1-Chloroethyl chloroformate → (4-Isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride salt

HRID 73039

Reaction equation

HRID 73039 reaction equation
[Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:38][CH:37]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[N:40]=2)[O:36][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH3:35])[CH:26]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:16]1)C1C=CC=CC=1>ClCCCl>[ClH:1].[CH:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:17]3([O:36][CH:37]([C:39]4[O:43][N:42]=[C:41]([CH3:44])[N:40]=4)[CH2:38][NH:15][CH2:16]3)[CH2:18][CH2:19]2)=[O:24])=[CH:26][C:27]=1[CH3:35])([CH3:34])[CH3:33]

Participants

4

Reactant 2

HCID 5213051-Chloroethyl chloroformate3×HCID 66548173[8-Benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Product 1

HCID 68292455(4-Isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride saltYield 47.8%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Procedure

A solution of 1-chloroethyl chloroformate (89 μL, 0.80 mmol) in DCE (0.1 mL) was added to a stirred solution of [8-benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (67 mg, 0.13 mmol) in DCE (488 μL) under an atmosphere of nitrogen and the reaction mixture was heated to reflux. After 1 hour, an additional aliquot of 1-chloroethyl chloroformate (89 μL, 0.80 mmol) was added and the reaction mixture was heated to reflux for a further 8 hours. After 8 hours, an additional 1-chloroethyl chloroformate (89 μL, 0.80 mmol) was added and the reaction mixture was heated to reflux for a further 15 hours. The excess solvent was removed under reduced pressure and the carbamate intermediate was dissolved in MeOH (2 mL) and heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, filtered and purified by Waters mass directed LC/MS-HPLC: (10-99% ACN/H2O (5 mM HCl)) to afford (4-isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride salt (28 mg, 47%). ESI-MS m/z calc. 414.2. Found 415.7 (M+1)+; Retention time: 1.54 minutes (3 min run).

Workup

  1. temperaturethe reaction mixture was heated to reflux
  2. temperaturethe reaction mixture was heated
  3. temperatureto reflux for a further 8 hours
  4. waitAfter 8 hours
  5. temperaturethe reaction mixture was heated
  6. temperatureto reflux for a further 15 hours
  7. customThe excess solvent was removed under reduced pressure
  8. dissolutionthe carbamate intermediate was dissolved in MeOH (2 mL)
  9. temperatureheated
  10. temperatureat reflux for 1 hour
  11. filtrationfiltered
  12. custompurified by Waters mass

Sources & evidence

ORD record
ord-47b3fdcbccb14cc7bd064f82d2950e69
Source dataset
uspto-grants-2014_09
Patent number
US08828996B2

Linked notes

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