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 1971175노트

반응식

HRID 1971175 반응식
[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

참가 물질

13

반응물 7

HCID 5943Carbon TetrachlorideHCID 8471Triethylamine2회HCID 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

생성물 1

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

시약·촉매·용매 5

HCID 6228Dimethylformamide용매HCID 6342Acetonitrile용매HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매HCID 25517Ammonium Chloride용매

반응 조건

온도
50 °C

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-2e2807f114874c74a050767bd9dcad6f
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08431574B2

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