Ethylenediamine → US9611269, Example 12

HRID 571486ノート

反応式

HRID 571486 の反応式
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:28]([CH2:30][C:31]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][N:55](COCC[Si](C)(C)C)[C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:34][N:33]([C:35]2[CH:36]=[CH:37][C:38]([C:41]([OH:43])=O)=[N:39][CH:40]=2)[CH2:32]1)#[N:29].Cl.[F:67][C:68]1([F:73])[CH2:71][CH:70]([NH2:72])[CH2:69]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+].C(N)CN>C(Cl)Cl>[C:28]([CH2:30][C:31]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:32][N:33]([C:35]2[CH:36]=[CH:37][C:38]([C:41]([NH:72][CH:70]3[CH2:71][C:68]([F:73])([F:67])[CH2:69]3)=[O:43])=[N:39][CH:40]=2)[CH2:34]1)#[N:29]

参加物

8

反応物 6

HCID 3301EthylenediamineHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 516892Sodium BicarbonateHCID 225009573,3-Difluorocyclobutamine hydrochlorideHCID 711436565-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylic acid

生成物 1

HCID 71143563US9611269, Example 12

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

A mixture of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (60.0 mg, 0.14 mmol), 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylic acid (48.4 mg, 0.0913 mmol), 3,3-difluorocyclobutanamine hydrochloride (20. mg, 0.14 mmol, Molbridge: Cat. #MB00001399) and N,N-diisopropylethylamine (64 μL, 0.36 mmol) in methylene chloride (2 mL) was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×2 mL). The combined organic layers were washed with water (1 mL), concentrated and dried under reduced pressure. The residue was dissolved in dichloromethylene (1 mL) and trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 1.5 hours, and concentrated under reduced pressure. The residue was dissolved in methanol (2.5 mL). Ethylenediamine (0.21 mL, 3.2 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=490.1. 1H NMR (300 MHz, DMSO-d6): δ 12.50 (br, 1H), 9.01 (s, 1H), 8.93 (d, J=7.8 Hz, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.70 (dd, J=3.4, 2.5 Hz, 1H), 7.15 (dd, J=3.5, 1.5 Hz, 1H), 7.04 (dd, J=8.6, 2.8 Hz, 1H), 4.63 (d, J=9.0 Hz, 2H), 4.36 (d, J=8.9 Hz, 2H), 4.23 (m, 1H), 3.73 (s, 2H), 2.80 (m, 4H).

後処理

  1. extractionextracted with dichloromethylene (2×2 mL)
  2. washThe combined organic layers were washed with water (1 mL)
  3. concentrationconcentrated
  4. customdried under reduced pressure
  5. dissolutionThe residue was dissolved in dichloromethylene (1 mL)
  6. stirringThe mixture was stirred at room temperature for 1.5 hours
  7. concentrationconcentrated under reduced pressure
  8. dissolutionThe residue was dissolved in methanol (2.5 mL)
  9. stirringThe reaction mixture was stirred at room temperature for 2 hours
  10. custompurified by RP-HPLC (pH=10)

出典と根拠

ORDレコード
ord-3e4114120c2d43e2b9fbac916222ee40
出典データセット
uspto-grants-2015_05
特許番号
US09023840B2

反応ノート

読み込み中…