Development of a New Synthesis for the Large-Scale Preparation of Triple Reuptake Inhibitor (-)-GSK1360707 Vassil I. Elitzin, Kimberly A. Harvey, Hyunjung Kim, Matthew Salmons, Matthew J. Sharp*, Elie A. Tabet, and Matthew A. Toczko Chemical Development, GlaxoSmithKline, Research Triangle Park, North Carolina 27709 Matthew.j.sharp@gsk.com Supporting Information: Selected NMR spectra and X-ray crystal structure of GSK1360707 L-tartrate
Cl Cl Me N Me Me Et 4a
Cl Cl Me N Me Me Et 4a
Cl Cl N Et Me Me 12 Me
Cl Cl N Et Me Me 12 Me
Cl Cl H 3 P 4 Me N H (-) GSK1360707 Phosphate
Cl Cl H 3 P 4 Me N H (-) GSK1360707 Phosphate
Basic Structure Report for X4688A2 Compound: GSK1360707 L-Tartrate GSK1360707 Serotonin/Noradrenaline/Dopamine Reuptake Inhibitor - Depression Created by: W. Clegg & L. Russo Issue date: 18 February, 2008 Cl Cl NH 2 + H H H GSK1360707 L-Tartrate (1S,6R)-6-(3,4-Dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane, (2R,3R)-tartaric acid salt (1:1) The asymmetric unit contains a cation and a hydrogen tartrate counter-ion of GSK1360707 L- Tartrate (Figure 1). The final R1 value [I>2σ(I)] was 6.11 %. The structure confirms the atomic connectivity shown in the ISIS Draw sketch above, with bond lengths and angles being consistent with this. The absolute structure was unambiguously determined on the basis of anomalous dispersion effects (C1, S; C6, R; C22, R; C24, R).
Figure 1. A view of a cation and anion of GSK1360707 L-Tartrate from the X4688A2 crystal structure, showing the numbering scheme employed. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius.
Table 1. Sample and crystal data for X4688A2. Identification code X4688A2 Compound number GSK1360707 L-Tartrate Project/Programme/F.S. 13607 Chemist's labbook U24959-168-3 X-ray labbook N4622-13 Crystallization labbook U24776-144-3 Crystallization solvents Ethanol and water Crystallization method Slow cooling with seeding Moiety formula [C 14 H 18 Cl 2 N] + (C 4 H 5 6 ) Empirical formula C 18 H 23 Cl 2 N 7 Formula weight 436.27 Temperature Wavelength Crystal size Crystal habit Crystal system 150(2) K 0.71073 Å 0.78 x 0.32 x 0.04 mm Colourless plate rthorhombic Space group P2 1 2 1 2 1 Unit cell dimensions a = 7.154(4) Å α= 90 Volume 2036(2) Å 3 Z 4 Density (calculated) 1.423 Mg/m 3 Absorption coefficient 0.358 mm -1 b = 7.629(5) Å β= 90 c = 37.31(3) Å γ = 90 F(000) 912
Table 2. Data collection and structure refinement for X4688A2. Diffractometer Radiation source Data collection method Nonius KappaCCD diffractometer Normal focus sealed tube, MoKα ω scans and φ scans Theta range for data collection 5.10 to 25.00 Index ranges -7 h 8, -8 k 8, -43 l 44 Reflections collected 13161 Independent reflections 3454 [R(int) = 0.0704] Coverage of independent reflections 97.5 % Variation in check reflections Absorption correction N/A Numerical