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

HRID 2075762Notes

Reaction equation

HRID 2075762 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.[NH:34]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@@H:35]([C:42](O)=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CC(C)N=C=NC(C)C>C1COCC1>[C:48]([O:47][C:45](=[O:46])[NH:34][C@H:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]([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:43])([CH3:51])([CH3:49])[CH3:50]

Participants

5

Reactant 3

HCID 12734DiisopropylcarbodiimideHCID 2755953(2R)-2-{[(tert-butoxy)carbonyl]amino}-2-phenylacetic acidHCID 135974994Piperidine-2(S)-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenyl}-amide

Product 1

HCID 135974992[2-(2(S)-{4-[3-(5-Chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenylcarbamoyl}-piperidin-1-yl)-2-oxo-1(R)-phenyl-ethyl]-carbamic acid tert-butyl esterYield 54%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of compound 10A (1.0 g, 2.15 mmol) and BOC-D-Phg-OH (11A, 0.65 g, 2.58 mmol) was added anhydrous THF (30 mL) and the resultant mixture was stirred at rt for 5 min. DIPC (0.40 mL, 2.58 mmol) was added slowly at rt. The final reaction mixture was stirred at rt overnight. The solvent was removed and the residua were dissolved in small amount of ethyl acetate. Solid was removed by filtration. The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 3/1, 2/1, 1/1 and 2/3). The product was recrystallized from hexanes-ethyl acetate gave the title compound (12A, 0.81 g) as white crystals in 54% yield. 1H NMR (CDCl3, 500 MHz) δ 10.60 (s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.81 (d, 2H, J=8.0 Hz), 7.77 (s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.41 (m, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.96 (d, 1H, J=9.0 Hz), 5.58 (d, 1H, J=3.5 Hz), 5.53 (d, 2H, J=3.5 Hz), 4.31 (s, 2H), 4.06 (d, 2H, J=3.5 Hz), 3.86 (d, 1H, J=13.0 Hz), 3.16 (t, 1H, J=13.0 Hz), 2.48 (d, 1H, J=13.5 Hz), 2.00 (s, 1H), 1.61 (br s, 2H), 1.56-1.30 (m, 11H), 0.88 (m, 1H). LCMS (ESI) m/z 720.27 (MNa+), 698.22 (MH+), 642.10, 598.15, 345.16 (100), 289.14. HPLC: tR=5.25 min.

Workup

  1. customThe final reaction mixture
  2. customThe solvent was removed
  3. dissolutionthe residua were dissolved in small amount of ethyl acetate
  4. customSolid was removed by filtration
  5. customThe filtrate was purified by silica column chromatography
  6. washeluting with hexanes-ethyl acetate (v/v 3/1, 2/1, 1/1 and 2/3)
  7. customThe product was recrystallized from hexanes-ethyl acetate

Sources & evidence

ORD record
ord-a42041a92010496aa8ce3490d2294546
Source dataset
uspto-grants-2011_04
Patent number
US07923004B2

Reaction notes

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