反式-2-甲基环丙烷羧酸

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Add oxalyl chloride (2 M in dichloromethane, (0.291 mL, 0.583 mmol) to a stirred solution of (R,R)-2-methylcyclopropanecarboxylic acid (0.06 g, 0.58 mmol) and DMF (1 drop-catalytic) in toluene (1 mL). Stir 3 h and add the now formed acid chloride to a stirred solution of 4-(5-amino-4-methylisothiazol-3-yl)phenol (0.060 g, 0.291 mmol) and pyridine (0.07 g, 0.87 mmol) in THF (1 mL). Stir 1 h and dilute with EtOAc (300 mL), and wash with 1 N NaOH (2 times 100 mL) then water (100 mL), dry (MgSO4) and evaporate. Crystallize from chloroform and hexane. Yield: 64.6%. ES-MS: m/e 289.0 (m+1). Stir 1 h wash with 1 N NaOH (2 times 100 mL) water (100 mL), dry (MgSO4) evaporate Crystallize from chloroform and hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Add oxalyl chloride (2 M in dichloromethane, (0.291 mL, 0.583 mmol) to a stirred solution of (R,R)-2-methylcyclopropanecarboxylic acid (0.06 g, 0.58 mmol) and DMF (1 drop-catalytic) in toluene (1 mL). Stir 3 h and add the now formed acid chloride to a stirred solution of 4-(5-amino-4-methylisothiazol-3-yl)phenol (0.060 g, 0.291 mmol) and pyridine (0.07 g, 0.87 mmol) in THF (1 mL). Stir 1 h and dilute with EtOAc (300 mL), and wash with 1 N NaOH (2 times 100 mL) then water (100 mL), dry (MgSO4) and evaporate. Crystallize from chloroform and hexane. Yield: 64.6%. ES-MS: m/e 289.0 (m+1). Stir 1 h wash with 1 N NaOH (2 times 100 mL) water (100 mL), dry (MgSO4) evaporate Crystallize from chloroform and hexane

反应条件: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Racemic trans-2-methylcyclopropanecarboxylic acid (20 g, 0.2 mol) is dissolved in ethyl acetate (200 mL). (S)-2-Amino-3-phenyl-1-propanol [also known as (S)-phenylalaninol] (15.6 g, 0.103 mol, 0.51 equiv) is added in one portion, and the mixture heated to 65-70° C. After crystallization, which may be facilitated by seeding, the suspension is stirred at room temperature 20 h, then filtered; and the crystals are washed with ethyl acetate (2×15 mL). The crystals are dried at 40° C. under vacuum for 3 h: mass 18.4 g (37% molar yield, enantiomeric composition by chiral GC=85/15, chiral GC method below). The crystals are re-suspended in 370 mL ethyl acetate; the suspension is heated to reflux for 1 h, cooled to room temperature overnight, and the crystals filtered, washed and dried as above: mass 16.7 g (91% yield, chiral composition 96/4). A second purification in ethyl acetate (170 mL) as above affords (S)-2-amino-3-phenyl-1-propanol (R,R)-2-methylcyclopropanecarboxylic acid (1:1) salt (16.12 g, 96.5% yield, chiral composition 99/1=98% ee; 32% overall yield from racemic trans-2-methylcyclopropanecarboxylic acid). is added in one portion After crystallization, which filtered and the crystals are washed with ethyl acetate (2×15 mL) The crystals are dried at 40° C. under vacuum for 3 h the suspension is heated to reflux for 1 h cooled to room temperature overnight the crystals filtered washed dried as above: mass 16.7 g (91% yield, chiral composition 96/4) A second purification in ethyl acetate (170 mL) as above affords

