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Acta Crystallogr Sect E Struct Rep Online. 2010 December 1; 66(Pt 12): o3258.
Published online 2010 November 20. doi:  10.1107/S1600536810047707
PMCID: PMC3011444

(2R,4R)-1-(tert-But­oxy­carbon­yl)-4-meth­oxy­pyrrolidine-2-carb­oxy­lic acid

Abstract

In the title compound, C11H19NO5, the five-membered pyrrolidine ring adopts an envelope conformation. The dihedral angles between the carboxyl group plane, the pyrrolidine ring and the meth­oxy group are 59.50 (3) and 62.02 (1)°, respectively. In the crystal, inter­molecular O—H(...)O hydrogen bonds link the mol­ecules into chains along [100]. The absolute configuration is assigned in accord with that of (2R,4R)-1-(tert-but­oxy­carbon­yl)-4-hy­droxy­pyrrolidine-2-carb­oxy­lic acid, which was the starting material in the synthesis.

Related literature

The title compound is an inter­mediate in the preparation of the direct FXa inhibitor, eribaxaban {systematic name: (2R,4R)-N 1-(4-chlorophenyl)-N 2-[2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl]-4-methoxypyrrolidine-1,2-dicarboxamide}. For background to the bioactivity and applications of eribaxaban, see: Perzborn (2009 [triangle]); Kohrt et al. (2007 [triangle]). For the synthesis of other derivatives with proline, see: Van Huis et al. (2009 [triangle]); Bigge et al. (2003 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o3258-scheme1.jpg

Experimental

Crystal data

  • C11H19NO5
  • M r = 245.27
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o3258-efi1.jpg
  • a = 6.4299 (13) Å
  • b = 9.784 (2) Å
  • c = 10.279 (2) Å
  • β = 90.12 (3)°
  • V = 646.7 (2) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.10 mm−1
  • T = 293 K
  • 0.26 × 0.20 × 0.10 mm

Data collection

  • Rigaku Saturn CCD area-detector diffractometer
  • Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005) [triangle] T min = 0.975, T max = 0.990
  • 7923 measured reflections
  • 1601 independent reflections
  • 1059 reflections with I > 2σ(I)
  • R int = 0.059

Refinement

  • R[F 2 > 2σ(F 2)] = 0.037
  • wR(F 2) = 0.086
  • S = 0.94
  • 1601 reflections
  • 163 parameters
  • 1 restraint
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.13 e Å−3
  • Δρmin = −0.16 e Å−3

Data collection: CrystalClear (Rigaku, 2005) [triangle]; cell refinement: CrystalClear [triangle]; data reduction: CrystalClear [triangle]; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810047707/kp2285sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810047707/kp2285Isup2.hkl

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

Acknowledgments

The authors thank the State Key Laboratory of Elemento-organic Chemistry, Nankai University, for the data collection.

supplementary crystallographic information

Comment

Eribaxaban is a direct FXa inhibitors and has a high affinity for human FXa. Clinical data with eribaxaban in the prevention of VTE in TKR patients have recently been presented (Perzborn, 2009; Kohrt et al., 2007).

The title compound (Fig. 1), (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid is important intermediate in the preparation of Eribaxaban. Some derivatives of Eribaxaban have been reported with high affinity for human FXa (Van Huis et al., 2009; Bigge et al., 2003). Herein, the synthesis and the crystal structure of the title compound are reported; the absolute configuration is assigned by the use of (2R,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid as the starting material for the synthesis.

The pyrrolidine ring of the title compound adopts an envelope conformation with the C3 lying out of the plane. The dihedral angles between the carboxyl group plane, pyrrolidine ring and methoxy system are 120.50 (3)° and 117.98 (1)°, respectively. In the crystal structure, intermolecular O—H···O interactions contribute to the stabilization of the packing. Each molecule is a donor and acceptor for 2 hydrogen bonds (TAble 1).

