# US 7,608,714 B2 · Production of dolasetron

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- Number: US 7,608,714 B2
- Document ID: US7608714B2
- Status: Granted
- Kind: B2
- Application number: 11/650,294
- Filed: 2007-01-05
- Published: 2007-08-30
- Granted: 2009-10-27
- Earliest claimed: 2006-01-05
- Assignees: TEVA Gyógyszergyár Zártkörüen Müködö Részvénytársaság
- Inventors: Janos Hajko; Tivadar Tamas; Adrienne Kovacsne-Mezei; Erika Magyar Molnarne; Csaba Peto; Csaba Szabo
- Web page: https://patentgrep.com/patent/US7608714B2

## CPC

- C07D 471/18: Bridged systems
- A61P 25/06: Antimigraine agents
- C07D 303/40: by ester radicals
- C07D 451/14: containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention provides an improved process for the preparation of Dolasetron salts, in particularly Dolasetron mesylate. Also provided are intermediates for the process and methods of preparing the intermediates.

## Claims

### Claim 1

A crystalline 7-methoxycarbonyl-9-(methoxycarbonylmethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-9-azabicyclo[3.3.1]nonane (PAN) compound of the following formula,
characterized by an XRD diffraction pattern having peaks at about 10.1, 15.3, and 18.2 degrees two-theta, ±0.2 degrees two-theta.

### Claim 2 (depends on 1)

The crystalline PAN of claim 1, wherein the crystalline PAN is further characterized by the XRD diffraction pattern having peaks at about 10.1, 12.6, 13.4, 15.3, 18.2, 18.9, 19.2, 23.5, and 25.4 degrees two-theta, ±0.2 degrees two-theta.

### Claim 3 (depends on 2)

The crystalline PAN of claim 2, wherein the crystalline PAN is characterized having a PXRD pattern as depicted in the PXRD illustrated by FIG. 7.

### Claim 4

A quaternary ammonium salt of a 7-methoxycarbonyl-9-(methoxycarbonylmethyl)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-9-azabicyclo[3.3.1]nonane compound (a PAN salt) of formula VIIs,
wherein R1 and R2 are methyl and Z is methanesulfonic acid (PAN-MsOH) and the quaternary ammonium salt is crystalline PAN-MsOH characterized by an XRD diffraction pattern having peaks at about 7.3, 11.6, and 14.6 degrees two-theta, ±0.2 degrees two-theta.

### Claim 5 (depends on 4)

The quaternary ammonium salt of claim 4, wherein crystalline PAN-MsOH is further characterized by the XRD diffraction pattern having peaks at about 6.7, 12.5, 15.9, 17.1, 17.9, 19.0, 20.4, 22.2, and 23.8 degrees two-theta, ±0.2 degrees two-theta.

### Claim 6 (depends on 5)

The quaternary ammonium salt of claim 5, wherein the crystalline PAN-MsOH is characterized having a PXRD pattern as depicted in FIG. 3.

### Claim 7

An isolated endo-9-alkoxycarbonyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]-8-azatricyclo[5.3.1.03,8]undecan-10-one compound (a PQO compound) of formula IX,
wherein R is a C1-6 alkyl or a C6-8 aryl.

### Claim 8 (depends on 7)

The isolated compound of claim 7, wherein R is methyl (PQO).

### Claim 9 (depends on 8)

The isolated compound of claim 8, wherein the isolated compound is crystalline PQO characterized by an XRD diffraction pattern having peaks at about 7.3, 14.7, and 17.2 degrees two-theta.

### Claim 10 (depends on 9)

The isolated compound of claim 9, wherein crystalline PQO is further characterized by the XRD diffraction pattern having peaks at about 10.7, 15.3, 17.6, 18.2, and 21.4 degrees two-theta, ±0.2 degrees two-theta.

### Claim 11 (depends on 10)

The isolated compound of claim 10, wherein the crystalline PQO is characterized having a PXRD pattern as depicted in FIG. 5.

### Claim 12

A 7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-acyloxy-9-azabicyclo[3.3.1]nonane compound (a PivAN compound) of formula XIII
wherein R1, R2 and R3 are independently C1-6 alkyl or C6-8 aryl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R1 and R2 are methyl and R3 is tert-butyl.

