2-[2-(2-chloroethoxy)ethoxy]ethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of freshly distilled N-methylaniline (116 g, 1.1 mol), potassium carbonate (175 g, 1.25 mol), sodium iodide (4 g, 0.025 mol), 2-[2-(2-chloroethoxy)ethoxy]ethanol (168 g, 1 mol), and 900 mL of butanol was heated at reflux for 72 hours under nitrogen with vigorous stirring. After cooling and filtration the butanol was evaporated at reduced pressure to leave a tan oil. The oil was fractionally distilled in vacuo, yielding 150 g (63%) as a colorless oil, bp 190°-191° C. (0.13 mm). was heated at reflux for 72 hours under nitrogen with vigorous stirring After cooling filtration the butanol was evaporated at reduced pressure to leave a tan oil The oil was fractionally distilled in vacuo yielding 150 g (63%) as a colorless oil, bp 190°-191° C. (0.13 mm)

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

Procedure: One hundred grams (0.59 mole) of 2-[2-(2-chloroethoxy)ethoxy]-ethanol (Aldrich 16,297-3) was added to a solution of 450 g. (3 mol) of sodium iodide in 2.5 l acetone and stirred, in the dark, for 5 hours at reflux and then at room temperature for 16 hours. The precipitate was filtered and the acetone evaporated off at 30° C. The residue was dissolved in chloroform, extracted with saturated sodium chloride solution, and then with saturated sodium bisulfate solution. The chloroform extract was dried (MgSO4) and evaporated at room temperature to yield 137 g. (53%) of the title compound. in the dark, for 5 hours at reflux The precipitate was filtered the acetone evaporated off at 30° C The residue was dissolved in chloroform extracted with saturated sodium chloride solution The chloroform extract was dried (MgSO4) evaporated at room temperature to yield 137 g

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

Procedure: One hundred grams (0.59 mole) of 2-[2-(2-chloroethoxy)ethoxy]-ethanol (Aldrich 16,297-3) was added to a solution of 450 g. (3 mol) of sodium iodide in 2.5 l acetone and stirred, in the dark, for 5 hours at reflux and then at room temperature for 16 hours. The precipitate was filtered and the acetone evaporated off at 30° C. The residue was dissolved in chloroform, extracted with saturated sodium chloride solution, and then with saturated sodium bisulfate solution. The chloroform extract was dried (MgSO4) and evaporated at room temperature to yield 137 g. (53%) of the title compound. in the dark, for 5 hours at reflux The precipitate was filtered the acetone evaporated off at 30° C The residue was dissolved in chloroform extracted with saturated sodium chloride solution The chloroform extract was dried (MgSO4) evaporated at room temperature to yield 137 g

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

Procedure: A process for preparing (-)-2-{[2-(2-Amino-ethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, the compound of formula XXIV: ##STR77## wherein 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassium phthalimide, in dimethylformamide in the heated state, to form 2-[2-(2-phthalimido-ethoxy)ethoxy]ethanol, the compound of formula XIV: ##STR78## which is converted by means of Jones reagent to 2-[2-(2-phthalimidoethoxy)ethoxy] acetic acid, the compound of formula XV ##STR79## which is treated with carbonyldiimidazole and Meldrum's acid in the presence of pyridine in methylene chloride to obtain the compound of formula XVI: ##STR80## which is then reacted with (R)-2-phenyl-2-methoxyethanol, the compound of formula XVII ##STR81## to obtain the β-keto ester of formula XVIII ##STR82## which is condensed in the presence of ammonium formate in ethanol with a benzylidene compound of formula XIX ##STR83## to obtain (4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XX ##STR84## and then: either: this compound is subjected to the action of aqueous sodium bicarbonate solution to obtain (4R,4'R/4S,4'R)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-1,4-dihydropyridine, the compound of formula XXI: ##STR85## which is treated after separation by HPLC in the heated state with a mixture of glyme and sodium ethylate to obtain a mixture containing (-)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}-methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, the compound of formula XXII: ##STR86## and its homolog substituted at the 5-position with an ethoxycarbonyl radical, or: the compound of formula XX is separated by chromatography on a silica column, using a mixture of methylene chloride and ethyl acetate (95:5 V/V) as eluant, to obtain the less polar isomer of 4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, which is then subjected to the action of sodium ethanolate in the presence of glyme in solution in ethanol to obtain a mixture containing the compound of formula XXII and its homolog substituted at the 5-position with an ethoxycarbonyl radical, which is then subjected to the action of carbonyldiimidazole in solution in a halogenated alkane at room temperature to obtain a mixture containing (-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XXIII: ##STR87## and its homolog substituted at the 5-position with an ethoxycarbonyl radical, which mixture is then separated by (reverse phase) HPLC to obtain (-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, which is then brought to reflux in ethanol in the presence of hydrazine hydrate to give the compound of formula XXIV, which can then be salified with a pharmaceutically-compatible organic or inorganic acid.

