Morpholine → Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate

HRID 1430873Notes

Reaction equation

HRID 1430873 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([Cl:30])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH:19]([C:27]([O-:29])=O)[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].CCN(C(C)C)C(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1.C1(C)C=CC=CC=1>[Cl:30][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH:19]([C:27]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:29])[CH2:18]2)=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 8083MorpholineHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 3028194LithiumHCID 867085704-(3-((Tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate

Product 1

HCID 86708569Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate, lithium salt (200 mg, 0.452 mmol) was azeotroped 3× with toluene and 4 Å molecular sieves were added. THF (3 mL) was added, followed by DIPEA (0.118 mL, 0.677 mmol), morpholine (0.117 mL, 1.355 mmol), and T3P (0.538 mL, 0.903 mmol). The reaction was stirred at rt for 1 h. The reaction mixture was filtered through a small pad of celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-4% MeOH/DCM). Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (112 mg) was obtained as an off-white solid.

Workup

  1. additionwere added
  2. filtrationThe reaction mixture was filtered through a small pad of celite
  3. washrinsing with EtOAc
  4. customThe solvent was removed in vacuo
  5. customthe material was purified by flash column chromatography (0-4% MeOH/DCM)

Sources & evidence

ORD record
ord-2556de87deec437799c5f1b89ec7ec9a
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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