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

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

doi:10.1107/S1600536808008593

organic compounds

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ISSN: 2056-9890

Volume 64| Part 5| May 2008| Page o800

doi:10.1107/S1600536808008593

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

M Nirmala,^a B. R. Sreekanth,^a Peddy Vishweshwar,^a ^* J. Moses Babu ^a and Y Anjaneyulu ^b

^aDepartment of Analytical Research, Discovery Research, Dr Reddy's Laboratories Ltd, Miyapur, Hyderabad 500 049, India, and ^bCentre for Atmospheric Science, Jawaharlal Nehru Technological University, Hyderabad 500 072, India
^*Correspondence e-mail: vishweshwarp@drreddys.com

(Received 26 March 2008; accepted 31 March 2008; online 4 April 2008)

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 ); de Gonzalo et al. (2001 ); Barnes et al. (1988 ); Ibers (1999 ).

Experimental

Crystal data

C₁₂H₁₇FNO⁺·Cl⁻
M_r = 245.72
Monoclinic, P 2₁
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 ) T_min = 0.863, T_max = 0.939
6813 measured reflections
2421 independent reflections
2163 reflections with F² > 2σ(F²)
R_int = 0.036

Refinement

R[F² > 2σ(F²)] = 0.065
wR(F²) = 0.203
S = 1.13
2421 reflections
158 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.54 e Å⁻³
Δρ_min = −0.37 e Å⁻³
Absolute structure: Flack (1983 ), 938 Friedel Pairs
Flack parameter: −0.11 (13)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯Cl1ⁱ	0.81 (7)	2.35 (7)	3.114 (4)	160 (6)
N1—H11⋯Cl1	0.83 (5)	2.56 (5)	3.234 (5)	140 (4)
N1—H12⋯Cl1ⁱⁱ	0.84 (5)	2.41 (5)	3.144 (5)	147 (6)
Symmetry codes: (i) x-1, y, z; (ii) x, y+1, z.

Data collection: CrystalClear (Pflugrath, 1999 ); cell refinement: CrystalClear; 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.

Supporting information

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

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

checkCIF report

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.

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

	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.

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

Crystal data top

C₁₂H₁₇FNO⁺·Cl⁻	F(000) = 260.00
M_r = 245.72	D_x = 1.335 Mg m⁻³
Monoclinic, P2₁	Mo Kα radiation, λ = 0.71070 Å
Hall symbol: P 2yb	Cell parameters from 3399 reflections
a = 7.697 (4) Å	θ = 1.5–27.4°
b = 5.958 (3) Å	µ = 0.30 mm⁻¹
c = 13.393 (8) Å	T = 298 K
β = 95.505 (5)°	Block, colorless
V = 611.4 (6) Å³	0.50 × 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^-1	R_int = 0.036
ω scans	θ_max = 27.4°
Absorption correction: multi-scan (Jacobson, 1998)	h = −9→9
T_min = 0.863, T_max = 0.939	k = −5→7
6813 measured reflections	l = −17→17
2421 independent reflections

Refinement top

Refinement on F²	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.065	w = 1/[σ²(F_o²) + (0.1198P)² + 0.1259P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.203	(Δ/σ)_max = 0.006
S = 1.13	Δρ_max = 0.54 e Å⁻³
2421 reflections	Δρ_min = −0.37 e Å⁻³
158 parameters	Absolute structure: Flack (1983), 938 Friedel Pairs
0 restraints	Absolute structure parameter: −0.11 (13)

Crystal data top

C₁₂H₁₇FNO⁺·Cl⁻	V = 611.4 (6) Å³
M_r = 245.72	Z = 2
Monoclinic, P2₁	Mo Kα radiation
a = 7.697 (4) Å	µ = 0.30 mm⁻¹
b = 5.958 (3) Å	T = 298 K
c = 13.393 (8) Å	0.50 × 0.40 × 0.20 mm
β = 95.505 (5)°

Data collection top

Rigaku Mercury diffractometer	2421 independent reflections
Absorption correction: multi-scan (Jacobson, 1998)	2163 reflections with F² > 2σ(F²)
T_min = 0.863, T_max = 0.939	R_int = 0.036
6813 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.065	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.203	Δρ_max = 0.54 e Å⁻³
S = 1.13	Δρ_min = −0.37 e Å⁻³
2421 reflections	Absolute structure: Flack (1983), 938 Friedel Pairs
158 parameters	Absolute structure parameter: −0.11 (13)
0 restraints

