1-bromoprop-1-yne

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

Procedure: Employing the procedure of Example 10 with 321 mg (1.01 mmole) of cis-2-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-piperidinol, 82 microliter (1.06 mmole) or propynyl bromide and 292 mg (2.12 mmole) of potassium carbonate affords 205 mg (57%) of the title compound as an oil.

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

Procedure: Compounds III-A, III-B and III-D were prepared by a modification of the procedure of Zaugg, Swett and Stone (5). In a stirred solution of sodium ethylate prepared from 0.23 g (0.01 mol) of sodium metal and 50 ml of absolute ethanol was dissolved 0.01 mol of the appropriate nitro- or chloroindazole. To such solution was added 2.38 g (0.02 mol) of propynyl bromide, and the reaction mixture was stirred for 24 hours at room temperature during which time sodium bromide precipitated. The reaction mixture was poured into 100 ml of water and the oily layer was extracted with ether. The ether layer was separated, washed with water, 10% potassium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give the desired N-(2-propynyl) indazoles. To prepare compound III-C, a mixture of 10 g (0.043 mol) of 3-chloro-6-nitroindazole, 6.9 g (0.043 mol) of anhydrous potassium carbonate and 0.10 g (0.086 mol) of propynyl bromide was placed in 100 ml of acetone. The reaction mixture was refluxed for 24 hours, and then poured into 100 ml of water. The oily layer was extracted with ether, and the ether layer was separated, washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give N-(2-propynyl)-3-chloro-6-nitroindazole. To prepare compound III-C The reaction mixture was refluxed for 24 hours The oily layer was extracted with ether the ether layer was separated washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution dried (Na2SO4) concentrated in vacuo The residue was recrystallized from 95% ethanol

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

Procedure: 8.57 g of 2-trifluoromethyl-1H-indole described in J. Org. Chem. (1983) 48-3233 and 10 ml of tetrahydrofuran were mixed together under an inert atmosphere at +5° C. and after 15 minutes, 2.4 g of sodium hydride in oil were added. After 2 minutes, 4.5 ml of 2-bromo-propyne were introduced and the resulting mixture was stirred for 30 minutes at +5° C., then for one hour at 25° C. Another 4.5 ml of bromo-propyne were added and the mixture was stirred for 4 hours and then poured into an iced solution of monosodium phosphate and extracted with ethyl ether. The extracts were concentrated to dryness by distillation under reduced pressure and the residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (95/5) to obtain 8.88 g of 1-(2-propynyl)-2-trifluoromethyl-(1H)-indole melting at 59° C. for one hour at 25° C the mixture was stirred for 4 hours extracted with ethyl ether The extracts were concentrated to dryness by distillation under reduced pressure the residue was chromatographed over silica eluted with a mixture of hexane and ethyl acetate (95/5)

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

Procedure: Compounds III-A, III-B and III-D were prepared by a modification of the procedure of Zaugg, Swett and Stone (5). In a stirred solution of sodium ethylate prepared from 0.23 g (0.01 mol) of sodium metal and 50 ml of absolute ethanol was dissolved 0.01 mole of the appropriate nitro- or chloroindazole. To such solution was added 2.38 g (0.02 mol) of propynyl bromide, and the reaction mixture was stirred for twenty-four hours at room temperature during which time sodium bromide precipitated. The reaction mixture was poured into 100 ml of water and the oily layer was extracted with ether. The ether layer was separated, washed with water, 10% potassium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give the desired N-(2-propynyl) indazoles. To prepare compound III-C, a mixture of 10 g (0.043 mol) of 3-chloro-6-nitroindazole, 6.9 g (0.043 mol) of anhydrous potassium carbonate and 0.10 g (0.086 mol) of propynyl bromide was placed in 100 ml of acetone. The reaction mixture was refluxed for twenty-four hours, and then poured into 100 ml of water. The oily layer was extracted with ether, and the ether layer was separated, washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give N-(2-propynyl)-3-chloro-6-nitroindazole. To prepare compound III-C The reaction mixture was refluxed for twenty-four hours The oily layer was extracted with ether the ether layer was separated washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution dried (Na2SO4) concentrated in vacuo The residue was recrystallized from 95% ethanol

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

Procedure: Employing the procedure of Example 10 with 321 mg (1.01 mmole) of cis-2-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-piperidinol, 82 microliter (1.06 mmole) or propynyl bromide and 292 mg (2.12 mmole) of potassium carbonate affords 205 mg (57%) of the title compound as an oil.

