Ethylenediamine → US9611269, Example 12

HRID 571486노트

반응식

HRID 571486 반응식
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]

참가 물질

8

반응물 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

생성물 1

HCID 71143563US9611269, Example 12

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-3e4114120c2d43e2b9fbac916222ee40
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09023840B2

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