ditert-butyl hydrogen phosphate

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

Procedure: To a well stirred suspension of di-tert-butyl hydrogen phosphate (4.7 g, 22.47 mmol) in water (186 ml) was added sodium bicarbonate (7.5 g, 89.52 mmol) followed by tetra-n-butylammomium hydrogen sulphate (760 mg, 2.238 mmol). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added dichloromethane (112 ml) at 0° C. and it was stirred for 10 min followed by the addition of chloromethyl chlorosulphate (4.4 g, 26.85 mmol) in dichloromethane (75 ml) at same temperature. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was separated, washed with brine and evaporated under reduced pressure to yield 3.04 g of product as pale yellow oil. The reaction mixture was stirred at room temperature for 15 min it was stirred for 10 min The organic layer was separated washed with brine evaporated under reduced pressure

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

Procedure: A solution of the di-tert-butyl hydrogen phosphate obtained in step a) was dissolved in acetone (10 ml) and cooled to 0° C. To this solution was added a 10% aqueous solution of tetramethylammonium hydroxide (2.4 ml, 2.6 mmol), and the homogeneous solution was evaporated under reduced pressure to provide a solid, which was crystallized from refluxing 1,2-dimethoxyethane to provide tetramethylammonium ditert-butyl hydrogen phosphate as a white solid. the homogeneous solution was evaporated under reduced pressure to provide a solid, which was crystallized from refluxing 1,2-dimethoxyethane

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

Procedure: A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate (54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassium permanganate (99.7 g) was divided into three equal portions of 33.2 g and each portion was added over one hour. During the addition, the maximum temperature observed was 21.6° C. Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for thirty minutes. Decolorizing carbon (13.4 g) was added and the reaction was heated to 60° C. for fifteen minutes. The suspension was filtered (very slowly) and washed with deionized water (250 mL). The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min. The suspension was filtered and the filter cake was washed with deionized water (250 mL). The filtrate was cooled to 0° C. in an ice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2 mL) was added to acidify the solution to pH=1. A white precipitate immediately formed. The slurry was continued to stir at 0° C. for ten minutes. The white solid was filtered and washed with cold deionized water (219 mL). The filter cake was dissolved in chloroform (500 mL) and was dried over sodium sulfate. The dried solution was filtered, washed with chloroform, and concentrated in vacuo to afford a white solid (87.4 g, 46.2% yield). NMR analysis indicated pure product. 1H NMR (300 MHz): δ 1.45 (s, 18H); 31P NMR (121 MHz): δ −604.30. each portion was added over one hour During the addition observed was 21.6° C Once the addition Decolorizing carbon (13.4 g) was added the reaction was heated to 60° C. for fifteen minutes The suspension was filtered (very slowly) and washed with deionized water (250 mL) The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min The suspension was filtered the filter cake was washed with deionized water (250 mL) The filtrate was cooled to 0° C. in an ice/water bath Concentrated HCl (157.2 mL) was added A white precipitate immediately formed to stir at 0° C. for ten minutes The white solid was filtered washed with cold deionized water (219 mL) The filter cake was dissolved in chloroform (500 mL) was dried over sodium sulfate The dried solution was filtered washed with chloroform concentrated in vacuo

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

Procedure: A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate (54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassium permanganate (99.7 g) was divided into three equal portions of 33.2 g and each portion was added over one hour. During the addition, the maximum temperature observed was 21.6° C. Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for thirty minutes. Decolorizing carbon (13.4 g) was added and the reaction was heated to 60° C. for fifteen minutes. The suspension was filtered (very slowly) and washed with deionized water (250 mL). The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min. The suspension was filtered and the filter cake was washed with deionized water (250 mL). The filtrate was cooled to 0° C. in an ice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2 mL) was added to acidify the solution to pH=1. A white precipitate immediately formed. The slurry was continued to stir at 0° C. for ten minutes. The white solid was filtered and washed with cold deionized water (219 mL). The filter cake was dissolved in chloroform (500 mL) and was dried over sodium sulfate. The dried solution was filtered, washed with chloroform, and concentrated in vacuo to afford a white solid (87.4 g, 46.2% yield). NMR analysis indicated pure product. 1H NMR (300 MHz): δ 1.45 (s, 18H); 31P NMR (121 MHz): δ −604.30. each portion was added over one hour During the addition observed was 21.6° C Once the addition Decolorizing carbon (13.4 g) was added the reaction was heated to 60° C. for fifteen minutes The suspension was filtered (very slowly) and washed with deionized water (250 mL) The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min The suspension was filtered the filter cake was washed with deionized water (250 mL) The filtrate was cooled to 0° C. in an ice/water bath Concentrated HCl (157.2 mL) was added A white precipitate immediately formed to stir at 0° C. for ten minutes The white solid was filtered washed with cold deionized water (219 mL) The filter cake was dissolved in chloroform (500 mL) was dried over sodium sulfate The dried solution was filtered washed with chloroform concentrated in vacuo

