ethyl (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This solution was taken for condensation reaction with (RS)-3-quinuclidinol in the next stage to prepare Solifenacin and its diastereomer.

Conditions: temp:12.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

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. 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 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. The product was extracted with ethyl acetate (100 ml) at 25-30° C Then the organic layer was washed with water (30 ml) it was treated with carbon (0.5 g) at 25-30° C. for 30 min The carbon was removed by filtration through hyflo the residue was washed with ethyl acetate (20 ml) Thereafter, the filtrate was concentrated under reduced pressure at 40-50° C.

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl chloroformate (5.61 g) was slowly added to a mixture of methylene chloride (100 ml), (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (10 g) and triethylamine (5.32 g) at 5-15° C. over a period of 30 min. Thereafter, the reaction mass was warmed to 25-30° C. and stirred at 25-30° C. for 1 h. The reaction solution was sequentially washed with water (50 ml), 3% w/w hydrochloric acid (50 ml), water (50 ml) and 5% w/w aqueous sodium chloride (50 ml) at 25-30° C. The solvent was removed under reduced pressure at 30-40° C. to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (13.0 g) as a pale yellow oil. Chromatographic Purity (By HPLC): 99.22%. Thereafter, the reaction The reaction solution was sequentially washed with water (50 ml), 3% w/w hydrochloric acid (50 ml), water (50 ml) and 5% w/w aqueous sodium chloride (50 ml) at 25-30° C The solvent was removed under reduced pressure at 30-40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to the process disclosed in U.S. Pat. No. 6,017,927, Solifenacin may be prepared by condensation of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (III) with ethyl chloroformate to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate of formula (IV), which is further reacted with (R)-(−)-3-quinuclidinol of formula (V) to produce Solifenacin (II). Solifenacin is converted to Solifenacin hydrochloride by treating with HCl.