Diisopropylethylamine → HCID 57868858, compound

HRID 1692979Notes

Reaction equation

HRID 1692979 reaction equation
[CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([S:42]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[C:10]5[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=5[N:12]=[CH:13][N:14]=4)[CH:17]=[N:18]3)[CH2:24]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 2760919Cyclopropanesulfonyl chlorideHCID 578688552-(3-(4-(7-((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Product 1

HCID 57868858HCID 57868858, compoundYield 81.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
2.5 °C

Procedure

To a oven dried 2 L round bottom flask equipped with the overhead stirring, a nitrogen inlet, a septa and a thermocouple was charged anhydrous tetrahydrofuran (THF, 800 mL), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (16, 38.6 g, 94.2 mmol) and N, N-diisopropylethylamine (DIEA, 22.0 mL, 126 mmol, 1.34 equiv) at room temperature. The resulting solution was then cooled to 0-5° C. before being charged with cyclopropanesulfonyl chloride (14.3 mL, 134 mmol, 1.42 equiv) portion wise over eight minutes via syringe at 0-5° C. After 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm gradually to room temperature. When HPLC showed that the reaction was complete after 22 h, the reaction mixture was concentrated under reduced pressure to remove about 400 mL of solvent. The residue was treated with ethyl acetate (EtOAc, 500 mL) and the resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL). The aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to yield the crude product (25) as an amber oil. The crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution) to afford {1-(cyclopropylsulfonyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25, 39.4 g, 48.4 g theoretical, 81.4% yield) as a light yellow oil, which solidified upon standing at room temperature in vacuum. For 25: 1H NMR (DMSO-d6, 300 MHz) 6 8.98 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 4.66 (d, 2H, J=9.5 Hz), 4.28 (d, 2H, J=9.3 Hz), 3.69 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 2.84 (m, 1H), 1.01 (m, 4H), 0.82 (t, 2H, J=8.4 Hz), −0.12 (s, 9H) ppm; C23H31N7O3SSi (MW, 513.69), LCMS (EI) m/e 514 (M++H) and 536 (M++Na).

Workup

  1. customTo a oven dried 2 L round bottom flask
  2. customequipped with the overhead
  3. customthe ice bath was removed
  4. temperatureto warm gradually to room temperature
  5. waitwas complete after 22 h
  6. concentrationthe reaction mixture was concentrated under reduced pressure
  7. customto remove about 400 mL of solvent
  8. additionThe residue was treated with ethyl acetate (EtOAc, 500 mL)
  9. washthe resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL)
  10. extractionThe aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL)
  11. dry with materialThe combined organic fractions were dried over magnesium sulfate (MgSO4)
  12. concentrationconcentrated under reduced pressure
  13. customto yield the crude product (25) as an amber oil
  14. customThe crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution)

Sources & evidence

ORD record
ord-93653b5217ab4470869debd75808dcd7
Source dataset
uspto-grants-2012_04
Patent number
US08158616B2

Reaction notes

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