1,1'-Carbonyldiimidazole → tert-butyl (4aR,7aR)-2-benzamido-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate

HRID 338118Notes

Reaction equation

HRID 338118 reaction equation
[NH2:1][C@:2]1([C:16]2[S:20][N:19]=[CH:18][CH:17]=2)[C@H:6]([CH2:7]O)[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:21]([NH:29][C:30]1[S:31][CH2:7][C@@H:6]2[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@:2]2([C:16]2[S:20][N:19]=[CH:18][CH:17]=2)[N:1]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 68284Benzoyl isothiocyanateHCID 86762492tert-Butyl (3R,4R)-3-amino-4-(hydroxymethyl)-3-isothiazol-5-yl-pyrrolidine-1-carboxylate

Product 1

HCID 86762226tert-butyl (4aR,7aR)-2-benzamido-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

tert-Butyl (3R,4R)-3-amino-4-(hydroxymethyl)-3-isothiazol-5-yl-pyrrolidine-1-carboxylate (148.10 g, 494.67 mmol) and tetrahydrofuran (1.48 L) are added together and the solution is cooled to 0° C. Benzoyl isothiocyanate (82.34 g, 504.56 mmol) is added over 5 minutes and the reaction mixture is stirred for 30 minutes at 0° C. and then warmed to room temperature over 1 hour. 1,1′-Carbonyldiimidazole (92.24 g, 568.87 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. The mixture is heated to 65° C. and stirred for a further 12 hours. The reaction mixture is concentrated under reduced pressure and the oily residue is partitioned between water (1.5 L) and ethyl acetate (1.5 L). The pH is adjusted with citric acid 50% w/w aq. solution to 4.0 and the organic layer is separated. The aqueous layer is extracted with MTBE (2×500 mL), the organics are combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is slurried in MTBE (740.50 mL) at 60° C. then at room temperature for 45 minutes. The solid is collected, washed with MTBE (4×150 mL), and dried under vacuum overnight to give the title compound as an off white solid (162.68 g, 74.0%). ES/MS (m/e): 445 (M+H), ee=99.5%.

Workup

  1. temperaturewarmed to room temperature over 1 hour
  2. stirringthe reaction mixture is stirred at room temperature for 2 h
  3. temperatureThe mixture is heated to 65° C.
  4. stirringstirred for a further 12 hours
  5. concentrationThe reaction mixture is concentrated under reduced pressure
  6. customthe oily residue is partitioned between water (1.5 L) and ethyl acetate (1.5 L)
  7. customthe organic layer is separated
  8. extractionThe aqueous layer is extracted with MTBE (2×500 mL)
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. customevaporated under reduced pressure
  12. customis slurried in MTBE (740.50 mL) at 60° C.
  13. waitat room temperature for 45 minutes
  14. customThe solid is collected
  15. washwashed with MTBE (4×150 mL)
  16. customdried under vacuum overnight

Sources & evidence

ORD record
ord-367d374593a44e7b8b44278c5c3408a8
Source dataset
uspto-grants-2014_11
Patent number
US08889856B2

Reaction notes

Loading…