Methyl 3-(cyclo­propyl­meth­oxy)-4-hy­droxy­benzoate

Hou, J.-J.; Cheng, X.-C.; Wang, R.-L.; Wang, S.-Q.

doi:10.1107/S1600536810026826

organic compounds

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ISSN: 2056-9890

Volume 66| Part 8| August 2010| Page o2004

https://doi.org/10.1107/S1600536810026826

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ADDENDA AND ERRATA

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Methyl 3-(cyclopropylmethoxy)-4-hydroxybenzoate

Jing-Jing Hou,^a Xian-Chao Cheng,^a Run-Ling Wang ^a ^* and Shu-Qing Wang ^a

^aSchool of Pharmacy, Tianjin Medical University, Tianjin 300070, People's Republic of China
^*Correspondence e-mail: wangrunling2008@yahoo.cn

(Received 4 July 2010; accepted 7 July 2010; online 14 July 2010)

In the title compound, C₁₂H₁₄O₄, the dihedral angle between the benzene ring and the cyclopropyl ring is 60.3 (4)°. In the crystal structure, molecules are linked by intermolecular O—H⋯O hydrogen bonds into chains running parallel to [101].

Related literature

For bond-length and angle data for related structures, see: Bradley et al. (1992 ); Fifer & White (2005 ). During the development of PDE4 (phosphodiesterase-4) inhibitors, roflumilast was synthesized as the positive control in the bioactivity screening and the title compound was prepared as an intermediate. For the synthesis of roflumilast, see: Bose et al. (2005 ).

Experimental

Crystal data

C₁₂H₁₄O₄
M_r = 222.23
Monoclinic, P 2₁ /n
a = 9.2326 (18) Å
b = 7.4747 (15) Å
c = 16.105 (3) Å
β = 102.22 (3)°
V = 1086.3 (4) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 113 K
0.24 × 0.22 × 0.12 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer
Absorption correction: multi-scan (CrystalClear; Rigaku, 2005 ) T_min = 0.976, T_max = 0.988
7033 measured reflections
1904 independent reflections
1614 reflections with I > 2σ(I)
R_int = 0.031

Refinement

R[F² > 2σ(F²)] = 0.036
wR(F²) = 0.100
S = 1.06
1904 reflections
148 parameters
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O1ⁱ	0.84	2.00	2.7808 (14)	153
Symmetry code: (i) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

Data collection: CrystalClear (Rigaku, 2005); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S1600536810026826/rz2473sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536810026826/rz2473Isup2.hkl

checkCIF report

Comment top

Roflumilast is an effective phosphodiesterase-4 inhibitor (PDE4 inhibitor), which can be used in the treatment of asthma, inflammation, bronchitis, allergy and other disorders related to immune system, heart and kidney. During the development of our own PDE4 inhibitors, roflumilast was synthesized as the positive control in the bioactivity screening, and the title compound, methyl 3-(cyclopropylmethoxy)-4-hydroxybenzoate, was prepared as an intermediate. The crystallographic analysis of the title compound described herein further confirms the phenolic hydroxyl substituted position of the title compound.

In title compound (Fig. 1), bond lengths and angles are normal and in a good agreement with those reported previously (Bradley et al., 1992; Fifer & White, 2005). Atoms O1—O4/C1—C8 are coplanar, with a maximum displacement of 0.028 (3) Å for atom O4. The dihedral angle between the benzene ring (C3—C8) and cyclopropyl ring (C10—C12) is 60.3 (4)°. In the crystal structure, molecules interact through intermolecular O—H···O hydrogen bonds (Table 1) to form chains running parallel to the [101] direction.

Related literature top

For bond-length and angle data for related structures, see: Bradley et al. (1992); Fifer & White (2005). During the development of PDE4 (phosphodiesterase-4) inhibitors, roflumilast was synthesized as the positive control in the bioactivity screening and the title compound was prepared as an intermediate. For the synthesis of roflumilast, see: Bose et al. (2005).

Experimental top

A solution of 3,4-dihydroxymethyl benzoate (1.68 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) in acetone (50 ml) was added to a solution of cyclopropylmethyl bromide (1.35 g, 10 mmol) in acetone (50 ml). The reaction mixture was stirred at 40 ° C for 18 h, and then was filtered. The filtrate was evaporated in a rotary evaporator to get the dried crude product. Pure title compound (0.43 g, 18% yield) was obtained by flash column chromatography (Bose et al., 2005). Crystals suitable for X-ray diffraction were obtained through slow evaporation of a solution of the pure title compound in ethyl acetate/n-hexane (1:10 v/v).

