1,1'-Carbonyl-di-(1,2,4-triazole) → N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((N-(2-(dimethylamino)ethyl)acetamido)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1778001Notes

Reaction equation

[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:50][CH3:51])[C:30]1[C:39]([CH2:40][N:41]([CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])[C:42](=[O:44])[CH3:43])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]([CH2:45][CH2:46][N:47]([CH3:48])[CH3:49])[C:42](=[O:44])[CH3:43])=[C:30]([CH:29]([O:28][CH3:27])[O:50][CH3:51])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]

Participants

Conditions

Temperature: 0 °C

Procedure

A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 631 mg, 3.28 mmol) in anhydrous DMF (4 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (539 mg, 3.28 mmol) and DMF (4 ml) cooled at 0° C. After stirring for 30 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h, after which a solution of N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)acetamide (intermediate 198, 460 mg, 1.313 mmol) in DMF (4 ml) was added. The reaction mixture was continued to stir for 48 h at room temperature and quenched by pouring it into aqueous NaHCO3. The reaction mixture was diluted with EtOAc, phases were separated and the water phase was extracted with EtOAc and DCM. The combined organic phases were dried using Na2SO4, filtered and evaporated. The crude product was purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 5, H2O/MeCN 70:30 to 40:60 in 25 min). Fractions containing the product were collected, diluted with water and basified with NaHCO3. The mixture was concentrated and extracted with DCM, dried using Na2SO4, filtered, concentrated and dried to yield the title compound as a colorless foamy solid. (UPLC-MS 3) tR 0.73 min, ESI-MS 569.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.55 (s, 0.6H), 13.52 (s, 0.4H), 8.28 (s, 1H), 7.53 (s, 1H), 7.51 (s, 0.4H), 7.40 (s, 0.6H), 6.98-6.91 (m, 1H), 5.41 (s, 0.6H), 5.40 (s, 0.4H), 4.70 (s, 0.8H), 4.65 (s, 1.2H), 3.96-3.90 (m, 2H), 3.53 (t, 2H), 3.42-3.24 (m, 13H), 2.86 (t, 0.8H), 2.81 (t, 1.2H), 2.36 (t, 1.2H), 2.30 (t, 0.8H), 2.17-2.08 (m, 7.8H), 1.96 (s, 1.2H), 1.94-1.86 (m, 2H).

Workup

temperatureto warm to room temperature
stirringstirred for approximately 2 h
stirringto stir for 48 h at room temperature
customquenched
additionby pouring it into aqueous NaHCO3
additionThe reaction mixture was diluted with EtOAc, phases
customwere separated
extractionthe water phase was extracted with EtOAc and DCM
customThe combined organic phases were dried
filtrationfiltered
customevaporated
customThe crude product was purified by reversed phase preparative HPLC
washeluting with a gradient of MeCN and water (RP 5, H2O/MeCN 70:30 to 40:60 in 25 min)
additionFractions containing the product
customwere collected
additiondiluted with water and basified with NaHCO3
concentrationThe mixture was concentrated
extractionextracted with DCM
customdried
filtrationfiltered
concentrationconcentrated
customdried

Sources & evidence

ORD record: ord-a0ff8689e86d4bf6b7d88a9386b3c0bf
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09266883B2

Reaction notes

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