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Acta Crystallogr Sect E Struct Rep Online. 2008 May 1; 64(Pt 5): o800.
Published online 2008 April 4. doi:  10.1107/S1600536808008593
PMCID: PMC2961281

(3S,4R)-4-(4-Fluoro­phen­yl)-3-(hydroxy­meth­yl)piperidinium chloride1

Abstract

The title compound, C12H17FNO+·Cl, is a degradation impurity of paroxetine hydro­chloride hemihydrate (PAXIL), an anti­depressant belonging to the group of drugs called selective serotonin reuptake inhibitors (SSRIs). Similar to the paroxetine hydro­chloride salt with protonation having taken place on the basic piperidine ring, the degradation impurity also exists as the hydro­chloride salt. The cyclic six-membered piperidinium ring adopts a chair conformation with the hydroxy­methyl and 4-fluoro­phenyl groups in the equatorial positions. The ions form a tape along the b axis through charge-assisted N+—H(...)Cl hydrogen bonds; these tapes are connected by O—H(...)Cl hydrogen bonds along the a axis.

Related literature

For related literature, see: Bower et al. (2007 [triangle]); de Gonzalo et al. (2001 [triangle]); Barnes et al. (1988 [triangle]); Ibers (1999 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-0o800-scheme1.jpg

Experimental

Crystal data

  • C12H17FNO+·Cl
  • M r = 245.72
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-0o800-efi1.jpg
  • a = 7.697 (4) Å
  • b = 5.958 (3) Å
  • c = 13.393 (8) Å
  • β = 95.505 (5)°
  • V = 611.4 (6) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.30 mm−1
  • T = 298 K
  • 0.50 × 0.40 × 0.20 mm

Data collection

  • Rigaku Mercury diffractometer
  • Absorption correction: multi-scan (Jacobson, 1998 [triangle]) T min = 0.863, T max = 0.939
  • 6813 measured reflections
  • 2421 independent reflections
  • 2163 reflections with F 2 > 2σ(F 2)
  • R int = 0.036

Refinement

  • R[F 2 > 2σ(F 2)] = 0.065
  • wR(F 2) = 0.203
  • S = 1.13
  • 2421 reflections
  • 158 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.54 e Å−3
  • Δρmin = −0.37 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 938 Friedel Pairs
  • Flack parameter: −0.11 (13)

Data collection: CrystalClear (Pflugrath, 1999 [triangle]); cell refinement: CrystalClear; data reduction: CrystalStructure (Rigaku/MSC, 2006 [triangle]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: X-SEED (Barbour, 2001 [triangle]); software used to prepare material for publication: CrystalStructure.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808008593/tk2259sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808008593/tk2259Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

We are grateful to Dr Reddy’s Discovery Research for encouragement. We thank Dr Vijay Vittal Mathad and Mr Naveen Kumar Kolla for providing the sample of paroxetine hydrochloride hemihydrate, and Dr Vyas for valuable suggestions.

supplementary crystallographic information

Comment

The title compound (I), is a degradation impurity of paroxetine hydrochloride hemihydrate, an orally administered psychotropic drug (PAXIL) (Barnes et al., 1988). The crystal structure of paroxetine hydrochloride hemihydrate has been reported (Ibers, 1999). Herein, we report the synthesis and crystal structure of (I).

Compound (I) was isolated during degradation studies of paroxetine hydrochloride hemihydrate. The paroxetine drug is available in the market as hemihydrate. However, compound (I) is in the anhydrous form, Fig. 1. Similar to the paroxetine hydrochloride salt with protonation having taken place on the basic piperidine ring, the degradation impurity also exists as a hydrochloride salt. The absolute configurations of C7 and C8 atoms were established as R and S, respectively, consistent with paroxetine hydrochloride hemihydrate. The six-membered piperidinium ring is in the usual chair conformation with the hydroxylmethyl and 4-fluorophenyl in equatorial positions. The crystal packing shows the formation of a molecular tape along the b axis through the charge-assisted N+—H···Cl hydrogen bonds (Fig. 2 and Table 1). The tapes thus formed are connected by O—H···Cl- hydrogen bonds along the a axis.

