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2,6-Lutidine → 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid

HRID 1614917
Notes
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Reaction equation

HRID 1614917 reaction equation
[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH2:23][CH2:24][P:25]([O:28]CC)([CH3:27])=[O:26])[C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Si](I)(C)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH3:31][C:2]([CH3:1])([CH3:32])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH2:23][CH2:24][P:25]([OH:28])([CH3:27])=[O:26])[C:14]([CH:16]2[CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21]2)=[O:15])[CH:6]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 85247Trimethylsilyl iodideHCID 670359145-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid

Product 1

HCID 529173045-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acidYield 36.3%

Reagents, catalysts & solvents

1
HCID 6342AcetonitrileSolvent

Procedure

5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (108 mg, 0.225 mmol) was dissolved in acetonitrile (3 mL). This solution was cooled in an ice bath and TMSI (160 μL, 1.12 mmol) was added dropwise. The reaction turned yellow and some precipitate was formed. After approximately 1 minute 2,6-lutidine (156 μL, 1.35 mmol) was added, resulting in a clear solution. The ice bath was removed and the reaction was stirred at room temperature for 2 hours. Additional TMSI (50 μL) and 2,6-lutidine (50 μL) were added. After 45 minutes the reaction was determined by LC/MS to be complete. The reaction was cooled in an ice bath and additional 2,6-lutidine (100 μL) was added, followed by MeOH (2 mL). The reaction was warmed to room temperature and concentrated under vacuum. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (37 mg, 36%) was isolated from the residue by reverse phase HPLC. MS (m/z): 453.93 [M+H]+; 31P NMR (161.9 MHz, CD3OD): d 49.909.

Workup

  1. temperatureThis solution was cooled in an ice bath
  2. customsome precipitate was formed
  3. customresulting in a clear solution
  4. customThe ice bath was removed
  5. additionAdditional TMSI (50 μL) and 2,6-lutidine (50 μL) were added
  6. waitAfter 45 minutes the reaction was determined by LC/MS
  7. temperatureThe reaction was cooled in an ice bath
  8. additionadditional 2,6-lutidine (100 μL) was added
  9. temperatureThe reaction was warmed to room temperature
  10. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-f01d81f40cd04c93817e07b38ba35577
Source dataset
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08765722B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes