Pioglitazone hydro­chloride

The title compound [systematic name: ()-5-({4-[2-(5-ethyl-2-pyridinio)­ethoxy]­phenyl}methyl)­thia­zolidine-2,4-dione chlor­ide], C₁₉H₂₁N₂O₃S⁺·Cl⁻, is an oral antidiabetic agent. In the crystal structure, the mol­ecules are linked by N—H...Cl hydrogen bonds into chains.

Key indicators

• Single-crystal X-ray study
• T = 173 K
• Mean [sigma](C-C) = 0.005 Å
• R factor = 0.035
• wR factor = 0.074
• Data-to-parameter ratio = 12.5

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT222_ALERT_3_B Large Non-Solvent    H     Ueq(max)/Ueq(min) ...       4.96 Ratio

Alert level C
PLAT029_ALERT_3_C _diffrn_measured_fraction_theta_full Low .......       0.98
PLAT220_ALERT_2_C Large Non-Solvent    C     Ueq(max)/Ueq(min) ...       2.62 Ratio
PLAT301_ALERT_3_C Main Residue  Disorder .........................       7.00 Perc.
PLAT340_ALERT_3_C Low Bond Precision on C-C bonds (x 1000) Ang ...          5
PLAT366_ALERT_2_C Short? C(sp?)-C(sp?) Bond  C14    -   C15    ...       1.37 Ang.
PLAT410_ALERT_2_C Short Intra H...H Contact  H13    ..  H17D    ..       1.98 Ang.

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           25.65
           From the CIF: _reflns_number_total               3274
           Count of symmetry unique reflns         1945
           Completeness (_total/calc)            168.33%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured      1329
           Fraction of Friedel pairs measured     0.683
           Are heavy atom types Z>Si present          yes

   0 ALERT level A = In general: serious problem
   1 ALERT level B = Potentially serious problem
   6 ALERT level C = Check and explain
   1 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   3 ALERT type 2 Indicator that the structure model may be wrong or deficient
   4 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion

---

Computing details

Data collection: X-AREA (Stoe & Cie, 2001); cell refinement: X-AREA; data reduction: X-AREA; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP in SHELXTL-Plus (Sheldrick, 1991); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 1990).

(±)-5-({4-[2-(5-ethyl-2-pyridinio)ethoxy]phenyl}methyl)thiazolidine-2,4-dione chloride

Crystal data

C19H21N2O3S^+·Cl^−	F(000) = 412
Mr = 392.89	Dx = 1.356 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 5341 reflections
a = 10.0696 (17) Å	θ = 3.8–25.5°
b = 9.4318 (16) Å	µ = 0.33 mm^−1
c = 10.1752 (19) Å	T = 173 K
β = 95.178 (14)°	Plate, colourless
V = 962.4 (3) Å^3	0.43 × 0.28 × 0.11 mm
Z = 2

Data collection

Stoe IPDS-II two-circle diffractometer	3274 independent reflections
Radiation source: fine-focus sealed tube	2480 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.036
ω scans	θmax = 25.7°, θmin = 4.0°
Absorption correction: multi-scan (MULABS; Spek, 1990; Blessing, 1995)	h = −11→12
Tmin = 0.872, Tmax = 0.965	k = −11→11
4956 measured reflections	l = −12→12

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.035	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.074	w = 1/[σ^2(Fo^2) + (0.0375P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.83	(Δ/σ)max < 0.001
3274 reflections	Δρmax = 0.17 e Å^−3
262 parameters	Δρmin = −0.20 e Å^−3
5 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.07 (7)

