Patent Application
20080275241
This specification claims priority from 1610/MUM/2005 dt 23/12/2005 and 1635/MUM/2005 dt 29.12.2005
The present disclosure relates to a process for the preparation of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one or Dolasetron base of structural formula (A) and a process for the preparation of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one mesylate or Dolasetron mesylate of structural formula (1).
Further, it relates to novel crystalline polymorphs of Dolasetron base of structural formula (A) and industrial processes for producing the same. Furthermore, it discloses a process for producing Form I of Dolasetron base.
Dolasetron is an antinauseant and antiemetic agent. It is a selective serotonin 5-HT3 receptor antagonist and is indicated for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. Dolasetron is a well-tolerated drug with few side effects.
Synthesis of Dolasetron base is not very widely reported in literature. However, EP0266730/U.S. Pat. No. 4,906,755 describes process for the preparation endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one methanesulfonate or Dolasetron mesylate, 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-1,1-dicarboxylate (3), which on hydrolysis and decarboxylation gave 3-cyclopentene-1-carboxylic acid (4). The compound (4) was further treated with thionyl chloride and pyridine in ethanol to obtain ethyl 3-cyclopentene-1-carboxylate (5). Compound (5) was oxidized to 4-ethoxycarbonyl-1,2-cyclopentanediol (6) by using N-methylmorpholine N-oxide in the presence of osmium tetroxide catalyst. The diol (6) was cleaved to the β-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 hydroxyl 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-2H-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-quinolizin-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 monohydrate (Scheme I) with a yield of 66%. No further purification is described.
The above process uses column chromatography for purification of compounds (9) and (10), which is expensive, time consuming and impractical on an industrial scale. The above patent does not disclose the yield and purity of Dolasetron mesylate obtained and so also for the intermediates. In addition, Osmium tetroxide used for preparation of compound (6) is toxic, has a corrosive action on eyes and hence difficult to use at industrial scale. Also this process uses high volume of water during preparation of the compound (8); preparation of compound (II) from compound (10) is tedious, because the workup involves several extractions with ethyl acetate and preparation of compound (I) in presence of silver tetrafluoroborate involves the use of expensive silver compound.
Another method described in EP0339669 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-1,4-dichloro-2-butene (2) in presence of lithium hydride in dimethyl formamide to give dimethyl-3-cyclopentene-1,1-dicarboxylate (12), which was decarbomethylated to obtain methyl-3-cyclopentene-1-carboxylate (13). This compound (13) was treated with m-chloroperbenzoic acid in dichloromethane to obtain 1-methoxycarbonyl-3-cyclopenteneoxide (14). The compound (13) on ozonolysis gave β-methoxycarbonylglutaraldehyde (15) or the epoxide (14) was reacted with periodic acid to obtain the β-methoxycarbonylglutaraldehyde (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-(methoxycarbonylethyl)-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 hydroxyl group as a tetrahydropyranyl ether (18a) or treated with methylal to protect the hydroxyl group to obtain 3-methoxymethoxy-7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonan-3-ol (18b).
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 trifluoroacetic anhydride in dichloromethane to endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one or Dolasetron base (A), which was then converted into Dolasetron mesylate (1) (not shown in Scheme II) by treating with methanesulphonicacid in acetone (Scheme II).
Disadvantages of this process are:
The process is not only time consuming but also expensive on an industrial scale. The patent does not disclose purity of Dolasetron base obtained nor for any of the intermediates.
The process as described in EP 0266730 involves treatment of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base) with a solution of methane sulfonic acid in ethanol to provide Dolasetron mesylate monohydrate. EP 0339669 describes crystallization of crude Dolasetron mesylate by dissolution in aqueous isopropanol and regeneration by adding ether. The polymorphic form obtained by the processes described in U.S. Pat. No. 4,906,755/EP 0266730 and EP 0339669 is designated herein as Dolasetron mesylate Form I.
