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

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.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.037
• wR factor = 0.086
• Data-to-parameter ratio = 9.8

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for         C8
PLAT355_ALERT_3_C Long    O-H Bond (0.82A)   O3     -   H3     ...       1.01 Ang.
PLAT910_ALERT_3_C Missing # of FCF Reflections Below Th(Min) .....          2
PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L=  0.600         10
PLAT913_ALERT_3_C Missing # of Very Strong Reflections in FCF ....         11

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           27.74
           From the CIF: _reflns_number_total               1601
           Count of symmetry unique reflns         1613
           Completeness (_total/calc)             99.26%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no
PLAT199_ALERT_1_G Check the Reported _cell_measurement_temperature        293 K
PLAT200_ALERT_1_G Check the Reported   _diffrn_ambient_temperature        293 K
PLAT791_ALERT_4_G Note: The Model has Chirality at C2     (Verify)          R
PLAT791_ALERT_4_G Note: The Model has Chirality at C4     (Verify)          R
PLAT981_ALERT_1_G No non-zero f" Anomalous Scattering Values Found          ?

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

   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
   4 ALERT type 3 Indicator that the structure quality may be low
   3 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. 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).

Related literature

The title compound is an intermediate in the preparation of the direct FXa inhibitor, e,ribaxaban. For background to the bioactivity and applications of eribaxaban, see: Perzborn (2009); Kohrt et al. (2007). For the synthesis of other derivatives with proline, see: Van Huis et al. (2009); Bigge et al. (2003).

S2. 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.

S3. Refinement

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

Computing details

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

Figures

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

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

Crystal data

C11H19NO5	F(000) = 264
Mr = 245.27	Dx = 1.260 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P2yb	Cell parameters from 1953 reflections
a = 6.4299 (13) Å	θ = 3.2–27.8°
b = 9.784 (2) Å	µ = 0.10 mm^−1
c = 10.279 (2) Å	T = 293 K
β = 90.12 (3)°	Prism, colorless
V = 646.7 (2) Å^3	0.26 × 0.20 × 0.10 mm
Z = 2

Data collection

Rigaku Saturn CCD area-detector diffractometer	1601 independent reflections
Radiation source: rotating anode	1059 reflections with I > 2σ(I)
Confocal monochromator	Rint = 0.059
ω and φ scans	θmax = 27.7°, θmin = 3.2°
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005)	h = −8→8
Tmin = 0.975, Tmax = 0.990	k = −12→12
7923 measured reflections	l = −13→13

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)] = 0.037	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.086	w = 1/[σ^2(Fo^2) + (0.0494P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.94	(Δ/σ)max < 0.001
1601 reflections	Δρmax = 0.13 e Å^−3
163 parameters	Δρmin = −0.16 e Å^−3
1 restraint	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction 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 (Ų)

