1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → Bavisant dihydrochloride anhydrous

HRID 1192763Notes

Reaction equation

HRID 1192763 reaction equation
[ClH:1].[N:2]1([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30]1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[CH:29]1([N:32]2[CH2:37][CH2:36][N:35]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[CH:17][CH:16]=3)=[O:15])[CH2:34][CH2:33]2)[CH2:31][CH2:30]1

Participants

7

Reactant 4

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27292554-[(Morpholin-4-yl)methyl]benzoic acid--hydrogen chloride (1/1)HCID 27960291-Hydroxybenzotriazole hydrateHCID 47420041-Cyclopropylpiperazine

Product 1

HCID 66712477Bavisant dihydrochloride anhydrous

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
22.5 °C

Procedure

A 100-L glass-lined reactor was charged with toluene (45.00 kg) and stirred at ˜20-25° C. To the stirring toluene was added 4-(4-morpholinylmethyl)benzoic acid hydrochloride (6.50 kg, 93.5%, 24.04 mol), 1-hydroxybenzotriazole monohydrate (2.32 kg, 15.13 mol), 1-cyclopropylpiperazine (3.50 kg, 27.07 mol) and acetonitrile (9.00 kg). The resulting off-white slurry was stirred under N2 at ˜20-25° C. for 40 minutes. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.50 kg, 27.07 mol) was added, followed by an acetonitrile (1.20 kg) rinse. After the addition, the reaction mixture was stirred at ˜20-25° C. overnight. Water (32.50 kg) and aqueous saturated sodium carbonate (19.50 L) were then added to the stirring suspension. The suspension was stirred for an additional 30 minutes. The resulting biphasic solution was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a 50% brine solution [water (19.50 L)/brine (19.50 L)]. To the stirred organic phase was then added anhydrous sodium sulfate (2.86 kg) and the resulting mixture was stirred at ˜20-25° C. for 1.5 hours. The solid sodium sulfate was filtered off and the filter cake was washed with acetonitrile (15.30 kg). The filtrate was transferred to a clean 100-L glass-lined reactor and stirred at ˜20-25° C. Water (0.47 kg) and 5/6N HCl in 2-propanol were added to precipitate the title compound as the corresponding bis-hydrochloride salt as a solid. The solid was filtered, washed with acetonitrile (10.2 kg) and dried (60 Torr, ˜40-45° C.) to a constant weight to yield the title compound as a white solid.

Workup

  1. stirringThe resulting off-white slurry was stirred under N2 at ˜20-25° C. for 40 minutes
  2. washrinse
  3. additionAfter the addition
  4. stirringthe reaction mixture was stirred at ˜20-25° C. overnight
  5. additionWater (32.50 kg) and aqueous saturated sodium carbonate (19.50 L) were then added to the stirring suspension
  6. stirringThe suspension was stirred for an additional 30 minutes
  7. washthe organic phase was washed with a 50% brine solution [water (19.50 L)/brine (19.50 L)]
  8. stirringadded anhydrous sodium sulfate (2.86 kg) and the resulting mixture was stirred at ˜20-25° C. for 1.5 hours
  9. filtrationThe solid sodium sulfate was filtered off
  10. washthe filter cake was washed with acetonitrile (15.30 kg)
  11. stirringstirred at ˜20-25° C
  12. additionWater (0.47 kg) and 5/6N HCl in 2-propanol were added
  13. customto precipitate the title compound as the corresponding bis-hydrochloride salt as a solid
  14. filtrationThe solid was filtered
  15. washwashed with acetonitrile (10.2 kg)
  16. customdried (60 Torr, ˜40-45° C.) to a constant weight

Sources & evidence

ORD record
ord-fbe38c60c5834cb5b6354917f0f6c755
Source dataset
uspto-grants-2014_03
Patent number
US08680273B2

Reaction notes

Loading…