The ability of the compound to exhibit more than one orientation or conformation of molecule within the crystal lattice is called polymorphism. Many organic compounds including active pharmaceutical ingredients (API's) exhibit polymorphism.
Drug substance existing in various polymorphic forms differs from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties, thus affecting dissolution, bioavailability and handling characteristics of the substance.
Rate of dissolution of an API's in patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administrated API can reach the patient bloodstream. Flowability affects the ease with which the material is handled while processing a pharmaceutical product.
Investigation of crystal polymorphism is an essential step in pharmaceutical research due to the influence of solid-state properties on dosage form.
As the polymorphs are known to possess different spectroscopic properties, technique such as X-Ray powder diffraction (XRPD), Fourier transformer Infrared (FT-IR) spectroscopy, Solid State 13C-NMR, and thermal method of analysis are keys to identify and characterize the new polymorphs or existing polymorphs.
The discovery of new polymorphs with same or better pharmaceutical equivalence and bioequivalence as that of the known polymorphs provides an opportunity to improve the performance characteristic of the pharmaceutical product.
The prior art describes isolation of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one or Dolasetron base as an oil. It is desirable to have the product in the solid form than oil, as solid is easy to handle and easy to purify.
Dolasetron base is isolated as a solid in EP 0339669. However, there is no evidence of polymorphism.
WO2006056081 discloses purification of Dolasetron base using strong acid especially methanesulphonic acid in presence of acid halide.
In our endeavour to develop a process for the preparation of Dolasetron base, we have surprisingly discovered novel polymorphic forms of Dolasetron base.
An object of the disclosure is to provide a simple, economical and industrial process for the preparation of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one or Dolasetron base.
One more object of the disclosure is to provide a simple, economical and industrial process for the preparation of substantially pure endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one methanesulfonate or Dolasetron mesylate.
Another object of the disclosure is to provide a process to prepare Form I of Dolasetron base.
Yet another object is to provide novel polymorphic forms of Dolasetron base having improved stability, compressibility and bioavailability and industrial processes for producing them.
Accordingly, the present disclosure provides a process for producing endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base) having structural formula (A).
In one aspect, the present invention provides a process for producing endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one mesylate (Dolasetron mesylate) having structural formula (I).
In another aspect, the present disclosure provides a process for producing polymorphic Form I of Dolasetron base.
In one aspect, the present invention provides a crystalline polymorphic Form II of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base).
In another aspect, the present invention relates to a process for producing the polymorphic Form II of Dolasetron base.
In yet another aspect, the present invention provides a crystalline polymorphic Form III of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base).
In one aspect, the present invention relates to a process for producing polymorphic Form III of Dolasetron base.
In yet another aspect, the present invention provides a crystalline polymorphic Form IV of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base).
In a further aspect, the present invention relates to a process for producing polymorphic Form IV of Dolasetron base.
In one aspect, the present invention provides a crystalline polymorphic Form V of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base).
In another aspect, the present invention relates to a process for producing polymorphic Form V of Dolasetron base.
The present disclosure provides a process for the preparation of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one having structural formula (A) (Dolasetron base) comprising:
with thionyl chloride or hydrochloric acid in an alcohol to obtain a compound having structural formula (V);
The present disclosure also provides a process for preparation of Dolasetron mesylate or endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one methanesulfonate of structural formula (1) in high yield and substantial purity comprising:
The organic solvent is selected from alcohols such as methanol, ethanol, and isopropanol, halogenated solvents such as dichloromethane and chloroform, ketones such as acetone and methyl ethyl ketone or mixture thereof, preferably acetone.
The base is selected from sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium carbonate, preferably sodium carbonate.
The Dolasetron base used for preparing its acid addition salt is selected from Dolasetron base Form I, Dolasetron base Form II, Dolasetron base Form III, Dolasetron base Form IV and Dolasetron base Form V.
