Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"An improved process for the preparation of Dolasetron Mesylate"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under
the Companies ACT, 1956
(c) ADDRESS: B.S.D. Marg, Station Road Govandi,
Mumbai400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

An improved process for the preparation of Dolasetron Mesylate
TECHNICAL FIELD
The present invention relates to an improved process for the preparation of endo-
hexahydro-8-(3-indotylcarbonyloxy)-2,6-methano-2H-quinolizin-3 (4H)-one
methanesulfonate commonly known as Dolasetron Mesylate having formula 1.

Dolasetron mesylate is a selective serotonin inhibitor useful in the prevention of nausea and vomiting associated with moderately emetogenic cancer therapy and prevention of post-operative nausea and vomiting.
BACKGROUND AND PRIOR ART
Synthesis of Dolasetron Mesylate is not very widely reported in literature. EP 0266730 / US 4906755 describes process for the preparation endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one methanesulfonate or Dolasetron mesylate (1) by the condensation of diethyl malonate with cis-1,4-dichloro-2-butene (2) in presence of lithium hydride in dimethylformamide to give diethyl-3-cyclopentene-l,l-dicarboxylate (3), which on hydrolysis and
2

decarboxylation gave 3-cyclopentene-I-carboxylic acid (4). The compound (4)
was further treated with thionyl chloride and pyridine in ethanol to obtained ethyl
3-cyclopentene-l-carboxylate (5). Compound (5) was oxidized to 4-
ethoxycarbonyl-l,2-cyclopentanediol (6) by using N-methylmorpholine N-oxide
in the presence of osmium tetroxide catalyst. The diol (6) was cleaved to the 8-
ethoxycarbonylglutaraldehyde (7) using sodium periodate and used directly in the
next reaction. Robinson-Schopf cyclisation of the compound (7) with potassium
hydrogen phthalate, acetonedicarboxylic acid and glycine ethyl ester
hydrochloride resulted in the pseudopelletierine derivative i.e. 7-ethoxycarbonyl-
9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-one (8). The ketone group
of compound (8) was reduced with sodiumborohydride in ethanol to give 7-
ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (9).
The reduced alcohol (9) was treated with dihydropyran to protect the hydroxy
group as a tetrahydropyranyl ether (10). Dieckmann cyclisation of the compound
(10) using strong base (potassium t-butoxide) followed by aqueous acid hydrolysis
and decarboxylation gave the desired alcohol. The resulting alcohols can exist in
two conformations - axial and equatorial. The main product obtained by above
procedure was the axial alcohol OR endo-hexahydro-8-hydroxy-2,6-methano-2l-I-
quinolizin-3-(4H)-one (11) and it can be separated from the equatorial isomer by
crystallization of the camphorsulfonate or tetrafluoroborate salt. The
tetrafluoroborate salt of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinoIizin-3-(4H)-one (11) was further reacted with 3-indolecarboxylic acid chloride in presence of silver tetrafluoroborate in anhydrous nitroethane at -78°C to endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one or Dolasetron base, which was further converted into Dolasetron mesylate (1) (scheme I).
However on following the process as described the overall yield obtained is about 1-1.5%.
3

SCHEME 1

The main disadvantage of this process is the use of column chromatography for purification of compounds (9) and (10), which is expensive, time consuming and impractical on an industrial scale. The patent does not disclose the yield and purity of dolasetron mesylate obtained and so also for the intermediates. Osmium
4

