prop-2-ynoxybenzene

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:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 0.5-L reactor (#1) was equipped with a thermometer, an addition funnel, an overhead stirrer, and a nitrogen inlet. 150 mL of THF was charged followed by 27.5 g (0.21 mole) of phenyl propargyl ether. The solution was cooled to −20° C. 100 mL (0.25 mole) of n-butyllithium in hexanes was charged into an addition funnel. This solution was added to the reactor at a temperature between −25 and −35° C. The temperature was controlled by the rate of addition and the mixture was stirred for 1 h at −25 to −35° C. A second 1-L reactor (#2) was equipped with a thermometer, an overhead stirrer and a cannulation device. 120 mL of THF was charged followed by 9.4 g (0.42 mol) of paraformaldehyde as a solid in one portion. The resulting suspension was stirred for 5 min. and cooled to 5–10° C. The contents of reactor #1 were cannulated into reactor #2 maintaining temperature in reactor #2 between 5 and 15° C. The temperature in reactor #1 was maintained below −15° C. The cooling bath from reactor #2 was removed and the reaction mixture was allowed to warm up slowly to 20–25° C. Stirring was continued for 16 h at ambient temperature. 200 mL of water was added to the reaction mixture and the mixture was stirred for 15–30 min at ambient temperature. The reaction mixture was extracted twice with 200 mL and then 100 mL of ethyl acetate. The combined organic solution was washed with 200 mL of water. The organic solution was dried with 50 g of anhydrous sodium sulfate. The drying agent was filtered off and rinsed with 50 mL of ethyl acetate. The filtrate was transferred into a 1-L reactor fitted with an overhead stirrer. Pyridine (67 mL, 0.83 mol) was charged followed by acetic anhydride (39 mL, 0.42 mol). The solution was stirred overnight at ambient temperature. The solution was washed sequentially with water (200 mL), sodium bicarbonate solution (2×150 mL) until pH=7–8, hydrochloric acid solution (2×150 mL) until pH=1–3, and brine (1×150 mL). The solution was dried with anhydrous sodium sulfate (50 g). The drying agent was filtered off, and the filtrate was concentrated in vacuo at a temperature that did not exceed 60° C. to yield 37 g (87% yield, HPLC strength 65%) of product as a dark-red slightly viscous fluid. This solution was added to the reactor at a temperature between −25 and −35° C The temperature was controlled by the rate of addition The resulting suspension was stirred for 5 min. cooled to 5–10° C The contents of reactor #1 were cannulated into reactor #2 between 5 and 15° C The temperature in reactor #1 was maintained below −15° C The cooling bath from reactor #2 was removed to warm up slowly to 20–25° C Stirring was continued for 16 h at ambient temperature 200 mL of water was added to the reaction mixture the mixture was stirred for 15–30 min at ambient temperature The reaction mixture was extracted twice with 200 mL The combined organic solution was washed with 200 mL of water The organic solution was dried with 50 g of anhydrous sodium sulfate The drying agent was filtered off rinsed with 50 mL of ethyl acetate The filtrate was transferred into a 1-L reactor fitted with an overhead stirrer The solution was stirred overnight at ambient temperature The solution was washed sequentially with water (200 mL), sodium bicarbonate solution (2×150 mL) until pH=7–8, hydrochloric acid solution (2×150 mL) until pH=1–3, and brine (1×150 mL) The solution was dried with anhydrous sodium sulfate (50 g) The drying agent was filtered off the filtrate was concentrated in vacuo at a temperature that did not exceed 60° C. to yield 37 g (87% yield, HPLC strength 65%) of product as a dark-red slightly viscous fluid