In accordance to Scheme III, a process for the preparation of 3-cyclopentene-1-carboxylic acid ester (5) is disclosed, said process comprising: reacting 3-cyclopentene-1-carboxylic acid (4) with anhydrous HCl gas or concentrated hydrochloric acid or thionyl chloride in an alcohol, wherein the alcohol is either methanol or ethanol; treating the compound (5) with m-chloroperbenzoic acid in a solvent selected from dichloromethane, toluene and ethyl acetate to obtain the corresponding epoxide (19); reacting the compound (19) with periodic acid under nitrogen atmosphere to obtain compound (7); treating the compound (7) with potassium hydrogen phthalate, acetonedicarboxylic acid and glycine ester hydrochloride in water to obtain pseudopelletierine derivative (8); reducing the compound (8) with sodiumborohydride in an alcohol and further treating with an organic acid to obtain compound (9), wherein the organic acid is selected from formic acid, methane sulphonic acid and acetic acid; treating the compound (9) with silyl halide in presence of imidazole in an organic solvent to obtain compound (20), wherein the organic solvent is selected from ketones, esters and ethers, preferably from acetone, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, N,N-dimethyl formamide, ethyl acetate and acetonitrile.
Scheme III given below shows the complete process as a flow chart:
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 other protecting groups such as dihydropyran (75%) or methylal (84%).
The compound (20) is treated with a strong base in toluene and further treated with an organic acid in an organic solvent to form compound (21). The organic solvent is selected from halogenated solvents, ethers and esters. The organic solvent is preferably selected from methylene chloride, chloroform, ethyl acetate, isopropyl acetate, diethyl ether and diisopropyl ether, or mixture thereof. The organic acid is selected from formic acid and acetic acid.
The compound (21) is heated with hydrochloric acid in water to give compound (II). Hydrochloric acid and water are used in the ratio of 1:2 volumes. The ratio of compound (21) to water in the reaction is about 1:8 to 1:10. The reaction mixture is concentrated and the residue obtained is treated with an organic solvent and filtered. The filtrate is concentrated to obtain compound (11). The organic solvent is selected from alcohols and halogenated solvent preferably methanol, ethanol, isopropanol, n-butanol, dichloromethane, chloroform or mixture thereof. The reaction mixture is extracted with an organic solvent selected from ethylacetate, isopropanol or n-butanol. Alternately the reaction mixture is saturated with an inorganic salt and extracted with an organic solvent selected from ethylacetate or n-butanol or isopropanol.
The compound (11) is 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 is in the range of 1:1.1 to 1:2. Dolasetron base thus obtained is isolated by conventional method. Dolasetron base is solubilized in acetone and converted into its mesylate salt using methane sulphonic acid. The resultant mesylate salt is dissolved in water and extracted with a halogenated solvent or ester to remove traces of impurity. The halogenated solvent is selected from dichloromethane and chloroform, and the ester is selected from methyl acetate, ethyl acetate and isopropyl acetate. The aqueous layer is basified with a base to obtain Dolasetron base. The base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide or mixture thereof. Dolasetron base thus obtained is treated with methane sulphonic acid in a mixture of acetone and water to provide Dolasetron mesylate.
The present disclosure teaches a process for preparation of Form 1 of Dolasetron base or endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.
The process for producing polymorphic Form I of endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one (Dolasetron base), comprises dissolving Dolasetron base in a solubilizing solvent at a temperature in the range of about 25° C. to 90° C. and optionally adding anti-solvent to precipitate into a solid.
Dolasetron base is dissolved in a solubilizing solvent selected from aliphatic ketones, aliphatic nitriles, aliphatic esters and cyclic ethers, or mixture thereof at a temperature in the range of about 25° C. to 90° C. to get a clear solution. The aliphatic ketone is acetone, aliphatic nitrile is acetonitrile, aliphatic ester is ethyl acetate, and the cyclic ether is tetrahydrofuran (THF) or 1,4-dioxane. The dissolved solid is obtained by cooling the solution at a temperature range of about 0° C. to 20° C. or alternately by addition of miscible anti-solvent. The anti-solvent is selected from a group consisting of aliphatic hydrocarbons and aliphatic ethers, or mixture thereof. The anti-solvent is selected from diethyl ether (DEE), diisopropyl ether (DIPE), n-hexane and n-heptane, or mixture thereof. When the ketone is used as a solvent, the antisolvent used is aliphatic hydrocarbon.
