Sodium Carbonate → 5-[7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine

HRID 1775472Notes

Reaction equation

HRID 1775472 reaction equation
Cl[C:2]1[C:3]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][C:15]([F:18])([F:17])[CH2:14]3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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].C(Cl)Cl>[F:17][C:15]1([F:18])[CH2:16][CH:13]([N:10]2[C:4]3[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:27]4[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=4)[C:3]=3[CH2:12][CH2:11]2)[CH2:14]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 1184361744-chloro-7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

Product 1

HCID 1184365935-[7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amineYield 95%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a suspension of 4-chloro-7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (844 mg, 2.89 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (920 mg, 4.20 mmol) in 1,4-dioxane (24 mL), was added 1 M aqueous solution of Na2CO3 (9 mL, 8.68 mmol) at room temperature. The reaction was purged with nitrogen for a few minutes before adding PdCl2(dppf)-DCM (354 mg, 0.434 mmol). The reaction was heated at 120° C. for 1 h in a microwave reactor. The mixture was cooled to room temperature and filtered through Celite® rinsing with EtOAc. The filtrate was concentrated and DCM was added, resulting in precipitation that was filtered to give a crude title compound (768 mg, ˜80% purity). The mother liquor was purified via silica gel chromatography using a gradient of EtOAc/heptane to afford an additional 250 mg of the title compound as a white solid (95% purity). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2 H), 7.08 (s, 2 H), 4.51-4.36 (m, 1 H), 3.71 (t, J=8.2 Hz, 2 H), 3.22 (t, J=8.2 Hz, 2 H), 3.13-2.94 (m, 2 H), 2.94-2.80 (m, 2 H), 2.47 (s, 3 H). m/z (APCI+) for C15H16F2N6S 351.1 (M+H)+.

Workup

  1. customThe reaction was purged with nitrogen for a few minutes
  2. temperatureThe mixture was cooled to room temperature
  3. filtrationfiltered through Celite®
  4. washrinsing with EtOAc
  5. concentrationThe filtrate was concentrated
  6. additionDCM was added
  7. customresulting in precipitation that
  8. filtrationwas filtered
  9. customto give a crude title compound (768 mg, ˜80% purity)
  10. customThe mother liquor was purified via silica gel chromatography

Sources & evidence

ORD record
ord-699f06a86b91416bbdaaf91f62f4ef64
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

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