Max. and min. transmission 0.959 and 0.835 Structure solution technique Direct methods Structure solution program SHELXTL V6.12 (Bruker, 2001) Refinement technique Full-matrix least-squares on F 2 Refinement program SHELXTL V6.12 (Bruker, 2001) Function minimized Σ w(fo 2 - Fc 2 ) 2 Data / restraints / parameters 3454 / 5 / 269 Goodness-of-fit on F 2 1.117 /σ max 0.000 Final R indices 2468 data; I>2σ(I) R1 = 0.0611, wr2 = 0.0977 all data R1 = 0.1008, wr2 = 0.1083 Weighting scheme w = 1/[σ 2 (Fo 2 ) + (0.0220P) 2 + 1.7281P] where P = [MAX(Fo 2, 0) + 2Fc 2 ]/3 Absolute structure parameter -0.09(12) Largest diff. peak and hole 0.274 and -0.233 eå -3 Refinement summary: rdered Non-H atoms, XYZ Freely refined rdered Non-H atoms, U Freely refined - anisotropic H atoms (on carbon), XYZ Idealized positions riding on attached atoms H atoms (on carbon), U Appropriate multiple of U(eq) for bonded atom H atoms (on heteroatoms), XYZ Refined with distance restraints [DFIX N-H 0.88(1) Å, -H 0.84(1) Å] H atoms (on heteroatoms), U Appropriate multiple of U(eq) for bonded atom Disordered atoms No disorder modelled
Table 3. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å 2 ) for X4688A2. U eq is defined as one third of the trace of the orthogonalized U ij tensor. x y z U eq C1 0.5842(6) 0.6364(6) 0.12639(10) 0.0291(11) C2 0.5645(6) 0.5736(5) 0.08801(10) 0.0275(10) N3 0.6151(5) 0.7115(4) 0.06204(9) 0.0228(8) C4 0.5037(6) 0.8731(6) 0.06771(10) 0.0323(11) C5 0.5671(6) 0.9594(5) 0.10237(10) 0.0304(11) C6 0.5853(6) 0.8334(6) 0.13385(10) 0.0294(10) C7 0.4217(7) 0.7236(6) 0.14420(12) 0.0439(13) C8 0.7050(7) 0.5177(6) 0.14875(11) 0.0426(13) 9 0.8833(5) 0.5111(4) 0.13252(8) 0.0436(8) C10 1.0105(9) 0.4021(7) 0.15127(16) 0.0723(19) C11 0.7139(6) 0.9010(5) 0.16267(10) 0.0285(11) C12 0.6455(7) 0.9698(6) 0.19443(11) 0.0423(12) C13 0.7653(8) 1.0366(7) 0.22028(11) 0.0464(14) C14 0.9550(7) 1.0333(6) 0.21473(12) 0.0391(12) C15 1.0237(7) 0.9667(6) 0.18310(12) 0.0388(12) C16 0.9051(7) 0.9028(5) 0.15729(11) 0.0316(11) Cl17 0.6728(3) 1.1202(3) 0.25928(4) 0.0962(7) Cl18 1.1089(2) 1.1154(2) 0.24617(4) 0.0738(5) 19 0.3814(4) 0.0205(3) -0.03505(7) 0.0273(7) 20 0.6861(4) -0.0322(3) -0.03502(7) 0.0231(7) C21 0.5415(6) 0.0682(5) -0.03975(10) 0.0178(9) C22 0.5844(5) 0.2531(5) -0.05192(10) 0.0177(9) 23 0.7758(4) 0.2888(3) -0.05699(7) 0.0235(7) C24 0.4973(5) 0.3785(5) -0.02464(9) 0.0184(9) 25 0.5570(3) 0.3407(3) 0.01054(6) 0.0192(6) C26 0.5247(5) 0.5702(5) -0.03576(10) 0.0184(9) 27 0.4707(4) 0.6134(3) -0.06597(7) 0.0279(7) 28 0.6047(4) 0.6700(3) -0.01318(6) 0.0219(6)
Table 4. Selected bond lengths (Å) for X4688A2. C1-C7 1.495(6) C1-C8 1.504(6) C1-C2 1.516(5) C1-C6 1.529(6) C2-N3 1.475(5) N3-C4 1.484(5) C4-C5 1.520(6) C5-C6 1.523(6) C6-C7 1.491(6) C6-C11 1.506(6) C8-9 1.414(6) 9-C10 1.417(5) C11-C16 1.383(6) C11-C12 1.385(5) C12-C13 1.387(6) C13-C14 1.373(7) C13-Cl17 1.721(5) C14-C15 1.376(6) C14-Cl18 1.726(5) C15-C16 1.373(6) 19-C21 1.214(4) 20-C21 1.299(5) C21-C22 1.513(5) C22-23 1.409(4) C22-C24 1.530(5) C24-25 1.410(4) C24-C26 1.533(5) C26-27 1.236(4) C26-28 1.272(4)
