(3-chloro-2-fluorophenyl)methanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: (3-Chloro-2-fluorophenyl)methanamine (1.0 g, 6.27 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (1.12 g, 6.96 mmol) in methanol (10 ml). The mixture was heated at 70 C for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate) to yield N-(3-chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide (1.3 g, 4.5 mmol, 65% yield) as a colorless viscous oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.23-7.40 (m, 2H), 7.07 (t, J=7.9 Hz, 1H), 4.93 (s, 1H), 4.54 (s, 2H), 3.50-3.74 (m, 4H), 1.18-1.35 (m, 6H). MS (LC/MS) R.T.=1.78; [M+H]+=289.17. The mixture was heated at 70 C for 1 h The mixture was purified by chromatography (Biotage: 100% ethyl acetate)

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

Procedure: To a diastreoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (312 mg, 1.21 mmol), 3-chloro-2-fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH2Cl2 (6 mL) was added DIPEA (0.623 mL, 3.64 mmol). The resulting solution was stirred at RT under nitrogen overnight. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro-2-fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further stirred overnight at RT under N2. The mixture was poured into an aqueous solution of HCl 1N (pH-1) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.55 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.95 min, and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.45 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.89 min. the mixture was further stirred overnight at RT under N2 extracted with CH2Cl2 (2×) The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60)

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

Procedure: To a solution of (2S,3S,4S)-4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (195 g, 0.782 mmol) in CH2Cl2 (10 mL) were added 3-chloro-2-fluoro-benzylamine (150 mg, 0.94 mmol), propylphosphonic anhydride (50% in EtOAc, 0.346 mL, 1.17 mmol) and DIPEA (0.41 mL, 2.35 mmol). The reaction mixture was stirred 1 h at RT, then quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC): 391.3/393.1 [M+H]+, 435.4/437.4 [M+HCOO]−; tR (HPLC conditions f): 1.95 min. quenched by addition of a saturated aqueous solution of NaHCO3 extracted with CH2Cl2 (×2) The combined organic extracts were dried (Na2SO4) filtered concentrated The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) 1.95 min.

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

Procedure: To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.55 g, 5.89 mmol) in CH2Cl2 (50 mL) were added 3-chloro-2-fluoro-benzylamine (1.03 g, 6.48 mmol), propylphosphonic anhydride (50% in EtOAc, 5.20 mL, 8.83 mmol) and DIPEA (3.08 mL, 17.7 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 7:3) to give (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.35; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.12 min and (2R,3R,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.5; MS (UPLC): 405.1/407.2 [M+H]+, 349.0/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.20 min. concentrated The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 7:3)

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

Procedure: To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (500 mg, 1.90 mmol) in DMF (20 mL) were added 3-chloro-2-fluoro-benzylamine (330 mg, 2.1 mmol), HBTU (1.4 g, 3.8 mmol) and DIPEA (1.32 mL, 7.6 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water (50 mL). After extraction with ETOAc (3×30 mL), the organic phases were joined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.37; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.12 min. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.59 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.20 (br.d, 1H), 4.47-4.26 (m, 3H), 4.19 (ddd, 1H), 3.81-3.65 (m, 1H), 3.54-3.40 (m, 1H), 3.36 (s, 3H), 1.42 and 1.27 (2 s, 9H). After extraction with ETOAc (3×30 mL) washed with brine dried over Na2SO4 filtered concentrated The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2S,3R,4R)-4-azido-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (440 mg, 1.16 mmol) in methanol (3 mL) was hydrogenated with palladium on carbon 10% (124 mg, 1.16 mmol) overnight. The reaction mixture was filtered over a glass fiber filter, washed with methanol and evaporated in vacuo. The residue was dissolved in THF (2 mL) and a 10% aqueous Na2CO3 (3.09 mL, 1.11 mmol) solution was added. The reaction mixture was cooled at 0° C. then FmocOSu dissolved in THF (7 mL) was added and stirred for 2 h at RT. The reaction mixture was concentrated in vacuo to leave a residue which was dissolved in EtOAc (10 mL) and treated with saturated aq. NH4Cl solution. The mixture was extracted with EtOAc (3×20 mL) and the organic layers were collected, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMF (3 mL) then 3-chloro-2-fluoro benzylamine (267 mg, 1.67 mmol) and HBTU (526 mg, 1.38 mmol), DIPEA (292 μl, 1.67 mmol) were added. The resulting orange solution was stirred overnight at RT. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:2) afforded the title compound. MS (UPLC/MS): 624/626 [M+H]+, 668/670 [M+HCOO]−; tR (HPLC conditions f): 2.65 min. The reaction mixture was filtered over a glass fiber filter washed with methanol evaporated in vacuo The residue was dissolved in THF (2 mL) was added The reaction mixture was concentrated in vacuo to leave a residue which The mixture was extracted with EtOAc (3×20 mL) the organic layers were collected dried over MgSO4 filtered concentrated The residue was dissolved in DMF (3 mL) The resulting orange solution was stirred overnight at RT Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:2)

