Diisopropylethylamine → HCID 86680099, compound

HRID 1915893Notes

Reaction equation

HRID 1915893 reaction equation
C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].FC1C(N)CCCN(C2NN=CC=2[N+]([O-])=O)C1.[NH2:75][C:76]1[CH:77]=[N:78][N:79]([CH2:96][CH:97]([F:99])[F:98])[C:80]=1[N:81]1[CH2:87][CH2:86][CH:85]([F:88])[CH:84]([NH:89][C:90](=[O:95])[C:91]([F:94])([F:93])[F:92])[CH2:83][CH2:82]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:99][CH:97]([F:98])[CH2:96][N:79]1[C:80]([N:81]2[CH2:82][CH2:83][CH:84]([NH:89][C:90](=[O:95])[C:91]([F:94])([F:93])[F:92])[CH:85]([F:88])[CH2:86][CH2:87]2)=[C:76]([NH:75][C:55]([C:43]2[N:44]=[C:45]([C:47]3[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=3[F:54])[S:46][C:42]=2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:57])[CH:77]=[N:78]1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 86679951HCID 86679951, compoundHCID 86680100HCID 86680100, compound

Product 1

HCID 86680099HCID 86680099, compoundYield 88.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of PyBOP (692 mg, 1.33 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (372 mg, 1.05 mmol) in DCM (40 mL) was stirred at room temperature for 30 min. A solution of Intermediate 51, N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (354 mg, 0.95 mmol) and DIPEA (0.28 mL, 1.62 mmol) in DCM (40 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4-(1-(2,2-difluoroethyl)-5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (600 mg, 0.84 mmol) which was dissolved in HCl in 1,4-dioxane (4 M, 10 mL, 40.0 mmol) and MeOH (10 mL) and heated in a sealed pressure vessel behind a blast shield at 60° C. for 16 hr. The solvents were removed under reduced pressure and the residue re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7 N ammonia in MeOH/DCM to give 203 as an off-white solid (197 mg, 40% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.00 (s, 1H), 7.37-7.29 (m, 1H), 7.09-6.99 (m, 2H), 6.31-6.01 (m, 3H), 4.56-4.28 (m, 3H), 3.39-3.13 (m, 5H), 2.32-2.17 (m, 1H), 2.14-1.94 (m, 2H), 1.77-1.64 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 516 (M+1).

Workup

  1. washwashed with water (20 mL)
  2. customThe organic layer was separated
  3. custompassed through a phase separation cartridge
  4. concentrationconcentrated under reduced pressure
  5. customPurification via silica gel column chromatography (0-5% MeOH/DCM)

Sources & evidence

ORD record
ord-54a53410de19404f8eae860b0ee1a8a1
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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