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

Procedure: To a 1 L flask under Argon was added CuI (7.86 g, 41.2 mmol) and Pd(PPh3)4 (5 g, 4.3 mmol). The catalyst was covered With 600 mL of degassed THF, cis-1,2-dichloroethylene (50 g, 516 mmol), and butylamine (68 mL, 688 mmol). Phenoxy-2-propyne (45g, 340 mmol) was added neat over 10 min and the reaction mixture stirred for 5.5 h. Air was bubbled through the reaction mixture for 15 min and the reaction filtered through a pad of celite and washed with pentane. The filtrate was washed with water and brine and the aqueous fractions extracted with ether. The organic fractions were combined, dried (MgSO4), filtered through celite and concentrated. The residue was chromatographed over silica gel (hexane) to give 44.3 g of a yellow oil (67%). Air was bubbled through the reaction mixture for 15 min the reaction filtered through a pad of celite washed with pentane The filtrate was washed with water and brine the aqueous fractions extracted with ether dried (MgSO4) filtered through celite concentrated The residue was chromatographed over silica gel (hexane)

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

Procedure: This compound was obtained by coupling 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-phenoxy-2-propyne as described in example 1. Chromatographic isolation and crystallization from ethyl acetate gave colorless crystals with m.p. 160°-162° C. This compound was obtained Chromatographic isolation and crystallization from ethyl acetate gave colorless crystals with m.p. 160°-162° C.

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

Procedure: This compound was obtained by coupling 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-phenoxy-2-propyne as described in example 1. Chromatographic isolation and crystallization from ethyl acetate gave colorless crystals with m.p. 160°-162° C. This compound was obtained Chromatographic isolation and crystallization from ethyl acetate gave colorless crystals with m.p. 160°-162° C.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-iodo-6-methylamino adenosine (50 mg) and prop-2-ynyloxybenzene (0.022 mL, 0.16 mmol) in N,N-dimethylformamide (1 ml) and triethylamine (0.021 mL, 0.16 mmol) at 23 C was added copper iodide (5 mg, 0.026 mmol) and dichlorobis-(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) catalyst. After being stirred in a sealed reaction-vial at 80° C. for 6 hours, the reaction was concentrated in vacuo, and the residue purified by preparatory thin layer chromatography (methylene chloride:methanol 9:1) to afford (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol, a compound of Formula I. MS: 412.1 (M+1). the reaction was concentrated in vacuo the residue purified by preparatory thin layer chromatography (methylene chloride:methanol 9:1)

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

Procedure: Referring to FIG. 39, chlorosulfonic acid (19.9 mL, 0.299 mol) was added dropwise to (prop-2-yn-1-yloxy)benzene (17.2 g, 0.130 mol) in dichloromethane (100 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour and then poured into ice-water and extracted with dichloromethane. The extract was washed with water, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (17.9 g, 60%). extracted with dichloromethane The extract was washed with water dried (MgSO4) evaporated The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Referring to FIG. 39, phenol (14.6 g. 0.155 mol), propargyl bromide (19 m 0.171 mol) and potassium carbonate (32.1 g, 0.232 mol) in DMF (100 mL) were heated at 85° C. overnight. The reaction was diluted with water and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep) to give product as an oil (17.2 g, 84%). extracted with ether The extract was washed with brine dried (MgSO4) evaporated The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep)

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

Procedure: Referring to FIG. 39, chlorosulfonic acid (19.9 mL, 0.299 mol) was added dropwise to (prop-2-yn-1-yloxy)benzene (17.2 g, 0.130 mol) in dichloromethane (100 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour and then poured into ice-water and extracted with dichloromethane. The extract was washed with water, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (17.9 g, 60%). extracted with dichloromethane The extract was washed with water dried (MgSO4) evaporated The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Referring to FIG. 39, phenol (14.6 g, 0.155 mol), propargyl bromide (19 mL, 0.171 mol) and potassium carbonate (32.1 g, 0.232 mol) in DMF (100 mL) were heated at 85° C. overnight. The reaction was diluted with water and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep) to give product as an oil (17.2 g, 84%). extracted with ether The extract was washed with brine dried (MgSO4) evaporated The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep)