Triethylamine → 7-cyclopentyl-2-[5-((3aR,8aS)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

HRID 627351노트

반응식

HRID 627351 반응식
[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC([N:71]1[C@@H:75]2[CH2:76][NH:77][CH2:78][CH2:79][CH2:80][C@@H:74]2[CH2:73][CH2:72]1)=O)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C.[Pd].CO>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:77]4[CH2:78][CH2:79][CH2:80][C@@H:74]5[CH2:73][CH2:72][NH:71][C@@H:75]5[CH2:76]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]

참가 물질

9

반응물 4

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 583154726-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acidHCID 67355838(3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester

생성물 1

HCID 673553587-cyclopentyl-2-[5-((3aR,8aS)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

시약·촉매·용매 4

HCID 23938Palladium촉매HCID 887Methanol용매HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

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온도
23 °C

실험 절차

A solution of 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) nicotinic acid (5 eq of Lithium Chloride) (0.088 g, 0.146 mmol), HBTU (0.086 mg, 0.226 mmol, 1.6 eq) and triethylamine (0.100 mL, 0.717 mmol, 4.9 eq) in DMF (3 mL) was stirred at 23° C. for 5 minutes, then (3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester (0.040 mg, 0.146 mmol, 1.0 eq) was added and the reaction stirred at 23° C. for 1.5 hr. The reaction mixture was diluted with Ethyl Acetate, the mixture washed with 0.5M HCl (aq), then water (3×), brine, the organic layer dried (Na2SO4), filtered, and the filtrate concentrated. The crude was purified using chromatography (Methanol/CH2Cl2) giving a white solid. To the resulting solid (42 mg) was added 10% Pd/C (15 mg) followed by methanol (5 mL). The suspension was blanketed with H2 balloon with stirring for 6 hr. The contents of the reaction were filtered through Celite and the filtrate concentrated to a white solid that was burified by trituration from Ethyl Acetate/Heptane followed by chromatography (methanol/CH2Cl2) mixtures gave 7-cyclopentyl-2-[5-((3aR,8aS)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide. (20 mg, 0.039 mmol, 27%). 1H NMR (400 MHz, MeOD) δ ppm 1.62-1.84 (m, 5H) 1.84-1.99 (m, 2H) 1.99-2.20 (m, 4H) 2.31 (dd, J=13.05, 5.02 Hz, 1H) 2.47-2.62 (m, 2H) 2.63-2.80 (m, 1H) 3.18-3.27 (m, 1H) 3.38-3.61 (m, 2H) 3.77 (d, J=13.05 Hz, 1H) 3.84-3.98 (m, 1H) 4.04 (t, J=7.53 Hz, 1H) 4.06-4.19 (m, 1H) 4.80 (quin, J=9.03, 8.87 Hz, 1H) 6.67 (s, 1H) 7.93 (dd, J=8.78, 2.26 Hz, 1H) 8.45 (d, J=2.01 Hz, 1H) 8.53 (d, J=8.53 Hz, 1H) 8.82 (s, 1H); HRMS calc for m/z=517.3039 and found m/z=517.3044 (M+H)+.

후처리

  1. washthe mixture washed with 0.5M HCl (aq)
  2. dry with materialwater (3×), brine, the organic layer dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationthe filtrate concentrated
  5. customThe crude was purified
  6. customgiving a white solid
  7. stirringwith stirring for 6 hr
  8. filtrationThe contents of the reaction were filtered through Celite
  9. concentrationthe filtrate concentrated to a white solid

출처 및 근거

ORD 기록
ord-0df8d7f527fe45a1979b808a305269ae
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09309252B2

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