Trifluoroacetic acid → HCID 178502413, compound

HRID 1521808Notes

Reaction equation

HRID 1521808 reaction equation
C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:52]=[CH:51][C:21]3[C:22]4[CH:32]=[CH:31][C:30]([C:33]5[NH:37][C:36]([C@@H:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43]([O:45]C(C)(C)C)=O)=[N:35][C:34]=5[Cl:50])=[CH:29][C:23]=4[O:24][CH2:25][CH2:26][CH2:27][O:28][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.FC(F)(F)[C:55]([OH:57])=[O:56].C(N([CH:66]([CH3:68])[CH3:67])CC)(C)C.O.[N:70]1(O)[C:74]2C=CC=CC=2N=N1.[CH3:80]CN=C=NCCCN(C)C.Cl.[CH3:92][O:93][C:94]([NH:96][C@@H:97]([CH:101]([CH3:103])[CH3:102])C(O)=O)=[O:95]>C(Cl)Cl>[CH3:80][O:57][C:55]([NH:70][C@@H:74]([CH:66]([CH3:67])[CH3:68])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:52]=[CH:51][C:21]3[C:22]4[CH:32]=[CH:31][C:30]([C:33]5[NH:37][C:36]([C@@H:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:45])[C@@H:97]([NH:96][C:94](=[O:95])[O:93][CH3:92])[CH:101]([CH3:103])[CH3:102])=[N:35][C:34]=5[Cl:50])=[CH:29][C:23]=4[O:24][CH2:25][CH2:26][CH2:27][O:28][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:5])=[O:56]

Participants

8

Reactant 6

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 178451929HCID 178451929, compound

Product 1

HCID 178502413HCID 178502413, compoundYield 67.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of (S)-tert-butyl 2-(5-(11-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonin-3-yl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2a, 0.05 g, 0.07 mmol) at 0° C. in DCM (1 ml) was added trifluoroacetic acid (0.17 g, 1.50 mmol). The reaction mixture was warmed to 25° C. and stirred for 2 hours after which all the volatiles were removed under reduced pressure. The contents were taken up in ACN (8 ml) and cooled to 0° C. after which diisopropylethyl amine (DIPEA) (0.06 g, 0.45 mmol), 1H-benzo-[d][1,2,3]-triazol-1-ol hydrate (0.03 g, 0.19 mmol) and EDCl (0.04 g, 0.19 mmol) were added. The reaction mixture was stirred for 10 minutes after which (S)-2-((methoxycarbonyl)-amino)-3-methylbutanoic acid (0.03 g, 0.19 mmol) was added. The reaction mixture was gradually warmed to 25° C. and stirred for 18 hr. The reaction mixture was evaporated to dryness followed by addition of crushed ice to precipitate solid product. The solid product was filtered and purified by preparative HPLC yielded an off-white solid (0.04 g, 40%) of methyl ((S)-1-((S)-2-(5-(11-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonin-3-yl)-4-chloro-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate. m/z 845.4 (M++1); 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.67-7.20 (m, 7H), 5.26-5.43 (m, 2H), 4.42-4.27 (m, 6H), 3.85-3.58 (m, 10H), 3.14-2.97 (m, 2H), 2.37 (br m, 2H), 2.12-1.97 (m, 8H), 1.12-0.81 (m, 12H).

Workup

  1. customwere removed under reduced pressure
  2. additionwere added
  3. additionwas added
  4. temperatureThe reaction mixture was gradually warmed to 25° C.
  5. stirringstirred for 18 hr
  6. customThe reaction mixture was evaporated to dryness
  7. additionfollowed by addition of crushed ice
  8. customto precipitate solid product
  9. filtrationThe solid product was filtered
  10. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-f4612db06a6d4efa8cbee81a7783165b
Source dataset
uspto-grants-2015_07
Patent number
US09073943B2

Reaction notes

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