Hydrochloric Acid → HCID 67682288, compound

HRID 1751592Notes

Reaction equation

HRID 1751592 reaction equation
[F:1][C:2]1([F:59])[C:14]2[CH:13]=[C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4C(OC(C)(C)C)=O)=[N:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:32]1[CH:33]=[CH:34][C:35]3[N:39]=[C:38]([C@@H:40]4[C@@H:45]5[CH2:46][C@@H:42]([CH2:43][CH2:44]5)[N:41]4[C:47](=[O:57])[C@@H](NC(OC)=O)C(C)C)[NH:37][C:36]=3[CH:58]=1)=[CH:6][CH:7]=2.Cl.O1C[CH2:65][O:64][CH2:63]C1.[CH3:67][O:68][C:69]([NH:71][C@H:72]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:73]([OH:75])=O)=[O:70].CCOC([C:87](C#N)=[N:88]OC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N([CH:115]([CH3:117])[CH3:116])CC)(C)C.C[OH:119]>>[CH3:65][O:64][C:63]([NH:88][C@@H:87]([CH:115]([CH3:116])[CH3:117])[C:47]([N:41]1[C@H:40]([C:38]2[NH:37][C:36]3[CH:58]=[C:32]([C:5]4[CH:4]=[C:3]5[C:8]([C:9]6[CH:10]=[CH:11][C:12]([C:15]7[NH:19][C:18]([C@@H:20]8[CH2:24][CH2:23][CH2:22][N:21]8[C:73](=[O:75])[C@H:72]([NH:71][C:69](=[O:70])[O:68][CH3:67])[C:76]8[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=8)=[N:17][CH:16]=7)=[CH:13][C:14]=6[C:2]5([F:59])[F:1])=[CH:7][CH:6]=4)[CH:33]=[CH:34][C:35]=3[N:39]=2)[C@@H:45]2[CH2:46][C@H:42]1[CH2:43][CH2:44]2)=[O:57])=[O:119]

Participants

8

Reactant 7

HCID 313Hydrochloric AcidHCID 887MethanolHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 67682549HCID 67682549, compoundHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 67682288HCID 67682288, compoundYield 24%

Conditions

Temperature
0 °C

Procedure

A solution of (S)-tert-butyl 2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (106 mg, 0.13 mmol), methanol (1.5 mL), and 4M HCl in dioxane (1.5 mL, 6 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after thirty minutes. The resulting residue was dissolved in a 4:1 dichloromethane:dimethylformamide solution (1.3 mL). To this solution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (28 mg, 0.13 mmol) and COMU (56 mg, 0.13 mmol) and the reaction was cooled to 0° C. Diisopropylethylamine (0.092 mL, 0.53 mmol) was added and the reaction was stirred at 0° C. for twenty minutes. The reaction was quenched by the addition of formic acid (0.05 mL) and thoroughly concentrated. The resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA) to yield methyl (R)-2-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (28 mg, 24%). LCMS-ESI+: calculated for C50H50F2N8O6: 897.0; observed [M+1]+: 898.1.

Workup

  1. concentrationThe reaction was thoroughly concentrated after thirty minutes
  2. dissolutionThe resulting residue was dissolved in a 4:1 dichloromethane
  3. customThe reaction was quenched by the addition of formic acid (0.05 mL)
  4. concentrationthoroughly concentrated
  5. customThe resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-7ade1a5c5c244eeaba637272cf298a1d
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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