Experimental

CH3I (22 g, 0.155 mol) and 60%(w/w)NaH (15 g, 0.625 mol) were dissolved in THF(300 ml), and the resulting mixture was cooled to 273 K in an ice bath. (R,R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester(35 g, 0.151 mol)was then added in portions while maintaining a reaction temperature of 278 K or less. The reaction was allowed to warm to 293 K overnight. To the reaction mixture was added H2O (100 ml), 1 N HCl(100 ml) and NaCl(42 g). The layers were separated, and the organic layer was dried over MgSO4, filtered and concentrated to the white solid (37 g). Colourless single crystals suitable for X-ray diffraction were obtained by recrystallisation from methanol.

Refinement

All H atoms were geometrically positioned (C—H 0.93–0.98 Å) and treated as riding, with Uiso(H) = 1.2Ueq(C).

Figures

Fig. 1.
The structure of C11H19NO5 with all non-H atom-labelling scheme and ellipsoids drawn at the 50% probability level.

Crystal data

C11H19NO5F(000) = 264
Mr = 245.27Dx = 1.260 Mg m3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P2ybCell parameters from 1953 reflections
a = 6.4299 (13) Åθ = 3.2–27.8°
b = 9.784 (2) ŵ = 0.10 mm1
c = 10.279 (2) ÅT = 293 K
β = 90.12 (3)°Prism, colorless
V = 646.7 (2) Å30.26 × 0.20 × 0.10 mm
Z = 2

Data collection

Rigaku Saturn CCD area-detector diffractometer1601 independent reflections
Radiation source: rotating anode1059 reflections with I > 2σ(I)
confocalRint = 0.059
ω and [var phi] scansθmax = 27.7°, θmin = 3.2°
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005)h = −8→8
Tmin = 0.975, Tmax = 0.990k = −12→12
7923 measured reflectionsl = −13→13

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.037H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.086w = 1/[σ2(Fo2) + (0.0494P)2] where P = (Fo2 + 2Fc2)/3
S = 0.94(Δ/σ)max < 0.001
1601 reflectionsΔρmax = 0.13 e Å3
163 parametersΔρmin = −0.16 e Å3
1 restraintExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.55 (4)

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 (Å2)

