Hydrochloric Acid → HCID 178463541, compound

HRID 1192523Notes

Reaction equation

HRID 1192523 reaction equation
[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2.Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.C(N(CC)C(C)C)(C)C.Cl.O>C(O)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH:14][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 962WaterHCID 81531DiisopropylethylamineHCID 58368472HCID 58368472, compoundHCID 583686166-Bromo-9-(tetrahydro-2H-pyran-2-YL)-9H-purine

Product 1

HCID 178463541HCID 178463541, compoundYield 62%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 887MethanolSolvent

Conditions

Temperature
20 °C

Procedure

A solution of the single enantiomer of 1-[5-chloro-8-(3-fluorophenyl)cinnolin-7-yl]ethanamine (0.52 g, 1.7 mmol) from Step B, 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.73 g, 2.6 mmol), and N,N-diisopropylethylamine (0.90 mL, 5.1 mmol) in ethanol (9 mL) was heated at 90° C. for 21 hours. The reaction mixture was concentrated to give the crude THP-purine intermediate which was used without further purification. A solution of this material in methanol (10 mL) was treated with 1 M hydrogen chloride in water (15 mL, 15 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was concentrated and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/minute). The pure fractions were neutralized with ammonium hydroxide to pH˜7 and concentrated to remove all of the acetonitrile and most of the water. The solid that precipitated was filtered, washed with water, and dried to give the desired product (0.44 g, 62%). % ee>99.9. LCMS for C21H16ClFN7 (M+H)+: m/z=420.1; Found: 419.9. 1H NMR (300 MHz, DMSO-d6): δ 12.9 (br s, 1 H), 9.47 (d, J=5.9 Hz, 1 H), 8.50-8.38 (m, 2H), 8.26 (d, J=5.9 Hz, 1 H), 8.14 (br s, 1 H), 8.06 (d, J=10.8 Hz, 1 H), 7.64-7.52 (m, 2H), 7.37-7.22 (m, 2H), 5.36 (br s, 1H), 1.48 (d, J=6.7 Hz, 3H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customto give the crude THP-purine intermediate which
  3. customwas used without further purification
  4. concentrationThe reaction mixture was concentrated
  5. custompurified by RP-HPLC (XBridge C18 column
  6. washeluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/minute)
  7. concentrationconcentrated
  8. customto remove all of the acetonitrile
  9. customThe solid that precipitated
  10. filtrationwas filtered
  11. washwashed with water
  12. customdried

Sources & evidence

ORD record
ord-44e8adeed382463c8f1d8acd12b30e20
Source dataset
uspto-grants-2014_03
Patent number
US08680108B2

Reaction notes

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