Structure description top

For bond-length and angle data for related structures, see: Bradley et al. (1992); Fifer & White (2005). During the development of PDE4 (phosphodiesterase-4) inhibitors, roflumilast was synthesized as the positive control in the bioactivity screening and the title compound was prepared as an intermediate. For the synthesis of roflumilast, see: Bose et al. (2005).

Computing details top

Data collection: CrystalClear (Rigaku, 2005); cell refinement: CrystalClear (Rigaku, 2005); data reduction: CrystalClear (Rigaku, 2005); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

Fig. 1. The molecular structure of the title compound, with displacement ellipsoids drawn at the 40% probability level.

Methyl 3-(cyclopropylmethoxy)-4-hydroxybenzoate top

Crystal data top

C₁₂H₁₄O₄	F(000) = 472
M_r = 222.23	D_x = 1.359 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 3285 reflections
a = 9.2326 (18) Å	θ = 2.4–27.9°
b = 7.4747 (15) Å	µ = 0.10 mm⁻¹
c = 16.105 (3) Å	T = 113 K
β = 102.22 (3)°	Block, colourless
V = 1086.3 (4) Å³	0.24 × 0.22 × 0.12 mm
Z = 4

Data collection top

Rigaku Saturn CCD area-detector diffractometer	1904 independent reflections
Radiation source: rotating anode	1614 reflections with I > 2σ(I)
Confocal monochromator	R_int = 0.031
Detector resolution: 7.31 pixels mm^-1	θ_max = 25.0°, θ_min = 2.4°
ω and φ scans	h = −10→10
Absorption correction: multi-scan (CrystalClear; Rigaku, 2005)	k = −8→8
T_min = 0.976, T_max = 0.988	l = −14→19
7033 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.036	H-atom parameters constrained
wR(F²) = 0.100	w = 1/[σ²(F_o²) + (0.070P)²] where P = (F_o² + 2F_c²)/3
S = 1.06	(Δ/σ)_max = 0.001
1904 reflections	Δρ_max = 0.27 e Å⁻³
148 parameters	Δρ_min = −0.18 e Å⁻³
0 restraints	Extinction correction: SHELXTL (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.137 (12)

Crystal data top

C₁₂H₁₄O₄	V = 1086.3 (4) Å³
M_r = 222.23	Z = 4
Monoclinic, P2₁/n	Mo Kα radiation
a = 9.2326 (18) Å	µ = 0.10 mm⁻¹
b = 7.4747 (15) Å	T = 113 K
c = 16.105 (3) Å	0.24 × 0.22 × 0.12 mm
β = 102.22 (3)°

