2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecane → Hydrochloric Acid

HRID 1811574Notes

Reaction equation

HRID 1811574 reaction equation
[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([Cl:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([Si](C)(C)[O:28][CH2:29][CH2:30][S:31][C:32]1[N:37]=[C:36]([CH3:38])[C:35]([NH2:39])=[CH:34][CH:33]=1)(C)(C)C.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:39][C:35]3[C:36]([CH3:38])=[N:37][C:32]([S:31][CH2:30][CH2:29][OH:28])=[CH:33][CH:34]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[ClH:22]

Participants

8

Reactant 4

HCID 45712432,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecaneHCID 23676156Sodium t-butoxideHCID 51050526Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylateHCID 586715776-[2-(Tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-pyridin-3-ylamine

Product 2

HCID 313Hydrochloric AcidHCID 247396354-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.00 g, 3.03 mmol), 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-pyridin-3-ylamine (0.85 g, 2.85 μmol), palladium acetate (0.0379 g, 0.169 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.120 mL, 0.338 mmol), and sodium 2-methylpropan-2-olate (0.437 g, 4.55 mmol) in 20 mL dioxane were heated at 80° C. for 14 h. Mixture was transferred into a separatory funnel and extracted with CH2Cl2 and brine. Organic phases were dried over MgSO4, filtered, and concentrated. To the residue, 4M HCl in dioxane (ca. 10 mL) was added and stirred at room temperature for 1 h. Mixture was purified by HPLC; fractions containing pure product were collected, ammonium hydroxide was added (ca 5 mL), and partly concentrated. Residue was extracted with 1M NaOH and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated to give 4-{6-[6-(2-hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester as a yellowish solid (HCl salt, 219 mg, 15%). 1HNMR (CDCl3, 400 MHz) δ 1.25-1.27 (d, J=6.3 Hz, 6H), 1.76-1.83 (m, 2H), 1.99-2.05 (m, 2H), 2.50 (s, 3H), 3.27-3.29 (m, 2H), 3.37-3.44 (m, 2H), 3.76-3.82 (m, 2H), 3.95 (s, 3H), 3.95-4.01 (m, 2H), 4.91-4.97 (m, 1H), 5.33-5.38 (m, 1H), 5.66-5.68 (m, 1H), 6.82 (s, 1H), 5.33-5.38 (m, 1H), 5.66-5.68 (m, 1H), 6.82 (s, 1H), 7.21-7.23 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 8.17-8.19 (d, J=8.5 Hz, 1H). Exact mass calculated for C22H31N5O5S 477.2 found 478.4 (MH+).

Workup

  1. customMixture was transferred into a separatory funnel
  2. extractionextracted with CH2Cl2 and brine
  3. dry with materialOrganic phases were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. additionTo the residue, 4M HCl in dioxane (ca. 10 mL) was added
  7. customMixture was purified by HPLC
  8. additionfractions containing pure product
  9. customwere collected
  10. additionammonium hydroxide was added (ca 5 mL)
  11. concentrationpartly concentrated
  12. extractionResidue was extracted with 1M NaOH and CH2Cl2
  13. dry with materialOrganic phases were dried over MgSO4
  14. filtrationfiltered
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-9e3c70e2fb884ecfa699028451a16ba4
Source dataset
uspto-grants-2013_01
Patent number
US08362248B2

Reaction notes

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