Patent Application
20080064691
The invention will now be illustrated by the following examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C. and under an atmosphere of an inert gas such as argon;
(ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60° C.;
(iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a Bond Elut column is referred to, this means a column containing 10 g or 20 g or 50 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, Calif., USA under the name “Mega Bond Elut SI”; “Mega Bond Elut” is a trademark; where a Biotage cartridge is referred to this means a cartridge containing KP-SIL™ silica, 60μ, particle size 32-63 mM, supplied by Biotage, a division of Dyax Corp., 1500 Avon Street Extended, Charlottesville, Va. 22902, USA;
(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
(v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vi) where given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-δ6) as solvent unless otherwise indicated, other solvents (where indicated in the text) include deuterated chloroform CDCl3;
(vii) chemical symbols have their usual meanings; SI units and symbols are used;
(viii) reduced pressures are given as absolute pressures in Pascals (Pa); elevated pressures are given as gauge pressures in bars;
(ix) solvent ratios are given in volume:volume (v/v) terms;
(x) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported and unless otherwise stated the value quoted is (M−H)−;
(xi) The following abbreviations are used:
Certain intermediates described hereinafter within the scope of the invention may also possess useful activity, and are provided as a further feature of the invention. Particular examples of such interemdiates are Intermediates 52 and 53, each of which are provided as a further independent aspect of the invention.
Methyl (1R,2R)-2-aminoindane-1-carboxylate trifluoroacetic acid salt (Intermediate 5; 1.8 g, 5.9 mmol), 2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (Intermediate 3; 1.4 g, 5.9 mmol) and DIPEA (2.0 mL, 11.8 mmol) were dissolved in DCM (25 mL). HOBT (796 mg, 5.9 mmol) and EDCI (1.4 g, 7.4 mmol) were added and the mixture stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (50 mL), washed with water (2×25 mL), brine (25 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by silica gel chromatography (3:1, iso-hexane:ethyl acetate) to give the title compound (1.7 g, 71%) as a pale yellow foam.
1H NMR (CDCl3) δ: 2.98 (dd, 1H), 3.62 (dd, 1H), 4.15 (d, 1H), 5.2 (m, 1H), 6.36 (d, 1H), 6.65 (s, 1H), 7.3 (m, 4H), 10.02 (s, 1H); MS m/z 407/409 (M−H).
Methyl (1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino} indane-1-carboxylate (Example 1; 1.0 g, 3.18 mmol) was dissolved in THF (10 mL), hydrochloric acid (2.0 mL, 6M aqueous) added and the mixture stirred at 60° C. for 30 h. Evaporation of the volatiles under reduced pressure gave the title compound (1.1 g, 88%) as a pale brown foam.
1H NMR 8: 2.95 (dd, 1H), 3.38 (dd, 1H), 4.08 (d, 1H), 4.95 (m, 1H), 7.1 (s, 1H), 7.25 (m, 4H), 8.57 (d, 1H), 12.35 (s, 1H), 12.56 (s, 1H); MS m/z 395, 397, 399.
tert-Butyl [(1R,2R)-1-(aminocarbonyl)-2,3-dihydro-1H-inden-2-yl]carbamate (Intermediate 15; 75 mg, 0.27 mmol) was dissolved in TFA (2 mL) and stirred at ambient temperature for 2 h, the volatiles removed by evaporation under reduced pressure and the crude residue co-evaporated with CHCl3 (2×2 mL). The residue was dissolved in DCM (5 mL), 2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (Intermediate 3; 63.0 mg, 0.27 mmol), DIPEA (94 μl, 0.54 mmol), HOBT (36 mg, 0.27 mmol) and EDCI (65 mg, 0.34 mmol) added and the mixture stirred at ambient temperature for 20 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (10 mL), washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (2: 1, ethyl acetate:iso-hexane) to give the title compound (50 mg, 47%) as a pale yellow solid.
1H NMR 8: 2.95 (dd, 1H), 3.38 (dd, 1H), 3.6 (m, 2H), 3.98 (d, 1H), 4.93 (m, 1H), 7.1 (s, 1H), 7.24 (m, 4H), 7.63 (s, 1H), 8.5 (d, 1H); MS m/z 394, 396, 398.
N-[(1R,2R)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Intermediate 16; 286 mg, 0.56 mmol) was dissolved in THF (5 mL), tetrabutylammonium fluoride (2 mL, 1M in THF, 2.0 mmol) added and the mixture stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (15 mL), washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was crystallized (ethyl acetate) to give the title compound (120 mg, 57%) as a colourless solid.
1H NMR 8: 2.9 (dd, 1H), 3.3 (m, 1H), 3.68 (m, 2H), 4.55 (m, 1H), 4.75 (t, 1H), 7.2 (m, 4H), 7.39 (m, 1H), 8.5 (d, 1H), 12.35 (s, 1H); MS m/z 381, 383, 385.
N-[(1R,2R)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Intermediate 17; 320 mg, 0.7 mmol) was dissolved in THF (10 mL), tetrabutylammonium fluoride (5 mL, 1M in THF, 5.0 mmol) added and the mixture stirred at ambient temperature for 4 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (15 mL), washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was crystallized (ethyl acetate:iso-hexane, 1:1) to give the title compound (160 mg, 66%) as a colourless solid.
1H NMR δ: 2.93 (dd, 1H), 3.32 (m, 1H), 3.73 (m, 2H), 4.55 (m, 1H), 4.8 (t, 1H), 7.1 (s, 1H), 7.22 (m, 4H), 7.4 (m, 1H), 8.45 (d, 1H), 11.9 (s, 1H); MS m/z 345, 347.
(1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}indane-1-carboxylic acid (Example 2; 99 mg, 0.25 mmol), (3aR,6aS)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole (36 mg, 0.25 mmol) and DIPEA (44 μl, 0.25 mmol) were dissolved in DCM (5 mL). HOBT (34 mg, 0.25 mmol) and EDCI (60 mg, 0.313 mmol) were added and the mixture stirred at ambient temperature for 6 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (15 mL), washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in ethanol (3 mL), hydrochloric acid (0.2 mL, 2M aqueous) added, and the solution stirred at ambient temperature for 4 h. The volatiles were removed under reduced pressure to give the title compound (70 mg, 58%) as a pale yellow foam.
1H NMR δ: 2.95 (dd, 1H), 3.4 (m, 4H), 3.83 (m, 1H), 4.1 (m, 4H), 4.42 (m, 1H), 4.9 (m, 1H), 7.17 (m, 5H), 8.6 (m, 1H), 12.4 (m, 1H); MS m/z 480, 482.
The following examples were made by a similar process to Example 6 using (1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}indane-1-carboxylic acid (Example 2) and the appropriate commercially available amine.
2,3-Dichloro-N-[(1R,2R)-1-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 4; 1.2 g, 3.15 mmol) and triethylamine (658 μl, 4.73 mmol) were dissolved in THF (20 mL). Methanesulphonyl chloride (397 mg, 3.47 mmol) in THF (5 mL) was added and the mixture stirred at ambient temperature for 3 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (50 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (1.45 g, 100%) as a pale brown foam.
1H NMR (CDCl3) δ: 2.95 (dd, 1H), 3.5 (dd, 1H), 3.62 (m, 1H), 4.45 (dd, 1H), 4.65 (dd, 1H), 4.8 (m, 1H), 6.4 (d, 1H), 6.75 (s, 1H), 7.25 (m, 4H), 9.8 (s, 1H); MS m/z 481, 483 (M+Na).
N-[(1S,2R)-1-(Aminomethyl)-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Intermediate 18; 115 mg, 0.3 mmol), acetic acid (36 μl, 0.6 mmol) and DIPEA (52 μl, 0.3 mmol) were dissolved in DCM (2.5 mL). HOBT (41 mg, 0.3 mmol) and EDCI (72 mg, 0.375 mmol) were added and the mixture stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (25 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (2:1, ethyl acetate:iso-hexane) to give the title compound (1.45 g, 100%) as a pale brown foam.
1H NMR δ: 1.8 (s, 3H), 2.9 (dd, 1H), 3.3 (m, 4H), 4.45 (m, 1H), 7.1 (s, 1H), 7.22 (m, 4H), 7.94 (m, 1H), 8.43 (d, 1H), 12.31 (s, 1H); MS m/z 422, 424, 426.