Data collection top

Rigaku Saturn CCD area-detector diffractometer	1904 independent reflections
Absorption correction: multi-scan (CrystalClear; Rigaku, 2005)	1614 reflections with I > 2σ(I)
T_min = 0.976, T_max = 0.988	R_int = 0.031
7033 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.036	0 restraints
wR(F²) = 0.100	H-atom parameters constrained
S = 1.06	Δρ_max = 0.27 e Å⁻³
1904 reflections	Δρ_min = −0.18 e Å⁻³
148 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
O1	1.20469 (11)	0.31399 (12)	0.41048 (5)	0.0325 (3)
O2	1.30178 (9)	0.17490 (11)	0.31110 (5)	0.0271 (3)
O3	0.89725 (9)	0.09184 (11)	0.06138 (5)	0.0239 (3)
H3	0.8217	0.1289	0.0271	0.036*
O4	0.65026 (9)	0.22515 (10)	0.10058 (5)	0.0201 (3)
C1	1.44532 (14)	0.17415 (17)	0.36957 (8)	0.0298 (3)
H1A	1.4785	0.2976	0.3822	0.045*
H1B	1.5174	0.1108	0.3436	0.045*
H1C	1.4368	0.1136	0.4223	0.045*
C2	1.19019 (14)	0.24965 (14)	0.33996 (8)	0.0216 (3)
C3	1.04746 (14)	0.24370 (13)	0.27724 (7)	0.0192 (3)
C4	1.03704 (13)	0.16800 (14)	0.19666 (7)	0.0186 (3)
H4	1.1222	0.1169	0.1817	0.022*
C5	0.90327 (13)	0.16755 (13)	0.13899 (7)	0.0170 (3)
C6	0.77661 (13)	0.23945 (13)	0.16152 (7)	0.0175 (3)
C7	0.78714 (14)	0.31575 (15)	0.24153 (7)	0.0211 (3)
H7	0.7020	0.3661	0.2568	0.025*
C8	0.92302 (14)	0.31775 (15)	0.29883 (8)	0.0217 (3)
H8	0.9305	0.3704	0.3533	0.026*
C9	0.51186 (13)	0.27000 (15)	0.12305 (7)	0.0215 (3)
H9A	0.5102	0.3987	0.1374	0.026*
H9B	0.4996	0.1998	0.1732	0.026*
C10	0.38989 (13)	0.22846 (15)	0.04938 (7)	0.0213 (3)
H10	0.3932	0.1075	0.0233	0.026*
C11	0.32129 (13)	0.37525 (17)	−0.00999 (8)	0.0274 (3)
H11A	0.3624	0.4974	0.0009	0.033*
H11B	0.2860	0.3447	−0.0707	0.033*
C12	0.23882 (13)	0.29816 (16)	0.05244 (8)	0.0241 (3)
H12A	0.1526	0.2203	0.0301	0.029*
H12B	0.2291	0.3730	0.1017	0.029*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0332 (6)	0.0402 (5)	0.0194 (5)	−0.0017 (4)	−0.0049 (4)	−0.0076 (4)
O2	0.0191 (5)	0.0353 (5)	0.0232 (5)	−0.0006 (3)	−0.0039 (4)	−0.0021 (4)
O3	0.0193 (5)	0.0356 (5)	0.0146 (4)	0.0066 (3)	−0.0014 (3)	−0.0044 (4)
O4	0.0138 (5)	0.0270 (5)	0.0183 (4)	0.0017 (3)	0.0006 (3)	−0.0009 (3)
C1	0.0184 (7)	0.0340 (7)	0.0312 (7)	−0.0028 (5)	−0.0080 (6)	0.0015 (6)
C2	0.0234 (7)	0.0186 (6)	0.0203 (6)	−0.0035 (4)	−0.0006 (5)	0.0027 (5)
C3	0.0224 (7)	0.0165 (6)	0.0166 (6)	−0.0030 (4)	−0.0003 (5)	0.0020 (4)
C4	0.0177 (6)	0.0190 (6)	0.0189 (6)	0.0004 (4)	0.0034 (5)	0.0012 (5)
C5	0.0205 (6)	0.0164 (6)	0.0132 (6)	−0.0008 (4)	0.0016 (5)	0.0002 (4)
C6	0.0178 (6)	0.0163 (6)	0.0172 (6)	−0.0011 (4)	0.0008 (5)	0.0031 (4)
C7	0.0208 (7)	0.0206 (6)	0.0223 (6)	0.0002 (5)	0.0058 (5)	−0.0016 (5)
C8	0.0272 (7)	0.0204 (6)	0.0168 (6)	−0.0031 (5)	0.0029 (5)	−0.0024 (5)
C9	0.0172 (7)	0.0242 (6)	0.0235 (6)	0.0031 (4)	0.0054 (5)	0.0004 (5)
C10	0.0163 (7)	0.0237 (6)	0.0233 (6)	0.0012 (4)	0.0031 (5)	−0.0016 (5)
C11	0.0205 (7)	0.0353 (7)	0.0259 (7)	0.0040 (5)	0.0041 (5)	0.0060 (5)
C12	0.0165 (7)	0.0284 (6)	0.0271 (7)	0.0005 (5)	0.0041 (5)	0.0007 (5)

Geometric parameters (Å, º) top

O1—C2	1.2144 (14)	C6—C7	1.3936 (17)
O2—C2	1.3389 (15)	C7—C8	1.3913 (18)
O2—C1	1.4541 (14)	C7—H7	0.9500
O3—C5	1.3625 (13)	C8—H8	0.9500
O3—H3	0.8400	C9—C10	1.4855 (16)
O4—C6	1.3604 (14)	C9—H9A	0.9900
O4—C9	1.4394 (15)	C9—H9B	0.9900
C1—H1A	0.9800	C10—C12	1.4993 (17)
C1—H1B	0.9800	C10—C11	1.5043 (16)
C1—H1C	0.9800	C10—H10	1.0000
C2—C3	1.4816 (16)	C11—C12	1.4988 (17)
C3—C8	1.3845 (18)	C11—H11A	0.9900
C3—C4	1.4002 (16)	C11—H11B	0.9900
C4—C5	1.3792 (16)	C12—H12A	0.9900
C4—H4	0.9500	C12—H12B	0.9900
C5—C6	1.4028 (17)