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
Cl1	0.84700 (8)	1.04424 (7)	0.30091 (7)	0.0413 (2)
O1	0.7412 (2)	0.8025 (2)	0.7798 (2)	0.0442 (6)
C2	0.7244 (3)	0.7220 (3)	0.6599 (3)	0.0393 (8)
H2A	0.6458	0.7559	0.6031	0.047*
H2B	0.7123	0.6202	0.6791	0.047*
C3	0.8506 (3)	0.7450 (3)	0.5930 (3)	0.0387 (7)
H3A	0.8581	0.8466	0.5704	0.046*
H3B	0.9285	0.7200	0.6551	0.046*
C11	0.6450 (4)	0.7889 (3)	0.8672 (3)	0.0408 (8)
C12	0.5246 (4)	0.7200 (3)	0.8399 (3)	0.0459 (8)
H12	0.5034	0.6747	0.7572	0.055*
C13	0.4353 (4)	0.7186 (4)	0.9363 (4)	0.0579 (11)
H13	0.3520	0.6719	0.9184	0.069*
C14	0.4644 (5)	0.7840 (4)	1.0588 (4)	0.0601 (12)
C15	0.5853 (5)	0.8491 (4)	1.0827 (4)	0.0568 (11)
H15	0.6080	0.8924	1.1660	0.068*
C16	0.6745 (4)	0.8530 (3)	0.9888 (3)	0.0476 (9)
H16	0.7575	0.9001	1.0072	0.057*
C17	0.3732 (7)	0.7983 (6)	1.1705 (6)	0.0372 (16)	0.660 (11)
H17A	0.2843	0.8328	1.1349	0.045*	0.660 (11)
H17B	0.4113	0.8676	1.2366	0.045*	0.660 (11)
C17'	0.3414 (11)	0.7263 (18)	1.1331 (10)	0.046 (3)	0.340 (11)
H17C	0.2635	0.7902	1.1180	0.055*	0.340 (11)
H17D	0.3151	0.6300	1.1019	0.055*	0.340 (11)
C21	0.3599 (5)	0.6538 (6)	1.2352 (5)	0.0328 (14)	0.660 (11)
H21	0.3185	0.5843	1.1695	0.039*	0.660 (11)
C21'	0.3918 (9)	0.7241 (13)	1.2754 (9)	0.036 (3)	0.340 (11)
H21'	0.4243	0.8193	1.3073	0.043*	0.340 (11)
S22	0.51855 (8)	0.58585 (9)	1.31002 (8)	0.0452 (2)
C23	0.4497 (3)	0.5414 (4)	1.4576 (3)	0.0406 (7)
O23	0.5067 (3)	0.4735 (3)	1.5462 (3)	0.0670 (8)
N24	0.3248 (2)	0.5972 (3)	1.4607 (2)	0.0404 (6)
H24	0.274 (4)	0.586 (4)	1.531 (3)	0.064 (10)*
C25	0.2730 (4)	0.6694 (4)	1.3520 (3)	0.0505 (9)
O25	0.1645 (3)	0.7265 (3)	1.3422 (3)	0.0633 (7)
C31	0.8535 (3)	0.6576 (3)	0.4696 (3)	0.0354 (7)
N32	0.8643 (3)	0.7268 (3)	0.3565 (3)	0.0376 (7)
H32	0.868 (3)	0.808 (3)	0.359 (3)	0.026 (9)*
C33	0.8737 (4)	0.6605 (4)	0.2409 (3)	0.0426 (8)
H33	0.8827	0.7153	0.1639	0.051*
C34	0.8708 (4)	0.5160 (3)	0.2315 (3)	0.0452 (9)
C35	0.8561 (4)	0.4409 (3)	0.3478 (3)	0.0404 (8)
H35	0.8501	0.3404	0.3455	0.048*
C36	0.8504 (3)	0.5116 (3)	0.4660 (3)	0.0396 (8)
H36	0.8442	0.4595	0.5450	0.047*
C37	0.8849 (6)	0.4391 (5)	0.1034 (4)	0.0779 (14)
H37A	0.9448	0.3570	0.1227	0.093*
H37B	0.7963	0.4009	0.0712	0.093*
