1,1,1-Trifluoropropan-2-yl carbonochloridate → 1,1,1-Trifluoropropan-2-yl 4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

HRID 1894000ノート

反応式

HRID 1894000 の反応式
Cl.F[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1.[F:30][C:31]([F:39])([F:38])[CH:32]([O:34][C:35](Cl)=[O:36])[CH3:33]>C(Cl)Cl>[CH3:12][S:9]([C:7]1[CH:8]=[CH:3][C:4]([NH:13][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:25][CH2:26][N:27]([C:35]([O:34][CH:32]([CH3:33])[C:31]([F:39])([F:38])[F:30])=[O:36])[CH2:28][CH2:29]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1)(=[O:11])=[O:10]

参加物

4

反応物 2

HCID 582703481,1,1-Trifluoropropan-2-yl carbonochloridateHCID 67038626N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt

生成物 1

HCID 670386641,1,1-Trifluoropropan-2-yl 4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate収率 51%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒2 回

実験手順

To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-ylchloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1 H), 8.31 (brs, 1 H), 8.14 (s, 1 H), 7.59-7.78 (m, 2 H), 5.18-5.34 (m, 1 H), 4.78-4.93 (m, 1 H), 4.22-4.41 (m, 4 H), 3.47-3.55 (m, 2 H), 3.04 (s, 3 H), 2.88-3.07 (m, 2 H), 1.79 (m, 2 H), 1.60-1.75 (m, 2 H), 1.42 (d, J=6.60 Hz, 3 H). LRMS (ESI) 548 (M+H)+.

後処理

  1. additionwas added DIEP (70 μL, 0.40 mmol, Aldrich)
  2. customevaporated under the reduced pressure
  3. customto yield the crude product which
  4. customwas purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid)

出典と根拠

ORDレコード
ord-c6a1771905c1444eaf6a5e6b75cd5671
出典データセット
uspto-grants-2013_08
特許番号
US08513265B2

反応ノート

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