Trifluoroacetic acid → N-(3-fluoro-4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

HRID 2241350Notes

Reaction equation

COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:49][CH:48]4[CH:44]([CH2:45][NH:46][CH2:47]4)[CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:43][CH:44]4[CH:48]([CH2:47][NH:46][CH2:45]4)[CH2:49]3)[C:11]=12

Participants

Reactant 2

HCID 6422Trifluoroacetic acid

HCID 68512954N-(3-fluoro-4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

Product 1

HCID 59304400N-(3-fluoro-4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamideYield 18.4%

Conditions

Temperature: 80 °C

Procedure

A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (13.8 mg, 0.0200 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product, which was further purified by preparative HPLC to afford the desired product (2.1 mg, 13.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 571 (M+1). 1H NMR (400 MHz, CD3OD δ 11.92 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 8.21 (d, 1H), 8.03 (d, 1H), 7.65 (m, 2H), 7.48 (d, 1H), 7.41 (m, 1H), 7.26 (m, 2H), 6.26 (d, 1H), 3.74 (d, 2H), 3.57 (m, 2H), 3.08-3.38 (m, 6H).

Workup

customThe solvent was removed
customthe residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1
customv/v) to give product, which
customwas further purified by preparative HPLC

Sources & evidence

ORD record: ord-8ecf5f8e8949437ab1107e796eea7816
Source dataset: uspto-grants-2010_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07723330B2

Reaction notes

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