| Molecular Formula | C29H32N2O6S |
| Molar Mass | 536.64 |
| Physical and Chemical Properties | Chemical Properties Simodil Fumarate (Semotiadil Fumarate):C29H32N2O6S?C4H4O4. [116476-14-3]. Crystallized from ethanol, melting point 134-135 ℃. [α]D23 195 ° (dimethyl sulfoxide). |
| Use | Use calcium antagonist. For the treatment of diseases of the cardiovascular system. |
| Raw Materials | N,N-Dimethylformamide Chloroform Magnesium sulfate Sodium bicarbonate Silica gel Mineral oil Fumaric acid 1-Bromo-3-chloropropane Midinyanglin |
Starting from the racemic compound (I), the final racemic product is synthesized and then resolved. Compound (I)(30.1g,0.10 mo1) is dissolved in 60ml of dry dimethylformamide, sodium hydride (60% mineral oil suspension, 4.80g,0.12 mo1) is added dropwise at 0 ℃ in 40ml of dry solution of dimethylformamide, and then stirred at room temperature for 30min. 1-bromo-3-chloropropane (18.9g,0.12 mo1) was added to a solution in 30ml of dry dimethylformamide and stirred at room temperature for 2h. Pour into 700ml of water, extract with ethyl acetate, the extract is washed with water and hydrochloric acid, anhydrous magnesium sulfate is dried, and then concentrated under reduced pressure. The precipitated crystals were washed with methanol to obtain 33.3g compound (II) with 88% yield and melting point of 97-99 ℃.
Compound (II)(11.3g,30.0 mo1) N-methyl-N-[2-[3,4-(methylene dioxy) phenoxy] ethyl] amine (III, 6.15g,31.5 mmo1) is dissolved in 60ml of dried dimethylformamide, sodium bicarbonate (7.56g,90 mmo1) and sodium iodide (8.99g,60 mmo1) are added, and stirred at 70-80. After cooling, 200ml of water was added for water treatment and then extracted with ethyl acetate. The extract is washed with water and salt water, anhydrous magnesium sulfate is dried, and concentrated in vacuum. The remaining oil was chromatography with silica gel and eluted with chloroform-methanol (50:1) to obtain an oily racemic simodil product. Dissolve it in ethyl acetate and add an ethanol solution with a slight excess of fumaric acid. The precipitated crystals were collected by filtration and recrystallized with ethanol to obtain 13.3g of racemic imodil fumarate with a 68% yield.
Silamodil (10.73g,20.0 mmo1) was dissolved in 15ml of acetone, (+)-mandelic acid (1.52g,10.0 mmo1) was added in 18ml of cyclohexane solution, and stirred at room temperature for 1 day. Filter to collect the precipitated precipitate, dry to obtain 5.92g of white powder (+)-fumarate; Then recrystallize with acetone to obtain 4.40g of white crystal with melting point of 114~115 ℃ and [α]D23 +206 (C = 1.1, dimethyl sulfoxide). The filtrate is concentrated under reduced pressure, the remaining oil is dissolved in 40ml of dichloromethane, 20ml of 0.5mol/L sodium hydroxide is added for treatment, then washed with salt water and dried with anhydrous magnesium sulfate. Filtration, concentration, residue dissolved in 14ml of acetone. Add (-)-mandelic acid (1.52g,10.0 mmo1) in 14ml of cyclohexane solution, stir at room temperature for 1h, and then place in the refrigerator for 2h. The precipitate was filtered and collected to obtain 5.97g of (-)-mandelic acid salt of white powder. Recrystallization with acetone to obtain 4.67g of white crystal with melting point of 114~115 ℃ and [α]D23-214 (C = 1.0, dimethyl sulfoxide).
