176.75 (14)C3—C7—C8—C9−0.3 (2)
C7—C3—C4—C50.8 (2)C7—C8—C9—C1−0.2 (2)
O2—C4—C5—C6154.54 (16)F1—C1—C9—C8179.88 (15)
C3—C4—C5—C6−27.50 (19)C2—C1—C9—C80.3 (3)
C7—O1—C6—C5−52.00 (18)O1—C6—C10—O310.0 (2)
C7—O1—C6—C1073.59 (16)C5—C6—C10—O3134.74 (16)
C4—C5—C6—O153.01 (17)O1—C6—C10—O4−170.78 (12)
C4—C5—C6—C10−70.43 (17)C5—C6—C10—O4−46.00 (17)
C6—O1—C7—C8−156.25 (14)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O4—H4···O2i0.841.812.6474 (19)171
C5—H5B···Cg1ii0.992.513.4521 (19)160

Symmetry codes: (i) x+1/2, −y+1/2, −z; (ii) x−1, y, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CI2987).

References

  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Higashi, T. (1995). ABSCOR Rigaku Corperation, Tokyo, Japan.
  • Kurono, M., Kondo, Y., Yamaguchi, T., Miura, K., Usui, T., Terada, N., Asano, K., Mizuno, K., Matsubara, A., Kato, N., Sawai, K., Unno, T., Ozawa, H. & Fukushima, M. (1989). US Patent No. 4861792.
  • Mealy, N. (1996). Drugs Future, 21, 261–265.
  • Mitsuru, O., Yudiharu, M., Shigeru, S., Oka, M., Matsumoto, Y., Sugiyama, S., Tsuruta, N. & Matsushima, M. (2000). J. Med. Chem.43, 2479–2483. [PubMed]
  • Rigaku/MSC (2005). CrystalClear Rigaku/MSC, The Woodlands, Texas, USA.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Yamaguchi, T., Miura, K., Usui, T., Unno, R., Matsumoto, Y., Fukushima, M., Mizuno, K., Kondo, Y., Baba, Y. & Kurono, M. (1994). Arzneim. Forsch.44, 344–348. [PubMed]

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