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

	x	y	z	U_iso*/U_eq
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)
N1	0.3679 (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)
C7	0.0988 (3)	0.7497 (7)	0.2628 (2)	0.0460 (9)
C8	0.0506 (4)	0.7783 (6)	0.1502 (2)	0.0504 (10)
C9	0.1889 (4)	0.6685 (7)	0.0934 (2)	0.0545 (11)
C10	0.4156 (4)	0.7361 (10)	0.2348 (2)	0.0583 (10)
C11	0.2796 (4)	0.8529 (7)	0.2909 (2)	0.0545 (10)
C12	−0.1260 (5)	0.6790 (8)	0.1137 (3)	0.0607 (14)
Cl1	0.50505 (12)	0.23916 (19)	0.10014 (7)	0.0599 (3)
H1	−0.216 (9)	0.388 (14)	0.144 (5)	0.11 (2)*
H2	−0.28790	1.26510	0.36350	0.0910*
H3	−0.07640	1.14260	0.26370	0.0780*
H5	−0.04120	0.56700	0.41370	0.0700*
H6	−0.25160	0.68700	0.51450	0.0860*
H7	0.10910	0.58820	0.27590	0.0550*
H8	0.04830	0.93910	0.13470	0.0600*
H11	0.432 (6)	0.658 (9)	0.099 (3)	0.062 (14)*
H12	0.378 (10)	0.869 (7)	0.095 (5)	0.12 (2)*
H91	0.18390	0.50730	0.10290	0.0650*
H92	0.16270	0.69860	0.02230	0.0650*
H101	0.52820	0.80710	0.25100	0.0700*
H102	0.42530	0.58030	0.25570	0.0700*
H111	0.27690	1.01140	0.27430	0.0650*
H112	0.31030	0.83830	0.36250	0.0650*
H121	−0.21760	0.75500	0.14550	0.0730*
H122	−0.14830	0.69780	0.04160	0.0730*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0734 (18)	0.145 (3)	0.120 (2)	0.001 (2)	0.0353 (17)	−0.061 (2)
O1	0.0611 (19)	0.076 (2)	0.094 (2)	−0.0245 (16)	−0.0043 (17)	0.0047 (18)
N1	0.0510 (15)	0.0604 (19)	0.0638 (17)	−0.0101 (18)	0.0179 (13)	−0.010 (2)
C1	0.050 (2)	0.095 (4)	0.078 (2)	−0.005 (2)	0.0143 (19)	−0.031 (2)
C2	0.065 (2)	0.066 (2)	0.097 (3)	0.009 (2)	0.002 (2)	−0.026 (2)
C3	0.064 (2)	0.057 (2)	0.074 (2)	0.0021 (19)	0.0046 (19)	−0.002 (2)
C4	0.0491 (17)	0.0488 (19)	0.0537 (17)	−0.0014 (15)	0.0063 (14)	−0.0020 (15)
C5	0.0510 (17)	0.069 (2)	0.0563 (18)	−0.0044 (18)	0.0103 (14)	0.0036 (19)
C6	0.058 (2)	0.097 (4)	0.062 (2)	−0.010 (2)	0.0187 (16)	−0.010 (2)
C7	0.0420 (14)	0.0472 (16)	0.0491 (15)	−0.0047 (16)	0.0056 (11)	−0.0011 (16)
C8	0.0494 (16)	0.052 (2)	0.0494 (16)	−0.0049 (14)	0.0024 (12)	0.0050 (14)
C9	0.055 (2)	0.060 (2)	0.0492 (17)	−0.0112 (15)	0.0088 (14)	−0.0045 (15)
C10	0.0421 (15)	0.070 (2)	0.0624 (19)	−0.004 (2)	0.0035 (13)	−0.011 (2)
C11	0.0438 (17)	0.067 (2)	0.0523 (17)	−0.0049 (16)	0.0025 (13)	−0.0104 (18)
C12	0.052 (2)	0.072 (3)	0.057 (2)	−0.0043 (17)	−0.0006 (15)	0.0019 (18)
Cl1	0.0573 (4)	0.0551 (5)	0.0682 (5)	−0.0063 (4)	0.0106 (3)	−0.0025 (4)

Geometric parameters (Å, º) top

F1—C1	1.355 (6)	C8—C12	1.520 (5)
O1—C12	1.412 (6)	C10—C11	1.515 (5)
O1—H1	0.81 (7)	C2—H2	0.9300
N1—C10	1.481 (4)	C3—H3	0.9300
N1—C9	1.479 (5)	C5—H5	0.9300
N1—H12	0.84 (5)	C6—H6	0.9300
N1—H11	0.83 (5)	C7—H7	0.9800
C1—C6	1.370 (8)	C8—H8	0.9800
C1—C2	1.347 (8)	C9—H91	0.9700
C2—C3	1.390 (6)	C9—H92	0.9700
C3—C4	1.377 (6)	C10—H101	0.9700
C4—C5	1.377 (5)	C10—H102	0.9700
C4—C7	1.517 (4)	C11—H111	0.9700
C5—C6	1.385 (6)	C11—H112	0.9700
C7—C11	1.535 (4)	C12—H121	0.9700
C7—C8	1.528 (4)	C12—H122	0.9700
C8—C9	1.515 (5)

