Dichloromethane → Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 589160Notes

Reaction equation

HRID 589160 reaction equation
[F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:24][Si:25]([CH3:71])([CH3:70])[CH2:26][CH2:27][O:28][CH2:29][N:30]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:69])([CH3:68])[CH3:67])[C:31]1[N:36]2[N:37]=[CH:38][C:39]([C:40]3[CH:41]=[N:42][C:43](Cl)=[CH:44][CH:45]=3)=[C:35]2[N:34]=[C:33]([CH:47]2[CH2:53][CH:52]3[N:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH:49]([CH2:50][CH2:51]3)[CH2:48]2)[CH:32]=1>O1CCOCC1.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]>[CH3:69][Si:66]([CH3:67])([CH3:68])[CH2:65][CH2:64][O:63][CH2:62][N:30]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:24])([CH3:71])[CH3:70])[C:31]1[N:36]2[N:37]=[CH:38][C:39]([C:40]3[CH:41]=[N:42][C:43]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=4)=[CH:44][CH:45]=3)=[C:35]2[N:34]=[C:33]([CH:47]2[CH2:53][CH:52]3[N:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH:49]([CH2:50][CH2:51]3)[CH2:48]2)[CH:32]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 62657Potassium Phosphate, TribasicHCID 27821943-Fluoro-4-methoxyphenylboronic acidHCID 86674906Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Product 1

HCID 66584726Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

3-Fluoro-4-methoxyphenylboronic acid (2.79 mmol, 475.7 mg), K3PO4 (4.20 mmol, 890.4 mg), and PdCl2(dppf).CH2Cl2 (0.14 mmol, 114.3 mg) were added to a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.40 mmol, 1000 mg) in dioxane (12 mL) and H2O (1.5 mL). The resulting solution was stirred at 150° C. under microwave condition for 1 h. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=3.31 Min (5 min run, UV254nm) Mass calculated for, M+H 805.42, observed LC/MS m/z 805.17 (M+H).

Workup

  1. extractionextracted with ethyl acetate (×2)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried with Na2SO4
  4. customEvaporation and purification by column chromatography

Sources & evidence

ORD record
ord-c0d427cd7b454114b400c367c0638cd8
Source dataset
uspto-grants-2016_01
Patent number
US09227971B2

Reaction notes

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