Veradoline

Originator

Veradoline Hydrochloride,JINGTIAN PORTLINK Co., Ltd.

Uses

Analgesic.

Manufacturing Process

Synthesis of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline:
N-Acetyl-3,4-dimethoxyphenethylamine:
To a stirred solution of β-(3,4-dimethoxyphenyl)-ethylamine (100 g, 0.552 m) and triethylamine (66.6 g, 0,66 m) in CHCl 3 (1 liter) was added acetyl chloride (47.1 g, 0.60 mole) dropwise over a period of 30 min and the mixture stirred overnight. The mixture was washed with 3x500 ml H 2 O, dried over MgSO 4 and evaporated to a solid. The solid was dissolved in 500 ml hot CCl 4 , 300 ml cyclohexane added and allowed to cool slowly. The crystallized solid was collected by filtration and dried to afford N-acetyl-3,4- dimethoxyphenethylamine as a white solid, 112.1 g (91% yield). MP: 99- 100°C.
3,4-Dihydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride:
To a stirred solution of N-acetyl-3,4-dimethoxyphenethylamine (112.1 g, 0.502 m) in toluene (600 ml) maintained at 90-95°C was added dropwise phosphorusoxychloride (180.9 g, 112 ml, 1.179 mole) over a period of 1 hour. The mixture was heated to reflux for 2 hr, cooled to ambient temperature, and the solid hydrochloride salt collected by filtration, 170.4 g (wet with toluene). MP: (after drying) 202-203°C.
1,2,3,4-Tetrahydro-6,7-dimethoxy-l-methylisoquinoline:
To a stirred solution of 3,4-dihydro-6,7-dimethoxy-1-methylisoquioline hydrochloride (47.0 g, 0.229 m) and NaOH (5 g) in absolute methanol (500 ml) was added NaBH 4 (34.6g, 0.917 m) and the mixture stirred for 2 hr (TLC complete) and allowed to stand overnight. The mixture was cooled in an ice bath, treated carefully with 20% HCl until pH 1 was achieved and then heated to 500 for 1 hr. The solvent was then removed on the aspirator and the residue dissolved in 1 liter H 2 O.The solution was basified to pH 11 with NaOH (20%) and extracted with 3 x 250 ml CHCl 3 . The extracts were dried over MgSO 4 and evaporated to give 1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline as an oil, 47.6 g (100% yield).
Alternative method:
A solution of 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride (58.4 g, 0.24 m) in 1 liter of methanol and 5% Pd/C (5 g) were combined under nitrogen in a pressure bottle and the mixture hydrogenated at 40 psi and ambient temperature on a Parr apparatus for 18 hr. The catalyst was removed by filtration and the solvent evaporated. The residue was dissolved in H 2 O (1 liter), basified to pH 11 with 50% NaOH and extracted with CHCl 3 , (3x300 ml). The extracts were dried over MgSO 4 and evaporated to dryness (aspirator, then high vacuum) to give 1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline, 35.2 g (70% yield).
N-(4-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline:
To a stirred solution of 1,2,3,4-tetrahydro 6,7-dimethoxy-1-methyl- isoquinoline (35.2 g, 0.17 m) in methylene chloride (50 ml) under nitrogen at ambient temperature was added p-nitrophenylacetic acid (31.4 g,0.17 m) and then portionwise dicyclohexylcarbodiimide (37.0 g, 0.18 m) and the mixture stirred for 3 hr. The precipitated solid was removed by filtration and the filtrate evaporated to an oily residue. The residue was treated with 500 ml methanol and the solid precipitate collected by filtration to give, after drying, N-(4 nitro-phenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline as a yellow solid, 66.0 g (100% yield). The product contains a small amount of dicyclohexylurea.
The N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline may be obtained by either Method A or Method B:
Method A:
The extracts were dried over MgSO 4 and evaporated to an oily residue. The residue was dissolved in 300 ml of 1:1 methanol:isopropanol and treated with HCl gas until acidic. Upon cooling, a yellow solid was obtained which was collected by filtration and air dried to give 66.4 g (100%) N-(4- nitrophenethyl)-1,2,3,4-tetrahydro-1-methylisoquinoline hydrochloride. The product was slightly wet with isopropanol.
N-(4-Aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline:
N-(4-Nitrophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline N-(4-Nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline (62.9 g, 0.17 m) was added portion-wise to 500 ml of 1 M borane in THF which was diluted with 500 ml THF and maintained under nitrogen. The mixture was stirred at ambient temperature for 1 hr then heated to reflux for 4 hr. The mixture was then cooled in an ice bath and treated carefully with 20% HCl (250 ml). The mixture was refluxed for 1 hr, cooled and then the solvents evaporated on an aspirator. Water (1 liter) was added and the solution basified to pH 11 with 50% NaOH, then extracted with CHCl 3 (3 x 300 ml).
The extracts were dried over MgSO 4 and evaporated to an oily residue. The residue was dissolved in 300 ml of 1:1 methanol:isopropanol and treated with HCl gas until acidic. Upon cooling, a yellow solid was obtained which was collected by filtration and air dried to give 66.4 g (100%) N-(4- nitrophenethyl)-1,2,3,4-tetrahydro-1-methylisoquinoline hydrochloride. The product was slightly wet with isopropanol.
N-(4-Aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- methylisoquinoline:
A solution of N-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7,8-dimethoxy-1- methylisoquinoline hydrochloride (66.3 g, 0.17 m) in methanol (1 liter) and water (10 ml) was placed in an 1100 ml pressure bottle and 5% Pd/C catalyst (5.0 g) added under nitrogen. The mixture was hydrogenated at 40 psi in a Parr apparatus for 20 hr. The catalyst was removed by filtration and the solvent evaporated leaving an oily residue. The residue was dissolved in 95% ethanol (300 ml) and after 24 hr a solid had crystallized out which was collected by filtration and air dried giving 44.3 g (82%) of N-(4- aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline monohydrochloride. The free base could be obtained by basifying a solution of this salt with NaOH and extracting with CHCl 3 . Evaporation of the solvent and crystallization of the resulting oil from cyclohexane gives the base in 80% efficiency as a white solid. MP: 102-103°C on drying at 600 for 26 hr under high vacuum.

Therapeutic Function

Analgesic

Raw materials

Preparation Products