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Sodium hydride → 5-amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

HRID 2386679
Notes
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Reaction equation

HRID 2386679 reaction equation
[H-].[Na+].[C:3]([C:5]1[C:6]([NH:13][C:14](=[O:16])[CH3:15])=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1)#[N:4].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CS(C)=O>[NH2:4][C:3]1[C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24])[C:14](=[O:16])[CH:15]=1.[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][CH2:18][N:13]([C:6]1[C:5]([C:3]#[N:4])=[CH:10][N:9]=[C:8]([S:11][CH3:12])[N:7]=1)[C:14](=[O:16])[CH3:15])([CH3:28])([CH3:27])[CH3:26]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 24758Sodium hydride2×HCID 607486(3-Bromopropoxy)(tert-butyl)dimethylsilane2×HCID 57929456N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide

Product 2

HCID 579294635-amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-oneYield 22%
HCID 68996226
N-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
85 °C

Procedure

Sodium hydride (60% suspension in mineral oil, 468 mg) was added portionwise, at RT, under argon atmosphere, to a solution of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide (2.03 g, 9.75 mmol) in anhydrous DMSO (20 mL) and the resulting mixture was stirred at RT for 40 min. (3-Bromopropoxy)-tert-butyldimethylsilane (3.39 mL, 14.63 mmol) was then added dropwise over a period of 2 min at RT and the reaction mixture was stirred for 2 h. The resulting mixture was then heated at 85° C. for 2 h; a second portion of NaH (60% suspension in mineral oil, 78 mg) was then added and was followed after 30 min by (3-bromopropoxy)-tert-butyldimethylsilane (0.45 mL). The resulting mixture was heated at 85° C. for 1 h, cooled and quenched with water. The resulting mixture was extracted with EtOAc (3×50 mL); the combined organic layers were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 800 mg (22% yield) of 5-amino-8-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one and 600 mg of uncyclized N-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide which was converted in the title compound by treatment with lithium bis(trimethylsilyl)amide as described in Preparation 2 Step C.

Workup

  1. additionwas then added dropwise over a period of 2 min at RT
  2. temperatureThe resulting mixture was heated at 85° C. for 1 h
  3. temperaturecooled
  4. customquenched with water
  5. extractionThe resulting mixture was extracted with EtOAc (3×50 mL)
  6. washthe combined organic layers were washed with water
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated under reduced pressure
  10. customThe crude residue was purified by flash chromatography

Sources & evidence

ORD record
ord-61f46468eaac492f8c98ccfad16813d8
Source dataset
uspto-grants-2012_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08268840B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes