methyl 3-amino-5-bromobenzoate

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: To a solution of 3-amino-5-bromo-benzoic acid methyl ester (D12) (460 mg, 2.0 mmol, 1 equiv) in CH2Cl2 (10 ml) at room temperature was added NEt3 (306 μl, 2.2 mmol, 1.1 equiv) then 4-chlorobutyrylchloride (247 μl, 2.2 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 16 h and then diluted with AcOEt. The organic phase was washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-(4-chloro-butanoylamino)-benzoic acid methyl ester (D13) (530 mg, 79%) as a pale yellow oil. RT=2.88 s The organic phase was washed with 2N aqueous HCl solution dried over MgSO4 concentrated in vacuo

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

Procedure: To a solution of 3-bromo-5-nitro-benzoic acid methyl ester (D11) (12.1 g, 46.5 mmol, 1 equiv) in MeOH (200 ml) was added SnCl2 (44 g, 233 mmol, 5 equiv). The resulting mixture was stirred at reflux for 4 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ice-cold AcOEt and H2O. The aqueous phase was basified with 2N aqueous NaOH solution until a white precipitate appeared, then slowly with 12.5N aqueous NaOH solution until this precipitate disappeared. The temperature was kept below 10° C. during this addition. The two layers were separated and the aqueous phase extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 3-amino-5-bromo-benzoic acid methyl ester (D12) (9.9 g, 93%) as a brown solid. at reflux for 4 h concentrated in vacuo The residue was partitioned between ice-cold AcOEt and H2O The temperature was kept below 10° C. during this addition The two layers were separated the aqueous phase extracted with AcOEt The combined organic layers were washed with brine dried over MgSO4 concentrated in vacuo

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

Procedure: To a stirred solution of methyl 3-amino-5-bromobenzoate (5.2 g, 23 mmol) in water (80 mL) and H2SO4 (60 mL) was added dropwise a solution of NaNO2 (1.9 g, 28 mmol) in water (10 mL) at 0° C. The reaction mixture was added to a mixture of water (180 mL) and H2SO4 (240 mL). The mixture was heated at reflux for 30 minutes before being cooled to room temperature. The resulting mixture was poured into crushed ice and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford 3-bromo-5-hydroxybenzoic acid (3.8 g, 78% yield), which was directly used in next step. 1H NMR (400 MHz, d-DMSO) δ 10.27 (s, 1H), 7.43 (t, J=1.6 Hz, 1H), 7.28 (dd, J=1.2, 2.0 Hz, 1H), 7.15 (t, J=2.0 Hz, 1H). The mixture was heated at reflux for 30 minutes The resulting mixture was poured into crushed ice extracted with ethyl acetate (100 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a stirred solution of methyl 3-bromo-5-nitrobenzoate (1.0 g, 3.8 mmol) in methanol (30 mL) was added NiCl2-6H2O (1.8 g, 7.6 mmol) and NaBH4 (430 mg, 11 mmol) successively at 0° C. The reaction mixture was stirred for 30 seconds and was then quenched by the addition of water. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-amino-5-bromobenzoate (860 mg, 97% yield). 1H NMR (400 MHz, d-DMSO) δ 7.14 (dd, J=2.0, 2.4 Hz, 1H), 7.11 (t, J=2.4 Hz, 1H), 6.94 (t, J=2.8 Hz, 1H), 5.72 (brs, 2H), 3.79 (s, 3H). was then quenched by the addition of water The mixture was extracted with ethyl acetate (30 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a stirred solution of methyl 3-bromo-5-nitrobenzoate (1.0 g, 3.8 mmol) in methanol (30 mL) was added NiCl2-6H2O (1.8 g, 7.6 mmol) and NaBH4 (430 mg, 11 mmol) successively at 0° C. The reaction mixture was stirred for 30 seconds and was then quenched by the addition of water. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-amino-5-bromobenzoate (860 mg, 97% yield). 1H NMR (400 MHz, d-DMSO) δ 7.14 (dd, J=2.0, 2.4 Hz, 1H), 7.11 (t, J=2.4 Hz, 1H), 6.94 (t, J=2.8 Hz, 1H), 5.72 (brs, 2H), 3.79 (s, 3H). was then quenched by the addition of water The mixture was extracted with ethyl acetate (30 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a stirred solution of methyl 3-amino-5-bromobenzoate (5.2 g, 23 mmol) in water (80 mL) and H2SO4 (60 mL) was added dropwise a solution of NaNO2 (1.9 g, 28 mmol) in water (10 mL) at 0° C. The reaction mixture was added to a mixture of water (180 mL) and H2SO4 (240 mL). The mixture was heated at reflux for 30 minutes before being cooled to room temperature. The resulting mixture was poured into crushed ice and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford 3-bromo-5-hydroxybenzoic acid (3.8 g, 78% yield), which was directly used in next step. 1H NMR (400 MHz, d-DMSO) δ 10.27 (s, 1H), 7.43 (t, J=1.6 Hz, 1H), 7.28 (dd, J=1.2, 2.0 Hz, 1H), 7.15 (t, J=2.0 Hz, 1H). The mixture was heated at reflux for 30 minutes The resulting mixture was poured into crushed ice extracted with ethyl acetate (100 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a stirred solution of methyl 3-bromo-5-nitrobenzoate (1.0 g, 3.8 mmol) in methanol (30 mL) was added NiCl2.6H2O (1.8 g, 7.6 mmol) and NaBH4 (430 mg, 11 mmol) successively at 0° C. The reaction mixture was stirred for 30 seconds and was then quenched by the addition of water. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-amino-5-bromobenzoate (860 mg, 97% yield). 1H NMR (400 MHz, d-DMSO) δ 7.14 (dd, J=2.0, 2.4 Hz, 1H), 7.11 (t, J=2.4 Hz, 1H), 6.94 (t, J=2.8 Hz, 1H), 5.72 (brs, 2H), 3.79 (s, 3H). was then quenched by the addition of water The mixture was extracted with ethyl acetate (30 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a mixture of N-Boc-trans-4-fluoro-L-proline (500 mg, 2.14 mmol), methyl 3-amino-5-bromobenzoate (592 mg, 2.57 mmol) and HBTU (1.22 g, 3.22 mmol) in DMF (6 mL) was added DIPEA (734 μl, 4.29 mmol) and the resulting solution was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane 100% to c-hexane/EtOAc 70:30) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:2)=0.8; MS (LC/MS): 467.0/469.0 [M+Na]+, 345.1/347.0 [MH−Boc]+, 443.1/445.1 [M−H]−; tR (HPLC conditions a): 3.77 min. extracted three times with EtOAc The combined organic layers were washed twice with water dried over Na2SO4 filtered concentrated The crude residue was purified by flash column chromatography on silica gel (c-hexane 100% to c-hexane/EtOAc 70:30)

