| 95% |
Stage #1: (R)-N-(1-benzylpyrrolidine-3-yl)acetamide With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Heating / reflux;
Stage #2: With sodium hydroxide; water In tetrahydrofuran at 5℃; for 1h; |
I.11
To a mechanically stirred solution of N-[(3R)-1-(phenylmethyl)- 3-pyrrolidinyl]acetamide (157.4 g, 721 mmol) in tetrahydrofuran (THF) (300 ml) at ambient temperature was added lithium aluminum hydride (1.3L, 1.3 mol, 1 M in THF) dropwise over 1.5 hrs. The reaction was heated at reflux for 6 hrs, and then allowed to stir at ambient temperature overnight. The reaction was cooled to 50C and quenched by the very slow addition of water (80 ml_) followed by 15% NaOH (80 ml_) and additional water (240 ml_). This mixture was allowed to stir for 1 hr before filtering. The filter cake was rinsed with THF (2 X 400 ml_), and the filtrate was concentrated. Fresh THF (500 ml_) was added, and the mixture was concentrated again to afford the desired crude product as a yellow oil (140.1 g, 95%): 1H NMR (400 MHz, CDCI3) δ ppm 7.18 - 7.32 (m, 5 H), 3.57 (d, J = 1 .64 Hz, 2 H), 3.24 - 3.33 (m, 1 H), 2.72 (dd, J = 9.25, 6.78 Hz, 1 H), 2.45 - 2.63 (m, 3 H), 2.31 (dd, J = 9.35, 5.14 Hz, 1 H), 2.05 - 2.16 (m, 1 H), 1 .53 (dddd, J = 13.06, 7.93, 5.40, 5.27 Hz, 1 H), 1.06 (t, J = 7.14 Hz, 3 H). |
| 94% |
With lithium aluminium tetrahydride In tetrahydrofuran at -40℃; Reflux; |
1 6.2.2 Synthesis of (R)-1-benzyl-N-methylpyrrolidin-3-amine, 3aa
General procedure: A tert-butyl (R)-(1-benzylpyrrolidin-3-yl)carbamate 2aa (3.20g, 11.6mmol) solution in 58.0mL of 61 tetrahydrofuran was placed in a 100mL round-bottom flask. After it was cooled at -40°C, 62 lithium aluminum hydride (2.64g, 69.6mmol) was slowly added to the stirred mixture. The reaction mixture was refluxed for 4h and then cooled down to -40°C. The reaction was quenched with 2.70mL of deionized 46 water, 2.70mL of 15% 63 sodium hydroxide solution, and 8.10mL of deionized water. Then, Celite 545 was added and the mixture was stirred for 30min before being filtered through a Celite 545 pad. The filtered solution was concentrated under reduced pressure and the residue was extracted with dichloromethane three times. Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash column chromatography (methanol: dichloromethane: ammonium hydroxide=5:90:5 |
| 0.94% |
With lithium aluminium tetrahydride In tetrahydrofuran Reflux; |
33 Example 33. (R)-3-(3-(ethyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)-3-oxopropanenitrile
2.00 g of (R)-1-benzylpyrrolidine-3-amine was added to a 50-mL round-bottomed flask and then dissolved with 14.7 mL of dichloromethane (CH2Cl2). 1.07 mL of acetic anhydride was added into the solution and then stirred overnight at room temperature. The resulting fraction was concentrated under reduced pressure without purification and then further under vacuum. As a result, 2.12 g of (R)-N-(1-benzylpyrrolidine-3-yl)acetamide was obtained with a yield of about 85.0%. (0231) 2.11 g of (R)-N-(1-benzylpyrrolidine-3-yl)acetamide was added to a 100-mL round-bottomed flask. After 47.6 mL of tetrahydrofuran and 1.61 g of lithium aluminum hydride (LiAlH4) were sequentially added thereto, the reaction mixture was refluxed overnight, and then cooled at 0°C. 2.00 mL of deionized water was slowly added to the reaction mixture while cooling. After the reaction mixture was stirred for about 5 minutes, 1.50 mL of a 15% sodium hydroxide (NaOH) aqueous solution was added thereto. The reaction mixture was further stirred for about 5 minutes, and then 3.80 mL of deionized water was added thereto to terminate the reaction. The reaction mixture was filtered through a Celite 545 filter agent. The resulting filtrate was distilled under reduced pressure. As a result, 1.85 g of (R)-1-benzyl-N-ethylpyrrolidine-3-amine was obtained with a yield of about 94.0%. (0232) 1.85 g of (R)-1-benzyl-N-ethylpyrrolidine-3-amine was added to a 100-mL round-bottomed flask, and then 46.0 mL of deionized water and 1.46 g of 6-chloro-7-deazapurine were sequentially added thereto. After 1.56 g of potassium carbonate (K2CO3) was added to the reaction mixture, the reaction mixture was refluxed for about 18 hours and then cooled at room temperature. The reaction mixture was extracted three times with 10.0 mL of dichloromethane (CH2Cl2) to collect an organic phase. The collected organic phase was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=0.100→1:80→1:50). As a result, 296 mg of (R)-N-(1-benzylpyrrolidine-3-yl)-N-ethyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 10.0%. (0233) 296 mg of (R)-N-(1-benzylpyrrolidine-3-yl)-N-ethyl-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 25-mL round-bottomed flask and then dissolved with 9.20 mL of methanol. After 330 mg of a 10w/w% palladium/ carbon (Pd/C) was added thereto, a hydrogen-containing balloon was installed on the reaction flask. The reaction mixture was vigorously stirred overnight and then filtered through a Celite 545 filter agent. The resulting filtrate was concentrated under reduced pressure and then further under vacuum. As a result, 189 mg of (R)-N-ethyl-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 88.8%. (0234) 117 mg of (R)-N-ethyl-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask and then dissolved with 2.10 mL of dichloromethane (CH2Cl2). After 0.0610 mL of chloroacetyl chloride was added to the solution, the reaction mixture was treated with 0.223 mL of N,N-diisopropylethylamine and then stirred at room temperature for about 1 hour. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=0:100→1:80→1:50). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 96.0 mg of (R)-2-chloro-1-(3-(ethyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)ethane-1-one was obtained with a yield of about 61.0%. (0235) 96.0 mg of (R)-2-chloro-1-(3-(ethyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)ethane-1-one was added into a 5-mL round-bottomed flask and then dissolved with 2.00 mL of N,N-dimethylformamide. 40.4 mg of potassium cyanide was added to the solution, and the reaction mixture was stirred at about 30°C to about 40°C for about 1 hour. After the reaction mixture was concentrated under reduced pressure, 10.0 mL of deionized water and 10.0 mL of dichloromethane (CH2Cl2) were added into the resulting residue and then stirred for about 5 minutes to separate an organic phase. The organic phase was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=0.100→1:80→1:50). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 50.9 mg of (R)-3-(3-(ethyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)-3-oxopropanenitrile was obtained with a yield of about 55.0%. (0236) 1H NMR (400 MHz, CDCl3) 510.47 (s, 1H), 8.34 (s, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 5.55-5.53 (m, 1H), 4.05-3.90 (m, 2H), 3.83-3.63 (m, 2H), 3.55-3.44 (m, 3H), 2.42-2.27 (m, 3H), 1.42 (q, J = 6.8 Hz, 3H). (0237) LRMS (ESI) calcd for (C15H18N6O + H+) 299.2, found 299.1. |
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