4-Hydroxybenzaldehyde → HCID 178486393, compound

HRID 253222Notes

Reaction equation

[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1.[OH:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH3:27][O:26][C:23]1[C:22]([O:28][CH3:29])=[CH:21][C:20]2[C:3]3[C:4]([CH:7]4[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)=[N:5][NH:6][C:2]=3[N:1]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([OH:30])=[CH:32][CH:33]=3)[C:25]=2[CH:24]=1

Participants

Reactant 3

HCID 1264-Hydroxybenzaldehyde

HCID 6422Trifluoroacetic acid

HCID 178488430HCID 178488430, compound

Product 1

HCID 178486393HCID 178486393, compoundYield 61%

Procedure

A solution of 1,1-dimethylethyl 4-{5-amino-4-[3,4-bis(methyloxy)phenyl]-1H-pyrazol-3-yl}piperidine-1-carboxylate (0.39 g, 0.97 mmol) and 4-hydroxybenzaldehyde (0.12 g, 0.97 mmol) was heated to 72° C. in trifluoroacetic acid (5 mL) for 18 h. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC (CH3CN/H2O with 0.1% TFA) to give 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetate (0.24 g, 61%). 53 mg (0.12 mmol) 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetate was dissolved in ethanol (10 mL) and it was treated with polymer bound Hunig's base (Argonaut Technologies Inc. PS-DIEA, 3.44 mmol/g) for 30 minutes to adjust the pH to 7. The resin was filtered off and the filtrate was concentrated to dryness. The residue was treated with hydrogen chloride (4M in 1,4-dioxane, 3.0 mL). The precipitating solid was collected by filtration to result in 4-[7,8-bis(methyloxy)-1-piperidin-4-yl-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol hydrochloride (42 mg, 89%). 1H-NMR (400 MHz, d6-DMSO): 9.18 (s, 1H), 8.78 (s, 1H), 7.48 (d, 2H), 7.44 (d, 2H), 6.88 (d, 2H), 4.00, 3.68 (2 s, 2×3H), 3.34 (m, 2H), 3.16 (m, 2H), 2.22 (m, 2H), 2.02 (m, 2H), 1.22 (m, 1H), MS (EI) for C23H24N4O3: 405.1 (MH+).

Workup

customThe solvent was evaporated under reduced pressure
customthe residue was purified by reverse phase HPLC (CH3CN/H2O with 0.1% TFA)

Sources & evidence

ORD record: ord-2af2cd18b3a249a68bba6d6705c27452
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07872014B2

Reaction notes

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