Diethyl Ether → HCID 59632037, compound

HRID 2369091Notes

Reaction equation

HRID 2369091 reaction equation
[N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[N:16]=[C:15](C(OC)=O)[CH:14]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:29][Mg]Br.CC[O:34][CH2:35][CH3:36]>C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[N:16]=[C:15]([C:35]([OH:34])([CH3:36])[CH3:29])[CH:14]=3)=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 59633017HCID 59633017, compoundHCID 178418573HCID 178418573, compound

Product 1

HCID 59632037HCID 59632037, compoundYield 31%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a cooled (−78° C.) solution of methyl 5-(4-(azetidine-1-carbonyl)phenyl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (138 mg, 0.35 mmol) in THF (5 mL) was added methylmagnesium bromide (0.3 mL of a 3.0M solution in ether, 0.9 mmol). The resulting brown solution was allowed to slowly warm to ambient temperature overnight. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and EtOAc. The aqueous was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow film. This crude product was purified by flash column chromatography eluting with a gradient of 0% to 10% MeOH in CH2Cl2. The main peak was collected and was ˜85% pure by HPLC. This material was further purified by reverse phase preparative HPLC eluting with MeCN/H2O with 0.1% TFA. The product fractions from the HPLC were made basic by the careful addition of solid Na2CO3. The resulting mixture was concentrated to remove most of the MeCN. The resulting aqueous suspension was extracted with CH2Cl2 (3×), and the combined extracts were dried over Na2SO4 overnight, filtered and concentrated under reduced pressure to afford azetidin-1-yl(4-(1-(2-chlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)phenyl)methanone (43 mg, 31% yield) as a pale brown powder. 1H NMR (400 MHz CDCl3): δ 7.54-7.48 (2H, m), 7.46-7.40 (2H, m), 7.39-731 (2H, m), 7.24-7.19 (2H, m), 6.54 (1H, s), 4.32-4.16 (4H, m), 2.63 (1H, s), 2.38-2.28 (2H, m), 1.68 (6H, s). MS(ES): 396 [M+H]+.

Workup

  1. customThe reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and EtOAc
  2. extractionThe aqueous was extracted with EtOAc (3×)
  3. washthe combined organic extracts were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto afford a yellow film
  8. customThis crude product was purified by flash column chromatography
  9. washeluting with a gradient of 0% to 10% MeOH in CH2Cl2
  10. customThe main peak was collected
  11. customThis material was further purified by reverse phase preparative HPLC
  12. washeluting with MeCN/H2O with 0.1% TFA
  13. additionThe product fractions from the HPLC were made basic by the careful addition of solid Na2CO3
  14. concentrationThe resulting mixture was concentrated
  15. customto remove most of the MeCN
  16. extractionThe resulting aqueous suspension was extracted with CH2Cl2 (3×)
  17. dry with materialthe combined extracts were dried over Na2SO4 overnight
  18. filtrationfiltered
  19. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-4c8496a386a24299b3c86ba7be6fb8d0
Source dataset
uspto-grants-2014_04
Patent number
US08703805B2

Reaction notes

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