C12—O1—H1	118 (6)	C4—C5—H5	119.00
C9—N1—C10	114.0 (3)	C6—C5—H5	119.00
C9—N1—H12	105 (5)	C1—C6—H6	121.00
C10—N1—H11	107 (3)	C5—C6—H6	121.00
H11—N1—H12	106 (6)	C4—C7—H7	107.00
C10—N1—H12	119 (5)	C8—C7—H7	107.00
C9—N1—H11	105 (3)	C11—C7—H7	107.00
F1—C1—C2	118.7 (5)	C7—C8—H8	108.00
F1—C1—C6	118.5 (5)	C9—C8—H8	108.00
C2—C1—C6	122.8 (4)	C12—C8—H8	108.00
C1—C2—C3	118.7 (5)	N1—C9—H91	109.00
C2—C3—C4	121.2 (4)	N1—C9—H92	109.00
C3—C4—C7	123.1 (3)	C8—C9—H91	109.00
C5—C4—C7	119.4 (3)	C8—C9—H92	109.00
C3—C4—C5	117.5 (3)	H91—C9—H92	108.00
C4—C5—C6	122.5 (5)	N1—C10—H101	109.00
C1—C6—C5	117.1 (4)	N1—C10—H102	109.00
C8—C7—C11	109.0 (2)	C11—C10—H101	109.00
C4—C7—C11	112.3 (3)	C11—C10—H102	110.00
C4—C7—C8	113.9 (2)	H101—C10—H102	108.00
C9—C8—C12	108.7 (3)	C7—C11—H111	110.00
C7—C8—C9	109.4 (2)	C7—C11—H112	110.00
C7—C8—C12	113.5 (3)	C10—C11—H111	110.00
N1—C9—C8	113.5 (3)	C10—C11—H112	110.00
N1—C10—C11	110.7 (3)	H111—C11—H112	108.00
C7—C11—C10	110.4 (3)	O1—C12—H121	110.00
O1—C12—C8	108.3 (3)	O1—C12—H122	110.00
C1—C2—H2	121.00	C8—C12—H121	110.00
C3—C2—H2	121.00	C8—C12—H122	110.00
C2—C3—H3	119.00	H121—C12—H122	108.00
C4—C3—H3	119.00

C10—N1—C9—C8	51.5 (5)	C5—C4—C7—C11	−103.8 (4)
C9—N1—C10—C11	−52.1 (6)	C4—C5—C6—C1	0.8 (6)
F1—C1—C2—C3	−178.5 (4)	C4—C7—C8—C9	−176.0 (3)
C6—C1—C2—C3	2.4 (8)	C4—C7—C8—C12	−54.5 (4)
F1—C1—C6—C5	178.4 (4)	C11—C7—C8—C9	57.7 (4)
C2—C1—C6—C5	−2.5 (7)	C11—C7—C8—C12	179.3 (3)
C1—C2—C3—C4	−0.5 (7)	C4—C7—C11—C10	172.4 (3)
C2—C3—C4—C5	−1.1 (6)	C8—C7—C11—C10	−60.4 (4)
C2—C3—C4—C7	178.6 (4)	C7—C8—C9—N1	−53.7 (4)
C3—C4—C5—C6	1.0 (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—O1	64.0 (4)
C3—C4—C7—C11	76.5 (4)	N1—C10—C11—C7	56.7 (5)
C5—C4—C7—C8	131.7 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···Cl1ⁱ	0.81 (7)	2.35 (7)	3.114 (4)	160 (6)
N1—H11···Cl1	0.83 (5)	2.56 (5)	3.234 (5)	140 (4)
N1—H12···Cl1ⁱⁱ	0.84 (5)	2.41 (5)	3.144 (5)	147 (6)

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

Experimental details

Crystal data
Chemical formula	C₁₂H₁₇FNO⁺·Cl⁻
M_r	245.72
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	298
a, b, c (Å)	7.697 (4), 5.958 (3), 13.393 (8)
β (°)	95.505 (5)
V (Å³)	611.4 (6)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.30
Crystal size (mm)	0.50 × 0.40 × 0.20

Data collection
Diffractometer	Rigaku Mercury diffractometer
Absorption correction	Multi-scan (Jacobson, 1998)
T_min, T_max	0.863, 0.939
No. of measured, independent and observed [F² > 2σ(F²)] reflections	6813, 2421, 2163
R_int	0.036
(sin θ/λ)_max (Å⁻¹)	0.648

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.065, 0.203, 1.13
No. of reflections	2421
No. of parameters	158
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.54, −0.37
Absolute structure	Flack (1983), 938 Friedel Pairs
Absolute structure parameter	−0.11 (13)

Computer programs: CrystalClear (Pflugrath, 1999), CrystalStructure (Rigaku/MSC, 2006), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), X-SEED (Barbour, 2001).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···Cl1ⁱ	0.81 (7)	2.35 (7)	3.114 (4)	160 (6)
N1—H11···Cl1	0.83 (5)	2.56 (5)	3.234 (5)	140 (4)
N1—H12···Cl1ⁱⁱ	0.84 (5)	2.41 (5)	3.144 (5)	147 (6)

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

Footnotes

†DRL publication number: 693.

Acknowledgements

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.

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