4-Fluorophenylboronic acid → 1-[7-(2-Chlorophenyl)-8-(4-fluorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-4-ethylaminopiperidine-4-carboxylic acid amide

HRID 2054413Notes

Reaction equation

HRID 2054413 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29](I)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C(O)C.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1

Participants

7

Reactant 2

HCID 2856454-Fluorophenylboronic acidHCID 596557211-[7-(2-Chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-4-ethylaminopiperidine-4-carboxylic Acid Amide

Product 1

HCID 113756131-[7-(2-Chlorophenyl)-8-(4-fluorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-4-ethylaminopiperidine-4-carboxylic acid amideYield 266%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 1140TolueneSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 1-[7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1i; 20 mg, 0.037 mmol) and 4-fluorophenylboronic acid (7.8 mg, 0.056 mmol) in ethanol (1.3 ml), toluene (1.3 ml) and 2M aqueous Na2CO3 (0.3 ml) was degassed (3×) by pulling a vacuum followed by refilling with nitrogen gas. Tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) was added and the mixture was heated at 80° C. for 5 hours. After cooling to room temperature, the mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-3% methanol in methylene chloride as eluant afforded a light yellow oil, which was crystallized from diethyl ether, and dried, in vacuo, to afford 1A-1 (11 mg, 58%) as a colorless solid: +ESI MS (M+1) 508.4; 1H NMR (400 MHz, CD3OD) δ 7.46-7.34 (m, 4H), 7.32 (dd, J=8.7, 5.4 Hz, 2H), 6.96 (t, J=8.7 Hz), 4.70-4.58 (br m, 2H), 4.40-4.25 (br m, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.46 (s, 3H), 2.20-2.12 (br m, 2H), 1.83-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).

Workup

  1. customwas degassed (3×)
  2. temperatureAfter cooling to room temperature
  3. extractionthe mixture was extracted from water with ethyl acetate
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered through a 0.45 μm
  7. filtrationfilter disk
  8. concentrationconcentrated, in vacuo

Sources & evidence

ORD record
ord-b4aa9e49570c4ad6bff8e0e539a91513
Source dataset
uspto-grants-2008_02
Patent number
US07329658B2

Reaction notes

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