Diphosgene → Formate

HRID 2279932Notes

Reaction equation

HRID 2279932 reaction equation
[Cl:1][C:2]1[CH:3]=[N+:4]([O-:38])[CH:5]=[C:6]([Cl:37])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[O:39]=[C:40](Cl)[O:41][C:42](Cl)(Cl)Cl.[CH:47]([N:50]([CH:53](C)C)[CH2:51]C)(C)[CH3:48].CN1CC[C@@H](O)C1>C(#N)C>[CH:21]([OH:22])=[O:20].[Cl:1][C:2]1[CH:3]=[N+:4]([O-:38])[CH:5]=[C:6]([Cl:37])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][N:29]([C:40]([O:41][C@@H:42]2[CH2:48][CH2:47][N:50]([CH3:53])[CH2:51]2)=[O:39])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH:21]([O-:22])=[O:20]

Participants

7

Reactant 4

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 69513321-Methyl-3-pyrrolidinol, (-)-HCID 130473159HCID 130473159, compound

Product 2

HCID 283FormateYield 696.9%HCID 131733495HCID 131733495, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

A solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoroanilino)methyl]thiophene-2-carboxylate (177 mg, 0.306 mmol) in acetonitrile (6 mL) was added with diphosgene (75 μL, 0.61 mmol) and the reaction mixture was stirred at room temperature for 5 minutes. After which time, a solution of diisopropylethylamine (341 μl, 2.0 mmol) and (R)-1-methylpyrrolidin-3-ol (220 μl, 2.0 mmol) in acetonitrile (3 mL) was added over 10 minutes. The brown mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The crude product was dissolved in chloroform (70 mL) and the organic layer was washed with HCl 1M (50 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude material was purified by flash chromatography (on a reverse phase C18 60 g column). The collected fractions were evaporated under vacuum and the product was further purified by means of preparative HPLC (Fraction Lynx). The collected fractions were evaporated in vacuo at 45° C. The residue was treated with acetone and diethyl ether to give the title compound as a formate salt as a foam (32 mg, 15%).

Workup

  1. stirringThe brown mixture was stirred at room temperature for 1 h
  2. customthe solvent was removed in vacuo
  3. dissolutionThe crude product was dissolved in chloroform (70 mL)
  4. washthe organic layer was washed with HCl 1M (50 mL)
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. customevaporated under vacuum
  7. customThe crude material was purified by flash chromatography (on a reverse phase C18 60 g column)
  8. customThe collected fractions were evaporated under vacuum
  9. customthe product was further purified by means of preparative HPLC (Fraction Lynx)
  10. customThe collected fractions were evaporated in vacuo at 45° C
  11. additionThe residue was treated with acetone and diethyl ether

Sources & evidence

ORD record
ord-914b3f0df82f4a99899720c3228dc452
Source dataset
uspto-grants-2015_09
Patent number
US09133185B2

Reaction notes

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