Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/76—Benzo[c]pyrans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

• the present disclosure relates to an improved process for the preparation of isochroman structured alpha2A adrenoceptor agonist, namely 2-(5-methoxyisochroman-l-yl)-4,5- dihydro-lH-imidazole (I) and a pharmaceutically acceptable salts thereof, such as a sulfate salt (la), and to a novel intermediate compound used in the process, namely N-( 2- aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate (V).
• Compound of formula (I) exhibits agonistic activities on adrenergic alpha2 receptors, especially on alpha2A receptor, and can thus be used in the treatment of a disorder, condition or disease where an alpha2A agonist is indicated to be useful, particularly for use as a sedative or analgesic agent, and for use in the treatment of anxiety.
• WO 2013/150173 discloses a process for the preparation of the compound of formula (I) and salts thereof through a 2-(5-bromoisochroman-l-yl)-4,5-dihydro-lH-imidazole intermediate of formula (X) as shown in scheme 1.
• This process of scheme 1 comprises refluxing the mixture of 2-(2-bromophenyl)ethanol, TFA and 2,2-dihydroxyacetic acid to obtain 5 -bromoisochroman-l -carboxylic acid which is further mixed with methanol and trimethylsilylchloride to form methyl 5-bromoisochroman-
• the sulfate salt (la) of compound of formula (I) is prepared from isolated 2-(5- methoxyisochroman-l-yl)-4,5-dihydro-lH-imidazole of formula (I) in ethanol by adding sulfuric acid in ethanol.
• WO 2013/150173 discloses also another process for preparing derivatives of formula (I).
• compound of formula (Y) is prepared through ethyl 5-methoxyisochroman-l- carboxylate intermediate of formula (IV) according to scheme 2.
• This process of scheme 2 comprises reacting 2-(2-methoxyphenyl)ethanol with ethyl 2- oxoacetate in toluene to form ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate which is further treated with pyridine, 4-dimethylaminopyridine and acetyl chloride to form ethyl 2- acetoxy-2-(2-methoxyphenethoxy)acetate.
• the isolated ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate is dissolved in dichloromethane and treated with AICI 3 to form ethyl 5-methoxyisochroman-l-carboxylate of formula (IV).
• the intermediate compound of formula (Y) is finally reacted with ethylenediamide in the presence of trimethylauminium and toluene to form the 4,5-dihydroimidazole compound of formula (Z).
• an object of the present disclosure is to provide a novel process for the preparation of 2-(5-methoxyisochroman-l-yl)-4,5-dihydro-lH-imidazole of formula (I) and
• Another object of the present disclosure is to provide a process for the preparation of a novel intermediate /V-(2-aminocthyl)-5-mcthoxyisochroman- 1 -carboxamide monohydrate of formula (V) and a process for the preparation of 2-(5-methoxyisochroman-l-yl)-4,5-dihydro- lH-imidazole of formula (I) and a sulfate salt thereof using said intermediate of formula (V).
• Another object of the present disclosure is to provide a novel intermediate /V-(2-aminocthyl)- 5-methoxyisochroman-l -carboxamide monohydrate of formula (V).
• the process of the present disclosure can be summarized, but not limited, according to the following general reaction scheme 3 wherein, if not clearly otherwise stated, all abbreviations and expressions have the meanings well known to the person skilled in the art of organic chemistry.
• the present disclosure relates to a novel process for the preparation of 2-(5- methoxyisochroman-l-yl)-4,5-dihydro-lH-imidazole of formula (I) and a pharmaceutically acceptable salts thereof, such as 2-(5-methoxyisochroman-l-yl)-4,5-dihydro-lH-imidazole hydrogensulfate of formula (la).
• the present disclosure relates to a process for the preparation of 2-(5- methoxyisochroman-l-yl)-4,5-dihydro-lH-imidazole of formula (I) or a pharmaceutically acceptable salt thereof
• the present disclosure relates to above process, further comprising the step of converting the compound of formula (I) to 2-(5-methoxyisochroman-l-yl)-4,5- dihydro -lH-imidazole hydrogensulfate of formula (la)
• the present disclosure relates to a process for the preparation of compound of formula (I), comprising the steps of
• the present disclosure relates to above process wherein, the step b) is carried out by treating the reaction mixture with ethanol- water solution and adding sulfuric acid.
• the present disclosure relates to a process for the preparation of compound of formula (I), comprising the steps of
• extraction solvent e.g. methylene chloride
• inorganic base e.g.NaOH
• the present disclosure relates to process for the preparation of N-( 2- aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate of formula (V).
