Sodium Methoxide → Razuprotafib sodium

HRID 60063Notes

Reaction equation

HRID 60063 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:7]([NH:9][C@H:10]([C:23]1[N:24]=[C:25]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[S:26][CH:27]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19](=[O:22])(=[O:21])[O-:20])=[CH:14][CH:13]=1)=[O:8])=[O:4].C[NH+](C)C.C[O-].[Na+:46]>CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:7]([NH:9][C@H:10]([C:23]1[N:24]=[C:25]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[S:26][CH:27]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][S:19](=[O:21])(=[O:20])[O-:22])=[CH:16][CH:17]=1)=[O:8])=[O:4].[Na+:46]

Participants

4

Reactant 2

HCID 10942334Sodium Methoxide3×HCID 131737074HCID 131737074, compound

Product 1

HCID 90403964Razuprotafib sodium

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
22 °C

Procedure

trimethyl-ammonium (4-((S)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)-phenyl)sulfamate (70) was added to a stirred reactor containing methanol (MeOH) (4.87 vol.) and sodium methoxide (25% solution in MeOH) (0.093 eq.). Sodium methoxide (25% solution in MeOH) (1.08 eq.) was added over 5 minutes while maintaining the temperature at 19 to 25° C. The resulting mixture was stirred at 19-25° C. for 30 to 60 minutes then 2 portions of sodium methoxide (25% solution in MeOH) (0.14 eq. and 0.07 eq.) are added over 30 minutes while maintaining the temperature at 19 to 25° C. The resulting mixture was stirred for 30 to 60 minutes while maintaining the temperature at 19 to 25° C. The reaction mixture was then filtered and the filter cake washed with methanol (MeOH). The filtrates and cake washes are concentrated under reduced pressure at 30 to 40° C. to approximately 8 volumes. The reaction mixture was cooled to 19 to 25° C. and methyl t-butyl ether (10 vol) was then added. The reaction mixture was then stirred for 15 to 20 minutes. The resulting solids are isolated by filtration and the filter cake was washed with MTBE. The wet cake was dried under vacuum at room temperature or 35-40° C. for a minimum of 2 hours to afford the desired product.

Workup

  1. temperaturewhile maintaining the temperature at 19 to 25° C
  2. stirringThe resulting mixture was stirred for 30 to 60 minutes
  3. temperaturewhile maintaining the temperature at 19 to 25° C
  4. filtrationThe reaction mixture was then filtered
  5. washthe filter cake washed with methanol (MeOH)
  6. concentrationThe filtrates and cake washes are concentrated under reduced pressure at 30 to 40° C. to approximately 8 volumes
  7. temperatureThe reaction mixture was cooled to 19 to 25° C.
  8. additionmethyl t-butyl ether (10 vol) was then added
  9. stirringThe reaction mixture was then stirred for 15 to 20 minutes
  10. customThe resulting solids are isolated by filtration
  11. washthe filter cake was washed with MTBE
  12. customThe wet cake was dried under vacuum at room temperature or 35-40° C. for a minimum of 2 hours

Sources & evidence

ORD record
ord-04766aa3e2db448581fc4b7628cd43fd
Source dataset
uspto-grants-2016_09
Patent number
US09440963B2

Reaction notes

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