反应条件: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Racemic trans-2-methylcyclopropanecarboxylic acid (20 g, 0.2 mol) is dissolved in ethyl acetate (200 mL). (S)-2-Amino-3-phenyl-1-propanol [also known as (S)-phenylalaninol] (15.6 g, 0.103 mol, 0.51 equiv) is added in one portion, and the mixture heated to 65-70° C. After crystallization, which may be facilitated by seeding, the suspension is stirred at room temperature 20 h, then filtered; and the crystals are washed with ethyl acetate (2×15 mL). The crystals are dried at 40° C. under vacuum for 3 h: mass 18.4 g (37% molar yield, enantiomeric composition by chiral GC=85/15, chiral GC method below). The crystals are re-suspended in 370 mL ethyl acetate; the suspension is heated to reflux for 1 h, cooled to room temperature overnight, and the crystals filtered, washed and dried as above: mass 16.7 g (91% yield, chiral composition 96/4). A second purification in ethyl acetate (170 mL) as above affords (S)-2-amino-3-phenyl-1-propanol (R,R)-2-methylcyclopropanecarboxylic acid (1:1) salt (16.12 g, 96.5% yield, chiral composition 99/1=98% ee; 32% overall yield from racemic trans-2-methylcyclopropanecarboxylic acid). is added in one portion After crystallization, which filtered and the crystals are washed with ethyl acetate (2×15 mL) The crystals are dried at 40° C. under vacuum for 3 h the suspension is heated to reflux for 1 h cooled to room temperature overnight the crystals filtered washed dried as above: mass 16.7 g (91% yield, chiral composition 96/4) A second purification in ethyl acetate (170 mL) as above affords

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 0° C. solution of (1R,2R)-2-methylcyclopropanecarboxylic acid (2.0 g, 20.0 mmol) in anhydrous acetone (100 mL) was added triethylamine (2.87 mL, 20.6 mmol) and ethyl chloroformate (1.96 mL, 20.6 mL). The cold bath was removed and the reaction was allowed to warm to room temperature for 30 min before the addition of sodium azide (1.36 g, 21.00 mmol) in water (20 mL). The reaction was maintained at room temperature for 1 h, then diluted with DCM (300 mL) and water (200 mL). The layers were separated and the organic was washed with water (2×100 mL) and brine (100 mL) then dried over MgSO4 and concentrated to provide (1R,2R)-2-methylcyclopropanecarbonyl azide (1.8 g, 72% yield) which was used directly in the next reaction. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.58 (m, 1H), 1.35-1.42 (m, 1H), 1.28-1.34 (m, 1H), 1.14 (d, J=6.0 Hz, 3H), 0.79-0.87 (m, 1H). The cold bath was removed The layers were separated the organic was washed with water (2×100 mL) and brine (100 mL) then dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared from 2-[2-(2-methoxyethoxy)ethoxy]ethanamine and trans-2-methylcyclopropanecarboxylic acid using steps A and B in the procedure described for the synthesis of Intermediate 3.6.1. MS (ES, M+H) 232.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared from 2-(2-methoxyethoxy)ethanamine and trans-2-methylcyclopropanecarboxylic acid using steps A and B in the procedure described for the synthesis of Intermediate 3.6.1.

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (1R,2R)-2-methylcyclopropanecarboxylic acid (44 g, 0.44 mol) in dichloromethane (600 mL) was added 1,1′-carbonyldiimidazole (79 g, 0.45 mol) portion-wise at 20° C. The reaction was stirred at 25° C. for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (52 g, 0.53 mol) was added portion-wise and stirring was continued at 25° C. for 16 hours. The reaction mixture was washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 2% to 20% ethyl acetate in petroleum ether) provided the product as a colorless oil. Yield: 52 g, 363 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.19 (s, 3H), 1.80-1.86 (m, 1H), 1.30-1.38 (m, 1H), 1.17 (dt, J=8.5, 4.3 Hz, 1H), 1.12 (d, J=6 Hz, 3H), 0.64 (ddd, J=8.2, 6.1, 3.8 Hz, 1H). stirring was continued at 25° C. for 16 hours The reaction mixture was washed with water (100 mL) The organic layer was dried over sodium sulfate filtered concentrated in vacuo