Sodium Hydroxide → (2S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid

HRID 472885Notes

Reaction equation

HRID 472885 reaction equation
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:32]=2[CH3:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:32]=2[CH3:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 68053272(2S)-ethyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate

Product 1

HCID 66693244(2S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acidYield 55.9%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
75 °C

Procedure

A solution of (2S)-ethyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.025 g, 0.043 mmol) in MeOH (2 mL) was treated with 1.0 M NaOH (0.215 mL, 0.215 mmol) and the reaction was stirred with heating (75° C. oil bath) for 16 hrs. The reaction was concentrated under reduced pressure to give a white paste. This was partitioned between 0.1N HCl (5 mL) and CH2Cl2 (5 mL). The layers were separated and the organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure, affording an off-white solid. The product was purified by preparative-HPLC. Product fractions were pooled and concentrated to 1/2 volume and the resulting solid was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure, affording the product, (2S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (0.014 g, 0.024 mmol, 55.9% yield), as an off-white solid. 1H NMR (500 MHz, CDCl3) d: 7.69-7.64 (m, 1H), 7.57 (dt, J=7.0, 1.7 Hz, 1H), 7.36-7.28 (m, 2H), 6.89 (d, J=10.7 Hz, 1H), 5.06 (s, 1H), 4.30 (t, J=5.2 Hz, 2H), 2.77-2.69 (m, 5H), 2.53-2.48 (m, 3H), 2.14 (m, 2H), 1.91 (s, 3H), 1.21-1.17 (m, 9H). LCMS (M+H)=552.4. The following examples 159-164 were prepared according to the procedure for Example 158 using appropriate esters.

Workup

  1. concentrationThe reaction was concentrated under reduced pressure
  2. customto give a white paste
  3. customThis was partitioned between 0.1N HCl (5 mL) and CH2Cl2 (5 mL)
  4. customThe layers were separated
  5. dry with materialthe organic layer was dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customaffording an off-white solid
  9. customThe product was purified by preparative-HPLC
  10. concentrationconcentrated to 1/2 volume
  11. extractionthe resulting solid was extracted with CH2Cl2 (2×10 mL)
  12. dry with materialThe combined organic extracts were dried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-5e98fe36272a4ec3b71fc0ea77f759f8
Source dataset
uspto-grants-2014_01
Patent number
US08633200B2

Reaction notes

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