Crystal structure of pirfenidone (5-methyl-1-phenyl-1H-pyridin-2-one): an active pharmaceutical ingredient (API)

The crystal structure of pirfenidone, [5-methyl-1-phenyl­pyridin-2(1H)-one], an active pharmaceutical ingredient (API) approved in Europe and Japan for the treatment of idiopathic pulmonary fibrosis (IPF), is reported here for the first time. It was crystallized from toluene by the temperature gradient technique, and crystallizes in the chiral monoclinic space group P2₁.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.037
• wR factor = 0.095
• Data-to-parameter ratio = 16.8

checkCIF/PLATON results

No syntax errors found



Datablock: I


Alert level C
PLAT923_ALERT_1_C S    Values in the CIF and FCF Differ by .......      0.017 Check
PLAT978_ALERT_2_C Number C-C Bonds with Positive Residual Density.          0 Info

Alert level G
PLAT032_ALERT_4_G Std. Uncertainty on Flack Parameter Value High .      0.400 Report
PLAT199_ALERT_1_G Reported _cell_measurement_temperature ..... (K)        293 Check
PLAT200_ALERT_1_G Reported   _diffrn_ambient_temperature ..... (K)        293 Check

   0 ALERT level A = Most likely a serious problem - resolve or explain
   0 ALERT level B = A potentially serious problem, consider carefully
   2 ALERT level C = Check. Ensure it is not caused by an omission or oversight
   3 ALERT level G = General information/check it is not something unexpected

   3 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

---

Computing details

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT (Bruker, 2010); program(s) used to solve structure: SHELXT2017 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2017 (Sheldrick, 2015b); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2017 (Sheldrick, 2015b), PLATON (Spek, 2009) and publCIF (Westrip, 2010).

5-Methyl-1-phenylpyridin-2(1H)-one

Crystal data

C12H11NO	Dx = 1.269 Mg m^−3
Mr = 185.22	Melting point: 375 K
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
a = 6.2525 (8) Å	Cell parameters from 2547 reflections
b = 7.797 (1) Å	θ = 3.3–27.2°
c = 10.2810 (13) Å	µ = 0.08 mm^−1
β = 104.744 (2)°	T = 293 K
V = 484.70 (11) Å^3	Plate, colourless
Z = 2	0.50 × 0.45 × 0.05 mm
F(000) = 196

Data collection

Bruker SMART APEX CCD diffractometer	1879 reflections with I > 2σ(I)
ω scans	Rint = 0.019
Absorption correction: multi-scan (SADABS; Bruker, 2010)	θmax = 27.2°, θmin = 2.1°
Tmin = 0.692, Tmax = 0.746	h = −8→8
4547 measured reflections	k = −9→10
2128 independent reflections	l = −13→13

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.037	w = 1/[σ^2(Fo^2) + (0.0528P)^2 + 0.0476P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.095	(Δ/σ)max < 0.001
S = 1.04	Δρmax = 0.11 e Å^−3
2128 reflections	Δρmin = −0.20 e Å^−3
127 parameters	Absolute structure: Flack x determined using 762 quotients [(I^+)-(I^-)]/[(I^+)+(I^-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: 0.3 (4)