tetroxide used for preparation of compound (6) is toxic, has a corrosive action on eyes and hence difficult to use at industrial scale. Other disadvantages of this process are, use of high volume of water during preparation of the compound (8); preparation of compound (11) from compound (10) is tedious, because the workup involves several extractions with ethyl acetate and preparation of compound (1) in presence of silvertetrafluoroborate involves the use of expensive silver compound.
Another process described in EP 0339669 provides a process for the preparation of
endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one
methanesulfonate or Dolasetron mesylate (1) by the condensation of dimethyl
malonate with cis-l,4-dichloro-2-butene (2) in presence of lithium hydride in
dimethyfformamide to give dimethyl-β-cyclopentene-l,l-dicarboxylate (12),
which was decarbomethylated to obtain methyl-3-cyclopentene-l-carboxylate
(13). This compound (13) was treated with m-chloroperbenzoic acid in
dichloromethane to obtain l-methoxycarbonyl-3-cyclopenteneoxide (14). The
compound (13) on ozonolysis gave (3-methoxycarbonylglutaraldehyde (15) OR the
oxide (14) was reacted with periodic acid to obtain the B-
methoxycarbonylglParaldehyde (15), which was used directly in the next reaction.
Robinson-Schopf cyclisation of the compound (15) with potassium hydrogen
phthalate, acetonedicarboxylic acid and glycine ethyl ester hydrochloride gave the
pseudopelletierine derivative i.e. 7-methoxycarbonyl-9-(methoxycarbonylmethyl)-
9-azabicyclo [3.3.1] nonan-3-one (16). The ketone group of compound (16) was
reduced with sodiumborohydride in methanol to give 7-methoxycarbonyl-9-
(methoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (17). The reduced
alcohol (17) was treated with dihydropyran to protect the hydroxy group as a
tetrahydropyranyl ether (18a) OR treated with methylal to protect the hydroxy
group to obtain 3-methoxymethoxy-7-methoxycarbony!-9-
(methoxycarbonylrnethyl)-9-azabicyclo[3.3.1 ]nonan-3-ol (18b).
5

SCHEME II

Dieckmann cyclisation of the compound (18) using strong base (potassium t-butoxide) followed by aqueous acid hydrolysis and decarboxylation gave the endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11). The alcohol (11) was further reacted with 3-indolecarboxylic acid in presence of
6

trifluoroacetic anhydride in dichloromethane to endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one or Dolasetron base, which was then converted into Dolasetron mesylate (1) (scheme II).
Major disadvantages of this process are,
use of high volume of water for preparation of compound (16) and preparation of compound (11) from compound (18) which is tedious because at the time of workup, ethyl acetate extractions take up longer period (20 h);
The process is not only time consuming but also expensive on an industrial scale.
The patent does not disclose purity of dolasetron obtained nor for any of the
intermediates.
However on following the process as described, the overall yield obtained is about
3-3.5%.
The present invention attempts to overcome problems encountered in prior art.
Silvertetrafluoroborate is not used in the process.
Use of silyl protecting group improves the yield substantially.
OBJECTS OF THE PRESENT INVENTION
An object of the invention is to provide a simple, economical and industrially feasible process for the preparation of highly pure endo-hexahydro-8-(3-indolylcarbony!oxy)-2,6-methano-2H-quinolizin-3 (4H)-one methanesulfonate of the formula (1) or Dolasetron mesylate.
7

Another object of the present invention is to provide an improved process for Dolasetron mesylate, which avoids the use of column chromatography.
A further object of the present invention is to provide an environmentally friendly process.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of highly pure Dolasetron mesylate OR endo-hexahydro-8-{3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3 (4H)-one methanesulfonate (1). Commercially available 3-cyclopentene-1-carboxylic acid (4) was treated with thionyl chloride in alcohol OR alcoholic HC1 to obtain the ester (5). The compound (5) was treated with m-chloroperbenzoic acid in dichloromethane to obtain an epoxide compound (19) which was then reacted with periodic acid to provide the dialdehyde compound (7). Robinson-Schopf cyclisation of the compound (7) with potassium hydrogen phthalate, acetonedicarboxylic acid and glycine ester hydrochloride gave the pseudopelletierine derivative i.e. bicyclic ketone (8). The ketone group of compound (8) was reduced with sodiumborohydride in alcohol and further treated with an organic acid to obtain the reduced compound (9). The reduced alcohol (9) was treated with silyl halide to protect the hydroxy group to provide a silylprotected compound (20). Dieckmann cyclisation of the compound (20) using strong base (potassium t-butoxide) in toluene and treatment with organic acid-ethylacetate mixture gave the B-ketoester compound (21). The compound (21) was hydrolysed with concentrated hydrochloric acid in water or organic solvent for hydrolysis and decarboxylated to obtain the endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11). The alcohol (11) was further reacted with 3-indole carboxylic acid in presence of trifluoroacetic anhydride in dichloromethane to give endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-
8

2H-quinolizin-3(4H)-one or Dolasetron base, which was further converted into Dolasetron mesylate (1) (scheme III).
Scheme III

