Acetic Acid → HCID 135974981, compound

HRID 2075757Notes

Reaction equation

HRID 2075757 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N=C=NC(C)C)(C)C.O[Li].O.C(O)(=O)C>CN(C)C1C=CN=CC=1.C1COCC1.O.C(OCC)(=O)C>[C:29]([O:28][C:26]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](=[O:40])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)=[CH:4][CH:3]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]

Participants

10

Reactant 5

HCID 176Acetic AcidHCID 12734DiisopropylcarbodiimideHCID 168937Lithium hydroxide, monohydrateHCID 688618(2R)-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acidHCID 135974913HCID 135974913, compound

Product 1

HCID 135974981HCID 135974981, compoundYield 72.6%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 2-[4-(4-Amino-phenylethynyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-4-chloro-phenol (2A) (7.08 g, 20.0 mmol), N-Boc-2(R)-piperidinecarboxylic acid (3A) (18.35 g, 80.0 mmol) and 4-dimethylaminopyridine (DMAP, 0.978 g, 8.0 mmol) in anhydrous THF (100 mL) was cooled to 0° C. with and ice-water bath. N,N′-Diisopropylcarbodiimide (DIPC, 12.39 mL, 80.0 mmol) was added slowly to the above solution. The ice-water bath was removed and the reaction mixture was stirred at rt overnight. Water (˜5 mL) and methanol (100 mL) were added. The mixture was cooled to 0° C. A solution of LiOH.H2O (17.0 g, 405 mmol) in water (60 mL) were added slowly. The mixture was stirred at 0° C. for 2 h. It was then neutralized with acetic acid (23 mL, 402 mmol). The mixture was diluted with ethyl acetate (˜200 mL), and washed with brine, and dried over sodium sulfate. It was filtered, concentrated and filtered again to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3) to provide the title compound (4A, 8.2 g) as a yellowish solid in 72.6% yield. 1H NMR (CDCl3, 500 MHz) δ 10.59 (s, 1H), 8.67 (d, 1H, J=1.5 Hz), 8.40 (br s, 1H), 7.77 (s, 1H), 7.54 (s, 4H), 7.20 (dd, 1H, J=9.0, 1.5 Hz), 6.96 (d, 1H, J=9.0 Hz), 4.88 (s, 1H), 4.31 (t, 2H, J=4.5 Hz), 4.06 (t, 3H, J=4.5 Hz), 3.75 (br s, 1H), 2.87 (t, 1H, J=12.0 Hz), 2.34 (m, 3H), 1.90-1.20 (m, 15H). LCMS (ESI) m/z 587.15 (MNa+), 565.16 (MH+), 465.19 (100), 354.09; HPLC: tR=5.22 min.

Workup

  1. customThe ice-water bath was removed
  2. additionWater (˜5 mL) and methanol (100 mL) were added
  3. temperatureThe mixture was cooled to 0° C
  4. stirringThe mixture was stirred at 0° C. for 2 h
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationIt was filtered
  8. concentrationconcentrated
  9. filtrationfiltered again
  10. customto remove diisopropylurea
  11. customThe filtrate was purified with silica column chromatography
  12. washeluting with hexanes-ethyl acetate (v/v 1/1, 2/3)

Sources & evidence

ORD record
ord-a38e5a64531641e39615c367924dbfc2
Source dataset
uspto-grants-2011_04
Patent number
US07923004B2

Reaction notes

Loading…