Hydrochloric Acid → HCID 86708747, compound

HRID 1751458Notes

Reaction equation

HRID 1751458 reaction equation
C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]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:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=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:67]([OH:69])=O)=[O:64].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[CH3:61][O:62][C:63](=[O:64])[NH:65][CH:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]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:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:24][CH:25]=2)=[CH:18][N:19]=1)=[O:69]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 62657Potassium Phosphate, TribasicHCID 596264N-Methoxycarbonyl-2-phenylglycineHCID 696718604,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 86708747HCID 86708747, compoundYield 49%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.04 g, 0.05 mmol) in CH2Cl2 (0.5 mL) and MeOH (0.05 mL) was added HCl (in dioxanes, 4 M, 0.3 mL, 1.2 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The solid was slurried with CH2Cl2 (0.5 mL). Methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.07 mmol) and Potassium Phosphate (0.03 g, 0.14 mmol) were added and the resulting slurry was cooled to 0° C. (external, ice). COMU (0.03 g, 0.06 mmol) was added and the reaction was stirred at room temperature for 2 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated and purified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide to provide {2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (0.02 g, 49%). LCMS-ESI+: calc'd for C49H50F2N8O7: 900.38 (M+); Found: 901.4 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. temperaturethe resulting slurry was cooled to 0° C. (external, ice)
  3. stirringthe reaction was stirred at room temperature for 2 h
  4. filtrationfiltered through celite
  5. concentrationThe filtrate was concentrated
  6. custompurified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA))
  7. customto provide

Sources & evidence

ORD record
ord-b13510228146491a996d0a20e809d739
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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