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

Procedure: To a stirred solution of methyl 3-amino-5-bromobenzoate (5.2 g, 23 mmol) in water (80 mL) and H2SO4 (60 mL) was added dropwise a solution of NaNO2 (1.9 g, 28 mmol) in water (10 mL) at 0° C. The reaction mixture was added to a mixture of water (180 mL) and H2SO4 (240 mL). The mixture was heated at reflux for 30 minutes before being cooled to room temperature. The resulting mixture was poured into crushed ice and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford 3-bromo-5-hydroxybenzoic acid (3.8 g, 78% yield), which was directly used in next step. 1H NMR (400 MHz, d-DMSO) δ 10.27 (s, 1H), 7.43 (t, J=1.6 Hz, 1H), 7.28 (dd, J=1.2, 2.0 Hz, 1H), 7.15 (t, J=2.0 Hz, 1H). The mixture was heated at reflux for 30 minutes The resulting mixture was poured into crushed ice extracted with ethyl acetate (100 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a stirred solution of methyl 3-bromo-5-nitrobenzoate (1.0 g, 3.8 mmol) in methanol (30 mL) was added NiCl2-6 H2O (1.8 g, 7.6 mmol) and NaBH4 (430 mg, 11 mmol) successively at 0° C. The reaction mixture was stirred for 30 seconds and was then quenched by the addition of water. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-amino-5-bromobenzoate (860 mg, 97% yield). 1H NMR (400 MHz, d-DMSO) δ 7.14 (dd, J=2.0, 2.4 Hz, 1H), 7.11 (t, J=2.4 Hz, 1H), 6.94 (t, J=2.8 Hz, 1H), 5.72 (brs, 2H), 3.79 (s, 3H). was then quenched by the addition of water The mixture was extracted with ethyl acetate (30 mL×3) The combined organic layers were washed with brine and water dried over anhydrous Na2SO4 concentrated under vacuum