3-chloro-2-(chloromethyl)prop-1-ene

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:0.00; pressure:0.00; stir:

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: A solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in International patent application publication WO2006/046030, Example 9)(0.12 M) in DMF was treated with KOtBu (2.1 eq.) in one portion; the resulting mixture was stirred for 30 min at RT then treated dropwise with 3-chloro-2-(chloromethyl)prop-1-ene (1.1 eq.). The resulting solution was stirred at RT overnight before being quenched by addition of HCl (1N) and extracted into EtOAc. The combined organic layers were washed with sat. aq. NaHCO3 and brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 85:15) affording the product as a yellow oil (97%). (ES+) m/z 402 (M+H)+. The resulting solution was stirred at RT overnight before being quenched by addition of HCl (1N) extracted into EtOAc The combined organic layers were washed with sat. aq. NaHCO3 and brine before being dried (Na2SO4) filtered concentrated in vacuo The crude material was purified by FC (PE/EtOAc 85:15)

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

Procedure: To a suspension of NaH (3.81 g, 95.4 mmol) in DMF (80 mL) is add dropwise a solution of N-Cbz-N′-Boc-hydrazine (12.1 g, 45.4 mmol) in DMF (20 mL). The reaction mixture is stirred about 20 minutes and 3-chloro-2-chloromethyl-propene ( 5.8 mL, 50 mmol) is added dropwise and the reaction is allowed to stir at room temperature unit the reaction is complete by TLC. The reaction solution is partitioned between ethyl acetate and water, the water layer being extracted several times more with solvent. The combined organic layers are dried, filtered, and concentrated to afford the desired product as a clear oil which is used without further purification. to stir at room temperature unit the reaction The reaction solution is partitioned between ethyl acetate and water the water layer being extracted several times more with solvent The combined organic layers are dried filtered concentrated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 60% Sodium hydride in oil (26 g, 0.65 mol, 2.17 eq) was added in one portion in a stream of argon at 5° C. to a solution of 3-chloro-2-(chloromethyl)prop-1-ene (35 mL, 0.3 mol, 1 eq) in dimethylformamide (500 mL). Then a solution of tert-butyl (2-hydroxyethyl)carbamate (48.3 g, 0.3 mol, 1 eq) in THF (500 mL) was added, and the reaction mixture was heated to 25° C. and stirred at this temperature for 2 h. The reaction mixture was then neutralized with glacial AcOH (4.5 mL) and evaporated in a water aspirator in vacuo at 45-55° C. using a 15-cm reflux condenser. The residue was poured with water (300 mL) and extracted with a mixture of ethylacetate (200 mL), hexane (100 mL) and chloroform (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The combined aqueous layer was extracted with a mixture of ethylacetate (150 mL) and hexane (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The extracts were filtered sequentially through silica gel (25 g) and sodium sulphate (50 mL), eluting with chloroform (100 mL). The filtrate was evaporated, and the residue was distilled in vacuo to give title compound as a colorless oil (bp 76-79° C. at 0.7 mm Hg) (35.8 g, 0.168 mol, 53%). evaporated in a water aspirator in vacuo at 45-55° C. reflux condenser The residue was poured with water (300 mL) extracted with a mixture of ethylacetate (200 mL), hexane (100 mL) and chloroform (50 mL) The organic layer was separated washed with water (2×100 mL) and brine The combined aqueous layer was extracted with a mixture of ethylacetate (150 mL) and hexane (50 mL) The organic layer was separated washed with water (2×100 mL) and brine The extracts were filtered sequentially through silica gel (25 g) and sodium sulphate (50 mL) eluting with chloroform (100 mL) The filtrate was evaporated the residue was distilled in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 60% Sodium hydride in oil (26 g, 0.65 mol, 2.17 eq) was added in one portion in argon flow at 5° C. to a solution of 3-chloro-2-chloromethyl-1-propene (35 mL, 0.3 mol, 1 eq) in dimethylformamide (500 mL). Then a solution of tert-butyl (2-hydroxyethyl)carbamate (48.3 g, 0.3 mol, 1 eq) in THF (500 mL) was added, and the reaction mixture was heated to 25° C. and stirred at this temperature for 2 h. Then the reaction mixture was neutralized with glacial AcOH (4.5 mL) and evaporated in water aspirator vacuum at 45-55° C. using a 15-cm reflux condenser. The residue was poured with water (300 mL) and extracted with a mixture of ethyl acetate (200 mL), hexane (100 mL) and chloroform (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The combined aqueous layer was extracted with a mixture of ethyl acetate (150 mL) and hexane (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The extracts were filtered sequentially through silica gel (25 g) and sodium sulfate (50 mL) eluting with chloroform (100 mL). The filtrate was evaporated, and the residue was distilled in vacuum to give title compound as a colorless oil (bp 76-79° C. at 0.7 mmHg) (35.8 g, 0.177 mol, 56%) evaporated in water at 45-55° C. reflux condenser The residue was poured with water (300 mL) extracted with a mixture of ethyl acetate (200 mL), hexane (100 mL) and chloroform (50 mL) The organic layer was separated washed with water (2×100 mL) and brine The combined aqueous layer was extracted with a mixture of ethyl acetate (150 mL) and hexane (50 mL) The organic layer was separated washed with water (2×100 mL) and brine The extracts were filtered sequentially through silica gel (25 g) and sodium sulfate (50 mL) eluting with chloroform (100 mL) The filtrate was evaporated the residue was distilled in vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of hydroxymethylphosphonic acid diethylester (0.84 g, 5 mmol), 1-chloro-2-chloromethyl-2-propene (0.95 g, 7.6 mmol) and tetrabutylammonium iodine (0.18 g, 0.5 mmol) in anhydrous tetrahydrofuran (10 ml), sodium hydride is added (0.24 g, 6 mmol 60% in oil) at 0° C. The mixture is stirred overnight at 20° C. The reaction mixture is hydrolyzed with a saturated solution of ammonium chloride, extracted with ethyl acetate and the title product is obtained by flash chromatography on silica gel (0.35 g, 27%). is added (0.24 g, 6 mmol 60% in oil) at 0° C extracted with ethyl acetate

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