Process for the preparation of 4-acetoxy-2.alpha.-benzoyloxy-5.b

Details Process for the preparation of 4-acetoxy-2.alpha.-benzoyloxy-5.b Process for the preparation of 4-acetoxy-2.alpha.-benzoyloxy-5.b

1997-04-25

2000-02-08

Trinh, Ba K.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549511, C07D30500

Patent

active

060229853

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the preparation of 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate.
4-Acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.,10.beta.-trihydrox y-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tertbutoxycarbonylamino-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-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.,10.beta.-trihydro xy-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate has a substantially greater stability than that of the anhydrous product.
According to the invention, 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate can be obtained by crystallization of 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-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 of the product obtained under defined conditions of temperature, pressure and humidity.
For the implementation of the process according to the invention, it may be particularly advantageous
to dissolve the 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, firstly purified by chromatography, in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature preferably of between 40 and 60.degree. C.,
to optionally remove the residual chromatography solvents by co-distillation under reduced pressure, replacing the volume of solvent distilled off with pure alcohol,
to add optionally purified water at the same temperature,
then, after optionally initiating the crystallization and cooling to a temperature close to 0.degree. C., to separate the crystals obtained from 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate crystals thus obtained, and then to dry them under reduced pressure in a controlled-humidity atmosphere.
Generally, the purified 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-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-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.,10.beta.-trihydro xy-9-oxo-tax-11-en-13.alpha.-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 close to 40.degree. C. until a thick syrup is obtained which is difficult to stir. It may be advantageous to repeat this operation several times which leads to the removal of the residual solvents contained in the purified product used.
After completing the removal of the residual solvents, the syrup obtained is taken up in a quantity of alcohol of between 3.5 and 6 parts by weight relative to the 4-acetoxy-2.alpha.-benzoyloxy-5.beta., 20-epoxy-1,7.beta.,10.beta.-trihydroxy-9-oxo-tax-11-en-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
After optionally separating insoluble impurities by filtration, water which is preferably purified is added such that the water/alcohol weight ratio is close to 2/1.
The crystallization is initiated and then the mixture is cooled slowly down to a temperature close to 0.degree. C.
The 4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,7.beta.,10.beta

REFERENCES:
patent: 5229526 (1993-07-01), Holton
Wani et al, J. Am. Chem. Soc., 93(9), pp. 2325-2327, 1971.
Miller et al, J. Org. Chem., vol. 46, No. 7, pp. 1469-1474, 1981.

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