Hexahydro-lH-furo[3,4-c]pyrrole

 

 

 

hexahydro-lH-furo[3,4-c]pyrrole; (2a)

 

 

Synthesis of substituent R (hexahydro-lH-furo[3,4-c]pyrrole; 2a) was out as shown in Scheme-3 and the stepwise procedure is depicted below:
Schem -3:

Substituted R² (2a)


Step-1 : 1 -Benzyl -pyrrolidine-3,4-dicarbQxylic acid dimethyl ester (10
N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (8, 21.4g) and dimethyl maleate (9, lOg) were dissolved in DCM (200 ml). To the reaction mixture TFA (0.54ml, 6.94mmol) was added and stirred for 3h. After completion of reaction, reaction mixture was neutralized with saturated NaHC0₃ solution (100 ml). Organic layer was washed with water, brine solution, dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to get l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10) as a light yellow color oil (16.7g, 87% yield).
lH NMR: (CDC1₃, 400 MHz): 6 7.25-7.13 (m, 5H), 3.72 (s, 2H), 3.58 (s, 6H), 3.26- 3.20 (m, 2H), 3.08-3.04 (m, 2H), 3.04-2.63 (m, 2H); ESI-MS: (+ve mode) 277.9 (M+H)⁺ (60 %), 299.9 (M+Na) (80 %).; HPLC: 90 %.


Step-2: (l-Benzylpyn:olidine-3,4-divOdimethanol (11)
l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10, 15g), dissolved in THF (30 ml) was added to a suspension of LiAlH₄ (4.3g) and stirred for 2h at 25 °C. Reaction mixture was quenched with water (2 ml) and 2N NaOH solution (2 ml). The reaction mixture was filtered, dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to get (l-Benzylpyrrolidine-3,4-diyl)dimethanol (11) as a yellow color oil (1 1.6 g, 97% yield).
1H NMR: (CDCI3, 400 MHz): δ 7.25-7.13 (m, 5H), 3.67 (s, 2H), 3.64-3.47 (m, 4H), 2.70-2.65 (m, 2H), 2.44-2.39 (m, 2H), 2.15-2.1 l(m, 2H); ESI-MS: (+ve mode) 222.1 (M+H)⁺ (85%); HPLC: 94 %.


Step-3: 5-Benzyl-hexahvdro-furo[^"3,4-c pyrrole (12) A mixture of l-Benzylpyrrolidine-3,4-diyl)dimethanol (11, lOg) and PTSA
(1.94g) in dry toluene (100 ml) was refluxed at 140 °C for 16h. The reaction mixture was cooled and basified with IN NaOH solution (100 ml), organic layer was separated off, washed with water, brine solution and dried to yield 5-Benzyl-hexahydro-furo[3,4- cjpyrrole (12) as an oil (5.9 g, 64% yield).
1H NMR: (CDCI3_, 400 MHz): δ 7.05-7.23 (m, 5H), 3.77-3.67 (s, 4H), 3.49 (s, 2H), 2.27-2.25 (m, 4H) 2.26-2.25 (m, 2H); ESI-MS: (+ve mode) 204.2 (M+H)⁺ (89%); HPLC: 84 %.


Step-4: hexahydro-lH-furo|^"3,4-c|pyrrole (2a)
5-Benzyl-hexahydro-furo[3,4-c]pyrrole (12, 5g) was dissolved in EtOH (50 ml) and hydrogenated in presence of 10 % Pd/C (0.5 g) at 60 psi. Filtered the reaction mixture was filtered, evaporated to dryness to get hexahydro-lH-furo[3,4-c]pyrrole (2a) as a colorless oil (2.56g, 92% yield). 1H NMR: (CDCI3_, 400 MHz): δ 3.67-3.58 (m, 4H) 3.43-3.33 (m, 2H), 2.97-2.88 (m, 4H); ESI-MS: (+ve mode) 1 13.8 (M+H)⁺ (55%); GC: 92 %.

///////WO2014061031