organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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Methyl 3-(cyclo­propyl­meth­­oxy)-4-hy­dr­oxy­benzoate

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[Bradley, G., Ward, T. J., White, J. C., Coleman, J., Taylor, A. & Rhodes, K. F. (1992). J. Med. Chem. 35, 1515-1520.]); Fifer & White (2005[Fifer, N. L. & White, J. M. (2005). Org. Biomol. Chem. 3, 1776-1780.]). 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[Bose, P., Sachdeva, Y. P., Rathore, R. S. & Kumar, Y. (2005). Patent WO 2005/026095 A1.]).

[Scheme 1]

Experimental

Crystal data
  • C12H14O4

  • Mr = 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[Rigaku. (2005). CrystalClear. Rigaku Corporation, Tokyo, Japan.]) Tmin = 0.976, Tmax = 0.988

  • 7033 measured reflections

  • 1904 independent reflections

  • 1614 reflections with I > 2σ(I)

  • Rint = 0.031

Refinement
  • R[F2 > 2σ(F2)] = 0.036

  • wR(F2) = 0.100

  • S = 1.06

  • 1904 reflections

  • 148 parameters

  • H-atom parameters constrained

  • Δρmax = 0.27 e Å−3

  • Δρmin = −0.18 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA 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[Rigaku. (2005). CrystalClear. Rigaku Corporation, Tokyo, Japan.]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information


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).

Refinement top

All H atoms were found on difference maps and included in the final cycles of refinement using a riding model, with C—H = 0.95–1.00 Å, O—H = 0.84 Å, and with Uiso(H) = 1.2Ueq(C) for aryl and methylene H atoms and 1.5Ueq(C, O) for the methyl and hydroxy H atoms.

