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Acta Crystallogr Sect E Struct Rep Online. 2010 June 1; 66(Pt 6): o1354.
Published online 2010 May 15. doi:  10.1107/S1600536810017095
PMCID: PMC2979458

Prasugrel, a new medicine for preventing blockages in the arteries

Abstract

Prasugrel {systematic name: 5-[(2-cyclo­propyl­carbon­yl)(2-fluoro­phen­yl)meth­yl]-4,5,6,7-tetra­hydro­thieno[3,2-c]pyridin-2-yl acetate}, C20H20FNO3S, is a new third-generation thienopyridine which was recently approved for clinical use as a more potent blocker of the platelet P2Y12 receptor than clopidogrel, which was previously used for this purpose. The mol­ecule features a tetra­hydro­thienopyridine system with the tetra­hydro­pyridine ring showing a half-chair conformation; the dihedral angle formed by the the planes of the benzene and thio­phene rings is 83.17 (3)°.

Related literature

For the biological activity of the title compound, see: Farid et al. (2008 [triangle]). For details of the synthesis, see: Sun et al. (2009 [triangle]).

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Object name is e-66-o1354-scheme1.jpg

Experimental

Crystal data

  • C20H20FNO3S
  • M r = 373.43
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1354-efi1.jpg
  • a = 7.910 (2) Å
  • b = 9.943 (3) Å
  • c = 12.450 (4) Å
  • α = 112.938 (5)°
  • β = 90.644 (5)°
  • γ = 92.591 (6)°
  • V = 900.3 (5) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.21 mm−1
  • T = 291 K
  • 0.32 × 0.28 × 0.26 mm

Data collection

  • Bruker SMART CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 2000 [triangle]) T min = 0.936, T max = 0.947
  • 5345 measured reflections
  • 3201 independent reflections
  • 2379 reflections with I > 2σ(I)
  • R int = 0.027

Refinement

  • R[F 2 > 2σ(F 2)] = 0.106
  • wR(F 2) = 0.198
  • S = 1.08
  • 3201 reflections
  • 235 parameters
  • H-atom parameters constrained
  • Δρmax = 0.73 e Å−3
  • Δρmin = −0.26 e Å−3

Data collection: SMART (Bruker, 2000 [triangle]); cell refinement: SAINT (Bruker, 2000 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810017095/ya2121sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810017095/ya2121Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

The authors thank the Program for Young Excellent Talents in Southeast University for financial support.

supplementary crystallographic information

Comment

Prasugrel was recently approved for clinical use in combination with aspirin as an option for preventing blockages in the arteries in patients with acute coronary syndromes who are undergoing treatment via percutaneous coronary intervention (Farid et al., 2008). Both enantiomers of prasugrel show similar activity, therefore it was approved for use in its racemic form. The synthesis of prasugrel has been published recently (Sun et al., 2009). Herein we report its crystal structure (Fig. 1).

The tetrahydropyridine ring of the bicyclic thienopyridine system shows a half-chair conformation with the N1 and C8 atoms displaced by -0.408 (7) Å and 0.411 (7) Å from the plane of C5, C6, C7 and C9 atoms, which are coplanar within 0.003 Å. The dihedral angle formed by the the planes of the benzene and thiophene rings (C11-C16 and C3, C4, C5, C6, S1, respectively) is equal to 83.17 (3)°.

Experimental

The description of the seven-step synthesis of the title compound is published by Sun et al. (2009). Here we report the details for the two final steps of the synthesis.

Synthesis of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl) -5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one. Under N2 atmosphere, 5,6,7,7a-tetrahydrothieno[3,2-c] pyridin-2(4H)-one hydrochloride (19.1 g, 0.1 mol) and N,N-diisopropylformamide (27.1 g, 0.21 mol) were dissolved in 60 ml of CH3CN. 2-Bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (28.1 g, 0.11 mol) was added to the solution at 40°C. The mixture was stirred for 8 h and poured into H2O (500 ml), then extracted with ethyl acetate (50 ml x 3). The organic phase was collected and washed with saturated NaCl solution (80 ml x 4), then dried with anhydrous Na2SO4 and filtered. The filtrate was distilled in vacuo and the solvent was removed. The residue was separated with column chromatography and pale-yellow oil of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,\ 2-c]pyridin-2(4H)-one was obtained (12 g. 41%).