### Claim 14

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.

### Claim 15 (depends on 14)

The method of claim 14, wherein R1 and R2 are methyl.

### Claim 16 (depends on 14)

The method of claim 14, wherein the ether protecting group is cyclic ether, the C3-8 ester is ethylacetate, and the acid is methanesulfonic acid.

### Claim 17 (depends on 16)

The method of claim 16, wherein the cyclic ether is tetrahydropyran.

### Claim 18 (depends on 14)

The method of claim 14, wherein a solution of the acid in the C3-8 ester is added drop-wise to a solution of the HAN compound and a substance comprising an ethereal protecting group at a temperature of about 30° C. to about 50° C.

### Claim 19 (depends on 18)

The method of claim 18, wherein a PAN salt is recovered by a process of drying a precipitate obtained by adding drop-wise the solution of the acid in the C3-8 ester to the solution comprising the HAN and the ether protecting group.

### Claim 20 (depends on 19)

The method of claim 19, further comprising converting the PAN salt of formula VIIs to a Dolasetron (DLS) salt of formula VIIIs,
wherein, 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, maleic 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.

### Claim 21 (depends on 14)

The method of claim 14, wherein the mixture in step b) is heated to a temperature of about 40° C. to about 60° C. for a period of about 15 minutes to about 1 hour.

### Claim 22 (depends on 21)

The method of claim 21, wherein the heated mixture is cooled to a temperature of about 5° C. to about 20° C. for a period of about 1 to about 4 hours.

### Claim 23 (depends on 14)

The method of claim 14, wherein the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate.

### Claim 24 (depends on 14)

The method of claim 14, further comprising converting the PAN compound of formula VII to a Dolasetron (DLS) salt of formula VIIIs, wherein, 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, maleic 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.

### Claim 25 (depends on 14)

The method of claim 14, and 30 to 32, further preparing an endo-9-alkoxycarbonyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]-8-azatricyclo[5.3.1.03,8]undecan-10-one compound (a PQO compound) of formula IX,
comprising
a) combining the PAN compound of formula VII
a metal alkoxide, and a polar aprotic organic solvent to form a mixture;
b) heating the mixture;
c) reacting the mixture of step b) with a weak acid forming a reaction mixture; and
d) adding a base to the reaction mixture of step c),
wherein R, R1 and R2 are a C1-6 alkyl or C6-8 aryl.

### Claim 26 (depends on 25)

The method of claim 25, wherein R, R1, and R2 are methyl.

### Claim 27 (depends on 25)

The method of claim 25, wherein the weak acid has a pKa of not less than 1, selected from the group consisting of formic acid, acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic acid.

### Claim 28 (depends on 25)

The method of claim 25, wherein the polar a-protic organic solvent is selected from the group consisting of C2-8 ethers having a boiling point of about 60° C. to about 100° C., and wherein the metal alkoxide is selected from a group consisting of lithium alcoholates, sodium alcoholates and potassium alcoholates, and wherein the alcoholate moiety contains 1 to 4 carbons.

### Claim 29 (depends on 28)

The method of claim 28, wherein the metal alkoxide is potassium tert-butoxide.

### Claim 30 (depends on 25)

The method of claim 25, wherein the mixture of step a) is heated to a temperature of about 40° C. to about 120° C.

### Claim 31 (depends on 30)

The method of claim 30, wherein the heated mixture is cooled to a temperature of about 0° C. to about 30° C., prior to the addition of the acid.

### Claim 32 (depends on 25)

The method of claim 25, wherein the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate.

### Claim 33 (depends on 25)

The method of claim 25, further comprising recovering the PQO compound of formula IX.

### Claim 34 (depends on 14)

The method of claim 14, further preparing an endo-5-hydroxy-8-azatricyclo[5.3.1.03,8]undecan-10-one salt (a HQO salt) of formula IIs
comprising
a) combining the PAN compound of formula VII,
a metal alkoxide, and a polar aprotic organic solvent forming a mixture; and
b) adding to the mixture of step a) an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid forming the HQO salt of formula IIs,
wherein, R1 and R2 are a C1-6 alkyl or C6-8 aryl, and Y is an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid.

