Hydrochloric Acid → Serazapine

HRID 648924Notes

Reaction equation

HRID 648924 reaction equation
[CH3:1][N:2]1[CH2:27][C:26](=O)[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10]3[CH:4]2[C:3]1=O.B#B.Cl>O1CCCC1.CO>[CH3:1][N:2]1[CH2:27][CH2:26][N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10]3[CH:4]2[CH2:3]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 6328200DiboronHCID 14155422HCID 14155422, compound

Product 1

HCID 60677Serazapine

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

A mixture of methyl 1,3,4,16b-tetrahydro-2-methyl-1,4-dioxo-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate (1.48 kg) in tetrahydrofuran (52 L) is heated to reflux under an atmosphere of nitrogen and then a solution of diborane in tetrahydrofuran (1M, 9.47 L) is added over a period of one hour. The reaction mixture is maintained at reflux for 20 hours, at which time it is treated sequentially with methanol (4 L) (slow, cautious addition) and a solution of hydrogen chloride in methanol (7.5N, 1.6 L). The mixture is stirred, refluxed for 2 hours and evaporated in vacuo, and the solid residue obtained is triturated with acetone (4 L) for 1 hour, collected, washed with acetone (4×500 ml) and dried (18 hours, 50°/0.5 mm Hg) to yiled methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate hydrochloride, mp 272°-273° . This salt is suspended in dichloromethane and sufficient ammonium hydroxide (28%) in water is added to liberate the free base. The basic mixture is stirred for 45 minutes, the aqueous layer is removed and discarded and the organic layer is washed with water. The dichloromethane is evaporated in vacuo and the residual foam dissolved in boiling 2-propanol. The solution is filtered to remove a small amount of insolubles, then allowed to cool overnight for complete crystallization. The obtained solid is purified by recrystallization from 2-propanol. The solution is allowed to cool gradually while stirring overnight. The resulting crystals are collected by filtration, washed with 2-propanol and dried (16 hours, 80°/3 mm Hg) to yield methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate, mp 157°-159°, the compound of formula I wherein R1 is methyl, R2 and R3 are hydrogen and R4 is methoxycarbonyl.

Workup

  1. temperatureis heated
  2. temperatureto reflux under an atmosphere of nitrogen
  3. temperatureThe reaction mixture is maintained
  4. temperatureat reflux for 20 hours, at which time it
  5. temperaturerefluxed for 2 hours
  6. customevaporated in vacuo
  7. customthe solid residue obtained
  8. customis triturated with acetone (4 L) for 1 hour
  9. customcollected
  10. washwashed with acetone (4×500 ml)
  11. dry with materialdried (18 hours, 50°/0.5 mm Hg) to yiled methyl 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxylate hydrochloride, mp 272°-273°
  12. additionsufficient ammonium hydroxide (28%) in water is added
  13. stirringThe basic mixture is stirred for 45 minutes
  14. customthe aqueous layer is removed
  15. washthe organic layer is washed with water
  16. customThe dichloromethane is evaporated in vacuo
  17. dissolutionthe residual foam dissolved
  18. filtrationThe solution is filtered
  19. customto remove a small amount of insolubles
  20. temperatureto cool overnight for complete crystallization
  21. customThe obtained solid is purified by recrystallization from 2-propanol
  22. temperatureto cool gradually
  23. stirringwhile stirring overnight
  24. filtrationThe resulting crystals are collected by filtration
  25. washwashed with 2-propanol
  26. customdried (16 hours, 80°/3 mm Hg)

Sources & evidence

ORD record
ord-9e355d04dc654088bc20f8d18c8640f0
Source dataset
uspto-grants-1988_04
Patent number
US04737496

Reaction notes

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