(3R)-3-[tert-butyl(dimethyl)silyl]oxy-4-chlorobutanal

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+). stirring was continued at room temperature for 1 h extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 After the removal of solvent the residue was purified by column chromatography (10-20% EtOAc/Hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+). stirring was continued at room temperature for 1 h extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 After the removal of solvent the residue was purified by column chromatography (10-20% EtOAc/Hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-3-(tert-Butyldimethylsilyloxy)-4-chlorobutanal was prepared by the same route as (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal starting from (S)-2-hydroxysuccinic acid. 1H NMR (400 MHz, CDCl3) δ 9.72 (dd, J=1.6, 2.2 Hz, 1H), 4.33-4.28 (m, 1H), 3.46 (dd, J=4.7, 11.1 Hz, 1H), 3.39 (dd, J=6.4, 11.1 Hz, 1H), 2.68 (dd, J=1.5, 4.7 Hz, 1H), 2.62 (dd, J=2.3, 6.8 Hz, 1H), 0.79 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (2.13 g, 104.7 mmol) in CH3Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction, mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H). Then the temperature was warmed to room temperature gradually The mixture was filtered the cake was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure purified by column chromatography (PE)

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (2.13 g, 104.7 mmol) in CH3Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction, mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H). Then the temperature was warmed to room temperature gradually The mixture was filtered the cake was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure purified by column chromatography (PE)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+). stirring was continued at room temperature for 1 h extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 After the removal of solvent the residue was purified by column chromatography (10-20% EtOAc/Hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)—N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)—((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+). stirring was continued at room temperature for 1 h extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 After the removal of solvent the residue was purified by column chromatography (10-20% EtOAc/Hexane)

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (27.9 g, 104.7 mmol) in CH2Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H). Then the temperature was warmed to room temperature gradually The mixture was filtered the cake was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure purified by column chromatography (PE)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-(5-((S)—((R)-3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)(4-chloro-2-fluorophenyl)methyl)thiazol-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was made by the procedure used for 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)—((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide, starting from (S)—N-(5-(amino(4-chloro-2-fluorophenyl)methyl)thiazol-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (90%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.43-7.32 (m, 5H), 7.20 (dd, J=1.5, 8.3 Hz, 1H), 4.93 (s, 1H), 4.39-4.34 (m, 1H), 2.69 (dd, J=6.1, 9.8 Hz, 1H), 2.49-2.45 (m, 2H), 2.34 (dd, J=3.9, 9.9 Hz, 1H), 2.10-1.99 (m, 1H), 1.62-1.55 (m, 1H), 1.52-1.49 (m, 2H), 1.24-1.19 (m, 2H), 0.83 (s, 9H), 0.01 (s, 3H), −0.01 (s, 3H); HPLC ret. time 3.79 min, 10-99% CH3CN, 5 min run; ESI-MS 666.3 m/z (MH+).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-3-(tert-Butyldimethylsilyloxy)-4-chlorobutanal was prepared by the same route as (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal starting from (S)-2-hydroxysuccinic acid. 1H NMR (400 MHz, CDCl3) δ 9.72 (dd, J=1.6, 2.2 Hz, 1H), 4.33-4.28 (m, 1H), 3.46 (dd, J=4.7, 11.1 Hz, 1H), 3.39 (dd, J=6.4, 11.1 Hz, 1H), 2.68 (dd, J=1.5, 4.7 Hz, 1H), 2.62 (dd, J=2.3, 6.8 Hz, 1H), 0.79 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)—((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+). stirring was continued at room temperature for 1 h extracted with EtOAc The combined organic layers were washed with brine dried over MgSO4 After the removal of solvent the residue was purified by column chromatography (10-20% EtOAc/Hexane)

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (27.9 g, 104.7 mmol) in CH2Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H). Then the temperature was warmed to room temperature gradually The mixture was filtered the cake was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure purified by column chromatography (PE)