N-[(1S,2R)-1-(Aminomethyl)-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Intermediate 18; 115 mg, 0.3 mmol), formic acid (14 mg, 0.3 mmol) and DIPEA (52 μl, 0.3 mmol) were dissolved in DCM (2.5 mL). HOBT (41 mg, 0.3 mmol) and EDCI (72 mg, 0.375 mmol) were added and the mixture stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (25 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (1:1, ethyl acetate:iso-hexane) to give the title compound (95 mg, 77%) as a colourless foam.
1H NMR 6: 2.9 (dd, 1H), 3.4 (m, 4H), 4.5 (m, 1H), 7.15 (s, 1H), 7.25 (m, 4H), 8.05 (s, 1H), 8.12 (s, 1H), 8.48 (d, 1H), 12.35 (s, 1H); MS m/z 408, 410, 412.
N-[(1S,2R)-1-(Aminomethyl)-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Intermediate 18; 1.2 g, 3.2 mmol), acetoxyacetic acid (373 mg, 3.2 mmol) and HOBT (432 mg, 3.2 mmol) were dissolved in DCM (20 mL). EDCI (767 mg, 4.0 mmol) was added and the mixture stirred at ambient temperature for 3 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (50 mL), washed with water (2×20 mL), brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in THF:MeOH (1:1, 30 mL), K2CO3 (1.0 g) added and the mixture stirred at ambient temperature for 1 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (50 mL), washed with water (3×20 mL), brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ethyl acetate) to give the title compound (1.05 g, 75%) as a cream powder.
1H NMR 6: 2.9 (dd, 1H), 3.25 (dd, 1H), 3.38 (m, 1H), 3.45 (m, 2H), 3.78 (s, 2H), 4.48 (m, 1H), 5.4 (s, 1H), 7.13 (s, 1H), 7.2 (m, 4H), 7.8 (m, 1H), 8.45 (d, 1H), 12.32 (s, 1H); MS m/z 438, 440,442.
((1R,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl methanesulfonate (Intermediate 19; 800 mg, 1.9 mmol) was dissolved in anhydrous dimethylacetamide (10 mL), sodium methane thiolate (147 mg, 2.1 mmol) added and the mixture stirred at ambient temperature for 24 h. Citric acid (10 mL, 2M aqueous) was added and the mixture extracted with ethyl acetate (30 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (4:1, iso-hexane:ethyl acetate) to give the title compound (560 mg, 78%) as a pale yellow solid.
1H NMR (CDCl3) δ: 2.18 (s, 3H), 2.95 (m, 3H), 3.4 (m, 1H), 3.58 (dd, 1H), 4.75 (m, 1H), 6.35 (d, 1H), 6.62 (s, 1H), 7.25 (m, 3H), 7.38 (m, 1H), 10.79 (s, 1H); MS m/z 375, 377 (M−H).
2,3-Dichloro-N-((1S,2R)-1-{[(methylthio)amino]methyl}-2,3-dihydro-1H-inden-2-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 14; 1.0 g, 2.65 mmol) was dissolved in methanol:THF (1:1, 10 mL), oxone (205 mg, 0.33 mmol) added and the mixture stirred at ambient temperature for 3 h. The mixture was poured into water (25 mL) and extracted with ethyl acetate (2×20 mL). The organic extract was washed with water (20 mL), brine (20 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (19:1, ethyl acetate:methanol) to give the title compound (250 mg, 24%) as a colourless solid.
1H NMR 8: 2.58 (s, 1.5H), 2.62 (s, 1.5H), 3.1 (m, 3H), 3.65 (m, 1H), 4.55 (m, 1H), 7.02 (m, 1H), 7.15 (s, 1H), 7.22 (m, 3H), 7.37 (m, 1H), 8.48 (m, 1H), 11.83 (s, 1H); MS m/z 391, 393.
2,3-Dichloro-N-((1S,2R)-1-{[(methylthio)amino]methyl}-2,3-dihydro-1H-inden-2-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 14; 250 mg, 0.663 mmol) was dissolved in methanol:THF (1:1, 10 mL), oxone (410 mg, 0.663 mmol) added and the mixture stirred at ambient temperature for 24 h. The mixture was poured into water (25 mL) and extracted with ethyl acetate (2×20 mL). The organic extract was washed with water (20 mL), brine (20 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (1:1, ethyl acetate:iso-hexane) to give the title compound (200 mg, 74%) as a colourless solid.
1H NMR δ: 2.94 (dd, 1H), 3.06 (s, 3H), 3.25 (m, 1H), 3.55 (m, 2H), 4.75 (m, 1H), 4.59 (m, 1H), 7.0 (s, 1H), 7.15 (s, 1H), 7.22 (m, 3H), 7.48 (m, 1H), 8.44 (d, 1H), 11.84 (s, 1H); MS m/z 407/409.
((1R,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl methanesulfonate (Intermediate 19; 800 mg, 1.92 mmol), thiomorpholine (1.98 g, 19.2 mmol) and DIPEA (1.36 g, 8.0 mmol) in acetonitrile (20 mL) was heated in a microwave reactor at 150° C. for 5 mins. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (35 mL), washed with water (2×20 mL), brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (2: 1, iso-hexane:ethyl acetate) to give the title compound (440 mg, 53%) as a pale yellow solid.
1H NMR 6: 2.57 (m, 4H), 2.7 (m, 4H), 2.83 (dd, 1H), 3.22 (m, 3H), 3.41 (m, 1H), 4.43 (m, 1H), 7.2 (s, 1H), 7.17 (m, 4H), 7.4 (m, 1H), 8.28 (d, 1H), 11.81 (s, 1H); MS m/z 432, 434.
2-Chloro-N-[(1S,2R)-1-(thiomorpholin-4-ylmethyl)-2,3-dihydro-1H-inden-2-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 17; 180 mg, 0.417 mmol) was dissolved in 1:1 methanol:THF (5 mL), oxone (127.5 mg, 0.21 mmol) added and the mixture stirred at ambient temperature for 24 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic extract was washed with water (10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (19: 1, ethyl acetate:methanol) to give the title compound (85 mg, 46%) as a colourless solid.
1H NMR 8: 2.56 (m, 1H), 2.7 (m, 5H), 2.9 (m, 5H), 3.25 (m, 1H), 3.41 (m, 1H), 4.27 (m, 1H), 7.01 (s, 1H), 7.17 (m, 4H), 7.4 (m, 1H), 8.3 (d, 1H), 11.82 (s, 1H); MS m/z 448, 450.
2-Chloro-N-[(1S,2R)-1-(thiomorpholin-4-ylmethyl)-2,3-dihydro-1H-inden-2-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 17; 280 mg, 0.65 mmol) was dissolved in anhydrous THF (10 mL), m-chloroperbenzoic acid (373 mg, 1.3 mmol) added and the mixture stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (20 mL), washed with water (2×5 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (9:1, DCM:methanol) to give the title compound (190 mg, 63%) as a colourless solid.
1H NMR 8: 2.95 (m, 9H), 3.17 (d, 2H), 3.35 (m, 1H), 3.55 (m, 1H), 4.05 (m, 1H), 7.05 (s, 1H), 7.14 (s, 1H), 7.27 (m, 3H), 7.58 (m, 1H), 8.54 (d, 1H), 11.87 (s, 1H); MS m/z 464, 466.
Ethylene glycol (4 mL), water (3 mL) and 8M potassium hydroxide (1 mL) was added to (+/−)-trans-Ethyl[optionally -1-(methylthio)-2,3-dihydro-1H-inden-2-yl]carbamate (Intermediate 20, 200 mg, 0.80 mmol) and the reaction was heated to 100° C. for 1 h then at 110° C. for 16 h. The residue was taken up in ether (30 mL) and water (10 mL) and the organic layer was dried (MgSO4), filtered and evaporated which was used in the subsequent coupling without further purification. 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Intermediate 4, 113 mg, 0.56 mmol), DCM (10 mL), HOBt (86 mg, 0.56 mmol), DIPEA (0.12 MnL, 0.70 mmol) and EDCI (134 mg, 0.70 mmol) was added to the residue obtained from the first step and the reaction was stirred at ambient temperature for 16 h. The reaction was diluted with DCM (50 mL), extracted with 1M HCl (aqueous) (15 mL) then saturated aqueous NaHCO3 (20 mL) and the organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography (Eluent: 1:4 to 1:2 EtOAc:hexanes) afforded the title compound (120 mg, 59% over 2 steps) as a white solid.
1H NMR (DMSO) δ: 2.95 (dd, 1H), 3.39 (dd, 1H), 4.31 (d, 1H), 4.68 (m, 1H), 7.01 (s, 1H), 7.16 (s, 1H), 7.28 (m, 3H), 7.33 (m, 1H), 8.50 (d, 1H), 11.88 (s, 1H); MS m/z 361, 363 [optionally M−H]−.
