JPWO2019106238A5 - - Google Patents

Claims (14)

Formula (I)

2-(5-Methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (V) or a pharmaceutically acceptable salt thereof

N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of is reacted with hexamethyldisilazane under acidic conditions and in the presence of a non-reactive solvent to give formula (I) by obtaining 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of and optionally converted to a pharmaceutically acceptable salt thereof. The compound of formula (I) is converted to formula (Ia)

2-(5-Methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogensulfate. a) N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V) in a non-reactive solvent with hexamethyldisilazane in the presence of a catalytic amount of acid and b) the resulting 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I) without isolation from the reaction mixture. 2-(5-Methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole to 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H of formula (Ia) - The production method according to claim 1 or 2, comprising the step of converting to hydrogen sulfate of imidazole. A process according to claim 3, wherein step b) is carried out by treating the reaction mixture with an ethanol-water solution and adding sulfuric acid. a) N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V) in xylene is treated with hexamethyldisilazane at a temperature above 80° C. in a catalytic amount. reacting in the presence of sulfuric acid to give 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I);
b) without isolation of the 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I) formed, water and HCl are added to the reaction mixture to give the reaction of formula ( converting the compound of I) to its hydrogen sulfate salt;
c) isolating the aqueous phase;
d ) adding an extraction solvent and an inorganic base;
e) isolating the organic phase;
f) adding ethanol-water solution and sulfuric acid to form 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogen sulfate of formula (Ia);
g) distilling off the extraction solvent;
h) adding ethanol to the ethanol-water solution;
i) crystallizing 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogen sulfate of formula (Ia) by cooling and optionally seeding and j) isolating the crystalline compound of formula ( Ia ). Formula (V)

A method for producing N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of
a) Formula (II)

of 2-(2-methoxyphenyl)ethanol is reacted with ethyl 2-oxoacetate in the presence of a tertiary aliphatic amine in a solvent , then acetic anhydride is added to the reaction mixture to give formula (III)

producing ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of
b) Ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III) is added to a mixture of tin tetrachloride and a chlorinated hydrocarbon solvent to give formula (IV)

and c) ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) in an aliphatic or aromatic hydrocarbon solvent and in a catalytic amount with ethylenediamine in the presence of an acid to produce N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V). a) Formula (II)

2-(2-methoxyphenyl)ethanol of formula (III) is reacted with ethyl 2-oxoacetate in the presence of a tertiary aliphatic amine in a solvent , then acetic anhydride is added to the reaction mixture to give ethyl of formula (III) producing 2-acetoxy-2-(2-methoxyphenethoxy)-acetate;

b) Ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III) is added to a mixture of tin tetrachloride and a chlorinated hydrocarbon solvent to give ethyl 5-methoxyisochroman-1 of formula (IV). - producing a carboxylate;

c) without isolation of the ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) formed, water, NaOH and ethanol are added to the reaction mixture to give 5-methoxyisochroman-1 of formula (IVa) - obtaining sodium carboxylate;

d) treating sodium 5-methoxyisochroman-1-carboxylic acid of formula (IVa) with acid in water and isolating the 5-methoxyisochroman-1-carboxylic acid of formula (IVb) formed process;

e ) reacting 5-methoxyisochroman-1-carboxylic acid of formula (IVb) in an organic solvent with ethanol in the presence of acid to give ethyl 5-methoxyisochroman-1-carboxylate of formula (IV); generating a; and

f) Ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) is reacted with ethylenediamine in an aliphatic or aromatic hydrocarbon solvent in the presence of a catalytic amount of acid to give N- 7. The method of claim 6 , comprising the step of producing (2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate. a) reacting 2-(2-methoxyphenyl)ethanol of formula (II) with ethyl 2-oxoacetate in toluene and in the presence of trimethylamine, after which acetic anhydride is added to the reaction mixture to give a compound of formula (III); producing ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate;
b) Ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III) in dichloromethane is added to a mixture of tin tetrachloride and dichloromethane to give ethyl 5-methoxyisochroman-1 of formula (IV). - producing a carboxylate;
c) water, NaOH and ethanol are added to the reaction mixture without isolating the formed ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) from the reaction mixture to give 5-methoxyisochroman of (IVa) - obtaining sodium 1-carboxylate;
d) treating sodium 5-methoxyisochroman-1-carboxylate of formula (IVa) with HCl in water to isolate the 5-methoxyisochroman-1-carboxylic acid of formula (IVb) produced. ;
e) 5-methoxyisochroman-1-carboxylic acid of formula (IVb) in toluene is reacted with ethanol in the presence of HCl to give ethyl 5-methoxyisochroman-1-of formula (IV) in toluene solution. and f) the toluene solution of ethyl 5-methoxyisochroman-1-carboxylate obtained from step e) is reacted with ethylenediamine in the presence of a catalytic amount of acetic acid to give formula (V) The method according to claim 7 , comprising the step of producing N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of further g) adding a water-immiscible organic solvent and water followed by gradual addition of acid to extract the reaction mixture; and h) N-(2-aminoethyl)-5- of formula (V) A process according to any one of claims 6 to 8 , comprising crystallizing methoxyisochroman-1-carboxamide monohydrate from the aqueous phase by adding a strong base . A process according to any one of claims 1-5 , wherein the compound of formula (V) is prepared according to any one of claims 6-9 . Formula (V)

of the compound of formula (I)

or a pharmaceutically acceptable salt thereof. Formula (V)

of the compound of formula (Ia)

use in the manufacture of compounds of A compound of formula (V).

Formula (I)

or formula (Ia)

14. The compound of claim 13 used as an intermediate for making a compound of