Diisopropylethylamine → HCID 86680116, compound

HRID 1915915Notes

Reaction equation

HRID 1915915 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:65]([O:69][C:70]([NH:72][C:73]1[S:77][C:76]([C:78]2[C:83]([F:84])=[CH:82][CH:81]=[CH:80][C:79]=2[F:85])=[N:75][C:74]=1[C:86](O)=[O:87])=[O:71])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[F:85][C:79]1[CH:80]=[CH:81][CH:82]=[C:83]([F:84])[C:78]=1[C:76]1[S:77][C:73]([NH:72][C:70](=[O:71])[O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[C:74]([C:86](=[O:87])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:11]([OH:14])[CH2:12][CH2:13]2)[N:75]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 86680117HCID 86680117, compound

Product 1

HCID 86680116HCID 86680116, compoundYield 23.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyazepan-4-yl)-2,2,2-trifluoroacetamide (504 mg, 1.57 mmol) in DCM (20 mL) was added DIPEA (1.65 mL, 9.42 mmol), PyBOP (1.17 mg, 2.20 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (559 mg, 1.57 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (240 mg, 23%). This solid (240 mg, 0.36 mmol) was stirred with HCl in 1,4-dioxane (4 M, 6 mL, 24 mmol) in MeOH (5 mL) at room temperature for 18 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 333. LCMS (ES+) m/z 464 (M+1)

Workup

  1. washwashed with water (20 mL)
  2. customThe organic layer was separated
  3. dry with materialdried over MgSO4
  4. customthe solvent removed under reduced pressure
  5. customPurification via silica gel column chromatography (0 to 100% EtOAc/heptane)

Sources & evidence

ORD record
ord-7b659699015d47e0a391c1a66634c0bc
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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