The (+)-mandelate (4.40g,6.38 mmo1) obtained above is suspended in 27ml of dichloromethane, treated with saturated sodium bicarbonate, washed with salt water, and dried with anhydrous magnesium sulfate. Filter, concentrate, dissolve the residue in 9ml of ethyl acetate, add fumaric acid (0.74g,6.38 mmo1) in a hot solution of 18ml of ethanol, stir at room temperature for 1h, and then place in the refrigerator for 10h. The precipitate was collected by filtration and recrystallized with 18ml of ethanol to obtain 3.38g(+)-simodil (100
Compound (I) (202.7g, 673mmo1) and compound (IV) (312.3g, 1.01mo1) are dissolved in 850ML of dimethylformamide, and N, n’ s are added under ice bath cooling- Dicyclohexylcarbodiimide (DCC, 208.3g, 1.01mo1) in 500ml pyridine solution and 4- (dimethylamino) pyridine (13.3g, 1.01mo1) were stirred at room temperature for 4H. Pour the reaction solution into the mixture of water ethyl acetate (6 l:1.7 L), add oxalic acid (30.3g, 337mmo1), and stir at room temperature for 15min. The precipitation was removed by filtration, the filtrate was stratified, and the water layer was extracted with ethyl acetate. The extract is combined with the organic layer, washed with water and brine, dried with anhydrous magnesium sulfate, and concentrated to obtain brown oil. 171.6g compound (V) was obtained by silica gel chromatography and elution with hexane benzene ethyl acetate (1:5:2), with a yield of 48%; And 179.6g of compound (ⅵ) in 45% yield< br /> At 0 ℃, add sodium borohydride (58.6g, 1.55mo1) to calcium dichloride (179.8g, 1.62mo1) in 460ml tetrahydrofuran suspension to obtain calcium borohydride solution. At -10 ℃, add a solution of compound (V) (183.1g, 309mmol) in 1.2L ethanol and ammonium chloride (165.8g, 3.10mo1), and stir for 12h. After treatment with 2.5L 1mol/l hydrochloric acid, concentrate under reduced pressure, and then extract with ethyl acetate. The extract was washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was eluted with hexane ethyl acetate chloroform (1:1:8) by silica gel column chromatography and recrystallized with benzene to obtain 69.9g (+) - (I) in 75% yield, melting point 161 ~ 162 ℃, [α] D23+40° (c=1.17, chloroform)< br /> (+) - (Ⅰ) (10.0g, 33.2mmo1) and diethyl azodicarboxylate (17.4g, 99.6mmo1) are dissolved in dry dimethoxyethane tetrahydrofuran (10ml:1.55m1) mixture. Under the protection of nitrogen, 0 ~ 5 ℃ and stirring, add the above mixed liquid dropwise to the solution of 3-bromo-1-propanol (13.8g, 99.6mmo1) and triphenylphosphine (26.1g, 99.6mmo1) in 100ml of dry dimethylformamide in 25min. After treatment with 30ml0.5mol/l hydrochloric acid, it is concentrated under reduced pressure. The precipitated crystals were removed by filtration. The filtrate was chromatographed with silica gel and eluted with hexane benzene ethyl acetate (5:15:1). Recrystallization with isopropanol gave 2.53g (+) - (Ⅶ) in 18.1% yield< br /> (+) - (Ⅶ) (2.43g, 5.75mmo1) is dissolved in 60ml acetone, sodium iodide (8.62g, 57.5mmo1) is added and refluxed for 20h. Evaporate the solvent, dissolve the residue in ethyl acetate, wash with water and salt water, and dry with anhydrous magnesium sulfate. Evaporate the solvent, dissolve the residue in 25ml of dry dimethylformamide, add compound (III) (1.46G, 7.48mmo1) and triethylamine (0.58g, 5.75mmo1), and stir at 50 ℃ for 1.5h. Pour into water and extract with ethyl acetate. The extract was washed with brine, dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was chromatographed on silica gel column and eluted with chloroform methanol (50:1) to obtain oily (+) - smodil. Dissolve it in ethyl acetate, add slightly excessive ethanol solution of fumaric acid, filter the precipitated crystal, and then recrystallize it with ethanol to obtain 2.1lg (+) - smodil fumarate, with a yield of 56.2%< br /> (-) - smodil fumarate can also be obtained from (-) - (I)