Diisopropylethylamine → HCID 86706138, compound

HRID 2176293Notes

Reaction equation

HRID 2176293 reaction equation
FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C@H:19]([NH:21][C:22]([C:24]3([CH3:35])[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[C@@H:31]([NH2:33])[CH3:32])[NH:25]3)=[O:23])[CH3:20])=[N:16]2)=[CH:11][CH:10]=1.[OH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C@H:19]([NH:21][C:22]([C:24]3([CH3:35])[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[C@@H:31]([NH:33][C:38](=[O:39])[C@@H:37]([OH:36])[CH:41]([CH3:43])[CH3:42])[CH3:32])[NH:25]3)=[O:23])[CH3:20])=[N:16]2)=[CH:11][CH:10]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 853180(S)-2-Hydroxy-3-methylbutanoic acidHCID 86706139HCID 86706139, compound

Product 1

HCID 86706138HCID 86706138, compoundYield 39%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of ((S)-2-{3-[(R)-1-(7-bromo-quinolin-2-yl)-thylcarbamoyl]-3-methyl-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.92 g, 3.5 mmol) in dichloromethane (15 mL) at 0° C. was added trifluoroacetic acid (3 mL). The reaction mixture was allowed to warm to room temperature and then stirred for 4 h. The reaction mixture was concentrated and the residue was co-evaporated with toluene (3×) to give 1-((S)-2-amino-propionyl)-3-methyl-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide trifluoroacetate salt (3.5 mmol) as a brown oil. LCMS (m/z) 448.0, 450.0 [M+H], Tr=1.22 min. 1-((S)-2-Amino-propionyl)-3-methyl-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide trifluoroacetate salt (3.5 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to 0° C. (S)-2-Hydroxy-3-methyl-butyric acid (458 mg, 3.8 mmol), N,N-diisopropylethylamine (5 mL, 28.0 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (1.86 g, 4.2 mmol) were added. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic solution was washed with citric acid (10%), saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 20:1 to afford the title compound (745 mg, 39% over 2 steps) as a white foam and as a 1:4 mixture of diastereoisomers. LCMS (m/z) 548.0, 550.0 [M+H], Tr=2.21 min.

Workup

  1. customLCMS (m/z) 448.0, 450.0 [M+H], Tr=1.22 min
  2. additionwere added
  3. customThe solvent was evaporated
  4. dissolutionthe residue was dissolved in ethyl acetate
  5. washThe organic solution was washed with citric acid (10%), saturated sodium hydrogen carbonate solution and brine
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customthe solvent was evaporated
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with a gradient of ethyl acetate/methanol 1:0 to 20:1

Sources & evidence

ORD record
ord-8506d27e9b694803b175ea8637b33cfd
Source dataset
uspto-grants-2015_06
Patent number
US09062092B2

Reaction notes

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