Water → HCID 118436696, compound

HRID 1775483Notes

Reaction equation

HRID 1775483 reaction equation
Cl.[CH3:2][C@:3]1([N:8]2[C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36].O>C(Cl)Cl>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([C:16]2[C:11]3[CH2:10][CH2:9][N:8]([C@@:3]4([CH3:2])[CH2:7][CH2:6][N:5]([CH:31]5[CH2:35][CH2:34][NH:33][C:32]5=[O:36])[CH2:4]4)[C:12]=3[N:13]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:22][N:21]=1

Participants

5

Reactant 3

HCID 962WaterHCID 101034713-Bromopyrrolidin-2-oneHCID 118436187HCID 118436187, compound

Product 1

HCID 118436696HCID 118436696, compoundYield 48%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of the product of Example 4, Step 2, 5-{7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine hydrochloride (320 mg, 0.764 mmol) and TEA (232 mg, 2.29 mmol) in DCM (16 mL) was added 3-bromo-pyrrolidin-2-one (188 mg, 1.15 mmol) at 25° C. The mixture was stirred at 40° C. for 3 days, whereupon water (10 mL) was added. The mixture was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated to give a crude product (400 mg) as a yellow solid. The residue was purified by preparative TLC (silica gel, 10:1 DCM/MeOH) to give the racemic title compound (170 mg, 48%) as a yellow solid. This material was separated by preparative SFC column (AS, 250 mm×30 mm, 10 μm), mobile phase: 45% MeOH and NH3 in H2O, with a flowrate of 80 mL/min) to give the title compounds: Enantiomer 1 (Example 6), retention time 6.23 min (50 mg, 29%) as a yellow solid and enantiomer 2, retention time 6.21 min (19 mg) as a yellow solid. Enantiomer 1: SFC Retention time: 6.23 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.76-3.68 (m, 10 H), 3.43-3.33 (m, 5 H), 3.14-3.12 (m, 2 H), 3.05-3.00 (m, 1 H), 2.89-2.85 (m, 1 H), 2.56-2.53 (m, 1 H), 2.35-2.30 (m, 1 H), 2.14-2.10 (m, 1H), 2.00-1.95 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+. Enantiomer 2 (Example 7): SFC Retention time 6.21 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.82-3.68 (m, 12 H), 3.46-3.40 (m, 1 H), 3.36-3.33 (m, 1 H), 3.14-3.10 (m, 3 H), 3.03-3.00 (m, 1 H), 2.95-2.90 (m, 1 H), 2.54-2.51 (m, 1 H), 2.40-2.35 (m, 1 H), 2.14-2.11 (m, 1 H), 2.04-2.02 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+.

Workup

  1. additionwas added
  2. extractionThe mixture was extracted with DCM (20 mL×3)
  3. washThe combined organic layers were washed with brine (20 mL×3)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give a crude product (400 mg) as a yellow solid
  8. customThe residue was purified by preparative TLC (silica gel, 10:1 DCM/MeOH)

Sources & evidence

ORD record
ord-214f2a95683b417db7a5d51c2912bdff
Source dataset
uspto-grants-2016_02
Patent number
US09260439B2

Reaction notes

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