The XRPD of Dolasetron base Form I exhibit following peaks. (
DSC of Dolasetron base Form I show two characteristic exotherms at 97° C. and 228° C. (
FT-IR spectrum of Dolasetron base Form I shows characteristic absorption at 3494, 1726, 1687, 1581, 1525, 1450, 1309, 1288, 1265, 1180, 1107, 1066, 1031, 950, 798, 765, 738, 717 cm−1 (
Further, the present invention provides novel polymorphic forms of Dolasetron base viz. Form II, Form III, Form IV and Form V and processes for producing the same.
Dolasetron base is dissolved in aliphatic ethers at a temperature between about 60° C. to 80° C., preferably about 70° C. to 80° C. The clear solution is cooled to a temperature between about −5° C. to 20° C., preferably about 2° C. to 7° C. The suspension was stirred at the same temperature for 2 hr. The separated solid is isolated by filtration and dried at about 50° C.-70° C. to obtain the crystalline product.
Another process for producing the polymorphic Form II of Dolasetron base, comprises: dissolving Dolasetron base in acetone at a temperature ranging between about 20° C. and 40° C. and adding diisopropyl ether to obtain the crystalline product. The XRPD of Dolasetron base Form II exhibits following peaks (
DSC of Dolasetron base Form II shows two endotherms, one at 225° C. followed by a second at 236° C. (
FT-IR spectrum of Dolasetron base Form II shows characteristic absorption at 3280, 1716, 1685, 1523, 1433, 1307, 1238, 1180, 1068, 1029, 79, 754, 717 cm−1 (
Dolasetron base is dissolved in a solubilizing solvent like in aliphatic alcohols or in polar aprotic solvent selected from N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide (DMA), or cyclic ethers selected from tetrahydrofuran (THF) and 1,4-dioxane or mixture thereof at a temperature range of about 25° C. to 30° C. The clear solution is cooled and the solid is obtained by adding water as an anti-solvent. The separated solid is then isolated by filtration and dried at about 50° C. to 70° C. to obtain crystalline Dolasetron base Form III.
In another process, Dolasetron base is dissolved in a solubilizing solvent like in cyclic ethers selected from tetrahydrofuran (THF) and 1,4-dioxane, in aliphatic esters selected from ethyl acetate, in aliphatic alcohols selected from n-propanol and isopropanol, or mixture thereof at a temperature in the range of about 70° C. to 110° C. The clear solution is cooled and the separated solid is then isolated by filtration and dried at about 50° C. to 70° C. to obtain crystalline Dolasetron base Form III. The XRPD of Dolasetron base Form III exhibits following peaks (
DSC of Dolasetron base Form III shows a first endotherm at 113° C. and the second endotherm at 229° C. (
FT-IR spectrum of Dolasetron base Form III shows characteristic absorption at 3490, 1726, 1687, 1504, 1448, 1375, 1309, 1182, 1143, 1066, 1029, 798, 765, 740 cm−1 (
Dolasetron base is dissolved in aromatic hydrocarbons, lower aliphatic alcohols, chlorinated hydrocarbon or mixture thereof at a temperature in the range of about 40° C. to 110° C. The clear solution is allowed to cool and the separated solid is isolated by filtration and dried at about 50° C. to 70° C. to obtain crystalline Dolasetron base Form IV. The aromatic hydrocarbon is toluene; lower aliphatic alcohol is selected from methanol or ethanol; and chlorinated hydrocarbon is chloroform or methylene dichloride (MDC). The XRPD of Dolasetron base Form IV exhibits following peaks (
DSC of Dolasetron base Form IV shows a small endotherm at 98° C. followed by two endotherms first at 229.5° C. and second at 235.9° C. (
FT-IR spectrum of Dolasetron base Form IV shows characteristic absorption at 3498, 1726, 1687, 1504, 1450, 1377, 1309, 1265, 1240, 1180, 1145, 1105, 1085, 1066, 1031, 912, 798, 767, 736 cm−1 (
