Diisopropylethylamine → HCID 86680101, compound

HRID 1915894Notes

Reaction equation

HRID 1915894 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[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:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[F:86][C:80]1[CH:81]=[CH:82][CH:83]=[C:84]([F:85])[C:79]=1[C:77]1[S:78][C:74]([NH:73][C:71](=[O:72])[O:70][C:66]([CH3:68])([CH3:67])[CH3:69])=[C:75]([C:87](=[O:88])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:23])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]([O:14][CH3:15])[CH2:12][CH2:13]2)[N:76]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 86680102HCID 86680102, compound

Product 1

HCID 86680101HCID 86680101, compoundYield 86.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of Intermediate 54, N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)-2,2,2-trifluoroacetamide (150 mg, 0.45 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (580 mg, 1.12 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (159 mg, 0.45 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 (70-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-methoxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (260 mg, 0.39 mmol) which was stirred with HCl in 1,4-dioxane (4 M, 4.8 mL, 19.3 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvent was removed under reduced pressure and the resulting solid was dissolved in MeOH/water (10 mL/10 mL) and to this was added K2CO3 (267 mg, 19.3 mmol). The reaction mixture was heated at 65° C. for 3 hr. The MeOH was removed under reduced pressure and the aqueous residue was diluted with water (5 mL) and extracted with 5% MeOH in DCM (2×75 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 217 as a beige solid (144 mg, 67% over 3 steps). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.84 (s, 1H), 7.38-7.28 (m, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.15 (s, 2H), 3.72 (s, 3H), 3.37 (s, 3H), 3.36-3.25 (m, 2H), 3.22-3.08 (m, 3H), 3.07-2.99 (m, 1H), 2.17-2.10 (m, 1H), 2.02-1.93 (m, 1H), 1.88-1.65 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 478 (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 (70-80% EtOAc/isohexane)

Sources & evidence

ORD record
ord-bf13b28725a1469ea1a7247b6538389d
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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