	x	y	z	Uiso*/Ueq
O1	0.9616 (2)	0.74085 (17)	0.56702 (14)	0.0482 (4)
O2	1.2349 (3)	0.63017 (18)	0.30520 (17)	0.0550 (5)
O3	1.1022 (3)	0.83878 (17)	0.27707 (17)	0.0505 (5)
H3	1.253 (5)	0.861 (4)	0.262 (3)	0.093 (11)*
O4	0.4931 (2)	0.92660 (17)	0.24970 (16)	0.0472 (5)
O5	0.6949 (2)	0.80182 (16)	0.10995 (13)	0.0462 (5)
N1	0.7106 (2)	0.7625 (2)	0.32240 (16)	0.0387 (4)
C1	1.0873 (3)	0.7059 (2)	0.2972 (2)	0.0383 (5)
C2	0.8634 (3)	0.6534 (2)	0.3036 (2)	0.0375 (5)
H2	0.8304	0.6019	0.2244	0.045*
C3	0.8259 (4)	0.5636 (2)	0.4235 (2)	0.0490 (6)
H3A	0.7087	0.5027	0.4103	0.059*
H3B	0.9482	0.5099	0.4448	0.059*
C4	0.7804 (4)	0.6680 (2)	0.5283 (2)	0.0461 (6)
H4	0.7092	0.6269	0.6028	0.055*
C5	0.6428 (3)	0.7725 (3)	0.45841 (19)	0.0454 (6)
H5A	0.4968	0.7493	0.4670	0.054*
H5B	0.6654	0.8638	0.4924	0.054*
C6	1.1031 (4)	0.6610 (3)	0.6413 (2)	0.0632 (8)
H6A	1.0289	0.6135	0.7084	0.095*
H6B	1.2057	0.7197	0.6801	0.095*
H6C	1.1706	0.5960	0.5856	0.095*
C7	0.6240 (3)	0.8376 (2)	0.2284 (2)	0.0381 (5)
C8	0.6706 (4)	0.8926 (2)	−0.0042 (2)	0.0463 (6)
C9	0.7760 (5)	1.0273 (3)	0.0251 (3)	0.0712 (9)
H9A	0.7098	1.0697	0.0983	0.107*
H9B	0.7650	1.0863	−0.0493	0.107*
H9C	0.9200	1.0115	0.0447	0.107*
C10	0.7858 (5)	0.8146 (4)	−0.1077 (2)	0.0734 (9)
H10A	0.9256	0.7975	−0.0791	0.110*
H10B	0.7884	0.8672	−0.1865	0.110*
H10C	0.7167	0.7291	−0.1235	0.110*
C11	0.4450 (5)	0.9100 (4)	−0.0410 (3)	0.0750 (9)
H11A	0.3765	0.8229	−0.0382	0.113*
H11B	0.4356	0.9469	−0.1274	0.113*
H11C	0.3794	0.9714	0.0191	0.113*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0579 (10)	0.0464 (10)	0.0402 (8)	−0.0032 (8)	−0.0090 (7)	0.0051 (7)
O2	0.0423 (9)	0.0491 (10)	0.0735 (11)	0.0155 (9)	−0.0065 (7)	−0.0084 (8)
O3	0.0326 (9)	0.0405 (10)	0.0783 (12)	0.0026 (8)	0.0053 (7)	0.0105 (9)
O4	0.0349 (9)	0.0452 (10)	0.0614 (10)	0.0048 (8)	0.0058 (7)	0.0067 (7)
O5	0.0514 (9)	0.0497 (10)	0.0374 (9)	0.0110 (8)	−0.0016 (6)	0.0051 (7)
N1	0.0300 (9)	0.0469 (11)	0.0393 (10)	0.0032 (9)	0.0017 (7)	0.0045 (8)
C1	0.0368 (13)	0.0415 (13)	0.0364 (11)	0.0045 (10)	−0.0013 (9)	−0.0039 (9)
C2	0.0378 (11)	0.0365 (12)	0.0384 (11)	−0.0004 (10)	−0.0062 (8)	−0.0033 (9)
C3	0.0561 (16)	0.0360 (13)	0.0548 (14)	−0.0073 (11)	−0.0064 (11)	0.0074 (10)
C4	0.0509 (14)	0.0451 (15)	0.0424 (12)	−0.0089 (11)	0.0027 (10)	0.0084 (10)
C5	0.0411 (12)	0.0557 (15)	0.0393 (12)	−0.0021 (12)	0.0076 (9)	0.0029 (11)
C6	0.0698 (17)	0.073 (2)	0.0469 (15)	0.0031 (16)	−0.0158 (12)	0.0085 (13)
C7	0.0270 (10)	0.0422 (13)	0.0451 (12)	−0.0051 (10)	0.0012 (9)	0.0042 (10)
C8	0.0563 (15)	0.0457 (14)	0.0367 (12)	−0.0018 (11)	−0.0070 (10)	0.0064 (9)
C9	0.100 (2)	0.0617 (19)	0.0519 (16)	−0.0284 (18)	0.0041 (15)	0.0033 (13)
C10	0.103 (2)	0.076 (2)	0.0412 (14)	0.0196 (19)	0.0010 (14)	0.0007 (14)
C11	0.072 (2)	0.076 (2)	0.078 (2)	0.0082 (17)	−0.0301 (15)	0.0039 (16)

Geometric parameters (Å, º)

