Cesium fluoride → tert-butyl 3-{4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylate

HRID 1775462Notes

Reaction equation

HRID 1775462 reaction equation
Cl[C:2]1[C:3]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.[F-].[Cs+]>O1CCOCC1.O.CCOC(C)=O.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]>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[C:3]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:19]4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[N:7]=2)=[CH:38][N:39]=1

Participants

8

Reactant 3

HCID 25953Cesium fluorideHCID 177502122-Aminopyrimidine-5-boronic acid, pinacol esterHCID 118436598tert-butyl 3-{4-chloro-2[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylate

Product 1

HCID 118436691tert-butyl 3-{4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylateYield 100%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirred mixture of tert-butyl 3-{4-chloro-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylate (8.33 g, 20.32 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (9.88 g, 44.7 mmol) and CsF (9.26 g, 61 mmol) in 1,4-dioxane (250 mL) and water (50 mL) was added Pd(dppf)2Cl2 (2.23 g, 3.05 mmol) under nitrogen. The mixture was heated under reflux for 18 h. The mixture was diluted with EtOAc (300 mL) and washed with water (300 mL), brine (300 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of petroleum ether/EtOAc (from 1:1 to 0:1) to give 9.52 g (100%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2 H), 6.97 (s, 2 H), 4.75-4.67 (m, 1 H), 4.63-4.56 (m, 1 H), 4.26-4.13 (m, 3 H), 4.08-4.00 (m, 2 H), 3.90-3.84 (m, 1 H), 3.71-3.64 (m, 3 H), 3.56 (dd, J=11.3, 3.0 Hz, 1 H), 3.40 (dt, J=11.7, 2.7 Hz, 1H), 3.17-3.02 (m, 3 H), 1.39 (s, 9 H), 1.15 (d, J=6.7 Hz, 3 H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux for 18 h
  3. washwashed with water (300 mL), brine (300 mL×2)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by silica gel column chromatography
  7. washeluting with a gradient of petroleum ether/EtOAc (from 1:1 to 0:1)

Sources & evidence

ORD record
ord-16bcad50673f40faad9d9829fd0a77da
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

Loading…