2,6-Lutidine → HCID 24888984, compound

HRID 546049Notes

Reaction equation

HRID 546049 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1[C:25](=[O:26])[CH2:24]CC1=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].N1C(C)=CC=CC=1C.C(OCC)(=[O:65])C>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][C@@H:25]([OH:26])[CH2:24][OH:65])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]

Participants

7

Reactant 5

HCID 79372,6-LutidineHCID 8857Ethyl AcetateHCID 11776TriphenylphosphineHCID 67184N-bromobutanimideHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 24888984HCID 24888984, compoundYield 35%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Triphenylphosphine (172 mg, 0.66 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (133 mg, 0.75 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, 146 mg, 0.44 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The reaction was chilled to 0° C. and the combined solution of 3-(3-amino-pyrazol-1-yl)-propane-(R)-1,2-diol (69 mg, 0.44 mmol) and 2,6-lutidine (154 μL, 1.32 mmol) in methylene chloride (4 mL) was added. The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (73 mg, 35%) as a pale pink powder: ESI-LRMS m/e calcd for C21H28ClN3O5S [M+] 469.1, found 470.1 [M+H+], 452.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.20 (m, 2H, CH2), 1.41-1.94 (m, 8H, 4×CH2), 2.14-2.26 (m, 1H, CH), 3.02 (br.s., 2H, 2×OH), 3.27 (s, 3H, SO2CH3), 3.44-3.53 (m, 1H, CH of OCH2), 3.56 (dd, J=11.4, 4.2 Hz, 1H, CH of OCH2), 3.63 (t, J=7.6 Hz, 1H, CH), 3.91-4.11 (m, 3H, OCH and NCH2), 6.65 (d, J=2.3, 1H, Ar), 7.29 (d, J=2.3, 1H, Ar), 7.48 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.07 (d, Jo=8.2, 1H, Ar), 8.44 (s, 1H, NH).

Workup

  1. dissolutionwas completely dissolved
  2. stirringit was stirred at 0° C. for 15 min
  3. temperaturewarmed to 25° C.
  4. stirringstirred for 30 min
  5. temperatureThe reaction was chilled to 0° C.
  6. stirringto stir at 0° C. for 30 min
  7. washwashed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL)
  8. dry with materialThe organic layer was dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-76e224a97b3a40ae96fa854e6f5de5db
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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