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 1808992ノート

反応式

HRID 1808992 の反応式
[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]

参加物

6

反応物 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

生成物 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)-収率 74.1%

試薬・触媒・溶媒 2

HCID 23938Palladium触媒HCID 887Methanol溶媒

実験手順

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+).

後処理

  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

出典と根拠

ORDレコード
ord-65a4af5c0dd34fa59808f3609c8598e9
出典データセット
uspto-grants-2013_01
特許番号
US08362002B2

反応ノート

読み込み中…