Title of Invention	"4-ACETOXY-2Alpha -BENZOYLOXY-5Beta ,20-EPOXY-1, 7Beta, 10Beta-TRIHYDROXY-9-OXO-TAK-11-EN-13Alpha-YL(2R,3S)-3-TERT-BUTOXY-CARBONYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE TIHYDRATE"
Abstract	4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 10ß-trihydroxy-9-oxo-tax- 1 l-en-13α-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3- phenylpropionate trihydrate whenever prepared by crystallizing 4- acetoxy-2α-benzoyloxy-5ß,20-epoxy-1 ,7ß, 10ß-trihydroxy-9-oxo-tax-11-en- 13α-yl (2 R, 3S) -3 -tert-butoxycarbonylamino-2 -hydroxy-3-phenyl- propionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms wherein the water: alcohol weight ratio is used is about 2:1, and then drying the product obtained under defined conditions of temperature, pressure and humidity.

Title of Invention

"4-ACETOXY-2Alpha -BENZOYLOXY-5Beta ,20-EPOXY-1, 7Beta, 10Beta-TRIHYDROXY-9-OXO-TAK-11-EN-13Alpha-YL(2R,3S)-3-TERT-BUTOXY-CARBONYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE TIHYDRATE"

Abstract

4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 10ß-trihydroxy-9-oxo-tax- 1 l-en-13α-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3- phenylpropionate trihydrate whenever prepared by crystallizing 4- acetoxy-2α-benzoyloxy-5ß,20-epoxy-1 ,7ß, 10ß-trihydroxy-9-oxo-tax-11-en- 13α-yl (2 R, 3S) -3 -tert-butoxycarbonylamino-2 -hydroxy-3-phenyl- propionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms wherein the water: alcohol weight ratio is used is about 2:1, and then drying the product obtained under defined conditions of temperature, pressure and humidity.

