2-Dimethylaminopyridine → HCID 86704072, compound

HRID 2206380Notes

Reaction equation

HRID 2206380 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[Cl:56][C:57]1[C:58]([F:100])=[C:59]([C@@H:63]2[C@:67]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][C:71]=3[F:77])([C:68]#[N:69])[C@H:66]([CH2:78][C:79]([CH3:82])([CH3:81])[CH3:80])[NH:65][C@H:64]2[C:83]([NH:85][C:86]2[CH:97]=[CH:96][C:89]([C:90]([O:92][CH2:93][CH2:94]O)=[O:91])=[CH:88][C:87]=2[O:98][CH3:99])=[O:84])[CH:60]=[CH:61][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([O:12][CH2:94][CH2:93][O:92][C:90](=[O:91])[C:89]1[CH:96]=[CH:97][C:86]([NH:85][C:83]([C@H:64]2[C@H:63]([C:59]3[CH:60]=[CH:61][CH:62]=[C:57]([Cl:56])[C:58]=3[F:100])[C@:67]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][C:71]=3[F:77])([C:68]#[N:69])[C@H:66]([CH2:78][C:79]([CH3:80])([CH3:81])[CH3:82])[NH:65]2)=[O:84])=[C:87]([O:98][CH3:99])[CH:88]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 218852-DimethylaminopyridineHCID 81531DiisopropylethylamineHCID 2684712-N-Boc-aminopropionic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 72550676HCID 72550676, compound

Product 1

HCID 86704072HCID 86704072, compoundYield 73%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (S)-L-(2-(tert-butoxycarbonylamino)propanoic acid (Chem-Impex, 13.6 mg, 0.072 mmol), HATU (Bachem, 27.3 mg, 0.072 mmol), N,N-diisopropylethylamine (18.6 mg, 0.025 mL, 0.144 mmol) and dimethylaminopyridine (Aldrich, 2.2 mg, 0.018 mmol) in dimethyl formamide (8 mL) was stirred for 10 min before 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 1, 19 mg, 0.028 mmol) in dimethyl formamide (1 mL) was added. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed successively with aqueous sodium bicarbonate solution, water (3×15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (hexane/ethyl acetate, 95/5 to 65/35) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((S)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester as a white solid (17 mg, 71% yield). MS (ES+) m/z calcd. for C41H47Cl2F2N4O8 [(M+H)+]: 831. found: 831.

Workup

  1. additionwas added
  2. washwashed successively with aqueous sodium bicarbonate solution, water (3×15 mL) and brine (15 mL)
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationconcentrated
  5. customThe crude material was purified by flash chromatography (hexane/ethyl acetate, 95/5 to 65/35)

Sources & evidence

ORD record
ord-52a7c57bd019420599ea26c1c40c3fd1
Source dataset
uspto-grants-2016_06
Patent number
US09371280B2

Reaction notes

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