Triethylamine → N-[(3-bromo-4-fluorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide

HRID 662007노트

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HRID 662007 반응식
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=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].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[F:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][C:40]=1[F:41]

참가 물질

6

반응물 4

HCID 8471TriethylamineHCID 2724902(3-Bromo-4-fluorophenyl)methanamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 578193746-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid

생성물 1

HCID 57819367N-[(3-bromo-4-fluorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide수율 9.4%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (900 mg, 1.989 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (406 mg, 1.989 mmol), HBTU (905 mg, 2.387 mmol) and Et3N (1.386 mL, 9.94 mmol) in DCM was stirred at room temperature overnight. The reaction did not go to completion overnight. An additional equivalent of each reagent was added and the reaction stirred over the weekend. The reaction mixture 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 using flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). However, this product batch was not pure. It was purified with a Gilson HPLC. Product crashed out from the HPLC solution. The solid was filtered to obtain N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (120 mg) as a solid. The mother liquor was purified with a Gilson HPLC to obtain another batch of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (160 mg). LC-MS m/z 638.4 (M+H)+, 0.89 min (ret time).

후처리

  1. customdid not go to completion overnight
  2. additionAn additional equivalent of each reagent was added
  3. stirringthe reaction stirred over the weekend
  4. customThe reaction mixture was quenched with saturated NaHCO3
  5. extractionextracted with DCM twice
  6. washThe combined organic layers were washed with brine
  7. concentrationconcentrated under vacuum
  8. customto give the crude residue
  9. customIt was then purified
  10. washeluting with 0 to 100% ethyl acetate in hexane (product
  11. customIt was purified with a Gilson HPLC
  12. filtrationThe solid was filtered

출처 및 근거

ORD 기록
ord-a79ddaed34bc404bada7ea5348b5325b
출처 데이터셋
uspto-grants-2011_12
특허 번호
US08084449B2

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