Experimental

Paroxetine hydrochloride hemihydrate (1.5 gr, 3.5 mmol) was taken in a conical flask and dissolved in acetonitrile and tetrahydrofuran solvent mixture (1:1, 20 ml v/v). About 80 ml of 3% hydrogen peroxide was added to the solution and stirred at 60 °C for 48 h. Chloroform and water was added to the solution and the organic and aqueous layers were separated using separating flask. Benzene was added to the aqueous layer and the product (I) was isolated by drying the solution. Single crystals were obtained during purification of (I) from chloroform and methanol. The product was characterized by mass spectroscopy (M+1 at m/z 210) and NMR.

Refinement

The H atoms bonded to the N and O atoms were located in a difference map and refined isotropically, see Table 1 for distances. The remaining H atoms were positioned geometrically and refined in the riding model approximation with C—H = 0.93 - 0.97 Å, and with U(H) set to 1.2Ueq(C).

Figures

Fig. 1.
Molecular structure of (I) showing the atom numbering scheme. The displacement ellipsoids are drawn at the 50% probability level. H-atoms are shown by small circles of arbitrary radii.
Fig. 2.
Crystal packing for (I). The molecular tape is sustained through the charge-assisted N+—H···Cl hydrogen bonds, shown as dashed lines.

Crystal data

C12H17FNO+·ClF000 = 260.00
Mr = 245.72Dx = 1.335 Mg m3
Monoclinic, P21Mo Kα radiation λ = 0.71070 Å
Hall symbol: P 2ybCell parameters from 3399 reflections
a = 7.697 (4) Åθ = 1.5–27.4º
b = 5.958 (3) ŵ = 0.30 mm1
c = 13.393 (8) ÅT = 298 K
β = 95.505 (5)ºBlock, colorless
V = 611.4 (6) Å30.50 × 0.40 × 0.20 mm
Z = 2

Data collection

Rigaku Mercury diffractometer2163 reflections with F2 > 2σ(F2)
Detector resolution: 7.31 pixels mm-1Rint = 0.036
ω scansθmax = 27.4º
Absorption correction: multi-scan(Jacobson, 1998)h = −9→9
Tmin = 0.863, Tmax = 0.939k = −5→7
6813 measured reflectionsl = −17→17
2421 independent reflections

Refinement

Refinement on F2  w = 1/[σ2(Fo2) + (0.1198P)2 + 0.1259P] where P = (Fo2 + 2Fc2)/3
R[F2 > 2σ(F2)] = 0.065(Δ/σ)max = 0.006
wR(F2) = 0.203Δρmax = 0.54 e Å3
S = 1.13Δρmin = −0.37 e Å3
2421 reflectionsExtinction correction: none
158 parametersAbsolute structure: Flack (1983), 938 Friedel Pairs
H atoms treated by a mixture of independent and constrained refinementFlack parameter: −0.11 (13)