O1—C6	1.421 (3)	C4—H4	0.9800
O1—C4	1.422 (3)	C5—H5A	0.9700
O2—C1	1.206 (3)	C5—H5B	0.9700
O3—C1	1.320 (3)	C6—H6A	0.9600
O3—H3	1.00 (3)	C6—H6B	0.9600
O4—C7	1.231 (3)	C6—H6C	0.9600
O5—C7	1.347 (3)	C8—C10	1.506 (3)
O5—C8	1.480 (3)	C8—C11	1.508 (4)
N1—C7	1.335 (3)	C8—C9	1.512 (4)
N1—C2	1.464 (3)	C9—H9A	0.9600
N1—C5	1.469 (3)	C9—H9B	0.9600
C1—C2	1.530 (3)	C9—H9C	0.9600
C2—C3	1.533 (3)	C10—H10A	0.9600
C2—H2	0.9800	C10—H10B	0.9600
C3—C4	1.513 (3)	C10—H10C	0.9600
C3—H3A	0.9700	C11—H11A	0.9600
C3—H3B	0.9700	C11—H11B	0.9600
C4—C5	1.530 (3)	C11—H11C	0.9600
C6—O1—C4	113.5 (2)	O1—C6—H6A	109.5
C1—O3—H3	108 (2)	O1—C6—H6B	109.5
C7—O5—C8	121.67 (18)	H6A—C6—H6B	109.5
C7—N1—C2	125.79 (17)	O1—C6—H6C	109.5
C7—N1—C5	121.89 (19)	H6A—C6—H6C	109.5
C2—N1—C5	112.03 (17)	H6B—C6—H6C	109.5
O2—C1—O3	123.9 (2)	O4—C7—N1	123.01 (19)
O2—C1—C2	122.1 (2)	O4—C7—O5	125.3 (2)
O3—C1—C2	113.93 (19)	N1—C7—O5	111.70 (19)
N1—C2—C1	113.13 (18)	O5—C8—C10	101.8 (2)
N1—C2—C3	101.81 (17)	O5—C8—C11	111.5 (2)
C1—C2—C3	112.11 (17)	C10—C8—C11	110.7 (2)
N1—C2—H2	109.8	O5—C8—C9	108.62 (19)
C1—C2—H2	109.8	C10—C8—C9	111.2 (2)
C3—C2—H2	109.8	C11—C8—C9	112.5 (2)
C4—C3—C2	102.49 (18)	C8—C9—H9A	109.5
C4—C3—H3A	111.3	C8—C9—H9B	109.5
C2—C3—H3A	111.3	H9A—C9—H9B	109.5
C4—C3—H3B	111.3	C8—C9—H9C	109.5
C2—C3—H3B	111.3	H9A—C9—H9C	109.5
H3A—C3—H3B	109.2	H9B—C9—H9C	109.5
O1—C4—C3	112.24 (19)	C8—C10—H10A	109.5
O1—C4—C5	105.62 (19)	C8—C10—H10B	109.5
C3—C4—C5	103.28 (17)	H10A—C10—H10B	109.5
O1—C4—H4	111.7	C8—C10—H10C	109.5
C3—C4—H4	111.7	H10A—C10—H10C	109.5
C5—C4—H4	111.7	H10B—C10—H10C	109.5
N1—C5—C4	103.27 (19)	C8—C11—H11A	109.5
N1—C5—H5A	111.1	C8—C11—H11B	109.5
C4—C5—H5A	111.1	H11A—C11—H11B	109.5
N1—C5—H5B	111.1	C8—C11—H11C	109.5
C4—C5—H5B	111.1	H11A—C11—H11C	109.5
H5A—C5—H5B	109.1	H11B—C11—H11C	109.5
C7—N1—C2—C1	85.8 (2)	C7—N1—C5—C4	179.02 (19)
C5—N1—C2—C1	−100.3 (2)	C2—N1—C5—C4	4.8 (2)
C7—N1—C2—C3	−153.7 (2)	O1—C4—C5—N1	89.6 (2)
C5—N1—C2—C3	20.2 (2)	C3—C4—C5—N1	−28.4 (2)
O2—C1—C2—N1	166.64 (19)	C2—N1—C7—O4	178.7 (2)
O3—C1—C2—N1	−16.0 (2)	C5—N1—C7—O4	5.3 (3)
O2—C1—C2—C3	52.2 (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—O4	18.7 (3)
C1—C2—C3—C4	84.0 (2)	C8—O5—C7—N1	−162.41 (18)
C6—O1—C4—C3	−71.9 (2)	C7—O5—C8—C10	175.9 (2)
C6—O1—C4—C5	176.29 (19)	C7—O5—C8—C11	−65.9 (3)
C2—C3—C4—O1	−72.3 (2)	C7—O5—C8—C9	58.5 (3)
C2—C3—C4—C5	40.9 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O4^i	1.00 (3)	1.68 (4)	2.672 (2)	169 (4)

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