Diisopropylethylamine → HCID 71539969, compound

HRID 1915848Notes

Reaction equation

HRID 1915848 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]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=O)(C)(C)C.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][C@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][C@H:65]1[CH3:77])=[O:57]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 86680064HCID 86680064, compound

Product 1

HCID 71539969HCID 71539969, compoundYield 22%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of PyBOP (313 mg, 0.60 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (153 mg, 0.43 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (133 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) in DCM (10 mL) were 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. The isolated intermediate was re-dissolved in DCM (6 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure and the residue re-dissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by preparative HPLC gave 112 as a white solid (41 mg, 22% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.38-7.25 (m, 1H), 7.03 (t, J=9.0 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.93 (m, 4H), 2.59 (dd, J=12.5, 9.5 Hz, 1H), 0.88 (d, J=6.3 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 434 (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. dissolutionThe isolated intermediate was re-dissolved in DCM (6 mL)
  6. additionTFA (2 mL) added
  7. stirringThe mixture was stirred at room temperature for 4 hr
  8. concentrationThe mixture was concentrated under reduced pressure
  9. dissolutionthe residue re-dissolved in DCM (50 mL)
  10. washwashed with saturated aqueous NaHCO3 (2×10 mL)
  11. customThe organic layer was separated
  12. custompassed through a phase separation cartridge
  13. concentrationconcentrated under reduced pressure
  14. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-106f43bcdf234d53b4c2a72987ca6662
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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