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

Procedure: A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate (54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassium permanganate (99.7 g) was divided into three equal portions of 33.2 g and each portion was added over one hour. During the addition, the maximum temperature observed was 21.6° C. Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for thirty minutes. Decolorizing carbon (13.4 g) was added and the reaction was heated to 60° C. for fifteen minutes. The suspension was filtered (very slowly) and washed with deionized water (250 mL). The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min. The suspension was filtered and the filter cake was washed with deionized water (250 mL). The filtrate was cooled to 0° C. in an ice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2 mL) was added to acidify the solution to pH=1. A white precipitate immediately formed. The slurry was continued to stir at 0° C. for ten minutes. The white solid was filtered and washed with cold deionized water (219 mL). The filter cake was dissolved in chloroform (500 mL) and was dried over sodium sulfate. The dried solution was filtered, washed with chloroform, and concentrated in vacuo to afford a white solid (87.4 g, 46.2% yield). NMR analysis indicated pure product. 1H NMR (300 MHz): δ 1.45 (s, 18H); 31P NMR (121 MHz): δ −604.30. each portion was added over one hour During the addition observed was 21.6° C Once the addition Decolorizing carbon (13.4 g) was added the reaction was heated to 60° C. for fifteen minutes The suspension was filtered (very slowly) and washed with deionized water (250 mL) The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min The suspension was filtered the filter cake was washed with deionized water (250 mL) The filtrate was cooled to 0° C. in an ice/water bath Concentrated HCl (157.2 mL) was added A white precipitate immediately formed to stir at 0° C. for ten minutes The white solid was filtered washed with cold deionized water (219 mL) The filter cake was dissolved in chloroform (500 mL) was dried over sodium sulfate The dried solution was filtered washed with chloroform concentrated in vacuo

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

Procedure: A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate (54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassium permanganate (99.7 g) was divided into three equal portions of 33.2 g and each portion was added over one hour. During the addition, the maximum temperature observed was 21.6° C. Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for thirty minutes. Decolorizing carbon (13.4 g) was added and the reaction was heated to 60° C. for fifteen minutes. The suspension was filtered (very slowly) and washed with deionized water (250 mL). The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min. The suspension was filtered and the filter cake was washed with deionized water (250 mL). The filtrate was cooled to 0° C. in an ice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2 mL) was added to acidify the solution to pH=1. A white precipitate immediately formed. The slurry was continued to stir at 0° C. for ten minutes. The white solid was filtered and washed with cold deionized water (219 mL). The filter cake was dissolved in chloroform (500 mL) and was dried over sodium sulfate. The dried solution was filtered, washed with chloroform, and concentrated in vacuo to afford a white solid (87.4 g, 46.2% yield). NMR analysis indicated pure product. 1H NMR (300 MHz): δ 1.45 (s, 18H); 31P NMR (121 MHz): δ −604.30. each portion was added over one hour During the addition observed was 21.6° C Once the addition Decolorizing carbon (13.4 g) was added the reaction was heated to 60° C. for fifteen minutes The suspension was filtered (very slowly) and washed with deionized water (250 mL) The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min The suspension was filtered the filter cake was washed with deionized water (250 mL) The filtrate was cooled to 0° C. in an ice/water bath Concentrated HCl (157.2 mL) was added A white precipitate immediately formed to stir at 0° C. for ten minutes The white solid was filtered washed with cold deionized water (219 mL) The filter cake was dissolved in chloroform (500 mL) was dried over sodium sulfate The dried solution was filtered washed with chloroform concentrated in vacuo

