Glycine → HCID 90023918, compound

HRID 523985Notes

Reaction equation

HRID 523985 reaction equation
[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]

Participants

5

Reactant 3

HCID 750GlycineHCID 10942334Sodium MethoxideHCID 118160981HCID 118160981, compound2×

Product 1

HCID 90023918HCID 90023918, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
110 °C

Procedure

A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 8e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 8e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-6-(3,5-difluoro-phenoxy)-isoquinoline-3-carboxamido]acetic acid.

Workup

  1. customA pressure glass reaction flask which
  2. customcap lid
  3. customcan be fitted with a magnetic stirrer
  4. customThe reaction
  5. customThe reaction
  6. temperaturecan then be cooled to 20-25° C.
  7. customThe reaction
  8. filtrationfiltered
  9. washwashed with methanol
  10. customdried under vacuum
  11. dissolutiondissolved in water
  12. extractionextracted with ethyl acetate
  13. customto remove impurities to below 0.1%
  14. customThe ethyl acetate can be removed
  15. additionan acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour
  16. filtrationfiltered
  17. washthe solid washed with water (3×), cold acetone (5-10° C., 2×)
  18. additionthe flask can be charged with acetone
  19. temperaturerefluxed for at least 8 h
  20. temperatureslowly cooled to 5-10° C.
  21. stirringstirred for at least 2-3 h
  22. filtrationfiltered
  23. washwashed with cold acetone (5-10° C., 3×)
  24. customdried under vacuum

Sources & evidence

ORD record
ord-be02976f2dad4378a24e8f6929e5ebc9
Source dataset
uspto-grants-2016_05
Patent number
US09340511B2

Reaction notes

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