Methanesulfonic Acid → Dirlotapide

HRID 490001Notes

Reaction equation

HRID 490001 reaction equation
[Na+].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:31]([O-:33])=O.CS(O)(=O)=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:63]([N:70]([CH3:81])[C:71](=[O:80])[C@H:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[NH2:73])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>ClCCl.C(N(CC)CC)C>[CH2:63]([N:70]([CH3:81])[C:71](=[O:80])[C@@H:72]([NH:73][C:31]([C:4]1[N:3]([CH3:2])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([NH:12][C:13]([C:15]1[C:16]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[CH:9][CH:10]=2)=[O:33])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1

Participants

8

Reactant 5

HCID 6395Methanesulfonic AcidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 689529311-Methyl-5-[4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamido]-1h-indole-2-carboxylic acid sodium saltHCID 68956159(S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride

Product 1

HCID 9917862Dirlotapide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent2×

Conditions

Temperature
2.5 °C

Procedure

1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt (16.0 g), from step (d) alternative A, methanesulfonic acid (2.24 mL), 1-hydroxybenzotriazole hydrate (5.32 g) and N-[3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride (8.66 g) were combined in dichloromethane (384 mL) at 0-5° C. and the mixture stirred for 1 hour. Triethylamine (4.78 ml mL) was added followed by a slurry of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride (11.1 g), from step (e), in dichloromethane (48 mL) was added slowly, maintaining 0-5° C. The resulting slurry was allowed to warm to room temperature overnight. Further triethylamine (2.4 mL) was added at 0° C. After approximately 2 hours, the mixture was twice washed with saturated aqueous sodium hydrogen carbonate (2×200 mL), once washed with 0.5M aqueous hydrochloric acid solution (200 mL) and once washed with demineralized water (200 mL) adjusting to pH=6 with aqueous sodium hydrogen carbonate solution, providing a dichloromethane solution of (S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide.

Workup

  1. additionwas added slowly
  2. temperatureto warm to room temperature overnight
  3. waitAfter approximately 2 hours
  4. washthe mixture was twice washed with saturated aqueous sodium hydrogen carbonate (2×200 mL)
  5. washonce washed with 0.5M aqueous hydrochloric acid solution (200 mL)
  6. washonce washed with demineralized water (200 mL)

Sources & evidence

ORD record
ord-77edc39e4a984f6eb328a2a1cc490787
Source dataset
uspto-grants-2005_12
Patent number
US06979692B2

Reaction notes

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