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
[Figure 1] 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
C12H14O4F(000) = 472
Mr = 222.23Dx = 1.359 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ynCell parameters from 3285 reflections
a = 9.2326 (18) Åθ = 2.4–27.9°
b = 7.4747 (15) ŵ = 0.10 mm1
c = 16.105 (3) ÅT = 113 K
β = 102.22 (3)°Block, colourless
V = 1086.3 (4) Å30.24 × 0.22 × 0.12 mm
Z = 4
Data collection top
Rigaku Saturn CCD area-detector
diffractometer
1904 independent reflections
Radiation source: rotating anode1614 reflections with I > 2σ(I)
Confocal monochromatorRint = 0.031
Detector resolution: 7.31 pixels mm-1θmax = 25.0°, θmin = 2.4°
ω and ϕ scansh = 1010
Absorption correction: multi-scan
(CrystalClear; Rigaku, 2005)
k = 88
Tmin = 0.976, Tmax = 0.988l = 1419
7033 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.036H-atom parameters constrained
wR(F2) = 0.100 w = 1/[σ2(Fo2) + (0.070P)2]
where P = (Fo2 + 2Fc2)/3
S = 1.06(Δ/σ)max = 0.001
1904 reflectionsΔρmax = 0.27 e Å3
148 parametersΔρmin = 0.18 e Å3
0 restraintsExtinction correction: SHELXTL (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.137 (12)
Crystal data top
C12H14O4V = 1086.3 (4) Å3
Mr = 222.23Z = 4
Monoclinic, P21/nMo Kα radiation
a = 9.2326 (18) ŵ = 0.10 mm1
b = 7.4747 (15) ÅT = 113 K
c = 16.105 (3) Å0.24 × 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)
Tmin = 0.976, Tmax = 0.988Rint = 0.031
7033 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0360 restraints
wR(F2) = 0.100H-atom parameters constrained
S = 1.06Δρmax = 0.27 e Å3
1904 reflectionsΔρmin = 0.18 e Å3
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
xyzUiso*/Ueq
O11.20469 (11)0.31399 (12)0.41048 (5)0.0325 (3)
O21.30178 (9)0.17490 (11)0.31110 (5)0.0271 (3)
O30.89725 (9)0.09184 (11)0.06138 (5)0.0239 (3)
H30.82170.12890.02710.036*
O40.65026 (9)0.22515 (10)0.10058 (5)0.0201 (3)
C11.44532 (14)0.17415 (17)0.36957 (8)0.0298 (3)
H1A1.47850.29760.38220.045*
H1B1.51740.11080.34360.045*
H1C1.43680.11360.42230.045*
C21.19019 (14)0.24965 (14)0.33996 (8)0.0216 (3)
C31.04746 (14)0.24370 (13)0.27724 (7)0.0192 (3)
C41.03704 (13)0.16800 (14)0.19666 (7)0.0186 (3)
H41.12220.11690.18170.022*
C50.90327 (13)0.16755 (13)0.13899 (7)0.0170 (3)
C60.77661 (13)0.23945 (13)0.16152 (7)0.0175 (3)
C70.78714 (14)0.31575 (15)0.24153 (7)0.0211 (3)
H70.70200.36610.25680.025*
C80.92302 (14)0.31775 (15)0.29883 (8)0.0217 (3)
H80.93050.37040.35330.026*
C90.51186 (13)0.27000 (15)0.12305 (7)0.0215 (3)
H9A0.51020.39870.13740.026*
H9B0.49960.19980.17320.026*
C100.38989 (13)0.22846 (15)0.04938 (7)0.0213 (3)
H100.39320.10750.02330.026*
C110.32129 (13)0.37525 (17)0.00999 (8)0.0274 (3)
H11A0.36240.49740.00090.033*
H11B0.28600.34470.07070.033*
C120.23882 (13)0.29816 (16)0.05244 (8)0.0241 (3)
H12A0.15260.22030.03010.029*
H12B0.22910.37300.10170.029*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0332 (6)0.0402 (5)0.0194 (5)0.0017 (4)0.0049 (4)0.0076 (4)
O20.0191 (5)0.0353 (5)0.0232 (5)0.0006 (3)0.0039 (4)0.0021 (4)
O30.0193 (5)0.0356 (5)0.0146 (4)0.0066 (3)0.0014 (3)0.0044 (4)
O40.0138 (5)0.0270 (5)0.0183 (4)0.0017 (3)0.0006 (3)0.0009 (3)
C10.0184 (7)0.0340 (7)0.0312 (7)0.0028 (5)0.0080 (6)0.0015 (6)
C20.0234 (7)0.0186 (6)0.0203 (6)0.0035 (4)0.0006 (5)0.0027 (5)
C30.0224 (7)0.0165 (6)0.0166 (6)0.0030 (4)0.0003 (5)0.0020 (4)
C40.0177 (6)0.0190 (6)0.0189 (6)0.0004 (4)0.0034 (5)0.0012 (5)
C50.0205 (6)0.0164 (6)0.0132 (6)0.0008 (4)0.0016 (5)0.0002 (4)
C60.0178 (6)0.0163 (6)0.0172 (6)0.0011 (4)0.0008 (5)0.0031 (4)
C70.0208 (7)0.0206 (6)0.0223 (6)0.0002 (5)0.0058 (5)0.0016 (5)
C80.0272 (7)0.0204 (6)0.0168 (6)0.0031 (5)0.0029 (5)0.0024 (5)
C90.0172 (7)0.0242 (6)0.0235 (6)0.0031 (4)0.0054 (5)0.0004 (5)
C100.0163 (7)0.0237 (6)0.0233 (6)0.0012 (4)0.0031 (5)0.0016 (5)
C110.0205 (7)0.0353 (7)0.0259 (7)0.0040 (5)0.0041 (5)0.0060 (5)
C120.0165 (7)0.0284 (6)0.0271 (7)0.0005 (5)0.0041 (5)0.0007 (5)
Geometric parameters (Å, º) top
O1—C21.2144 (14)C6—C71.3936 (17)
O2—C21.3389 (15)C7—C81.3913 (18)
O2—C11.4541 (14)C7—H70.9500
O3—C51.3625 (13)C8—H80.9500
O3—H30.8400C9—C101.4855 (16)
O4—C61.3604 (14)C9—H9A0.9900
O4—C91.4394 (15)C9—H9B0.9900
C1—H1A0.9800C10—C121.4993 (17)
C1—H1B0.9800C10—C111.5043 (16)
C1—H1C0.9800C10—H101.0000
C2—C31.4816 (16)C11—C121.4988 (17)
C3—C81.3845 (18)C11—H11A0.9900
C3—C41.4002 (16)C11—H11B0.9900
C4—C51.3792 (16)C12—H12A0.9900
C4—H40.9500C12—H12B0.9900
C5—C61.4028 (17)
C2—O2—C1116.08 (9)C3—C8—C7120.58 (11)
C5—O3—H3109.5C3—C8—H8119.7
C6—O4—C9118.13 (9)C7—C8—H8119.7
O2—C1—H1A109.5O4—C9—C10108.28 (9)
O2—C1—H1B109.5O4—C9—H9A110.0
H1A—C1—H1B109.5C10—C9—H9A110.0
O2—C1—H1C109.5O4—C9—H9B110.0
H1A—C1—H1C109.5C10—C9—H9B110.0
H1B—C1—H1C109.5H9A—C9—H9B108.4
O1—C2—O2123.32 (11)C9—C10—C12117.02 (10)
O1—C2—C3123.75 (12)C9—C10—C11120.08 (10)
O2—C2—C3112.92 (10)C12—C10—C1159.87 (8)
C8—C3—C4119.77 (11)C9—C10—H10116.0
C8—C3—C2118.84 (10)C12—C10—H10116.0
C4—C3—C2121.38 (12)C11—C10—H10116.0
C5—C4—C3120.08 (12)C12—C11—C1059.90 (8)
C5—C4—H4120.0C12—C11—H11A117.8
C3—C4—H4120.0C10—C11—H11A117.8
O3—C5—C4118.40 (11)C12—C11—H11B117.8
O3—C5—C6121.48 (10)C10—C11—H11B117.8
C4—C5—C6120.10 (10)H11A—C11—H11B114.9
O4—C6—C7125.49 (11)C11—C12—C1060.23 (8)
O4—C6—C5114.69 (10)C11—C12—H12A117.7
C7—C6—C5119.81 (11)C10—C12—H12A117.7
C8—C7—C6119.63 (12)C11—C12—H12B117.7
C8—C7—H7120.2C10—C12—H12B117.7
C6—C7—H7120.2H12A—C12—H12B114.9
C1—O2—C2—O10.02 (15)C4—C5—C6—O4177.57 (9)
C1—O2—C2—C3179.41 (9)O3—C5—C6—C7179.98 (10)
O1—C2—C3—C81.07 (16)C4—C5—C6—C71.75 (15)
O2—C2—C3—C8179.54 (9)O4—C6—C7—C8178.38 (9)
O1—C2—C3—C4179.92 (10)C5—C6—C7—C80.86 (16)
O2—C2—C3—C40.69 (14)C4—C3—C8—C70.76 (16)
C8—C3—C4—C50.13 (16)C2—C3—C8—C7179.63 (10)
C2—C3—C4—C5178.71 (9)C6—C7—C8—C30.39 (16)
C3—C4—C5—O3179.66 (9)C6—O4—C9—C10174.90 (9)
C3—C4—C5—C61.38 (15)O4—C9—C10—C12168.23 (9)
C9—O4—C6—C78.73 (15)O4—C9—C10—C1199.07 (12)
C9—O4—C6—C5170.55 (9)C9—C10—C11—C12105.72 (12)
O3—C5—C6—O40.66 (14)C9—C10—C12—C11110.76 (12)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3—H3···O1i0.842.002.7808 (14)153
Symmetry code: (i) x1/2, y+1/2, z1/2.

