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

Chen, P.; Qian, S.; Shi, Z.-Q.; Wu, Y.

doi:10.1107/S1600536809054555

organic compounds

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Volume 66| Part 2| February 2010| Page o274

https://doi.org/10.1107/S1600536809054555

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

Pei Chen,^a Shan Qian,^a Zhe-Qin Shi ^a and Yong Wu ^a ^*

^aKey Laboratory of Drug Targeting of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China
^*Correspondence e-mail: wyong@scu.edu.cn

(Received 12 December 2009; accepted 18 December 2009; online 9 January 2010)

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 ); Mitsuru et al. (2000 ). For related structures, see: Kurono et al. (1989 ); Yamaguchi et al. (1994 ).

Experimental

Crystal data

C₁₀H₇FO₄
M_r = 210.16
Orthorhombic, P 2₁ 2₁ 2₁
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 ) 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[F² > 2σ(F²)] = 0.027
wR(F²) = 0.073
S = 1.12
1212 reflections
137 parameters
H-atom parameters constrained
Δρ_max = 0.17 e Å⁻³
Δρ_min = −0.15 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O4—H4⋯O2ⁱ	0.84	1.81	2.6474 (19)	171
C5—H5B⋯Cg1ⁱⁱ	0.99	2.51	3.4521 (19)	160
Symmetry codes: (i) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z]$ ; (ii) x-1, y, z. Cg1 is the centroid of the C1–C3/C7–C9 ring.

Data collection: CrystalClear (Rigaku/MSC, 2005 ); cell refinement: CrystalClear; data reduction: CrystalClear; 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.

Supporting information

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

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536809054555/ci2987Isup2.hkl

checkCIF report

Comment top

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 top

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).

Experimental top

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.

Structure description top

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).

Computing details top

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 top

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 top

Crystal data top

C₁₀H₇FO₄	F(000) = 432
M_r = 210.16	D_x = 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) Å³	Block, colourless
Z = 4	0.28 × 0.23 × 0.22 mm

Data collection top

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

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)] = 0.027	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.073	H-atom parameters constrained
S = 1.12	w = 1/[σ²(F_o²) + (0.0448P)²] where P = (F_o² + 2F_c²)/3
1212 reflections	(Δ/σ)_max = 0.001
137 parameters	Δρ_max = 0.17 e Å⁻³
0 restraints	Δρ_min = −0.15 e Å⁻³

Crystal data top

C₁₀H₇FO₄	V = 871.5 (3) Å³
M_r = 210.16	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 5.3472 (11) Å	µ = 0.14 mm⁻¹
b = 12.748 (3) Å	T = 113 K
c = 12.785 (3) Å	0.28 × 0.23 × 0.22 mm

Data collection top

Rigaku Saturn CCD area-detector diffractometer	1212 independent reflections
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)	1049 reflections with I > 2σ(I)
T_min = 0.962, T_max = 0.970	R_int = 0.045
8640 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.027	0 restraints
wR(F²) = 0.073	H-atom parameters constrained
S = 1.12	Δρ_max = 0.17 e Å⁻³
1212 reflections	Δρ_min = −0.15 e Å⁻³
137 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 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) top

	x	y	z	U_iso*/U_eq
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 (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
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) top

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) top

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O2ⁱ	0.84	1.81	2.6474 (19)	171
C5—H5B···Cg1ⁱⁱ	0.99	2.51	3.4521 (19)	160

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

Experimental details

Crystal data
Chemical formula	C₁₀H₇FO₄
M_r	210.16
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	113
a, b, c (Å)	5.3472 (11), 12.748 (3), 12.785 (3)
V (Å³)	871.5 (3)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.14
Crystal size (mm)	0.28 × 0.23 × 0.22

Data collection
Diffractometer	Rigaku Saturn CCD area-detector
Absorption correction	Multi-scan (ABSCOR; Higashi, 1995)
T_min, T_max	0.962, 0.970
No. of measured, independent and observed [I > 2σ(I)] reflections	8640, 1212, 1049
R_int	0.045
(sin θ/λ)_max (Å⁻¹)	0.657

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.027, 0.073, 1.12
No. of reflections	1212
No. of parameters	137
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.15

Computer programs: CrystalClear (Rigaku/MSC, 2005), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 (Farrugia, 1997).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O2ⁱ	0.84	1.81	2.6474 (19)	171
C5—H5B···Cg1ⁱⁱ	0.99	2.51	3.4521 (19)	160

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

References

Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565. CrossRef IUCr Journals Google Scholar
Higashi, T. (1995). ABSCOR. Rigaku Corperation, Tokyo, Japan. Google Scholar
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Mealy, N. (1996). Drugs Future, 21, 261–265. CAS Google Scholar
Mitsuru, O., Yudiharu, M., Shigeru, S., Oka, M., Matsumoto, Y., Sugiyama, S., Tsuruta, N. & Matsushima, M. (2000). J. Med. Chem. 43, 2479–2483. Web of Science PubMed Google Scholar
Rigaku/MSC (2005). CrystalClear. Rigaku/MSC, The Woodlands, Texas, USA. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
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. CAS Google Scholar

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CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 66| Part 2| February 2010| Page o274

https://doi.org/10.1107/S1600536809054555

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