Sodium Bicarbonate → N5-(1-Cyclopropylpiperidin-4-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine

HRID 510038Notes

Reaction equation

HRID 510038 reaction equation
[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[CH:26]1([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH:26]1([N:29]2[CH2:34][CH2:33][CH:32]([NH:21][C:17]3[C:18]([NH2:20])=[N:19][C:14]([C:7]4[C:8]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[N:5]([CH2:4][C:3]5[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=5[F:1])[N:6]=4)=[N:15][CH:16]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:27]1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydride2×HCID 162276291-Cyclopropylpiperidin-4-one2×HCID 219348172-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5-pyrimidinediamine

Product 1

HCID 68075726N5-(1-Cyclopropylpiperidin-4-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamineYield 60.4%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolvent2×HCID 887MethanolSolvent

Procedure

200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 182 mg (1.312 mmol) of 1-cyclopropyl-4-piperidinone were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-cyclopropyl-4-piperidinone, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added and the mixture was stirred vigorously for 10 min. Subsequently, the mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 165 mg of the title compound were obtained (60% of theory).

Workup

  1. stirringthe mixture was stirred at RT for 2.5 h
  2. waitSubsequently, within 2 days
  3. stirringthe mixture was stirred vigorously for 10 min
  4. extractionSubsequently, the mixture was extracted with water and ethyl acetate
  5. customThe phases were separated
  6. extractionthe aqueous phase was extracted twice with ethyl acetate
  7. washThe combined organic phases were washed with saturated aqueous sodium chloride solution
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. custompurified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient)

Sources & evidence

ORD record
ord-ce0ca099fc314e529cb618ce0efb281f
Source dataset
uspto-grants-2015_08
Patent number
US09096592B2

Reaction notes

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