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles
Refinement. Refinement was performed using all reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F2. R-factor (gt) are based on F. The threshold expression of F2 > 2.0 σ(F2) is used only for calculating R-factor (gt).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/Ueq
F1−0.4169 (4)1.0551 (8)0.5003 (3)0.1111 (13)
O1−0.1239 (4)0.4486 (7)0.1385 (3)0.0778 (11)
N10.3679 (4)0.7472 (8)0.1251 (2)0.0576 (10)
C1−0.2900 (5)0.9849 (10)0.4441 (4)0.0738 (16)
C2−0.2390 (6)1.1230 (9)0.3728 (4)0.0764 (14)
C3−0.1118 (5)1.0490 (8)0.3135 (3)0.0651 (12)
C4−0.0374 (4)0.8397 (6)0.3271 (2)0.0505 (10)
C5−0.0914 (5)0.7080 (9)0.4028 (2)0.0584 (11)
C6−0.2175 (5)0.7774 (10)0.4632 (3)0.0715 (16)
C70.0988 (3)0.7497 (7)0.2628 (2)0.0460 (9)
C80.0506 (4)0.7783 (6)0.1502 (2)0.0504 (10)
C90.1889 (4)0.6685 (7)0.0934 (2)0.0545 (11)
C100.4156 (4)0.7361 (10)0.2348 (2)0.0583 (10)
C110.2796 (4)0.8529 (7)0.2909 (2)0.0545 (10)
C12−0.1260 (5)0.6790 (8)0.1137 (3)0.0607 (14)
Cl10.50505 (12)0.23916 (19)0.10014 (7)0.0599 (3)
H1−0.216 (9)0.388 (14)0.144 (5)0.11 (2)*
H2−0.287901.265100.363500.0910*
H3−0.076401.142600.263700.0780*
H5−0.041200.567000.413700.0700*
H6−0.251600.687000.514500.0860*
H70.109100.588200.275900.0550*
H80.048300.939100.134700.0600*
H110.432 (6)0.658 (9)0.099 (3)0.062 (14)*
H120.378 (10)0.869 (7)0.095 (5)0.12 (2)*
H910.183900.507300.102900.0650*
H920.162700.698600.022300.0650*
H1010.528200.807100.251000.0700*
H1020.425300.580300.255700.0700*
H1110.276901.011400.274300.0650*
H1120.310300.838300.362500.0650*
H121−0.217600.755000.145500.0730*
H122−0.148300.697800.041600.0730*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
F10.0734 (18)0.145 (3)0.120 (2)0.001 (2)0.0353 (17)−0.061 (2)
O10.0611 (19)0.076 (2)0.094 (2)−0.0245 (16)−0.0043 (17)0.0047 (18)
N10.0510 (15)0.0604 (19)0.0638 (17)−0.0101 (18)0.0179 (13)−0.010 (2)
C10.050 (2)0.095 (4)0.078 (2)−0.005 (2)0.0143 (19)−0.031 (2)
C20.065 (2)0.066 (2)0.097 (3)0.009 (2)0.002 (2)−0.026 (2)
C30.064 (2)0.057 (2)0.074 (2)0.0021 (19)0.0046 (19)−0.002 (2)
C40.0491 (17)0.0488 (19)0.0537 (17)−0.0014 (15)0.0063 (14)−0.0020 (15)
C50.0510 (17)0.069 (2)0.0563 (18)−0.0044 (18)0.0103 (14)0.0036 (19)
C60.058 (2)0.097 (4)0.062 (2)−0.010 (2)0.0187 (16)−0.010 (2)
C70.0420 (14)0.0472 (16)0.0491 (15)−0.0047 (16)0.0056 (11)−0.0011 (16)
C80.0494 (16)0.052 (2)0.0494 (16)−0.0049 (14)0.0024 (12)0.0050 (14)
C90.055 (2)0.060 (2)0.0492 (17)−0.0112 (15)0.0088 (14)−0.0045 (15)
C100.0421 (15)0.070 (2)0.0624 (19)−0.004 (2)0.0035 (13)−0.011 (2)
C110.0438 (17)0.067 (2)0.0523 (17)−0.0049 (16)0.0025 (13)−0.0104 (18)
C120.052 (2)0.072 (3)0.057 (2)−0.0043 (17)−0.0006 (15)0.0019 (18)
Cl10.0573 (4)0.0551 (5)0.0682 (5)−0.0063 (4)0.0106 (3)−0.0025 (4)

Geometric parameters (Å, °)

