Maleic Acid → 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea maleate

HRID 63365Notes

Reaction equation

HRID 63365 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[N:37][CH:36]=[C:35]([CH2:39][CH3:40])[N:34]=4)[CH:27]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]\[C:51]([OH:53])=[O:52]>CC(=O)CC>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]\[C:51]([OH:53])=[O:52].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[N:37][CH:36]=[C:35]([CH2:39][CH3:40])[N:34]=4)[CH:27]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

4

Reactant 2

HCID 444266Maleic AcidHCID 918276051-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea

Product 1

HCID 1183059601-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea maleateYield 78.7%

Reagents, catalysts & solvents 1

HCID 6569Methyl Ethyl KetoneSolvent2×

Conditions

Temperature
60 °C

Procedure

2-Butanone (750 mL) was added to 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea (7.50 g) and the mixture was stirred. The mixture was warmed to 60° C. over 20 min. A solution of maleic acid (1.39 g) in 2-butanone (12 mL) was added to the mixture over 5 min. Spontaneous crystallisation occurred after approximately half of the maleic acid solution was added. The mixture was stirred for 30 min at 60° C. then cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3) then stirred for 30 min at 5° C. then heated to 65° C. over 30 min then stirred for 30 min at 65° C. then cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3) then stirred for 30 min at 5° C. then heated to 65° C. over 30 min then stirred for 30 min at 65° C. then cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3). The product was filtered and washed twice with 2-butanone (50 mL), subsequently dried at 45° C. in vacuo to give 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea maleate (Form 2) (7.0 g).

Workup

  1. customSpontaneous crystallisation
  2. additionwas added
  3. stirringThe mixture was stirred for 30 min at 60° C.
  4. temperaturethen cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3)
  5. stirringthen stirred for 30 min at 5° C.
  6. temperaturethen heated to 65° C. over 30 min
  7. stirringthen stirred for 30 min at 65° C.
  8. temperaturethen cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3)
  9. stirringthen stirred for 30 min at 5° C.
  10. temperaturethen heated to 65° C. over 30 min
  11. stirringthen stirred for 30 min at 65° C.
  12. temperaturethen cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3)
  13. filtrationThe product was filtered
  14. washwashed twice with 2-butanone (50 mL)
  15. customsubsequently dried at 45° C. in vacuo

Sources & evidence

ORD record
ord-deff34e4aebb42ecaff8e55faa5cd880
Source dataset
uspto-grants-2016_09
Patent number
US09447076B2

Reaction notes

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