Diisopropylethylamine → HCID 90220161, compound

HRID 2199781Notes

Reaction equation

HRID 2199781 reaction equation
FC1C(O[C:9](=[O:31])[NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[S:18][C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[C:20]([C:22]#[N:23])[N:21]=3)[CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH2:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][NH:37]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:22]([C:20]1[N:21]=[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:9]([N:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:36]3)=[O:31])[CH2:12]2)[S:18][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[N:23]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 422478IsoindolineHCID 118556246HCID 118556246, compound

Product 1

HCID 90220161HCID 90220161, compoundYield 50.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of crude {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid pentafluorophenyl ester (˜50 μmol) in tetrahydrofuran (1 mL) was cooled to 0° C. under an atmosphere of argon and isoindoline (12.6 mg, 106 μmol) and diisopropylethylamine (20 μL, 115 μmol) were added. The reaction mixture was stirred at 0° C. for 1 hour then warmed to ambient temperature and stirred for an additional hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL), poured into water (10 mL) and extracted with ethyl acetate (4×5 mL). The combined organic extracts were washed with brine (2×5 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography using a 12 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo to a yellow solid. The yellow solid was taken up in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a yellow viscous oil (11.3 mg, 50%).

Workup

  1. temperaturethen warmed to ambient temperature
  2. stirringstirred for an additional hour
  3. customThe reaction was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL)
  4. additionpoured into water (10 mL)
  5. extractionextracted with ethyl acetate (4×5 mL)
  6. washThe combined organic extracts were washed with brine (2×5 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by reverse phase chromatography
  11. washeluted from 10% acetonitrile in water up to 100% acetonitrile
  12. additionThe product containing fractions
  13. concentrationconcentrated in vacuo to a yellow solid
  14. dry with materialdried over sodium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-20f0b056470147c7b9589768b8ed59ca
Source dataset
uspto-grants-2016_06
Patent number
US09359345B2

Reaction notes

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