1H NMR
Lithium hydroxide (300 mg, 7.16 mmol) was added to methyl [optionally ((1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)thio]acetate (Intermediate 29, 1.63 g, 3.58 mmol) in THF:water (4:1, 50 mL) and stirred at ambient temperature for 2.5 h. The reaction was acidified (pH=1) with 1M HCl (aqueous) and extracted with EtOAc (2×30 mL) and the organic layer was dried (MgSO4), filtered and evaporated to afford the title compound (1.60 g, 100%) as a foamy solid.
1H NMR (DMSO) δ: 2.93 (dd, 1H), 3.41 (m, 2H), 3.62 (d, 1H), 4.45 (m, 1H), 4.63 (m, 1H), 7.10 (s, 1H), 7.30 (m, 4H), 8.58 (d, 1H), 12.35 (s, 1H). MS m/z 463, 465 [optionally M+Na]+.
Dimethylamine (0.68 mL, 2.0M in THF, 1.36 mmol), DIPEA (0.16 mL, 0.91 mmol) and HBTU (378 mg, 0.10 mmol) was added to a stirred solution of [((1R,2R)-2-{[(2,3-Dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)thio]acetic acid (Example 23; 400 mg, 0.91 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 2 h. The reaction was quenched by addition of saturated aqueous NaHCO3 (20 mL) and diluted with DCM (20 mL). The organic layer was separated and washed with 1M HCl (aqueous) (15 mL), dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:1 EtOAc:hexanes to EtOAc) afforded the title compound (349 mg, 82%) as a white foam.
1H NMR (DMSO) δ: 2.78 (s, 3H), 2.91 (dd, 1H), 2.95 (s, 3H), 3.38 (m, 1H), 3.63 (s, 2H), 4.44 (d, 1H), 4.64 (m, 1H), 7.10 (s, 1H), 7.24 (m, 3H), 7.36 (m, 1H), 8.58 (d, 1H), 12.36 (s, 1H); MS m/z 490, 492 [optionally M+Na]+.
m-CPBA (70-75%, 150 mg, 0.61 mmol) was added to a solution of 2,3-dichloro-N-((1R,2R)-1-{[2-(dimethylamino)-2-oxoethyl]thio}-2,3-dihydro-1H-inden-2-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 24; 285 mg, 0.61 mmol) in DCM (7 mL) and the reaction was stirred at ambient temperature for 30 mins. A further portion of m-CPBA (75 mg, 0.30 mmol) was added and the reaction was stirred at ambient temperature for a further 1 h. The reaction was quenched by addition of sat. aqueous NaHCO3 (20 mL) and diluted with DCM (20 mL). The organic layer was separated, dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:2, EtOAc:hexanes to EtOAc) afforded the title compound (150 mg, 49%) as a white foam.
1H NMR (DMSO) δ: 2.77 (s, 3H), 3.05 (m, 4H), 3.31 (s, 3H), 3.52 (dd, 1H), 4.64 (d, 1H), 4.75 (d, 1H), 5.22 (m, 1H), 5.28 (s, 1H), 7.13 (s, 1H), 7.31 (m, 1H), 7.38 (m, 2H), 7.57 (d, 1H), 8.83 (d, 1H), 12.40 (s, 1H), MS m/z 522, 524 [optionally M+Na]+.
The following example was prepared by the method of Example 23 using (+/−)-trans-methyl [(-2-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)thio]acetate (Intermediate 30) as the methyl ester.
1H NMR δ: 3.00 (dd, 1H), 3.40 (m, 4H), 3.59 (d, 1H), 4.51 (s, 1H), 4.68 (m, 1H), 7.08 (s, 1H), 7.20 (s, 1H), 7.35 (m, 4H), 8.57 (d, 1H), 11.95 (s, 1H); MS m/z 429, 431 [optionally M+Na]+.
EDCI (32 mg, 0.169 mmol), HOBT (26 mg, 0.169 mmol) and dimethylamine (0.135 mL, 2.0M in THF, 0.270 mmol) was added to a solution of (+/−)-trans-(-2-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)thio]acetic acid (Example 26; 755 mg, 0.135 mmol), in THF (5 mL) and the mixture stirred at ambient temperature for 2 h. The reaction was diluted with EtOAc (50 mL) then extracted with 1M HCl (aqueous) (15 mL) then saturated aqueous NaHCO3 (20 mL) and the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:1, EtOAc:hexanes to EtOAc) afforded the title compound (25 mg, 43%) as a white solid.
1H NMR 6: 2.80 (s, 3H), 2.95 (dd, 1H), 3.01 (s, 3H), 3.38 (dd, 1H), 2.67 (m, 2H), 4.43 (s, 1H), 4.68 (m, 1H), 7.02 (s, 1H), 7.15 (s, 1H), 7.28 (m, 3H), 7.34 (m, 1H), 8.53 (d, 1H), 11.87 (s, 1H); MS m/z 456, 458 [optionally M+Na]+.
The following examples were prepared by the method of Intermediate 29, using either tert-butyl {(1R,2R)-1-[(2-hydroxyethyl)thio]-2,3-dihydro-1H-inden-2-yl}carbamate (Intermediate 28) or (+/−)-trans-methyl{-2-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-1-yl}acetate (Intermediate 32) as the carbamate and 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Intermediate 4) or 5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Intermediate 3) as the carboxylic acid.
1H NMR δ: 2.85 (m, 3H), 3.12 (m, 1H), 3.68 (dd, 1H), 3.90 (m, 2H), 4.45 (m, 1H), 4.86 (m, 1H), 6.30 (d, 1H), 6.62 (s, 1H), 7.27 (m, 3H), 7.38 (m, 1H), 9.52 (s, 1H); MS m/z 425, 427 [optionally M+Na]+.
1H NMR (DMSO) δ: 2.70 (d, 2H), 2.87 (dd, 1H), 3.20 (dd, 1H), 3.57 (s, 3H), 3.58 (m, 1H), 4.42 (quin, 1H), 7.00 (s, 1H), 7.17 (m, 4H), 8.39 (d, 1H), 11.81 (s, 1H); MS m/z 389, 391 [M]+.
The following example was prepared by the method of Example 23, using (+/−)-trans-methyl-(-2-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)acetate (Example 29) as the ester.
1H NMR (DMSO) δ: 2.60 (m, 2H), 2.87 (dd, 1H), 3.20 (dd, 1H), 3.57 (m, 1H), 4.41 (quin, 1H), 7.02 (d, 1H), 7.18 (m, 4H), 8.40 (d, 1H), 11.81 (s, 1H); MS m/z 375, 377 [optionally M]+.
EDCI (64 mg, 0.33 mmol), HOBT (41 mg, 0.27 mmol) and dimethylamine (2.0M in THF, 0.20 mL, 0.40 mmol) was added to a solution of (+/−)-trans-(-2-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)acetic acid (Example 30; 100 mg, 0.27 mmol), in THF (6 mL) and the mixture was stirred at ambient temperature for 2 h. The reaction was diluted with EtOAc (50 mL) then extracted with 1M HCl (aq.) (15 mL), sat. aqueous NaHCO3 (20 mL) and the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent: 1:1, EtOAc:hexanes) afforded the title compound (69 mg, 64%) as a white solid.
1H NMR (DMSO) δ: 2.71 (m, 2H), 2.86 (s, 3H), 2.87 (m, 1H), 2.95 (s, 3H), 3.68 (m, 1H), 4.46 (quin, 1H), 7.03 (s, 1H), 7.18 (m, 5H), 8.45 (d, 1H), 11.81 (s, 1H); MS m/z 424, 426 [optionally M+Na]+.
The following examples were made by method of Example 31 using (+/−)-trans-(-2-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)acetic acid (Example 30) as the carboxylic acid and the appropriate commercially available amine.
((1R,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl methanesulfonate (Intermediate 19; 424.5 mg, 1 mmol) in DMF (2 mL) was added to a solution of mercaptoethanol (0.42 mL, 6 mmol) and DBU (0.38 mL, 2.5 mmol) in DMF (4 mL) which had been heated at 60° C. for 10 minutes, heating was continued at 60° C. for 5 h, the reaction mixture was cooled, poured into saturated NaHCO3 and the precipitate isolated by filtration. The resulting solid was taken up in EtOAc (30 mL) and water (15 mL), the organic layer was separated, washed with water (15 mL) and brine (15 mL) and dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (EtOAc:hexane 1:9) to afford the title compound (170 mg, 42%).
