Tert-butyl 3-oxopyrrolidine-1-carboxylate → 3-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 519138Notes

Reaction equation

HRID 519138 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.O=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]

Participants

5

Reactant 3

HCID 471360Tert-butyl 3-oxopyrrolidine-1-carboxylateHCID 5003444Sodium cyanoborohydrideHCID 86727520(R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one

Product 1

HCID 867275283-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl esterYield 92%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A solution of (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #148, Step D, 2.4 g, 10.32 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (Aldrich, 2.0 g, 6.23 mmol) was stirred at 15° C. for 10 min and then acetic acid (7 mL) was added. The reaction mixture was stirred for 30 min and sodium cyanoborohydride (0.68 g, 11 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 100% EtOAc) to give 3-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.3 g, 53%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 6.20 (d, J=8.4 Hz, 1H), 5.63-5.53 (m, 1H), 4.73 (m, 1H), 4.52-4.41 (m, 2H), 4.06-3.99 (m, 1H), 3.62-3.37 (m, 2H), 3.15-2.92 (m, 1H), 2.10 (m, 1H), 1.64 (m, 1H), 1.38 (s, 9H), 1.30 (m, 3H). LCMS (Table 1, Method 2) Rt=1.059 min.; MS m/z: 424 [M+Na]+.

Workup

  1. stirringThe reaction mixture was stirred at ambient temperature overnight
  2. concentrationthen concentrated in vacuo
  3. customThe residue was purified by column chromatography on silica gel (eluting with 100% EtOAc)

Sources & evidence

ORD record
ord-060ca93b6f3f4b0abe0751e8cf5f79cf
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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