Potassium Carbonate → (S)-2-fluoro-5-(1-((4-(5-(3-fluoro-4-(morpholinomethyl)phenyl)-pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile

HRID 1478584Notes

Reaction equation

HRID 1478584 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=5)[C:29]#[N:30])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.[F:45][C:46]1[CH:58]=[C:57](B2OC(C)(C)C(C)(C)O2)[CH:56]=[CH:55][C:47]=1[CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:32][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:57]6[CH:56]=[CH:55][C:47]([CH2:48][N:49]7[CH2:54][CH2:53][O:52][CH2:51][CH2:50]7)=[C:46]([F:45])[CH:58]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)=[CH:31][C:28]=1[C:29]#[N:30]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 438110633-Fluoro-4-(N-morpholinomethyl)phenylboronic acid, pinacol esterHCID 118364734(S)-5-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-2-fluorobenzonitrile

Product 1

HCID 73505573(S)-2-fluoro-5-(1-((4-(5-(3-fluoro-4-(morpholinomethyl)phenyl)-pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrileYield 93.7%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Procedure

In a pressure tube reactor, ((S)-5-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-2-fluorobenzonitrile (40 mg, 0.08 mmol) was added, and then K2CO3 (33 mg, 0.24 mmol) was added. Pd(dppf)2Cl2 (3 mg, 0.004 mmol) was further added, and then 1,4-dioxane (2 mL) and water (0.5 mL) were added. 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl)morpholine (12 g, 0.13 mmol) was added, and then stirred at room temperature under nitrogen gas for 10 minutes, followed by stirring at 85° C. for 2 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Column chromatography using 5% dichloromethane/methanol gave (S)-2-fluoro-5-(1-((4-(5-(3-fluoro-4-(morpholinomethyl)phenyl)-pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile (46 mg, 0.075 mmol) with a yield of 46%.

Workup

  1. stirringby stirring at 85° C. for 2 hours
  2. extractionthe organic layer was extracted with ethyl acetate and water
  3. customthe extra water was removed by sodium sulfate
  4. concentrationfollowed by concentration under reduced pressure

Sources & evidence

ORD record
ord-57b536cbe3664e1a9e670ea85463937a
Source dataset
uspto-grants-2016_08
Patent number
US09403831B2

Reaction notes

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