4-Methylmorpholine → 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl ester

HRID 545986

Reaction equation

HRID 545986 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40](NC2C=CN(C)N=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[C:55]([O:59][C:60]([N:62]1[CH:66]=[CH:65][C:64]([NH2:67])=[N:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[C:55]([O:59][C:60]([N:62]1[CH:66]=[CH:65][C:64]([NH:67][C:40](=[O:41])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)=[N:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 11776TriphenylphosphineHCID 67184N-bromobutanimideHCID 51358380tert-Butyl 3-amino-1H-pyrazole-1-carboxylateHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 671887073-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl esterYield 99.3%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Triphenylphosphine (1.61 g, 6.15 mmol) was dissolved in methylene chloride (60 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (1.24 g, 6.97 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.36 g, 4.1 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for another 30 min. The mixture was cooled to 0° C. and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (0.75 g, 4.1 mmol) was added followed by N-methyl-morpholine (540 μL, 4.92 mmol). The mixture was continued to stir at 0-4° C. for 4 h. The reaction was diluted with ethyl acetate (150 mL), washed with water (50 mL), aqueous 0.1 M hydrochloric acid (2×50 mL) and saturated aqueous brine solution (2×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl ester (2.02 g, 99%) as a light yellow oil: ESI-LRMS m/e calcd for C23H30ClN3O5S [M+] 495.2, found 496.4 [M+H+], 395.5 [M−CO2tBu+H+].

Workup

  1. dissolutionwas completely dissolved
  2. stirringit was stirred at 0° C. for 15 min
  3. temperaturewarmed to 25° C.
  4. stirringstirred for another 30 min
  5. temperatureThe mixture was cooled to 0° C.
  6. stirringto stir at 0-4° C. for 4 h
  7. washwashed with water (50 mL), aqueous 0.1 M hydrochloric acid (2×50 mL) and saturated aqueous brine solution (2×50 mL)
  8. dry with materialThe organic layer was dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-00119d80bc624eb1a288342d5bf6590e
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Linked notes

Loading…