Crystal structure of (R)-6-fluoro-2-[(S)-oxiran-2-yl]chroman

The title compound, C₁₁H₁₁FO₂, is a building block in the synthesis of the active pharmaceutical ingredient DL-nebivolol. The synthesis starting from the enanti­omerically pure (R)-6-fluoro-4-oxo-3,4-di­hydro-2H-chromene-2-carb­oxy­lic acid resulted in a mixture of two stereoisomers, namely (R)-6-fluoro-2-[(S)-oxiran-2-yl]chroman and (R)-6-fluoro-2-[(R)-oxiran-2-yl]chroman. The mixture was separated by column chromatography but only one stereoisomer crystallized. The X-ray structure analysis revealed that the solid consisted of the R,S isomer. A similar procedure was repeated for (S)-6-fluoro-4-oxo-3,4-di­hydro-2H-chromene-2-carb­oxy­lic acid and, in this case, the S,R isomer was produced as a crystalline solid. Thus, all four stereoisomers of the title epoxide were obtained and their absolute configuration was assigned. The crystal studied was refined as an inversion twin.

1. Related literature

For the synthesis of the enanti­opure title product, see: Jas et al. (2011). For pharmacological properties of nebivolol, see: Van Lommen et al. (1990). For a study of related isomers, see: Horiguchi et al. (1997). For the determination of absolute structure, see: Flack (2003).

2. Experimental

2.1. Crystal data

• C₁₁H₁₁FO₂

• M_r = 194.20

• Monoclinic, P 2₁

• a = 9.3742 (3) Å

• b = 4.76845 (12) Å

• c = 11.0212 (3) Å

• β = 114.202 (4)°

• V = 449.35 (3) ų

• Z = 2

• Cu Kα radiation

• μ = 0.94 mm⁻¹

• T = 100 K

• 0.05 × 0.05 × 0.02 mm

2.2. Data collection

• Agilent SuperNova Dual Source diffractometer with an Atlas detector

• Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012) T_min = 0.64, T_max = 1

• 14207 measured reflections

• 1847 independent reflections

• 1820 reflections with I > 2σ(I)

• R_int = 0.050

2.3. Refinement

• R[F² > 2σ(F²)] = 0.032

• wR(F²) = 0.092

• S = 1.10

• 1847 reflections

• 128 parameters

• 1 restraint

• H-atom parameters constrained

• Δρ_max = 0.20 e Å⁻³

• Δρ_min = −0.16 e Å⁻³

• Absolute structure: crystal refined as an inversion twin (Flack, 2003)

• Absolute structure parameter: 0.0 (2)

Data collection: CrysAlis PRO (Agilent, 2012); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2.

Supporting information

S1. Structural commentary

6-Fluoro-2-(oxiran-2-yl)chroman (Fig. 1) is a building block in the synthesis of dl-nebivolol. This active pharmaceutical ingredient is a highly cardioselective vasodilatory β-receptor blocker used in treatment of hypertension.

The synthesis starts from enanti­opure 2-chloro-1-(6-fluoro-chroman-2-yl)-1-ethanol (Jas et al., 2011) that is transformed into enanti­opure 6-fluoro-4-oxo-3,4-di­hydro-2H-chromene-2-carb­oxy­lic acid. Formation of the epoxide from the carb­oxy­lic acid results in a new stereogenic center and a mixture of two stereoisomers is formed from each enanti­opure form: R,S and R,R from the R enanti­omer of the acid and S,R and S,S from the S enanti­omer. The mixtures of stereoisomers can be separated by column chromatography and all four stereoisomers in the reactions can be isolated in a pure form (Fig. 2). These epoxide inter­mediates can be further used in a ring-opening reaction with benzyl­amine to yield, after catalytic hydrogenation, nebivolol isomer with four chiral center.

Of the four stereisomers of the title compound only two form solids, and the remaining two are liquids under normal conditions. X-ray structural analysis from a single crystal of a solid stereoisomer obtained from (R)-6-fluoro-4-oxo-3,4-di­hydro-2H-chromene-2-carb­oxy­lic acid revealed that it has R,S configuration at the stereogenic centers (Fig. 1). Crystal data for this stereoisomer are reported in this paper. As expected, X-ray structural analysis of the solid epoxide obtained from the S enanti­omer of the acid revealed the S,R configuration at the stereogenic centers.

