Diisopropylethylamine → 1-Piperidinecarboxylic acid, 2-[1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl]-3-hydroxy-3-azetidinyl]-, 1,1-dimethylethyl ester, (2R)-

HRID 1717587Notes

Reaction equation

HRID 1717587 reaction equation
[OH:1][C:2]1([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.CCN(C(C)C)C(C)C.[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])C(F)=O>[Pd].CO>[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([C:6]([N:4]2[CH2:5][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([OH:1])[CH2:3]2)=[O:8])[CH:45]=[CH:46][C:47]=1[F:48]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 594691583,4-Difluoro-2-(2-fluoro-4-iodoanilino)benzoyl fluorideHCID 670516791,1-dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate

Product 1

HCID 670516811-Piperidinecarboxylic acid, 2-[1-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl]-3-hydroxy-3-azetidinyl]-, 1,1-dimethylethyl ester, (2R)-Yield 74.1%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

1,1-Dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate 1H NMR (400 MHz, CDCl3): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C26H29F3IN3O4: 576 M-C4H9+).

Workup

  1. filtrationThe suspension was then filtered through a celite pad
  2. concentrationconcentrated
  3. customthen dried in vacuo to a colorless solid
  4. customprepared
  5. customThe reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid
  6. washthe organic layer washed with brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationthen filtered
  9. concentrationconcentrated
  10. customPurification of the residue by silica gel flash chromatography

Sources & evidence

ORD record
ord-e389d92d1898424fabd140f9e6017f72
Source dataset
uspto-grants-2010_09
Patent number
US07803839B2

Reaction notes

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