Ethyl Acetate → (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate

HRID 1400755Notes

Reaction equation

HRID 1400755 reaction equation
[CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 86670277(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole tolueneHCID 86710812Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate

Product 1

HCID 86710814(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetateYield 77.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
-35 °C

Procedure

To a stirred yellow solution of ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (22 g, 40.6 mmol) in anhydrous toluene (800 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (16.25 mL, 16.25 mmol). The mixture was cooled to −35° C. and catechoborane (7.11 mL, 56.9 mmol) was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. A this point LCMS indicated approx 60% conversion, so mixture was cooled to −35° C. and 3.5 mL of catechoborane was added and stirred at −15° C. for 2 h. At his point LCMS indicates completion of reaction. Mixture was then dluted with EtOAc (1 L) and sat. Na2CO3 (300 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×200 mL) each time vigorously stirring for 30 min, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (17 g, 31.3 mmol, 77% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.19-8.10 (m, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.58-7.52 (m, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.86-6.82 (m, 1H), 6.10 (dd, J=10.8, 5.1 Hz, 1H), 5.57 (d, J=5.2 Hz, 1H), 5.48 (d, J=16.9 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.35 (dq, J=10.8, 7.2 Hz, 1H), 4.23 (dq, J=10.7, 7.1 Hz, 1H), 4.03 (dt, J=5.2, 1.5 Hz, 2H), 2.65 (s, 3H), 2.00 (d, J=14.5 Hz, 2H), 1.84 (br. s., 2H), 1.36 (s, 3H), 1.29-1.24 (m, 3H). LCMS (M+H)=543.4.

Workup

  1. additioncatechoborane (7.11 mL, 56.9 mmol) was added over 5 min
  2. temperaturethe reaction mixture was slowly warmed to −15° C.
  3. temperatureso mixture was cooled to −35° C.
  4. addition3.5 mL of catechoborane was added
  5. stirringstirred at −15° C. for 2 h
  6. customcompletion of reaction
  7. stirringThe mixture was stirred vigorously for 30 min
  8. washthe organic phase washed
  9. stirringvigorously stirring for 30 min
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customthe residue was purified by silica gel chromatography (5-70% EtOAc/hexane)

Sources & evidence

ORD record
ord-c150133efa884c08b0e4fb8e63ba9a19
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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