Sodium Chloride → HCID 443938, compound

HRID 1620435Notes

Reaction equation

HRID 1620435 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:26](OCC)=[O:27])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:26]([N:17]1[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:27])[CH2:2]2

Participants

6

Reactant 4

HCID 5234Sodium ChlorideHCID 15381(+-)-3-QuinuclidinolHCID 24758Sodium hydrideHCID 25178885Ethyl (1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Product 1

HCID 443938HCID 443938, compoundYield 93.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
12.5 °C

Procedure

(RS)-3-Quinuclidinol (7.23 g) was added to a solution of (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (10 g) in toluene (50 ml) at 25-30° C. under nitrogen atmosphere. Sodium hydride (60% w/w, 0.27 g) was added to the mixture and the reaction mass was heated to reflux for 24 h. The by-product ethanol was removed azeotropically with toluene and fresh toluene was added to maintain volume of reaction mass. The reaction mass was cooled to 10-15° C. and 10% w/w sodium chloride solution (30 ml) was added slowly at 10-25° C. Then the reaction mass was stirred for about 10 min and toluene layer was separated. The organic layer was then extracted with ˜18% w/w aqueous hydrochloric acid (100 ml) at 10-30° C. The aqueous layer was cooled to 5-10° C. and pH was adjusted to 7.0-7.5 using 40% w/w aqueous sodium hydroxide solution (36 ml). Thereafter, the pH was further adjusted to 9.5-10 using 10% w/w aqueous sodium hydroxide solution (11 ml). The product was extracted with ethyl acetate (100 ml) at 25-30° C. Then the organic layer was washed with water (30 ml) and then it was treated with carbon (0.5 g) at 25-30° C. for 30 min. The carbon was removed by filtration through hyflo and the residue was washed with ethyl acetate (20 ml). Thereafter, the filtrate was concentrated under reduced pressure at 40-50° C. to produce 12 g of (1S)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid (3RS)-1-azabicyclo[2.2.2]oct-3-yl ester (Solifenacin and its diastereomer) as a pale yellow oil.

Workup

  1. temperaturethe reaction mass was heated
  2. temperatureto reflux for 24 h
  3. customThe by-product ethanol was removed azeotropically with toluene and fresh toluene
  4. additionwas added
  5. temperatureto maintain
  6. customvolume of reaction mass
  7. customtoluene layer was separated
  8. extractionThe organic layer was then extracted with ˜18% w/w aqueous hydrochloric acid (100 ml) at 10-30° C
  9. temperatureThe aqueous layer was cooled to 5-10° C.
  10. extractionThe product was extracted with ethyl acetate (100 ml) at 25-30° C
  11. washThen the organic layer was washed with water (30 ml)
  12. additionit was treated with carbon (0.5 g) at 25-30° C. for 30 min
  13. customThe carbon was removed by filtration through hyflo
  14. washthe residue was washed with ethyl acetate (20 ml)
  15. concentrationThereafter, the filtrate was concentrated under reduced pressure at 40-50° C.

Sources & evidence

ORD record
ord-665da199200c42c18712a4fe12ca5c02
Source dataset
uspto-grants-2014_07
Patent number
US08772491B2

Reaction notes

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