Sodium hydride → Methyl {4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}(4-fluorobenzyl)carbamate

HRID 510049Notes

Reaction equation

HRID 510049 reaction equation
[NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:15]2)[N:3]=1.[H-].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:15]2)[N:3]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 680214-Fluorobenzyl bromideHCID 24794430Vericiguat Impurity 100

Product 1

HCID 57330719Methyl {4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}(4-fluorobenzyl)carbamate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Under argon, 100 mg (0.245 mmol) of methyl {4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate (preparation described in WO 2008/031513, example 9) were initially charged in tetrahydrofuran (10.0 ml) and the suspension was cooled to 0° C. Subsequently, 9.8 mg (0.245 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 30.5 μl (0.245 mmol) of 4-fluorobenzyl bromide were added dropwise and the reaction mixture was stirred at RT overnight. Subsequently, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed twice with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 91.8 mg (72% of theory) of the title compound in solid form.

Workup

  1. stirringthe reaction mixture was stirred at RT overnight
  2. washthe organic phase was washed twice with saturated aqueous sodium hydrogencarbonate solution
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated by rotary evaporation
  6. customThe residue was separated by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient)
  7. concentrationthe product fractions were concentrated

Sources & evidence

ORD record
ord-fc639f3971bd4ac1b179ded443969dcf
Source dataset
uspto-grants-2015_08
Patent number
US09096592B2

Reaction notes

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