Table 5. Selected bond angles ( ) for X4688A2. C7-C1-C8 117.9(4) C7-C1-C2 119.2(4) C8-C1-C2 112.8(4) C7-C1-C6 59.1(3) C8-C1-C6 119.2(3) C2-C1-C6 118.9(3) N3-C2-C1 111.9(3) C2-N3-C4 111.5(3) N3-C4-C5 108.7(3) C4-C5-C6 114.1(4) C7-C6-C11 119.2(4) C7-C6-C5 119.2(4) C11-C6-C5 112.7(4) C7-C6-C1 59.4(3) C11-C6-C1 118.0(4) C5-C6-C1 118.7(3) C6-C7-C1 61.6(3) 9-C8-C1 107.6(3) C8-9-C10 112.9(4) C16-C11-C12 118.0(4) C16-C11-C6 120.3(4) C12-C11-C6 121.7(4) C11-C12-C13 121.0(5) C14-C13-C12 119.9(4) C14-C13-Cl17 121.0(4) C12-C13-Cl17 119.1(4) C13-C14-C15 119.3(4) C13-C14-Cl18 121.4(4) C15-C14-Cl18 119.2(4) C16-C15-C14 120.8(5) C15-C16-C11 120.9(4) 19-C21-20 123.7(3) 19-C21-C22 120.9(4) 20-C21-C22 115.4(3) 23-C22-C21 114.7(3) 23-C22-C24 111.4(3) C21-C22-C24 107.5(3) 25-C24-C22 111.6(3) 25-C24-C26 114.1(3) C22-C24-C26 111.4(3) 27-C26-28 125.8(4) 27-C26-C24 117.4(3) 28-C26-C24 116.7(3)
Table 6. Selected torsion angles ( ) for X4688A2. C7-C1-C2-N3 88.9(5) C8-C1-C2-N3-126.4(4) C6-C1-C2-N3 20.3(5) C1-C2-N3-C4-55.9(4) C2-N3-C4-C5 70.5(4) N3-C4-C5-C6-46.8(5) C4-C5-C6-C7-55.1(5) C4-C5-C6-C11 157.9(4) C4-C5-C6-C1 13.8(6) C8-C1-C6-C7-106.8(4) C2-C1-C6-C7 108.6(4) C7-C1-C6-C11 109.0(4) C8-C1-C6-C11 2.2(6) C2-C1-C6-C11-142.4(4) C7-C1-C6-C5-108.8(4) C8-C1-C6-C5 144.4(4) C2-C1-C6-C5-0.2(6) C11-C6-C7-C1-107.2(4) C5-C6-C7-C1 107.9(4) C8-C1-C7-C6 109.0(4) C2-C1-C7-C6-108.1(4) C7-C1-C8-9 -155.6(4) C2-C1-C8-9 59.3(4) C6-C1-C8-9 -87.3(5) C1-C8-9-C10-179.9(4) C7-C6-C11-C16 139.6(4) C5-C6-C11-C16-73.3(5) C1-C6-C11-C16 71.0(5) C7-C6-C11-C12-43.3(6) C5-C6-C11-C12 103.8(5) C1-C6-C11-C12-111.9(5) C16-C11-C12-C13-0.8(7) C6-C11-C12-C13-178.0(4) C11-C12-C13-C14-0.7(8) C11-C12-C13-Cl17-179.9(4) C12-C13-C14-C15 1.3(8) Cl17-C13-C14-C15-179.5(3) C12-C13-C14-Cl18 179.9(4) Cl17-C13-C14-Cl18-1.0(7) C13-C14-C15-C16-0.5(7) Cl18-C14-C15-C16-179.0(3) C14-C15-C16-C11-1.1(7) C12-C11-C16-C15 1.7(6) C6-C11-C16-C15 178.9(4) 19-C21-C22-23 -178.7(3) 20-C21-C22-23 1.1(5) 19-C21-C22-C24 56.8(5) 20-C21-C22-C24-123.3(3) 23-C22-C24-25 -72.3(4) C21-C22-C24-25 54.2(4) 23-C22-C24-C26 56.5(4) C21-C22-C24-C26-177.0(3) 25-C24-C26-27 -178.1(3) C22-C24-C26-27 54.4(4) 25-C24-C26-28 3.2(5) C22-C24-C26-28 -124.2(3)
Table 7. Anisotropic atomic displacement parameters (Å 2 ) for X4688A2. The anisotropic atomic displacement factor exponent takes the form: -2π 2 [ h 2 a* 2 U 11 +... + 2hka* b* U 12 ]. U 11 U 22 U 33 U 23 U 13 U 12 C1 0.034(3) 0.030(3) 0.023(2) 0.002(2) 0.000(2) -0.014(2) C2 0.028(2) 0.025(2) 0.030(2) 0.001(2) -0.0001(19) -0.009(2) N3 0.0270(18) 0.020(2) 0.0217(18) -0.0012(16) -0.0033(18) 0.0045(17) C4 0.036(3) 0.031(3) 