Tetrahydrofuran → (S)-ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate

HRID 472882

Reaction equation

HRID 472882 reaction equation
[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C(=O)=O.C(#N)C.[B]1OC2C(=CC=CC=2)O1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]

Participants

9

Reactant 5

HCID 8028TetrahydrofuranHCID 6327445BenzcatechinboraneHCID 9838490(R)-2-Methyl-CBS-oxazaborolidineHCID 86587134Acetonitrile dry iceHCID 86670292Ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate

Product 1

HCID 86670293(S)-ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetateYield 88.8%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
-40 °C

Procedure

To a stirred suspension of ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (3.45 g, 8.80 mmol) in anhydrous toluene (200 ml) was added 1.1 M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole in toluene (3.20 ml, 3.52 mmol). The mixture was cooled (−40° C., dry ice/acetonitrile) and a solution of 1.0 M catecholborane in THF (17.59 ml, 17.59 mmol) was added over 1 min. The mixture was maintained at −40° C. for 2 hrs, and then warmed to room temperature with stirring for 16 hrs. The reaction was diluted with EtOAc (600 mL) and sat. Na2CO3 (200 mL). The mixture was stirred vigorously for 30 min, the layers were separated, and the organic layer washed with sat Na2CO3 (5×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography, eluting with 10%-30% EtOAc in hexanes, affording the product, (S)-ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (3.08 g, 7.81 mmol, 84% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 7.85-7.79 (m, 1H), 7.69 (dt, J=7.1, 1.6 Hz, 1H), 7.40-7.32 (m, 2H), 5.71 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.02 (br. s., 1H), 2.60 (s, 3H), 2.47 (s, 3H), 1.21 (t, J=7.2 Hz, 3H). LCMS (M+H)=394.2. Chiral column analysis indicated 98.1% chiral purity (ee: 96.2%).

Workup

  1. temperaturewarmed to room temperature
  2. stirringThe mixture was stirred vigorously for 30 min
  3. customthe layers were separated
  4. washthe organic layer washed
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude product was purified by flash silica gel column chromatography
  9. washeluting with 10%-30% EtOAc in hexanes

Sources & evidence

ORD record
ord-75a2f7e3f69f464f86879e88943d25eb
Source dataset
uspto-grants-2014_01
Patent number
US08633200B2

Linked notes

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