Trimethylsilyl triflate → (S)-1-((S)-2-{(S)-2-[(E)-4-[2-((R)-1-Hydroxy-ethyl)-quinolin-7-yl]-2-(2-methoxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyrylamino}-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285393Notes

Reaction equation

HRID 2285393 reaction equation
[Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23](OC(C)(C)C)=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[OH:55][C@@H:56]([C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][C:62](/[CH:68]=[CH:69]/[C:70]([CH2:75][CH2:76][O:77][CH3:78])(C)[C:71](O)=O)=[CH:63][CH:64]=2)[N:59]=1)[CH3:57].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:32][C:2]([Cl:33])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23](=[O:24])[C:70]([CH2:75][CH2:76][O:77][CH3:78])([CH3:71])/[CH:69]=[CH:68]/[C:62]2[CH:61]=[C:60]3[C:65]([CH:66]=[CH:67][C:58]([C@H:56]([OH:55])[CH3:57])=[N:59]3)=[CH:64][CH:63]=2)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]

Participants

8

Reactant 5

HCID 65367Trimethylsilyl triflateHCID 81531Diisopropylethylamine2×HCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 86706028(S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methylbutyrylamino)-propionyl]-hexahydropyridazine-3-carboxylic acid 2,2,2-trichloroethyl esterHCID 86709684(E)-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-(2-methoxy-ethyl)-2-methyl-but-3-enoic acid

Product 1

HCID 86709683(S)-1-((S)-2-{(S)-2-[(E)-4-[2-((R)-1-Hydroxy-ethyl)-quinolin-7-yl]-2-(2-methoxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyrylamino}-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterYield 66.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.24 g, 2.38 mmol) in anhydrous dichloromethane (40 mL) was cooled to 0° C. before adding trimethylsilyl trifluoromethanesulfonate (660 μL, 3.62 mmol). The reaction mixture was stirred at 0° C. for 1.5 h before addition of N,N-diisopropylethylamine (1.65 mL, 9.47 mmol). The reaction mixture was then evaporated to dryness and the residue was dissolved in N,N-dimethylformamide (20 mL) and added to a stirred solution of crude (E)-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-(2-methoxy-ethyl)-2-methyl-but-3-enoic acid (2.43 g) and N,N-diisopropylethylamine (1.65 mL, 9.47 mmol) in N,N-dimethylformamide (50 mL). The reaction was treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (1.37 g, 3.78 mmol) and stirred at room temperature for 3 h. It was evaporated then purified by silica gel chromatography eluting with iso-hexanes/dichloromethane/methanol 1:1:0 to 0:1:0 to 0:98:2 to 0:24:1 to yield the title product (1.17 g, 66%) as a pale yellow solid and as a mixture of diastereoisomers. LCMS (m/z) 742.3, 744.2, 746.2 [M+H], Tr=2.15 min.

Workup

  1. customThe reaction mixture was then evaporated to dryness
  2. dissolutionthe residue was dissolved in N,N-dimethylformamide (20 mL)
  3. customIt was evaporated
  4. customthen purified by silica gel chromatography
  5. washeluting with iso-hexanes/dichloromethane/methanol 1:1:0 to 0:1:0 to 0:98:2 to 0:24:1

Sources & evidence

ORD record
ord-c860b69da4904623ab26f1e0822c07e8
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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