Dicyclohexylcarbodiimide → Albaconazole

HRID 2393282ノート

反応式

HRID 2393282 の反応式
[NH2:1][C@H:2]([CH3:19])[C@:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH:20]1C=CC2N(O)N=NC=2C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH2:40])[C:34](=[CH:38][CH:39]=1)[C:35](O)=[O:36].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C.C(N)=N>CN1C(=O)CCC1.O>[Cl:30][C:31]1[CH:32]=[C:33]2[C:34]([C:35](=[O:36])[N:1]([C@H:2]([CH3:19])[C@:3]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])([OH:10])[CH2:4][N:5]3[CH:9]=[N:8][CH:7]=[N:6]3)[CH:20]=[N:40]2)=[CH:38][CH:39]=1

参加物

8

反応物 5

HCID 10868DicyclohexylcarbodiimideHCID 666462-Amino-4-chlorobenzoic acidHCID 757711-HydroxybenzotriazoleHCID 160693Formamidine acetateHCID 10967497(2R,3R)-3-Amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

生成物 1

HCID 208952Albaconazole収率 67%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 13387N-methyl-2-pyrrolidone溶媒

実験手順

To a solution of (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (250 mg, 0.93 mmol) (obtained as described in Bartroli et al J. Org. Chem, 1995, 60, 3000-3012) in NMP (5 mL) was added HOBT (132 mg, 0.98 mmol, 1.05 eq). Next, 4-chloroanthranilic acid (160 mg, 0.93 mmol, 1 eq) and DCC (202 mg, 0.98 mmol, 1.05 eq) was added and the mixture was stirred at room temperature for 18 h. Then, formamidine acetate (437 mg, 4.19 mmol, 4.5 eq) was added and the mixture was heated at 130° C. for 24 h. Water (75 mL) was added and the solid formed was collected by filtration and was then partitioned between aqueous 1N NaOH solution and EtOAc. The aqueous phase was discarded and the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated and the residue purified by flash chromatography (hex: EtOAc 1:5) and recrystallized from a EtOAc: hexane: ether mixture to give the title product (268 mg, 67%) as a white solid: mp 116°-122° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.57 (s, 1H, N=CH--N), 8.26 (d, J=8.5Hz, 1H, arom), 7.74 (s, 2H, triazole), 7.7-7.3 (m, 3H, arom), 6.9-6.7 (m, 2H, arom), 5.91 (dq, Jd =2, Jq =7, 1H, MeCH), 5.53 (d, J=2, 1H, OH), 5.14 (d, J=14, 1H, CH(H)), 4.00 (d, J=14, 1H, CH(H)), 1.29 (d, J=7, 3H, CHMe); GC/MS 224 (Tr--CH2COHAr, C10H8F2N3O), 207 (N-ethylheterocycle, C10H9ClN2O); [a]D =-7.9° (c 1, CHCl3). Analysis calculated for C20H16ClF2N5O2 : C 55.63; H 3.73; N 16.22. Found: C 55.23; H 4.09; N 16.13.

後処理

  1. temperaturethe mixture was heated at 130° C. for 24 h
  2. customthe solid formed
  3. filtrationwas collected by filtration
  4. customwas then partitioned between aqueous 1N NaOH solution and EtOAc
  5. washthe organic phase was washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customthe residue purified by flash chromatography (hex: EtOAc 1:5)
  10. customrecrystallized from a EtOAc

出典と根拠

ORDレコード
ord-cd702d14e32944c4b3333d4eb32066ac
出典データセット
uspto-grants-1998_09
特許番号
US05807854

反応ノート

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