C2—O2—C1	116.08 (9)	C3—C8—C7	120.58 (11)
C5—O3—H3	109.5	C3—C8—H8	119.7
C6—O4—C9	118.13 (9)	C7—C8—H8	119.7
O2—C1—H1A	109.5	O4—C9—C10	108.28 (9)
O2—C1—H1B	109.5	O4—C9—H9A	110.0
H1A—C1—H1B	109.5	C10—C9—H9A	110.0
O2—C1—H1C	109.5	O4—C9—H9B	110.0
H1A—C1—H1C	109.5	C10—C9—H9B	110.0
H1B—C1—H1C	109.5	H9A—C9—H9B	108.4
O1—C2—O2	123.32 (11)	C9—C10—C12	117.02 (10)
O1—C2—C3	123.75 (12)	C9—C10—C11	120.08 (10)
O2—C2—C3	112.92 (10)	C12—C10—C11	59.87 (8)
C8—C3—C4	119.77 (11)	C9—C10—H10	116.0
C8—C3—C2	118.84 (10)	C12—C10—H10	116.0
C4—C3—C2	121.38 (12)	C11—C10—H10	116.0
C5—C4—C3	120.08 (12)	C12—C11—C10	59.90 (8)
C5—C4—H4	120.0	C12—C11—H11A	117.8
C3—C4—H4	120.0	C10—C11—H11A	117.8
O3—C5—C4	118.40 (11)	C12—C11—H11B	117.8
O3—C5—C6	121.48 (10)	C10—C11—H11B	117.8
C4—C5—C6	120.10 (10)	H11A—C11—H11B	114.9
O4—C6—C7	125.49 (11)	C11—C12—C10	60.23 (8)
O4—C6—C5	114.69 (10)	C11—C12—H12A	117.7
C7—C6—C5	119.81 (11)	C10—C12—H12A	117.7
C8—C7—C6	119.63 (12)	C11—C12—H12B	117.7
C8—C7—H7	120.2	C10—C12—H12B	117.7
C6—C7—H7	120.2	H12A—C12—H12B	114.9

C1—O2—C2—O1	−0.02 (15)	C4—C5—C6—O4	−177.57 (9)
C1—O2—C2—C3	−179.41 (9)	O3—C5—C6—C7	179.98 (10)
O1—C2—C3—C8	1.07 (16)	C4—C5—C6—C7	1.75 (15)
O2—C2—C3—C8	−179.54 (9)	O4—C6—C7—C8	178.38 (9)
O1—C2—C3—C4	179.92 (10)	C5—C6—C7—C8	−0.86 (16)
O2—C2—C3—C4	−0.69 (14)	C4—C3—C8—C7	0.76 (16)
C8—C3—C4—C5	0.13 (16)	C2—C3—C8—C7	179.63 (10)
C2—C3—C4—C5	−178.71 (9)	C6—C7—C8—C3	−0.39 (16)
C3—C4—C5—O3	−179.66 (9)	C6—O4—C9—C10	−174.90 (9)
C3—C4—C5—C6	−1.38 (15)	O4—C9—C10—C12	−168.23 (9)
C9—O4—C6—C7	−8.73 (15)	O4—C9—C10—C11	−99.07 (12)
C9—O4—C6—C5	170.55 (9)	C9—C10—C11—C12	−105.72 (12)
O3—C5—C6—O4	0.66 (14)	C9—C10—C12—C11	110.76 (12)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O1ⁱ	0.84	2.00	2.7808 (14)	153

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

Experimental details

Crystal data
Chemical formula	C₁₂H₁₄O₄
M_r	222.23
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	113
a, b, c (Å)	9.2326 (18), 7.4747 (15), 16.105 (3)
β (°)	102.22 (3)
V (Å³)	1086.3 (4)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.10
Crystal size (mm)	0.24 × 0.22 × 0.12

Data collection
Diffractometer	Rigaku Saturn CCD area-detector
Absorption correction	Multi-scan (CrystalClear; Rigaku, 2005)
T_min, T_max	0.976, 0.988
No. of measured, independent and observed [I > 2σ(I)] reflections	7033, 1904, 1614
R_int	0.031
(sin θ/λ)_max (Å⁻¹)	0.595

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.036, 0.100, 1.06
No. of reflections	1904
No. of parameters	148
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.27, −0.18

Computer programs: CrystalClear (Rigaku, 2005), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O1ⁱ	0.84	2.00	2.7808 (14)	153.4

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

Acknowledgements

This research was supported by the National Natural Science Foundation of China (20972112), the Key Program of Tianjin Natural Science Foundation (09JCZDJC21600), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20091202110010) and the Tianjin Medical University Science Foundation (2009ky16).

References

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