Diisopropylethylamine → 1-{2-[(1R,3S,5R)-3-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide

HRID 1527601Notes

Reaction equation

HRID 1527601 reaction equation
FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([CH2:21][C:22]([OH:24])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[NH:48]1)=[O:46].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[N:48]1[C:22](=[O:24])[CH2:21][N:13]1[C:14]2=[CH:15][N:16]=[C:17]([CH3:20])[CH:18]=[C:19]2[C:11]([C:8]([NH2:9])=[O:10])=[N:12]1)=[O:46]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68283470(3-Carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)acetic acid trifluoroacetate saltHCID 86673879(1R,3S,5R)-2-Aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoro methoxy-phenyl)-amide trifluoroacetate

Product 1

HCID 682842411-{2-[(1R,3S,5R)-3-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)acetic acid trifluoroacetate salt (3.87 g, 11.1 mmol; prepared as described in Scheme A27) in DMF (45 mL) were successively added (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoro methoxy-phenyl)-amide trifluoroacetate salt (5.00 g, 11.1 mmol), DIPEA (7.77 mL, 44.5 mmol) and HBTU (5.06 g, 13.3 mmol). The reaction mixture was stirred at 25° C. for 2 h and was then concentrated in vacuo. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 5% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined and volatiles were evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 8 to 9 by addition of an aqueous saturated solution of NaHCO3, and then was extracted with CH2Cl2 (×3). The combined organic extracts were dried (phase separator) and concentrated under vacuum to afford the title compound as a white solid. MS: 521 [M+H]+; tR (HPLC conditions c): 3.81 min.

Workup

  1. concentrationwas then concentrated in vacuo
  2. customThe residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 50 mL/min, eluent: 5% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA)
  3. customvolatiles were evaporated under reduced pressure
  4. additionThe resulting aqueous solution was adjusted to pH 8 to 9 by addition of an aqueous saturated solution of NaHCO3
  5. extractionwas extracted with CH2Cl2 (×3)
  6. customThe combined organic extracts were dried (phase separator)
  7. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-b97f13c87dd14ef08aa3d2944e6f7dd4
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

Loading…