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

Procedure: A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate (54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassium permanganate (99.7 g) was divided into three equal portions of 33.2 g and each portion was added over one hour. During the addition, the maximum temperature observed was 21.6° C. Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for thirty minutes. Decolorizing carbon (13.4 g) was added and the reaction was heated to 60° C. for fifteen minutes. The suspension was filtered (very slowly) and washed with deionized water (250 mL). The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min. The suspension was filtered and the filter cake was washed with deionized water (250 mL). The filtrate was cooled to 0° C. in an ice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2 mL) was added to acidify the solution to pH=1. A white precipitate immediately formed. The slurry was continued to stir at 0° C. for ten minutes. The white solid was filtered and washed with cold deionized water (219 mL). The filter cake was dissolved in chloroform (500 mL) and was dried over sodium sulfate. The dried solution was filtered, washed with chloroform, and concentrated in vacuo to afford a white solid (87.4 g, 46.2% yield). NMR analysis indicated pure product. 1H NMR (300 MHz): δ 1.45 (s, 18H); 31P NMR (121 MHz): δ −604.30. each portion was added over one hour During the addition observed was 21.6° C Once the addition Decolorizing carbon (13.4 g) was added the reaction was heated to 60° C. for fifteen minutes The suspension was filtered (very slowly) and washed with deionized water (250 mL) The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min The suspension was filtered the filter cake was washed with deionized water (250 mL) The filtrate was cooled to 0° C. in an ice/water bath Concentrated HCl (157.2 mL) was added A white precipitate immediately formed to stir at 0° C. for ten minutes The white solid was filtered washed with cold deionized water (219 mL) The filter cake was dissolved in chloroform (500 mL) was dried over sodium sulfate The dried solution was filtered washed with chloroform concentrated in vacuo

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

Procedure: To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (7.30 g, 12.30 mmol) in acetonitrile (60 mL) was added dropwise a solution of DBU (0.374 g, 0.371 mL, 2.46 mmol) in trichloroacetonitrile (17.8 g, 12.3 mL, 123 mmol) at r.t. under argon. The reaction mixture was stirred for 5 h at r.t. until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated complete conversion. The reaction mixture was evaporated to dryness at reduced pressure and the residue was suspended in acetonitrile (60 mL). Phosphoric acid di-tert-butyl ester (3.36 g, 15.99 mmol) was added and the reaction mixture was stirred for approximately 3.5 h at r.t. under argon until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated that the reaction was complete. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with water (5 times). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to afford a red solid. The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80) to yield the title compound as a red solid. 1H-NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 8.08 (d, 1H), 7.70-7.65 (m, 2H), 7.47 (t, 1H), 7.11 (s, 1H), 7.11-7.07 (m, 1H), 6.77 (d, 1H), 6.44 (t, 1H), 5.97 (d, 1H), 5.39 (d, 1H), 3.49-3.08 (m, 6H), 2.39 (s, 3H), 1.45 (s, 18H), 1.41 (s, 9H), 0.87-0.56 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −12.1. LCMS: [M+1]+=786.4, Rt(1)=2.53 min., Rt(2)=1.62 min. The reaction mixture was evaporated to dryness at reduced pressure The reaction mixture was concentrated at reduced pressure the residue was partitioned between EtOAc and water The layers were separated the organic phase was washed with water (5 times) The organic phase was dried over Na2SO4 concentrated at reduced pressure to afford a red solid The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80)

