N-Iodosuccinimide → 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol

HRID 597912Notes

Reaction equation

HRID 597912 reaction equation
[CH3:1][CH:2]1[CH2:8][N:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5][C:4]2[N:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:3]1=2.C1C(=O)N([I:27])C(=O)C1>C(O)(C(F)(F)F)=O.CC(O)=O>[I:27][C:17]1[C:16]([OH:19])=[N:15][C:4]2[CH2:5][CH2:6][N:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH2:8][CH:2]([CH3:1])[C:3]=2[CH:18]=1

Participants

5

Reactant 2

HCID 120273N-IodosuccinimideHCID 178430708HCID 178430708, compound

Product 1

HCID 1784307093-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-olYield 98.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

To a solution of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol hydrobromide (1.76 g, 6.79 mmol) in DCM (50 ml) and DMF (10 ml) was added Et3N (2.90 ml, 20.7 mmol) and TFAA (1.00 ml, 6.90 mmol). The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and parted between sat. aq. NaHCO3 and EtOAc. The organic phase was dried, concentrated in vacuo and purified by column chromatography to yield 1.46 g (77%) of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (DMSO-d6) δ 11.43 (br s, 1H), 7.30 (m, 1H), 6.18 (m, 1H), 3.95-3.42 (m, 4H), 3.06-2.96 (m, 2H), 2.95-2.87 (m, 1H), 1.12 (2× d, 3H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.36 g, 4.96 mmol) and NIS (1.12 g, 4.96 mmol) in TFA (2 ml) and AcOH (36 ml) was stirred at room temperature for 16 h. Evaporation of TFA and AcOH followed by chromatographic purification of the resulting residue gave 1.95 g (98%) of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 4.17-3.41 (m, 4H), 3.20-2.94 (m, 3H), 1.26 (2× d, 3H) ppm. A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (50.0 mg, 125 μmol) and K2CO3 (17.3 mg, 125 μmol) in MeOH (10 ml) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 20.2 mg (53%) of 3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.90 (s, 1H), 3.09-2.80 (m, 7H), 1.28 (d, 3H) ppm.

Workup

  1. customEvaporation of TFA and AcOH
  2. customfollowed by chromatographic purification of the resulting residue

Sources & evidence

ORD record
ord-198a4fb05e3a4969b24d8eefba6517b3
Source dataset
uspto-grants-2011_03
Patent number
US07897595B2

Reaction notes

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