4-chlorobutyl carbonochloridate

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

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

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

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

Procedure: To a solution of bimatoprost boronate b-1 (529 mg, 1.10 mmol) in THF was added DMAP (6.9 mg, 0.055 mmol). The solution was cooled to 0° C. and successively slowly added pyridine (0.22 mL, 2.75 mmol) and 4-chlorobutyl chloroformate (0.375 mL, 2.75 mmol). Allowed to stir at ambient temperature over 2 days. Added more pyridine (89 uL, 1.11 mmol) and 4-chlorobutyl chloroformate (150 uL, 1.10 mmol) and stirred for another 24 h. The resultant mixture was concentrated under reduced pressure, residue partitioned with ethyl acetate and water. Washed organic layer with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 808 mg (134%) of a crude oil, which was used without further purification. stirred for another 24 h The resultant mixture was concentrated under reduced pressure, residue partitioned with ethyl acetate and water Washed organic layer with brine, dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of bimatoprost (Cayman Chemicals 16820, Lot 188757; 123 mg, 0.30 mmol) in DCM (3 mL) at 0° C. was added DMAP (39 mg, 0.31 mmol) followed by the slow addition of 4-chlorobutyl chloroformate (43 uL, 0.31 mmol). After 3 days at ambient temperature, the mixture was diluted with DCM and washed with water (1×) and brine (1×). The DCM layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture of regioisomers and diacylated products was submitted to column chromatography (ethyl acetate-hexane 25-100%, followed by methanol-dichloromethane (5-15%) to provide as the major component isolated, 11-acylated chloride g-1 (25 mg, 15%) as a colorless oil. washed with water (1×) and brine (1×) The DCM layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The crude mixture of regioisomers and diacylated products to provide as the major component isolated

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

Procedure: To a solution of bimatoprost boronate b-1 (529 mg, 1.10 mmol) in THF was added DMAP (6.9 mg, 0.055 mmol). The solution was cooled to 0° C. and successively slowly added pyridine (0.22 mL, 2.75 mmol) and 4-chlorobutyl chloroformate (0.375 mL, 2.75 mmol). Allowed to stir at ambient temperature over 2 days. Added more pyridine (89 uL, 1.11 mmol) and 4-chlorobutyl chloroformate (150 uL, 1.10 mmol) and stirred for another 24 h. The resultant mixture was concentrated under reduced pressure, residue partitioned with ethyl acetate and water. Washed organic layer with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 808 mg (134%) of a crude oil, which was used without further purification. stirred for another 24 h The resultant mixture was concentrated under reduced pressure, residue partitioned with ethyl acetate and water Washed organic layer with brine, dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of bimatoprost (Cayman Chemicals 16820, Lot 188757; 123 mg, 0.30 mmol) in DCM (3 mL) at 0° C. was added DMAP (39 mg, 0.31 mmol) followed by the slow addition of 4-chlorobutyl chloroformate (43 uL, 0.31 mmol). After 3 days at ambient temperature, the mixture was diluted with DCM and washed with water (1×) and brine (1×). The DCM layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture of regioisomers and diacylated products was submitted to column chromatography (ethyl acetate-hexane 25-100%, followed by methanol-dichloromethane (5-15%) to provide as the major component isolated, 11-acylated chloride g-1 (25 mg, 15%) as a colorless oil. washed with water (1×) and brine (1×) The DCM layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The crude mixture of regioisomers and diacylated products to provide as the major component isolated

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

Procedure: To a solution of bimatoprost (Cayman Chemicals 16820, Lot 188757; 123 mg, 0.30 mmol) in DCM (3 mL) at 0° C. was added DMAP (39 mg, 0.31 mmol) followed by the slow addition of 4-chlorobutyl chloroformate (43 uL, 0.31 mmol). After 3 days at ambient temperature, the mixture was diluted with DCM and washed with water (1×) and brine (1×). The DCM layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture of regioisomers and diacylated products was submitted to column chromatography (ethyl acetate-hexane 25-100%, followed by methanol-dichloromethane (5-15%) to provide as the major component isolated, 11-acylated chloride g-1 (25 mg, 15%) as a colorless oil. washed with water (1×) and brine (1×) The DCM layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The crude mixture of regioisomers and diacylated products to provide as the major component isolated

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

Procedure: 100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 82 μl (2 molar equivalents) of 4-chlorobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product (formula shown hereinabove) were isolated as an orange powder (yield=85%) which was characterized as follows: The solvent was then evaporated under reduced pressure

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

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

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