Tetrahydrofuran → [1(S)-Benzyl-2-(2(R)-{4-[3-(5-chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenylcarbamoyl}-piperidin-1-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester

HRID 2075759Notes

Reaction equation

HRID 2075759 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.[N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])([CH3:46])[C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1COCC1.C(N=C=NC(C)C)(C)C>O>[C:50]([O:49][C:47](=[O:48])[N:34]([C@@H:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:33])=[N:9][N:10]([CH2:30][CH2:31][OH:32])[CH:11]=2)=[CH:20][CH:19]=1)=[O:44])[CH3:46])([CH3:53])([CH3:51])[CH3:52]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 12734DiisopropylcarbodiimideHCID 7010602Boc-N-Me-Phe-OHHCID 135974922Piperidine-2(R)-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenyl}-amide

Product 1

HCID 135974969[1(S)-Benzyl-2-(2(R)-{4-[3-(5-chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenylcarbamoyl}-piperidin-1-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl esterYield 42.4%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a mixture of compound 5A (6.50 g, 13.98 mmol) and BOC-N-Me-Phe-OH (6A, 9.76 g, 34.94 mmol) was added anhydrous THF (350 mL) and the resultant mixture was stirred at rt for 10 min. Diisopropylcarbodiimide (DIPC, 5.41 mL, 34.94 mmol) was added slowly at rt. The reaction mixture was stirred at rt overnight. Water (˜10 mL) was added to the above mixture and the reaction mixture was stirred at rt for 3 hour. Solvent was removed and the residua were dissolved in ethyl acetate. It was filtered to remove solid (diisopropylurea). The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3, 1/2) to provide the title compound (7A, 4.3 g) as foam-like powder in 42.3% yield. 1H NMR (CDCl3, 500 MHz) δ 10.63 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 7.76 (s, 1H), 7.63 (m, 1H), 7.52 (d, 2H, J=7.5 Hz), 7.40-7.10 (m, 7H), 6.96 (d, 1H, J=8.0 Hz), 5.35 (br s, 1H), 5.13 (m, 1H), 4.29 (s, 2H), 4.05 (s, 2H), 3.81 (m, 1H), 3.20 (t, 1H, J=8.0 Hz), 3.09 (m, 2H), 2.94 (s, 3H), 2.87 (m, 1H), 2.35 (m, 1H), 1.75-1.10 (m, 12H), 0.74 (m, 1H). LCMS (ESI) m/z 748.26 (MNa+), 726.27 (MH+), 670.21, 626.20, 465.10, 373.18, 317.14 (100). HPLC: tR=5.70 min.

Workup

  1. stirringthe reaction mixture was stirred at rt for 3 hour
  2. customSolvent was removed
  3. dissolutionthe residua were dissolved in ethyl acetate
  4. filtrationIt was filtered
  5. customto remove solid (diisopropylurea)
  6. customThe filtrate was purified by silica column chromatography
  7. washeluting with hexanes-ethyl acetate (v/v 1/1, 2/3, 1/2)

Sources & evidence

ORD record
ord-729824c2512d4c429173b6eb1eaad963
Source dataset
uspto-grants-2011_04
Patent number
US07923004B2

Reaction notes

Loading…