Methyl chloroformate → HCID 58169881, compound

HRID 384024Notes

Reaction equation

HRID 384024 reaction equation
[F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[C:24](=[O:36])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:61]([O:63][CH3:64])=[O:62].[NH4+].[Cl-]>O1CCCC1.O.C(Cl)Cl>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[C:24](=[O:36])[CH:23]([C:61]([O:63][CH3:64])=[O:62])[CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1

Participants

8

Reactant 4

HCID 6586Methyl chloroformateHCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 58169880HCID 58169880, compound2×

Product 1

HCID 58169881HCID 58169881, compoundYield 90.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of phenylmethyl(5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-1-carboxylate (Intermediate 33, 85 mg) in Tetrahydrofuran (THF) (2 ml), at −78° C., LiHMDS (0.257 ml, 0.257 mmol) was added and left stirring at this temperature for 1 hr. methyl chloroformate (0.019 ml, 0.245 mmol) was added at the same temperature and the reaction was left at this temperature for 2 hrs. To the solution was added NH4Cl saturated solution, followed by DCM and water. The two phases were separated and the aqueous one was extracted with DCM. The combined organic layers were filtered through a phase separator tube and the solvent was removed in vacuo obtaining the title compound (83 mg) as a white foam. This batch was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (s, 1H) 7.67 (s, 2H) 7.24-7.48 (m, 5H) 6.85-7.00 (m, 2H) 6.70-6.84 (m, 1H) 5.09-5.29 (m, 3H) 4.34 (d, 1 H) 3.99 (t, 1H) 3.70 (s, 3H) 2.65 (s, 3H) 2.58-3.44 (m, 2H) 2.34 (s, 3H) 1.54-2.45 (m, 6H) 1.47 (d, 3H); Mixture of two diastereoisomers ratio ˜50:50 (for example visible on the signal of CH(6) see annotation in the spectrum). The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.

Workup

  1. waitleft
  2. waitthe reaction was left at this temperature for 2 hrs
  3. customThe two phases were separated
  4. extractionthe aqueous one was extracted with DCM
  5. filtrationThe combined organic layers were filtered through a phase separator tube
  6. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-0957c42e832f40bd972730cee3c4fc94
Source dataset
uspto-grants-2013_02
Patent number
US08367692B2

Reaction notes

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