0

9

DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided a process for preparation of Dolasetron mesylate OR endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3 (4H)-one methanesulfonate of the formula (1) in high yield and high purity comprising:

a. Reacting compound (4), with thionyl chloride in alcohol or
alcoholic hydrochloric acid or anhydrous HC1 gas to form compound (V);

Formula (V)
b. The compound (V) is treated with m-chloroperbenzoic acid in
dichloromethane to give an epoxide compound (XIX),


:o
ROOC

Formula (XIX)
10

c. The epoxide compound (XIX) was treated with periodic acid to
give compound (VII);

Formula (VII)
d. Robinson-Schopf cyclisation of the compound (VII) with
potassium hydrogen phthalate, acetonedicarboxylic acid and glycine ester
hydrochloride to obtain pseudopelletierine derivative (VIII);

Formula (VIII)
e. Reducing the compound (VIII) with sodiumborohydride in
alcohol followed by treatment with organic acid to obtain compound (IX);

Formula (IX)
f. The compound (IX) is protected as a silyl derivative (XX) by
treating (IX) with a silyl halide, in organic solvent (wherein Z = silyl group)
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The compound (XX) is treated with a strong base to form
compound (XXI);
COOR

Formula (XXI)
h. The compound (XXI) is treated with acid in water or organic
solvent followed by decarboxylation to yield compound (11);

