2,6-Lutidine → HCID 70674683, compound

HRID 2365736Notes

Reaction equation

HRID 2365736 reaction equation
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:31]([O:35][C:36](=[O:45])[CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1)([CH3:34])([CH3:33])[CH3:32].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:31]([O:35][C:36](=[O:45])[CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH:44][C:8](=[O:9])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:40]1)([CH3:34])([CH3:32])[CH3:33]

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 67190548HCID 67190548, compoundHCID 70945341(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid

Product 1

HCID 70674683HCID 70674683, compoundYield 94%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol,) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 3-(3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (prepared as in US 20080021032, Example 8, 92 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then dried over sodium sulfate, filtered and the filtrate was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (145 mg, 94%) as a white foam: HR-ES(+) m/e calcd for C27H33N4O4F3 [M+H]+ 535.2527, observed 535.2526; 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.01 (dd, J=7.67, 12.79 Hz, 2H), 7.71-7.82 (m, 1H), 7.56 (d, J=2.13 Hz, 1H), 6.39 (d, J=2.13 Hz, 1H), 4.96-5.14 (m, 2H), 4.71 (d, J=18.33 Hz, 1H), 4.19 (t, J=6.50 Hz, 2H), 2.72 (t, J=6.61 Hz, 2H), 0.77-2.09 (m, 20H).

Workup

  1. concentrationAfter this time, the reaction mixture was then concentrated in vacuo
  2. dissolutionthe resulting residue was dissolved in methylene chloride (4 mL)
  3. additionadded dropwise to a separate reaction flask
  4. additioncontaining
  5. customThe resulting reaction mixture
  6. customthe stirred room temperature
  7. customfor 2 h
  8. customThe reaction mixture was quenched by the addition of methanol
  9. additiondiluted with methylene chloride
  10. washwashed with a 1 N aqueous hydrochloric acid solution
  11. dry with materialThe organic layer was then dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationthe filtrate was then concentrated in vacuo with silica gel (2.0 g)
  14. custompurified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-2fbf561da8db42999807a7d08eecb2d8
Source dataset
uspto-grants-2014_04
Patent number
US08697705B2

Reaction notes

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