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

Procedure: To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-4-{[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, 0.20 mmol) in methanol (5 mL), 1M sodium hydroxide 0.40 mL, 0.40 mmol) was added. The solution was stirred for 2 h at RT then was diluted with water, the methanol was removed under reduced pressure. The aqueous layer was washed with Et2O (2×25 mL). The aqueous layer was acidified until pH 3 with 2N HCl and extracted with EtOAc (2×25 mL), dried with Na2SO4, filtered and concentrated. To the residue (80 mg, 0.17 mmol), (3-chloro-2-fluorophenyl)methanamine (33.9 mg, 0.21 mmol) and HBTU (101 mg, 0.26 mmol) dissolved in DMF (5 mL) was added DIPEA (0.06 mL, 0.35 mmol). The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 592/594 [M+H]+, 636/638 [M+HCOO]−; tR (HPLC conditions f): 2.49 min. the methanol was removed under reduced pressure The aqueous layer was washed with Et2O (2×25 mL) extracted with EtOAc (2×25 mL) dried with Na2SO4 filtered concentrated The reaction mixture was stirred for 16 h at RT The reaction mixture was quenched with water extracted with EtOAc washed with brine dried over Na2SO4 filtered concentrated Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) 2.49 min.

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

Procedure: The title compound was prepared as a TFA salt according to Scheme D5 (steps A and B) from 3-chloro-2-fluoro-benzylamine and (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. MS (LC-MS): 274.9 [M+H]+; tR (HPLC conditions b): 2.23 min. 2.23 min.

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluoro-3-chlorobenzylamine (1 g, 6.27 mmol) and TEA (1.05 mL, 7.52 mmol) in THF (20.9 mL) was added acryloyl chloride (0.61 mL, 7.52 mmol) dropwise and the reaction mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted in EtOAc, HCl 1N was added and the layers separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were dried, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (xyclohexane/EtOAc gradient 100:0 to 1:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 5:5)=0.41; MS (LC/MS): 214.0 [M+H]+; tR (HPLC conditions b): 3.35 min. the layers separated The aqueous layer was extracted again with EtOAc the combined organic layers were dried filtered concentrated to dryness The crude residue was purified by flash column chromatography on silica gel (xyclohexane/EtOAc gradient 100:0 to 1:1)

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

Procedure: To a solution of (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (800 mg, 3.46 mmol; prepared according to J. Amer. Chem. Soc. 2005, 127, 15923-15932) in CH2Cl2 (35 mL) were added successively 3-chloro-2-fluorobenzylamine (0.435 mL, 3.46 mmol), HBTU (1.97 g, 5.19 mmol), DIPEA (1.21 mL, 6.92 mmol). After stirring at RT for 18 h, the reaction mixture was diluted with CH2Cl2 and the organics were washed with water (2×), 0.1N aqueous HCl (2×), aqueous NaHCO3 solution (2×) and brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:2 to 4:1 then EtOAc) to afford the title compound as a colorless wax. TLC Rf (EtOAc/c-hexane 1:1)=0.32; MS (LC/MS): 373 [M+H]+, 395 [M+Na]+, 767 [2M+Na]+; tR (HPLC conditions C): 4.42 min. the organics were washed with water (2×), 0.1N aqueous HCl (2×), aqueous NaHCO3 solution (2×) and brine dried (phase separator) concentrated in vacuo The crude product was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:2 to 4:1