Formula (11)
i. The compound (11) is reacted with indole-3-carboxylic acid in
presence of trifluoroacetic acid anhydride to yield Dolasetron base;
and purifying Dolasetron base by recrystallization with organic solvents.
k. Dolasetron base is converted into its mesylate and then
recrystallized from a mixture of solvents to highly pure compound (1).
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[R = Et, Me, OCH2Ph, Rl = Et, Me, OCH2Ph & Z = trimethyl silyl, isopropyl dimethyl silyl, t-butyldimethyl silyl, t-butyldiphenyl silyl, tribenzyl silyl, triisopropyl silyl].
According to the present invention there is provided a process for the preparation of 3-cyclopentene-l-carboxylic acid ester (5), comprising reaction of 3-cyclopentene-1-carboxylic acid (4) with anhydrous HC1 gas or concentrated mineral acid or thionyl chloride in alcohol. The alcohol may be selected from methanol and ethanol.
The compound (5) was treated with m-chloroperbenzoic acid in a solvent selected from dichloromethane and ethyl acetate to obtain the corresponding epoxide (19).
The compound (19) was reacted with periodic acid under nitrogen atmosphere to obtain compound (7).
The compound (7) was treated with potassium hydrogen phthalate: acetonedicarboxylic acid and glycine ester hydrochloride in water to oblain pseudopelletierine derivative (8).
The ratio of compound (19) to water in the reaction was 1: 8 to 10.
The compound (8) was reduced with sodiumborohydride in alcohol and further treated with an organic acid to obtain compound (9). The organic acid is selected from formic acid, methane sulfonic acid and acetic acid.
The compound (9) was treated with silyl halide in presence of imidazole in organic solvent to obtain compound (20).
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Wherein Z = silyl group selected from isopropyl dimethyl silyl, t-butyldimethyl silyl, t-butyldiphenyl silyl, tribenzyl silyl, triisopropyl silyl and trimethyl silyl. The solvent may be selected from ketones, esters and ethers. The solvent may be further selected preferably from acetone, tetrahydrofuran, dioxan, dichloromethane, chloroform, N, N-dimethyl formamide, ethyl acetate and acetonitrile.
A major advantage of the use of silyl protecting group is that it yields greater than 95 % of compound (20) as compared to, use of dihydropyran (75%) or methylal (84%).
The compound (20) was treated with a strong base in toluene and further treated with organic acid and organic solvent to form compound (21). The organic solvent may be selected from halogenated solvents, ethers and esters. The organic solvent may be preferably selected from methylene chloride, chloroform, ethyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether or mixtures thereof. The organic acid maybe selected from formic acid and acetic acid.
The compound (21) was heated with hydrochloric acid in water to give compound (11). Hydrochloric acid and water are used in the ratio of 1:2 volumes. The reaction mixture was concentrated and residue obtained was treated with organic
solvents, filtered the inorganic salts and filtrate concentrated to obtain compound (11). The organic solvent is selected from alcohols and halogenated solvent preferably methanol, ethanol, isopropanol, butanol, dichloromethane, chloroform or mixture thereof.
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The reaction mixture may be extracted with an organic solvent selected from ethylacetate and n-butanol.
The compound (11) was reacted with indole-3-carboxylic acid in presence of trifluoroacetic acid anhydride in dichloromethane to give Dolasetron base. The ratio of indole-3-carboxylic acid and trifluoro acetic anhydride used are in the range of 1.1 to 2 equivalents.
Dolasetron base thus obtained may be purified by any conventional method. Dolasetron may be recrystallized from a solvent selected from alcohols, ketones, ethers, esters and aliphatic or aromatic hydrocarbons. Solvent for recrystallisation maybe selected preferably from ethanol, methanol, n-propanol, isopropanol acetone, methylisobutyl ketone, methylethylketone, hexane, toluene, xylene, methylene chloride, chloroform and mixtures thereof.
Dolasetron base was then converted into its mesylate salt using methane sulphonic acid in organic solvent. The organic solvent may be selected from alcohols, halogenated solvent and ketones. Solvent may be preferably selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, acetone, methyl ethyl ketone or mixture thereof.
Dolasetron mesylate may be purified by dissolving in a solubilizing solvent and adding an antisolvent, to obtain highly pure compound (I). The solubilizing solvent is selected from alcohols, ketones and water or mixture thereof and antisolvent is selected from ethers, esters and halogenated solvents. The solubilizing solvent
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maybe preferably selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, water and mixture thereof and the antisolvent maybe preferably selected from diethyl ether, diisopropyl ether, ethyl acetate, dichloromethane, chloroform and mixture thereof.
