Hydrochloric Acid → (1-{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 1053492Notes

Reaction equation

HRID 1053492 reaction equation
C([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:46][CH2:45]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:60])([F:59])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:72][O:73][C:74]([NH:76][CH:77]([CH:81]([CH3:83])[CH3:82])C(O)=O)=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[CH3:72][O:73][C:74](=[O:75])[NH:76][CH:77]([C:6]([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:45][CH2:46]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:51])[CH3:52])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:59])([F:60])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=[O:5])[CH:81]([CH3:83])[CH3:82]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 138211012-((Methoxycarbonyl)amino)-3-methylbutanoic acidHCID 666212893-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

Product 1

HCID 66621102(1-{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterYield 61.9%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 614 (115 mg, 0.138 mmol) was dissolved in methylene chloride (2 mL) and HCl in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2-(L) Methoxycarbonylamino-3-methyl-butyric acid 611 (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/MeCN w/ 0.1% TFA) to yield compound 6 (76 mg). LCMS-ESI+: calc'd for C49H64F2N8O6: 888.9 (M+). Found: 890.0 (M+H+). 1H-NMR: 300 MHz, (dmso-d6) δ: 8.20-7.99 (m, 8H), 7.73 (s, 2H), 7.37-7.27 (m, 2H), 5.25 (dd, J=7.2 Hz, 1H), 4.78 (s, 1H) 4.54 (s, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.87 (m, 1H), 3.74 (m, 1H), 3.55 (s, 3H), 3.53 (s, 3H), 2.75 (m, 1H), 2.25 (m, 2H), 2.09-2.04 (m, 2H), 1.88-1.79 (m, 2H), 1.54 (m, 1H), 0.94-0.77 (m, 15H) 0.63 (m, 4H) ppm. 19F-NMR: 282 MHz, (dmso-d6) δ: −109.1 ppm [−74.8 ppm TFA].

Workup

  1. customall volatiles were removed in vacuo
  2. customThe crude material was used in the next step without further purification
  3. dissolutionThe crude material was dissolved in DMF (1.5 mL)
  4. stirringThe reaction was stirred at room temperature
  5. waitAfter 20 minutes
  6. washwas washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine
  7. dry with materialwas dried over sodium sulfate
  8. filtrationFiltration and removal of solvents in vacuo
  9. customgave the crude material, which
  10. customwas purified by RP-HPLC (eluent: water/MeCN w/ 0.1% TFA)

Sources & evidence

ORD record
ord-7690b57ebc784c1c8901a530706c71d7
Source dataset
uspto-grants-2016_07
Patent number
US09393256B2

Reaction notes

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