1H NMR δ: 2.6 (t, 2H), 2.9 (m, 2H), 3.0 (dd, 1H), 3.3 (m, 1H), 3.4 (m, 1H), 3.5 (m, 2H), 4.5 (m, 1H), 4.7 (m, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 7.2 (m, 3H), 7.4 (m, 1H), 8.4 (d, 1H), 11.8 (s, 1H); MS m/z 407.
The following examples were made by the process of Example 34 using ((1R,2R)-2-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl methanesulfonate (Intermediate 19) as the mesylate and the appropriate commercially known thiol.
((1R,2R)-2-{[(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl methanesulfonate (Intermediate 19; 424.5 mg, 1 mmol) in DMF (2 mL) was added to a solution of thioacetic acid (91.2 mg, 1.2 mmol) and cesium carbonate (220 mg, 0.65 mmol) in DMF (10 mL). The solution was stirred for 16 hrs at ambient temperature then filtered. Water (15 mL) and EtOAc (50 mL) were added, the organic layer was separated, washed with water (2×20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (EtOAc/CH2Cl2 0-1%) to afford the title compound (200 mg, 50%).
1H NMR (CDCl3, 300 MHz) δ: 2.3 (s, 3H), 2.9 (dd, 1H), 3.2 (m, 2H), 3.3 (m, 1H), 3.5 (dd, 1H), 4.5 (m, 1H), 6.5 (d, 1H), 6.7 (s, 1H), 6.9 (s, 1H), 7.2 (m, 3H), 7.3 (m, 1H), 10.2 (s, 1H); MS m/z 404.
2-Chloro-N-((1R,2R)-1-{[(2-hydroxyethyl)thio]methyl}-2,3-dihydro-1H-inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 34; 574 mg, 1.41 mmol) in THF (11 mL) was treated with m-CPBA (694 mg, 70-75%, 2.82 mmol) and the mixture was stirred at ambient temperature for 16 h before evaporated to dryness. Saturated NaHCO3 (20 mL) and EtOAc (40 mL) were added and the organic layer was separated, washed with saturated NaHCO3 (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated to afford the title compound (473 mg, 76%) as a solid.
1H NMR 6: 2.9 (dd, 1H), 3.2-3.4 (m, 3H), 3.6 (d, 2H), 3.8 (m, 3H), 4.6 (m, 1H), 5.2 (m, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 7.2 (m, 3H), 7.5 (m, 1H), 8.4 (d, 1H), 11.8 (s, 1H); MS m/z 439 (M+H).
The following examples were made by the process of Example 41, using the appropriate thioether (Example 35, Example 36 or Example 37).
2-Chloro-N-{(1R,2R)-1-[({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}thio)methyl]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 39; 517 mg, 1.09 mmol) in DCM (20 mL) was treated with m-CPBA (496 mg, 70-75%, 1.6 mmol) in DCM (10 mL), the mixture was stirred at 0° C. for 1 h, saturated NaHCO3 (10 mL) and saturated sodium hydrogen sulphite (10 mL) were added and the mixture stirred for 10 mins. The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (eluent gradient: 30-100% EtOAc in DCM) to afford 2-chloro-N-{(1R,2R)-1-[({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}sulfonyl)methyl]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (271 mg); 1H NMR (CDCl3) δ: 1.3 (s, 3H), 1.4 (s, 3H), 2.9 (dd, 1H), 3.0 (dd, 1H), 3.4-3.7 (m, 3H), 3.75 (dd, 1H), 3.8-4.0 (m, 2H), 4.2 (m, 1H), 4.7 (m, 2H), 6.7 (s, 1H), 6.9 (m, 2H), 7.2 (m, 4H), 10.1 (s, 1H); MS m/z: 509 (M+H) and 2-Chloro-N-[(1R,2R)-1-[({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}sulfinyl)methyl]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (131 mg); HPLC RT 2.31 mins (HPLC specification: Waters 2790 Separations module, Column: Phenomenex Synergi 4u MAX-RP 8A (50×2 mm), Mobile phase:Acetonitrile:Water:Formic acid, 49.5:49.5:1, Flow rate/operating pressure: 1.1 ml/min at 200 psi); MS m/z: 493 (M+H).
2-Chloro-N-{(1R,2R)-1-[({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}sulfonyl)methyl]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 46; 271 mg, 0.53 mmol) was stirred at 60° C. for 2 h with a mixture of acetic acid (5 mL) and water (1 mL). The solvent was evaporated to afford the title compound as a white solid (222 mg, 89%). 1H NMR δ: 2.9 (dd, 1H), 3.1-3.4 (m, 5H), 3.6 (d, 2H), 3.8 (m, 1H), 4.0 (m, 1H), 4.6 (m, 1H), 4.8 (m, 1H), 5.3 (m, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 7.2 (m, 3H), 7.5 (m, 1H), 8.4 (d, 1H), 11.8 (s, 1H); MS m/z 469.
2-Chloro-N-{(1R,2R)-1-[({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}sulfinyl)methyl]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 45; 131 mg, 0.27 mmol) was stirred for 2 h at 60° C. with a mixture of acetic acid (5 mL) and water (1 mL). The solvent was evaporated to afford the title compound as a white solid (80 mg, 67%).
1H NMR 8: 3.0 (m, 5H), 3.3-3.4 (m, 3H), 3.7 (m, 1H), 3.9 (m, 1H), 4.5 (m, 1H), 4.7 (m, 1H), 5.1 (m, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 7.2 (m, 3H), 7.4 (m, 1H), 8.5 (m, 1H), 11.8 (s, 1H); MS m/z 453.
2-Chloro-N-((1R,2R)-1 {[(2-hydroxyethyl)sulfonyl]methyl}-2,3-dihydro-1H-inden-2-yl)-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 41; 385 mg, 0.879 mmol) in THF (7 mL) was treated first with triethylamine (0.257 mL, 1.87 mmol) then by the dropwise addition of mesyl chloride (0.071 mL, 0.923 mmol) at 0° C. and the resultant solution was allowed to warm to ambient temperature and stirred for 16 h. The mixture was filtered and the filtrate evaporated to dryness. Water (15 mL) and EtOAc (30 mL) were added and the organic layer was separated, washed with water (15 mL) and brine (15 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (EtOAc:toluene, 1:9) to afford the title compound (175 mg, 45%).
1H NMR (CDCl3) δ: 3.0 (dd, 1H), 3.4 (dd, 1H), 3.5 (d, 1H), 3.6 (d, 1H), 3.9 (m, 1H), 4.6 (m, 1H), 6.2 (1H, d), 6.5 (d, 1H), 6.7-6.9 (m, 4H), 7.2 (m, 3H), 7.3 (m, 1H), 10.2 (s, 1H); MS m/z 421.
2-Chloro-N-[(1R,2R)-1-[(ethenylsulfonyl)methyl]-2,3-dihydro-1H-inden-2-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 49; 80 mg, 0.19 mmol) was dissolved in methanol (5 mL) and stirred with imidazole (129 mg, 1.9 mmol) at ambient temperature for 24 h. The resultant white solid was isolated by filtration, stirred with EtOAc for 15 mins, isolated by filtration and dried under vacuum over phosphorous pentoxide (P2O5) to afford the title compound (70 mg, 75%) as a solid.
1H NMR 8: 2.9 (dd, 1H), 3.3 (dd, 1H), 3.5 (m, 2H), 3.8 (m, 3H), 4.4 (m, 2H), 4.6 (m, 1H), 6.8 (s, 1H), 6.9 (m, 4H), 7.0 (s, 1H), 7.15 (s, 1H), 7.2 (m, 3H), 7.4 (m, 1H), 7.7 (s, 1H), 8.4 (d, 1H), 11.8 (s, 1H); MS m/z 489.
Triethylamine (0.12 mL, 0.87 mmol), HOBT (30 mg, 0.22 mmol), 1-[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]-N-(2-hydroxyethyl)methanesulfonamide hydrochloride (Intermediate 33, 61 mg, 0.20 mmol) and EDCI (42 mg, 0.22 mmol) were added to a suspension of 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Intermediate 4; 32 mg, 0.16 mmol) in DMF (5 mL). The reaction was stirred at ambient temperature for approximately 16 h. The reaction mixture was diluted with water (10 mL) and washed with EtOAc (20 mL). The organic layer was washed with water (2×10 mL), 1M citric acid (10 mL), saturated sodium bicarbonate solution (10 mL) and evaporated to give the title compound (38 mg, 42%) as a cream solid.
