Formaldehyde → 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol

HRID 1717606Notes

Reaction equation

HRID 1717606 reaction equation
[NH2:1][C@H:2]([C:4]1([OH:27])[CH2:7][N:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:9])[CH2:5]1)[CH3:3].[CH2:28]=O.[BH4-].[Na+]>CO.C=O>[F:17][C:12]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:10]([C:8]([N:6]2[CH2:7][C:4]([C@@H:2]([NH:1][CH3:28])[CH3:3])([OH:27])[CH2:5]2)=[O:9])[CH:15]=[CH:14][C:13]=1[F:16]

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 4311764Sodium borohydride3×HCID 16222192HCID 16222192, compound

Product 1

HCID 594692121-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-olYield 22.2%

Reagents, catalysts & solvents 2

HCID 712FormaldehydeCatalystHCID 887MethanolSolvent

Procedure

To 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (87.4 mg, 0.18 mmol), prepared using procedures similar to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (˜50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC. The clean material was converted to its hydrochloride salt to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). 1H NMR (400 MHz, CD3OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62 (dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H), 1.29 (br m, 3H); MS (EI) for C19H19F3IN3O2: 506 (MH+).

Workup

  1. stirringUpon stirring an additional 1.25 h
  2. stirringthe mixture was stirred 3 days at rt
  3. stirringthe mixture was stirred at rt for 30 min
  4. customAfter quenching with 1 N HCl
  5. customthe reaction mixture was purified directly by preparative HPLC

Sources & evidence

ORD record
ord-01c23b6d2be540eda2eaf80432c2b90d
Source dataset
uspto-grants-2010_09
Patent number
US07803839B2

Reaction notes

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