Hydrochloric Acid → HCID 44612367, compound

HRID 655583Notes

Reaction equation

HRID 655583 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]([CH2:26][O:27][CH3:28])[CH2:15][CH2:16][N:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[C@H:19]([OH:25])[CH2:18]2)[C:10](=[O:29])[C@@H:9]1[CH3:30])=[O:7])(C)(C)C.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]=C=O)[CH:36]=[CH:37][C:38]=1[F:39]>O1CCOCC1>[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]([CH2:26][O:27][CH3:28])[CH2:15][CH2:16][N:17]3[CH2:24][CH2:23][C:20]4([CH2:22][CH2:21]4)[C@H:19]([OH:25])[CH2:18]3)[C:10](=[O:29])[C@@H:9]2[CH3:30])=[O:7])[CH:36]=[CH:37][C:38]=1[F:39]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 27346323-Chloro-4-fluorophenyl isocyanateHCID 68538825HCID 68538825, compound2×

Product 1

HCID 44612367HCID 44612367, compoundYield 95.1%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (intermediate 23; 47 mg, 0.11 mmol) in 1,4-dioxane (0.5 mL) was cooled to 0° C. and treated with hydrogen chloride solution (4 M in 1,4-dioxane, 0.28 mL, 1.1 mmol) The ice bath was removed, the reaction mixture stirred for 4 h, then 4-methylmorpholine (112 mg, 1.1 l mmol) and N,N-dimethylformamide (1 mL) were added. To this reaction mixture was added 3-chloro-4-fluorophenyl isocyanate (19 mg 0.11 mmol), then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution gradient 98:2:0.25 to 90:10:0.25) furnished the title compound (52 mg, 95%). Light yellow gum, MS (ISP)=497.3 (M+H)+.

Workup

  1. customwas removed
  2. addition4-methylmorpholine (112 mg, 1.1 l mmol) and N,N-dimethylformamide (1 mL) were added
  3. customafter 16 h the reaction mixture was partitioned between water and ethyl acetate
  4. extractionextracted with ethyl acetate
  5. dry with materialThe combined organic phases were dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-a173015411574d7dae112bf97bec55a1
Source dataset
uspto-grants-2011_12
Patent number
US08071586B2

Reaction notes

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