Sodium hydride → (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene

HRID 1503949Notes

Reaction equation

HRID 1503949 reaction equation
[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14](Cl)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:24]1([C@H:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[H-].[Na+]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:36][CH:33]4[CH2:32][CH2:31][CH:30]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH2:35][CH2:34]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 86695093(R)-5-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-4-chloro-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-D]pyrimidine2×HCID 178521573HCID 178521573, compound

Product 1

HCID 86695110(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraeneYield 87%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

For the preparation of the starting material 25.1, see Example 25. Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (528 mg, 2.85 mmol, 1.50 equiv) in freshly distilled THF (30 mL) was added sodium hydride (304 mg, 7.60 mmol, 4.01 equiv, 60% dispersion in mineral oil) portionwise at 0° C. under nitrogen. The resulting mixture was stirred for 30 min in a water/ice bath. Then a solution of (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (700 mg, 1.90 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the resulting solution was allowed to react, with stirring, for an additional 4 hr at 55° C. in an oil bath. After completion, the reaction was quenched by the addition of 20 mL of saturated aqueous NH4Cl and extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:0) to afford the desired (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (850 mg, 87%) as a colorless oil. MS (ES): m/z 518 [M+H]+.

Workup

  1. customInto a 100-mL round-bottom flask purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. customto react
  4. stirringwith stirring, for an additional 4 hr at 55° C. in an oil bath
  5. customAfter completion, the reaction was quenched by the addition of 20 mL of saturated aqueous NH4Cl
  6. extractionextracted with 3×80 mL of ethyl acetate
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated under vacuum
  10. customThe residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:0)

Sources & evidence

ORD record
ord-a4e55fde85b7445d8c4b54221c17c8c8
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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