Trifluoroacetic acid → 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-[2-(1H-imidazol-1-yl)ethoxy]ethanone

HRID 870592Notes

Reaction equation

HRID 870592 reaction equation
FC(F)(F)C(O)=O.[N:8]1([CH2:13][CH2:14][O:15][CH2:16][C:17]([O:19]C(C)(C)C)=O)[CH:12]=[CH:11][N:10]=[CH:9]1.C(N(C(C)C)CC)(C)C.[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH:34]1[NH:42][C:43]1[N:44]=[CH:45][C:46]2[CH2:52][NH:51][CH2:50][CH2:49][C:47]=2[N:48]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH:34]1[NH:42][C:43]1[N:44]=[CH:45][C:46]2[CH2:52][N:51]([C:17](=[O:19])[CH2:16][O:15][CH2:14][CH2:13][N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)[CH2:50][CH2:49][C:47]=2[N:48]=1

Participants

8

Reactant 6

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86726522N-(indan-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amineHCID 86726555Tert-butyl 2-(2-imidazol-1-ylethoxy)acetate

Product 1

HCID 867265561-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-[2-(1H-imidazol-1-yl)ethoxy]ethanoneYield 22%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Add trifluoroacetic acid (2 mL) dropwise to a solution of tert-butyl 2-(2-imidazol-1-ylethoxy)acetate (0.375 g; 1.0 equiv; 1.66 mmoles) in dichloromethane (10 mL). Stir at room temperature for 4 hours and then concentrate the mixture. Redissolve the remaining residue in dimethylformamide (5 mL) and add diisopropylethylamine (1.45 mL; 5 equiv; 8.31 mmoles) followed by N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.44 g; 1.0 equiv; 1.65 mmoles). Add O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.69 g; 1.1 equiv; 1.81 mmoles) and stir at room temperature for 16 hours. Pour the reaction mixture into saturated aqueous sodium bicarbonate solution (200 mL) and extract with dichloromethane (2×200 mL). Wash the combined organic extracts with saturated aqueous sodium bicarbonate solution (100 mL), dry over sodium sulfate, filter, and concentrate to give the crude product. Purify this residue by column chromatography (0 to 20% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-[2-(1H-imidazol-1-yl)ethoxy]ethanone (0.152 g; 22%) as a light brown solid: MS (m/z): 419(M+1).

Workup

  1. concentrationconcentrate the mixture
  2. dissolutionRedissolve the remaining residue in dimethylformamide (5 mL)
  3. extractionextract with dichloromethane (2×200 mL)
  4. washWash the combined organic extracts with saturated aqueous sodium bicarbonate solution (100 mL)
  5. dry with materialdry over sodium sulfate
  6. filtrationfilter
  7. concentrationconcentrate
  8. customto give the crude product
  9. customPurify this residue by column chromatography (0 to 20% methanol in dichloromethane)

Sources & evidence

ORD record
ord-2c24e323a474495484c0ab67fdaeacc4
Source dataset
uspto-grants-2015_03
Patent number
US08969555B2

Reaction notes

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