1H NMR 8: 2.96 (m, 3H), 3.33 (m, 5H), 3.63 (m, 1H), 4.56 (m, 1H), 4.71 (t, 1H), 7.03 (s, 1H), 7.14 (s, 1H), 7.21 (m, 4H), 7.51 (m, 1H), 8.46 (d, 1H), 11.86 (s, 1H); MS m/z 454.1.
The following example was made by the process used in Example 51 using 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Intermediate 4) as the carboxylic acid and methyl N-({[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methyl}sulfonyl)glycinate (Intermediate 34) as the amine.
1H-NMR (CDCl3) δ: 2.9 (dd, 1H), 3.4 (m, 2H), 3.6 (dd, 1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.1 (s, 2H), 5.1 (m, 1H), 6.5 (d, 1H), 6.6 (s, 1H), 6.8 (s, 1H), 7.2 (m, 3H), 7.3 (m, 1H), 9.0-10.0 (br, 1H); MS m/z 482.
Methyl N-{[((1R,2R)-2-{[1-(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)vinyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl]sulfonyl}glycinate (Example 52; 10 mg, 0.02 mmol) in THF:MeOH (3:1, 0.4 mL) was treated with 1N lithium hydroxide (0.04 mL, 0.04 mmol) and the solution was stirred at ambient temperature for 2 h, then evaporated to dryness and acidified with 1N hydrochloric acid . The resultant solid was isolated by filtration, washed with water and dried over phosphorous pentoxide (P2O5) to give the title compound (8.3 mg, 86%) as a white solid.
1H NMR δ: 2.9 (dd, 1H), 3.3 (dd, 1H), 3.5 (m, 2H), 3.7 (m, 1H), 3.8 (s, 2H), 4.6 (m, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 7.2 (m, 4H), 7.7 (m, 2H), 8.7 (m, 2H), 11.5-13.0 (br, 1H); MS m/z 468 (M+H).
The following examples were made by the process used for Example 52 using 2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (Intermediate 3) as the acid and the appropriate amine (Intermediates 35 to 38):
1H NMR 6: 1.39 (dd, 3H), 2.94 (dt, 1H), 3.43 (m, 1H), 3.85 (m, 1H), 4.58 (m, 2H), 7.12 (s, 1H), 7.26 (m, 4H), 8.57 (dd, 1H), 12.38 (s, 1H), 12.52 (s, 1H); MS m/z 455.1.
1H NMR δ: 1.39 (dd, 3H), 2.94 (dt, 1H), 3.43 (m, 1H), 3.85 (m, 1H), 4.58 (m, 2H), 7.01 (s, 1H), 7.12 (s, 1H), 7.26 (m, 4H), 8.51 (dd, 1H), 11.90 (s, 1H), 12.53 (s, 1H); MS m/z 421.2.
Methanolic sodium methoxide solution (5 mL, 28% w/v solution, 25.9 mmol) was diluted with MeOH (10 ml) and was cooled to −25° C. under nitrogen. A solution of 3,4-dichloro-5-carbonyl-4H-thieno[3,2,b]pyrrole (DE 2814798; 1.2 g. 6.63 mmol) and methyl azidoacetate (3.0 g, 26.09 mmol) in MeOH (15 ml) was added dropwise, maintaining the temperature at −25° C. On completion of addition the solution was allowed to warm to 5° C. over a period of approximately 16 hours. The solution was added to saturated aqueous ammonium chloride (250 ml) and the mixture was extracted using dichloromethane. The combined organic layers were concentrated at ambient temperature. The residue was taken up in xylene (30 ml) and this solution was added dropwise to xylene (120 ml) under reflux. The solution was heated under reflux for 30 minutes before being cooled and concentrated. The title compound was purified by crystallization (EtOAc/isohexane) to afford the title compound (1.08 g, 65%) as a solid.
1H NMR (CDCl3) δ: 9.2 (1H, br), 7.0 (1H, s), 3.9 (3H, s); m/z 248.2.
This was made using an analogous procedure to Intermediate 1 starting from the corresponding aldehyde (Gronowitz et al. Tetrahedron, Vol. 32, 1976, p. 1403).
1H NMR (CDCl3) 9.4-9.2 (1H, br), 7.0 (1H, s), 6.9 (1H, s), 3.9 (3H, s); m/z 214
2,3-Dichloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Intermediate 1; 1.22 g, 5.66 mmol) was taken up in MeOH (10 ml) and was heated under reflux. Aqueous lithium hydroxide (3.0 ml, 2.0 M, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 1 hour before being cooled and concentrated. Water (15 ml) was added and the solution was neutralized using aqueous hydrochloric acid (5.66 mL, 2.0 M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound (1.18 g, 100%) as a yellow solid
1H NMR (CDCl3) δ: 7.0 (1H, s); m/z 234.2.
1H NMR (CDCl3) δ: 12.6-12.7 (1H, b), 12.0-12.1 (1H, b), 7.15 (1H, s), 6.9 (1H, s); m/z 183.
Methyl (1R,2R)-2-[(tert-butoxycarbonyl)amino]indane-1-carboxylate (Intermediate 6; 1.3 g, 4.43 mmol) was dissolved in DCM (5 mL), TFA (5 mL) added and the mixture stirred at ambient temperature for 4 h. The volatiles were removed under reduced pressure to give the title compound (1.35 g, 100%) as a foam.
1H NMR (CDCl3) δ: 3.1 (dd, 1H), 3.45 (dd, 1H), 3.74 (s, 3H), 4.27 (d, 1H), 4.4 (m, 1H), 7.3 (m, 1H).
(1R,2R)-2-[(tert-Butoxycarbonyl)amino]indane-1-carboxylic acid (Intermediate 7; 1.85 g, 6.65 mmol) was dissolved in methanol (25 mL) and isohexane (25 mL), trimethylsilyldiazomethane (7.0 mL, 2.0M in hexane, 1.4 mmol) was added and the mixture stirred at ambient temperature for 24 h. The volatiles were removed by evaporation and the crude residue purified by silica gel chromatography (8: 1, iso-hexane:ethyl acetate) to give the title compound (1.3 g, 68%) as a foam.
1H NMR (CDCl3) δ: 1.42 (s, 9H), 2.81 (dd, 1H), 3.48 (dd, 1H), 3.75 (s, 3H), 3.97 (d, 1H), 4.75 (m, 2H), 7.25 (m, 4H).
To a solution of tert-butyl [optionally (1R,2R)-1-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]carbamate (Intermediate 8; 1.75 g, 6.65 mmol) in CCl4 (20 mL) and CH3CN (20 mL) was added sodium metaperiodate (5.7 g, 26.6 mmol) in water (30 mL) and ruthenium trichloride hydrate (138 mg, 0.665 mmol) and the mixture stirred at ambient temperature for 3 h. Ethyl acetate (100 mL) was added, the organic phase separated, washed with water (2×10 mL), brine (25 mL), dried (MgSO4), filtered and the volatiles removed under reduced pressure to give the title compound (1.9 g, 100%) as a brown foam.
1H NMR 8: 1.39 (s, 9H), 2.78 (dd, 1H), 3.02 (dd, 1H), 3.85 (d, 1H), 4.5 (m, 1H), 7.2 (m, 4H).
Tetrabutylammonium fluoride (10.0 mL, 2.0M in THF, 20.0 mmol) was added to a solution of tert-butyl [optionally (1R,2R)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl]carbamate (Intermediate 9; 4.1 g, 10.9 mmol) in THF (50 mL) and stirred at ambient temperature for 4 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was triturated (4:1, iso-hexane:ethyl acetate), filtered and dried to give the title compound (1.5 g, 54%) as white solid.
1H NMR 8: 1.44 (s, 9H), 2.78 (dd, 1H), 3.15 (m, 2H), 3.61 (m, 1H), 3.75 (m, 1H), 4.07 (m, 1H), 4.7 (m, 1H), 7.19 (m, 4H), 7.37 (m, 1H).
(1R,2R)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl]amine (Intermediate 10; 3.1 g, 11.2 mmol) and triethylamine (3.1 mL, 22.4 mmol) were dissolved in DCM (40 mL). Di-tert-butyl dicarbonate (2.9 g, 13.4 mmol) in DCM (10 mL) was added and the mixture stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (75 mL), washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by silica gel chromatography (16: 1, iso-hexane:ethyl acetate) to give the title compound (4.2 g, 100%) as a colourless oil.
1H NMR δ: 0.3 (d, 6H), 0.85 (s, 9H), 1.42 (s, 9H), 2.75 (dd, 1H), 3.15 (m, 2H), 3.79 (m, 1H), 3.95 (m, 1H), 4.05 (m, 1H), 7.15 (m, 4H), 7.3 (m, 1H).
