Hydrochloric Acid → (S)-5-(4-(3-methylmorpholino)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine

HRID 63803Notes

Reaction equation

HRID 63803 reaction equation
B.C1COCC1.[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:17]3=[CH:27][C:28]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:34][CH2:33]4)=O)=[CH:29][N:16]3[N:15]=2)=[C:10]([C:42]([F:45])([F:44])[F:43])[CH:9]=1.Cl>O1CCCC1>[CH3:26][C@@H:21]1[N:20]([C:18]2[C:17]3=[CH:27][C:28]([CH2:30][N:32]4[CH2:33][CH2:34][N:35]([S:38]([CH3:41])(=[O:39])=[O:40])[CH2:36][CH2:37]4)=[CH:29][N:16]3[N:15]=[C:14]([C:11]3[C:10]([C:42]([F:45])([F:43])[F:44])=[CH:9][C:8]([NH2:7])=[N:13][CH:12]=3)[N:19]=2)[CH2:25][CH2:24][O:23][CH2:22]1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 2723981Borane;tetrahydrofuranHCID 117988364(S)-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-(3-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone

Product 1

HCID 72550013(S)-5-(4-(3-methylmorpholino)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amineYield 56.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

At −40° C., 1 M borane-THF (80 mL) was added dropwise to the solution of compound 24c (1.8 g, 3.17 mmol) in 50 mL of tetrahydrofuran. After the reaction proceeded 0.5 hours at this temperature, the reaction system was refluxed for 2 hours, and then cooled to below 0° C. 100 mL of concentrated hydrochloric acid was added dropwise and afterwards refluxed for 1 hour. When most of hydrochloric acid was removed by rotation evaporation, the pH of the solution was adjusted to about 8 by using saturated sodium carbonate solution. After extracted for three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by column chromatography with dichloromethane/methanol (40:1) to afford white solid (56.9%). m.p. 262° C. 1H NMR (300 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.68 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.77 (s, 2H), 4.87 (br s, 1H), 4.47 (br s, 1H), 3.96 (br s, 1H), 3.77-3.41 (m, 8H), 3.11 (s, 6H), 2.87 (s, 3H), 1.32 (s, 3H). LC-MS: 555 (M+1).

Workup

  1. temperaturethe reaction system was refluxed for 2 hours
  2. temperaturecooled to below 0° C
  3. temperatureafterwards refluxed for 1 hour
  4. customWhen most of hydrochloric acid was removed by rotation evaporation
  5. extractionAfter extracted for three times with ethyl acetate
  6. dry with materialthe organic phase was dried over anhydrous sodium sulfate
  7. customthe solvent was removed under reduced pressure
  8. customto give the crude product
  9. customThe crude product was purified by column chromatography with dichloromethane/methanol (40:1)

Sources & evidence

ORD record
ord-6e04b7f790824db88df79c8c85216c42
Source dataset
uspto-grants-2016_09
Patent number
US09447101B2

Reaction notes

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