Sodium Bicarbonate → HCID 59548318, compound

HRID 1621864Notes

Reaction equation

HRID 1621864 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:19][C:20]3[CH:21]=[N:22][C:23]([O:27][CH3:28])=[C:24]([F:26])[CH:25]=3)=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14](OC)=[O:15])[N:3]=1.[CH2:29]([Mg]Br)[CH3:30].C([O-])(O)=O.[Na+].CC(O)C.C(Cl)Cl>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:18]=[C:13]([C:14]3([OH:15])[CH2:30][CH2:29]3)[CH:12]=[N:11][C:10]=2[NH:19][C:20]2[CH:21]=[N:22][C:23]([O:27][CH3:28])=[C:24]([F:26])[CH:25]=2)[N:3]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 21966342Isopropanol methylene chlorideHCID 66612160HCID 66612160, compoundHCID 178418443HCID 178418443, compound2×

Product 1

HCID 59548318HCID 59548318, compoundYield 7%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

To a slurry of methyl 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.400 g, 1.038 mmol) and titanium(iv) isopropoxide (0.365 mL, 1.246 mmol) in 8 mL THF at ambient temperature was added ethylmagnesium bromide 1.0 M solution in THF (5.61 mL, 5.61 mmol) over 2-3 min. The reaction became dark brown and warm, with bubbling. The reaction was cooled briefly with an ice bath and then allowed to stir at ambient temperature. After 1 h, an additional 2.4 equiv 1.0 M ethylmagnesium bromide in THF was added at ambient temperature. After 30 min, the reaction was cooled to 0° C. and quenched with ice and sat'd aq. NH4Cl. The reaction was partitioned between sat'd aqueous NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and ethyl acetate once, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by RPHPLC (Gradient, Acetonitrile+0.1% TFA/water+0.1% TFA) provided 0.070 g of a sticky orange film. The material was treated with sat'd aq. NaHCO3 and 10% iPrOH/DCM. The aq. layer was extracted 3×10% iPrOH/DCM and combined organics dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)cyclopropanol (0.027 g, 0.070 mmol, 7% yield) as a yellow solid. m/z (ESI, +ve ion) 384 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.90 (s, 1H), 8.82 (d, J=2.5Hz, 1H), 8.29-8.48 (m, 2H), 8.20 (d, J=2.5 Hz, 1H), 7.91 (br. s., 1H), 7.75 (br. s., 1H), 6.03 (s, 1H), 3.93 (s, 3H), 2.44 (s, 3H), 1.04-1.13 (m, 2H), 0.86-0.98 (m, 2H).

Workup

  1. temperaturewarm
  2. customwith bubbling
  3. temperatureThe reaction was cooled briefly with an ice bath
  4. waitAfter 30 min
  5. temperaturethe reaction was cooled to 0° C.
  6. customquenched with ice
  7. customThe reaction was partitioned between sat'd aqueous NH4Cl and DCM
  8. extractionThe aqueous layer was extracted with DCM 3 times, and ethyl acetate once
  9. dry with materialthe combined organics were dried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customPurification by RPHPLC (Gradient, Acetonitrile+0.1% TFA/water+0.1% TFA)
  13. customprovided 0.070 g of a sticky orange film
  14. extractionThe aq. layer was extracted 3×10% iPrOH/DCM
  15. dry with materialcombined organics dried over sodium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-066abe21fc214769ab2df2c65aeed35f
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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