(1S,2S)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl methanesulfonate (Intermediate 11; 7.2 g, 20.2 mmol) was dissolved in DMA (50 mL), sodium azide (3.94 g, 60.6 mmol) added and the mixture stirred at 60° C. for 7 h. The mixture was poured into ethyl acetate (250 mL), washed with water (6×75 mL), brine (100 mL) and dried (MgSO4). Palladium on carbon (500 mg, 10% w/w) was added, the mixture stirred under a hydrogen atmosphere for 6 h, filtered through Celite and the volatiles removed under reduced pressure to give the title compound (5.2 g, 93%) as a pale brown oil.
1H NMR 6: 0.07 (d, 6H), 0.9 (s, 9H), 2.58 (dd, 1H), 2.89 (m, 1H), 3.1 (dd, 1H), 3.3 (broad s, 2H), 3.41 (m, 1H), 3.85 (m, 2H), 7.2 (m, 4H).
(1S,2S)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)indan-2-ol (Intermediate 12; 6.3 g, 22.65 mmol) and triethylamine (4.7 mL, 34.0 mmol) were dissolved in DCM (90 mL) at 5° C. Methanesulfonyl chloride (2.86 g, 24.9 mmol) in DCM (10 mL) was added and the mixture stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (150 mL), washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by silica gel chromatography (6: 1, iso-hexane:ethyl acetate) to give the title compound (7.2 g, 89%) as a colourless oil.
1H NMR 6: 0.03 (d, 6H), 0.85 (s, 9H), 3.19 (s, 3H), 3.21 (m, 2H), 3.45 (m, 1H), 3.95 (m, 2H), 5.45 (m, 1H), 7.22 (m, 4H).
(1R,2S)-1-(Hydroxymethyl)-1,3-dihydro-2H-inden-2-one (Intermediate 13; 9.0 g, 54.8 mmol) and imidazole (4.5 g, 65.8 mmol) were dissolved in DCM (75 mL) at 10° C. tert-Butyldimethylchlorosilane (9.1 g, 60.3 mmol) in DCM (25 mL) was added, the mixture allowed to warm to ambient temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (150 mL), washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by silica gel chromatography (16:1, iso-hexane:ethyl acetate) to give the title compound (9.5 g, 62%) as a colourless oil.
1H NMR δ: 0.03 (d, 6H), 0.9 (s, 9H), 2.78 (dd, 1H), 3.0 (dd, 1H), 3.1 (m, 1H), 3.9 (m, 2H), 4.54 (m, 1H), 4.68 (d, 1H), 7.2 (m, 4H).
Methyl (1R,2S)-2-hydroxyindane-1-carboxylate (Intermediate 14; 10.56 g, 55.0 mmol) was dissolved in dry THF (100 mL) under a nitrogen atmosphere at 0° C. LiBH4 (55.0 mL, 2.0M in THF, 110.0 mmol) was added and the reaction stirred between 0 to 5° C. for 0.5 h, allowed to warm to ambient temperature and stirred for a further 2 h. The mixture was poured into saturated NaHCO3, extracted with ethyl acetate (200 mL) and the organic phase washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (9.1 g, 93%) as a colourless oil.
1H NMR δ: 2.7 (m, 1H), 2.95 (m, 1H), 3.05 (m, 1H), 3.55 (m, 1H), 3.8 (m, 1H), 4.55 (m, 3H), 7.2 (m, 4H).
(Reference:Didier, E et al Tetrahedron 47(27), 4941-4958, 1991) De-ionised water (20 L) was warmed to 34° C., bakers yeast (3 Kg) added and the mixture stirred for 0.5 hr. Methyl 2-oxoindane-1-carboxylate (40 g, 0.21 mmol) was added, the suspension stirred for 3 days and filtered through Celite. The aqueous filtrate was extracted with ethyl acetate (4×2.5 L) and the organic extracts dried (MgSO4), filtered and the volatiles removed by evaporation under reduced pressure. The crude residues were purified by flash silica gel chromatography (4:1 iso-hexane:ethyl acetate) the solvent evaporated and the resultant solid recrystallised from iso-hexane/ethyl acetate to give the title compound (10.8 g, 27%) as colourless needles.
Mp=72.5-73.5° C. (lit=73.2° C.)
[∝]D=+48.7° (C=1.0, CHCl3) (lit=+48.3°)
1H NMR δ: 2.85 (dd, 1H), 3.04 (dd, 1H), 3.61 (s, 3H), 4.1 (d, 1H), 4.76 (m, 1H), 5.2 (d, 1H), 7.2 (m, 4H).
(1R,2R)-2-[(tert-butoxycarbonyl)amino]indane-1-carboxylic acid (Intermediate 7, 1.35 g, 4.87 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihdroquinoline (1.32 g, 5.36 mmol) and ammonium carbonate (1.16 g, 14.61 mmol) were dissolved in CHCl3 (25 mL) and the mixture stirred at ambient temperature for 24 h. The reaction was filtered and the volatiles removed by evaporation under reduced pressure. The crude residue was dissolved in ethyl acetate, washed with 0.5M hydrochloric acid (10 mL), water (10 mL), saturated NaHCO3 (10 mL), brine (10 mL), dried (MgSO4), filtered and the volatiles removed by evaporation under reduced pressure. The residue was purified by flash silica gel chromatography (1:1 iso-hexane:ethyl acetate) to give the title compound (750 mg, 56%) as a colourless solid.
1H NMR (CDCl3) δ: 1.43 (s, 9H), 2.78 (dd, 1H), 3.46 (dd, 1H), 3.9 (m, 1H), 4.58 (m, 1H), 4.95 (m, 1H), 7.22 (m, 4H), 7.38 (m, 1H); MS m/z 299 (M+Na).
[(1R,2R)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl]amine (Intermediate 10; 277.0 mg, 1.0 mmol), 2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (Intermediate 3; 236 mg, 1.0 mmol) and DIPEA (174 μl, 1.0 mmol) were dissolved in DCM (10 mL). HOBT (135 mg, 1 mmol) and EDCI (240 mg, 1.25 mmol) were added and the mixture stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (25 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (6: 1, iso-hexane:ethyl acetate) to give the title compound (286 mg, 56%) as an orange foam.
1H NMR δ: 0.03 (d, 6H), 0.85 (s, 9H), 2.9 (dd, 1H), 3.35 (m, 1H), 4.93 (m, 1H), 7.17 (s, 1H), 7.23 (m, 4H), 7.38 (m, 1H), 8.5 (d, 1H), 12.37 (s, 1H).
[(1R,2R)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-2-yl]amine (Intermediate 10; 277 mg, 1.0 mmol), 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (201 mg, 1.0 mmol) and DIPEA (174 μl, 1.0 mmol) were dissolved in DCM (10 mL). HOBT (135 mg, 1 mmol) and EDCI (240 mg, 1.25 mmol) were added and the mixture stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (25 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (6:1 iso-hexane:ethyl acetate) to give the title compound (320 mg, 70%) as a yellow foam.
1H NMR 8: 0.03(d, 6H), 0.85 (s, 9H), 2.9 (dd, 1H), 3.35 (m, 1H), 3.9 (m, 2H), 4.58 (m, 1H), 7.05 (s, 1H), 7.2 (m, 4H), 7.38 (m, 1H), 8.4 (d, 1H), 11.87 (s, 1H).
((1R,2R)-2-{[(2,3-Dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)methyl methanesulfonate (Example 10; 920 mg, 2.0 mmol) and sodium azide (260 mg, 4.0 mmol) in dimethyl acetamide (10 mL) was heated to 60° C. for 10 h, cooled, poured into ethyl acetate (50 mL), washed with water (6×20 mL), brine (20 mL), dried (MgSO4) filtered and evaporated. The residue was dissolved in THF, triphenylphosphine (1.05 g, 4.0 mmol) added and stirred at 60° C. for 24 h. The volatiles were removed under reduced pressure and the crude residue purified by ion exchange chromatography (Dowex 50W X2, H+ form; 6: 1, THF:water followed by 2% ammonia in 6: 1, THF:water) to give the title compound (600 mg, 79%) as a pale brown solid.
1H NMR 8: 2.9 (d, 2H), 2.92 (dd, 1H), 3.15 (m, 1H), 3.3 (dd, 1H), 4.6 (m, 1H), 7.15 (s, 1H), 7.2 (m, 3H), 7.3 (m, 1H), 8.48 (d, 1H), 11.8 (s, 1H); MS m/z 378, 380, 382.
