Sodium Carbonate → Tert-butyl 4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

HRID 1484051Notes

Reaction equation

HRID 1484051 reaction equation
Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=12.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Cl[C:42]1[N:47]=[C:46]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][C@H:49]2[CH3:54])[CH:45]=[C:44]([C:55]2([S:58]([CH3:61])(=[NH:60])=[O:59])[CH2:57][CH2:56]2)[N:43]=1.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].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:54][C@H:49]1[N:48]([C:46]2[CH:45]=[C:44]([C:55]3([S:58]([CH3:61])(=[NH:60])=[O:59])[CH2:57][CH2:56]3)[N:43]=[C:42]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]4[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=34)[N:47]=2)[CH2:53][CH2:52][O:51][CH2:50]1

Participants

9

Reactant 5

HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 56592975tert-Butyl 4-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylateHCID 86660214(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine

Product 1

HCID 86660222Tert-butyl 4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylateYield 46.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.906 g, 1.25 mmol) was added to tert-butyl 4-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.24 g, 4.17 mmol), potassium acetate (2.87 g, 29.21 mmol) and bis(pinacolato)diboron (4.73 g, 18.63 mmol) in dioxane (100 ml) under nitrogen. The resulting solution was stirred at reflux for 3 days to afford an approximate 2:1 mixture of boc to de-boc product. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.02 mmol), (3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (0.318 g, 0.96 mmol), 2M aqueous sodium carbonate solution (0.577 mL, 1.15 mmol) under nitrogen. The reaction mixture was stirred at 90° C. for 6 hours. The reaction mixture was concentrated, diluted with EtOAc (400 ml), and then washed sequentially with water (300 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and then evaporated directly onto silica (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.227 g, 46%); 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40-1.61 (3H, m), 1.68 (9H, s), 1.76 (1H, dd), 3.09 (3H, d), 3.24 (1H, m), 3.52 (1H, t), 3.67 (1H, dd), 3.79 (2H, d), 4.00 (1H, dd), 4.19 (1H, s), 4.56 (1H, s), 7.00 (1H, d), 7.57 (1H, d), 8.00 (1H, d), 9.25 (1H, s), 9.37 (1H, s); m/z: (ES+) MH+, 513.19.

Workup

  1. temperatureat reflux for 3 days
  2. customto afford
  3. additionan approximate 2:1 mixture of boc to de-boc product
  4. stirringThe reaction mixture was stirred at 90° C. for 6 hours
  5. concentrationThe reaction mixture was concentrated
  6. additiondiluted with EtOAc (400 ml)
  7. washwashed sequentially with water (300 ml) and saturated brine (75 ml)
  8. dry with materialThe organic layer was dried over MgSO4
  9. filtrationfiltered
  10. customevaporated directly onto silica (30 g)
  11. customThe resulting powder was purified by flash chromatography on silica
  12. washeluting with a gradient of 0 to 5% MeOH in DCM
  13. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-f853223bdd004425b195158b43f5a7ac
Source dataset
uspto-grants-2016_08
Patent number
US09421213B2

Reaction notes

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