C38	0.9358 (5)	0.5198 (5)	−0.0044 (4)	0.0860 (15)
H38A	0.9418	0.4576	−0.0808	0.129*
H38B	1.0245	0.5571	0.0245	0.129*
H38C	0.8752	0.5987	−0.0289	0.129*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0490 (5)	0.0321 (3)	0.0437 (4)	−0.0015 (4)	0.0096 (4)	−0.0041 (3)
O1	0.0506 (16)	0.0399 (12)	0.0435 (12)	−0.0119 (11)	0.0118 (12)	−0.0079 (10)
C2	0.042 (2)	0.0359 (16)	0.0406 (18)	−0.0035 (14)	0.0058 (16)	−0.0056 (13)
C3	0.0360 (19)	0.0384 (16)	0.0419 (18)	−0.0028 (15)	0.0038 (16)	−0.0051 (14)
C11	0.048 (2)	0.0312 (16)	0.045 (2)	0.0022 (15)	0.0139 (18)	0.0082 (14)
C12	0.050 (2)	0.0388 (18)	0.049 (2)	−0.0009 (16)	0.0089 (18)	0.0063 (15)
C13	0.038 (2)	0.057 (2)	0.079 (3)	0.0084 (18)	0.009 (2)	0.032 (2)
C14	0.059 (3)	0.078 (3)	0.044 (2)	0.028 (2)	0.012 (2)	0.027 (2)
C15	0.067 (3)	0.065 (2)	0.038 (2)	0.025 (2)	0.005 (2)	0.0126 (17)
C16	0.062 (3)	0.0412 (19)	0.0396 (19)	0.0043 (17)	0.0046 (19)	0.0068 (14)
C17	0.050 (4)	0.031 (3)	0.030 (3)	0.003 (3)	−0.003 (3)	−0.007 (2)
C17'	0.046 (7)	0.062 (9)	0.030 (6)	−0.008 (6)	0.003 (5)	0.005 (6)
C21	0.033 (3)	0.030 (3)	0.034 (3)	0.002 (2)	−0.003 (2)	−0.010 (2)
C21'	0.037 (6)	0.035 (6)	0.036 (6)	0.008 (5)	0.000 (5)	−0.004 (5)
S22	0.0356 (5)	0.0528 (5)	0.0473 (4)	0.0098 (4)	0.0048 (4)	0.0098 (4)
C23	0.0395 (19)	0.0381 (15)	0.0432 (17)	−0.0055 (16)	−0.0020 (15)	0.0043 (16)
O23	0.0604 (19)	0.0765 (19)	0.0624 (17)	0.0123 (15)	−0.0036 (16)	0.0318 (15)
N24	0.0382 (15)	0.0463 (14)	0.0368 (13)	−0.0019 (14)	0.0039 (13)	0.0036 (12)
C25	0.044 (2)	0.065 (2)	0.0438 (19)	0.0090 (18)	0.0102 (18)	0.0136 (17)
O25	0.0423 (16)	0.0859 (19)	0.0629 (16)	0.0257 (15)	0.0112 (14)	0.0189 (14)
C31	0.0257 (18)	0.0387 (17)	0.0419 (17)	0.0023 (13)	0.0028 (15)	0.0024 (14)
N32	0.0342 (17)	0.0287 (15)	0.0495 (18)	−0.0016 (13)	0.0018 (14)	−0.0030 (12)
C33	0.039 (2)	0.047 (2)	0.0412 (19)	−0.0038 (15)	0.0003 (18)	0.0013 (15)
C34	0.044 (2)	0.042 (2)	0.049 (2)	−0.0029 (15)	0.0017 (18)	−0.0098 (15)
C35	0.036 (2)	0.0332 (17)	0.052 (2)	0.0012 (14)	0.0037 (18)	−0.0065 (14)
C36	0.037 (2)	0.0324 (19)	0.049 (2)	0.0009 (13)	0.0040 (16)	0.0027 (13)
C37	0.117 (4)	0.064 (3)	0.054 (2)	−0.022 (3)	0.013 (3)	−0.019 (2)
C38	0.104 (4)	0.088 (3)	0.071 (3)	−0.005 (3)	0.041 (3)	−0.018 (2)