2-Chloro-N-[(1R,2R)-1-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 5; 347 mg, 1.0 mmol) and triethylamine (350 μl, 2.5 mmol) were dissolved in THF (10 mL). Methanesulphonyl chloride (126 mg, 1.1 mmol) in THF (5 mL) was added and the mixture stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (25 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (370 g, 87%) as a pale brown foam.
1H NMR δ: 2.95 (dd, 1H), 3.18 (s, 3H), 3.3 (dd, 1H), 3.58 (m, 1H), 4.45 (m, 1H), 4.58 (m, 2H), 7.02 (s, 1H), 7.15 (s, 1H), 7.23 (m, 3H), 7.35 (m, 1H), 8.48 (d, 1H), 11.86 (s, 1H); MS m/z 425.1/427.1.
Sodium hydride (92 mg, 60% in oil, 2.30 mmol) was added to a solution of trans-ethyl (1-chloro-2,3-dihydro-1H-inden-2-yl)carbamate (Bioorg. Med. Chem. Lett. 1657-1662, 1999; 500 mg, 2.09 mmol) in DMF (7.5 mL) at ambient temperature. The reaction was heated to 40° C. for 2 h then cooled to ambient temperature. Sodium thiomethoxide (161 mg, 2.30 mmol) was added and stirred at ambient temperature for 30 mins. The reaction was diluted with ether (50 mL) and 1M HCl (20 mL) and the organic layer was washed with saturated aqueous NaHCO3 (20 mL), dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:4 to 1:2 EtOAc:hexanes) afforded the title compound (200 mg, 38%) which solidified on standing.
1H NMR δ: 1.24 (m, 3H), 2.17 (s, 3H), 2.77 (dd, 1H), 3.50 (dd, 1H), 4.10 (m, 3H), 4.40 (m, 1H), 4.89 (br. s, 1H), 7.22 (m, 3H), 7.38 (m, 1H); MS m/z 204 [optionally M-SMe]+.
Sodium hydride (60% in oil, 84 mg, 2.08 mmol) was added to a solution of trans-ethyl (1-chloro-2,3-dihydro-1H-inden-2-yl)carbamate (Bioorg. Med. Chem. Lett. 1657-1662, 1999; 250 mg, 1.04 mmol) in THF (7.5 mL) at ambient temperature and stirred for a further 1 h. 2-thio-imidazole (1.04 mg, 1.04 mmol) was then added and stirred at ambient temperature for a further 1 h. The reaction was diluted with ether (50 mL) and water (20 mL) and the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:2 to 1:1 EtOAc:hexanes) afforded the title compound (170 mg, 54%) as a colourless oil.
1H NMR 8: 1.17 (t, 3H), 2.78 (dd, 1H), 3.27 (dd, 1H), 3.98 (m, 2H), 4.28 (m, 1H), 4.75 (d, 1H), 6.95 (s, 1H), 7.60 (s, 1H), 12.35 (s, 1H); MS m/z 304 [optionally M]+.
The following intermediate was prepared by the method of Intermediate 21, using trans-ethyl (1-chloro-2,3-dihydro-1H-inden-2-yl)carbamate (Bioorg. Med. Chem. Lett. 1657-1662, 1999) and 1,2,4-triazole-3-thiol.
1H NMR δ: 1.23 (t, 3H), 2.82 (dd, 1H), 3.59 (m, 4H), 4.10 (m, 2H), 4.45 (m, 1H), 5.12 (m, 1H), 5.97 (br. s, 1H), 7.25 (m, 4H), 8.17 (s, 1H), MS m/z 319 [optionally M]+.
THF (100 mL) followed by 1 M sodium hydroxide was added to (1S,2S)(+)-trans-1-amino-2-indanol (CAS Reg. No. 163061-74-3, 5.00 g, 33.55 mmol). Di-tert-butyl dicarbonate (7.30 g, 33.55 mmol) was then added and stirred for 16 h. The THF was removed in vacuo and the remaining aqueous layer was acidified to pH 2 with citric acid (5% w/v aqueous) and diluted with EtOAc (150 mL). The organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. The crude was triturated with hot ether:hexanes (1:1, 40 mL), the suspension cooled and filtered to afford the title compound (6.80 g, 81%) as a white solid.
1H NMR δ: 1.54 (s, 9H), 2.92 (dd, 1H), 3.28 (dd, 1H), 4.23 (s, 1H), 4.42 (m, 1H), 4.93 (t, 1H), 5.03 (s, 1H), 7.22 (m, 4H); MS m/z 313 [M+Na+MeCN]+.
Mesyl chloride (2.24 mL, 30.03 mmol) was added to a cooled (0° C.) solution of tert-butyl [(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 23, 6.80 g, 27.3 mmol) and triethylamine (4.01 mL, 30.03 mmol) in DCM (100 mL) ad stirred at 0° C. for 1 h. The reaction was quenched by addition of saturated aqueous NaHCO3 (100 mL), the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. The crude product was triturated with hot ether (40 mL), cooled and filtered to afford the title compound (8.11 g, 91%) as a white solid.
1H NMR 8: 1.45 (s, 9H), 3.18 (m, 4H), 3.47 (dd, 1H), 4.78 (s, 1H) 5.19 (m, 2H), 7.28 (m, 4H); MS m/z 350 [optionally M+Na]+.
1H NMR 8: 1.45 (s, 9H), 3.18 (m, 4H), 3.47 (dd, 1H), 4.78 (s, 1H) 5.19 (m, 2H), 7.28 (m, 4H); MS m/z 350 [optionally M+Na]+.
Sodium hexamethyldisilazide (NaHMDS, 10 mL, 1.0 M in THF, 10.00 mmol) was added slowly to a solution of (1S,2S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-2-yl methanesulfonate (Intermediate 24, 3.00 g, 9.17 mmol) in THF (40 mL) ensuring the internal temperature remained <20° C. After 30 mins methyl thioglycolate (0.90 mL, 10.00 mmol), NaHMDS (1.0 M in THF, 5 mL, 5.00 mmol) and DMF (10 mL) were added and the reaction was stirred at ambient temperature for 3 h. The reaction was quenched by the addition of water (100 mL) and ether (100 mL) and the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:4 to 1:2 EtOAc:hexanes) afforded the title compound (1.73 g, 55%) as a brown oil.
1H NMR 8: 1.43 (s, 9H), 2.75 (dd, 1H), 3.40 (d, 1H), 3.55 (m, 2H), 3.73 (s, 3H), 4.36 (m, 2H), 4.84 (s, 1H), 7.22 (m, 3H), 7.39 (m, 1H); MS m/z 360 [optionally M+Na]+.
1H NMR δ: 1.43 (s, 9H), 2.75 (dd, 1H), 3.40 (d, 1H), 3.55 (m, 2H), 3.73 (s, 3H), 4.36 (m, 2H), 4.84 (s, 1H), 7.22 (m, 3H), 7.39 (m, 1H).
Lithium borohydride (28 mg, 1.28 mmol) was added to a solution of methyl ({(1R,2R)-2-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-1-yl}thio)acetate (Intermediate 26, 216 mg, 0.64 mmol) in THF (5 mL) and the reaction was stirred under an argon atmosphere at ambient temperature for 5 h. A further portion of LiBH4 (28 mg, 1.28 mmol) was added and the reaction was stirred at ambient temperature for 16 h. The reaction was quenched with aqueous ammonium chloride (20 mL) and ether (40 ml), the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo to afford the title compound (196 mg, 99%) as a colourless oil.
1H NMR δ: 1.43 (s, 9H), 2.75 (m, 2H), 3.03 (m, 1H), 3.55 (dd, 1H), 3.86 (m, 2H), 4.30 (s, 1H), 4.40 (m, 1H), 4.81 (s, 1H), 7.21 (m, 3H), 7.38 (m, 1H); MS m/z 332 [optionally M+Na]+.
Trifluoroacetic acid (15 mL) was added to a solution of tert-butyl{(1R,2R)-1-[(2-hydroxyethyl)thio]-2,3-dihydro-1H-inden-2-yl}carbamate (Intermediate 26, 1.50 g, 4.45 mmol) in DCM followed by stirring at ambient temperature for 30 mins. The solvent was then removed in vacuo followed by re-evaporation from toluene (2×15 mL) followed by evaporation under high vacuum for 2 h. 5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Intermediate 3; 1.05 g, 4.45 mmol), DCM (40 mL), HOBT (681 mg, 4.45 mmol), DIPEA (2.32 mL, 13.35 mmol) and finally EDCI (1.07 g, 5.50 mmol) were added to the residue obtained from the first step and the reaction was stirred at ambient temperature for 16 h. The reaction was diluted with DCM (50 mL) then extracted with saturated aqueous NaHCO3 (40 mL) then 1M HCl and the organic layer was dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:4 to 1:1 EtOAc:hexanes) afforded the title compound (1.63 g, 80% over 2 steps) as a white solid.
