Diisopropylethylamine → HCID 178463182, compound

HRID 1014956Notes

Reaction equation

HRID 1014956 reaction equation
[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=[O:3])[CH3:2].[Cl:46][C:47]1[N:55]=[C:54]2[C:50]([N:51]=[CH:52][N:53]2[CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)=[C:49](Cl)[N:48]=1.C(N(CC)C(C)C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:49]2[N:48]=[C:47]([Cl:46])[N:55]=[C:54]3[C:50]=2[N:51]=[CH:52][N:53]3[CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 2702652,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 178463187HCID 178463187, compound2×

Product 1

HCID 178463182HCID 178463182, compound

Reagents, catalysts & solvents 1

HCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Conditions

Temperature
60 °C

Procedure

(2R,3R,4R,5R)-2-(2-Chloro-6-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 1) (5.2 mmol) was treated with 1:1 trifluoroacetic acid/dichloromethane (20 ml) for ca. 2 h. This was concentrated in vacuo and the residue was purified by SPE (SCX, 50 g), eluting sequentially with dichloromethane, methanol, 40% (2M ammonia in methanol): dichloromethane and 2M ammonia in methanol. The appropriate fraction was concentrated in vacuo and suspended in propan-2-ol (60 ml). To this was added N,N-diisopropylethylamine (4 m. eq.) and 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (prepared according to the method disclosed in WO2003080604A1) (1 m. eq.) and this was heated at 60° C. overnight. After cooling to room temperature, further 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.5 m. eq.) and N,N-diisopropylethylamine (4 ml) were added and this was heated at 60° C. for a further ca. 5 h. After cooling to room temperature, the reaction mixture was then concentrated in vacuo and the residue was partitioned between dichloromethane (ca. 60 ml) and water (ca. 60 ml). The organics were washed with water (ca. 60 ml), dried over magnesium sulfate and concentrated in vacuo to yield the title compound as an off-white crystalline solid, 4 g.

Workup

  1. concentrationThis was concentrated in vacuo
  2. customthe residue was purified by SPE (SCX, 50 g)
  3. washeluting sequentially with dichloromethane, methanol, 40% (2M ammonia in methanol)
  4. concentrationThe appropriate fraction was concentrated in vacuo
  5. additionTo this was added N,N-diisopropylethylamine (4 m. eq.) and 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (
  6. customprepared
  7. temperatureAfter cooling to room temperature
  8. temperaturethis was heated at 60° C. for a further ca. 5 h
  9. temperatureAfter cooling to room temperature
  10. concentrationthe reaction mixture was then concentrated in vacuo
  11. customthe residue was partitioned between dichloromethane (ca. 60 ml) and water (ca. 60 ml)
  12. washThe organics were washed with water (ca. 60 ml)
  13. dry with materialdried over magnesium sulfate
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-ab18236349c046bbb8844e3dbe231cfb
Source dataset
uspto-grants-2011_07
Patent number
US07985740B2

Reaction notes

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