Tris(hydroxymethyl)aminomethane → (4R,9aR)-6-Ethylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

HRID 11961

反応式

HRID 11961 の反応式
[CH2:1]([N:3]=C=O)[CH3:2].[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([CH2:27][O:28][CH2:29]CO)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(O)C(N)(CO)C[OH:35].C([O-])(=O)C.[NH4+]>CO.O.C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([CH2:27][O:28][C:29](=[O:35])[NH:3][CH2:1][CH3:2])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]

参加物

8

反応物 4

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 8022Ethyl isocyanateHCID 517165Ammonium AcetateHCID 69557393(4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester2 回

生成物 1

HCID 69557768(4R,9aR)-6-Ethylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester収率 215.4%

試薬・触媒・溶媒 3

HCID 887Methanol溶媒3 回HCID 962Water溶媒HCID 6344Dichloromethane溶媒2 回

反応条件

温度
140 °C

実験手順

Ethyl isocyanate (22 mL, 0.31 mmol) was added to a mixture of DMAP (0.008 g, 0.063 mmol) (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 15, intermediate b) (0.02 g, 0.063 mmol), 4 Å molecular sieves (0.02 g, crushed) and DCM (2 mL). The reaction vessel was sealed and heated at 140° C. in a CEM Discoverer™ microwave for 15 min. The reaction mixture was cooled to room temperature, DCM (2 mL) and AP-trisamine (2.49 mmol/g, 0.25 g, 0.63 mmol) were added, the reaction vessel was sealed and heated at 130° C. in a CEM Discoverer™ microwave for 5 min. The reaction mixture was filtered and the solid washed with DCM (4 mL) the filtrate was evaporated and the crude product purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.053 g, 22% yield) as a pale yellow oil: m/z 391.28 (MH+); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 2.98 min, 99%.

後処理

  1. customThe reaction vessel was sealed
  2. temperatureThe reaction mixture was cooled to room temperature
  3. customthe reaction vessel was sealed
  4. temperatureheated at 130° C. in a CEM Discoverer™ microwave for 5 min
  5. filtrationThe reaction mixture was filtered
  6. washthe solid washed with DCM (4 mL) the filtrate
  7. customwas evaporated
  8. customthe crude product purified by reverse phase preparative HPLC (Prep Nova-Pak HR

出典と根拠

ORDレコード
ord-89a1ffbd0a1940589eb615ed420e2337
出典データセット
uspto-grants-2006_08
特許番号
US07098337B2

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