(2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid → 4-Amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
Reaction equation
[C:1]([C@@:18]1(C(O)=O)[CH2:22][C@@H:21]([NH2:23])[CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:3]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2]>C(#N)C.N1CCCC1>[NH2:23][CH:21]1[CH2:20][N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:18]([C:1]([OH:3])=[O:2])[CH2:22]1Participants
Procedure
To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3 hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2 dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 1H NMR (CD3OD, 400 MHz) δ 1.44 (m, 9H), 2.51-2.74 (m, 2H), 3.64 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 7.30 (d, J=6.85 Hz, 1H), 7.58 (d, J=6.85 Hz, 1H), 7.79 (m, 1H), 7.91-7.99 (m, 2H), 8.56 (d, J=8.56 Hz, 1H). LC-MS (retention time: 1.707 min.), MS m/z 358 (MH+). Step 2:
Workup
- concentrationThen it was concentrated
Sources & evidence
- ORD record
- ord-eefbe397d5fd4491bb9c4d993fcee4bc
- Source dataset
- uspto-grants-2014_04
- Patent number
- US08710229B2
Reaction notes
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