Acetic Acid → HCID 178476634, compound

HRID 897859Notes

Reaction equation

HRID 897859 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH:35]=O.[C:42]([OH:45])(=[O:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:42]([OH:45])(=[O:44])[CH3:43].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:35][C:34]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:33]=1[Cl:32]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 678472-Chloro-6-fluorobenzaldehydeHCID 5049666Sodium triacetoxyborohydride2×HCID 20817210HCID 20817210, compound

Product 1

HCID 178476634HCID 178476634, compoundYield 24.4%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 2-chloro-6-fluorobenzaldehyde (0.076 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional three equivalents of sodium triacetoxyborohydride (1.008 g, 0.00477 mol) were added in three 24 hour intervals, after which time all the starting material had been consumed. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile-0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give to give trans 3-{3-chloro-4-[(2-chloro-6-fluorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.074 g, 0.00011 mol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.52 (d, 1H), 7.35-7.47 (m, 4H), 6.99 (d, 1H), 5.75 (t, 1H), 4.55-4.66 (m, 1H), 4.57 (d, 2H), 2.25-2.61 (m, 1H), 2.16 (s, 3H), 1.91 (s, 3H), 1.87-2.09 (m, 4H), 1.37-1.53 (m, 2H);

Workup

  1. customafter which time all the starting material had been consumed
  2. customThe solvents were removed in vacuo
  3. customthe residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL)
  4. customThe phases were separated
  5. extractionthe aqueous phase was extracted with chloroform (2×25 mL)
  6. dry with materialThe combined organic phases were dried over magnesium sulfate
  7. customthe solvent was removed in vacuo
  8. customThe residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm
  9. wait30%-60% acetonitrile-0.1M ammonium acetate over 15 min
  10. customThe acetonitrile was removed in vacuo
  11. customto give

Sources & evidence

ORD record
ord-cb45409ec55a4bf49092c12484606f7b
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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