• the present disclosure relates to a process for the preparation of N-( 2- aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate of formula (V)
• ethyl 2-oxoacetate in suitable organic solvent, e.g. dichloromethane or toluene, and the presence of a tertiary aliphatic amine, e.g. trimethylamine or triethylamine, and subsequently adding acetic anhydride to the reaction mixture to form ethyl 2-acetoxy-2-(2- methoxyphenethoxy)acetate of formula (III);
• suitable organic solvent e.g. dichloromethane or toluene
• a tertiary aliphatic amine e.g. trimethylamine or triethylamine
• the present disclosure relates to a process for the preparation of N-( 2- aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate of formula (V), comprising the steps of
• ethyl 2-oxoacetate in suitable solvent, e.g. dichloromethane, and the presence of a tertiary aliphatic amine, e.g. trimethylamine or trimethylamine, and subsequently adding acetic anhydride to the reaction mixture to form ethyl 2-acetoxy-2-(2-methoxyphenethoxy)-acetate of formula (III);
• suitable solvent e.g. dichloromethane
• a tertiary aliphatic amine e.g. trimethylamine or trimethylamine
• the present disclosure relates to a process for the preparation of N-( 2- aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate of formula (V), comprising the steps of
• the present disclosure relates to a process for the preparation N-(2- aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate of formula (V) according to the above processes further comprising the steps of
• the present disclosure relates to a process for the preparation of 2-(5- methoxyisochroman-l-yl)-4,5-dihydro-lH-imidazole of formula (I) or a pharmaceutically acceptable salt thereof comprising the steps of
• the present disclosure relates to use of a compound of formula (V) in the preparation of the compound of formula (I) or a pharmaceutically acceptable salts thereof, such as a sulfate salt. In one embodiment the present disclosure relates to use of a compound of formula (V) in the preparation of the compound of formula (I) or a pharmaceutically acceptable salts thereof, such as sulfate salt, wherein the compound of formula (V) is prepared according to the method disclosed above.
• the present disclosure relates to a novel compound of formula (V). In one embodiment the present disclosure relates to the compound of formula (V), which is used as an intermediate for preparing compound of formula (I) or (la).
• the conversion of the compound of formula (II) to the compound of formula (III) involves a presence of a base. It was found that by changing the base from pyridine to a tertiary aliphatic amine, such as trimethylamine, the extra purification steps can be avoided. It was also found that when converting the compound of formula (III) to the compound of formula (IV) changing the addition order of reagents and using SnCU instead of AlCh reduces the formation of impurities. Moreover, the purification of compound of formula (IV) can be carried out via its sodium salt of formula (IVa) instead of using many distillations to dryness which is a difficult operation to handle in a large scale. In addition, this purification method is more effective.
• the starting materials such as compound of formula (II), are commercially available or can be prepared according to the methods known in the art.
• EXAMPLE 1 Preparation of ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate (III) A flask inserted with N was charged with dichloromethane (900mL) followed by 2-(2- methoxyphenyl)ethanol (II) (l50g, 1.0 equivalent). Then ethyl 2-oxoacetate in toluene (50%, l9lg, 0.95 equivalent) and trimethylamine (l99g, 2.0 equivalent) were subsequently added and the reaction mixture was stirred 1 hour. The bath temperature was adjusted to 0°C and acetic anhydride (16 lg, 1.6 equivalent) was added to the reaction mixture. The reaction mass was stirred lh at 0 ⁇ 5°C. The reaction mixture was stirred 2 hours at 20-30°C.
• A-(2-aminoethyl)-5-methoxyisochroman-l -carboxamide monohydrate (12 g) and xylene (60 ml) were charged.
• Sulfuric acid 93 % (0.3 ml) was added.
• Hexamethyldisilazane (26 ml) was added.
• the mixture was heated to l22°C and stirred for 4 hours at 122 ⁇ 3°C.
• the mixture was cooled.
• Water (60 ml) and 30 % HC1 (14 ml) were added slowly at 40 ⁇ 5°C.
• the mixture was heated to 60 ⁇ 3°C and stirred for 2 hours at 60 ⁇ 3°C.
• the phases were allowed to separate and the organic phase was separated off.
• Methylene chloride 80 ml was added to the water phase. 50 % NaOH (14 ml) was added gradually at 20 ⁇ 5°C. The phases were allowed to separate. The water phase was separated off. Water (30 ml) was added to the organic phase. The mixture was stirred for a few minutes. The phases were allowed to separate. The water phase was separated off. Ethanol (80 ml), water (15 ml) and sulfuric acid 93 % (2.4 ml) were added to the methylene chloride solution. Methylene chloride was distilled off under normal pressure. The ethanol-water solution was cooled to 70 ⁇ 5°C and ethanol (42 ml) was added. The solution was cooled to room temperature. Seed crystals were added during the cooling.
• the mixture was stirred overnight at room temperature.
• the mixture was cooled to 0-5°C and stirred about 4 hours at 0-5°C.
• the crystalline compound was filtered and washed with cold ethanol (20 ml).
• the product was dried under reduced pressure at 60-70°C.
• the yield was 11.07 g (74.9 %).
• the HPLC-purity was 99.9 %.

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• 2018
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