Hydrochloric Acid → Toreforant

HRID 57123Notes

Reaction equation

HRID 57123 reaction equation
S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].Cl.Cl.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([NH2:20])[C:14]=1[NH2:21].Cl.[CH3:23][C:24]1[C:29]([CH:30]=O)=[CH:28][N:27]=[C:26]([NH:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:12][C:13]1[C:14]2[N:21]=[C:30]([C:29]3[C:24]([CH3:23])=[N:25][C:26]([NH:32][CH2:33][CH2:34][CH2:35][CH:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)=[N:27][CH:28]=3)[NH:20][C:15]=2[CH:16]=[C:17]([CH3:19])[CH:18]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 656671Sodium PyrosulfiteHCID 23453402HCID 23453402, compoundHCID 462215604-Methyl-2-((3-(1-methylpiperidin-4-yl)propyl)amino)pyrimidine-5-carbaldehyde

Product 1

HCID 23650961Toreforant

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
22.5 °C

Procedure

In a 100 L glass-lined reactor, sodium metabisulfite (Na2S2O5) (1.96 kg, 9.79 mol) was dissolved in purified water (54.63 kg), followed by the addition of 3,5-dimethyl-1,2-benzenediamine-2HCl (2.07 kg, 9.86 mol) and the resultant mixture stirred at about 20-25° C. to effect solution. Next, concentrated hydrochloric acid (1.65 kg, 16.79 mol) was added, followed by addition of 4-methyl-2-((3-(1-methylpiperidin-4-yl)propyl)amino)pyrimidine-5-carbaldehyde, prepared as in STEP B above (2.74 kg, 9.79 mol) and the resultant mixture stirred at about 23-27° C. to effect solution. The resultant mixture was heated to about 57-62° C. and monitored for completion by HPLC. The reaction mixture was cooled to about 20-25° C. and then half of the volume (˜30 L) was then added, via a metering pump, to a stirring 50 L glass reactor system containing a solution of potassium carbonate (3.9 kg, 28.2 mol) dissolved in purified water (15 kg), resulting in the formation of a precipitate. The precipitated product was stirred for ˜1 h and then allowed to settle. The clear supernatant (˜20 L) was removed from the top of the 50 L reactor system and purified water (˜20 kg) was added. The resultant mixture was stirred for 10 min, filtered, washed with water (13 kg) and dried at 35-40° C. under vacuum to yield solid [5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine, compound 2. MS: [M+H]+=393, 1H NMR (600 MHz, Methanol-d6) δ, 1.38-1.43 (m, 2H), 1.43-1.52 (m, 2H), 1.53-1.61 (br m, 1H), 1.64-1.71 (m, 2H), 1.90-1.96 (br m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.54 (s, 3H), 2.74 (s, 3H), 2.78-2.86 (br m, 2H), 3.15-3.36 (m, 2H), 3.36-3.47 (m, 2H) 4.35 (s, 1H), 6.90 (s, 1H), 7.20 (s, 1H), 8.44 (br s, 1H).

Workup

  1. additionhalf of the volume (˜30 L) was then added, via a metering pump, to a stirring 50 L glass reactor system
  2. customresulting in the formation of a precipitate
  3. customThe clear supernatant (˜20 L) was removed from the top of the 50 L reactor system
  4. custompurified water (˜20 kg)
  5. additionwas added
  6. stirringThe resultant mixture was stirred for 10 min
  7. filtrationfiltered
  8. washwashed with water (13 kg)
  9. customdried at 35-40° C. under vacuum

Sources & evidence

ORD record
ord-ef1ce48a91ce4552aa2ba42a297c6d5c
Source dataset
uspto-grants-2016_09
Patent number
US09434715B2

Reaction notes

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