Dichloromethane → Tivantinib

HRID 541016Notes

Reaction equation

HRID 541016 reaction equation
[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C(Cl)Cl.C(Cl)Cl>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1

Participants

4

Reactant 2

HCID 6344DichloromethaneHCID 53251814HCID 53251814, compound

Product 1

HCID 11494412Tivantinib

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A feed solution for multicolumn chromatography (MCC) is prepared by dissolving Compound 8 DCM in methanol. The resulting DCM/methanol co-solvent is distilled until the residual level of DCM in the feed solution reaches a level acceptable for contact with the Chiral Stationary Phase (CSP), i.e., <0.1% by weight. The batch is diluted in a mixture of methanol/Acetonitrile (9:1) to a concentration of 50 mg/mL and introduced to the chromatographic system. Chiralpak AZ (CSP) can be utilized. The raffinate is monitored by chiral HPLC analysis and chromatographic parameters are tuned to obtain >99% chiral purity of (−)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (Compound 10 in Scheme I). Raffinate is pooled and concentrated batchwise as the separation proceeds. The collected raffinate is taken to a larger reactor and the volume is reduced. Compound 10 is then isolated by crystallization.

Workup

  1. customA feed solution for multicolumn chromatography (MCC) is prepared
  2. distillationThe resulting DCM/methanol co-solvent is distilled until the residual level of DCM in the feed solution
  3. additionThe batch is diluted in a mixture of methanol/Acetonitrile (9:1) to a concentration of 50 mg/mL
  4. additionintroduced to the chromatographic system

Sources & evidence

ORD record
ord-5e3948e127e245ea91e84558f62c66ae
Source dataset
uspto-grants-2014_10
Patent number
US08871933B2

Reaction notes

Loading…