Cesium carbonate → (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea

HRID 588210Notes

Reaction equation

HRID 588210 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:40][C:41]([CH3:54])([CH3:53])[C@@H:42]([NH:49][C:50]([NH2:52])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[OH:40][C:41]([CH3:54])([CH3:53])[C@@H:42]([NH:49][C:50]([NH:52][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 92170521(S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)ureaHCID 118271763(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol

Product 1

HCID 118271727(S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)ureaYield 77.4%

Reagents, catalysts & solvents 2

HCID 25112666BrettPhos PalladacycleCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
95 °C

Procedure

(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 500 mg, 1.097 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(ii) (88 mg, 0.110 mmol), cesium carbonate (893 mg, 2.74 mmol) and (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)urea (21B, 343 mg, 1.645 mmol) were taken up in an oven dried 2 mL round bottom flask equipped with magnetic stir bar and degassed 3× under nitrogen. Anhydrous dioxane (8 ml) was added the reaction was degassed 3× under nitrogen and heated to 95° C. for 14 hours. The crude reaction mixture was diluted with 2 mL DCM and filtered a syringe filter. The filtrate was concentrated in vacuo and the residue was purified on silica gel, 5-50% EtOAc/DCM to provide (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (533 mg, 0.849 mmol, 77% yield). MS: [M+H]+ m/z 628.

Workup

  1. customdried 2 mL round bottom flask
  2. customequipped with magnetic stir bar
  3. customdegassed 3× under nitrogen
  4. additionAnhydrous dioxane (8 ml) was added the reaction
  5. customwas degassed 3× under nitrogen
  6. customThe crude reaction mixture
  7. filtrationfiltered a syringe
  8. filtrationfilter
  9. concentrationThe filtrate was concentrated in vacuo
  10. customthe residue was purified on silica gel, 5-50% EtOAc/DCM

Sources & evidence

ORD record
ord-0ce2f73ce2cb4bc5aebace1725f91906
Source dataset
uspto-grants-2016_01
Patent number
US09226922B2

Reaction notes

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