Fumaric Acid → 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine fumarate methanolate

HRID 57125Notes

Reaction equation

HRID 57125 reaction equation
[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:28])=[N:13][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:15][CH:16]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:29])[CH:3]=1.O.O.O.O.[OH:34][CH:35](C(O)C(O)=O)C(O)=O.CC1C2N=C(C3C(C)=NC(NCCCC4CCN(C)CC4)=NC=3)NC=2C=C(C)C=1.[C:73]([OH:80])(=[O:79])/[CH:74]=[CH:75]/[C:76]([OH:78])=[O:77]>CCOC(C)=O.CO>[CH3:35][O-:34].[C:73]([O-:80])(=[O:79])/[CH:74]=[CH:75]/[C:76]([O-:78])=[O:77].[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:28])=[N:13][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[N:15][CH:16]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:29])[CH:3]=1

Participants

6

Reactant 3

HCID 444972Fumaric AcidHCID 23650961ToreforantHCID 1317319445-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine 2,3-dihydroxybutanedioate tetrahydrate

Product 1

HCID 1317319435-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine fumarate methanolate

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

To a 500 mL Erlenmeyer flask which contained 10.012 g (0.0255 mol) of 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)propyl]-2-pyrimidinamine), compound 2, was added 6.2155 g of fumaric acid (2.1 equivalents) and a stir bar. To that solid mixture, about 300 mL of 1:1 (weight ratio) hot MeOH:EtOAc were added while heating and stirring. The term “hot solvent” is used here so that such solvent is warm based on such solvent boiling point. In some embodiments, hot MeOH:EtOAc was used at a temperature of about 50° C. to 60° C. Additional solvent can be added until all the solids are completely dissolved. The solution mixture was allowed to heat at boiling temperature for another 10 min to give a yellow homogenous solution. The reaction mixture was removed from the heating plate and allowed to cool down to room temperature (rt) on the bench top. Precipitate formed as clusters in the bottom of the flask after 2 days. 13.0702 g of 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine fumarate methanolate (1:2:1), compound 4, as a light yellow solid crystalline were collected by vacuum filter. XRD profiles confirmed the unique pattern of the desired fumarate salt and according to IR-off gas analysis, this material is a methanol solvate of the fumarate salt (4.1% weight loss). Table 8 and FIG. 5 display the impurity profiles for compounds 2 and 4.

Workup

  1. temperaturewhile heating
  2. temperatureis warm
  3. customwas used at a temperature of about 50° C. to 60° C
  4. additionAdditional solvent can be added until all the solids
  5. dissolutionare completely dissolved
  6. temperatureto heat
  7. customfor another 10 min
  8. customto give a yellow homogenous solution
  9. customThe reaction mixture was removed from the heating plate
  10. customPrecipitate formed as clusters in the bottom of the flask after 2 days
  11. custom13.0702 g of 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine fumarate methanolate (1:2:1), compound 4, as a light yellow solid crystalline were collected by vacuum
  12. filtrationfilter

Sources & evidence

ORD record
ord-af1aa5b1854343308f83b7c468404034
Source dataset
uspto-grants-2016_09
Patent number
US09434715B2

Reaction notes

Loading…