Dolasetron base undergoes solid-state transformation into new crystalline Form V on heating. The heating is generally carried out in the temperature range of about 150° C. to 200° C. The XRPD of Dolasetron base Form V exhibits following peaks (
DSC of Dolasetron base Form V shows two endotherms, first at 224° C. followed by the second at 229° C. (
FT-IR spectrum of Dolasetron base Form V shows characteristic absorption at 1735, 1678, 1585, 1527, 1454, 1353, 1311, 1180, 1110, 1068, 1026, 912, 798, 769, 752, 715 cm−1 (
The crystallization process hitherto described to prepare the novel polymorphs comprises, dissolving Dolasetron base in the selected solvent either with or without heating, preferably with heating at or near boiling point of the solvent. The resultant solution is cooled to about −5° C. to 30° C. for several hours to regenerate the solid. Solid generated either by cooling or by using an anti solvent. The precipitated solids are isolated and dried at about ambient to 70° C. temperature.
The novel polymorphs of Dolasetron base are characterized by X-ray powder diffraction. X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panalytical diffractometer equipped with accelerator detector using Copper Kα (λ=1.5406 Å) radiation with scanning range between 4-50° 2θ at a scanning speed of 2°/min.
The novel polymorphs of Dolasetron base are characterized by Differential Scanning Calorimeter (DSC). The DSC was performed on Perkin Elmer Diamond DSC instrument. Samples of 2 mg to 3 mg weighed in aluminium crucibles with holes were scanned at a heating rate of 5° C. per minute under nitrogen atmosphere at a rate of 35 mL/min from the temperature range 50-250° C.
The novel polymorphs of Dolasetron base are characterized by Fourier-transform infrared (FT-IR) spectroscopy. The FT-IR spectrum was obtained on a FT-IR 8300, Shimadzu instrument, in the range of 4000-400 cm−1 with a resolution of 4 cm−1.
The present invention is described herein below with examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
A solution of 3-cyclopentene-1-carboxylic acid (500 g, 4.45 mole) in ethanol (500 mL) was stirred at 5-10° C. Then thionyl chloride (257.59 g, 2.16 mole) was added in a drop wise manner for 1 hr. 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 (2×250 mL). The ethyl acetate layer was washed with 10% sodium carbonate solution (500 mL), with water (2×500 mL) and concentrated to give ethyl-3-cyclopentene-1-carboxylate (5). Yield: 558 g, 89.42%.
A solution of ethyl-3-cyclopentene-1-carboxylate (5) (1 Kg, 7.13 mole) in dichloromethane (8 L) was stirred at 5-10° C. Then 70% meta-chloroperbenzoic acid (2.4 Kg, 9.73 mole) was added in lots for 1 hr at 5-10° C. The reaction mixture was stirred at 5-10° C. for 3 hr. The reaction was monitored using gas chromatography. The reaction mixture was filtered and cake washed with dichloromethane (2×1 L). The filtrate was washed with 10% sodium metabisulphite (5 L), 10% sodium carbonate (10 L), dried over sodium sulphate and concentrated to give 1-ethoxycarbonyl-3-cyclopenteneoxide (19). Yield: 1.1 Kg, 98.74%.
A suspension of periodic acid (1.5 Kg, 6.58 mole) in ethyl acetate (3 L) was stirred at 0-10° C. under nitrogen atmosphere. Then was added 1-ethoxycarbonyl-3-cyclopenteneoxide (19) (1 Kg, 6.40 mole) in ethyl acetate (3 L) in a drop wise manner at 0-10° C. for 1 hr. The reaction mixture was stirred at 0-10° C. for 4 hr. The reaction mixture was filtered through celite. The filtrate was washed with water (2×750 mL). The ethyl acetate layer was diluted with water (3 L). 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.
