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 1510490ノート

反応式

HRID 1510490 の反応式
[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.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:44][NH:45][C:46]([NH2:48])=[S:47].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>[NH2:48][C:46]1[S:47][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:44][N:45]=1

参加物

13

反応物 7

HCID 5943Carbon TetrachlorideHCID 8471Triethylamine2 回HCID 11776TriphenylphosphineHCID 757711-HydroxybenzotriazoleHCID 2723789ThiosemicarbazideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 116174244-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

生成物 1

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

試薬・触媒・溶媒 5

HCID 6228Dimethylformamide溶媒HCID 6342Acetonitrile溶媒HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒HCID 25517Ammonium Chloride溶媒

反応条件

温度
50 °C

実験手順

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), EDCl (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, t H), 7.25 (d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).

後処理

  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)

出典と根拠

ORDレコード
ord-1492bde2bccc4a4dadea332b112d902b
出典データセット
uspto-grants-2012_07
特許番号
US08211920B2

反応ノート

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