EXAMPLES
EXAMPLE 1: Ethyl-3-cyclopentene-l-carboxylate (5)
A solution of 3-cyclopentene-l-carboxylic acid (500 g, 4.45 moles) in ethanol (500 mL) was stirred at 5-10°C. Then thionyl chloride (257.59 g, 2.16 moles) was added in a drop wise manner for 1 h. After complete addition was over, the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into the water (1000 mL) and extracted with ethyl acetate (2x 250 mL). The ethyl acetate layer was washed with 10% sodium carbonate solution (500 mL), with water (2x500 mL) and concentrated to give ethyl-3-cyclopentene-1-carboxylate (5). Yield: 558g, 89.42%.
EXAMPLE 2: l-Ethoxycarbonyl-3-cyclopenteneoxide (19)
A solution of ethyl-3-cyclopentene-l-carboxylate (5) (1 Kg, 7.13 moles) in dichloromethane (8 lit) was stirred at 5-10°C. Then 70 % metachloro perbenzoic acid (2.4 Kg, 9.73 moles) was added in lots for 1 h at 5-10°C. The reaction mixture was stirred at 5-10°C for 3 h. The reaction was monitored using gas chromatography. The reaction mixture was filtered and cake washed with dichloromethane (2 x 1 lit). The filtrate was washed with 10 % sodium metabisulphite (5 lit), 10 % sodium carbonate (10 lit), dried over sodium sulphate and concentrated to give l-Ethoxycarbonyl-3-cydopenteneoxide (19) Yield: 1.1 Kg, 98.74%.
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EXAMPLE 3: β-ethoxycarbonylglutaraldehyde (8)
A suspension of periodic acid (1.5 Kg, 6.58 moles) in ethyl acetate (3 lit) was stirred at 0-10 C under nitrogen atmosphere. Then was added 1-ethoxycarbonyl-3-cyclopenteneoxide (19) (1 Kg, 6.40 moles) in ethyl acetate (3 lit) in a dropwise manner at 0-10°C for lh. The reaction mixture was stirred at 0-10°C for 4 h. The reaction mixture was filtered through celite. The filtrate was washed with water (2 x 750 ml). The ethyl acetate layer was diluted with water (3 lit). From this mixture ethyl acetate was evaporated at 30-35°C under vacuum and aqueous layer that remained contained β-ethoxycarbonylglutaraldehyde (7). This aqueous solution was directly used in the next step.
EXAMPLE 4: 7-ethoxycarbonyl-9-(ethoxycarbonylmethyI)-9-azabicyclo-[3.3.1]nonan-3-one (8)
A suspension of potassium hydrogen phthalate (2.5 Kg, 12.24 moles) in water (2 lit) was stirred at room temperature. Then acetonedicarboxylic acid (1.15 Kg, 8.23 moles) in water (1.4 lit) and glycine ethyl ester (1.15 Kg, 8.23 moles) in water (1.6 lit) were added to the reaction mixture at 15-20°C. The aqueous solution containing B-ethoxycarbonyl glutaraldehyde (7) was added in a dropwise manner for 1 h under nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature and the pH was adjusted to 8-8.5 by the addition of the potassium carbonate and extracted with ethyl acetate (3x1000 mL). The ethyl acetate layer was separated, washed with water and concentrated to give 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1 ]nonan-3-one (8). Yield: 1.05 Kg, 55.14%.
EXAMPLE 5: 7-ethoxycarbonyl-9-(ethoxycarbonyImethyl)-9-azabicyclo-[3.3.1]nonan-3-ol(9)
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To a solution of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-one (8) (450 g, 1.51 moles) in ethanol (4.5 lit) was added, sodiumborohydride (175 g, 4.62 moles) in a portion wise manner for 30 min at 10-15°C. The reaction mixture was stirred at room temperature for 2 h and the pH was adjusted to 7 by the addition of the acetic acid. The solid was filtered and the filtrate was concentrated to yellow residue. Water (1.2 lit) was added to the residue and the reaction mixture was basified using 10% potassium carbonate solution and extracted with ethyl acetate (3x600 mL). The ethyl acetate layer was separated and concentrated to give 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyc lo-[3.3.1]nonan-3-ol(9). Yield: 365 g, 80.56%.
EXAMPLE 6: 3-tertiary butyl dimethylsilyloxy-7-ethoxycarbonyI-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol(20)
A solution of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (9) (351 g, 1.17 moles), imidazole (239 g, 3.51 moles) and t-butyldimethylsilyl chloride (265 g, 1.7 moles) in N,N-dimethylformamide (700 mL) was stirred at 10°C for 30 min. The reaction mixture was stirred at room temperature for 2 h, after which it was poured into water (5 lit) and extracted with ethyl acetate (3x500 ml). The ethyl acetate layer was separated, washed with water (3x1000 mL) and concentrated to give 3-tertiary butyl dimethylsilyloxy 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (20). Yield: 480 g, 99.17%
EXAMPLE 7: endo-hexahydro-8-(t-butyldirnethylsilyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one(21)
A mixture of 3-tertiary butyl dimethylsilyloxy 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (20) (480 g, 1.16 moles) and potassium t-butoxide (235 g, 2.09 moles) in toluene (4.5 lit) was refluxed
18