S2. Synthesis and crystallization

(R)-6-Fluoro-2-[(S)-oxiran-2-yl]chroman was prepared from enanti­opure 2-chloro-1-(6-fluoro­chroman-2-yl)-1-ethanol according to the procedure reported by Jas et al. (2011).

Crystals suitable for X-ray analysis were obtained in a fraction from column chromatography with heptane/ethyl acetate as eluent.

S3. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. All C-bound H atoms were placed at calculated positions and refined as riding on their carriers with C—H = 1.00 Å (methine), 0.99 Å (methyl­ene) or 0.95 Å (aromatic) and with U_iso(H) = 1.2Ueq(C). TWIN/BASF refinement type in SHELXL-2014 (Sheldrick, 2015) was used to determine absolute configuration from anomalous scattering using the Flack method (Flack, 2003).

Related literature

For the synthesis of the enantiopure title product, see: Jas et al. (2011). For pharmacological properties of nebivolol, see: Van Lommen et al. (1990). For a study of related isomers, see: Horiguchi et al. (1997). For the determination of absolute structure, see: Flack (2003).

Structure description

6-Fluoro-2-(oxiran-2-yl)chroman (Fig. 1) is a building block in the synthesis of dl-nebivolol. This active pharmaceutical ingredient is a highly cardioselective vasodilatory β-receptor blocker used in treatment of hypertension.

The synthesis starts from enanti­opure 2-chloro-1-(6-fluoro-chroman-2-yl)-1-ethanol (Jas et al., 2011) that is transformed into enanti­opure 6-fluoro-4-oxo-3,4-di­hydro-2H-chromene-2-carb­oxy­lic acid. Formation of the epoxide from the carb­oxy­lic acid results in a new stereogenic center and a mixture of two stereoisomers is formed from each enanti­opure form: R,S and R,R from the R enanti­omer of the acid and S,R and S,S from the S enanti­omer. The mixtures of stereoisomers can be separated by column chromatography and all four stereoisomers in the reactions can be isolated in a pure form (Fig. 2). These epoxide inter­mediates can be further used in a ring-opening reaction with benzyl­amine to yield, after catalytic hydrogenation, nebivolol isomer with four chiral center.

Of the four stereisomers of the title compound only two form solids, and the remaining two are liquids under normal conditions. X-ray structural analysis from a single crystal of a solid stereoisomer obtained from (R)-6-fluoro-4-oxo-3,4-di­hydro-2H-chromene-2-carb­oxy­lic acid revealed that it has R,S configuration at the stereogenic centers (Fig. 1). Crystal data for this stereoisomer are reported in this paper. As expected, X-ray structural analysis of the solid epoxide obtained from the S enanti­omer of the acid revealed the S,R configuration at the stereogenic centers.

For the synthesis of the enantiopure title product, see: Jas et al. (2011). For pharmacological properties of nebivolol, see: Van Lommen et al. (1990). For a study of related isomers, see: Horiguchi et al. (1997). For the determination of absolute structure, see: Flack (2003).

Synthesis and crystallization

(R)-6-Fluoro-2-[(S)-oxiran-2-yl]chroman was prepared from enanti­opure 2-chloro-1-(6-fluoro­chroman-2-yl)-1-ethanol according to the procedure reported by Jas et al. (2011).

Crystals suitable for X-ray analysis were obtained in a fraction from column chromatography with heptane/ethyl acetate as eluent.

Refinement details

Crystal data, data collection and structure refinement details are summarized in Table 1. All C-bound H atoms were placed at calculated positions and refined as riding on their carriers with C—H = 1.00 Å (methine), 0.99 Å (methyl­ene) or 0.95 Å (aromatic) and with U_iso(H) = 1.2Ueq(C). TWIN/BASF refinement type in SHELXL-2014 (Sheldrick, 2015) was used to determine absolute configuration from anomalous scattering using the Flack method (Flack, 2003).

