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Triethylamine → 1,1-dimethylethyl (2S)-4-[(5'-{[({5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinyl}carbonyl)amino]methyl}-2'-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

HRID 662105
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HRID 662105 반응식
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:54][CH3:55])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]6[CH2:52][CH2:51][NH:50][C@@H:49]([CH3:53])[CH2:48]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N1C2=NC(CC)=C(CNC(C3C=C(C(O)=O)C=NC=3)=O)C(NC3CCOCC3)=C2C=N1)C.NCC1C=CC(F)=C(C2C=CC=C(CN3CCN([C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[C@@H](C)C3)C=2)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:54][CH3:55])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]6[CH2:52][CH2:51][N:50]([C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[C@@H:49]([CH3:53])[CH2:48]6)[CH:41]=5)[CH:34]=4)=[O:30])[CH:26]=[N:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
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참가 물질

7

반응물 5

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 251325161,1-dimethylethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylateHCID 44192863n-{[1,6-Diethyl-4-(tetrahydro-2h-pyran-4-ylamino)-1h-pyrazolo[3,4-b]pyridin-5-yl]methyl}-n'-[(6-fluoro-3'-{[(3s)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-3,5-pyridinedicarboxamide
HCID 57819387
5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinecarboxylic acid

생성물 1

HCID 866333501,1-dimethylethyl (2S)-4-[(5'-{[({5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinyl}carbonyl)amino]methyl}-2'-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

As an alternate process for preparing the compound of Example 131, a mixture of 5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinecarboxylic acid (50 mg, 0.110 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (45.7 mg, 0.110 mmol), HBTU (o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (50.3 mg, 0.133 mmol) and Et3N (0.046 ml, 0.331 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3, and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried under GeneVac and then combined to give the intermediate 1,1-dimethylethyl (2S)-4-[(5′-{[({5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-3-pyridinyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This intermediate was then dissolved in 2 mL of 25% TFA in DCM and stirred at room temperature for 3 h. The crude products were purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and the free base was obtained by adding 1 N NaOH, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-3,5-pyridinedicarboxamide as a solid (10 mg, 12.1%). LC-MS m/z 748 (M+H)+, 0.70 min (ret time).

후처리

  1. customThe reaction was quenched with saturated NaHCO3
  2. extractionextracted with DCM twice
  3. washThe combined organic layers were washed with brine
  4. concentrationconcentrated under vacuum
  5. customto give the crude residue
  6. customIt was then purified with a Gilson HPLC (with 0.1% TFA in the solvents),
  7. washeluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min
  8. customThe product fractions were dried under GeneVac

출처 및 근거

ORD 기록
ord-b5c783f4048e4da0949d3493ba67ddee
출처 데이터셋
uspto-grants-2011_12
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08084449B2

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