Cesium carbonate → tert-butyl 6'-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate

HRID 2209159Notes

Reaction equation

HRID 2209159 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.BrC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C3CC3)C=NC=2C=1.[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[C:48]2([CH2:66][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:64]2)[C:47]1=[O:74].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@@H:11]4[CH2:12][C:13](=[O:16])[NH:14][CH2:15]4)[CH3:10])=[N:7][C:2]([C:52]4[CH:53]=[C:54]5[C:49]([C:48]6([CH2:64][N:65]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:66]6)[C:47](=[O:74])[N:46]5[CH3:45])=[CH:50][CH:51]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 117843105(R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-onHCID 117844096(R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneHCID 123994433Tert-butyl 1'-methyl-2'-oxo-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3'-indoline]-1-carboxylate

Product 1

HCID 117843026tert-butyl 6'-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1'-methyl-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

In a 5 mL microwave vial, a mixture of (R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one and (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 2.71 (50 mg, 0.14 mmol), tert-butyl 1′-methyl-2′-oxo-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indoline]-1-carboxylate 7.59 (68 mg, 0.16 mmol), cesium carbonate (140 mg, 0.43 mmol), and PEPPSI-IPr catalyst (8.2 mg, 0.01 mmol) were taken up in dimethoxyethane (1.8 mL) and water (0.9 mL). After evacuating and backfilling with argon, mixture was heated at 100° C. for 90 minutes in a microwave reactor. After cooling to rt, reaction mixture was poured into water and extracted with ethyl acetate. Combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-10% methanol/dichloromethane) to yield tert-butyl 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methyl-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 3.84 (53 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H37N6O5: 573.27; found: 573.27.

Workup

  1. customAfter evacuating
  2. temperatureAfter cooling to rt
  3. customreaction mixture
  4. extractionextracted with ethyl acetate
  5. dry with materialCombined organics were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe resulting residue was purified via silica gel column chromatography (0-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-25c4703630864785b7fdbb0bc2f6b0f9
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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