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

Procedure: Compounds III-A, III-B and III-D were prepared by a modification of the procedure of Zaugg, Swett and Stone (5). In a stirred solution of sodium ethylate prepared from 0.23 g (0.01 mol) of sodium metal and 50 ml of absolute ethanol was dissolved 0.01 mol of the appropriate nitro- or chloroindazole. To such solution was added 2.38 g (0.02 mol) of propynyl bromide, and the reaction mixture was stirred for 24 hours at room temperature during which time sodium bromide precipitated. The reaction mixture was poured into 100 ml of water and the oily layer was extracted with ether. The ether layer was separated, washed with water, 10% potassium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give the desired N-(2-propynyl) indazoles. To prepare compound III-C, a mixture of 10 g (0.043 mol) of 3-chloro-6-nitroindazole, 6.9 g (0.043 mol) of anhydrous potassium carbonate and 0.10 g (0.086 mol) of propynyl bromide was placed in 100 ml of acetone. The reaction mixture was refluxed for 24 hours, and then poured into 100 ml of water. The oily layer was extracted with ether, and the ether layer was separated, washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give N-(2-propynyl)-3-chloro-6-nitroindazole. To prepare compound III-C The reaction mixture was refluxed for 24 hours The oily layer was extracted with ether the ether layer was separated washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution dried (Na2SO4) concentrated in vacuo The residue was recrystallized from 95% ethanol

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

Procedure: Compounds III-A, III-B and III-D were prepared by a modification of the procedure of Zaugg, Swett and Stone (5). In a stirred solution of sodium ethylate prepared from 0.23 g (0.01 mol) of sodium metal and 50 ml of absolute ethanol was dissolved 0.01 mol of the appropriate nitro- or chloroindazole. To such solution was added 2.38 g (0.02 mol) of propynyl bromide, and the reaction mixture was stirred for 24 hours at room temperature during which time sodium bromide precipitated. The reaction mixture was poured into 100 ml of water and the oily layer was extracted with ether. The ether layer was separated, washed with water, 10% potassium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give the desired N-(2-propynyl) indazoles. To prepare compound III-C, a mixture of 10 g (0.043 mol) of 3-chloro-6-nitroindazole, 6.9 g (0.043 mol) of anhydrous potassium carbonate and 0.10 g (0.086 mol) of propynyl bromide was placed in 100 ml of acetone. The reaction mixture was refluxed for 24 hours, and then poured into 100 ml of water. The oily layer was extracted with ether, and the ether layer was separated, washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from 95% ethanol to give N-(2-propynyl)-3-chloro-6-nitroindazole. To prepare compound III-C The reaction mixture was refluxed for 24 hours The oily layer was extracted with ether the ether layer was separated washed with water, 10% sodium hydroxide solution, saturated sodium chloride solution dried (Na2SO4) concentrated in vacuo The residue was recrystallized from 95% ethanol