Geometric parameters (Å, º)

O1—C11	1.379 (4)	C21—H21	1.0000
O1—C2	1.434 (4)	C21'—C25	1.573 (9)
C2—C3	1.510 (4)	C21'—S22	1.836 (9)
C2—H2A	0.9900	C21'—H21'	1.0000
C2—H2B	0.9900	S22—C23	1.760 (3)
C3—C31	1.505 (4)	C23—O23	1.208 (4)
C3—H3A	0.9900	C23—N24	1.366 (4)
C3—H3B	0.9900	N24—C25	1.362 (4)
C11—C12	1.381 (5)	N24—H24	0.93 (4)
C11—C16	1.385 (5)	C25—O25	1.214 (4)
C12—C13	1.390 (5)	C31—N32	1.336 (4)
C12—H12	0.9500	C31—C36	1.378 (4)
C13—C14	1.398 (6)	N32—C33	1.343 (4)
C13—H13	0.9500	N32—H32	0.76 (3)
C14—C15	1.366 (6)	C33—C34	1.366 (4)
C14—C17	1.531 (6)	C33—H33	0.9500
C14—C17'	1.604 (10)	C34—C35	1.399 (5)
C15—C16	1.370 (5)	C34—C37	1.509 (5)
C15—H15	0.9500	C35—C36	1.380 (4)
C16—H16	0.9500	C35—H35	0.9500
C17—C21	1.524 (7)	C36—H36	0.9500
C17—H17A	0.9900	C37—C38	1.465 (6)
C17—H17B	0.9900	C37—H37A	0.9900
C17'—C21'	1.491 (13)	C37—H37B	0.9900
C17'—H17C	0.9900	C38—H38A	0.9800
C17'—H17D	0.9900	C38—H38B	0.9800
C21—C25	1.546 (5)	C38—H38C	0.9800
C21—S22	1.823 (5)
C11—O1—C2	117.6 (2)	S22—C21—H21	110.2
O1—C2—C3	105.5 (3)	C17'—C21'—C25	106.1 (8)
O1—C2—H2A	110.6	C17'—C21'—S22	111.5 (9)
C3—C2—H2A	110.6	C25—C21'—S22	102.6 (5)
O1—C2—H2B	110.6	C17'—C21'—H21'	112.0
C3—C2—H2B	110.6	C25—C21'—H21'	112.0
H2A—C2—H2B	108.8	S22—C21'—H21'	112.0
C31—C3—C2	112.2 (3)	C23—S22—C21	92.44 (18)
C31—C3—H3A	109.2	C23—S22—C21'	90.7 (3)
C2—C3—H3A	109.2	O23—C23—N24	124.3 (3)
C31—C3—H3B	109.2	O23—C23—S22	124.5 (3)
C2—C3—H3B	109.2	N24—C23—S22	111.2 (2)
H3A—C3—H3B	107.9	C25—N24—C23	117.4 (3)
O1—C11—C12	124.7 (3)	C25—N24—H24	119 (2)
O1—C11—C16	115.4 (3)	C23—N24—H24	123 (2)
C12—C11—C16	119.9 (3)	O25—C25—N24	124.4 (3)
C11—C12—C13	118.3 (3)	O25—C25—C21	123.1 (3)
C11—C12—H12	120.8	N24—C25—C21	112.0 (3)
C13—C12—H12	120.8	O25—C25—C21'	122.2 (4)
C12—C13—C14	121.9 (4)	N24—C25—C21'	108.3 (4)
C12—C13—H13	119.1	N32—C31—C36	117.9 (3)
C14—C13—H13	119.1	N32—C31—C3	117.4 (3)
C15—C14—C13	118.0 (4)	C36—C31—C3	124.6 (3)
C15—C14—C17	114.4 (4)	C31—N32—C33	123.0 (3)
C13—C14—C17	127.5 (5)	C31—N32—H32	118 (2)
C15—C14—C17'	141.5 (6)	C33—N32—H32	119 (2)
C13—C14—C17'	99.3 (6)	N32—C33—C34	121.5 (3)
C14—C15—C16	121.2 (4)	N32—C33—H33	119.2
C14—C15—H15	119.4	C34—C33—H33	119.2
C16—C15—H15	119.4	C33—C34—C35	116.7 (3)
C15—C16—C11	120.7 (4)	C33—C34—C37	122.5 (3)
C15—C16—H16	119.7	C35—C34—C37	120.9 (3)
C11—C16—H16	119.7	C36—C35—C34	120.6 (3)
C14—C17—C21	108.9 (4)	C36—C35—H35	119.7
C14—C17—H17A	109.9	C34—C35—H35	119.7
C21—C17—H17A	109.9	C31—C36—C35	120.2 (3)
C14—C17—H17B	109.9	C31—C36—H36	119.9
C21—C17—H17B	109.9	C35—C36—H36	119.9