1H NMR δ: 2.84 (dd, 1H), 3.45 (d, 1H), 3.63 (d, 1H), 3.72 (m, 1H), 3.78 (s, 3H), 4.70 (d, 1H), 4.77 (m, 1H), 6.77 (d, 1H), 6.84 (d, 1H), 7.27 (m, 2H), 7.40 (m, 1H), 9.78 (s, 1H); MS m/z 477, 479 [optionally M+Na]+.
The following intermediate was made by the method of Intermediate 29, using (+/−)-trans-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-2-yl methanesulfonate (Intermediate 27) as the carbamate and 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Intermediate 4) as the acid.
1H NMR δ: 2.93 (dd, 1H), 3.35 (m, 1H), 3.55 (d, 1H), 3.58 (s, 3H), 3.70 (d, 1H), 4.43 (d, 1H), 4.62 (m, 1H), 6.98 (s, 1H), 7.13 (s, 1H), 7.25 (m, 4H), 8.50 (d, 1H), 11.88 (s, 1H); MS m/z 443, 445 [optionally M+Na]+.
Sodium hexamethyldisilazide (1.0 M in THF, 6 mL, 6.00 mmol) was added to a stirred solution of (+/−)-trans-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-2-yl methanesulfonate (Intermediate 25, 1.79 g, 5.46 mmol) in THF (24 mL) whilst keeping the internal temperature <20° C. After 30 mins dimethyl malonate (0.69 mL, 6.00 mmol) was added followed by NaHMDS (1.0 M in THF, 6 mL, 6.00 mmol) and the reaction was heated at 50° C. for 16 h. The reaction was cooled and then quenched with saturated aqueous ammonium chloride (50 mL) and ether (100 ml) and the aqueous layer was re-extracted with ether (50 mL) and the combined organic layers were dried (MgSO4), filtered and the volatiles removed in vacuo. Purification by column chromatography (eluent gradient: 1:3 to 1:2 EtOAc:hexanes) afforded the title compound (1.00 g, 50%) as a white solid after standing.
1H NMR 8: 1.45 (s, 9H), 2.78 (dd, 1H), 3.37 (dd, 1H), 3.72 (m, 8H), 4.40 (m, 1H), 4.78 (br. s, 1H), 7.20 (m, 4H); MS m/z 386 [optionally M+Na].
Sodium chloride (535 mg, 9.16 mmol) was added to a solution of (+/−)-trans-dimethyl{-2-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-1-yl}malonate (Intermediate 31; 830 mg, 2.29 mmol) in DMSO (8 mL) containing 4 drops of water and the reaction was heated to 160° C. for 5 h. The solvent was removed on a Genevac EZ-2 centrifugal evaporator and the residue was taken up in water (5 mL) and EtOAc (20 mL). The organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography 1:2 EtOAc:hexanes afforded the title compound (500 mg, 72%) as a colourless oil.
1H NMR (DMSO) δ: 1.45 (s, 9H), 2.78 (m, ÷H), 3.38 (m, 2H), 3.75 (s, 3H), 4.13 (m, 1H), 4.87 (br. s, 1H), 7.17 (m, 4H); MS m/z 386 [optionally M+Na+MeCN]+.
tert-Butyl [(1R,2R)-1-({[(2-hydroxyethyl)amino]sulfonyl}methyl)-2,3-dihydro-1H-inden-2-yl]carbamate (Intermediate 44, 1.25 g, 4.1 mmol) was dissolved in DCM (20 mL), HCl (4M in dioxane, 20 mL) was added and the solution stirred for 1 hr. The volatiles were removed in vacuo, the crude solid triturated in ether (40 mL) and filtering to afford the title compound (314 mg, 89%) as a white solid.
1H NMR δ: 2.94 (d, 1H), 3.11 (m, 2H), 3.47 (m, 5H), 3.75 (m, 1H), 4.07 (m, 1H), 4.88 (m, 1H), 7.26 (m, 3H), 7.45 (m, 2H), 8.30 (bs, 3H); MS m/z 271.3.
Intermediate 35
tert-Butyl [(1R,2R)-1-({[(2-hydroxyethyl)amino]sulfinyl}methyl)-2,3-dihydro-1H-inden-2-yl]carbamate (Intermediate 50, 729 mg, 2.1 mmol) was dissolved in DCM (30 mL) to this was added m-CPBA (558 mg, 2.3 mmol) and the solution stirred for 16 hours. The solution was washed with saturated sodium bicarbonate solution (4×15 mL) and evaporated to give a white solid. The crude material was purified by flash column chromatography (SiO2, eluent: 0-100% EtOAc/isohexane to give the title compound (436 mg, 57%) as a white solid.
1NMR ε: 1.40 (s, 9H), 2.78 (m, 1H), 3.05 (m, 3H), 3.35 (m, 5H), 4.05 (m, 1H), 4.72 (t, 1H), 7.16 (m, 5H), 7.48 (m, 1H); MS m/z 369.1.
Intermediates 39-43 were prepared by the method used for Intermediate 44, using Intermdiates 45 to 49 as the sulfinamide starting materials.
1H NMR (CDCl3)
S-({(1R,2R)-2-[(tert-Butoxycarbonyl)amino]-2,3-dihydro-1H-inden-1-yl}methyl)ethanethioate (Intermediate 51, 1.19 g, 3.7 mmol) was dissolved in DCM (20 mL) and cooled to −10° C. before addition of acetic anhydride (0.35 mL, 3.7 mmol) and thionyl chloride (SO2Cl2) (0.60 mL, 7.4 mmol). The solution was stirred for 1 hour, the solvents were removed by evaporation, then the resultant solid was dissolved in DCM (20 mL) before addition of ethanolamine (0.45 mL, 7.4 mmol). The reaction was stirred for 16 hours before the supernatant was purified by flash column chromatography on silica gel (eluent: 0-10% MeOH in DCM) to give the title compound (739 mg, 56%) as a white solid.
1H NMR 8: 1.40 (s, 9H), 2.75 (m, 1H), 3.05 (m, 5H), 3.48 (m, 2H), 4.06 (m, 1H), 4.64 (m, 1H), 6.07 (m, 1H), 7.22 (m, 6H); MS m/z 355.1.
Intermediates 45-49 were prepared by the method of Intermediate 50, using Intermediate 51 as the thioester and the appropriate commercially available amine.
1H NMR
{(1R,2R)-2-[(tert-Butoxycarbonyl)amino]-2,3-dihydro-1H-inden-1-yl}methyl methanesulfonate (1.314 g, 3.85 mmol) in DMF (10 mL) was added to a solution of thioacetic acid (351 mg, 4.62 mmol) and caesium carbonate (813 mg, 2.5 mmol) in DMF (30 mL). The solution was stirred at ambient temperature for 16 h then filtered. Water (20 mL) and ethyl acetate (100 mL) were added, the organic layer was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (eluent:EtOAc:toluene, 1:19) to afford the title compound (919 mg, 75%) as an oil which crystallised on standing.
1H NMR (CDCl3) δ: 1.4 (s, 9H), 2.4 (s, 3H), 2.8 (dd, 1H), 3.2 (m, 3H), 3.3 (dd, 1H), 4.1 (m, 1H), 4.8 (m, 1H), 7.2 (m, 3H), 7.3 (m, 1H).
1H NMR δ: 1.12 (t, 3H), 1.39 (dd, 3H), 2.94 (dt, 1H), 3.39 (m, 1H), 4.00 (m, 3H), 4.52 (dd, 1H), 4.69 (m, 1H), 7.12 (s, 1H), 7.26 (m, 4H), 8.59 (dd, 1H); MS m/z 483.1.
1H NMR δ: 1.12 (t, 3H), 1.39 (dd, 3H), 2.94 (dt, 1H), 3.39 (m, 1H), 4.00 (m, 3H), 4.52 (dd, 1H), 4.66 (m, 1H), 7.01 (s, 1H), 7.12 (s, 1H), 7.26 (m, 4H), 8.50 (dd, 1H); MS m/z 449.2
| Number | Date | Country | Kind |
|---|---|---|---|
| 0318463.7 | Aug 2003 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB04/03345 | 8/4/2004 | WO | 00 | 1/26/2006 |
