反应 #1597024

反应方程式

5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide

4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl 2-methyl pyrrolidine-1,2-dicarboxylate

Compound 25

4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl 2-methyl pyrrolidine-1,2-dicarboxylate

trichloromethyl carbonate

(S)-Methyl pyrrolidine-2-carboxylate hydrochloride

diisopropylethylamine

→

(S)-Methyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate

溶剂

pyridine

chloroform

chloroform

反应条件

后处理

1. 1
   洗涤the solution was washed with 1N aqueous HCl and water
2. 2
   干燥dried over magnesium sulfate
3. 3
   浓缩The dried solution was concentrated
4. 4
   洗涤The product was eluted in 20 percent ethyl acetate in hexanes
5. 5
   浓缩concentrated to a colorless oil
6. 6
   workup.DISSOLUTIONThis was dissolved in chloroform (10 mL)
7. 7
   其他the reaction solution was partitioned between 1N aqueous HCl and ethyl acetate
8. 8
   洗涤The ethyl acetate phase was washed with water
9. 9
   干燥brine, and dried over magnesium sulfate
10. 10
    浓缩Concentration
11. 11
    其他afforded an off-white solid which
12. 12
    其他was recrystallized from ethyl acetate/hexanes

实验过程

(S)-1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl 2-methyl pyrrolidine-1,2-dicarboxylate (Compound 25). (S)-Methyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was prepared following the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenlee et al with minor modification. A solution of 5.63 g (19.0 mmol) bis(trichloromethyl carbonate in chloroform (15 mL) was added dropwise to a solution of (S)-Methyl pyrrolidine-2-carboxylate hydrochloride (2.62 g., 15.82 mmol) and diisopropylethylamine (11.0 mL, 63.28 mmol) in chloroform (15 mL) at ice-bath temperature. After one hour, the solution was washed with 1N aqueous HCl and water, and dried over magnesium sulfate. The dried solution was concentrated and placed on a 85 mm i.d.×35 mm column of silica gel. The product was eluted in 20 percent ethyl acetate in hexanes and concentrated to a colorless oil. This was dissolved in chloroform (10 mL) and added to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (645 mg, 1.97 mmol) in pyridine (15 mL) containing 20 mg of 4-dimethylaminopyridine. After stirring for 120 hours at room temperature, the reaction solution was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate phase was washed with water, then brine, and dried over magnesium sulfate. Concentration afforded an off-white solid which was recrystallized from ethyl acetate/hexanes. The 1H NMR spectrum is complex and reveals the existence of rotational isomers due to restricted rotation about the pyrrolidine-1-carboxylate bond. 1HNMR (300 MHz, DMSO-d6): δ1.823-2.003 (m, 3H, pyrrolidine C4 methylene and pyrrolidine C3 syn-H), 2.213 (m, 1H, pyrrolidine C3 anti-H), 3.450 (m, 1H, pyrrolidine C5), 3.599 (m, 1H, pyrrolidine C5), 3.600 (s, 1.5H, methyl ester), 3.621 (s, 1.5H, methyl ester), 4.252 (m, 0.5H, pyrrolidine methine), 4.541 (m, 0.5H, pyrrolidine methine), 7.108 (d, J=8.5 Hz, 0.33H, H3), 7.216 (d, J=8.5 Hz, 0.33H, H3), 7.361 (d, J=9 Hz, 0.33H, H3), 7.545 (m, 0.33H, H4), 7.665 (m, 0.66H, H4), 7.763 (m, 0.66H, H6), 7.974 (m, 0.33H, H6), 8.133 (m, 0.66H, H6′), 8.287 (m, 1H, H5′), 8.302 (m, 0.33H, H3′), 8.539 (m, 0.33H, H3′), 8.446 (m, 0.33H, H3′), 8.822 (d, J=9.5 Hz, 0.33H, H6′), 10.313 (s, 0.33H, NH), 10.385 (s, 0.33H, NH), 11.367 (br s, 0.17H, NH), 12.519 (br s, 0.17H, NH).

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