Hydrochloric Acid → HCID 69675356, compound

HRID 1751471Notes

Reaction equation

HRID 1751471 reaction equation
C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH:44]7[CH2:45][CH:41]([CH2:42][CH2:43]7)[N:40]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:61][O:62][C:63]([NH:65][CH:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)C(O)=O)=[O:64].CCN(C(C)C)C(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[CH3:58][O:57][C:55](=[O:56])[NH:54][CH:47]([CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:46]([N:40]1[CH:39]([C:36]2[NH:35][C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:23]4[CH:22]=[CH:21][C:20]5[C:25](=[CH:26][CH:27]=[C:18]([C:15]6[NH:14][C:13]([CH:9]7[CH2:10][CH2:11][CH2:12][N:8]7[C:6](=[O:5])[CH:66]([NH:65][C:63]([O:62][CH3:61])=[O:64])[C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[N:17][CH:16]=6)[CH:19]=5)[CH:24]=4)=[CH:33][CH:32]=3)=[CH:38][N:37]=2)[CH:44]2[CH2:43][CH:42]1[CH2:41][CH2:45]2)=[O:59]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 596264N-Methoxycarbonyl-2-phenylglycineHCID 69675225HCID 69675225, compoundHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 69675356HCID 69675356, compoundYield 73.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-(5-{6-[4-(2-{2-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-2-azabicyclo[2.2.1]hept-3-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.26 g, 0.32 mmol) in CH2Cl2 (3.5 mL) and MeOH (0.2 mL) was added HCl (in dioxanes, 4 M, 1.6 mL, 6.4 mmol). The resulting solution was stirred at room temperature for 2 h and concentrated. The resulting solid was slurried in CH2Cl2 (3.5 mL) and DMF (0.5 mL). Methoxycarbonylamino-phenyl-acetic acid (0.08 g, 0.39 mmol) and DIPEA (0.250 mL, 1.43 mmol) were added and the solution was cooled to 0° C. (external, ice bath). COMU (0.16 g, 0.36 mmol) was added and the reaction was stirred at 0° C. for 3 h. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate and brine. The aqueous layers were back extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by preparative HPLC (Gemini, 15→60% MeCN in H2O (0.1% TFA)). The combined fractions were concentrated until the aqueous layer remained. A small amount of MeOH was added to make the solution homogenous before it was basified with saturated sodium bicarbonate. The resulting precipitate was filtered, washed with H2O, and dried in vacuo to provide [2-(3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (0.21 g, 72%). LCMS-ESI+: calc'd for C51H54N8O7: 890.41 (M+); Found: 891.95 (M+H+).

Workup

  1. concentrationconcentrated
  2. temperaturethe solution was cooled to 0° C. (external, ice bath)
  3. stirringthe reaction was stirred at 0° C. for 3 h
  4. washwashed with saturated sodium bicarbonate and brine
  5. extractionThe aqueous layers were back extracted with CH2Cl2
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude oil was purified by preparative HPLC (Gemini, 15→60% MeCN in H2O (0.1% TFA))
  9. concentrationThe combined fractions were concentrated until the aqueous layer
  10. additionA small amount of MeOH was added
  11. filtrationThe resulting precipitate was filtered
  12. washwashed with H2O
  13. customdried in vacuo

Sources & evidence

ORD record
ord-0b178eacbbb5471aa858a34a01e8be76
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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