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

Procedure: To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (7.30 g, 12.30 mmol) in acetonitrile (60 mL) was added dropwise a solution of DBU (0.374 g, 0.371 mL, 2.46 mmol) in trichloroacetonitrile (17.8 g, 12.3 mL, 123 mmol) at r.t. under argon. The reaction mixture was stirred for 5 h at r.t. until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated complete conversion. The reaction mixture was evaporated to dryness at reduced pressure and the residue was suspended in acetonitrile (60 mL). Phosphoric acid di-tert-butyl ester (3.36 g, 15.99 mmol) was added and the reaction mixture was stirred for approximately 3.5 h at r.t. under argon until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated that the reaction was complete. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with water (5 times). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to afford a red solid. The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80) to yield the title compound as a red solid. 1H-NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 8.08 (d, 1H), 7.70-7.65 (m, 2H), 7.47 (t, 1H), 7.11 (s, 1H), 7.11-7.07 (m, 1H), 6.77 (d, 1H), 6.44 (t, 1H), 5.97 (d, 1H), 5.39 (d, 1H), 3.49-3.08 (m, 6H), 2.39 (s, 3H), 1.45 (s, 18H), 1.41 (s, 9H), 0.87-0.56 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −12.1. LCMS: [M+1]+=786.4, Rt(1)=2.53 min., Rt(2)=1.62 min. The reaction mixture was evaporated to dryness at reduced pressure The reaction mixture was concentrated at reduced pressure the residue was partitioned between EtOAc and water The layers were separated the organic phase was washed with water (5 times) The organic phase was dried over Na2SO4 concentrated at reduced pressure to afford a red solid The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80)

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

Procedure: To a well stirred suspension of di-tert-butyl hydrogen phosphate (4.7 g, 22.47 mmol) in water (186 ml) was added sodium bicarbonate (7.5 g, 89.52 mmol) followed by tetra-n-butylammomium hydrogen sulphate (760 mg, 2.238 mmol). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added dichloromethane (112 ml) at 0° C. and it was stirred for 10 min followed by the addition of chloromethyl chlorosulphate (4.4 g, 26.85 mmol) in dichloromethane (75 ml) at same temperature. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was separated, washed with brine and evaporated under reduced pressure to yield 3.04 g of product as pale yellow oil. The reaction mixture was stirred at room temperature for 15 min it was stirred for 10 min The organic layer was separated washed with brine evaporated under reduced pressure

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

Procedure: To a well stirred suspension of di-tert-butyl hydrogen phosphate (4.7 g, 22.47 mmol) in water (186 ml) was added sodium bicarbonate (7.5 g, 89.52 mmol) followed by tetra-n-butylammomium hydrogen sulphate (760 mg, 2.238 mmol). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added dichloromethane (112 ml) at 0° C. and it was stirred for 10 min followed by the addition of chloromethyl chlorosulphate (4.4 g, 26.85 mmol) in dichloromethane (75 ml) at same temperature. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was separated, washed with brine and evaporated under reduced pressure to yield 3.04 g of product as pale yellow oil. The reaction mixture was stirred at room temperature for 15 min it was stirred for 10 min The organic layer was separated washed with brine evaporated under reduced pressure

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

Procedure: To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (7.30 g, 12.30 mmol) in acetonitrile (60 mL) was added dropwise a solution of DBU (0.374 g, 0.371 mL, 2.46 mmol) in trichloroacetonitrile (17.8 g, 12.3 mL, 123 mmol) at r.t. under argon. The reaction mixture was stirred for 5 h at r.t. until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated complete conversion. The reaction mixture was evaporated to dryness at reduced pressure and the residue was suspended in acetonitrile (60 mL). Phosphoric acid di-tert-butyl ester (3.36 g, 15.99 mmol) was added and the reaction mixture was stirred for approximately 3.5 h at r.t. under argon until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated that the reaction was complete. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with water (5 times). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to afford a red solid. The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80) to yield the title compound as a red solid. 1H-NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 8.08 (d, 1H), 7.70-7.65 (m, 2H), 7.47 (t, 1H), 7.11 (s, 1H), 7.11-7.07 (m, 1H), 6.77 (d, 1H), 6.44 (t, 1H), 5.97 (d, 1H), 5.39 (d, 1H), 3.49-3.08 (m, 6H), 2.39 (s, 3H), 1.45 (s, 18H), 1.41 (s, 9H), 0.87-0.56 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −12.1. LCMS: [M+1]+=786.4, Rt(1)=2.53 min., Rt(2)=1.62 min. The reaction mixture was evaporated to dryness at reduced pressure The reaction mixture was concentrated at reduced pressure the residue was partitioned between EtOAc and water The layers were separated the organic phase was washed with water (5 times) The organic phase was dried over Na2SO4 concentrated at reduced pressure to afford a red solid The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80)