Synthesis of prasugrel. 5-(2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-\ c]pyridin-2(4H)-one (3.31 g, 0.01 mol) was dissolved in the mixture of DMF (20 ml) and acetate anhydride (1.13 ml, 0.012 mol). NaH (0.44 g, 0.011 mol) was added at 0°C and stirred for 1 h at room temperature. The reaction solution was poured into iced water (50 ml) and extracted with ethyl acetate (30 ml x 3). The organic phase was separated and washed with saturated NaCl solution (50 ml x 4), then dried with anhydrous Na2SO4 and filtered. The filtrate was distilled in vacuo and the solvent was removed. The residue was washed in 10 ml of ether, and thus prasugrel, in the form of colorless solid, was obtained (2.5 g, 66%).

0.074 g (2 mmol) of prasugrel powder were dissolved in 20 ml of methanol and then slowly evaporated. After two weeks, colorless block crystals were obtained and collected [yield 83.8% (0.062 g)].

Refinement

All the H atoms were positioned geometrically and included in the refinement using riding model approximation with C—H = 0.93–0.97 Å and Uiso(H) = 1.2Ueq(C) [Uiso(H) = 1.5Ueq(C) for methyl H atoms]. Unfortunately, all crystals, finally formed after the prolonged crystallization, were of limited quality, which is reflected in rather poor accuracy of the structure.

Figures

Fig. 1.
Molecular structure of the title compound with thermal ellipsoids drawn at the 30% probability level.

Crystal data

C20H20FNO3SZ = 2
Mr = 373.43F(000) = 392
Triclinic, P1Dx = 1.378 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 7.910 (2) ÅCell parameters from 1069 reflections
b = 9.943 (3) Åθ = 2.2–21.9°
c = 12.450 (4) ŵ = 0.21 mm1
α = 112.938 (5)°T = 291 K
β = 90.644 (5)°Block, colorless
γ = 92.591 (6)°0.32 × 0.28 × 0.26 mm
V = 900.3 (5) Å3

Data collection

Bruker SMART CCD diffractometer3201 independent reflections
Radiation source: fine-focus sealed tube2379 reflections with I > 2σ(I)
graphiteRint = 0.027
[var phi] and ω scansθmax = 25.2°, θmin = 1.8°
Absorption correction: multi-scan (SADABS; Sheldrick, 2000)h = −9→9
Tmin = 0.936, Tmax = 0.947k = −11→10
5345 measured reflectionsl = −13→14

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.106Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.198H-atom parameters constrained
S = 1.08w = 1/[σ2(Fo2) + (0.0117P)2 + 3.2142P] where P = (Fo2 + 2Fc2)/3
3201 reflections(Δ/σ)max = 0.001
235 parametersΔρmax = 0.73 e Å3
0 restraintsΔρmin = −0.26 e Å3

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. 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 (Å2)

