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

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.

Key indicators

• Single-crystal X-ray study
• T = 113 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.027
• wR factor = 0.073
• Data-to-parameter ratio = 8.8

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L=  0.600         10
PLAT913_ALERT_3_C Missing # of Very Strong Reflections in FCF ....          7

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           27.85
           From the CIF: _reflns_number_total               1212
           Count of symmetry unique reflns         1221
           Completeness (_total/calc)             99.26%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no
PLAT791_ALERT_4_G The Model has Chirality at C6      (Verify) ....          S

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   2 ALERT level C = Check and explain
   2 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   2 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. 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.

Related literature

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

S2. 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.

S3. 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 U_iso(H) = 1.2U_eq(C) and 1.5U_eq(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.

Computing details

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

Figures

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

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

Crystal data

C10H7FO4	F(000) = 432
Mr = 210.16	Dx = 1.602 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 3184 reflections
a = 5.3472 (11) Å	θ = 1.6–27.8°
b = 12.748 (3) Å	µ = 0.14 mm^−1
c = 12.785 (3) Å	T = 113 K
V = 871.5 (3) Å^3	Block, colourless
Z = 4	0.28 × 0.23 × 0.22 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer	1212 independent reflections
Radiation source: rotating anode	1049 reflections with I > 2σ(I)
Confocal monochromator	Rint = 0.045
Detector resolution: 7.31 pixels mm^-1	θmax = 27.9°, θmin = 2.3°
ω and φ scans	h = −7→6
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)	k = −16→16
Tmin = 0.962, Tmax = 0.970	l = −16→16
8640 measured reflections

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)] = 0.027	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.073	H-atom parameters constrained
S = 1.12	w = 1/[σ^2(Fo^2) + (0.0448P)^2] where P = (Fo^2 + 2Fc^2)/3
1212 reflections	(Δ/σ)max = 0.001
137 parameters	Δρmax = 0.17 e Å^−3
0 restraints	Δρmin = −0.15 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 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 (Ų)

	x	y	z	Uiso*/Ueq
F1	0.8260 (2)	0.32440 (8)	0.43315 (9)	0.0336 (3)
O1	0.2480 (2)	0.03466 (8)	0.23160 (9)	0.0189 (3)
O2	0.1188 (2)	0.34646 (9)	0.17373 (10)	0.0230 (3)
O3	0.5538 (2)	0.03536 (10)	0.06321 (10)	0.0230 (3)
O4	0.2609 (3)	0.11076 (10)	−0.03716 (9)	0.0250 (3)
H4	0.3799	0.1179	−0.0795	0.037*
C1	0.6806 (3)	0.25426 (12)	0.38164 (13)	0.0200 (4)
C2	0.5057 (3)	0.29048 (13)	0.31336 (12)	0.0184 (4)
H2	0.4862	0.3636	0.3015	0.022*
C3	0.3547 (3)	0.21751 (12)	0.26079 (12)	0.0152 (3)
C4	0.1561 (3)	0.25266 (12)	0.19024 (12)	0.0154 (3)
C5	−0.0026 (3)	0.16808 (13)	0.14292 (12)	0.0175 (3)
H5A	−0.0588	0.1905	0.0726	0.021*
H5B	−0.1529	0.1573	0.1868	0.021*
C6	0.1404 (3)	0.06506 (12)	0.13377 (12)	0.0167 (3)
H6	0.0182	0.0095	0.1130	0.020*
C7	0.3894 (3)	0.10981 (12)	0.27966 (12)	0.0155 (4)
C8	0.5700 (3)	0.07625 (13)	0.35030 (12)	0.0182 (4)
H8	0.5923	0.0034	0.3630	0.022*
C9	0.7161 (4)	0.14813 (12)	0.40169 (12)	0.0200 (4)
H9	0.8396	0.1257	0.4502	0.024*
C10	0.3450 (3)	0.06823 (12)	0.05065 (13)	0.0174 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0418 (7)	0.0231 (5)	0.0358 (6)	−0.0017 (5)	−0.0248 (5)	−0.0041 (5)
O1	0.0218 (6)	0.0139 (5)	0.0211 (5)	−0.0031 (5)	−0.0003 (5)	0.0013 (4)
O2	0.0246 (7)	0.0158 (6)	0.0287 (6)	0.0020 (5)	−0.0091 (5)	0.0024 (5)
O3	0.0155 (6)	0.0265 (6)	0.0270 (6)	0.0037 (5)	0.0012 (5)	−0.0053 (5)
O4	0.0189 (6)	0.0340 (6)	0.0221 (6)	−0.0007 (6)	0.0050 (6)	0.0024 (5)
C1	0.0225 (10)	0.0191 (8)	0.0184 (7)	−0.0018 (7)	−0.0048 (7)	−0.0029 (7)
C2	0.0226 (10)	0.0146 (7)	0.0181 (7)	0.0007 (7)	−0.0026 (7)	−0.0004 (6)
C3	0.0155 (8)	0.0147 (7)	0.0155 (7)	0.0006 (6)	0.0004 (6)	0.0009 (6)
C4	0.0137 (8)	0.0165 (8)	0.0161 (7)	0.0007 (7)	0.0018 (6)	−0.0007 (6)
C5	0.0142 (8)	0.0182 (8)	0.0201 (8)	−0.0016 (7)	0.0011 (6)	−0.0024 (6)
C6	0.0151 (8)	0.0149 (7)	0.0201 (8)	−0.0027 (7)	0.0004 (6)	−0.0013 (6)
C7	0.0170 (9)	0.0140 (7)	0.0154 (7)	−0.0006 (7)	0.0045 (7)	−0.0012 (6)
C8	0.0226 (9)	0.0137 (7)	0.0181 (7)	0.0049 (7)	0.0033 (7)	0.0035 (6)
C9	0.0217 (9)	0.0229 (8)	0.0154 (7)	0.0042 (7)	−0.0006 (7)	0.0024 (6)
C10	0.0174 (9)	0.0133 (7)	0.0214 (8)	−0.0041 (7)	0.0010 (7)	−0.0048 (7)

