SK697A3 - Method for preparing 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 - Google Patents

Method for preparing 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 Download PDF

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Publication number
SK697A3
SK697A3 SK697A SK697A SK697A3 SK 697 A3 SK697 A3 SK 697A3 SK 697 A SK697 A SK 697A SK 697 A SK697 A SK 697A SK 697 A3 SK697 A3 SK 697A3
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Slovakia
Prior art keywords
beta
benzoyloxy
trihydroxy
acetoxy
3s
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SK697A
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Slovak (sk)
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SK280520B6 (en
Inventor
Jean-Rene Authelin
Jacques Doveze
Elie Fouque
Bernadette Mandard
Isabelle Taillepied
Original Assignee
Rhone Poulenc Rorer Sa
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Priority to FR9408479A priority Critical patent/FR2722191B1/en
Application filed by Rhone Poulenc Rorer Sa filed Critical Rhone Poulenc Rorer Sa
Priority to PCT/FR1995/000910 priority patent/WO1996001815A1/en
Publication of SK697A3 publication Critical patent/SK697A3/en
Publication of SK280520B6 publication Critical patent/SK280520B6/en
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=9465183&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=SK697(A3) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D305/00Heterocyclic compounds containing four-membered rings having one oxygen atoms as the only ring hetero atoms
    • C07D305/14Heterocyclic compounds containing four-membered rings having one oxygen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Abstract

A method for preparing 4-acetoxy-2 alpha -benzoyloxy-5 beta ,20-epoxy-1,7 beta ,10 beta -trihydroxy-9-oxo-tax-11-en-yl-13 alpha (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate trihydrate by crystallisation from a hydroalcoholic solution.

Description

A process for the preparation of the trihydrate of (2R, 3S) 4-acetoxy-2-benzoyloxy-5 B 1 20-epoxy-7.beta, 10.beta.-trihydroxy-9-oxo-tax-ll-en-13-yl-2-3terc.butoxykarbonylamino hydroxy-3-phenylpropionate

Technical field

The present invention relates to a process for the preparation of 4-acetoxy-2-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-ene-3-yl-3-tert-butoxycarbonylamino-2-hydroxy-3- phenylpropionate (2R, 3S).

BACKGROUND OF THE INVENTION

EP-0 253 738 and EP-0 336 841 disclose (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11- en-13-yl-3-terc.butoxykarbonylamino-

2-hydroxy-3-phenylpropionate having anti-cancer and anti-leukemic properties, and a process for preparing the compound is also described in these patents.

(2R, 3S) -4-Acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert. butoxycarbonylamino-2-hydroxy-3-phenylpropionate has significantly better stability than the same anhydrous product.

SUMMARY OF THE INVENTION

According to the invention, (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-ene-13ayl-3-tert-butoxycarbonylamino trihydrate can be Of 2-hydroxy-3-phenylpropionate obtained after crystallization of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl -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 specified temperature, pressure and humidity conditions.

After carrying out the process according to the invention, it may in particular be advantageous to:

dissolution of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7β, 106-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy -3-phenylpropionate, which has been previously purified by chromatography, in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature preferably between 40 and 60 ° C,

- the optional removal of residual chromatographic solvents by co-distillation under reduced pressure, replacing the volume of the distilled solvent with pure alcohol,

- addition of possibly purified water at the same temperature,

- and, if necessary, by crystallization by seeding and cooling to a temperature close to 0 ° C, separation of the obtained (2R, 3S) -4-acetoxy-2a-benzoyloxy-56,20-epoxy-1,76,10B-trihydroxy-9-oxo trihydrate crystals -tax-11-en-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate thus obtained, followed by drying under reduced pressure under a controlled humidity atmosphere.

Generally, (2R, 3S) -4-acetoxy-2a-benzoyloxy-56,20-epoxy-1,76,10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino-2- The hydroxy-3-phenylpropionate is dissolved in the excess aliphatic alcohol in the purified state. Preferably, the amount of alcohol is 8 to 12 parts by weight, based on 1 part by weight of (2R, 3S) -4-acetoxy-2a-benzoyloxy-56,20-epoxy-1,76,10B-trihydroxy-9-oxo-tax-11-ene -13?-yl-3-terc.butoxykarbony1amino-2-hydroxy-3-phenylpropionate.

Generally, the distillation of the alcohol is carried out under reduced pressure at a temperature close to 40 ° C until a thick syrup is obtained which is difficult to mix. It is advantageous to repeat this operation several times to remove residual solvents contained in the purified product used.