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

Procedure: 188 g of 2-[2-(2-Chloroethoxy)ethoxy]ethanol and 146 g of potassium phtalimide in 700 ml of dimethylformamide are brought to 95° C. for 17 hours.

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

Procedure: The subject of the present invention is also the process for preparing the (-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, wherein 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassium phthalimide, in dimethylformamide in the heated state, to form 2-[2-(2-phtalimidoethoxy)ethoxy]ethanol the compound of the formula XIV: ##STR14## which is converted by means of Jones reagent to 2-[2-(2-phtalimidoethoxy)ethoxy]acetic acid, the compound of the formula XV: ##STR15## which is treated with carbonyldiimidazole and Meldrum's acid in the presence of pyridine in methylene chloride to obtain the compound of formula XVI: ##STR16## which is then reacted with (R)-2-phenyl-2-methoxyethanol, the compound of formula XVII: ##STR17## to obtain the β-keto ester of formula XVIII: ##STR18## which is condensed in the presence of ammonium formate in ethanol with a benzylidene compound of formula XIX: ##STR19## to obtain (4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XX: ##STR20##

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

Procedure: A 25 ml reaction flask, equipped with a reflux condenser, an oil bath and a magnetic stirrer was charged with 2 g (11.9 mmol) of 2-[2-(2-chloroethoxy)-ethoxy]-ethanol (Fluka), 4 g of sodium iodide and 3 g of sodium hydrogencarbonate in 20 ml of Acetone. The reaction mixture is refluxed over night and when cold, filtered. The filtrate is concentrated at the rotavap, dissolved in 5 ml of CH2Cl2 and filtered again. Then the filtrate is concentrated again at the rotavap to yield 2.5 g of a yellow oil. The NMR shows a pure substance (CDCl3) 2.58 s broad (1H/OH); 3.22 t (2H/CH2-J); 3.53-3.77 m (10H/CH2—O). A 25 ml reaction flask equipped with a reflux condenser, an oil bath and a magnetic stirrer The reaction mixture is refluxed over night when cold, filtered The filtrate is concentrated at the rotavap dissolved in 5 ml of CH2Cl2 filtered again Then the filtrate is concentrated again at the rotavap

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An autoclave (capacity: 500 ml) was charged with 200 parts of methanol and 94.5 parts of triethylamine. After heating the mixture to 130° C., 135 parts of 2-[2-(2-chloro-ethoxy)ethoxy]ethanol was added over a period of 1 hour and the resulting mixture was heated at 130° C. for an additional 4 hours. Crystallization was performed as in Preparation 1 to obtain 205.0 parts of triethyl 2-[2-(2-hydroxy-ethoxy)ethoxy]ethylammonium chloride (yield: 95%). the resulting mixture was heated at 130° C. for an additional 4 hours Crystallization was performed as in Preparation 1

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution in which 2-(2-(2-chloroethoxy)ethoxy)ethanol (3.48 g, 20.63 mmol) of Chemical Formula 7 was dissolved in DMF (15 mL), sodium azide (4.02 g, 61.89 mmol) was added at room temperature, and the mixture was heated to 100° C. and stirred for 12 hours. After the reaction, DMF was removed by vacuum distillation, and the residue was partitioned to distilled water (40 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, and vacuum distilled, and the residue obtained was column chromatographed on silica gel (hexane/ethyl acetate (2:1)) to give 2-(2-(2-azidoethoxy)ethoxy)ethanol (3.05 g, 84%). 1H NMR (500 MHz, CDCl3) δ 3.72-3.74 (m, 2H), 3.65-3.69 (m, 6H), 3.60-3.62 (m, 2H), 3.39 (t, 2H, J=5.0 Hz). was removed by vacuum distillation the residue was partitioned to distilled water (40 mL) and ethyl acetate (150 mL) The organic layer was separated washed with saturated salted water (15 mL) dried with anhydrous sodium sulfate, and vacuum distilled the residue obtained chromatographed on silica gel (hexane/ethyl acetate (2:1))

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

Procedure: Commercial Cl(CH2CH2O)3H (abb. ClE3H) (2.0 mole) and dimethylamine (20.0 mole) were mixed in a flask (3.0 l) fitted with a condenser and stirred (RT) for 30 hours. TLC (Si-gel) examination showed the complete consumption of the ClE3H. Excess dimethylamine was removed by two consecutive evaporations under reduced pressure. The residual material was reconstituted in CHCl3, dried (MgSO4), filtered and evaporated to dryness to produce the product, 8-dimethylamino-3,6-dioxaoctanol. fitted with a condenser the complete consumption of the ClE3H Excess dimethylamine was removed by two consecutive evaporations under reduced pressure dried (MgSO4) filtered evaporated to dryness