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Acta Cryst. (2008). E64, o800    [ doi:10.1107/S1600536808008593 ]

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

M. Nirmala, B. R. Sreekanth, P. Vishweshwar, J. Moses Babu and Y. Anjaneyulu

Abstract top

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.

Comment top

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.

Related literature top

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

Experimental top

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 top

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).

Computing details top

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

Figures top
[Figure 1] 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.
[Figure 2] Fig. 2. Crystal packing for (I). The molecular tape is sustained through the charge-assisted N+—H···Cl hydrogen bonds, shown as dashed lines.
(3S,4R)-4-(4-Fluorophenyl)-3-(hydroxymethyl)piperidinium chloride top
Crystal data top
C12H17FNO+·Cl–F000 = 260.00
Mr = 245.72Dx = 1.335 Mg m−3
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 mm−1
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 top
Rigaku Mercury
diffractometer		2163 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 top
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 Å−3
S = 1.13Δρmin = −0.37 e Å−3
2421 reflectionsExtinction correction: none
158 parametersAbsolute structure: Flack (1983), 938 Friedel Pairs
H atoms treated by a mixture of
independent and constrained refinement		Flack parameter: −0.11 (13)
Crystal data top
C12H17FNO+·Cl–V = 611.4 (6) Å3
Mr = 245.72Z = 2
Monoclinic, P21Mo Kα
a = 7.697 (4) ŵ = 0.30 mm−1
b = 5.958 (3) ÅT = 298 K
c = 13.393 (8) Å0.50 × 0.40 × 0.20 mm
β = 95.505 (5)º
Data collection top
Rigaku Mercury
diffractometer		2421 independent reflections
Absorption correction: multi-scan
(Jacobson, 1998)		2163 reflections with F2 > 2σ(F2)
Tmin = 0.863, Tmax = 0.939Rint = 0.036
6813 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.065H atoms treated by a mixture of
independent and constrained refinement
wR(F2) = 0.203Δρmax = 0.54 e Å−3
S = 1.13Δρmin = −0.37 e Å−3
2421 reflectionsAbsolute structure: Flack (1983), 938 Friedel Pairs
158 parametersFlack parameter: −0.11 (13)
Special details top

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) top
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) top
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, °) top
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, °) top
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.
Table 1
Hydrogen-bond geometry (Å, °) top
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.
Acknowledgements top

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

references
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