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X-ray powder diffraction data for 5, 6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone, C20H25N3O3

Published online by Cambridge University Press:  13 July 2016

Qing Wang ,
Xia Zeng ,
Shan Shan Li ,
Xiao Li Ma  and
Hui Li
Qing Wang
Affiliation:
College of Chemical Engineering, Sichuan University, Chengdu 610065, China
Xia Zeng
Affiliation:
College of Chemical Engineering, Sichuan University, Chengdu 610065, China
Shan Shan Li
Affiliation:
College of Chemical Engineering, Sichuan University, Chengdu 610065, China
Xiao Li Ma
Affiliation:
College of Chemical Engineering, Sichuan University, Chengdu 610065, China
Hui Li*
Affiliation:
College of Chemical Engineering, Sichuan University, Chengdu 610065, China
*
a) Author to whom correspondence should be addressed. Electronic mail: lihuilab@sina.com

Abstract

X-ray powder diffraction data for 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone, C20H25N3O3, are reported [a = 5.989(2), b = 6.669(3), c = 24.605(5)Å, α = 84.466(7)°, β = 89.859(6)°, γ = 69.074(4)°, unit-cell volume V = 913.11 Å3, Z = 2, and space group P−1]. No detectable impurities were observed.

Keywords

pharmaceutical intermediateanticoagulantapixabansingle crystal

Information

Type
New Diffraction Data
Information
Powder Diffraction , Volume 31 , Issue 4 , December 2016 , pp. 288 - 291
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Copyright
Copyright © International Centre for Diffraction Data 2016 

I. INTRODUCTION

Apixaban (Eliquis®) is a novel oral pyrazole-based direct FXa inhibitor; this drug was developed by Bristol-Myers Squibb and Pfizer to treat and prevent thrombotic disorder (Watson et al., Reference Watson, Whiteside and Perry2011). Since May 2011, Apixaban has been approved for VTE prevention in adult elective hip or knee replacement patients in various countries, such as the USA, China, Brazil, Australia, New Zealand, and some European countries (Deeks, Reference Deeks2012). The title compound is an intermediate in the synthesis of the anticoagulant, Apixaban (Jiang and Ji, Reference Jiang and Ji2013). Presently, the crystal structure of the title compound has not been reported.

II. EXPERIMENTAL

A. Sample preparation

The sample (Figure 1) was prepared using 5-chloro-N-[4-(5,6-dihydro-3-(4-morpholinyl)-2-oxo-1(2H)-pyridinyl)phenyl]-pentanamide (CAS: 1643330-62-4) (Wang et al., Reference Wang, Xiang, Cen, Zhang, Huang, Zhou, Liu and Qiao2015). The melting point and measured density of the title compound are 203–205 °C and 1.274 g cm−3, respectively. Crystallization of the title compound at room temperature was successful using methanol as solvent. Then, parts of crystals were dried and ground into powder and mounted on a flat zero background plate.

Figure 1.

Synthesis of the title compound.

B. Diffraction data collection and reduction

X-ray powder diffraction measurement was performed at room temperature using an X'Pert PRO diffractometer (PANalytical Co., Ltd., Netherlands) with a PIXcel one-dimensional (1D) detector and CuKα radiation (generator setting: 40 kV and 40 mA). The sample was mounted on a flat zero background plate. The diffraction data were collected over the angular range from 4 to 50°2θ with a step size of 0.013 13°2θ and a counting time of 30 ms step−1.

The software package Material Studio 8.0 (Accelrys Co., Ltd., CA) was used to process the data in the Analytical & Testing Center (Sichuan University, Chengdu, China). The X-ray powder diffraction pattern (Figure 2) was pre-treated by subtracting the background, smoothing, and stripping off the Kα 2 component. Automatic indexing results were obtained by the X-cell method (Neumann, Reference Neumann2003). The preliminary cell from indexing was refined using the Pawley method (Pawley, Reference Pawley1981).

Figure 2.

X-ray powder diffraction pattern of title compound using CuKα radiation. The inset is the ORTEP drawing of molecular structure of title compound with the labeling of non-H atoms.

C. Single-crystal X-ray diffraction

X-ray diffraction data for the title compound were collected on an Xcalibur, Eos diffractometer. The crystal was kept at 293.15 K during data collection. The structure was solved with olex2 (Dolomanov et al., Reference Dolomanov, Bourhis, Gildea, Howard and Puschmann2009), a structure solution program using charge flipping and refined with ShelXL (Sheldrick, Reference Sheldrick2008) refinement package using least-squares minimization.

