methoxycyclopentane

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: 75.0 mL (75.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise to 100 mL of THF at −15˜−5° C. 11.0 g (37.5 mmol) of cinchonine was added at −15˜−5° C., 9.7 mL (120 mmol) of pyridine was added dropwise, and the mixture was stirred for 20 minutes. 15.6 g (30.0 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide was added at once by assisting by 25 mL of flowing THF at −15˜−5° C., and the mixture was stirred at the same temperature for 1 hour. 30.0 mL (30.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise at −15˜−5° C. over 40 minutes, and the mixture was stirred at the same temperature for 1 hour. 420 mL of ethyl acetate and 210 mL of 1N hydrochloric acid were added in this order at −15˜10° C., and the mixture was stirred at 15˜25° C. for 30 minutes. The organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water. After washing, the organic layer was concentrated to about 50 mL under heating and reduced pressure (inner temperature 20˜40° C.). 50 mL of ethyl acetate was added, followed by re-concentration procedure two times. 50 mL of ethyl acetate was added to the residue, the mixture was stirred at room temperature for 1 hour, 50 mL of IPE was added, and the mixture was stirred at room temperature. After stirred at 0˜10° C. for 1 hour, crystals were filtered, washed with 16 mL (×2) of IPE, and dried to obtain 17.0 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 93%, enantiomer excess 94.3% ee). the mixture was stirred at the same temperature for 1 hour the mixture was stirred at the same temperature for 1 hour the mixture was stirred at 15˜25° C. for 30 minutes The organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water After washing the organic layer was concentrated to about 50 mL under heating reduced pressure (inner temperature 20˜40° C.) 50 mL of ethyl acetate was added followed by re-concentration procedure two times 50 mL of ethyl acetate was added to the residue the mixture was stirred at room temperature for 1 hour 50 mL of IPE was added the mixture was stirred at room temperature After stirred at 0˜10° C. for 1 hour crystals were filtered washed with 16 mL (×2) of IPE dried

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: In a 50 ml recovery flask, 0.462 g (1.61 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 9.2 ml of cyclopentyl methyl ether were charged and dissolved under a nitrogen stream. After the addition of 0.666 g (4.82 mmol, 3.0 equivalents) of potassium carbonate and 0.736 g (3.21 mmol, 2.0 equivalents) of benzyl bromoacetate at room temperature, the mixture was stirred at room temperature for 19 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 100 ml of a saturated sodium bicarbonate aqueous solution, and was extracted twice with 100 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, n-hexane:ethyl acetate=4:1), thereby obtaining 0.128 g of [(4-cyanobenzyl)-(4-dipropylaminobutyl)amino]benzyl acetate (20) as a light yellow oily substance (yield: 18.3%). [HPLC: 97.8% (HPLC measurement conditions A)] dissolved under a nitrogen stream was extracted twice with 100 ml of chloroform The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution dried over anhydrous sodium sulfate concentrated purified by silica gel column chromatography (Chromatorex NH, n-hexane:ethyl acetate=4:1)

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

Procedure: In a 50 ml recovery flask, 0.462 g (1.61 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 9.2 ml of cyclopentyl methyl ether were charged and dissolved under a nitrogen stream. After the addition of 0.666 g (4.82 mmol, 3.0 equivalents) of potassium carbonate and 0.736 g (3.21 mmol, 2.0 equivalents) of benzyl bromoacetate at room temperature, the mixture was stirred at room temperature for 19 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 100 ml of a saturated sodium bicarbonate aqueous solution, and was extracted twice with 100 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, n-hexane:ethyl acetate=4:1), thereby obtaining 0.128 g of [(4-cyanobenzyl)-(4-dipropylaminobutyl)amino]benzyl acetate (20) as a light yellow oily substance (yield: 18.3%). [HPLC: 97.8% (HPLC measurement conditions A)] dissolved under a nitrogen stream was extracted twice with 100 ml of chloroform The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution dried over anhydrous sodium sulfate concentrated purified by silica gel column chromatography (Chromatorex NH, n-hexane:ethyl acetate=4:1)