Full Text	The present invention relates to a 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax- 1 l-en-13α-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate trihydrate. The present invention relates to 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1 .7ß,10ß-trihydroxy-9-oxo-tax-l l-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate whenever prepared by the process described below. 4-Acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, which has remarkable anticancer and antileukaemic properties, and its preparation are described in European Patents EP-0,253,738 and EP-0,336,841. It has been found that 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate has a substantially greater stability than the anhydrous product. According to the invention, 4-acetoxy-2α-benzoyloxy-ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate is obtained by crystallization of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, followed by drying the product obtained under defined conditions of temperature, pressure and humidity. For the implementation of the process of the invention, it is particularly advantageous - to dissolve the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, purified first by chromatography, in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature preferably of between 40 and 60°C, - to optionally remove residual chromatography solvents by co-distillation under reduced pressure, replacing the volume of solvent removed with pure alcohol, - to optionally add purified water at the same temperature, - then, after optionally initiating crystallization and cooling to a temperature of about 0°C, to separate the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9- oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl- propionate trihydrate crystals thus obtained, and then to dry them under reduced pressure in a controlled-humidity atmosphere. Generally, the purified 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-oxo-tax-l 1 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is dissolved in an excess of the aliphatic alcohol. Preferably, the quantity of alcohol is between 8 and 12 parts by weight relative to the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate used. Generally, the distillation of the alcohol is performed under reduced pressure at a temperature of about 40 °C until a thick syrup is obtained which is difficult to stir. Preferably, this operation is repeated several times. This leads to removal of the residual solvents contained in the purified product used. After completing removal of the residual solvents, the syrup obtained is normally taken up in a quantity of alcohol of between 3.5 and 6 parts by weight relative to the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate. After optionally separating insoluble impurities by filtration, water is added such that the watenalcohol weight ratio is about 2:1. According to a preferred embodiment the water used is in purified form. Ethanol is the preferred alcohol. Crystallization is initiated and then the mixture cooled slowly to a temperature of about 0°C. The 4-acetoxy~2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oßtrihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate trihydrate which crystallizes is separated, preferably by filtration or centrimgation, and then dried. Drying is usually performed under a reduced pressure of between 4 and 7 kPa, at a temperature of about 40°C in a controlled humidity atmosphere, the relative humidity being about 80%. For the implementation of the process, it is advantageous to perform the crystallization in the presence of ascorbic acid which is added during the dissolution of the optionally purified 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the alcohol. Normally up to 1% by weight of ascorbic acid is used. The trihydrate structure of the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-oxo-tax-l 1-en-l3α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is confirmed by X-ray diffraction, by thermogravimetric analysis and by differential scanning calorimetry. Thermogravimetric analysis shows a mass loss of 6.1% between 40 and 140°C, which corresponds to three molecules of water per one molecule of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Differential scanning calorimetry for assaying the bulk water and the water of hydration shows the absence of bulk water and an endothermic signal at 132.6°C corresponding to the dissociation of a hydrate. 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate trihydrate no longer exhibits hydroscopic character. Stability studies show that 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3 S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate is stable at 4°C, 25°C and 35°C in an atmosphere having 90% relative humidity for up to 18 months without modificatioi of its crystalline form. Under the same conditions, anhydrous 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß, 10ß-trihydroxy-9-oXo-tax-l l-en-13α-yl (2R,3S):3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate, which has a different crystalline form, changes slowly to the trihydrate form. The following examples illustrate the present invention. EXAMPLE 1 303 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate whose titre is 92.4% (0.314 mol) and 2.875 kg of absolute ethanol (d = 0.79) are introduced into a reactor protected from light. The mixture is heated at 40 °C until there is complete dissolution of the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3 S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate. The ethanol is then distilled off at a pressure close to 12 kPa until a syrup at the stirring limit is obtained. 0.983 kg of ethanol is added to the syrup and the distillation is again performed under the same conditions. 1.257 kg of ethanol are added to the syrup obtained and heated at 50°C until there is complete dissolution. The mixture is filtered hot and then 4.39 kg of purified water are added, over 1 hour, while the temperature is maintained at 50°C. After having initiated the crystallization, the mixture is cooled to 0°C over 4 hours. The crystals obtained are separated by filtration, washed with 0.909 kg and then 0.606 kg of an ethanol-water mixture (1-2 by weight) and then dried at 38°C under reduced pressure (5.07 kPa) in an atmosphere at 80% relative humidity for 48 hours. 266.5 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-l 1-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate are thus obtained. Analysis shows that its high-performance liquid chromatography titre is 98.7% (on a dry basis) and that the water content is 6.15%. EXAMPLE 2 110.0 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-tri-hydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate with a titre of 92.5% and 0.2224 g of ascorbic acid are dissolved, at a temperature of about 35 °C, in 1340 cm3 of ethanol. About 70% of the ethanol introduced is distilled off under reduced pressure (8 kPa) at a temperature of about 20°C. The mixture is heated to 50°C and then filtered. The filter is washed with 3 times 70.5 cm3 of ethanol and then 860.5 cm3 of purified water are added over 15 minutes at 50°C. The mixture is seeded with a few crystals of 4-acetoxy-2α-benzoyl-oxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate and then stirred for 30 minutes. 860.5 cm3 of purified water are then added over 3 hours at 50°C and then cooled over 3 hours down to a temperature of about 0°C. The slurry obtained is then filtered. The filtration cake is washed with 330 g of a water-ethanol mixture (2-1 by weight) and then with 220 g of the same mixture and then dried under reduced pressure (5 kPa) at 38°C under an atmosphere at 80% relative humidity. 110.2 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate are thus obtained with a yield of 98%. We Claim 1. 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß, 10ß-trihydroxy-9-oxo- tax-1 l-en-13α-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3- phenylpropionate trihydrate whenever prepared by crystallizing 4- acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß, 10ß-trihydroxy-9-oxo-tax- 11-en- 13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl- propionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms wherein the water: alcohol weight ratio is used is about 2:1, and then drying the product obtained under defined conditions of temperature, pressure and humidity. 2. Compound as claimed in claim 1, wherein the alcohol used is ethanol. 3. Compound as claimed in any one of claims 1 or 2, wherein drying is performed at a temperature of about 40°C, at a pressure of between 4 and 7 kPa and in an atmosphere having a relative humidity of about 80%. 4. Compound as claimed in any one of claims 1 to 3, wherein crystallization is performed in the presence of ascorbic acid. 5. Compound as claimed in claim 1, whenever prepared by a process substantially as hereinbefore described in Example 1 or 2.