F1—C11.355 (6)C8—C121.520 (5)
O1—C121.412 (6)C10—C111.515 (5)
O1—H10.81 (7)C2—H20.9300
N1—C101.481 (4)C3—H30.9300
N1—C91.479 (5)C5—H50.9300
N1—H120.84 (5)C6—H60.9300
N1—H110.83 (5)C7—H70.9800
C1—C61.370 (8)C8—H80.9800
C1—C21.347 (8)C9—H910.9700
C2—C31.390 (6)C9—H920.9700
C3—C41.377 (6)C10—H1010.9700
C4—C51.377 (5)C10—H1020.9700
C4—C71.517 (4)C11—H1110.9700
C5—C61.385 (6)C11—H1120.9700
C7—C111.535 (4)C12—H1210.9700
C7—C81.528 (4)C12—H1220.9700
C8—C91.515 (5)
C12—O1—H1118 (6)C4—C5—H5119.00
C9—N1—C10114.0 (3)C6—C5—H5119.00
C9—N1—H12105 (5)C1—C6—H6121.00
C10—N1—H11107 (3)C5—C6—H6121.00
H11—N1—H12106 (6)C4—C7—H7107.00
C10—N1—H12119 (5)C8—C7—H7107.00
C9—N1—H11105 (3)C11—C7—H7107.00
F1—C1—C2118.7 (5)C7—C8—H8108.00
F1—C1—C6118.5 (5)C9—C8—H8108.00
C2—C1—C6122.8 (4)C12—C8—H8108.00
C1—C2—C3118.7 (5)N1—C9—H91109.00
C2—C3—C4121.2 (4)N1—C9—H92109.00
C3—C4—C7123.1 (3)C8—C9—H91109.00
C5—C4—C7119.4 (3)C8—C9—H92109.00
C3—C4—C5117.5 (3)H91—C9—H92108.00
C4—C5—C6122.5 (5)N1—C10—H101109.00
C1—C6—C5117.1 (4)N1—C10—H102109.00
C8—C7—C11109.0 (2)C11—C10—H101109.00
C4—C7—C11112.3 (3)C11—C10—H102110.00
C4—C7—C8113.9 (2)H101—C10—H102108.00
C9—C8—C12108.7 (3)C7—C11—H111110.00
C7—C8—C9109.4 (2)C7—C11—H112110.00
C7—C8—C12113.5 (3)C10—C11—H111110.00
N1—C9—C8113.5 (3)C10—C11—H112110.00
N1—C10—C11110.7 (3)H111—C11—H112108.00
C7—C11—C10110.4 (3)O1—C12—H121110.00
O1—C12—C8108.3 (3)O1—C12—H122110.00
C1—C2—H2121.00C8—C12—H121110.00
C3—C2—H2121.00C8—C12—H122110.00
C2—C3—H3119.00H121—C12—H122108.00
C4—C3—H3119.00
C10—N1—C9—C851.5 (5)C5—C4—C7—C11−103.8 (4)
C9—N1—C10—C11−52.1 (6)C4—C5—C6—C10.8 (6)
F1—C1—C2—C3−178.5 (4)C4—C7—C8—C9−176.0 (3)
C6—C1—C2—C32.4 (8)C4—C7—C8—C12−54.5 (4)
F1—C1—C6—C5178.4 (4)C11—C7—C8—C957.7 (4)
C2—C1—C6—C5−2.5 (7)C11—C7—C8—C12179.3 (3)
C1—C2—C3—C4−0.5 (7)C4—C7—C11—C10172.4 (3)
C2—C3—C4—C5−1.1 (6)C8—C7—C11—C10−60.4 (4)
C2—C3—C4—C7178.6 (4)C7—C8—C9—N1−53.7 (4)
C3—C4—C5—C61.0 (5)C12—C8—C9—N1−178.2 (3)
C7—C4—C5—C6−178.8 (3)C7—C8—C12—O1−58.0 (4)
C3—C4—C7—C8−48.1 (5)C9—C8—C12—O164.0 (4)
C3—C4—C7—C1176.5 (4)N1—C10—C11—C756.7 (5)
C5—C4—C7—C8131.7 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O1—H1···Cl1i0.81 (7)2.35 (7)3.114 (4)160 (6)
N1—H11···Cl10.83 (5)2.56 (5)3.234 (5)140 (4)
N1—H12···Cl1ii0.84 (5)2.41 (5)3.144 (5)147 (6)

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

Footnotes

1DRL publication number: 693.

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: TK2259).

References

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  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
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