xyzUiso*/Ueq
O10.9616 (2)0.74085 (17)0.56702 (14)0.0482 (4)
O21.2349 (3)0.63017 (18)0.30520 (17)0.0550 (5)
O31.1022 (3)0.83878 (17)0.27707 (17)0.0505 (5)
H31.253 (5)0.861 (4)0.262 (3)0.093 (11)*
O40.4931 (2)0.92660 (17)0.24970 (16)0.0472 (5)
O50.6949 (2)0.80182 (16)0.10995 (13)0.0462 (5)
N10.7106 (2)0.7625 (2)0.32240 (16)0.0387 (4)
C11.0873 (3)0.7059 (2)0.2972 (2)0.0383 (5)
C20.8634 (3)0.6534 (2)0.3036 (2)0.0375 (5)
H20.83040.60190.22440.045*
C30.8259 (4)0.5636 (2)0.4235 (2)0.0490 (6)
H3A0.70870.50270.41030.059*
H3B0.94820.50990.44480.059*
C40.7804 (4)0.6680 (2)0.5283 (2)0.0461 (6)
H40.70920.62690.60280.055*
C50.6428 (3)0.7725 (3)0.45841 (19)0.0454 (6)
H5A0.49680.74930.46700.054*
H5B0.66540.86380.49240.054*
C61.1031 (4)0.6610 (3)0.6413 (2)0.0632 (8)
H6A1.02890.61350.70840.095*
H6B1.20570.71970.68010.095*
H6C1.17060.59600.58560.095*
C70.6240 (3)0.8376 (2)0.2284 (2)0.0381 (5)
C80.6706 (4)0.8926 (2)−0.0042 (2)0.0463 (6)
C90.7760 (5)1.0273 (3)0.0251 (3)0.0712 (9)
H9A0.70981.06970.09830.107*
H9B0.76501.0863−0.04930.107*
H9C0.92001.01150.04470.107*
C100.7858 (5)0.8146 (4)−0.1077 (2)0.0734 (9)
H10A0.92560.7975−0.07910.110*
H10B0.78840.8672−0.18650.110*
H10C0.71670.7291−0.12350.110*
C110.4450 (5)0.9100 (4)−0.0410 (3)0.0750 (9)
H11A0.37650.8229−0.03820.113*
H11B0.43560.9469−0.12740.113*
H11C0.37940.97140.01910.113*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0579 (10)0.0464 (10)0.0402 (8)−0.0032 (8)−0.0090 (7)0.0051 (7)
O20.0423 (9)0.0491 (10)0.0735 (11)0.0155 (9)−0.0065 (7)−0.0084 (8)
O30.0326 (9)0.0405 (10)0.0783 (12)0.0026 (8)0.0053 (7)0.0105 (9)
O40.0349 (9)0.0452 (10)0.0614 (10)0.0048 (8)0.0058 (7)0.0067 (7)
O50.0514 (9)0.0497 (10)0.0374 (9)0.0110 (8)−0.0016 (6)0.0051 (7)
N10.0300 (9)0.0469 (11)0.0393 (10)0.0032 (9)0.0017 (7)0.0045 (8)
C10.0368 (13)0.0415 (13)0.0364 (11)0.0045 (10)−0.0013 (9)−0.0039 (9)
C20.0378 (11)0.0365 (12)0.0384 (11)−0.0004 (10)−0.0062 (8)−0.0033 (9)
C30.0561 (16)0.0360 (13)0.0548 (14)−0.0073 (11)−0.0064 (11)0.0074 (10)
C40.0509 (14)0.0451 (15)0.0424 (12)−0.0089 (11)0.0027 (10)0.0084 (10)
C50.0411 (12)0.0557 (15)0.0393 (12)−0.0021 (12)0.0076 (9)0.0029 (11)
C60.0698 (17)0.073 (2)0.0469 (15)0.0031 (16)−0.0158 (12)0.0085 (13)
C70.0270 (10)0.0422 (13)0.0451 (12)−0.0051 (10)0.0012 (9)0.0042 (10)
C80.0563 (15)0.0457 (14)0.0367 (12)−0.0018 (11)−0.0070 (10)0.0064 (9)
C90.100 (2)0.0617 (19)0.0519 (16)−0.0284 (18)0.0041 (15)0.0033 (13)
C100.103 (2)0.076 (2)0.0412 (14)0.0196 (19)0.0010 (14)0.0007 (14)
C110.072 (2)0.076 (2)0.078 (2)0.0082 (17)−0.0301 (15)0.0039 (16)

Geometric parameters (Å, °)

