4-Methylmorpholine → (S)-3-{[2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carbonyl]-amino}-azepane-1carboxylic acid tert-butyl ester

HRID 30342Notes

Reaction equation

HRID 30342 reaction equation
[NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]([NH2:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]([NH:32][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[S:3][C:2]=2[NH2:1])=[O:9])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 34178419tert-Butyl (3S)-3-aminoazepane-1-carboxylateHCID 689579752-Amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid

Product 1

HCID 68957747(S)-3-{[2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carbonyl]-amino}-azepane-1carboxylic acid tert-butyl esterYield 50.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 2-amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid (1.0 g, 4.0 mmol) in anhydrous DMF (20 mL) is added (S)-3-amino-azepane-1-carboxylic acid tert-butyl ester (1.03 g, 4.8 mmol), BOP (2.6 g, 6.0 mmol) and NMM (0.6 mL, 5 mmol). The reaction mixture was stirred overnight at room temperature. The solution was diluted with water and EtOAc. The organic layer was separated and set aside. The remaining aqueous layer was extracted with EtOAc (2×) and then the combined organic extracts were pooled and washed with brine. The resultant EtOAc solution was dried over Na2SO4, filtered, and concentrated under vacuum to yield a brown solid. Purification was performed by ISCO MPLC (SiO2, 30-50% EtOAc/hexanes) to give 0.9 g (50%) of an off-white solid. 1H NMR (d6-DMSO δ 7.51, d, 0.5H; δ 7.46, s, 0.5H; δ 7.37, s, 0.5H; δ 7.36, d, 0.5H; δ 7.34, br s, 2H; δ 7.33, d, 2H; δ 6.93, d, 2H; δ 4.11, br s, 1H; δ 3.76, s, 3H; δ 3.61, dq, 1H; δ 3.47, m, 1H; δ 3.11, m, 2H; δ 1.73, m, 3H; δ 1.56, m, 2H; δ 1.42, s, 4.5H; δ 1.38, s+m, 5.5H;), LC/MS (APCI, ES, M+H=446).

Workup

  1. customThe organic layer was separated
  2. extractionThe remaining aqueous layer was extracted with EtOAc (2×)
  3. washwashed with brine
  4. dry with materialThe resultant EtOAc solution was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customto yield a brown solid
  8. customPurification

Sources & evidence

ORD record
ord-f5b87532c3774d9ca3f653fb256a3fd2
Source dataset
uspto-grants-2008_09
Patent number
US07423061B2

Reaction notes

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