Computing details

Data collection: CrysAlis PRO (Agilent, 2012); cell refinement: CrysAlis PRO (Agilent, 2012); data reduction: CrysAlis PRO (Agilent, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures

	Fig. 1. View of the molecular structure of the title compound with 50% probability displacement ellipsoids for the non-hydrogen atoms.
	Fig. 2. Reaction scheme for the synthesis of nebivolol

(R)-6-Fluoro-2-[(S)-oxiran-2-yl]chroman

Crystal data

C11H11FO2	F(000) = 204
Mr = 194.20	Dx = 1.435 Mg m^−3
Monoclinic, P21	Cu Kα radiation, λ = 1.54184 Å
a = 9.3742 (3) Å	Cell parameters from 7897 reflections
b = 4.76845 (12) Å	θ = 4.4–76.3°
c = 11.0212 (3) Å	µ = 0.94 mm^−1
β = 114.202 (4)°	T = 100 K
V = 449.35 (3) Å^3	Needle, colourless
Z = 2	0.05 × 0.05 × 0.02 mm

Data collection

Agilent SuperNova Dual Source diffractometer with an Atlas detector	1847 independent reflections
Radiation source: SuperNova (Cu) X-ray Source	1820 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.050
Detector resolution: 5.2474 pixels mm^-1	θmax = 76.5°, θmin = 4.4°
CCD rotation images, thick slices scans	h = −11→11
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012)	k = −5→5
Tmin = 0.64, Tmax = 1	l = −13→13
14207 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.032	H-atom parameters constrained
wR(F^2) = 0.092	w = 1/[σ^2(Fo^2) + (0.0529P)^2 + 0.0952P] where P = (Fo^2 + 2Fc^2)/3
S = 1.10	(Δ/σ)max < 0.001
1847 reflections	Δρmax = 0.20 e Å^−3
128 parameters	Δρmin = −0.16 e Å^−3
1 restraint	Absolute structure: crystal refined as an inversion twin (Flack, 2003)
0 constraints	Absolute structure parameter: 0.0 (2)

Special details

Experimental. Analyzes were recorded in the "Pole Chimie Moleculaire", the technological platform for chemical analysis and molecular synthesis (http://www.wpcm.fr) which relies on the Institute of the Molecular Chemistry of University of Burgundy and Welience"TM", a Burgundy University private subsidiary.

¹H and ¹³C NMR measurements were performed in deuterated methanol on Bruker Avance III, recorded at 500 MHz and 125 MHz, respectively. Chemical shifts (δ) and coupling constants are reported respectively in p.p.m. and hertz (Hz). The optical rotation was measured using a UV Visible Perkin Elmer Lambda 12, polarimeter at 589 nm. High-resolution mass spectrometry (HRMS) was performed in ESI a positive mode. The infrared spectrum (IR) was generated by ATR using a Spectrometer Infrared Avatar 370. A scan range of 4000 - 400 cm^-1 was used.

(2S,2R)-(6-fluoro-2-chromanyl)oxirane:

δ(¹H, DMSO-d6, 300 MHz, ppm): 1.72 (1H, m); 2.00 (1H, m); 2.74 (2H, m); 2.82 (2H, m); 3.17 (1H, ddd); 3.94 (1H, ddd); 6.77 (1H, dd); 6.92 (2H, m).

δ(¹³C DMSO-d6, 75.47MHz, ppm): 23.4, 23.7, 44.5, 52.3, 75.3, 113.7 (d, 23.2 Hz), 115.2 (d, 22.3 Hz), 117.2 (d, 8.2 Hz), 123.5(d, 7.5 Hz), 150.1 (d, 1.5 Hz), 156.0(d, 234.8 Hz).

[α]²⁹_D +67.5^o (c =1.0 in CHCl₃)

HRMS (ESI) for C₁₈H₂₁FNO₂[M+H]⁺ m/z = 195.08158, found m/z = 195.08120.