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

Procedure: 8.57 g of 2-trifluoromethyl-1H-indole described in J. Org. Chem. (1983) 48-3233 and 10 ml of tetrahydrofuran were mixed together under an inert atmosphere at +5° C. and after 15 minutes, 2.4 g of sodium hydride in oil were added. After 2 minutes, 4.5 ml of 2-bromo-propyne were introduced and the resulting mixture was stirred for 30 minutes at +5° C., then for one hour at 25° C. Another 4.5 ml of bromo-propyne were added and the mixture was stirred for 4 hours and then poured into an iced solution of monosodium phosphate and extracted with ethyl ether. The extracts were concentrated to dryness by distillation under reduced pressure and the residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (95/5) to obtain 8.88 g of 1-(2-propynyl)-2-trifluoromethyl-(1H)-indole melting at 59° C. for one hour at 25° C the mixture was stirred for 4 hours extracted with ethyl ether The extracts were concentrated to dryness by distillation under reduced pressure the residue was chromatographed over silica eluted with a mixture of hexane and ethyl acetate (95/5)

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

Procedure: 3-Fluorophenol (5.10 g, 45.5 mmol) was dissolved in DMF (10 mL) and potassium carbonate (7.55 g, 54.6 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. Bromoprop-1-yne (5.05 mL, 45.5 mmol) was added and the reaction was stirred overnight at ambient temperature. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated under reduced pressure to give a yellow oil (7.27 g) that was used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.30-7.23 (m, 1 H), 6.81-6.69 (m, 3 H), 4.70 (d, J=2.3 Hz, 2 H), 2.56 (t, 1 H); LCMS (m/z) ES+=151 (M+1). the reaction was stirred overnight at ambient temperature extracted with ethyl acetate washed with brine dried over sodium sulfate concentrated under reduced pressure

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

Procedure: To a stirred solution of 1.9 parts of sodium hydride dispersion 75% in 100 parts of hexamethylphosphoric triamide are added portionwise 16.2 parts of ethyl 4-(5-chloro-2-oxo-1-benzimidazolinyl)-1-piperidinecarboxylate (exothermic reaction: temperature rises to 40° C). After stirring for one hour at room temperature, there are added dropwise 8.9 parts of 3-bromo-2-propyne (exothermic reaction: temperature rises to about 40° C). Upon completion, stirring is continued overnight at 60° C. The reaction mixture is cooled, poured onto ice-water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The solid product is filtered off and dried, yielding ethyl 4-[5-chloro-1,3-dihydro-2-oxo-3-(2-propynyl)-2H-benzimidazol-1-yl]-1-piperidine-carboxylate; mp. 126.1° C. Upon completion, stirring is continued overnight at 60° C The reaction mixture is cooled poured onto ice-water the product is extracted with methylbenzene The extract is dried filtered evaporated The oily residue is triturated in 2,2'-oxybispropane The solid product is filtered off dried

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Propynylbromide (11.9 g.) was added to the sodium salt of N-(2-pyridyl)piperazine prepared from 16.3 g. of N-(2-pyridyl)piperazine and 4.8 g. of sodium hydride/50% mineral oil dispersion in 50 ml. of dry dimethylformamide. The mixture was stirred at 50° C. for 3 hours and then carefully poured into 3 volumes of cold water. This mixture was extracted with several portions of either and the combined ether extracts were washed twice with 10% aqueous hydrochloric acid. The acidic extract was made strongly alkaline by adding 40% aqueous sodium hydroxide under cooling. The mixture was then extracted several times with ether and the combined extracts were dried over magnesium sulfate. The latter was then removed by filtration, and the filtrate was evaporated to produce a brown oil. Distillation under reduced pressure gave N'-(2-pyridyl)-N-(2-propynyl)piperazine, b.p. 153°-4° C./3.5 mm, as a yellow oil which showed the expected NMR and IR spectra. prepared from 16.3 g This mixture was extracted with several portions of either and the combined ether extracts were washed twice with 10% aqueous hydrochloric acid The acidic extract by adding 40% aqueous sodium hydroxide under cooling The mixture was then extracted several times with ether the combined extracts were dried over magnesium sulfate The latter was then removed by filtration the filtrate was evaporated to produce a brown oil Distillation under reduced pressure

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

Procedure: An 11.61 g portion of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reacted with propynyl bromide as described in Example 6, giving N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynylacetamide, mp 98°-101° C.