Ammonia → HCID 57520619, compound

HRID 593359Notes

Reaction equation

HRID 593359 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=S)[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.C(OO)(C)(C)C.[NH3:33]>CO>[NH2:33][C:22]1[CH2:21][O:20][CH2:19][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][CH:6]3[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[CH2:8][CH2:7]3)[CH:13]=[CH:14][C:15]=2[F:26])([CH3:25])[N:23]=1

Participants

5

Reactant 3

HCID 222AmmoniaHCID 6410tert-Butyl hydroperoxide2×HCID 88771173HCID 88771173, compound

Product 1

HCID 57520619HCID 57520619, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

In a pressure tube (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione (58 mg, 0.15 mmol) was dissolved in a solution of ammonia in methanol (7M, 0.5 ml). Then tert-butyl hydroperoxide (70% in water) (0.07 ml, 0.74 mmol) was added. The tube was sealed and the mixture stirred for 4 hours at room temperature. For the workup, the solution was evaporated at reduced pressure. NMR analysis showed still starting material. The residue was redissolved in a solution ammonia in methanol (7M, 0.5 ml) and heated to 50° C. for 3 days. Thereafter, another 0.5 ml were added, then after 1 day another 0.071 ml (0.74 mmol) of tert-butyl hydroperoxide. After stirring at room temperature for 4.5 hours the reaction mixture was quenched with a saturated aqueous solution of sodium carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl)-amine was obtained as a white foam (33 mg, 60%); (calculated) C19H20ClFN4O [374.85]; (found) [M+H]+=375.

Workup

  1. customThe tube was sealed
  2. customFor the workup, the solution was evaporated at reduced pressure
  3. dissolutionThe residue was redissolved in a solution ammonia in methanol (7M, 0.5 ml)
  4. temperatureheated to 50° C. for 3 days
  5. additionThereafter, another 0.5 ml were added
  6. stirringAfter stirring at room temperature for 4.5 hours the reaction mixture
  7. customwas quenched with a saturated aqueous solution of sodium carbonate
  8. extractionextracted with ethyl acetate
  9. dry with materialThe combined organic layers were dried over sodium sulphate
  10. customevaporated at reduced pressure
  11. customThe crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent

Sources & evidence

ORD record
ord-239555df093a4749abf80c4449972efd
Source dataset
uspto-grants-2016_01
Patent number
US09242943B2

Reaction notes

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