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The mixture was filtered at 30 C., and the warm filtrate was used to rinse residual precipitate onto the filter. The filter cake was washed three times with 10 mL acetic acid at room temperature and dried in a vacuum oven at 55-60 C. under nitrogen flow for eighteen hours to give 9.32 g (1S,2S)-2-[2-[3-(1H-benimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol dioxalate as a white solid, containing one molecule of acetic acid of crystallization per molecule of the dioxalate acid addition salt. Preparation of mibefradil and mibefradil dihydrochloride.
2
sodium tungstate[ No CAS ]
platinum-on-carbon[ No CAS ]
[ 116666-63-8 ]
[1S,2S]-2-[2-[[3-(2-benzimidazolyl)propyl]methyl-N-oxidoamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dihydrogen peroxide; In methanol; dichloromethane; water;
EXAMPLE 13 0.425 g (1 mmol) of <strong>[116666-63-8][1S,2S]-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate</strong> is dissolved in 60 ml of methanol and subsequently treated with 10 ml of 6% hydrogen peroxide and 50 mg (0.15 mmol) of sodium tungstate. After stirring at room temperature for 20 hours 100 mg of platinum-on-carbon (5%) in 2 ml of water are added thereto and the mixture is stirred for a further hour. Thereupon, the mixture is filtered, the filtrate is concentrated, the residue is diluted with a small amount of methylene chloride and the mixture is chromatographed on silica gel with a 15:1 mixture of methylene chloride and methanol as the elution agent. There are thus obtained 0.18 g (35.2%) of a first diastereomer of [1S,2S]-2-[2-[[3-(2-benzimidazolyl)propyl]methyl-N -oxidoamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl- 2-naphthyl methoxyacetate with a Rf value of 0.33, [alpha]58920 =+39.4 (c=0.5%; methanol), and 0.276 g (54%) of a second diasteromer of the named compound with a Rf value of 0.26 (methylene chloride/methanol 6:1), [alpha]58920 =+34.8 (c=0.5%; methanol).
..., R3 signifies hydroxy, isobutyryloxy, methoxyacetyloxy or butylaminocarbonyloxy, R1 signifies fluorine, R2 signifies methyl, X signifies propylene, butylene, pentamethylene or hexamethylene, A signifies 2-benzimidazolyl or 2-benzthiazolyl and n signifies the number 1. 2-[2-[[3-(2-Benzimidazolyl)propyl]methylamino]-ethyl]-6-fluoro-1,2,3,4-tetrahydro-1alpha-isopropyl-2alpha--naphthyl methoxyacetate. [1S,2S]-2-[2-[[5-(2-Benzthiazolyl)pentyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2--naphthyl methoxyacetate. [1S.2S]-2-[2-[[3-(2-Benzimidazolyl)propyl]-methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1--isopropyl-2-naphthyl methoxyacetate.
A suitable calcium channel blocker can illustratively be selected from the following list: Arylalkylamines ... clentiazem diltiazem fendiline gallopamil mibefradil prenylamine semotiadil terodiline ...
A suitable calcium channel blocker can illustratively be selected from the following list: Aryklalkylamines ... clentiazem diltiazem fendiline gallopamil mibefradil prenylamine semotiadil terodiline ...
5
[ 116666-63-8 ]
[ 116666-60-5 ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium hydroxide; In ethanol; at 60.0℃; for 3.4h;Sealed tube;
A mixture of <strong>[116666-63-8]mibefradil</strong> (2 g, 4.04 mmol, 1.0 eq.), EtOH (20 mL 10 vol.) and IN NaOH 20 mL (lOvol), were taken in a sealed tube. The reaction mixture was stirred at 60 C for 3.4 h. The reaction mixture was cool to rt and concentrated under reduced pressure. The residue was taken in water (20 mL) and extracted with DCM. The organic layer was dried over Na2S04 and concentrated. The crude compound was purified on a COMBIFLASH column using 2.6-3% MeOH in DCM as eluent to afford (1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol (1.2 g, 60%). MS: 424.2 m/z (M+H)+.
(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate[ No CAS ]
(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl carbonate[ No CAS ]
Stage #1: mibefradil With sodium hydride In tetrahydrofuran for 0.5h; Inert atmosphere;
Stage #2: C13H17ClO3 In tetrahydrofuran for 16h;
19 Example 19: Synthesis of compound 18b
Under a N2 atmosphere, mibefradil (18a, 1 eq) is dissolved in anhydrous THF before addition of sodium hydride (1.2 eq). After stirring for 30 min, a solution of compound 8 (1.1 eq) in anhydrous THF is added, and the mixture is stirred for 16 h. The solvent is removed in vacuo and the crude material purified by flash chromatography to give 18b.
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