Sodium Carbonate → 2-(6-(benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide

HRID 595488Notes

Reaction equation

HRID 595488 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])[N:12]=2)=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[CH:3]=1.[N:25]1[S:26][N:27]=[C:28]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:29]=12.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:25]1[S:26][N:27]=[C:28]2[CH:33]=[C:32]([NH:34][C:2]3[N:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:20])=[C:11]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])[N:12]=4)=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[CH:3]=3)[CH:31]=[CH:30][C:29]=12

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 3143132,1,3-Benzothiadiazol-5-amineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 896896522-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide

Product 1

HCID 896897652-(6-(benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

To a stirred solution of (2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide (31) (100 mg, 0.283 mmol) in 1,4-Dioxane (10 mL), benzo[c][1,2,5]thiadiazol-5-amine (0.283 mmol, 1 equiv.), Na2CO3 (1.134 mmol, 4 equiv.) and Xanthphos (0.113 mmol, 0.4 equiv.) were added and degassed for 10 min. Pd2(dba)3 (0.113 mmol, 0.4 equiv.) was added and degassed once again for 10 min. Heated the reaction mixture at 115° C. for overnight. The reaction was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and MeOH:CHCl3 as eluent to afford 2-(6-(benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide [Example 90]. 1H NMR: 400 MHz, CD3OD: δ 1.42 (d, J=6.40 Hz, 6H), 1.83-1.84 (m, 2H), 2.71 (s, 3H), 3.51 (t, J=1.20 Hz, 2H), 3.72 (t, J=7.20 Hz, 2H), 3.81-3.83 (m, 1H), 6.28 (s, 1H), 7.67 (dd, J=2.00, 9.40 Hz, 1H), 7.89 (dd, J=9.60, 9.20 Hz, 1H), 8.47 (s, 1H), 8.64 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.896 min; LCMS (ES-API), m/z 466.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.335 min; Purity: 98.7%.

Workup

  1. customdegassed for 10 min
  2. customdegassed once again for 10 min
  3. temperatureThe reaction was cooled
  4. filtrationfiltered through small pad of celite
  5. customThe filtrate obtained
  6. concentrationwas concentrated
  7. customto provide crude material
  8. customThe crude material was purified by column chromatography through silica gel and MeOH

Sources & evidence

ORD record
ord-6c1627a25a5b4adeae1843fc08572884
Source dataset
uspto-grants-2016_01
Patent number
US09242976B2

Reaction notes

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