Synthesis
The general procedure for the synthesis of Fmoc-L-hydroxyproline from methyl 9-fluorenyl chloroformate and L-hydroxyproline is as follows:
Example 2: Synthesis of (2S,4R)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid
1. Sodium bicarbonate (80 g) and water (400 ml) were added to a solution of tetrahydrofuran (THF, 200 ml) containing (2S,4R)-4-hydroxy-L-proline (100 g) at 25-30 °C.
2. A solution of 9-fluorenylmethoxycarbonyl (Fmoc) chloride (226 g) dissolved in 200 ml of THF was added slowly.
3. The reaction mixture was stirred continuously at 25-30°C for 10-12 hours until the reaction was complete.
4. Upon completion of the reaction, the reaction was terminated by the addition of an appropriate amount of water.
5. The reaction mixture was washed with diisopropyl ether (DIPE) and subsequently acidified with 1N hydrochloric acid.
6. The acidified mixture was continued to be stirred for 2-3 hours to promote precipitation of the product.
7. The solid product was collected by filtration to give 150 g of Fmoc-L-hydroxyproline as a white solid.
Product Characterization:
1H NMR (300 MHz, DMSO-d6): δ 1.89-2.24 (m, 2H), 3.34-3.43 (m, 2H), 3.43-3.54 (m, 0.5H), 4.12-4.21 (m, 3H), 4.25 (s, 2H), 4.28-4.42 (m, 0.5H), 5.16 (brs, 1H) , 7.29-7.34 (m, 2H), 7.38-7.65 (m, 2H), 7.63-7.65 (m, 2H).
Melting point: 188-190°C.
Mass spectrum (M + H): 354.33.
References
[1] Tetrahedron Letters, 1994, vol. 35, # 51, p. 9509 - 9512
[2] Angewandte Chemie - International Edition, 2009, vol. 48, # 10, p. 1784 - 1787
[3] Patent: US9518048, 2016, B2. Location in patent: Page/Page column 24
