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3-Oxo-azetidine-1-carboxylic acid tert-butyl ester → 3-(7-Cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester

HRID 518985
Notes
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Reaction equation

HRID 518985 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C([BH3-])#N.[Na+]>CCO.CC(O)=O>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH:16]2[CH2:17][CH2:18]2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 5003444Sodium cyanoborohydrideHCID 867273366-Amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one

Product 1

HCID 867273373-(7-Cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl esterYield 41.5%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 702EthanolSolvent

Procedure

A solution of 6-amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.860 g, 3.16 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.703 g, 15.79 mmol) in EtOH (25 mL) and HOAc (2.5 mL) was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.073 g, 1.159 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 3) to give 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.560 g, 41%). The racemic product was separated by chiral SFC (Table 2, Method 6) to give 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 22%) and 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 20%).

Workup

  1. temperatureto reflux overnight
  2. concentrationconcentrated in vacuo
  3. customThe residue was purified by preparative HPLC (Table 3, Method 3)

Sources & evidence

ORD record
ord-1377736a7cbb456b8a472f2ae18bddb2
Source dataset
uspto-grants-2015_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09115151B2

Reaction notes

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