Production of dolasetron

A method of preparing a 7-methoxycarbonyl-9-(methoxycarbonylmethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-9-azabicyclo[3.3.1]nonane compound (a PAN compound) of formula VII, comprising

• a) preparing a 7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-ol compound (a HAN compound) of formula VI
• comprising combining an OAN compound of formula V
• or salts thereof, a reducing agent, and a solvent selected from the group consisting of water, water miscible organic solvents and mixtures thereof to form mixture to obtain an HAN compound of formula VI;
• b) mixing the HAN compound of formula VI, an ether protecting group, an acid, and a C3-8 ester to form a mixture;
• and
• c) adding a base to the mixture to obtain the PAN compound of formula VII, wherein R1 and R2 are independently a C1-6 alkyl or a C6-8 aryl.

A method of preparing a Dolasetron salt (a DLS-salt) of formula VIIIs

• comprising
• a) combining a CCA-ester of formula III,
• an oxidizing agent selected from the group consisting of:
• hydroperoxides, dialkyl peroxides, peroxyacids, peroxyesters, diacyl peroxides, persulphate, perborate and perphosphate, a catalyst and a solvent selected from the group consisting of water, water miscible organic solvents and mixtures thereof forming a first intermediate mixture containing a CCA epoxide of formula IV
• b) adding an oxidizing agent, a solvent selected from the group consisting of water and water miscible organic solvent to the forming a first intermediate mixture of the CCA epoxide of formula IV forming a second intermediate mixture;
• c) raising the pH of the second intermediate mixture;
• d) reacting the products in the second intermediate mixture with a pH 4 buffer, a glycine C1-4 ester or salts thereof, and a substance comprising a carbonyl moiety selected from the group consisting of 1,3-acetonedicarboxylic acids, acetone and a C1-4 ester thereof forming a third intermediate mixture containing an OAN compound of formula V
• e) adding to the third intermediate mixture of the OAN compound of formula V a reducing agent, and a solvent selected from the group consisting of water, water miscible organic solvents and mixtures thereof forming a fourth intermediate mixture containing an HAN compound of formula VI
• f) mixing the fourth intermediate mixture of the HAN compound of formula VI with a substance comprising an ether protecting group, an acid, and a C3-8 ester forming a fifth intermediate mixture;
• g) adding a base to the fifth intermediate mixture to obtain a PAN compound of formula VII
• h) further combining the fifth intermediate mixture of the PAN compound of formula VII with a metal alkoxide and a polar aprotic organic solvent forming a sixth intermediate mixture;
• i) heating the sixth intermediate mixture;
• j) adding to the sixth intermediate mixture an acid selected from the group consisting of:
• hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid forming a seventh intermediate mixture containing the HQO compound of formula II or a salt thereof of formula IIs
• k) adding a base to the seventh intermediate mixture of the HQO compound of formula II or salt thereof of formula IIs;
• l) further mixing with the seventh intermediate mixture an anhydride, 3-indole carboxylic acid, an organic solvent, and a catalyst;
• and
• m) reacting the product of step 1) with an acid to obtain the DLS-salt of formula VIIIs.
• wherein R1 and R2 are each independently a C1-6 alkyl or a C6-8 aryl, and X and Y are each independently an acid selected from the group consisting of:
• hydrochloric acid, hydrobromic acid, propionic acid, trichloroacetic acetic, trifluoroacetic acid, maleic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic acid, naphthalene carboxylic and dicarboxylic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids, preferably, methane sulfonic acid.

A method of preparing a 7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-acyloxy-9-azabicyclo[3.3.1]nonane compound (a PivAN compound) of formula XIII

• comprising combining a HAN compound of formula VI,
• an acylating agent selected from a group consisting of:
• carboxylic acid, carboxylic halogenides, carboxylic anhydrides, a base, and a solvent selected from a group consisting of a-protic organic solvents and mixtures thereof forming a mixture to obtain the PivAN compound of formula XIII;
• wherein, R1 and R2 and R3 are independently a C1-6 alkyl or a C6-8 aryl.

A method of preparing the compound endo-5-hydroxy-8-azatricyclo[5.3.1.03,8]undecan-10-one (HQO) of formula II

• comprising
• a) combining a PivAN compound of formula XIII,
• a metal alkoxide, and a polar aprotic organic solvent forming a mixture;
• b) heating the mixture;
• and
• c) adding to the mixture an acid selected from the group consisting of a hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid forming the HQO compound.

A method of preparing a Dolasetron salt (a DLS-salt) of formula VIIIs

• comprising
• a) combining a CCA-ester of formula III,
• an oxidizing agent selected from the group consisting of:
• hydroperoxides, dialkyl peroxides, peroxyacids, peroxyesters, diacyl peroxides, persulphate, perborate and perphosphate, a catalyst and a solvent selected from the group consisting of water, water miscible organic solvents and mixtures thereof forming a first intermediate mixture containing a CCA epoxide of formula IV
• b) adding to the first intermediate mixture of the CCA epoxide of formula IV an oxidizing agent, and a solvent selected from the group consisting of water and water miscible organic solvent to form a second intermediate mixture;
• c) raising the pH of the second intermediate mixture;
• d) reacting the products in the second intermediate mixture with a pH 4 buffer, a glycine C1-4 ester or salts thereof, and a substance comprising a carbonyl moiety selected from the group consisting of 1,3 acetonedicarboxylic acids, acetone and a C1-4 ester thereof to form a third intermediate mixture;
• containing an OAN compound of formula V
• e) adding to the third intermediate mixture of the OAN compound of formula V a reducing agent, and a solvent selected from the group consisting of water, water miscible organic solvents and mixtures thereof to form a fourth intermediate mixture containing an HAN compound of formula VI
• f) adding to the fourth intermediate mixture of the HAN compound of formula VI an acylating agent selected from the group consisting of:
• carboxylic acid, carboxylic halogenides, carboxylic anhydrides, a base, and a solvent selected from the group consisting of aprotic organic solvents and mixtures thereof to form a fifth intermediate mixture containing a PivAN compound of formula XIII
• g) adding to the fifth intermediate mixture of the PivAN compound of formula XIII a metal alkoxide, and a polar aprotic organic solvent to form a sixth intermediate mixture;
• h) heating the sixth intermediate mixture, and adding an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid to form a seventh intermediate mixture containing the HQO compound of formula II
• i) mixing the seventh intermediate mixture of the HQO compound of formula II with an anhydride, 3-indole carboxylic acid, an organic solvent, and a catalyst;
• and
• j) reacting the product of step i) with an acid to obtain the DLS-salt of formula VIIIs
• wherein R1, R2, and R3 are each independently a C1-6 alkyl or a C6-8 aryl, and X is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, fluoroboric acid, formic acid, acetic acid, propionic acid, trichloroacetic acetic, trifluoroacetic acid, nialeic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic acid, naphthalene carboxylic and dicarboxylic acids, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids, preferably, methane sulfonic acid.