organic compounds
(3S,4R)-4-(4-Fluorophenyl)-3-(hydroxymethyl)piperidinium chloride†
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
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
|
Data collection: CrystalClear (Pflugrath, 1999); cell 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
10.1107/S1600536808008593/tk2259sup1.cif
contains datablocks global, I. DOI:Structure factors: contains datablock I. DOI: 10.1107/S1600536808008593/tk2259Isup2.hkl
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
(M+1 at m/z 210) and NMR.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).
Data collection: CrystalClear (Pflugrath, 1999); cell
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).C12H17FNO+·Cl− | F(000) = 260.00 |
Mr = 245.72 | Dx = 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 |
Rigaku Mercury diffractometer | 2163 reflections with F2 > 2σ(F2) |
Detector resolution: 7.31 pixels mm-1 | Rint = 0.036 |
ω scans | θmax = 27.4° |
Absorption correction: multi-scan (Jacobson, 1998) | h = −9→9 |
Tmin = 0.863, Tmax = 0.939 | k = −5→7 |
6813 measured reflections | l = −17→17 |
2421 independent reflections |
Refinement on F2 | H atoms treated by a mixture of independent and constrained refinement |
R[F2 > 2σ(F2)] = 0.065 | w = 1/[σ2(Fo2) + (0.1198P)2 + 0.1259P] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.203 | (Δ/σ)max = 0.006 |
S = 1.13 | Δρmax = 0.54 e Å−3 |
2421 reflections | Δρmin = −0.37 e Å−3 |
158 parameters | Absolute structure: Flack (1983), 938 Friedel Pairs |
0 restraints | Absolute structure parameter: −0.11 (13) |
C12H17FNO+·Cl− | V = 611.4 (6) Å3 |
Mr = 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)° |
Rigaku Mercury diffractometer | 2421 independent reflections |
Absorption correction: multi-scan (Jacobson, 1998) | 2163 reflections with F2 > 2σ(F2) |
Tmin = 0.863, Tmax = 0.939 | Rint = 0.036 |
6813 measured reflections |
R[F2 > 2σ(F2)] = 0.065 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.203 | Δρmax = 0.54 e Å−3 |
S = 1.13 | Δρmin = −0.37 e Å−3 |
2421 reflections | Absolute structure: Flack (1983), 938 Friedel Pairs |
158 parameters | Absolute structure parameter: −0.11 (13) |
0 restraints |
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). |
x | y | z | Uiso*/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) | |
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* |
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) |
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) |
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− |
Mr | 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) |
Tmin, Tmax | 0.863, 0.939 |
No. of measured, independent and observed [F2 > 2σ(F2)] reflections | 6813, 2421, 2163 |
Rint | 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 |
Δρmax, Δρmin (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).
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.
References
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This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
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.