H17A—C17—H17B	108.3	C38—C37—C34	117.6 (3)
C21'—C17'—C14	104.6 (8)	C38—C37—H37A	107.9
C21'—C17'—H17C	110.8	C34—C37—H37A	107.9
C14—C17'—H17C	110.8	C38—C37—H37B	107.9
C21'—C17'—H17D	110.8	C34—C37—H37B	107.9
C14—C17'—H17D	110.8	H37A—C37—H37B	107.2
H17C—C17'—H17D	108.9	C37—C38—H38A	109.5
C25—C21—C17	109.0 (4)	C37—C38—H38B	109.5
C25—C21—S22	104.3 (3)	H38A—C38—H38B	109.5
C17—C21—S22	112.8 (5)	C37—C38—H38C	109.5
C25—C21—H21	110.2	H38A—C38—H38C	109.5
C17—C21—H21	110.2	H38B—C38—H38C	109.5
C11—O1—C2—C3	−173.7 (3)	C21'—S22—C23—O23	−162.9 (5)
O1—C2—C3—C31	175.5 (3)	C21—S22—C23—N24	−10.8 (3)
C2—O1—C11—C12	−9.8 (4)	C21'—S22—C23—N24	15.4 (5)
C2—O1—C11—C16	171.5 (3)	O23—C23—N24—C25	−178.9 (4)
O1—C11—C12—C13	−177.9 (3)	S22—C23—N24—C25	2.8 (4)
C16—C11—C12—C13	0.7 (5)	C23—N24—C25—O25	−178.6 (4)
C11—C12—C13—C14	−0.3 (5)	C23—N24—C25—C21	8.9 (5)
C12—C13—C14—C15	−0.7 (5)	C23—N24—C25—C21'	−23.7 (6)
C12—C13—C14—C17	176.2 (4)	C17—C21—C25—O25	51.2 (7)
C12—C13—C14—C17'	−170.9 (6)	S22—C21—C25—O25	171.8 (4)
C13—C14—C15—C16	1.3 (5)	C17—C21—C25—N24	−136.2 (5)
C17—C14—C15—C16	−176.0 (4)	S22—C21—C25—N24	−15.6 (5)
C17'—C14—C15—C16	165.7 (10)	C17—C21—C25—C21'	−47.3 (7)
C14—C15—C16—C11	−1.0 (5)	S22—C21—C25—C21'	73.3 (7)
O1—C11—C16—C15	178.6 (3)	C17'—C21'—C25—O25	−55.6 (12)
C12—C11—C16—C15	−0.1 (5)	S22—C21'—C25—O25	−172.7 (4)
C15—C14—C17—C21	−110.6 (6)	C17'—C21'—C25—N24	148.9 (9)
C13—C14—C17—C21	72.4 (7)	S22—C21'—C25—N24	31.7 (7)
C17'—C14—C17—C21	46.7 (9)	C17'—C21'—C25—C21	46.3 (10)
C15—C14—C17'—C21'	−13.8 (18)	S22—C21'—C25—C21	−70.9 (7)
C13—C14—C17'—C21'	152.2 (10)	C2—C3—C31—N32	120.8 (3)
C17—C14—C17'—C21'	−48.2 (8)	C2—C3—C31—C36	−61.5 (5)
C14—C17—C21—C25	177.5 (4)	C36—C31—N32—C33	−0.8 (5)
C14—C17—C21—S22	62.1 (6)	C3—C31—N32—C33	177.0 (3)
C14—C17'—C21'—C25	179.4 (7)	C31—N32—C33—C34	1.0 (6)
C14—C17'—C21'—S22	−69.5 (13)	N32—C33—C34—C35	0.6 (6)
C25—C21—S22—C23	14.3 (4)	N32—C33—C34—C37	−178.3 (4)
C17—C21—S22—C23	132.4 (4)	C33—C34—C35—C36	−2.4 (6)
C25—C21—S22—C21'	−72.4 (7)	C37—C34—C35—C36	176.5 (4)
C17—C21—S22—C21'	45.8 (7)	N32—C31—C36—C35	−1.0 (6)
C17'—C21'—S22—C23	−139.0 (9)	C3—C31—C36—C35	−178.7 (3)
C25—C21'—S22—C23	−25.7 (6)	C34—C35—C36—C31	2.7 (6)
C17'—C21'—S22—C21	−44.9 (8)	C33—C34—C37—C38	15.3 (7)
C25—C21'—S22—C21	68.4 (8)	C35—C34—C37—C38	−163.6 (4)
C21—S22—C23—O23	171.0 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N32—H32···Cl1	0.76 (3)	2.31 (3)	3.049 (3)	162 (3)
N24—H24···Cl1^i	0.93 (4)	2.22 (4)	3.144 (3)	176 (3)

Symmetry code: (i) −x+1, y−1/2, −z+2.