Water → HCID 71258382, compound

HRID 1468746Notes

Reaction equation

HRID 1468746 reaction equation
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:39])=[C:33]2[C:38]=1[O:37][CH2:36][CH2:35][CH2:34]2.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:31]1[C:32]([CH3:39])=[C:33]2[C:38](=[C:29]([F:28])[CH:30]=1)[O:37][CH2:36][CH2:35][CH2:34]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 596067662-(8-Fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 86691589HCID 86691589, compound

Product 1

HCID 71258382HCID 71258382, compoundYield 82.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 9.20 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.22 g, 11.04 mmol) and 2N Na2CO3 (9.20 mL, 18.39 mmol) in DMF (100 mL) was degassed and flushed with N2 for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.744 g, 0.644 mmol) was then added and the reaction was flushed with N2 for another 15 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and appearance of desired product. After cooling to rt, water was added (50 mL) and the mixture was extracted with ether (2×200 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was then purified by silica gel chromatography (5-60% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 7.58 mmol, 82% yield) as mixture of atrope isomers (approx 10% of minor atrope isomer was present). 1H NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.87 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.41 (qd, J=7.1, 3.1 Hz, 2H), 4.35 (dd, J=5.2, 4.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.80 (s, 3H), 2.79-2.73 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.22-1.19 (m, 4H), 1.18 (s, 9H). LCMS (M+H)=528.4.

Workup

  1. customwas degassed
  2. customflushed with N2 for 30 min
  3. customthe reaction was flushed with N2 for another 15 min
  4. customcompletion of reaction and appearance of desired product
  5. temperatureAfter cooling to rt
  6. extractionthe mixture was extracted with ether (2×200 mL)
  7. washThe organic phase was washed with brine (100 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was then purified by silica gel chromatography (5-60% EtOAc/hexane)

Sources & evidence

ORD record
ord-ece47feb141e48a8b7d340195a0c2651
Source dataset
uspto-grants-2015_04
Patent number
US09006235B2

Reaction notes

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