Trimethylsilyl triflate → HCID 67960564, compound

HRID 1427795Notes

Reaction equation

HRID 1427795 reaction equation
[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](OC(C)(C)C)=[O:41])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:73]([O:75][C@H:76]([CH2:82][CH2:83][CH:84]=[CH2:85])[C@@H:77](C)[C:78](O)=O)[CH3:74].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](=[O:41])[C@H:77]([CH3:78])[C@H:76]([O:75][CH2:73][CH3:74])[CH2:82][CH2:83][CH:84]=[CH2:85])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2]

Participants

7

Reactant 5

HCID 65367Trimethylsilyl triflateHCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86675874HCID 86675874, compoundHCID 86708884HCID 86708884, compound

Product 1

HCID 67960564HCID 67960564, compoundYield 60.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 3-vinyl-benzyl ester (300 mg, 0.42 mmol) in anhydrous dichloromethane (9 mL) was treated with trimethylsilyl trifluoromethanesulfonate (114 μL, 0.63 mmol). The reaction mixture was stirred at room temperature for 1.5 hours then N,N-diisopropylethylamine (293 μL, 1.68 mmol) was added. The reaction mixture was evaporated to give the crude amine as a colourless solid. A solution of (2R,3R)-3-ethoxy-2-methyl-hept-6-enoic acid (78 mg, 0.42 mmol) in anhydrous dichloromethane (8 mL) was cooled to 0° C. before adding N,N-diisopropylethylamine (2934, 1.68 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol). The mixture was stirred at 0° C. for 20 minutes before adding a solution of the crude amine in dichloromethane (8 mL). The reaction mixture was allowed to warm to room temperature and was stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was evaporated and purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to yield the title compound (200 mg, 60%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 6H), 0.88-0.99 (m, 6H), 0.97 (s, 9H), 1.08-1.30 (m, 8H), 1.34-1.60 (m, 3H), 1.61-1.87 (m, 4H), 2.09-2.26 (m, 3H), 2.38-2.55 (m, 2H), 3.39-3.72 (m, 4H), 4.24-4.36 (m, 2H), 4.91-5.19 (m, 4H), 5.30 (d, J=10.9 Hz, 1H), 5.70-5.90 (m, 3H), 6.53-6.84 (m, 6H), 6.97-7.50 (m, 1H), 7.21-7.44 (m, 4H). LCMS (m/z) 791.4 [M+H] Tr=6.01 min.

Workup

  1. customThe reaction mixture was evaporated
  2. customto give the crude amine as a colourless solid
  3. stirringThe mixture was stirred at 0° C. for 20 minutes
  4. temperatureto warm to room temperature
  5. stirringwas stirred under a nitrogen atmosphere for 16 hours
  6. customThe reaction mixture was evaporated
  7. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-af6c681bb204488c9168eb9d8b1281bd
Source dataset
uspto-grants-2015_01
Patent number
US08933015B2

Reaction notes

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