Full Text

The present invention relates to a 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax- 1 l-en-13α-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate trihydrate.
The present invention relates to 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1 .7ß,10ß-trihydroxy-9-oxo-tax-l l-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate whenever prepared by the process described below.
4-Acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, which has remarkable anticancer and antileukaemic properties, and its preparation are described in European Patents EP-0,253,738 and EP-0,336,841.
It has been found that 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate has a substantially greater stability than the anhydrous product.
According to the invention, 4-acetoxy-2α-benzoyloxy-ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate is obtained by crystallization of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, followed by drying the product obtained under defined conditions of temperature, pressure and humidity.
For the implementation of the process of the invention, it is particularly advantageous
- to dissolve the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, purified first by chromatography, in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature preferably of between 40 and 60°C,

- to optionally remove residual chromatography solvents by co-distillation under
reduced pressure, replacing the volume of solvent removed with pure alcohol,
- to optionally add purified water at the same temperature,
- then, after optionally initiating crystallization and cooling to a temperature of about
0°C, to separate the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-
oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-
propionate trihydrate crystals thus obtained, and then to dry them under reduced
pressure in a controlled-humidity atmosphere.
Generally, the purified 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-oxo-tax-l 1 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is dissolved in an excess of the aliphatic alcohol. Preferably, the quantity of alcohol is between 8 and 12 parts by weight relative to the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate used.
Generally, the distillation of the alcohol is performed under reduced pressure at a temperature of about 40 °C until a thick syrup is obtained which is difficult to stir. Preferably, this operation is repeated several times. This leads to removal of the residual solvents contained in the purified product used.
After completing removal of the residual solvents, the syrup obtained is normally taken up in a quantity of alcohol of between 3.5 and 6 parts by weight relative to the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate.
After optionally separating insoluble impurities by filtration, water is added such that the watenalcohol weight ratio is about 2:1. According to a preferred embodiment the water used is in purified form. Ethanol is the preferred alcohol.
Crystallization is initiated and then the mixture cooled slowly to a temperature of about 0°C.
The 4-acetoxy~2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oßtrihydroxy-9-oxo-tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate trihydrate which crystallizes is separated, preferably by filtration or

centrimgation, and then dried. Drying is usually performed under a reduced pressure of between 4 and 7 kPa, at a temperature of about 40°C in a controlled humidity atmosphere, the relative humidity being about 80%.
For the implementation of the process, it is advantageous to perform the crystallization in the presence of ascorbic acid which is added during the dissolution of the optionally purified 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the alcohol. Normally up to 1% by weight of ascorbic acid is used.
The trihydrate structure of the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß,1 Oß-trihydroxy-9-oxo-tax-l 1-en-l3α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is confirmed by X-ray diffraction, by thermogravimetric analysis and by differential scanning calorimetry.
Thermogravimetric analysis shows a mass loss of 6.1% between 40 and 140°C, which corresponds to three molecules of water per one molecule of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
Differential scanning calorimetry for assaying the bulk water and the water of hydration shows the absence of bulk water and an endothermic signal at 132.6°C corresponding to the dissociation of a hydrate.
4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate trihydrate no longer exhibits hydroscopic character.
Stability studies show that 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3 S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate is stable at 4°C, 25°C and 35°C in an atmosphere having 90% relative humidity for up to 18 months without modificatioi of its crystalline form.
Under the same conditions, anhydrous 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß, 10ß-trihydroxy-9-oXo-tax-l l-en-13α-yl (2R,3S):3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate, which has a different crystalline

form, changes slowly to the trihydrate form.
The following examples illustrate the present invention.
EXAMPLE 1
303 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate whose titre is 92.4% (0.314 mol) and 2.875 kg of absolute ethanol (d = 0.79) are introduced into a reactor protected from light. The mixture is heated at 40 °C until there is complete dissolution of the 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3 S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate. The ethanol is then distilled off at a pressure close to 12 kPa until a syrup at the stirring limit is obtained. 0.983 kg of ethanol is added to the syrup and the distillation is again performed under the same conditions. 1.257 kg of ethanol are added to the syrup obtained and heated at 50°C until there is complete dissolution. The mixture is filtered hot and then 4.39 kg of purified water are added, over 1 hour, while the temperature is maintained at 50°C. After having initiated the crystallization, the mixture is cooled to 0°C over 4 hours. The crystals obtained are separated by filtration, washed with 0.909 kg and then 0.606 kg of an ethanol-water mixture (1-2 by weight) and then dried at 38°C under reduced pressure (5.07 kPa) in an atmosphere at 80% relative humidity for 48 hours. 266.5 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-trihydroxy-9-oxo-tax-l 1-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate are thus obtained. Analysis shows that its high-performance liquid chromatography titre is 98.7% (on a dry basis) and that the water content is 6.15%.
EXAMPLE 2
110.0 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß,10ß-tri-hydroxy-9-oxo-tax-ll-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate with a titre of 92.5% and 0.2224 g of ascorbic acid are dissolved, at a temperature of about 35 °C, in 1340 cm3 of ethanol. About 70% of the ethanol introduced is distilled off under reduced pressure (8 kPa) at a temperature of about

