Sodium Hydroxide → Asenapine

HRID 2425537Notes

Reaction equation

HRID 2425537 reaction equation
[Cl-].[Cl-].[Cl-].[Al+3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C@H:18]3[CH2:19][N:20]([C:22](OCC)=O)[CH2:21][C@@H:17]3[C:16]=2[CH:34]=1.[OH-].[Na+]>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C@H:18]3[CH2:19][N:20]([CH3:22])[CH2:21][C@@H:17]3[C:16]=2[CH:34]=1

Participants

6

Reactant 4

HCID 14798Sodium HydroxideHCID 6451240Aluminum(III) ChlorideHCID 21226445Aluminium lithium hydrideHCID 57864748HCID 57864748, compound

Product 1

HCID 163091AsenapineYield 72.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-10 °C

Procedure

Aluminium trichloride (4.1 g, 30.8 mmol, 2 eq.) was added to THF (20 ml) at 0° C. while stirring under inert nitrogen atmosphere and cooling with an ice bath. LiAlH4 (3.6 g, 94.7 mmol, 6 eq.) was then added portionwise while stirring over 15 minutes. After the addition was complete the resulting grey mixture was stirred for 15 minutes at −10° C., while cooling with an ice-acetone bath. Additional THF (10 ml) was added. Then a solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-ethoxycarbonyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (Example 18; 5.4 g, 15.7 mmol) in THF (20 ml) was added dropwise over 15 minutes to the in situ prepared alane reagent while stirring and cooling at −10° C. After the addition was complete the reaction mixture was stirred for an additional hour at −10° C. and then for 30 minutes while warming to room temperature. The resulting reaction mixture was carefully poured out in portions to dilute aqueous NaOH (75 ml 30% NaOH and 175 ml water) in a 1000 ml Erlenmeyer flask. After 15 minutes stirring the mixture was extracted with toluene (3×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (asenapine) (3.26 g, 11.44 mmol) in 73% c.y. as a brown oil. According to LC-MS ca. 60% pure. MS: M+1=286, 288 found. 1H-NMR (CDCl3) δ (ppm) identical data as above.

Workup

  1. temperaturecooling with an ice bath
  2. stirringwhile stirring over 15 minutes
  3. additionAfter the addition
  4. stirringwas stirred for 15 minutes at −10° C.
  5. temperaturewhile cooling with an ice-acetone bath
  6. customprepared alane reagent
  7. stirringwhile stirring
  8. additionAfter the addition
  9. stirringwas stirred for an additional hour at −10° C.
  10. temperaturefor 30 minutes while warming to room temperature
  11. customThe resulting reaction mixture
  12. stirringAfter 15 minutes stirring the mixture
  13. extractionwas extracted with toluene (3×150 ml)
  14. dry with materialThe combined organic layers were dried with Na2SO4
  15. customEvaporation under vacuum

Sources & evidence

ORD record
ord-7f8f075cba054649a012600cc5c87421
Source dataset
uspto-grants-2011_06
Patent number
US07964739B2

Reaction notes

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