Carbamic acid, [(1S,2S)-2-aminocyclopentyl]-, 1,1-dimethylethyl ester (9CI)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-butyl N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate was synthesized by treating tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.27 (s, 9H) 1.42-1.54 (m, 2H) 1.56-1.65 (m, 2H) 1.80-1.88 (m, 1H) 1.96-2.01 (m, 1H) 3.88-3.96 (m, 1H) 4.03-4.09 (m, 1H) 6.91 (d, J=8.20 Hz, 1H) 7.41 (d, J=7.32 Hz, 1H) 8.18 (s, 1H). LCMS (ESI) 391 (M+H).

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl [(1S,2S)-2-aminocyclopentyl]carbamate (900 mg, 4.49 mmol) (purchased from Sigma Aldrich) was taken up in acetonitrile (13 mL). Potassium carbonate (932 mg, 6.74 mmol) and ethyl chloroacetate (0.577 mL, 5.39 mmol) were added, and the resulting mixture was heated to 55° C. overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in EtOAc, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford ethyl N-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}glycinate. The resulting mixture was cooled to room temperature concentrated under reduced pressure washed with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 6.78 ml, 54.9 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 10 g, 49.9 mmol) and DIPEA (26.2 ml, 150 mmol) in DMSO (160 ml) was heated at 140° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organics were washed with brine (3×100 ml), filtered through a hydrophobic frit, further dried over magnesium sulphate and then concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-40% ethyl acetate/petrol). Impure fractions were further purified by column chromatography (silica, 10-40% ethyl acetate/petrol) and combined to afford the title compound. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (200 ml) The aqueous layer was extracted with ethyl acetate (2×100 ml) The combined organics were washed with brine (3×100 ml) filtered through a hydrophobic frit further dried over magnesium sulphate concentrated in vacuo The resulting residue was purified by column chromatography (silica, 0-40% ethyl acetate/petrol) Impure fractions were further purified by column chromatography (silica, 10-40% ethyl acetate/petrol)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 2.0 g, 10.98 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol) and DIPEA (5.23 ml, 30.0 mmol) in DMSO (20 ml) was sealed and heated at 140° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml). The organics were washed with water (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 10-40% ethyl acetate/petrol) to afford the title compound. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml) The organics were washed with water (2×100 ml), brine (100 ml) dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (silica, 10-40% ethyl acetate/petrol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (CAS number 71701-92-3; 2.86 g, 10.98 mmol), DIPEA (1.74 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol), then by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound. The reaction was partitioned between ethyl acetate and water The phases were separated the aqueous layer was re-extracted with ethyl acetate (2×50 ml) The combined organics were washed with brine (50 ml) filtered through a hydrophobic frit concentrated in vacuo The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 2.011 g, 10.98 mmol) and DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (0-15% ethyl acetate/petrol) to afford the title compound. The reaction was partitioned between ethyl acetate and water The phases were separated the aqueous layer was re-extracted with ethyl acetate (2×50 ml) The combined organics were washed with brine (50 ml) filtered through a hydrophobic frit concentrated in vacuo The crude product was purified by column chromatography (0-15% ethyl acetate/petrol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 120 mg, 0.60 mmol), 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 134 mg, 0.60 mmol), TBTU (231 mg, 0.72 mmol) and DIPEA (0.116 g, 0.9 mmol) in DMF (3 ml) was stirred at room temperature for 2 hours. The reaction was diluted with water (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organics were washed with water (20 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% ethyl acetate/n-hexane) to afford the title compound. extracted with ethyl acetate (3×30 ml) The combined organics were washed with water (20 ml), brine (20 ml) dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (silica, 0-30% ethyl acetate/n-hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 1 g, 4.99 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 1.09 g, 5.99 mmol) and DIPEA (2.62 ml, 14.98 mmol) in DMSO (17 ml) was subjected to microwave irradiation at 140° C. for 1 hour. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound. irradiation at 140° C. for 1 hour The reaction was partitioned between ethyl acetate and water washed with water, brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 2.0 g, 10.98 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol) and DIPEA (5.23 ml, 30.0 mmol) in DMSO (20 ml) was sealed and heated at 140° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml). The organics were washed with water (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 10-40% ethyl acetate/petrol) to afford the title compound. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml) The organics were washed with water (2×100 ml), brine (100 ml) dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography (silica, 10-40% ethyl acetate/petrol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.50 mmol) and potassium carbonate (518 mg, 3.74 mmol) in DMF (5 ml) was added (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol). The reaction was stirred at room temperature for 24 hours. To this was then added further (bromomethyl)benzene (CAS number 100-39-0; 356 μl, 3.00 mmol) and stirring was continued for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with water (3×30 ml) and brine (30 ml). The organics were filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound. stirring was continued for 24 hours washed with water (3×30 ml) and brine (30 ml) The organics were filtered through a hydrophobic frit concentrated in vacuo This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the procedure for N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19) from tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.50 mmol), 2-fluoro-6-methoxybenzoic acid (CAS number 137654-21-8; 637 mg, 3.74 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tripropyl-, 2,4,6-trioxide (CAS number 68957-94-8; 50% in ethyl acetate, 2.2 ml, 3.74 mmol). Subsequent deprotection with HCl afforded the title compound. Prepared

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.497 mmol) in dry DCM (8.3 ml) was added triethylamine (1.74 ml, 12.48 mmol) and 2-chlorobenzoyl chloride (CAS number 609-65-4; 476 μl, 3.74 mmol). The reaction was stirred at room temperature for 72 hours. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol). The Boc protect intermediate was dissolved in 1,4-dioxane (8 ml) and to this was added HCl in 1,4-dioxane (4 M, 6.0 ml, 23.91 mmol). The reaction was stirred at room temperature for 17 hours and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound. The reaction was partitioned between DCM a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit concentrated in vacuo The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) was dissolved in 1,4-dioxane (8 ml) The reaction was stirred at room temperature for 17 hours concentrated in vacuo azeotropically distilled with toluene