0.030(2) -0.002(2) -0.006(2) 0.019(2) C5 0.035(3) 0.025(2) 0.031(2) -0.006(2) 0.001(2) 0.015(2) C6 0.032(3) 0.029(3) 0.027(2) -0.004(2) 0.0048(19) -0.006(2) C7 0.042(3) 0.053(3) 0.036(3) -0.013(2) 0.008(2) -0.011(3) C8 0.074(4) 0.027(3) 0.027(3) 0.008(2) -0.004(3) -0.017(3) 9 0.053(2) 0.0305(18) 0.0477(19) 0.0086(16) -0.0193(18) 0.0011(18) C10 0.096(5) 0.042(3) 0.080(4) 0.004(3) -0.041(4) 0.022(3) C11 0.042(3) 0.022(2) 0.021(2) 0.001(2) -0.002(2) -0.003(2) C12 0.046(3) 0.052(3) 0.029(3) -0.008(2) 0.000(2) 0.002(3) C13 0.073(4) 0.047(3) 0.019(2) -0.010(2) -0.005(3) -0.003(3) C14 0.054(3) 0.032(3) 0.031(3) -0.001(2) -0.017(2) -0.003(3) C15 0.043(3) 0.027(3) 0.046(3) 0.001(2) -0.009(2) 0.002(2) C16 0.040(3) 0.023(2) 0.032(2) -0.005(2) -0.004(2) 0.004(2) Cl17 0.1058(13) 0.1372(16) 0.0455(8) -0.0500(10) 0.0109(9) -0.0149(13) Cl18 0.0930(11) 0.0714(10) 0.0570(8) -0.0203(8) -0.0372(8) -0.0076(9) 19 0.0204(16) 0.0076(14) 0.0538(18) -0.0041(13) 0.0071(14) -0.0068(13) 20 0.0231(15) 0.0028(14) 0.0433(17) 0.0045(13) 0.0032(14) -0.0014(13) C21 0.028(2) 0.003(2) 0.023(2) -0.0029(16) 0.0017(19) -0.003(2) C22 0.018(2) 0.012(2) 0.024(2) 0.0005(18) -0.0007(18) -0.0057(18) 23 0.0207(16) 0.0131(15) 0.0366(18) 0.0076(13) 0.0009(13) -0.0019(12) C24 0.021(2) 0.010(2) 0.023(2) -0.0012(18) 0.0013(18) -0.0016(17) 25 0.0217(16) 0.0142(15) 0.0216(14) 0.0004(12) -0.0035(13) -0.0056(12) C26 0.013(2) 0.017(2) 0.026(2) -0.0040(19) 0.0024(18) 0.0075(18) 27 0.0430(18) 0.0154(15) 0.0255(15) 0.0026(13) -0.0070(14) 0.0014(14) 28 0.0296(15) 0.0075(13) 0.0285(14) -0.0011(12) -0.0037(13) -0.0038(13)
Table 8. Hydrogen atom coordinates and isotropic atomic displacement parameters (Å 2 ) for X4688A2. x y z U H2A 0.6460 0.4704 0.0843 0.033 H2B 0.4337 0.5367 0.0838 0.033 H3A 0.600(5) 0.681(5) 0.0393(4) 0.027 H3B 0.732(2) 0.749(5) 0.0638(11) 0.027 H4A 0.3691 0.8436 0.0692 0.039 H4B 0.5220 0.9546 0.0474 0.039 H5A 0.4766 1.0524 0.1088 0.036 H5B 0.6896 1.0163 0.0982 0.036 H7A 0.3054 0.7371 0.1301 0.053 H7B 0.4021 0.7004 0.1700 0.053 H8B 0.7152 0.5639 0.1735 0.051 H8A 0.6497 0.3988 0.1498 0.051 H10A 1.0262 0.4461 0.1758 0.108 H10B 1.1316 0.4028 0.1390 0.108 H10C 0.9617 0.2822 0.1520 0.108 H12 0.5145 0.9713 0.1986 0.051 H15 1.1548 0.9650 0.1791 0.047 H16 0.9551 0.8592 0.1354 0.038 H20 0.653(5) -0.132(2) -0.0280(9) 0.028 H22 0.5198 0.2720-0.0754 0.021 H23 0.845(5) 0.230(5) -0.0434(8) 0.028 H24 0.3596 0.3563-0.0252 0.022 H25 0.659(3) 0.391(5) 0.0150(10) 0.023 Table 9. Selected hydrogen bond information for X4688A2 (Å and ). D-H...A d(d-h) d(h...a) d(d...a) <(DHA) N3-H3A...28 0.887(10) 1.960(15) 2.825(5) 165(4) N3-H3B...27#1 0.887(10) 2.005(14) 2.877(5) 167(4) 20-H20...28#2 0.842(10) 1.642(11) 2.483(4) 176(4) 23-H23...25#3 0.839(10) 2.023(16) 2.833(4) 162(4) 25-H25...19#3 0.839(10) 1.885(13) 2.710(4) 167(4) #1 x+1/2,-y+3/2,-z #2 x,y-1,z #3 x+1/2,-y+1/2,-z