Pyridine → {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester

HRID 545990

Reaction equation

HRID 545990 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]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[C:55]([O:59][C:60](=[O:68])CN1C=CC(N)=N1)([CH3:58])([CH3:57])[CH3:56].N1C=CC=CC=1>C(Cl)Cl.O>[C:55]([O:59][C:60](=[O:68])[CH2:48][N:45]1[CH:46]=[CH:47][C:43]([NH:42][C:40](=[O:41])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:29]([Cl:28])[CH:30]=2)[CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)=[N:44]1)([CH3:58])([CH3:57])[CH3:56]

Participants

8

Reactant 5

HCID 1049PyridineHCID 11776TriphenylphosphineHCID 67184N-bromobutanimideHCID 62111572tert-butyl 2-(3-amino-1H-pyrazol-1-yl)acetateHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 67193401{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl esterYield 56%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Triphenylphosphine (1.66 g, 6.33 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (1.27 g, 7.17 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, 1.40 g, 4.22 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for 30 min. After such time, (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (833 mg, 4.22 mmol) and pyridine (1.03 mL, 6.33 mmol) were added and it was stirred at 25° C. for 16 h. The reaction was then diluted with water (30 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (1.20 g, 56%) as a white solid: ESI-LRMS m/e calcd for C24H32ClN3O5S [M+] 509.2, found 510.1 [M+H+].

Workup

  1. dissolutionwas completely dissolved
  2. stirringit was stirred at 0° C. for 20 min
  3. temperaturewarmed to 25° C.
  4. stirringstirred for 30 min
  5. stirringit was stirred at 25° C. for 16 h
  6. extractionextracted with methylene chloride (3×15 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customFlash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run)

Sources & evidence

ORD record
ord-cebee5e6af0d4205b588d6e72f8d3045
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Linked notes

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