When the removal of the remaining solvents is complete, the syrup obtained is taken up with an alcohol used in an amount equal to

3.5 to 6 parts by weight, based on 1 part by weight of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-ene -13 α-γ 1-3-tert-butoxycarbonylamino-

2-hydroxy-3-phenylpropionate.

After optionally removing the insoluble impurities by filtration, water, preferably purified water, is added in an amount such that the water / alcohol weight ratio is close to 2/1.

Crystallization is induced by seeding and the mixture is cooled slowly to a temperature close to 0 ° C.

Crystallized (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino-2- The hydroxy-3-phenylpropionate is separated, preferably by filtration or centrifugation, and subsequently dried. Drying is carried out under reduced pressure between 4 and 7 kPa, at a temperature close to 40 ° C and under a controlled humidity atmosphere, the relative humidity being close to 80%.

For carrying out the process of the invention, it is preferable to carry out crystallization in the presence of ascorbic acid, which is added in the dissolution of purified (2R, 3S) -4-acetoxy-2? -Benzoyloxy-5B, 20-epoxy-1,7β, 10B-trihydroxy-9-oxo tax-11-en-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in alcohol. Up to 1% by weight of ascorbic acid may be used.

It is particularly preferred to use ethanol as the alcohol for carrying out the process according to the invention.

(2R, 3S) -4-Acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino- 2-hydroxy-3-phenylpropionate is confirmed by X-ray diffraction, thermogravimetric analysis and differential calorimetric analysis.

Thus, thermogravimetric analysis shows a 6.1% weight loss in the temperature range between 40 and 140 ° C, corresponding to three water molecules per molecule of (2R, 3S) -4-acetoxy-2-benzoyloxy-5B, 20-epoxy-1,7B, 10.beta.-trihydroxy-9-oxo-tax-ll-EN13-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.

The method of determination of specific water content and hydration water by differential calorimetry analysis shows the absence of unbound water and the endothermic signal at 132.6 ° C corresponds to the dissociation of the hydrate.

(2R, 3S) -4-Acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy trihydrate -3-phenylpropionate is no longer hygroscopic.

Stability studies show that (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-ene-13-γ-3-tert-butoxycarbonylamino trihydrate -2-hydroxy-3-phenylpropionate show that it is stable at 4 ° C, 25 ° C and 35 ° C in an atmosphere with 90% relative humidity for up to 18 months without any modification of its crystalline form.

Under the same conditions, (2R, 3S) -4-acetoxy-2-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-ene-13ayl-3-tert-butoxycarbonylamino-2- hydroxy-3-phenylpropionate in anhydrous form, which has a different crystalline form, is slowly formed into the trihydrate form.

In the following, the invention will be explained in more detail by way of examples of a specific embodiment thereof, these examples being illustrative only and not in any way limiting of the scope of the invention, which is clearly defined by the wording of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

303 g of (2R, 3S) -

4-Acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7β, 10B-trihydroxy-9-oxotax-11-en-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate with a purity of 92 , 4% (0.314 mol) and 2.875 kg of absolute ethanol (d = 0.79). The resulting mixture is heated to 40 ° C until complete dissolution of (2R, 3S) -4-acetoxy-2α-benzoyloxy-5α, 20-epoxy-1,7B, 10B-trihydroxy-9oxo-tax- ll-en-13-yl 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Ethanol is then distilled under reduced pressure of 12 kPa until a syrup is obtained which is at the very limit of miscibility. 0.983 kg of ethanol are added to the syrup and the distillation is repeated under the same conditions. 1.257 kg of ethanol are added to the obtained syrup and the mixture is heated to 50 ° C until the solid is completely dissolved. The mixture is filtered hot, then 4.39 kg of purified water are added to the filtrate over one hour, maintaining the temperature at 50 ° C. After initiating the crystallization, the mixture was cooled to 0 and C for 4 hours. The separated crystals are collected by filtration, washed with 0.909 kg and then 0.606 kg of a 1: 2 mixture of ethanol and water, then dried at 38 ° C under reduced pressure (5.07 kPa) in an atmosphere with 80% relative humidity during 48 hours. This is obtained

266.5 g of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7β, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino trihydrate 2-hydroxy-3-phenylpropionate, in which a purity of 98.8% (purity related to dry weight) was determined by high performance liquid chromatography, the water content being 6.15%.