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. none

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

	x	y	z	Uiso*/Ueq
N1	0.7599 (2)	0.5275 (2)	0.62509 (16)	0.0382 (4)
O1	1.0951 (2)	0.6634 (3)	0.69330 (17)	0.0602 (5)
C1	0.9386 (3)	0.6188 (3)	0.6002 (2)	0.0437 (5)
C5	0.5769 (3)	0.4849 (3)	0.5233 (2)	0.0395 (5)
H5	0.460421	0.428046	0.545647	0.047*
C7	0.7635 (3)	0.4782 (3)	0.76141 (19)	0.0401 (5)
C4	0.5595 (3)	0.5219 (3)	0.3929 (2)	0.0430 (5)
C12	0.9445 (4)	0.3913 (3)	0.8390 (2)	0.0497 (5)
H12	1.066616	0.368712	0.805687	0.060*
C8	0.5830 (3)	0.5134 (3)	0.8108 (2)	0.0481 (5)
H8	0.462114	0.572084	0.758231	0.058*
C6	0.3599 (4)	0.4732 (3)	0.2835 (2)	0.0579 (6)
H6A	0.400128	0.387266	0.227127	0.087*
H6B	0.304346	0.572565	0.230447	0.087*
H6C	0.247695	0.428652	0.322817	0.087*
C11	0.9409 (5)	0.3383 (3)	0.9672 (2)	0.0616 (7)
H11	1.061057	0.278817	1.019737	0.074*
C3	0.7416 (4)	0.6079 (3)	0.3637 (2)	0.0527 (6)
H3	0.737708	0.633055	0.274701	0.063*
C2	0.9189 (4)	0.6537 (3)	0.4608 (2)	0.0540 (6)
H2	1.033979	0.710617	0.436893	0.065*
C9	0.5836 (4)	0.4604 (4)	0.9395 (2)	0.0623 (7)
H9	0.462501	0.484254	0.973553	0.075*
C10	0.7616 (5)	0.3728 (4)	1.0174 (2)	0.0649 (7)
H10	0.760634	0.337171	1.103577	0.078*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0355 (8)	0.0426 (9)	0.0362 (8)	0.0009 (8)	0.0084 (7)	0.0007 (7)
O1	0.0399 (8)	0.0725 (11)	0.0631 (11)	−0.0111 (8)	0.0038 (7)	−0.0046 (9)
C1	0.0368 (10)	0.0430 (12)	0.0524 (12)	0.0007 (9)	0.0134 (9)	−0.0023 (10)
C5	0.0380 (9)	0.0395 (11)	0.0398 (10)	−0.0026 (9)	0.0078 (8)	0.0011 (9)
C7	0.0411 (10)	0.0397 (11)	0.0362 (10)	−0.0013 (8)	0.0034 (8)	0.0002 (8)
C4	0.0524 (11)	0.0376 (11)	0.0376 (10)	−0.0009 (10)	0.0087 (9)	−0.0001 (9)
C12	0.0496 (12)	0.0478 (12)	0.0459 (12)	0.0081 (10)	0.0017 (10)	−0.0051 (10)
C8	0.0395 (10)	0.0602 (13)	0.0435 (11)	−0.0003 (10)	0.0082 (8)	0.0070 (11)
C6	0.0705 (15)	0.0570 (15)	0.0399 (11)	−0.0077 (13)	0.0026 (11)	−0.0004 (11)
C11	0.0708 (16)	0.0522 (14)	0.0469 (13)	0.0053 (12)	−0.0126 (12)	0.0046 (11)
C3	0.0694 (15)	0.0522 (14)	0.0410 (11)	−0.0091 (11)	0.0224 (11)	0.0002 (10)
C2	0.0559 (13)	0.0556 (14)	0.0576 (14)	−0.0113 (12)	0.0276 (11)	−0.0015 (11)
C9	0.0595 (14)	0.0851 (19)	0.0450 (13)	−0.0110 (13)	0.0183 (11)	0.0036 (13)
C10	0.0826 (19)	0.0688 (17)	0.0378 (12)	−0.0134 (16)	0.0054 (12)	0.0103 (12)

Geometric parameters (Å, º)

N1—C5	1.381 (2)	C8—C9	1.386 (3)
N1—C1	1.402 (2)	C8—H8	0.9300
N1—C7	1.448 (3)	C6—H6A	0.9600
O1—C1	1.232 (3)	C6—H6B	0.9600
C1—C2	1.432 (3)	C6—H6C	0.9600
C5—C4	1.349 (3)	C11—C10	1.375 (4)
C5—H5	0.9300	C11—H11	0.9300
C7—C8	1.378 (3)	C3—C2	1.338 (3)
C7—C12	1.384 (3)	C3—H3	0.9300
C4—C3	1.417 (3)	C2—H2	0.9300
C4—C6	1.501 (3)	C9—C10	1.376 (4)
C12—C11	1.386 (4)	C9—H9	0.9300
C12—H12	0.9300	C10—H10	0.9300
C5—N1—C1	121.93 (17)	C4—C6—H6A	109.5
C5—N1—C7	118.39 (16)	C4—C6—H6B	109.5
C1—N1—C7	119.67 (16)	H6A—C6—H6B	109.5
O1—C1—N1	120.88 (19)	C4—C6—H6C	109.5
O1—C1—C2	124.9 (2)	H6A—C6—H6C	109.5
N1—C1—C2	114.20 (18)	H6B—C6—H6C	109.5
C4—C5—N1	122.94 (19)	C10—C11—C12	120.7 (2)
C4—C5—H5	118.5	C10—C11—H11	119.7
N1—C5—H5	118.5	C12—C11—H11	119.7
C8—C7—C12	120.74 (19)	C2—C3—C4	121.7 (2)
C8—C7—N1	119.42 (17)	C2—C3—H3	119.1
C12—C7—N1	119.81 (19)	C4—C3—H3	119.1
C5—C4—C3	116.47 (19)	C3—C2—C1	122.6 (2)
C5—C4—C6	122.2 (2)	C3—C2—H2	118.7
C3—C4—C6	121.4 (2)	C1—C2—H2	118.7
C7—C12—C11	119.0 (2)	C10—C9—C8	120.6 (2)
C7—C12—H12	120.5	C10—C9—H9	119.7
C11—C12—H12	120.5	C8—C9—H9	119.7
C7—C8—C9	119.3 (2)	C11—C10—C9	119.7 (2)
C7—C8—H8	120.4	C11—C10—H10	120.2
C9—C8—H8	120.4	C9—C10—H10	120.2

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C8—H8···O1^i	0.93	2.33	3.203 (3)	156
C10—H10···O1^ii	0.93	2.46	3.310 (3)	152

Symmetry codes: (i) x−1, y, z; (ii) −x+2, y−1/2, −z+2.