Experimental details

Crystal data
Chemical formulaC12H14O4
Mr222.23
Crystal system, space groupMonoclinic, P21/n
Temperature (K)113
a, b, c (Å)9.2326 (18), 7.4747 (15), 16.105 (3)
β (°) 102.22 (3)
V3)1086.3 (4)
Z4
Radiation typeMo Kα
µ (mm1)0.10
Crystal size (mm)0.24 × 0.22 × 0.12
Data collection
DiffractometerRigaku Saturn CCD area-detector
diffractometer
Absorption correctionMulti-scan
(CrystalClear; Rigaku, 2005)
Tmin, Tmax0.976, 0.988
No. of measured, independent and
observed [I > 2σ(I)] reflections
7033, 1904, 1614
Rint0.031
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.036, 0.100, 1.06
No. of reflections1904
No. of parameters148
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.27, 0.18

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

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3—H3···O1i0.842.002.7808 (14)153.4
Symmetry code: (i) x1/2, y+1/2, z1/2.
 

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

First citationBose, P., Sachdeva, Y. P., Rathore, R. S. & Kumar, Y. (2005). Patent WO 2005/026095 A1.
First citationBradley, G., Ward, T. J., White, J. C., Coleman, J., Taylor, A. & Rhodes, K. F. (1992). J. Med. Chem. 35, 1515–1520.  CSD CrossRef PubMed CAS Web of Science
First citationFifer, N. L. & White, J. M. (2005). Org. Biomol. Chem. 3, 1776–1780.  Web of Science CSD CrossRef PubMed CAS
First citationRigaku. (2005). CrystalClear. Rigaku Corporation, Tokyo, Japan.
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals

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