O-Xylene → Lurasidone

HRID 1480592Notes

Reaction equation

HRID 1480592 reaction equation
S([O-])(=O)(=O)C.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([N:15]2[CH2:20][CH2:19][N+:18]3([CH2:28][C@H:27]4[C@@H:22]([CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:21]3)[CH2:17][CH2:16]2)=[N:7]1.[C:29]1(=[O:40])[C@H:37]2[C@H:32]([C@H:33]3[CH2:38][C@@H:36]2[CH2:35][CH2:34]3)[C:31](=[O:39])[NH:30]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(C)=CC=CC=1>C(O)(C)C>[CH:13]1[CH:12]=[CH:11][C:10]2[S:6][N:7]=[C:8]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][C@H:22]4[C@H:27]([CH2:28][N:30]5[C:31](=[O:39])[C@H:32]6[C@H:37]([C@H:36]7[CH2:38][C@@H:33]6[CH2:34][CH2:35]7)[C:29]5=[O:40])[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:19][CH2:20]3)[C:9]=2[CH:14]=1

Participants

6

Reactant 4

HCID 7237O-XyleneHCID 11430Potassium CarbonateHCID 10749555(3aR,4S,7R,7aS)-Hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione2×HCID 71578599(3aR,7aR)-4'-(1,2-Benzisothiazol-3-yl)octahydrospiro[2H-isoindole-2,1'-piperaziniuM] Methanesulfonate

Product 1

HCID 213046Lurasidone

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
65 °C

Procedure

100 g (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium mesylate of Formula (G) and 55 g (3aS,4R,7S,7aR)-hexahydro-4,7-methano-1H-isoindole-1,3-(2H)-dione of Formula (E), 55 g potassium carbonate, 400 mg dibenzo-18-crown-ether and 1000 mL xylene were added to round bottom flask at 25 to 35° C. The reaction mass was heated to 130° C. to 140° C. and stirred for 3 hours and cooled to 65° C. The reaction mixture was filtered and washed with 50 mL of xylene. The wet-cake was treated with 200 mL xylene at 65° C. for 30 min. The reaction mixture was cooled to 25° C. and filtered. The filtrate was washed with water and separated organic layer was dried over sodium sulfate, charcoalized and distilled under vacuum below 70° C. to obtain residue. The residue was treated with 200 mL isopropanol at 80 to 85° C. The reaction mass cooled to 25 to 35° C. and cooled to 0 to 5° C. The product was filtered and washed with isopropanol to afford the title compound as lurasidone free base of Formula (H). X-ray powder diffraction pattern (FIG. 3), DSC (FIG. 4).

Workup

  1. temperatureThe reaction mass was heated to 130° C. to 140° C.
  2. filtrationThe reaction mixture was filtered
  3. washwashed with 50 mL of xylene
  4. additionThe wet-cake was treated with 200 mL xylene at 65° C. for 30 min
  5. temperatureThe reaction mixture was cooled to 25° C.
  6. filtrationfiltered
  7. washThe filtrate was washed with water
  8. customseparated organic layer
  9. dry with materialwas dried over sodium sulfate
  10. distillationdistilled under vacuum below 70° C.
  11. customto obtain residue
  12. temperatureThe reaction mass cooled to 25 to 35° C.
  13. temperaturecooled to 0 to 5° C
  14. filtrationThe product was filtered
  15. washwashed with isopropanol

Sources & evidence

ORD record
ord-f80e3940d11b49c6aff261cbba586062
Source dataset
uspto-grants-2016_08
Patent number
US09409899B2

Reaction notes

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