III. RESULTS

Pawley refinement results confirmed that the title compound is triclinic with space group P−1 and unit-cell parameters: a = 5.989(2), b = 6.669(3), c = 24.605(5) Å, α = 84.466(7)°, β = 89.859(6)°, γ = 69.074(4)°, unit-cell volume V = 913.11 Å3, Z = 2, and ρ cal = 1.289 g cm−3 (Table I). The results are in good agreement with the single crystallographic data [a = 6.0164(5), b = 6.6483(8), c = 24.700(3) Å, α = 83.957(10)°, β = 89.451(9)°, γ = 69.222(10)°, unit-cell volume V = 918.17(18) Å3, Z = 2, and ρ cal = 1.286 g cm−3]. The detail single crystallographic data of title compound and the experimental data were listed in Table II and the fractional atomic coordinates were listed in Table III. The title compound is composed of four rings. Two 2-piperidone rings with sofa-half-chair-conformations are connected by phenyl ring, which are respectively twisted by 47.3(5)° (C5–N1–C6–C11) and 136.6(4)° (C12–N2–C9–C10). The morpholine ring with sofa-half-chair-conformation is attached to the piperidone ring twisted by −5.8(6)° (C17–N3–C15–C14). It is arranged without intramolecular and intermolecular H bonding (Figure 3).

Figure 3.

(Color online) Crystal packing of the title compound.

Table I.

X-ray powder diffraction data for 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone, C20H25N3O3. The d-values were calculated using CuKα 1 radiation (λ = 1.54056 Å).

Table II.

Crystal and experimental data of title compound.

Table III.

Fractional atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2 × 103).

SUPPLEMENTARY MATERIAL

The supplementary material for this article can be found at http://dx.doi.org/10.1017/S0885715616000385

ACKNOWLEDGEMENTS

This work was supported by the Applied Basic Research Project of Sichuan Province (Grant No. 2014JY0042), the Testing Platform Construction of Technology Achievement Transform of Sichuan Province (Grant No. 13CGPT0049), and the National Development and Reform Commission and Education of China (Grant No. 2014BW011).

References

Deeks, E. D. (2012). “Apixaban,” Drugs 72(9), 1271–1291.CrossRefGoogle ScholarPubMed
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K., and Puschmann, H. (2009). “OLEX2: a complete structure solution, refinement and analysis program,” J. Appl. Crystallogr. 42, 339–341.CrossRefGoogle Scholar
Jiang, J. and Ji, Y. (2013) “Alternate synthesis of apixaban (BMS-562247), an inhibitor of blood coagulation factor Xa”, Synth. Commun. 43(1), 72–79.Google Scholar
Neumann, M. A. (2003). “X-cell: a novel indexing algorithm for routine tasks and difficult cases,” J. Appl. Crystallogr. 36, 356–365.CrossRefGoogle Scholar
Pawley, G. S. (1981). “Unit-cell refinement from powder diffraction scans,” J. Appl. Crystallogr. 14(6), 357–361.CrossRefGoogle Scholar
Sheldrick, G. M. (2008). “Foundations of crystallography,” Acta Crystallogr. A 64, 112–122.Google Scholar
Wang, Y., Xiang, Y. Z., Cen, G. D., Zhang, J. B., Huang, L., Zhou, N., Liu, J., and Qiao, H. (2015). “Pyrazole derivative and medical application,” WO Pat., 2015070809.Google Scholar
Watson, J., Whiteside, G., and Perry, C. (2011). “Apixaban,” Drugs 71, 2079–2089.Google Scholar
Figure 0

Figure 1. Synthesis of the title compound.

Figure 1

Figure 2. X-ray powder diffraction pattern of title compound using CuKα radiation. The inset is the ORTEP drawing of molecular structure of title compound with the labeling of non-H atoms.

Figure 2

Figure 3. (Color online) Crystal packing of the title compound.

Figure 3

Table I. X-ray powder diffraction data for 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone, C20H25N3O3. The d-values were calculated using CuKα1 radiation (λ = 1.54056 Å).

Figure 4

Table II. Crystal and experimental data of title compound.

Figure 5

Table III. Fractional atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2 × 103).

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