IR (cm^-1) 3050, 3001, 2951, 1492, 1220

Data CCDC-1407326 contains the enantiomer structure of (S)-6-Fluoro-2-[(R)-oxiran-2-yl]chroman. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

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. Refined as a 2-component inversion twin.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.7376 (2)	0.5622 (5)	0.50701 (19)	0.0255 (4)
C6	0.8296 (2)	0.4711 (5)	0.4448 (2)	0.0254 (4)
H6	0.9095	0.3366	0.4870	0.030*
C5	0.8061 (2)	0.5754 (4)	0.32005 (19)	0.0226 (4)
C4	0.6872 (2)	0.7732 (4)	0.26151 (18)	0.0214 (4)
C3	0.5962 (2)	0.8655 (5)	0.3267 (2)	0.0255 (4)
H3	0.5165	1.0009	0.2857	0.031*
C2	0.6216 (2)	0.7604 (5)	0.4512 (2)	0.0261 (4)
H2	0.5608	0.8231	0.4968	0.031*
C7	0.9061 (2)	0.4801 (4)	0.24929 (19)	0.0253 (4)
H7A	0.8759	0.2868	0.2157	0.030*
H7B	1.0172	0.4770	0.3132	0.030*
C8	0.8876 (2)	0.6721 (5)	0.13380 (19)	0.0240 (4)
H8A	0.9306	0.5803	0.0755	0.029*
H8B	0.9458	0.8488	0.1678	0.029*
C9	0.7148 (2)	0.7350 (5)	0.05528 (19)	0.0235 (4)
H9	0.6568	0.5539	0.0267	0.028*
C10	0.6765 (2)	0.9185 (5)	−0.0645 (2)	0.0271 (4)
H10	0.5651	0.9814	−0.1082	0.033*
C11	0.7573 (2)	0.8967 (5)	−0.1530 (2)	0.0286 (5)
H11A	0.8377	0.7487	−0.1340	0.034*
H11B	0.6968	0.9384	−0.2485	0.034*
O1	0.65326 (15)	0.8871 (3)	0.13795 (13)	0.0246 (3)
O2	0.79031 (19)	1.1254 (4)	−0.06003 (15)	0.0329 (4)
F1	0.76157 (14)	0.4549 (3)	0.62882 (12)	0.0333 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0249 (9)	0.0259 (10)	0.0236 (9)	−0.0037 (8)	0.0079 (7)	−0.0017 (8)
C6	0.0206 (8)	0.0216 (10)	0.0299 (10)	0.0010 (7)	0.0064 (7)	0.0003 (8)
C5	0.0191 (8)	0.0202 (10)	0.0261 (9)	−0.0036 (8)	0.0070 (7)	−0.0049 (8)
C4	0.0185 (8)	0.0201 (10)	0.0238 (9)	−0.0035 (8)	0.0070 (7)	−0.0029 (8)
C3	0.0214 (9)	0.0265 (11)	0.0276 (9)	0.0035 (7)	0.0090 (7)	−0.0011 (8)
C2	0.0245 (9)	0.0274 (11)	0.0282 (10)	−0.0013 (8)	0.0128 (8)	−0.0051 (8)
C7	0.0224 (8)	0.0220 (10)	0.0303 (9)	0.0040 (8)	0.0097 (8)	−0.0013 (8)
C8	0.0180 (8)	0.0252 (10)	0.0288 (9)	0.0010 (7)	0.0096 (7)	−0.0042 (8)
C9	0.0201 (8)	0.0252 (11)	0.0266 (9)	0.0009 (7)	0.0109 (7)	−0.0042 (8)
C10	0.0225 (9)	0.0309 (11)	0.0273 (9)	0.0016 (8)	0.0096 (7)	−0.0015 (9)
C11	0.0272 (9)	0.0315 (11)	0.0286 (9)	−0.0033 (9)	0.0130 (8)	−0.0049 (9)
O1	0.0224 (6)	0.0275 (8)	0.0247 (6)	0.0066 (6)	0.0106 (5)	0.0019 (6)
O2	0.0442 (9)	0.0260 (9)	0.0323 (7)	−0.0047 (7)	0.0195 (6)	−0.0041 (6)
F1	0.0343 (6)	0.0384 (8)	0.0268 (6)	0.0030 (6)	0.0121 (5)	0.0062 (6)

Geometric parameters (Å, º)

