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 15927Notes

Reaction equation

HRID 15927 reaction equation
[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

Participants

13

Reactant 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

Product 1

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

Reagents, catalysts & solvents 5

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
50 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-f6d2477054d24096a391b79106993b2f
Source dataset
uspto-grants-2010_06
Patent number
US07732616B2

Reaction notes

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