A suspension of potassium hydrogen phthalate (2.5 Kg, 12.24 mole) in water (2 L) was stirred at room temperature. Then acetonedicarboxylic acid (1.15 Kg, 8.23 mole) in water (1.4 L) and glycine ethyl ester (1.15 Kg, 8.23 mole) in water (1.6 L) were added to the reaction mixture at 15° C. to 20° C. The aqueous solution containing 13-ethoxycarbonyl glutaraldehyde (7) was added in a drop wise manner for 1 hr under nitrogen atmosphere. The reaction mixture was stirred for 12 hr at room temperature and the pH was adjusted to 8-8.5 by the addition of the potassium carbonate and extracted with ethyl acetate (3×1000 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%.
To a solution of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-one (8) (450 g, 1.51 mole) in ethanol (4.5 L) was added, sodiumborohydride (175 g, 4.62 mole) in a portion wise manner for 30 min at 10-15° C. The reaction mixture was stirred at room temperature for 2 hr 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 L) was added to the residue and the reaction mixture was basified using 10% potassium carbonate solution and extracted with ethyl acetate (3×600 mL). The ethyl acetate layer was separated and concentrated to give 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (9). Yield: 365 g, 80.56%.
A solution of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (9) (351 g, 1.17 mole), imidazole (239 g, 3.51 mole) and t-butyldimethylsilyl chloride (265 g, 1.7 mole) in N,N-dimethylformamide (700 mL) was stirred at 10° C. for 30 min. The reaction mixture was stirred at room temperature for 2 hr, after which it was poured into water (5 L) and extracted with ethyl acetate (3×500 ml). The ethyl acetate layer was separated, washed with water (3×1000 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%.
1H NMR: 200 MHz, CDCl3; the chemical shifts expressed are in δ.
0.1 (s, 6H, 2×CH3); 0.93 (m, 15H, 5×CH3); 4.1 to 4.26 (m, 4H, 2×CH2); 1.27 to 3.47 (m, 13H, 5×CH2+3×CH).
A mixture of 3-(t-butyldimethylsilyloxy)-7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo-[3.3.1]nonan-3-ol (20) (480 g, 1.16 mole) and potassium t-butoxide (235 g, 2.09 mole) in toluene (4.5 L) was refluxed under nitrogen atmosphere for 2 hr. 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 L), the ethyl acetate layer was separated, washed with water and concentrated to obtain endo-hexahydro-8-(t-butyldimethylsilyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one (21). Yield: 270 g, 92.15%.
1H NMR: 200 MHz, CDCl3; the chemical shifts expressed are in δ.
0.08 (s, 6H, 2×CH3); 0.89 (m, 12H, 4×CH3); 4.1 to 4.23 (m, 4H, 2×CH2); 1.23 to 4.2 & 4.81 to 5.3 (m, 12H, 5×CH2+2×CH).
To the oily compound, endo-hexahydro-8-(t-butyldimethylsilyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one (21) (100 g, 0.39 mole) in water (200 mL) concentrated hydrochloric acid (50 mL) was added. The reaction mixture was refluxed for 16 hr, 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%.
To the oily compound, endo-hexahydro-8-(t-butyldimethylsilyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one (21) (100 g, 0.39 mole) in water (200 mL) was added concentrated hydrochloric acid (50 mL). 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 n-butanol layer was separated 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%.
To the oily compound endo-hexahydro-8-(t-butyldimethylsilyloxy)-2-ethoxycarbonyl-2,6-methano-2H-quinolizin-3-(4H)-one (21) (100 g, 0.39 mole) in water (200 mL) was added concentrated hydrochloric acid (50 mL). The reaction mixture was refluxed for 16 hr and cooled to room temperature and basified with potassium carbonate till pH becomes 8-8.5. This solution was saturated with sodium chloride and extracted with isopropanol. The isopropanol layer was separated and concentrated under reduced pressure to give residue. This residue was treated with dichloromethane and clear solution of dichloromethane was filtered and concentrated to provide endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11). Yield: 25.5 g, 35.64%.