C1—C6	1.374 (3)	C7—C8	1.519 (3)
C1—C2	1.381 (3)	C8—H8A	0.9900
C1—F1	1.366 (2)	C8—H8B	0.9900
C6—H6	0.9500	C8—C9	1.521 (2)
C6—C5	1.392 (3)	C9—H9	1.0000
C5—C4	1.399 (3)	C9—C10	1.500 (3)
C5—C7	1.514 (2)	C9—O1	1.456 (2)
C4—C3	1.393 (3)	C10—H10	1.0000
C4—O1	1.377 (2)	C10—C11	1.463 (3)
C3—H3	0.9500	C10—O2	1.439 (3)
C3—C2	1.387 (3)	C11—H11A	0.9900
C2—H2	0.9500	C11—H11B	0.9900
C7—H7A	0.9900	C11—O2	1.440 (3)
C7—H7B	0.9900
C6—C1—C2	122.35 (18)	C7—C8—H8B	109.9
F1—C1—C6	119.21 (18)	C7—C8—C9	108.92 (16)
F1—C1—C2	118.43 (17)	H8A—C8—H8B	108.3
C1—C6—H6	119.9	C9—C8—H8A	109.9
C1—C6—C5	120.12 (19)	C9—C8—H8B	109.9
C5—C6—H6	119.9	C8—C9—H9	108.9
C6—C5—C4	118.06 (17)	C10—C9—C8	115.48 (16)
C6—C5—C7	121.35 (18)	C10—C9—H9	108.9
C4—C5—C7	120.59 (17)	O1—C9—C8	110.18 (15)
C3—C4—C5	121.04 (18)	O1—C9—H9	108.9
O1—C4—C5	122.66 (16)	O1—C9—C10	104.31 (16)
O1—C4—C3	116.30 (17)	C9—C10—H10	115.1
C4—C3—H3	119.9	C11—C10—C9	122.88 (19)
C2—C3—C4	120.19 (19)	C11—C10—H10	115.1
C2—C3—H3	119.9	O2—C10—C9	117.62 (16)
C1—C2—C3	118.22 (17)	O2—C10—H10	115.1
C1—C2—H2	120.9	O2—C10—C11	59.51 (13)
C3—C2—H2	120.9	C10—C11—H11A	117.8
C5—C7—H7A	109.3	C10—C11—H11B	117.8
C5—C7—H7B	109.3	H11A—C11—H11B	115.0
C5—C7—C8	111.62 (16)	O2—C11—C10	59.42 (13)
H7A—C7—H7B	108.0	O2—C11—H11A	117.8
C8—C7—H7A	109.3	O2—C11—H11B	117.8
C8—C7—H7B	109.3	C4—O1—C9	115.60 (15)
C7—C8—H8A	109.9	C10—O2—C11	61.08 (13)
C1—C6—C5—C4	0.0 (3)	C7—C5—C4—O1	1.0 (3)
C1—C6—C5—C7	179.71 (17)	C7—C8—C9—C10	−178.77 (17)
C6—C1—C2—C3	1.3 (3)	C7—C8—C9—O1	63.4 (2)
C6—C5—C4—C3	0.7 (3)	C8—C9—C10—C11	38.9 (3)
C6—C5—C4—O1	−179.29 (18)	C8—C9—C10—O2	−31.0 (3)
C6—C5—C7—C8	−165.51 (18)	C8—C9—O1—C4	−49.5 (2)
C5—C4—C3—C2	−0.4 (3)	C9—C10—C11—O2	−105.1 (2)
C5—C4—O1—C9	17.2 (2)	C9—C10—O2—C11	113.8 (2)
C5—C7—C8—C9	−44.7 (2)	C10—C9—O1—C4	−174.00 (14)
C4—C5—C7—C8	14.2 (2)	O1—C4—C3—C2	179.56 (17)
C4—C3—C2—C1	−0.5 (3)	O1—C9—C10—C11	159.93 (19)
C3—C4—O1—C9	−162.78 (17)	O1—C9—C10—O2	90.0 (2)
C2—C1—C6—C5	−1.0 (3)	F1—C1—C6—C5	179.30 (18)
C7—C5—C4—C3	−178.99 (18)	F1—C1—C2—C3	−179.04 (19)