N-(tert-butoxycarbonyl)glycine → HCID 178463335、化合物

HRID 1943495ノート

反応式

HRID 1943495 の反応式
[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH2:29][CH3:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([NH:74][CH2:75][C:76](O)=[O:77])(OC(C)(C)C)=O>CN(C=O)C.C(OCC)(=O)C.O.C1COCC1>[NH2:74][CH2:75][C:76]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH2:29][CH3:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1)=[O:77]

参加物

9

反応物 4

HCID 78288N-(tert-butoxycarbonyl)glycineHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 178463334HCID 178463334、化合物

生成物 1

HCID 178463335HCID 178463335、化合物収率 44.9%

試薬・触媒・溶媒 4

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

実験手順

To a suspension containing 6-((trans)-4-aminocyclohexylamino)-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.025 g, 0.061 mmol), diisopropylethylamine (0.053 mL, 0.303 mmol), and BOP (0.080 g, 0.182 mmol) in DMF at room temperature was added BOC-glycine (0.021 g, 0.121 mmol). The resulting suspension was stirred 30 min at ambient temperature. The dark brown solution was diluted with ethyl acetate and water. The layers were separated and the aqueous phase extracted three times with 5 mL ethyl acetate. The organic extracts were combined, washed with water and 10% aq. lithium chloride five times before drying over anhydrous sodium sulfate. Filtration and concentration under reduced pressure revealed a white solid which was suspended in CH2Cl2 (0.5 mL) at room temperature. TFA (0.5 mL) was added, resulting in a homogeneous solution. After 30 min at room temperature, the crude material was diluted with 1 mL of THF and purified via preparative HPLC using a YMC ODS C-18 30×250 mm column with 10-100% B (Solvent A: 10% aq MeOH with 0.1% TFA; Solvent B: 90% aq. MeOH with 0.1% TFA) and a linear gradient over 30 min at 25 mL/min, monitoring at 220 nm (Rt=27.545 min) The appropriate fractions were concentrated and lyophilized overnight, furnishing 6-((trans)-4-(2-aminoacetamido)cyclohexylamino)-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (19 mg, 0.027 mmol, 44.9% yield) as a white foam. MS: [M+H]=470.0. HPLC: Rt=3.121 min. (Waters sunfire 4.6×50 mm C18.5 um 4 min/1 min hold time 0-100% (A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10% water-0.1% TFA).

後処理

  1. customThe layers were separated
  2. extractionthe aqueous phase extracted three times with 5 mL ethyl acetate
  3. washwashed with water and 10% aq. lithium chloride five times
  4. dry with materialbefore drying over anhydrous sodium sulfate
  5. filtrationFiltration and concentration under reduced pressure
  6. customwas suspended in CH2Cl2 (0.5 mL) at room temperature
  7. additionTFA (0.5 mL) was added
  8. customresulting in a homogeneous solution
  9. waitAfter 30 min at room temperature
  10. custompurified via preparative HPLC
  11. waita linear gradient over 30 min at 25 mL/min
  12. concentrationwere concentrated
  13. waitlyophilized overnight

出典と根拠

ORDレコード
ord-e35a51caff0846feaa28e0768a7865c2
出典データセット
uspto-grants-2013_03
特許番号
US08389527B2

反応ノート

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