under nitrogen atmosphere for 2 h. Acetic acid (140 mL) was added to the reaction
mixture at 10-15°C followed by water (500 mL). The reaction mixture was
extracted with ethyl acetate (3.0 lit), the ethyl acetate layer was separated, washed
with water and concentrated to obtain endo-hexahydro-8-(t-butyldimethyl
silyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one(21)
(21).
Yield: 270 g, 92.15%.
EXAMPLE 8: endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one(ll)
To the oily compound, endo-hexahydro-8-(t-butyldimethylsilyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one (21) (100 g, 0.39 moles) in water (200 mL) concentrated hydrochloric acid (50 mL) was added. The reaction mixture was refluxed for 16 h, cooled to room temperature and basified with potassium carbonate till pH becomes 8-8.5. This solution was concentrated under reduced pressure to obtain a residue. This residue was treated with 50%) methanol in dichloromethane to precipitate inorganic material. This inorganic material was separated by filtration and filtrate was concentrated to give endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11). Yield: 26 g, 36.34%.
EXAMPLE 9: endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-
one(11)
To the oily compound, 4-ethoxycarbonyl-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-one (21) (100 g, 0.39 moles) in water (200 mL) concentrated hydrochloric acid (50 mL) was added. The reaction mixture was refluxed for 16 h cooled to room temperature and basified with potassium carbonate till pH becomes 8-8.5. This solution was extracted with n-butanol. The butanol layer was separated
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and concentrated under reduced to give endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11). Yield: 25.5 g, 35.64%.
EXAMPLE 10: endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one(11)
To the oily compound 4-ethoxycarbonyl-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-one (21) (100 g, 0.39 moles) in water (200 mL) was added concentrated hydrochloric acid (50 mL). The reaction mixture was stirred at room temperature for 2 h, and extracted with dichloromethane (2x 200 ml). The aqueous acidic layer was separated and refluxed for 16 h, cooled to room temperature and basified with potassium carbonate till pH becomes 8-8.5. This solution was concentrated under reduced pressure and residue was obtained. This residue was treated with 50% methanol in dichloromethane to precipitate inorganic material. This inorganic material was separated by filtration and filtrate was concentrated to give endo4iexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11). Yield: 35 g, 48.9%.
EXAMPLE 11: endo-hexahydro-8-(3-indolyIcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base)
A solution of trifluoroacetic anhydride (121.8 g, 0.57 mole) in dichloromethane (750 mL) was stirred under nitrogen atmosphere and to this, indole-3-carboxylic acid (88 g, 0.54 moles) was added in a portion wise manner for 30 min at 0-5°C. The reaction mixture was stirred for further 30 min at 0-5°C. Then endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11) (50 g, 0.27 moles) in dichloromethane (500 mL) and dimethyl amino pyridine (0.42 g, 0.0039 moles) were added in a drop wise manner for 30 min at 0-5°C. The reaction mixture was stirred further for 12 h at room temperature. The reaction mixture was filtered and the collected solid washed with dichloromethane (100 mL). The solid
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was stirred in ethyl acetate (550 mL) and 10% sodium carbonate (500 mL)was further added. The ethyl acetate layer was separated, washed with water and concentrated to obtain crude dolasetron base (60 g). The crude base was recrystallized from ethyl acetate-hexane to give pure Dolasetron base. Yield: 50 g, 50.63%.
EXAMPLE 12: endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one mesylate
Dolasetron base (50 g, 0.15 moles) was dissolved in acetone (1000 mL) and methane sulphonic acid was added (10.70 mL) drop wise over a period of 30 min at 20°C. The reaction mixture was stirred further for 2 h. The solid formed was filtered, washed with cold acetone (50 mL) and dried. Yield (crude) 59 g, 90.71%.
EXAMPLE 13: Purification of endo-hexahydro-8-(3-indolylcarbonyIoxy)-2,6-methano-2H-quinolizin-3(4H)-one mesylate Dolasetron mesylate.
Dolasetron mesylate crude (59 g) was dissolved in hot 5% aqueous isopropanol (500 mL) treated with charcoal and filtered hot. Diethyl ether (50 ml) was added to the filtrate, the solid formed was filtered and dried. Yield 50 g, 82.71%. Purity: 99.9% (HPLC).
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We Claim,
1. An improved process for the preparation of endo-hexahydro-8-(3-
indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3 (4H)-one methanesulfonate having formula 1, comprising:
H


