Carbon Tetrachloride → 5-(5-Amino-[1,3,4]thiadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

HRID 421869Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 421869
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:43][NH:44][C:45]([NH2:47])=[S:46].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)Cl>CN(C=O)C.[NH4+].[Cl-].C(OCC)(=O)C.CC#N.C(Cl)Cl>[NH2:47][C:45]1[S:46][C:18]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:21])=[C:14]([F:15])[C:13](=[O:16])[N:12]([CH3:17])[CH:11]=2)=[N:43][N:44]=1

Komponenten

13

Edukt 7

HCID 5943Carbon TetrachlorideHCID 8471Triethylamine2×HCID 11776TriphenylphosphineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 2723789ThiosemicarbazideHCID 116174244-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Produkt 1

HCID 576368315-(5-Amino-[1,3,4]thiadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-oneAusbeute 33 %

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 6228DimethylformamideLösungsmittelHCID 6342AcetonitrileLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 25517Ammonium ChlorideLösungsmittel

Reaktionsbedingungen

Temperatur
50 °C

Versuchsvorschrift

A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), EDCI (214 mg, 1.11 mmol) and HOBt (151 mg, 1.11 mol) were stirred in DMF (10 mL) for 30 minutes. Thiosemicarbazide (51 mg, 0.562 mmol) and Et3N (0.116 mL, 1.5 mmol) were added. After 1 hour, the reaction mixture was diluted with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (5% to 10% MeOH in methylene chloride) gave 70 mg partially pure intermediate adduct. PPh3 (78 mg, 0.30 mmol), Et3N (0.10 mL, 0.74 mmol), and CCl4 (0.029 mL, 0.30 mmol) were added to a stirred suspension of intermediate adduct (40 mg, 0.093 mmol) in 1:1 methylene chloride:MeCN (4 mL). The reaction mixture was heated to 50° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (twice) (4% MeOH in methylene chloride) gave clean desired product (10 mg, 33%); MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.80 (s, 1H), 7.31 (dd, 1H), 7.25 (d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).

Aufarbeitung

  1. extractionextracted with ethyl acetate
  2. dry with materialThe combined organic extracts were dried (MgSO4)
  3. concentrationconcentrated under reduced pressure
  4. customPurification by flash column chromatography (5% to 10% MeOH in methylene chloride)
  5. customgave 70 mg partially pure intermediate adduct
  6. temperatureAfter cooling to room temperature
  7. washwashed with water
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated under reduced pressure
  10. customPurification by flash column chromatography (twice) (4% MeOH in methylene chloride)

Quellen und Nachweise

ORD-Eintrag
ord-56b4d5255a514bba9b3a6bb83172b7c6
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08101611B2

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