Dimethyl Sulfate → 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine

HRID 928183Notes

Reaction equation

HRID 928183 reaction equation
[CH3:1]C1CCCO1.[F:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][N:21]([CH3:23])[CH:22]=2)[N:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].S(OC)(OC)(=O)=O>>[F:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH3:1])=[C:10]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][N:21]([CH3:23])[CH:22]=2)[N:9]=1

Participants

5

Reactant 4

HCID 6497Dimethyl SulfateHCID 73012-MethyltetrahydrofuranHCID 62657Potassium Phosphate, TribasicHCID 178494310HCID 178494310, compound

Product 1

HCID 1180735462-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amineYield 86%

Conditions

Temperature
5 °C

Procedure

To a 100 L reactor fitted with a caustic scrubber was added 2-methyltetrahydrofuran (44.0 L), 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (2.20 kg, 8.36 mol, 1.00 eq) and potassium phosphate tribasic (7.10 kg, 33.43 mol mmol, 4.00 eq). The resulting mixture was stirred at 5° C. and dimethyl sulfate (1.42 kg, 11.28 mol, 1.35 eq) was added and the resulting mixture was stirred at 5° C. for 1 hr. The reaction was warmed from 5° C. to 15° C. over 2 hr and then held at 15° C. for 20 hr. The reaction mixture was cooled to 5° C. and quenched with water (44.0 L) while maintaining the internal temperature below 10° C. The mixture was then heated at 50° C. for 2 hr and then cooled to 10° C. and granulated for 2 hr. The product was isolated by filtration and washed with water (11.0 L) and then with 2-methyltetrahydrofuran (11.0 L). The cake was dried under vacuum at 40° C. for 8 hr to give the title compound (1.99 kg, 7.18 mol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H)3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.

Workup

  1. customTo a 100 L reactor fitted with a caustic scrubber
  2. stirringthe resulting mixture was stirred at 5° C. for 1 hr
  3. temperatureThe reaction was warmed from 5° C. to 15° C. over 2 hr
  4. temperatureThe reaction mixture was cooled to 5° C.
  5. customquenched with water (44.0 L)
  6. temperaturewhile maintaining the internal temperature below 10° C
  7. temperatureThe mixture was then heated at 50° C. for 2 hr
  8. temperaturecooled to 10° C.
  9. waitgranulated for 2 hr
  10. customThe product was isolated by filtration
  11. washwashed with water (11.0 L)
  12. customThe cake was dried under vacuum at 40° C. for 8 hr

Sources & evidence

ORD record
ord-102aceddb7f2410c86bbc86180579def
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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