CH3SO3H

Formula 1
a. Reacting compound (4) with thionyl chloride in alcohol to obtain
compound of formula (V);

Formula (V)
b. Treating compound (V) with m-chloroperbenzoic acid in a
solvent selected from dichloromethane or ethylacetate to provide an epoxide compound (XIX),


Formula (XIX)
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c. Treating compound (XIX) with periodic acid to obtain
compound (VII);

Formula (VII)
d. Robinson-Schopf cyclisation of the compound (VII) using
potassium hydrogen phthalate, acetonedicarboxylic acid and glycine ester
hydrochloride in water to obtain pseudopelletierine derivative (VIII);

Formula (VIII)
e. Reducing compound (VIII) with sodiumborohydride in alcohol
and further treating with organic acid to obtain compound (IX);

Formula (IX)
f. Protecting compound (IX) as a silyl derivative using silyl
reagent in organic solvent to obtain compound (XX);
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'

Formula (XX)
g. Treating compound (XX) with a strong base in toluene and
further treated with a mixture of organic acid and organic solvent to form compound (XXI);

Formula (XXI)
h. Treating compound (XXI) is treated with inorganic acid in a
suitable solvent to give compound (11);
0.

Formula (11)
i. Reacting compound (11) with indole-3-carboxylic acid in
presence of trifluoroacetic acid anhydride to obtain Dolasetron base;
j. Purifying Dolasetron base by recrystallization from organic
solvents;
k. Converting Dolasetron base into its mesylate salt by treating
with methane sulphonic acid in suitable organic solvent;
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I. Purifying Dolasetron mesylate by dissolving in a solubilizing
solvent and adding antisolvent to obtain highly pure compound (1).
2. The process as claimed in claim 1, wherein R = Et, Me, OCH2Ph
3. The process as claimed in claim 1, wherein Rl = Et, Me, OCH2Ph
4. The process as claimed in claim 1, wherein ratio of compound (XTX) to water is 1:8 to 10.
5. The process as claimed in claim la, wherein the alcohol is selected from selected from methanol and ethanol.
6. The process as claimed in claim le, wherein the alcohol is selected form methanol and ethanol.
7. The process as claimed in claim le, wherein the organic acid is selected from formic acid, methane sulfonic acid and acetic acid.
8. The process as claimed in claim 7, wherein the organic acid is acetic acid.
9. The process as claimed in If, wherein Z is selected from trimethyl silyl, isopropyl dimethyl silyl, t-butyldimethyl silyl, t-butyldiphenyl silyl, tribenzyl silyl, triisopropyl silyl, trimethyl silyl and t-butyldimethyl silyl.
10. The process as claimed in claim If, wherein the silyl reagent is t-butyldimethylsilyl chloride.
11. The process as claimed in claim If, wherein the organic solvent is selected from ketones, esters, and ethers.
12. The process as claimed in claim 11, wherein the solvent is selected from acetone, tetrahydrofuran, dioxan, dichloromethane, chloroform, N, N-dimethyl formamide, ethyl acetate, or acetonitrile, preferably N,N-dimethyl formamide.
13. The process as claimed in claim lg, wherein the organic acid is selected
from formic acid and acetic acid, preferably acetic acid.
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14. The process as claimed in claim lg, wherein the organic solvent is selected from halogenated solvents, ethers and esters.
15. The process as claimed in claim 14, wherein the organic solvent is selected from methylene chloride, chloroform, ethyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether and mixtures thereof, preferably ethyl acetate.
16. The process as claimed in claim lh, wherein the acid is hydrochloric acid.
17. The process as claimed in claim lh, wherein the organic solvent is selected from alcohols, ketones and halogenated solvents.
18. The process as claimed in claim 17, wherein the organic solvent is selected from methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dicloromethane, chloroform and mixtures thereof. preferably mixture of dichloromethane and methanol.
19. The process as claimed in claim li, wherein indole-3-carboxylic acid and trifluoro acetic anhydride are in the ratio of 1.1 to 2 equivalents.
20. The process as claimed in claim lj, wherein the organic solvent is selected from alcohols, ketones, ethers, esters and aliphatic or aromatic hydrocarbons.
21. The process as claimed in claim 20, wherein the organic solvent is selected from ethanol, methanol, n-propanol, isopropanol, acetone, methylisobutyl ketone, methylethylketone; hexane, toluene, xylene, methylene chloride, chloroform and mixtures thereof, preferably mixture of ethyl acetate and hexane.
22. The process as claimed in claim Ik, wherein the organic solvent is selected from alcohols, halogenated solvents and ketones
23. The process as claimed in claim 22, wherein the organic solvent is selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, acetone, methyl ethyl ketone or mixture thereof, preferably acetone.
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24. The process as claimed in claim II, wherein the solvent is selected from alcohols, ketones, water or mixture thereof.
25. The process as claimed in claim 24, wherein the solubilizing solvent is selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, water and mixture thereof, preferably mixture of isopropanol and water.
26. The process as claimed in claim 11 wherein the antisolvent is selected from ethers, halogenated solvents, esters or mixture thereof.
27. The process as claimed in claim 26 wherein the antisolvent is diisopropyl ether, diethyl ether, ethyl acetate, dichloromethane and chloroform, preferably diethyl ether.
28. The process as claimed in claim 1 wherein Dolasetron mesylate is obtained in a purity of 99.9%.
Dated this the 23rd day of Dec, 2005
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ABSTRACT
The present invention provides a process for preparation of highly pure Dolaselron mesylate OR endo-hexahydro-8-(3-indoly!carbonyloxy)-2,6-methano-2H-quinolizin-3 (4H)-one methanesulfonate (1) using a silyl protetcted compound as an intermediate.
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