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Stage #1: With hydrogenchloride; zinc In methanol; water at -5 - 0℃; Stage #2: With ammonia In dichloromethane; water at 30℃; for 0.25 h; Stage #3: at 20 - 25℃;
Example 23; Preparation of trans-(lR,2S)-2-(3, 4-difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt; [0127] Trans-(lR,2S)-2-(3,4-difluorophenyl)-l-nitrocyclopropane (215.0 g) was added to the pre-cooled methanolic hydrochloric acid (6.0percent to 7percent w/w HC1, 4300 ml), followed by cooling the mass to -5 to 0°C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at -5 to 0°C. The reaction mass was stirred further for 2 hours at -5 to 0°C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2 x 215 ml). The main filtrate and washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and then cooled to 10 to 15°C. 25percent Aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30°C. The resulting reaction mass was stirred for 15 minutes, followed the by layer separation. The resulting aqueous layer was extracted with dichloromethane (2 x 537.5 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was extracted thrice with aqueous hydrochloric acid (645 ml of cone, hydrochloric acid mixed with 1935 ml water, 3 x 865 ml). The aqueous acidic layer containing the product was combined and washed with dichloromethane (645 ml). Dichloromethane (1075 ml) was added to the acidic aqueous layer, followed by the addition of 25percent aqueous ammonia solution (1505 ml) while maintaining the temperature at below 30°C. The resulting reaction mass was extracted with dichloro methane (2 x 645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml) and evaporated to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(-)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining temperature at 20 to 25 °C. The resulting slurry was stirred further for 12 hours at 20 to 25 °C, followed by further cooling to 0 to 5°C. The cooled solution was stirred for 2 hours and the solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45°C to obtain 127 g of pure trans- (lR,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(-)-mandelate salt as a white solid (Yield : 36.61percent; HPLC Purity: 99.87percent by area; [R]25D = -97.0° (c 1, methanol)).
36.61%
Stage #1: With hydrogenchloride; zinc In deuteromethanol at -5 - 0℃; Stage #2: at 0 - 25℃; for 14 h;
Example 22 Preparation of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(?)-mandelate salt Trans-(1R,2S)-2-(3,4-difluorophenyl)-1-nitro cyclopropane (215.0 g) was added to the pre-cooled methanolic hydrochloric acid (6.0percent to 7percent w/w HCl, 4300 ml), followed by cooling the mass to ?5 to 0° C. Zinc dust (343.71 g) was added to the resulting mass over a period of 2 to 3 hours while maintaining the temperature at ?5 to 0° C. The reaction mass was stirred further for 2 hours at ?5 to 0° C. After completion of the reaction, the reaction mass was filtered through a hyflo bed and the bed was washed with methanol (2×215 ml). The main filtrate and washings were combined, followed by distillation under reduced pressure. The resulting residue was dissolved in dichloromethane (1075 ml) and then cooled to 10 to 15° C. 25percent Aqueous ammonia solution (1290 ml) was added to the cooled solution while maintaining the temperature at below 30° C. The resulting reaction mass was stirred for 15 minutes, followed the by layer separation. The resulting aqueous layer was extracted with dichloromethane (2×537.5 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was extracted thrice with aqueous hydrochloric acid (645 ml of conc. hydrochloric acid mixed with 1935 ml water, 3×865 ml). The aqueous acidic layer containing the product was combined and washed with dichloromethane (645 ml). Dichloromethane (1075 ml) was added to the acidic aqueous layer, followed by the addition of 25percent aqueous ammonia solution (1505 ml) while maintaining the temperature at below 30° C. The resulting reaction mass was extracted with dichloromethane (2×645 ml) and then combined with the main dichloromethane layer. The combined dichloromethane layer containing the product was washed with water (645 ml) and evaporated to dryness under reduced pressure. The resulting residue was dissolved in methanol (430 ml), followed slow addition of (R)-(?)-mandelic acid solution (107.5 g in 645 ml methanol) over a period of 40 to 60 minutes while maintaining temperature at 20 to 25° C. The resulting slurry was stirred further for 12 hours at 20 to 25° C., followed by further cooling to 0 to 5° C. The cooled solution was stirred for 2 hours and the solid was isolated by filtration. The resulting solid was washed with chilled methanol (215 ml). The solid was dried under reduced pressure at 40 to 45° C. to obtain 127 g of pure trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(?)-mandelate salt as a white solid (Yield: 36.61percent; HPLC Purity: 99.87percent by area; [R]25D=?97.0° (c 1, methanol)).
A solution of the compound of formula IX (1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl formamide (3.5 g, 17.7 mmol)Was added 30percent sodium hydroxide (21.3 g, 160.0 mmol)5.2percent sodium hypochlorite (30.0 g, 21.0 mmol),Stirring at 25 to 40 degrees for 16 hours,Plus 50 ml of isopropyl acetate extraction,The oil phase was dried with anhydrous sodium sulfate,Was added dropwise to a solution of R-mandelic acid (2.7 g, 17.7 mmol) dissolved in 20 ml of isopropyl acetate,10 minutes drop finished,Stirred at room temperature for 1 hour,0 to 5 degrees stirring for 3 hours,filter,Cold isopropyl acetate wash,60 degrees decompression drying,To give the compound of formula II (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylmethylamine-R-mandelate (4.0 g, 12.5 mmol). Yield 70.1percent.
46.4%
at 20 - 25℃; for 14 h;
500ml four-necked flask was added compound (21.0g, 0.11mol) and 30percent aqueous sodium hydroxide solution (127.8g, 0.96mol). Under stirring, temperature at 0 ~ 5 , was added dropwise 10.5percent aqueous sodium hypochlorite solution (188.8g, 0.27mol), about 1h dropwise. After stirring at 0 ~ 5 continued until the reaction solution clarified rapidly warmed to 55 , reaction was continued for 1h. The reaction solution was cooled to 0 ~ 5 . Temperature not exceeding 10 , was added dropwise concentrated hydrochloric acid (about 100g) adjusted pH8 ~ 9. Was added dichloromethane (200ml), liquid separation. The aqueous layer (100ml × 2) and extracted with methylene chloride, the organic layers were combined, washed with water (200ml × 2). Dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give a yellow oil compound (14.2g). Under stirring, temperature at 20 ~ 25 , methanol to the compound (60ml) was added dropwise a solution of D- mandelic acid (12.8g, 0.08mol) in methanol (76 ml of) solution dropwise for about 2h. At 20 ~ 25 , stirring was continued for 12h. Filtered cake was recrystallized from methanol to give a white solid compound (15.8g, 46.4percent), HPLC purity 99.7percent, ee value 99.9percent.
Reference：
[1] Patent: CN107892693, 2018, A, . Location in patent: Paragraph 0035; 0060; 0062; 0064; 0104; 0145
4
[ 611-71-2 ]
[ 376608-71-8 ]
Yield
Reaction Conditions
Operation in experiment
7.56 g
at 18 - 45℃; for 2.5 h;
To a solution of 9 g R-mandelic acid in 300 ml of methanol at 45 C, was added a solution of 10 g of 2-(3.4-difluorophenyl)cyclopropanamine in 300 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25 C, stirred for 1 h, then further cooled slowly to 18 C and maintained for another 1 h. The crystalized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 7.56 g of product as a white crystalline solid. 1H NMR in (400MHz, DMSO d6) 5 1 .13 -1 .16 (2H, m), 1.25 - 1.28 (2H, m), 2.20-2.23 (1 H, m), 2.65 - 2.67 (1 H, m), 4.64(1 H, s), 6.94 -6.96 (1 H, m). 7.1 1 -7.36 (8H, m)
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