Triethylamine → Leniolisib

HRID 242341Notes

Reaction equation

HRID 242341 reaction equation
C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])(C)(C)C.[CH2:36](N(CC)CC)[CH3:37].C(Cl)(=O)CC>Cl>[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@H:10]4[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:36][CH3:37])[CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 62324Propionyl chlorideHCID 57495325(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester2×

Product 1

HCID 57495353LeniolisibYield 65%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (29.04 g, 58.73 mmol) in 2-Me-THF (100 mL) was dropwise added into aqueous HCl solution (150 mL, 31%) over 15 min. The reaction mixture was partitioned between water (300 mL) and isopropyl acetate (100 mL) and the upper organic phase was discarded. The aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL), and the organic phase was collected and dried. Triethylamine (16.32 mL, 117.48 mmol) was added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was washed with water (110 mL) and the resulting organic phase was concentrated in vacuo to give a brown gum. The residue was recrystallized with isopropanol and methyl tert-butyl ether to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (17.2 g, 65% yield).

Workup

  1. customThe reaction mixture was partitioned between water (300 mL) and isopropyl acetate (100 mL)
  2. customThe aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL)
  3. customthe organic phase was collected
  4. customdried
  5. washThe reaction mixture was washed with water (110 mL)
  6. concentrationthe resulting organic phase was concentrated in vacuo
  7. customto give a brown gum
  8. customThe residue was recrystallized with isopropanol and methyl tert-butyl ether

Sources & evidence

ORD record
ord-cef9c3e32d5947b1a92f1960fb9a4062
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

Loading…