A solution of trifluoroacetic anhydride (413.7 g, 1.97 mole) in dichloromethane (1700 mL) was stirred under nitrogen atmosphere and to this, indole-3-carboxylic acid (302 g, 1.87 moles) was added in a portion wise manner for 30 min at −5° C. to 0° C. The reaction mixture was stirred further 30 min at −5° C. to 0° C. Then endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (170 g, 0.939 moles) in dichloromethane (850 mL) was added in a drop wise manner for 30 min at −5° C. to 0° C. and was added dimethyl amino pyridine (1.43 g). The reaction mixture was stirred further for 12 h at room temperature. The reaction mixture was filtered and the collected solid washed with dichloromethane (3×170 mL). The solid was stirred in water (2550 ml) and 10% sodium carbonate (1360 mL) for 30 min. The solid formed was filtered and washed with water. This solid was stirred with 5% methanesulphonic acid (850 mL) for 1 h and filtered to remove excess undissolved indole-3-carboxylic acid. The filtrate was extracted with ethyl acetate (3×340 ml) and the ethyl acetate layer was separated. The aqueous acidic layer was basified with 10% sodium carbonate (850 mL), solid was separated, filtered and washed with water. The wet solid was dried (Dolasetron base).
Yield: 127 g, 42%.
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 mole) was added in a portion wise manner for 30 min at 0° C. to 5° C. The reaction mixture was stirred for further 30 min at 0° C. to 5° C. Then endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one (11) (50 g, 0.27 mole) in dichloromethane (500 mL) and dimethyl amino pyridine (0.42 g, 0.0039 mole) were added in a drop wise manner for 30 min at 0° C. to 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 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%.
Dolasetron base (50 g, 0.15 mole) 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 hr. The solid formed was filtered, washed with cold acetone (50 mL) and dried. Yield (crude) 59 g, 90.77%.
Dolasetron base (119 g, 0.368 moles) was dissolved in acetone (2023 mL) and treated with activated charcoal (12 g). Filtered the mixture through hyflow and the clear solution was treated with water (24 mL) and methane sulphonic acid (38.96 g, 0.405 moles) at 25° C. to 30° C. The reaction mass was stirred further for 2 hr at 0° C. to 5° C. The solid formed was filtered, washed with acetone (3×120 mL) and dried. Yield (crude) 140 g, 87%.
Dolasetron mesylate (140 g) was taken in water (900 ml) and extracted with ethyl acetate (3×280 ml). The aqueous layer was separated, basified with 10% sodium carbonate (320 mL). The solid obtained was filtered, washed with water and dried. This solid was dissolved in acetone (2×100 mL) and treated with activated charcoal (12 g). Filtered the mixture through hyflow and clear solution was treated with water (20 mL) and methane sulphonic acid (32.72 g, 0.341 moles) at 25° C. to 30° C. The reaction mass was stirred further for 2 hr at 0° C. to 5° C. The solid formed was filtered, washed with acetone (3×100 mL) and dried. Yield 130 g, 93%. Purity: 99.9% (HPLC).
5 g of Dolasetron base was dissolved in 5 mL of acetone at 40° C. to 50° C. The hot solution was filtered and was allowed to cool to 0° C. to 5° C. and stirred for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form I.
5 g of Dolasetron base was dissolved in 5 mL of acetonitrile at 70° C. to 80° C. The hot solution was filtered and was allowed to cool to 0° C. to 5° C. and stirred for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form I.
0.5 g of Dolasetron base was dissolved in 10 mL of acetone at 25° C. to 30° C. temperature. To this clear solution 30 mL hexane was added drop wise under stirring. The solution was maintained at 30° C. for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form I.