xyzUiso*/Ueq
S10.98277 (19)0.7094 (2)0.12388 (13)0.0633 (5)
F10.8924 (5)0.9710 (5)−0.3950 (4)0.0885 (12)
C11.4971 (8)0.5727 (9)0.2034 (6)0.080 (2)
H1A1.50910.58060.28250.120*
H1B1.59070.62510.18610.120*
H1C1.49530.47160.15140.120*
C21.3386 (8)0.6352 (8)0.1886 (5)0.074 (2)
C31.1688 (7)0.6812 (7)0.0487 (5)0.0526 (15)
C41.1564 (7)0.7042 (6)−0.0503 (5)0.0533 (15)
H4A1.24430.6929−0.10160.064*
C50.9935 (7)0.7477 (6)−0.0677 (4)0.0482 (13)
C60.8868 (7)0.7542 (7)0.0175 (4)0.0528 (15)
C70.7093 (7)0.8012 (8)0.0226 (5)0.0643 (18)
H7A0.68540.86670.10140.077*
H7B0.63010.7167−0.00040.077*
C80.6913 (7)0.8786 (7)−0.0600 (5)0.0625 (17)
H8A0.57320.8971−0.06750.075*
H8B0.75540.9719−0.02890.075*
C90.9400 (7)0.7866 (7)−0.1670 (5)0.0538 (15)
H9A0.98940.8825−0.15550.065*
H9B0.98140.7164−0.23920.065*
C100.7071 (7)0.8485 (6)−0.2608 (5)0.0491 (14)
H10A0.75320.9498−0.23430.059*
C110.7730 (6)0.7596 (6)−0.3819 (4)0.0437 (13)
C120.8627 (7)0.8249 (6)−0.4420 (5)0.0475 (13)
C130.9202 (7)0.7512 (7)−0.5530 (5)0.0574 (16)
H13A0.98130.8007−0.59100.069*
C140.8856 (8)0.6067 (8)−0.6044 (5)0.0620 (16)
H14A0.92450.5550−0.67870.074*
C150.7937 (9)0.5342 (8)−0.5491 (6)0.0714 (19)
H15A0.76850.4341−0.58630.086*
C160.7382 (9)0.6108 (7)−0.4370 (5)0.0679 (18)
H16A0.67710.5613−0.39900.082*
C170.5147 (7)0.8444 (7)−0.2809 (5)0.0517 (14)
C180.4630 (8)0.9356 (7)−0.3427 (5)0.0654 (17)
H18A0.54741.0094−0.34540.079*
C190.2829 (9)0.9711 (9)−0.3429 (6)0.089 (2)
H19A0.20540.9357−0.29870.106*
H19B0.25901.0659−0.34290.106*
C200.3480 (9)0.8650 (9)−0.4476 (6)0.085 (2)
H20A0.36510.8935−0.51300.102*
H20B0.31150.7632−0.46880.102*
N10.7541 (5)0.7875 (5)−0.1760 (4)0.0494 (12)
O11.2404 (8)0.6812 (10)0.2594 (4)0.168 (4)
O21.3121 (5)0.6278 (5)0.0798 (3)0.0711 (13)
O30.4151 (5)0.7686 (5)−0.2536 (4)0.0692 (12)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
S10.0504 (9)0.1083 (14)0.0387 (8)0.0199 (9)0.0111 (6)0.0349 (8)
F10.092 (3)0.092 (3)0.090 (3)0.005 (2)0.024 (2)0.043 (3)
C10.070 (4)0.121 (6)0.063 (4)0.032 (4)0.006 (3)0.047 (4)
C20.064 (4)0.112 (6)0.045 (4)0.027 (4)0.005 (3)0.027 (4)
C30.045 (3)0.078 (4)0.039 (3)0.014 (3)0.009 (2)0.027 (3)
C40.047 (3)0.075 (4)0.044 (3)0.016 (3)0.014 (3)0.027 (3)
C50.046 (3)0.061 (4)0.039 (3)0.009 (3)0.004 (2)0.021 (3)
C60.047 (3)0.076 (4)0.034 (3)0.009 (3)0.002 (2)0.019 (3)
C70.047 (3)0.106 (5)0.040 (3)0.022 (3)0.008 (3)0.027 (3)
C80.053 (4)0.085 (5)0.040 (3)0.024 (3)0.002 (3)0.012 (3)
C90.048 (3)0.077 (4)0.042 (3)0.014 (3)0.009 (3)0.028 (3)
C100.048 (3)0.057 (4)0.044 (3)0.003 (3)0.001 (2)0.022 (3)
C110.038 (3)0.058 (4)0.041 (3)0.004 (2)−0.001 (2)0.026 (3)
C120.048 (3)0.045 (3)0.055 (3)0.004 (3)−0.003 (3)0.026 (3)
C130.054 (4)0.080 (5)0.053 (4)0.012 (3)0.012 (3)0.042 (4)
C140.066 (4)0.075 (5)0.047 (3)0.014 (3)0.007 (3)0.024 (3)
C150.087 (5)0.065 (4)0.057 (4)−0.001 (4)0.004 (4)0.018 (3)
C160.084 (5)0.074 (5)0.047 (4)0.005 (4)0.007 (3)0.024 (3)
C170.048 (3)0.069 (4)0.038 (3)0.005 (3)0.003 (3)0.021 (3)
C180.052 (4)0.086 (5)0.068 (4)0.005 (3)−0.002 (3)0.041 (4)
C190.066 (5)0.135 (7)0.072 (5)0.027 (5)−0.006 (4)0.047 (5)
C200.100 (6)0.108 (6)0.057 (4)0.007 (5)−0.014 (4)0.043 (4)
N10.045 (3)0.069 (3)0.037 (2)0.015 (2)0.005 (2)0.022 (2)
O10.121 (5)0.333 (10)0.051 (3)0.131 (6)0.019 (3)0.063 (5)
O20.060 (3)0.117 (4)0.050 (2)0.039 (3)0.012 (2)0.044 (3)
O30.049 (2)0.111 (4)0.061 (3)−0.007 (2)−0.005 (2)0.051 (3)

Geometric parameters (Å, °)

