Process for the preparation of 2-(5-methoxyisochroman-1 -yl)-4,5-dihydro-1 h-imidazole and the hydrogensulfate salt thereof

Patent metadata

Field	Value
Publication number	US-2020308152-A1
Application number	US-201816768093-A
Country	US
Kind code	A1
Filing date	Nov 30, 2018
Priority date	Dec 1, 2017
Publication date	Oct 1, 2020
Grant date	—

Abstract

The present disclosure relates to an improved process for the preparation of isochroman structured alpha2A adrenoceptor agonist, namely 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I) and a pharmaceutically acceptable salts thereof, such as 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogensulfate of formula (Ia), and to a novel intermediate compound used in the process, namely N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V). Alpha2A agonists are useful in the treatment of anxiety, and for use as a sedative or analgesic agent, and other diseases where alpha2A agonism is desired.

First claim

1 . A process for the preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I) or a pharmaceutically acceptable salt thereof:

comprising:
reacting N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V):

with a suitable condensation reagent under acidic conditions and in the presence of a non-reactive solvent, to obtain 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I), which is optionally converted to its pharmaceutically acceptable salt.

2 . The process according to claim 1 , further comprising the step of converting the compound of formula (I) to 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogensulfate of formula (Ia):

3 . The process according to claim 1 , comprising the steps of:
a) reacting N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V) in a suitable solvent with a suitable condensation reagent in the presence of a catalytic amount of an acid; and b) without isolating the formed 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I) from the reaction mixture, converting the 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole to 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogensulfate of formula (Ia).

4 . The process according to claim 3 , wherein step
b) is carried out by treating the reaction mixture with ethanol-water solution and adding sulfuric acid.

5 . The process according to claim 1 , wherein the condensation reagent is hexamethyldisilazane.

6 . The process according to claim 1 , comprising the steps of:
a) reacting N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V) in xylene with hexamethyldisilazane at an elevated temperature in the presence of a catalytic amount of sulphuric acid to obtain 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I); b) without isolating the formed 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole of formula (I), adding water and HCl to the reaction mixture to convert the compound of formula (I) to its hydrochloride salt; c) isolating the water phase; d) adding suitable extraction solvent and an inorganic base; e) isolating the organic phase; f) adding ethanol-water solution and sulphuric acid to form 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogensulfate of formula (Ia); g) distilling the solvent off; h) adding ethanol to the ethanol-water solution; i) crystallizing 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole hydrogensulfate of formula (Ia) by cooling and optionally seeding; and j) isolating the crystalline compound of formula (Ia).

7 . A process for the preparation of N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V):

comprising the steps of:
a) reacting 2-(2-methoxyphenyl)ethanol of formula (II):

with ethyl 2-oxoacetate in a suitable solvent and in the presence of a tertiary aliphatic amine and subsequently adding acetic anhydride to the reaction mixture to form ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III):

b) adding ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III) to the mixture of tin tetrachloride and a chlorinated hydrocarbon solvent to form ethyl 5-methoxyisochroman-1-carboxylate of formula (IV)

and
c) reacting the ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) with ethylene diamine in aliphatic or aromatic hydrocarbon solvent and in the presence of a catalytic amount of acid to form N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V).

8 . The process according to claim 7 , comprising the steps of:
a) reacting 2-(2-methoxyphenyl)ethanol of formula (II):

with ethyl 2-oxoacetate in a suitable solvent and in the presence of a tertiary aliphatic amine, and subsequently adding acetic anhydride to the reaction mixture to form ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III):

b) adding ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III) to the mixture of tin tetrachloride and a chlorinated hydrocarbon solvent to form ethyl 5-methoxyisochroman-1-carboxylate of formula (IV):

c) without isolating the formed ethyl 5-methoxyisochroman-1-carboxylate of formula (IV), adding water, NaOH and ethanol to the reaction mixture to obtain sodium 5-methoxyisochroman-1-carboxylate of formula (IVa):

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

e) reacting the 5-methoxyisochroman-1-carboxylic acid of formula (IVb) in suitable organic solvent with ethanol in the presence of suitable acid to form ethyl 5-methoxyisochroman-1-carboxylate of formula (IV):

and
f) reacting the ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) with ethylene diamine in aliphatic or aromatic hydrocarbon solvent and in the presence of a catalytic amount of acid to form N-(2-aminoethyl)-5-methoxyisochroman-1-carboxamide monohydrate of formula (V).

9 . The process according to claim 8 , comprising the steps of:
a) reacting 2-(2-methoxyphenyl)ethanol of formula (II) with ethyl 2-oxoacetate in toluene and in the presence of trimethylamine, and subsequently adding acetic anhydride to the reaction mixture to form ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III); b) adding ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate of formula (III) in dichloromethane to the mixture of tin tetrachloride and dichloromethane to form ethyl 5-methoxyisochroman-1-carboxylate of formula (IV); c) without isolating the formed ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) from the reaction mixture, adding water, NaOH and ethanol to the reaction mixture to obtain sodium 5-methoxyisochroman-1-carboxylate of formula (IVa); d) treating the sodium 5-methoxyisochroman-1-carboxylate of formula (IVa) with HCl in water, and isolating the formed 5-methoxyisochroman-1-carboxylic acid of formula (IVb); e) reacting 5-methoxyisochroman-1-carboxylic acid of formula (IVb) in toluene with ethanol in the presence of HCl to form ethyl 5-methoxyisochroman-1-carboxylate of formula (IV) in toluene solution; and f) reacting the ethyl 5-methoxyisochroman-1-carboxylate toluene solution obtained from step e) with ethylene d

Assignees

• Orion Corp

Inventors

• Laitinen Ilpo
• Leskinen Mikko
• Mäkelä Mikko

Classifications

• C07D405/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D311/76

  Benzo[c]pyrans · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07F7/10

  containing nitrogen {having a Si-N linkage} · CPC title