Acetyl chloride → HCID 178473782, compound

HRID 1021327Notes

Reaction equation

HRID 1021327 reaction equation
[Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[C:27](Cl)(=[O:29])[CH3:28].C1N=CN([C:36]([N:38]2[CH:42]=[N:41]C=C2)=[O:37])C=1.C(=O)(O)O.[NH2:47]C(N)=N.[C:51]([OH:60])(=[O:59])[C@@H:52]([C@H:54]([C:56]([OH:58])=[O:57])[OH:55])[OH:53]>CCO.CN(C=O)C.C(Cl)(Cl)Cl.ClCCl>[C:56]([C@@H:54]([C@H:52]([C:51]([OH:60])=[O:59])[OH:53])[OH:55])([OH:58])=[O:57].[C:42]([NH:38][C:36](=[O:37])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:17][CH:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:27](=[O:29])[CH3:28])[CH2:24][CH2:25]3)[CH2:19]2)[C:11]=1[F:26])(=[NH:41])[NH2:47]

Participants

10

Reactant 5

HCID 6367Acetyl chlorideHCID 682631,1'-CarbonyldiimidazoleHCID 286947Carbonic acid-guanidine (1:1)HCID 444305L-Tartaric acidHCID 86686244HCID 86686244, compound

Product 1

HCID 178473782HCID 178473782, compoundYield 84.9%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6212ChloroformSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (70 mg) and TEA (73 mg) were mixed with dichloromethane (2 ml), and acetyl chloride (22 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHCl3 and a 1 M aqueous NaOH solution, the organic layer was dried over Na2SO4, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (2 ml), and a 1 M TBAF/THF solution (0.3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHCl3 and a saturated aqueous ammonium chloride solution, and the organic layer was dried over Na2SO4. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DMF, and CDI (65 mg) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (140 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with EtOH (1 ml), and L-tartaric acid (16 mg) was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain 3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate L-tartrate (49 mg).

Workup

  1. additionwas added
  2. dry with materiala 1 M aqueous NaOH solution, the organic layer was dried over Na2SO4
  3. concentrationthe organic layer was concentrated under reduced pressure
  4. additionThe obtained residue was mixed with THF (2 ml)
  5. additiona 1 M TBAF/THF solution (0.3 ml) was added
  6. stirringby stirring at room temperature for 1 hour
  7. additionTo the reaction mixture were added CHCl3
  8. dry with materiala saturated aqueous ammonium chloride solution, and the organic layer was dried over Na2SO4
  9. concentrationThe reaction mixture was concentrated under reduced pressure
  10. customThe obtained residue was purified by silica gel column chromatography (CHCl3/MeOH)
  11. customThe purified product thus obtained
  12. additionwas added
  13. stirringby stirring at room temperature for 3 hours
  14. stirringby stirring at room temperature for 1 hour
  15. concentrationThe reaction mixture was concentrated under reduced pressure, water
  16. additionwas added
  17. filtrationthe insoluble matter was collected by filtration
  18. customThe obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH)
  19. customThe purified product thus obtained
  20. additionwas added
  21. stirringby stirring at room temperature for 1 hour
  22. filtrationThe precipitated solid was collected by filtration

Sources & evidence

ORD record
ord-27748371006c432ab7c0b25aae2b6b5f
Source dataset
uspto-grants-2014_05
Patent number
US08716470B2

Reaction notes

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