Diisopropylethylamine → 5-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxamide

HRID 2089440Notes

Reaction equation

HRID 2089440 reaction equation
C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([O:54][CH3:55])[C:48]=2[F:56])=[N:44][C:43]=1[C:57]([OH:59])=O)=O)(C)(C)C.[NH2:60][C:61]1[CH:62]=[N:63][N:64]([CH3:81])[C:65]=1[N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][NH:73]C(=O)OC(C)(C)C)[CH2:68][CH2:67]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([O:54][CH3:55])[C:48]=2[F:56])=[N:44][C:43]=1[C:57]([NH:60][C:61]1[CH:62]=[N:63][N:64]([CH3:81])[C:65]=1[N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][NH2:73])[CH2:68][CH2:67]1)=[O:59]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 58464964tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamateHCID 674370015-(Tert-butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylic acid

Product 1

HCID 584647885-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxamideYield 42%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of PyBOP (211 mg, 0.406 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylic acid (118 mg, 0.31 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (89 mg, 0.29 mmol) and DIPEA (81 μL, 0.46 mmol) in DCM (3 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was re-dissolved in DCM (10 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 354 as a white solid (31 mg, 42%). 1H NMR (400 MHz, d4-MeOD) δ 7.58 (s, 1H), 7.37-6.99 (m, 1H), 7.06 (t, J=10.0 Hz, 1H), 3.93 (s, 3H), 3.73 (s, 3H), 3.29-3.04 (m, 4H), 2.65 (d, J=6.5 Hz, 2H), 1.85 (d, J=12.4 Hz, 2H), 1.70-1.42 (m, 1H), 1.48-1.21 (m, 2H). LCMS (ES+) m/z 478 (M+1).

Workup

  1. washwashed with water
  2. customThe organic layer was separated
  3. custompassed through a phase separation cartridge
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)
  6. dissolutionThe isolated intermediate was re-dissolved in DCM (10 mL)
  7. additionTFA (2 mL) added
  8. stirringThe mixture was stirred at room temperature for 3 hr
  9. concentrationThe mixture was concentrated under reduced pressure
  10. customthe residue purified by preparative HPLC

Sources & evidence

ORD record
ord-08a6d0d91fb84adaa490439b28014106
Source dataset
uspto-grants-2013_05
Patent number
US08436001B2

Reaction notes

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