O1—C61.421 (3)C4—H40.9800
O1—C41.422 (3)C5—H5A0.9700
O2—C11.206 (3)C5—H5B0.9700
O3—C11.320 (3)C6—H6A0.9600
O3—H31.00 (3)C6—H6B0.9600
O4—C71.231 (3)C6—H6C0.9600
O5—C71.347 (3)C8—C101.506 (3)
O5—C81.480 (3)C8—C111.508 (4)
N1—C71.335 (3)C8—C91.512 (4)
N1—C21.464 (3)C9—H9A0.9600
N1—C51.469 (3)C9—H9B0.9600
C1—C21.530 (3)C9—H9C0.9600
C2—C31.533 (3)C10—H10A0.9600
C2—H20.9800C10—H10B0.9600
C3—C41.513 (3)C10—H10C0.9600
C3—H3A0.9700C11—H11A0.9600
C3—H3B0.9700C11—H11B0.9600
C4—C51.530 (3)C11—H11C0.9600
C6—O1—C4113.5 (2)O1—C6—H6A109.5
C1—O3—H3108 (2)O1—C6—H6B109.5
C7—O5—C8121.67 (18)H6A—C6—H6B109.5
C7—N1—C2125.79 (17)O1—C6—H6C109.5
C7—N1—C5121.89 (19)H6A—C6—H6C109.5
C2—N1—C5112.03 (17)H6B—C6—H6C109.5
O2—C1—O3123.9 (2)O4—C7—N1123.01 (19)
O2—C1—C2122.1 (2)O4—C7—O5125.3 (2)
O3—C1—C2113.93 (19)N1—C7—O5111.70 (19)
N1—C2—C1113.13 (18)O5—C8—C10101.8 (2)
N1—C2—C3101.81 (17)O5—C8—C11111.5 (2)
C1—C2—C3112.11 (17)C10—C8—C11110.7 (2)
N1—C2—H2109.8O5—C8—C9108.62 (19)
C1—C2—H2109.8C10—C8—C9111.2 (2)
C3—C2—H2109.8C11—C8—C9112.5 (2)
C4—C3—C2102.49 (18)C8—C9—H9A109.5
C4—C3—H3A111.3C8—C9—H9B109.5
C2—C3—H3A111.3H9A—C9—H9B109.5
C4—C3—H3B111.3C8—C9—H9C109.5
C2—C3—H3B111.3H9A—C9—H9C109.5
H3A—C3—H3B109.2H9B—C9—H9C109.5
O1—C4—C3112.24 (19)C8—C10—H10A109.5
O1—C4—C5105.62 (19)C8—C10—H10B109.5
C3—C4—C5103.28 (17)H10A—C10—H10B109.5
O1—C4—H4111.7C8—C10—H10C109.5
C3—C4—H4111.7H10A—C10—H10C109.5
C5—C4—H4111.7H10B—C10—H10C109.5
N1—C5—C4103.27 (19)C8—C11—H11A109.5
N1—C5—H5A111.1C8—C11—H11B109.5
C4—C5—H5A111.1H11A—C11—H11B109.5
N1—C5—H5B111.1C8—C11—H11C109.5
C4—C5—H5B111.1H11A—C11—H11C109.5
H5A—C5—H5B109.1H11B—C11—H11C109.5
C7—N1—C2—C185.8 (2)C7—N1—C5—C4179.02 (19)
C5—N1—C2—C1−100.3 (2)C2—N1—C5—C44.8 (2)
C7—N1—C2—C3−153.7 (2)O1—C4—C5—N189.6 (2)
C5—N1—C2—C320.2 (2)C3—C4—C5—N1−28.4 (2)
O2—C1—C2—N1166.64 (19)C2—N1—C7—O4178.7 (2)
O3—C1—C2—N1−16.0 (2)C5—N1—C7—O45.3 (3)
O2—C1—C2—C352.2 (3)C2—N1—C7—O5−0.3 (3)
O3—C1—C2—C3−130.4 (2)C5—N1—C7—O5−173.6 (2)
N1—C2—C3—C4−37.2 (2)C8—O5—C7—O418.7 (3)
C1—C2—C3—C484.0 (2)C8—O5—C7—N1−162.41 (18)
C6—O1—C4—C3−71.9 (2)C7—O5—C8—C10175.9 (2)
C6—O1—C4—C5176.29 (19)C7—O5—C8—C11−65.9 (3)
C2—C3—C4—O1−72.3 (2)C7—O5—C8—C958.5 (3)
C2—C3—C4—C540.9 (2)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O3—H3···O4i1.00 (3)1.68 (4)2.672 (2)169 (4)

Symmetry codes: (i) x+1, y, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: KP2285).

References

  • Bigge, C. F., et al. (2003). Patent WO 03045912A1.
  • Kohrt, J. T., et al. (2007). Chem. Biol. Drug Des.17, 100–112. [PubMed]
  • Perzborn, E. (2009). Hamostaseologie, 29, 260–267. [PubMed]
  • Rigaku (1998). RAPID-AUTO Rigaku Corporation, Tokyo, Japan.
  • Rigaku/MSC (2005). CrystalClear Rigaku/MSC, The Woodlands, Texas, USA.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Van Huis, C. A., et al. (2009). Bioorg. Med. Chem.17, 2501–2511. [PubMed]

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