1-Hydroxybenzotriazole → GDC-0152

HRID 1019512Notes

Reaction equation

HRID 1019512 reaction equation
[NH2:1][C@@H:2]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:12][C:13]1[S:17][N:16]=[N:15][C:14]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11])=[O:4].C[CH2:31][N:32](C(C)C)[CH:33]([CH3:35])[CH3:34].C1C=CC2N([OH:48])N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.O1CCOCC1>CN(C=O)C.CCOC(C)=O.CC#N.O1CCOCC1>[CH:24]1([C@H:2]([NH:1][C:34](=[O:48])[C@@H:33]([NH:32][CH3:31])[CH3:35])[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][C@H:6]2[C:10]([NH:12][C:13]2[S:17][N:16]=[N:15][C:14]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:11])=[O:4])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1

Participants

10

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 204431481,4-Dioxane hydrochlorideHCID 58911912HCID 58911912, compound

Product 1

HCID 46940575GDC-0152Yield 85%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 18 and DIPEA (5 eq.) in DMF (10-15 vol) was added the Boc-L-N-methyl Ala (1.5 eq), HOBt (1.4 eq), and EDC-HCl (1.4 eq). The reaction was stirred for 1 h, diluted with EtOAc (15 vol) and washed with 1M HCl (2×), NaHCO3 (1×), and brine (1×) (1:1 aq/org). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give afford Boc-protected conjugate product as a beige, foamy solid in ca. 85% yield. The Boc-protected product was dissolved in a solution of 4M HCl/dioxane (4-5 eq acid) and MeCN (0.25 volume eq to the dioxane solution) and stirred at RT for ca. 1 hr. The reaction was concentrated to dryness with toluene (2×) (same volume as deprotection solution) and the resulting solid was slurried in a solution of MTBE/EtOAc (70:30) (minimal volume necessary for easy stirring), filtered and collected to yield crude (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide (d) as an off-white free-flowing solid. The crude HCl salt was suspended in MeOH (4 vol minimum) and dissolved with stirring at 65° C. Warm isopropyl acetate (6-8 vol) was added in two portions, keeping the temperature at ca. 60° C. then the solution was allowed to cool with stirring. Crystallization took place rapidly, the suspension was stirred at RT for several hours, then stirred at 0° C. for an hour before the solid was collected by suction filtration. The crude product was washed with MeOH/iPrOAc (1:4, 2 vol) and dried to 19 as a white/off-white crystalline solid in ca. 80% yield.

Workup

  1. washwashed with 1M HCl (2×), NaHCO3 (1×), and brine (1×) (1:1 aq/org)
  2. extractionThe organic extract
  3. dry with materialwas dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto give
  7. customafford Boc-protected conjugate product as a beige, foamy solid in ca. 85% yield
  8. stirringstirred at RT for ca. 1 hr
  9. concentrationThe reaction was concentrated to dryness with toluene (2×) (same volume as deprotection solution)
  10. filtrationfiltered
  11. customcollected

Sources & evidence

ORD record
ord-3f05bc6311f2460e89381b65f42ea610
Source dataset
uspto-grants-2014_05
Patent number
US08716236B2

Reaction notes

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