### Claim 35 (depends on 34)

The method of claim 34, wherein R1 and R2 are methyl, and Y is HCl.

### Claim 36 (depends on 34)

The method of claim 34, wherein the polar a-protic organic solvent is selected from the group consisting of C2-8 ethers having a boiling point of about 60° C. to about 100° C., and wherein the metal alkoxide is selected from a group consisting of lithium alcoholates, sodium alcoholates and potassium alcoholates, and wherein the alcoholate moiety contains 1 to 4 carbons.

### Claim 37 (depends on 36)

The method of claim 36, wherein the metal alkoxide is potassium tert-butoxide.

### Claim 38 (depends on 34)

The method of claim 34, wherein the mixture in step a) is heated to a temperature of about 40° C. to about 120° C.

### Claim 39 (depends on 38)

The method of claim 38, wherein the heated mixture is cooled to a temperature of about 0° C. to about 30° C., prior to the addition of the acid.

### Claim 40 (depends on 34)

The method of claim 34, wherein the acid is either hydrochloric acid or camphorsulfonic acid.

### Claim 41 (depends on 34)

The method of claim 34, further comprising adding a base, wherein a HQO compound of formula II is obtained.

### Claim 42 (depends on 41)

The method of claim 41, wherein the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate.

### Claim 43 (depends on 41)

The method of claim 41, further comprising combining HQO, an alcohol and 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 acid, trifluoroacetic acid, maleic 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, benzenesulfonic acid, naphthalene sulfonic, and disulfonic acid forming a HQO salt of formula IIs.

### Claim 44 (depends on 43)

The method of claim 43, wherein the alcohol is a C1-4 alcohol.

### Claim 45 (depends on 43)

The method of claim 43, wherein the acid is methanesulfonic acid.

### Claim 46 (depends on 43)

The method of claim 43, further comprising adding a base, wherein the HQO compound of formula II is obtained as a purified compound.

### Claim 47 (depends on 41)

The method of claim 41, further converting HQO of formula II to a DLS-salt of formula VIIIs comprising
a) forming a reaction mixture of HQO in an organic solvent;
b) mixing the reaction mixture with an anhydride, indole-3-carboxylic acid, an organic solvent, and a catalyst to form a mixture containing Dolasetron; and
c) reacting the mixture with an acid, to obtain the DLS-salt of formula VIIIs.

### Claim 48 (depends on 47)

The method of claim 47, wherein the organic solvent is dichloromethane.

### Claim 49 (depends on 47)

The method of claim 47, wherein HQO and the catalyst are added at the same time to a solution of the anhydride, the organic solvent and the 3-indole-carboxylic acid, providing the reaction mixture.

### Claim 50 (depends on 49)

The method of claim 49, wherein the reaction mixture is heated to a temperature of about 25° C. to about 40° C. for a period of about 2 to about 18 hours, providing Dolasetron base.

### Claim 51 (depends on 47)

The method of claim 47, wherein the acid is methanesulfonic acid.

### Claim 52

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.

### Claim 53

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.

### Claim 54 (depends on 53)

The method of claim 53, wherein R1 and R2 are methyl and R3 is tert-butyl.

### Claim 55 (depends on 53)

The method of claim 53, wherein the a-protic organic solvent is selected from the group consisting of a C1-8 halogenated hydrocarbon, a C2-8 ester, a C2-8 ether, a C3-6 ketone, a C6-8 aromatic hydrocarbon, a C3-10 amide, and mixtures thereof.

### Claim 56 (depends on 55)

The method of claim 55, wherein the C1-8 halogenated hydrocarbon is methylene chloride.

### Claim 57 (depends on 53)

The method of claim 53, wherein the HAN compound and the solvent are combined first to form a solution which solution is cooled to a temperature of about −5° C. to about 15° C. prior to the addition of the base and of the acylating agent.

### Claim 58 (depends on 53)

The method of claim 53, wherein the base is selected from a group consisting sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate, trialkyl amines, and an N-containing heterocycle, wherein the acetylating agent is an acyl halogenide.