S1—C31.727 (5)C10—N11.460 (7)
S1—C61.731 (5)C10—C111.531 (7)
F1—C121.346 (6)C10—C171.535 (7)
C1—C21.464 (8)C10—H10A0.9800
C1—H1A0.9600C11—C121.355 (7)
C1—H1B0.9600C11—C161.380 (8)
C1—H1C0.9600C12—C131.381 (8)
C2—O11.150 (7)C13—C141.338 (8)
C2—O21.342 (7)C13—H13A0.9300
C3—C41.342 (7)C14—C151.368 (9)
C3—O21.385 (6)C14—H14A0.9300
C4—C51.418 (7)C15—C161.392 (8)
C4—H4A0.9300C15—H15A0.9300
C5—C61.346 (7)C16—H16A0.9300
C5—C91.494 (7)C17—O31.206 (7)
C6—C71.494 (7)C17—C181.467 (8)
C7—C81.515 (8)C18—C191.483 (8)
C7—H7A0.9700C18—C201.492 (9)
C7—H7B0.9700C18—H18A0.9800
C8—N11.480 (6)C19—C201.438 (9)
C8—H8A0.9700C19—H19A0.9700
C8—H8B0.9700C19—H19B0.9700
C9—N11.474 (6)C20—H20A0.9700
C9—H9A0.9700C20—H20B0.9700
C9—H9B0.9700
C3—S1—C690.2 (3)C17—C10—H10A109.4
C2—C1—H1A109.5C12—C11—C16116.7 (5)
C2—C1—H1B109.5C12—C11—C10121.3 (5)
H1A—C1—H1B109.5C16—C11—C10121.9 (5)
C2—C1—H1C109.5F1—C12—C11119.3 (5)
H1A—C1—H1C109.5F1—C12—C13116.8 (5)
H1B—C1—H1C109.5C11—C12—C13123.9 (6)
O1—C2—O2121.5 (6)C14—C13—C12118.3 (6)
O1—C2—C1125.3 (6)C14—C13—H13A120.9
O2—C2—C1113.1 (5)C12—C13—H13A120.9
C4—C3—O2122.4 (5)C13—C14—C15120.9 (6)
C4—C3—S1112.7 (4)C13—C14—H14A119.6
O2—C3—S1124.6 (4)C15—C14—H14A119.6
C3—C4—C5112.1 (5)C14—C15—C16119.7 (7)
C3—C4—H4A123.9C14—C15—H15A120.1
C5—C4—H4A123.9C16—C15—H15A120.1
C6—C5—C4113.0 (5)C11—C16—C15120.5 (6)
C6—C5—C9121.4 (5)C11—C16—H16A119.7
C4—C5—C9125.6 (5)C15—C16—H16A119.7
C5—C6—C7124.1 (5)O3—C17—C18122.7 (5)
C5—C6—S1112.0 (4)O3—C17—C10123.7 (5)
C7—C6—S1123.9 (4)C18—C17—C10113.6 (5)
C6—C7—C8108.0 (5)C17—C18—C19119.3 (6)
C6—C7—H7A110.1C17—C18—C20117.3 (6)
C8—C7—H7A110.1C19—C18—C2057.8 (4)
C6—C7—H7B110.1C17—C18—H18A116.5
C8—C7—H7B110.1C19—C18—H18A116.5
H7A—C7—H7B108.4C20—C18—H18A116.5
N1—C8—C7110.0 (5)C20—C19—C1861.4 (5)
N1—C8—H8A109.7C20—C19—H19A117.6
C7—C8—H8A109.7C18—C19—H19A117.6
N1—C8—H8B109.7C20—C19—H19B117.6
C7—C8—H8B109.7C18—C19—H19B117.6
H8A—C8—H8B108.2H19A—C19—H19B114.7
N1—C9—C5111.1 (4)C19—C20—C1860.8 (4)
N1—C9—H9A109.4C19—C20—H20A117.7
C5—C9—H9A109.4C18—C20—H20A117.7
N1—C9—H9B109.4C19—C20—H20B117.7
C5—C9—H9B109.4C18—C20—H20B117.7
H9A—C9—H9B108.0H20A—C20—H20B114.8
N1—C10—C11111.6 (4)C10—N1—C9109.7 (4)
N1—C10—C17112.8 (5)C10—N1—C8109.8 (4)
C11—C10—C17104.1 (4)C9—N1—C8108.6 (4)
N1—C10—H10A109.4C2—O2—C3121.6 (4)
C11—C10—H10A109.4

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: YA2121).

References

  • Bruker (2000). SMART and SAINT Bruker AXS Inc., Madison, Wisconsin, USA.
  • Farid, N. A., Payne, C. D., Ernest, C. S., Li, Y. G., Winters, K. J., Salazar, D. E. & Small, D. S. (2008). J. Clin. Pharmacol.48, 53–59. [PubMed]
  • Sheldrick, G. M. (2000). SADABS University of Göttingen, Germany.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Sun, Z.-G., Hou, J., Zou, Q., Wang, G.-P. & Zhang, Y. (2009). Zhongguo Yiyao Gongye Zazhi (Chin. J. Pharm.), 40, 244–246.

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