Example 2

At a temperature close to 35 ° C, 110.0 g of (2R, 3S) -4-acetoxy-2-benzoyloxy-5B, 20-epoxy-1,7B, 10β-trihydroxy-9-oxo-tax-11-en-13ayl-3 of tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate with a purity of 92.5% and 0.2224 g of ascorbic acid are dissolved in 1340 cm 3 of ethanol. About 70% of the ethanol introduced is distilled off under reduced pressure (8 kPa) at a temperature close to 20 ° C. The mixture was heated to 50 ° C and filtered. The filtrate is washed three times with 70.5 cm 3 of ethanol each, followed by 605.5 cm 3 of purified water at 50 ° C over minút5 minutes. The solution is seeded with several crystals of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxotax-11-en-13 α-γ-3-tert-butoxycarbonylamino trihydrate Of 2-hydroxy-3-phenylpropionate and the mixture is stirred for 30 minutes. Thereafter, 860.5 cm @ 3 of purified water are added at 50 DEG C. over a period of 3 hours, followed by cooling to a temperature in the region of 0 DEG C. over 3 hours. The suspension is filtered and the filter cake is washed with 330 g of a 2: 1 mixture of water and ethanol, followed by washing of the cake with 220 g of the same mixture and then dried under reduced pressure (5 kPa) at 38 ° C under 80 % relative humidity. 110.2 g of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-ene- trihydrate are thus obtained in 98% yield. 13 3terc.butoxykarbonylamino-yl-2-hydroxy-3-phenylpropionate.

Claims (5)

  1. PATENT CLAIMS
    A process for the preparation of (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11-en-13a-yl-3-tert-butoxycarbonylamino trihydrate -2-hydroxy-3-phenylpropionate, characterized in that (2R, 3S) -4-acetoxy-2a-benzoyloxy-5B, 20-epoxy-1,7B, 10B-trihydroxy-9-oxo-tax-11- The en-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is crystallized from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, and the product obtained is then dried under the specified temperature, pressure and humidity conditions.
  2. Method according to claim 1, characterized in that the water / alcohol weight ratio is close to 2/1.
  3. Method according to any one of claims 1 to 2, characterized in that the alcohol is ethanol.
  4. Method according to claim 1, characterized in that the drying is carried out at a temperature close to 40 ° C, at a pressure between 4 and 7 kPa and in an atmosphere with a relative humidity close to 80%.
  5. A process according to claim 1, characterized in that the crystallization is carried out in the presence of ascorbic acid.
SK6-97A 1994-07-08 1995-07-07 Method for preparing 4-acetoxy-2alpha-benzoyloxy-5alpha,20- -epoxy-1,7beta,10beta-trihydroxy-9-oxo-tax-11-en-13alpha- -yl(2r,3s)-3-tert-butoxycarbonylamino-2-hydroxy-3- -phenylpropionate trihydrate SK280520B6 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FR9408479A FR2722191B1 (en) 1994-07-08 1994-07-08 trihydrate process for preparing (2R, 3S) -3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate-4-benzoyloxy-5beta acetoxy2alpha, 20epoxy-1,7beta, 10beta trihydroxy-9-oxo-tax-11-en -13alpha-yl
PCT/FR1995/000910 WO1996001815A1 (en) 1994-07-08 1995-07-07 METHOD FOR PREPARING 4-ACETOXY-2α-BENZOYLOXY-5β,20-EPOXY-1,7β,10β-TRIHYDROXY-9-OXO-TAX-11-EN-13α-YL(2R,3S)-3-TERT-BUTOXYCARBONYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE TRIHYDRATE

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SK697A3 true SK697A3 (en) 1997-06-04
SK280520B6 SK280520B6 (en) 2000-03-13

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SK6-97A SK280520B6 (en) 1994-07-08 1995-07-07 Method for preparing 4-acetoxy-2alpha-benzoyloxy-5alpha,20- -epoxy-1,7beta,10beta-trihydroxy-9-oxo-tax-11-en-13alpha- -yl(2r,3s)-3-tert-butoxycarbonylamino-2-hydroxy-3- -phenylpropionate trihydrate

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NO314500B1 (en) 2003-03-31
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EP0770070A1 (en) 1997-05-02
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FR2722191A1 (en) 1996-01-12
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AU2930595A (en) 1996-02-09
JP3753155B2 (en) 2006-03-08
AT171702T (en) 1998-10-15
CO4410189A1 (en) 1997-01-09
NZ289455A (en) 1997-12-19
FI119246B (en) 2008-09-15
PL318195A1 (en) 1997-05-26
WO1996001815A1 (en) 1996-01-25
BR9508789A (en) 1997-10-21
DZ1905A1 (en) 2002-02-17
US6022985A (en) 2000-02-08
SI0770070T1 (en) 1998-12-31
TW419473B (en) 2001-01-21
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IN183947B (en) 2000-05-20
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GR3027558T3 (en) 1998-11-30

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