Acetic Acid → HCID 20817033, compound

HRID 432145Notes

Reaction equation

HRID 432145 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O)(=O)C.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([F:29])[CH:23]=3)[C:14]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:14]3[C:15](=[N:16][CH:17]=[N:18][C:13]=3[NH2:12])[N:19]([CH:30]3[CH2:35][CH2:34][CH:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:32][CH2:31]3)[N:20]=2)=[CH:23][C:24]=1[F:29]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 531671-MethylpiperazineHCID 5049666Sodium triacetoxyborohydride2×HCID 22347187HCID 22347187, compound2×

Product 1

HCID 20817033HCID 20817033, compoundYield 283.3%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

N-methylpiperazine (3.6 g, 0.036 mol) and acetic acid (2.17 g, 0.036 mol) were added to a suspension of 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (Intermediate R) (4.1 g, 0.012 mol) in dichloroethane (200 mL). Sodium triacetoxyborohydride (3.32 g, 0.016 mol) was then added portionwise to the reaction suspension. The reaction mixture was stirred at room temperature for 18 h. Additional sodium triacetoxyborohydride (1.79 g, 0.084 mol and 1.28 g, 0.06 mol) was added in two batches over 5 days. The reaction mixture was filtered, washed with dichloroethane (100 mL) and the filtrate was concentrated under reduced pressure to give 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (14.5 g, 0.034 mol). The yellow solid was purified and the cis/trans isomers were separated by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (93:5:2) as the eluent to give trans 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (lower running component) as a white solid (115 mg, 0.27 mmol). 1H NMR (DMSO-d6, 400 MHz) 8.19 (s, 1H), 7.18 (m, 2H), 6.88 (m, 1H), 5.46 (s, 2H), 4.60 (m, 1H), 2.35 (br m, 4H), 2.14 (s, 3H), 1.95 (br m, 6H), 1.44 (m, 2H), 1.26 (m, 4H), 0.86 (m, 2H). TLC (dichloromethane/methanol/ammonium hydroxide=95:5) Rf 0.31.

Workup

  1. filtrationThe reaction mixture was filtered
  2. washwashed with dichloroethane (100 mL)
  3. concentrationthe filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-ce7020b905884dc78588516665f53b37
Source dataset
uspto-grants-2003_12
Patent number
US06660744B1

Reaction notes

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