2,6-Lutidine → (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide

HRID 2365747Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2365747
[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([F:20])([F:19])[F:18])[C:9]1=[O:21])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:29][C:30]1([CH3:42])[O:34][C@@H:33]([C:35]2[N:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:32][O:31]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.CO>[CH3:29][C:30]1([CH3:42])[O:34][C@@H:33]([C:35]2[N:36]=[CH:37][C:38]([NH:41][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]=4[C:17]([F:20])([F:19])[F:18])[C:9]3=[O:21])[CH2:3][CH:2]([CH3:22])[CH3:1])=[N:39][CH:40]=2)[CH2:32][O:31]1

Komponenten

8

Edukt 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 533755855-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamineHCID 70945056(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid

Produkt 1

HCID 86673402(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amideAusbeute 44 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6228DimethylformamideKatalysatorHCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittel3×

Versuchsvorschrift

A solution of (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid (prepared as in Example 23, 79 mg, 0.25 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) at room temperature was treated with a solution of oxalyl chloride (2.0M in methylene chloride, 150 μL, 0.30 mmol) and stirred for 15 min. After this time, the reaction mixture was concentrated in vacuo and then diluted with methylene chloride (5 mL) and added to a flask containing a solution of 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared as in WO2004052869, Example 54, 98 mg, 0.50 mmol), 2,6-lutidine (100 μL, 0.50 mmol) in methylene chloride (2.5 mL) at room temperature. The reaction mixture was then stirred at room temperature for a period of 2 h. After this time, the reaction mixture was treated with methanol and then diluted with methylene chloride. The reaction mixture was then transferred to a separatory funnel and washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated with silica gel (2 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 40% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (54 mg, 44%) as a colorless sticky solid: HR-ES(+) m/e calcd for C24H27N4O4F3 [M+H]+ 493.2057, observed 493.2059; 1H NMR (400 MHz, CHLOROFORM-d) δ 9.37 (d, J=1.28 Hz, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=7.46 Hz, 1H), 7.82 (d, J=7.67 Hz, 1H), 7.64 (t, J=7.78 Hz, 1H), 5.20 (t, J=6.50 Hz, 1H), 5.13 (dd, J=6.93, 8.84 Hz, 1H), 4.68-4.78 (m, 1H), 4.55-4.65 (m, 1H), 4.42 (dd, J=6.82, 8.52 Hz, 1H), 3.95 (dd, J=6.29, 8.42 Hz, 1H), 2.00-2.13 (m, 1H), 1.88-2.00 (m, 1H), 1.53-1.69 (m, 1H), 1.44-1.52 (m, 6H), 0.97-1.07 (m, 6H).

Aufarbeitung

  1. concentrationAfter this time, the reaction mixture was concentrated in vacuo
  2. additiondiluted with methylene chloride (5 mL)
  3. additionadded to a flask
  4. stirringThe reaction mixture was then stirred at room temperature for a period of 2 h
  5. customThe reaction mixture was then transferred to a separatory funnel
  6. washwashed with a 1N aqueous hydrochloric acid solution
  7. dry with materialThe organic layer was then dried over magnesium sulfate
  8. filtrationfiltered
  9. customto remove the drying agent
  10. concentrationthe filtrate was concentrated with silica gel (2 g)
  11. custompurified via Biotage flash column chromatography (40 S silica gel column, 40% ethyl acetate/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-fed94d896653419f8321a08620ac4f1a
Quelldatensatz
uspto-grants-2014_04
Patentnummer
US08697705B2

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