Methyl iodide → 3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-(R)-methoxy-1-(R)-methyl propoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

HRID 990238

Reaction equation

HRID 990238 reaction equation
[CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].CI.[CH3:11]N1CCCN(C)C1=O.C(O[C:23]1[C:28]([C:29]2[NH:30][C:31](=[O:41])[C:32]3[C:33](=[C:35]([CH2:39][CH3:40])[N:36]([CH3:38])[N:37]=3)[N:34]=2)=[CH:27][C:26]([S:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)(=[O:44])=[O:43])=[CH:25][N:24]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CCOCC>[CH2:39]([C:35]1[N:36]([CH3:38])[N:37]=[C:32]2[C:31](=[O:41])[NH:30][C:29]([C:28]3[C:23]([O:5][C@H:3]([CH3:4])[C@H:2]([O:6][CH3:11])[CH3:1])=[N:24][CH:25]=[C:26]([S:42]([N:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH3:52])[CH2:49][CH2:50]4)(=[O:44])=[O:43])[CH:27]=3)=[N:34][C:33]=12)[CH3:40]

Participants

8

Reactant 6

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 225936(2R,3R)-ButanediolHCID 3251421Potassium bis(trimethylsilyl)amideHCID 1358163675-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-methyl-2,6-dihydro-7h-pyrazolo[4,3-d]pyrimidin-7-one

Product 1

HCID 1360364713-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-(R)-methoxy-1-(R)-methyl propoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneYield 6.6%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

(R,R)-2,3 butanediol (7.78 ml, 85 mmol) was added dropwise to an ice-cold solution of sodium hydride (3.74 g, 60% dispersion in mineral oil, 93.5 mmol) in ether (800 ml), and the solution stirred at room temperature for 30 minutes. Methyl iodide (5.6 ml, 89.3 mmol) was added dropwise and the reaction stirred under reflux for 48 hours. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10.24 ml, 85 mmol) was added and stirring continued for a further 90 minutes under reflux. The cooled reaction was washed with aqueous ammonium chloride solution (500 ml), dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ether:pentane (10:90 to 50:50) to give a pale yellow oil. The title compound of Example 78 (100 mg, 0.2 mmol) and potassium bis(trimethylsilyl)amide (121 mg, 0.61 mmol) in the intermediate alcohol (1 ml), was heated at 110° C. for 30 hours, then the reaction cooled and concentrated under reduced pressure. The residual brown solid was purified by column chromatography on silica gel using diethylamine:ethyl acetate (5:95) as eluant, and repeated using methanol:ethyl acetate (5:95) as eluant. The product was triturated with ether to afford the title compound (7 mg, 6%) as a white solid.

Workup

  1. stirringthe reaction stirred
  2. temperatureunder reflux for 48 hours
  3. stirringstirring
  4. waitcontinued for a further 90 minutes
  5. temperatureunder reflux
  6. customThe cooled reaction
  7. washwas washed with aqueous ammonium chloride solution (500 ml)
  8. dry with materialdried (MgSO4)
  9. customevaporated under reduced pressure
  10. customThe residual oil was purified by column chromatography on silica gel using an elution gradient of ether:pentane (10:90 to 50:50)
  11. customto give a pale yellow oil
  12. temperaturethe reaction cooled
  13. concentrationconcentrated under reduced pressure
  14. customThe residual brown solid was purified by column chromatography on silica gel
  15. customThe product was triturated with ether

Sources & evidence

ORD record
ord-0f071340f5524c798d9955a64e78ae89
Source dataset
uspto-grants-2002_10
Patent number
US06458951B2

Linked notes

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