0.5 g of Dolasetron base was dissolved in 20 mL of ethyl acetate at 70° C. to 80° C. temperature. The hot clear solution was added drop wise in 40 mL of hexane under stirring at maintained at 30° C. The solution was maintained at 30° C. for 2 hr under stirring. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form I.
0.5 g of Dolasetron base was dissolved in 10 mL of THF at 25° C. to 30° C. temperature. The clear solution was added drop wise in 30 mL of hexane under stirring and maintained at 0° C. to 5° C. The resultant solution was maintained at 0° C. to 5° C. for 2 hr under stirring. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form I.
0.5 g of Dolasetron base was dissolved in 10 mL of THF at 25° C. to 30° C. temperature. The clear solution was added drop wise in 40 mL of DIPE under stirring and maintained at 0° C. to 5° C. The resultant solution was maintained at 0° C. to 5° C. for 2 hr under stirring. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form I.
0.5 g of Dolasetron base was dissolved in 10 mL of acetone at 25° C. to 30° C. To this clear solution 30 mL of DIPE was added drop wise under stirring. The resultant solution was maintained at 30° for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form II.
0.5 g of Dolasetron base was dissolved in 70 mL of DIPE at 70° C. temperature. The hot solution was allowed to cool to 25° C. to 30° C. temperature. The suspension was stirred at the same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form II.
0.5 g of Dolasetron base was dissolved in 7 mL of DMSO at 25° C. to 30° C. The clear solution was added drop wise under stirring into 30 mL of water maintained at 0° C. to 5° C. The resultant solution was maintained at same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 5 mL DMF at 25° C. to 30° C. The clear solution was added drop wise under stirring into 30 mL of water maintained at 0° C. to 5° C. The resultant solution was maintained at same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 7 mL of DMA at 25° C. to 30° C. The clear solution was added drop wise under stirring into 30 mL of water maintained at 0° C. to 5° C. The resultant solution was maintained at same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 15 mL of ethanol at 25° C. to 30° C. The clear solution was added drop wise under stirring into 30 mL of water maintained at 0° C. to 5° C. The resultant solution was maintained at same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 10 mL of THF at 25° C. to 30° C. The clear solution was added drop wise under stirring into 30 mL of water maintained at 0° C. to 5° C. The resultant solution was maintained at same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 5 mL of 1,4-dioxane at 100° C. temperature. The hot solution was allowed to cool to 25° C. to 30° C. temperature. The suspension was stirred at the same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 15 mL of ethyl acetate 80° C. temperature. The hot solution was allowed to cool to 25° C. to 30° C. temperature. The suspension was stirred at the same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 5 mL of isopropyl alcohol at 80° C. temperature. The hot solution was allowed to cool to 25° C. to 30° C. temperature. The suspension was stirred at the same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 5 mL of n-propanol at 80° C. temperature. The hot solution was allowed to cool to 25° C. to 30° C. temperature. The suspension was stirred at the same temperature for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form III.
0.5 g of Dolasetron base was dissolved in 30 mL of toluene at 110° C. temperature. The hot solution was filtered and allowed to cool to room temperature. The suspension was stirred at the same temperature for 8 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form IV.
0.5 g of Dolasetron base was dissolved in 15 mL of MDC at reflux temperature. The hot solution was filtered and was allowed to cool to room temperature and stirred for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form IV.
0.5 g of Dolasetron base was dissolved in 10 mL of methanol at reflux temperature. The hot solution was filtered and was allowed to cool to room temperature and stirred for 2 hr. The separated solid was isolated by filtration and dried at 60° C. to get Dolasetron base Form IV.
0.5 g of Dolasetron base was taken in a clean and dry 100 mL round bottom flask fitted with air condenser. The flask was heated to 180° C. to 190° C. in an oil bath for 30 min. Then the flask was cooled to room temperature to obtain solid as Dolasetron base Form V.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1610/MUM/2005 | Dec 2005 | IN | national |
| 1635/MUM/2005 | Dec 2005 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN06/00500 | 12/22/2006 | WO | 00 | 7/16/2008 |