Geometric parameters (Å, º)

F1—C1	1.3557 (18)	C3—C4	1.464 (2)
O1—C7	1.366 (2)	C4—C5	1.499 (2)
O1—C6	1.4302 (19)	C5—C6	1.524 (2)
O2—C4	1.2305 (19)	C5—H5A	0.99
O3—C10	1.203 (2)	C5—H5B	0.99
O4—C10	1.325 (2)	C6—C10	1.526 (2)
O4—H4	0.84	C6—H6	1.00
C1—C2	1.360 (2)	C7—C8	1.390 (2)
C1—C9	1.390 (2)	C8—C9	1.372 (2)
C2—C3	1.403 (2)	C8—H8	0.95
C2—H2	0.95	C9—H9	0.95
C3—C7	1.406 (2)
C7—O1—C6	115.20 (12)	H5A—C5—H5B	108.0
C10—O4—H4	109.5	O1—C6—C5	111.60 (12)
F1—C1—C2	118.84 (14)	O1—C6—C10	109.14 (14)
F1—C1—C9	118.29 (15)	C5—C6—C10	112.98 (13)
C2—C1—C9	122.87 (16)	O1—C6—H6	107.6
C1—C2—C3	118.56 (15)	C5—C6—H6	107.6
C1—C2—H2	120.7	C10—C6—H6	107.6
C3—C2—H2	120.7	O1—C7—C8	117.44 (14)
C2—C3—C7	119.28 (15)	O1—C7—C3	122.30 (15)
C2—C3—C4	120.64 (14)	C8—C7—C3	120.25 (15)
C7—C3—C4	120.03 (14)	C9—C8—C7	120.09 (15)
O2—C4—C3	121.39 (14)	C9—C8—H8	120.0
O2—C4—C5	122.54 (15)	C7—C8—H8	120.0
C3—C4—C5	116.04 (13)	C8—C9—C1	118.95 (16)
C4—C5—C6	111.51 (13)	C8—C9—H9	120.5
C4—C5—H5A	109.3	C1—C9—H9	120.5
C6—C5—H5A	109.3	O3—C10—O4	124.77 (16)
C4—C5—H5B	109.3	O3—C10—C6	124.27 (15)
C6—C5—H5B	109.3	O4—C10—C6	110.96 (14)
F1—C1—C2—C3	−179.60 (15)	C6—O1—C7—C3	24.6 (2)
C9—C1—C2—C3	−0.1 (3)	C2—C3—C7—O1	179.64 (14)
C1—C2—C3—C7	−0.4 (2)	C4—C3—C7—O1	2.1 (2)
C1—C2—C3—C4	177.15 (14)	C2—C3—C7—C8	0.5 (2)
C2—C3—C4—O2	1.2 (2)	C4—C3—C7—C8	−177.00 (14)
C7—C3—C4—O2	178.73 (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—C5	0.8 (2)	C7—C8—C9—C1	−0.2 (2)
O2—C4—C5—C6	154.54 (16)	F1—C1—C9—C8	179.88 (15)
C3—C4—C5—C6	−27.50 (19)	C2—C1—C9—C8	0.3 (3)
C7—O1—C6—C5	−52.00 (18)	O1—C6—C10—O3	10.0 (2)
C7—O1—C6—C10	73.59 (16)	C5—C6—C10—O3	134.74 (16)
C4—C5—C6—O1	53.01 (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, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O2^i	0.84	1.81	2.6474 (19)	171
C5—H5B···Cg1^ii	0.99	2.51	3.4521 (19)	160

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