### Claim 59 (depends on 58)

The method of claim 58, wherein the acetylating agent is pivaloyl chloride.

### Claim 60 (depends on 53)

The method of claim 53, wherein the addition of the base and of the acylating agent to the HAN compound and the solvent provides a mixture which is maintained at a temperature of about 0° C. to about 80° C. for a period of about 1 day to about 20 days.

### Claim 61 (depends on 53)

The method of claim 53, further comprising converting the PivAN compound of formula XIII to a Dolasetron (DLS) salt of formula VIIIs, wherein, 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, maleic 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.

### Claim 62

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.

### Claim 63 (depends on 62)

The method of claim 62, wherein R1 and R2 are methyl and R3 is tert-butyl.

### Claim 64 (depends on 62)

The method of claim 62, wherein the acid in step c) is HCl or camphorsulfonic acid.

### Claim 65 (depends on 62)

The method of claim 62, wherein the polar a-protic organic solvent is selected from the group consisting of a C2-8 ether having a boiling point of about 60° C. to about 100° C., and wherein the metal alkoxide is selected from the group consisting of lithium alcoholates, sodium alcoholates and potassium alcoholate; wherein the alcoholate moiety contains 1 to 4 carbons.

### Claim 66 (depends on 65)

The method of claim 65, wherein the PivAN compound of formula XIII is dissolved in the polar a-protic organic solvent prior to adding the metal alkoxide.

### Claim 67 (depends on 65)

The method of claim 65, wherein the metal alkoxide is potassium tert-butoxide.

### Claim 68 (depends on 62)

The method of claim 62, wherein combining the PivAN compound of formula XIII, the polar a-protic organic solvent and the metal alkoxide forms a reaction mixture, which is heated to a temperature of about 40° C. to about 120° C. for a period of about 0.5 hours to about 8 hours.

### Claim 69 (depends on 68)

The method of claim 68, wherein the heated mixture is cooled to a temperature of about 0° C. to about 30° C.

### Claim 70 (depends on 69)

The method of claim 69, wherein prior to the addition of the acid, a solvent selected from the group consisting of water, water immiscible organic solvents and mixtures thereof is combined with the cooled reaction mixture.

### Claim 71 (depends on 70)

The method of claim 70, wherein the acidic mixture is heated to about the reflux temperature for a period of about 3 hours to about 24 hours.

### Claim 72 (depends on 71)

The method of claim 71, further comprising a step of recovering HQO of formula II wherein the heated mixture is cooled to a temperature of about 0° C. to about 30° C., adding a base, extracting the product with water immiscible organic solvent, and evaporating the water immiscible organic solvent.

### Claim 73 (depends on 72)

The method of claim 72, wherein a base selected from a group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate is added to the cooled acidic mixture.

### Claim 74 (depends on 72)

The method of claim 72, wherein the water immiscible organic solvent is selected from the group consisting of C2-8 esters, linear, branched or cyclic C2-8 ethers, C3-6 ketones and C5-8 aliphatic hydrocarbons, and C1-8 halogenated hydrocarbons.

### Claim 75 (depends on 62)

The method of claim 62, further converting HQO of formula II to a DLS-salt of formula VIIIs comprising
a) forming a reaction mixture of HQO in an organic solvent;
b) mixing the reaction mixture with an anhydride, indole-3-carboxylic acid, an organic solvent, and a catalyst to form a mixture containing Dolasetron; and
c) reacting the mixture with an acid, to obtain the DLS-salt of formula VIIIs.

### Claim 76 (depends on 75)

The method of claim 75, wherein the organic solvent is dichloromethane.

### Claim 77 (depends on 75)

The method of claim 75, wherein HQO and the catalyst are added at the same time to a solution of the anhydride, the organic solvent and the 3-indole-carboxylic acid, providing the reaction mixture.

### Claim 78 (depends on 77)

The method of claim 77, wherein the reaction mixture is heated to a temperature of about 25° C. to about 40° C. for a period of about 2 to about 18 hours, providing Dolasetron base.

### Claim 79 (depends on 75)

The method of claim 75, wherein the acid is methanesulfonic acid.

### Claim 80

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.