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

Procedure: under a nitrogen atmosphere, 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]acetaldehyde (a diastereomer mixture with a component ratio of 1:2, 0.20 g, 0.99 mmol), cyclopentyl methyl ether (4 ml), and sodium borohydride (0.05 g, 1.3 mmol) were placed into a 30-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and methanol (0.05 g) was added with stirring at 20° C., followed by stirring at the same temperature for 60 minutes. Next, a 5% aqueous sulfuric acid solution (1.3 g) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (2 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain 2-[(1R*,2S*)-1-methyl-2-(1-phenylethyl)cyclopropyl]ethanol (a diastereomer mixture with a component ratio of 1:2, 0.19 g, 0.93 mmol, 94% yield). equipped with a stirring apparatus, a dropping funnel by stirring at the same temperature for 60 minutes After stirring for 10 minutes the aqueous layer was separated the organic layer was washed twice with water (2 ml) The solvent was recovered under reduced pressure to obtain a condensed residue This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2)

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

Procedure: The same experiment as in Example 4 was carried out, except for using a mixed solvent of CPME and THF (1:1 by volume) instead of 50 ml of CPME. The resulting reaction mixture was analyzed by gas chromatography to confirm that 2-mesityl-2-propanol and α-methyl-2,4,6-trimethylstyrene were obtained in a yield of 66.8% and 14.7%, respectively. The resulting reaction mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a three-neck 250 mL round bottom flask, equipped with a mechanical stirrer, a nitrogen inlet, and a thermocouple was charged tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.8 g, 29.3 mmol), 2-propanol (41.6 mL) and 2.75 M HCl in 2-propanol (32 mL, 88 mmol). The mixture was heated to 55-65° C. until reaction completion. Distilled 2-propanol (−13%) to remove excess HCl. The reaction mixture was cooled to 5° C. and added 4-methylmorpholine (21 mL, 191 mmol) at a rate maintaining the temperature below 25° C. The mixture was stirred at room temperature for 30 min. (S)-3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (10.5 g, 30.8 mmol) and 2-propanol (24.5 mL) were added and the reaction mixture was cooled 0-5° C. Additional 2-propanol was added as required for rinse and to dilute reaction mixture to 10 vol total. Propanephosphonic anhydride (T3P) (50 wt % in EtOAc) (19.2 mL, 32.2 mmol) was added at a rate maintaining the temperature ≦10° C. The reaction mixture was warmed to room temperature. Upon reaction completion, water (10 mL, 1 vol) was added. CPME (100 mL) and then 1N aqueous NaOH (100 mL) were added. The mixture was stirred for 30 min and the layers were cut. The organic layer was consecutively washed with 1N aqueous NaOH (100 mL), 1N aqueous NH4OH (2×100 mL), and saturated aqueous NH4Cl (50 mL). The organic layer was washed with 14% aqueous NaCl (25 mL) and then concentrated to minimum stir volume at 65° C. under vacuum. CPME (100 mL) was added and the solution was distilled to minimum stir volume. CPME (100 mL) was added and the solution is distilled to minimum stir volume. CPME (100 mL) was added and the solution was heated to 50° C. Charcoal (7.35 g) was added. The mixture was stirred at 50° C. for 12 hours. The charcoal was filtered and the solution was distilled to minimum stir volume and CPME and heptane were added to obtain a final solution of 80 mL (8 vol) of a 35% CPME/heptane mixture. The mixture was heated to 70° C. to obtain a solution, and then cooled to 55° C. then seeded with 50 mg ((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate. The mixture was held at 55° C. for 1 h and then cooled to room temperature. Heptane (29 mL) was added and the mixture was cooled to 0-5° C., filtered and washed with 15% CPME/Heptane (2×15 mL) and heptane (2×15 mL). The filter cake was dried at ≦55° C. to give tert-butyl ((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate, isolated 14.1 g, 86% yield. To a three-neck 250 mL round bottom flask, equipped with a mechanical stirrer, a nitrogen inlet Distilled 2-propanol (−13%) to remove excess HCl The reaction mixture was cooled to 5° C. maintaining the temperature below 25° C were added the reaction mixture was cooled 0-5° C for rinse to dilute reaction mixture to 10 vol total maintaining the temperature ≦10° C The reaction mixture was warmed to room temperature was added The organic layer was consecutively washed with 1N aqueous NaOH (100 mL), 1N aqueous NH4OH (2×100 mL), and saturated aqueous NH4Cl (50 mL) The organic layer was washed with 14% aqueous NaCl (25 mL) concentrated to minimum stir volume at 65° C. under vacuum CPME (100 mL) was added the solution was distilled to minimum stir volume CPME (100 mL) was added the solution is distilled to minimum stir volume CPME (100 mL) was added the solution was heated to 50° C Charcoal (7.35 g) was added The mixture was stirred at 50° C. for 12 hours The charcoal was filtered the solution was distilled to minimum stir volume and CPME and heptane were added