Hydrazine hydrate (1:1) → HCID 178509473, compound

HRID 2365751Notes

Reaction equation

HRID 2365751 reaction equation
CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=[O:12])[CH:6]=1.[OH2:19].[NH2:20][NH2:21]>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[NH:21][N:20]=1)([O-:12])=[O:19]

Participants

4

Reactant 2

HCID 24654Hydrazine hydrate (1:1)HCID 86659132HCID 86659132, compound

Product 1

HCID 178509473HCID 178509473, compoundYield 100%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (0.3 g; 1.3 mmol) was combined with hydrazine monohydrate (0.07 mL; 1.4 mmol; Sigma-Aldrich) in 5 mL EtOH for 1 hour at RT. The reaction was concentrated in vacuo to yield 3-(3-nitrobenzyl)-5-amino-1H-pyrazole-4-carbonitrile (0.3 g; 1.3 mmol; ESI-MS m/z [M+H]+ found 244.5, calculated 244.1, 1H NMR (400 MHz, DMSO): δ 11.77 (s, 1H), 8.09 (d, J=8 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J=8 Hz, 1H), 7.60 (m, 1H), 6.33 (s, 2H), 3.96 (s, 2H)), which was subsequently combined with formamide (6 mL) and heated to 180° C. overnight. H20 was added to the cooled reaction and the precipitate was filtered and dried to yield 3-(3-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.26 g; 0.96 mmol; ESI-MS m/z [M+H]+ found 271.4, calculated 271.09; 1H NMR (400 MHz, DMSO): δ 8.18 (s, 1H), 8.10 (s, 1H), 8.06 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.58 (m, 1H), 7.22 (br, 2H), 4.51 (s, 2H)). The recovered intermediate (0.05 g; 0.18 mmol) was combined with bromocyclopentane (0.1 mL; 0.38 mmol), 0.125 g K2CO3, in 1 mL DMF and refluxed under argon for 2 hours. The reaction was filtered to remove solid K2CO3, and the filtrate was combined with brine and the organic product was extracted in CH2Cl2 to yield 3-(3-nitrobenzyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 339.5, calculated 339.15; 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H), 5.25 (pen, 8 Hz, 1H), 5.06 (br, 2H), 4.42 (s, 2H), 2.14 (m, 4H), 1.97 (m, 2H), 1.73 (m, 2H)). Reduction of this material was carried out as per Cmpd 1 to yield 3-(3-aminobenzyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 309.5, calculated 309.17). The reduced precursor was coupled to 3-(trifluoromethyl)phenyl isocyanate and purified as described for Cmpd 1 to yield Cmpd 3 1-(3-((4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 496.4, calculated 496.2; 1H NMR (400 MHz, DMSO): δ 9.22 (s, 1H), 8.93 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 7.50-7.60, (m, 2H), 7.43 (s, 1H), 7.18-7.22 (m, 3H), 6.90 (d, J=8 Hz, 1H), 5.20 (pentet, J=7 Hz, 1H), 4.40 (s, 2H), 1.98-2.13 (m, 4H), 1.85-1.95 (m, 2H), 1.62-1.73 (m, 2H); 13C NMR (400 MHz, DMSO): δ 24.76, 32.33, 33.48, 57.62, 98.34, 114.48, 117.01, 118.17, 118.46, 118.89, 122.13, 122.34, 122.66, 129.97 (q), 139.53, 140.11, 141.16, 145.37, 150.60, 152.32, 152.94, 154.38, 159.00 (q)).

Workup

  1. concentrationThe reaction was concentrated in vacuo

Sources & evidence

ORD record
ord-9f775395a2864666abf9872469153cea
Source dataset
uspto-grants-2014_04
Patent number
US08697709B2

Reaction notes

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