Stannane, tributyl(1-ethoxyethenyl)- → Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 2368969Notes

Reaction equation

HRID 2368969 reaction equation
[CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:60]([O:62][CH2:63][CH3:64])=[CH2:61])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:60]([O:62][CH2:63][CH3:64])=[CH2:61]

Participants

5

Reactant 2

HCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 67295256Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Product 1

HCID 66584950Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of compound tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (834 mg, 0.49 mmol), tributyl(1-ethoxyvinyl)tin (356 mg, 0.98 mmol), tetrakis(triphenylphosphine)palladium (56.9 mg, 0.049 mmol) in dioxane (6 mL) was degassed with argon for five minutes. It was then heated at 100° C. in a sealed tube for 16 h, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, the solvent was rotoevaporated, and the crude residue was redissolved in EtOAc, washed with 0.5 M KF solution, brine (1×25 mL), and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. The enol ether was then treated with 20% TFA/CH2Cl2 (10 mL) for 2 h at room temperature. Concentration afforded 5-(8-azabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one as an TFA salt. LCMS tR=0.67 Min (5 min run, UV254nm). Mass calculated for, M+ 450.2, observed LC/MS m/z 451.0 (M+H).

Workup

  1. customwas degassed with argon for five minutes
  2. customconsumption of starting material
  3. temperatureOn cooling
  4. dissolutionthe crude residue was redissolved in EtOAc
  5. washwashed with 0.5 M KF solution, brine (1×25 mL)
  6. dry with materialdried over MgSO4
  7. customThe solvent was removed in vacuo
  8. customthe residue was purified by column chromatography on silica gel
  9. washElution with EtOAc/Hexanes

Sources & evidence

ORD record
ord-aebc52fb71694ec2849e59631bf403b9
Source dataset
uspto-grants-2014_04
Patent number
US08703784B2

Reaction notes

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