Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-24
1999-12-14
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549511, C07D30514
Patent
active
060020229
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate.
4,10-Diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9-o xotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate (or paclitaxel) has noteworthy anticancer and antileukaemia properties.
4,10-Diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9-o xotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate may either be isolated from yew bark or prepared from baccatin III or from 10-desacetylbaccatin III according to the processes which are described more particularly in European patent applications EP 0,336,840 or EP 0,400,971 or in PCT international application WO 94/07878.
It has been found that 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate has a stability which is markedly superior to that of the anhydrous product.
According to the invention, 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate may be obtained after crystallization of 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, followed by drying of the product obtained under reduced pressure and then maintaining in a relative humidity of greater than 20% at a temperature in the region of 25.degree. C.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1a is an X-ray powder diagram of a product of the present invention.
FIG. 1b is an X-ray powder diagram of a product of the present invention.
FIG. 2a is an X-ray powder diagram of a product of the present invention.
FIG. 2b is an X-ray powder diagram of a product of the present invention.
In order to carry out the process according to the invention, it may be particularly advantageous 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate in an aliphatic alcohol containing 1 to 3 carbon atoms, inorganic base such as sodium hydrogen carbonate, greater than 20% at a temperature in the region of 25.degree. C.
Generally, the 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate is dissolved in an excess of the aliphatic alcohol, preferably methanol. The amount of alcohol is preferably between 6 and 12 parts by weight relative to the 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate used.
Generally, water is added such that the water/alcohol weight ratio is between 3/1 and 1/3. The water added may contain up to 10% (w/v) of an inorganic base such as sodium hydrogen carbonate, so that the pH of the reaction mixture is above or equal to 7, preferably between 7 and 8, before separation of the crystals.
The 4,10-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.-dihydroxy-9- oxotax-11-en-13.alpha.-yl (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate which crystallizes is separated out, preferably by filtration or centrifugation, and then dried. The drying is carried out under reduced pressure, between 1 and 7 kPa, at a temperature in the region of 40.degree. C. and the product obtained is optionally maintained in an atmosphere whose relative humidity is greater than 20% and at a temperature of between 0 and 60.degree. C., preferably in the region of 25.degree. C.
In order to carry out the process, it may be advantageous to perform the crystallization in the presence of ascorbic acid which is added duri
REFERENCES:
Wani et al, J. American Chemical Society, vol. 93 (9), May 1971, pp. 2325-2327.
Authelin Jean-Rene
Didier Eric
Leveiller Franck
Taillepied Isabelle
Rhone-Poulenc Rorer S.A.
Trinh Ba K.
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