Methyl chloroglyoxylate → Methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate

HRID 472856Notes

Reaction equation

HRID 472856 reaction equation
Br[C:2]1[C:3]([CH3:19])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=2)[C:7]=1Cl.[Li+].[Cl-].C1COCC1.[CH2:27]([Mg]Cl)[CH:28]([CH3:30])[CH3:29].C1COCC1.C([Mg]Cl)C(C)C.Cl[C:45](=[O:50])[C:46]([O:48][CH3:49])=[O:47]>CCOCC.[Cu]Br>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:5]3[N:4]=[C:3]([CH3:19])[C:2]([C:45](=[O:50])[C:46]([O:48][CH3:49])=[O:47])=[C:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:6]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1

Participants

8

Reactant 5

HCID 79846Methyl chloroglyoxylateHCID 68902752LiCl THFHCID 866702846-Bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidineHCID 178418368HCID 178418368, compoundHCID 178420649HCID 178420649, compound

Product 1

HCID 66691806Methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetateYield 34%

Reagents, catalysts & solvents 2

HCID 24593copper(I) bromideCatalystHCID 3283Diethyl EtherSolvent

Procedure

To a stirred solution of 6-bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (0.179 g, 0.5 mmol), copper(I) bromide (0.036 g, 0.250 mmol) and 0.5M LiCl/THF (8 ml, 4.00 mmol) was added 2M i-BuMgCl/THF (2.000 ml, 4.00 mmol) over 5 min at rt. After 2 h, LCMS indicated presence of mostly the unreacted starting material. More iBuMgCl (1 ml) was added and continued stirring at rt for additional 4 h and methyl 2-chloro-2-oxoacetate (0.736 ml, 8.00 mmol) added at once to the reaction mixture, and stirred for additional 1 h. Then, the reaction was diluted with Et2O (50 mL), quenched with Na2CO3 (1 mL), washed with 10 mL each water and brine, dried (Na2SO4), filtered and concentrated to give orange paste which was purified by prep-HPLC to afford methyl 2-(2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.0772 g, 0.170 mmol, 34.0% yield) as yellow oil which turned to yellow solid overtime and contaminated with about 15% of 2-(3-chlorophenyl)-7-isobutyl-5-methylpyrazolo[1,5-a]pyrimidine. 1H NMR (500 MHz, CDCl3) δ: 7.98 (d, J=1.8 Hz, 1H), 7.87-7.83 (m, 1H), 7.41-7.31 (m, 2H), 6.87 (s, 1H), 3.97 (s, 3H), 3.13 (d, J=7.3 Hz, 2H), 2.51 (s, 3H), 2.44 (dt, J=13.7, 6.8 Hz, 1H), 0.97 (d, J=6.7 Hz, 6H). LCMS (M+H) calcd for C20H21ClN3O3: 386.13. found: 386.3.

Workup

  1. stirringstirred for additional 1 h
  2. customquenched with Na2CO3 (1 mL)
  3. washwashed with 10 mL each water and brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give orange paste which
  8. customwas purified by prep-HPLC

Sources & evidence

ORD record
ord-394b6fd3f0e4414fbb7a1a268e828fd9
Source dataset
uspto-grants-2014_01
Patent number
US08633200B2

Reaction notes

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