20°C. The mixture is heated to 50°C and then filtered. The filter is washed with 3 times 70.5 cm3 of ethanol and then 860.5 cm3 of purified water are added over 15 minutes at 50°C. The mixture is seeded with a few crystals of 4-acetoxy-2α-benzoyl-oxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate and then stirred for 30 minutes. 860.5 cm3 of purified water are then added over 3 hours at 50°C and then cooled over 3 hours down to a temperature of about 0°C. The slurry obtained is then filtered. The filtration cake is washed with 330 g of a water-ethanol mixture (2-1 by weight) and then with 220 g of the same mixture and then dried under reduced pressure (5 kPa) at 38°C under an atmosphere at 80% relative humidity. 110.2 g of 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-1,7ß, 1 Oß-trihydroxy-9-oxo-tax-11 -en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate are thus obtained with a yield of 98%.

We Claim
1. 4-acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß, 10ß-trihydroxy-9-oxo-
tax-1 l-en-13α-yl (2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-
phenylpropionate trihydrate whenever prepared by crystallizing 4-
acetoxy-2α-benzoyloxy-5ß,20-epoxy-l,7ß, 10ß-trihydroxy-9-oxo-tax-
11-en- 13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl- propionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms wherein the water: alcohol weight ratio is used is about 2:1, and then drying the product obtained under defined conditions of temperature, pressure and humidity.
2. Compound as claimed in claim 1, wherein the alcohol used is
ethanol.
3. Compound as claimed in any one of claims 1 or 2, wherein drying
is performed at a temperature of about 40°C, at a pressure of
between 4 and 7 kPa and in an atmosphere having a relative
humidity of about 80%.
4. Compound as claimed in any one of claims 1 to 3, wherein
crystallization is performed in the presence of ascorbic acid.
5. Compound as claimed in claim 1, whenever prepared by a process
substantially as hereinbefore described in Example 1 or 2.

Documents:

1262-del-1999-abstract.pdf

1262-del-1999-claims.pdf

1262-del-1999-correspondence-others.pdf

1262-del-1999-correspondence-po.pdf

1262-del-1999-description (complete).pdf

1262-del-1999-form-1.pdf

1262-del-1999-form-13.pdf

1262-del-1999-form-18.pdf

1262-del-1999-form-2.pdf

1262-del-1999-form-3.pdf

1262-del-1999-gpa.pdf

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Patent Number

226223

Indian Patent Application Number

1262/DEL/1999

PG Journal Number

01/2009

Publication Date

02-Jan-2009

Grant Date

12-Dec-2008

Date of Filing

20-Sep-1999

Name of Patentee

AVENTIS PHARMA S.A. (FORMERLY KNOWN AS RHONE-POULENC RORER S.A.)

Applicant Address

20, AVENUE RAYMOND ARON, 92160 ANTONY, FRANCE.

Inventors:

#	Inventor's Name	Inventor's Address
1	JEAN RENE AUTHELIN	51, RESIDENCE LES CENDRENNES, 91180 SAINT GERMAN LES ARPAJON, FRANCE.
2	JACQUES DOVEZE	2, ALLEE DE LA SOURCE, 94130 VAUHALLAN, FRANCE.
3	ELIE FOUQUE	90 AVENUE DE BONNEUIL, 94100 SAINT MAUR DES FOSSES, FRANCE.
4	BERNADETTE MANDARD	LE MOULIN FEUILLET, 41110 MAREUIL SUR CHER, FRANCE.
5	ISABELLE TAILLEPIED	121 AVENUE GAMBETTA, 94700 MAISONS-ALFORT, FRANCE.

PCT International Classification Number

A60K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA