SK79098A3 - 4,10'beta'-diacetoxy-2'alpha'-benzoyloxy-5'beta',20-epoxy-1- -hydroxy-9-oxo-19-nor-cyclopropa[g]tax-11-ene-13'alpha'-yl- (2r,3s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, and method for preparing same - Google Patents

Abstract

Disclosed is a 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta,20 -epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[g]tax-11-en-13alpha-yl-( 2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate an d its preparation method by crystallisation from the water-alkali ne or water-ketone solution.

Description

Technical field

The invention relates to 4,10S-diacetoxy-2a-benzoyloxy-

- 5β, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa / g / tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy -3-phenylpropionate and its preparation.

BACKGROUND OF THE INVENTION

4,10E-Diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl- (2R, 3S) -3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate has remarkable anti-cancer and anti-leukemic properties.

4,10S-Diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl- (2R, 3S) -3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is prepared according to the method described in particular in PCT International Application WO 94/13654.

It has been found that 4,10E-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl-

The (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate has a significantly higher stability than the same product in anhydrous form.

SUMMARY OF THE INVENTION

According to the invention, 4,10E-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-0X0-19-nor-cyclopropa dihydrate (g)

-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained by crystallization of 4,10S-diacetoxy-2H-benzoyloxy-5β, 20-epoxy-1-hydroxy -9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or by recrystallization of the dihydrate from a mixture of water and aliphatic an alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 to 4 carbon atoms and subsequently drying the isolated product under reduced pressure and possibly maintaining the product in an environment with relative humidity greater than or equal to 40% or directly drying in an atmosphere the relative humidity is greater than or equal to 40%.

After carrying out the process according to the invention it may be particularly advantageous

- mention 4,10S-diacetoxy-2α-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13α-yl- (2R, 3S) - 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or a hydrate thereof in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in a ketone containing 3 to 4 carbon atoms, add water to the obtained solution, then add water again, separate the crystals obtained and then

I dry the crystals under reduced pressure and then optionally maintain them in an atmosphere whose relative humidity is greater than or equal to 40%, which means, for example, for a relative humidity of 40%, drying at a residual pressure of about

1.33 kPa for a temperature of 25 ° C and at a residual pressure of about 3.86 kPa for a temperature of 45 ° C, or to dry, the crystals directly in an atmosphere whose relative humidity is greater than or equal to 40%, i.e. % drying at a residual pressure of about 1.33 kPa at 25 ° C and at a residual pressure of about 3.86 kPa at 45 ° C.

Generally, 4,10S-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13O-yl- (2R, 3S) The 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate is dissolved in an excess of an aliphatic alcohol, preferably ethanol, or in an excess of a ketone, preferably acetone, preferably an amount of alcohol or ketone of 4 to 16 parts by volume. 4,10S-diacetoxy-2α-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl- (2R, 3S) -3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.

Generally, the water is added in an amount such that the final water / alcohol or water / ketone volume ratio is 1: 3 to 3: 1.

Crystallized 4,10E-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl- (2R, 3S) The 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is then separated, preferably by filtration or centrifugation. Drying or optionally maintaining in an atmosphere whose relative humidity is greater than or equal to 40% is carried out under reduced pressure, generally between 0.5 and 30 kPa, preferably at a pressure close to 5 kPa, at a temperature between 10 and 70 ° C, preferably at a temperature near 40 ° C.

Further, the active isotherm of the obtained product in water was studied. In this study, samples of 4,10B-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl- ( 2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate was intentionally dehydrated by intensive drying and then stored in controlled relative humidity (HR) atmospheres at 25 ° C. The water contents determined by ATG show that the products stabilize at a content close to 4% (between 3 and 5%) when the relative humidity is greater than or equal to 40% (for the dihydrate it constitutes a theoretical water content of 4.15%).

the results of this study are shown in the following table.

table

Activity isotherm in water at 25 ° C

Original drying conditions Original form, determined by DX Original ATG Relative humidity (%) Time of stay (days) Loss (ATG) Mold, determined by DX 0 18 0.8% / 34 at 170 ° C dihydrate 31 0.99% / 33 at 55 ° C dihydrate 5 55 1.69% / 32 at 63 ° C dihydrate 11 55 1.17% / 33 at 65 ° C dihydrate 20 31 2.06% / 34 at 61 ° C dihydrate 20 ° C, di hydrate 1.6% / 32 at 42 19 3.77% / 33 at 65 ° C dihydrate 48 h, 71 ° C 31 4.07% / 34 at 60 ° C dihydrate 1.3 kPa mass stability 58 19 3.30% / 34 at 63 ° C dihydrate at 200 ° C 31 3.59% / 34 at 65 ° C dihydrate 80 19 3.98% / 34 at 63 ° C dihydrate 31 4.22% / 34 at 65 ° C dihydrate 98 19 4.61% / 34 at 68 ° C dihydrate 31 4.63% / 34 at 65 ° C dihydrate 60, d i hydrate 0.76% / 32 at 0 35 0.85% / 31 at 60 ° C dihydrate 60 h, 170 ° C 4,6 kPa I 11 37 0.90% / 31 at 60 ° C dihydrate 20 35 0.95% / 32 at 54 ° C dihydrate 42 35 3.51% / 32 at 60 ° C dihydrate 58 35 2.35% / 32 at 60 ° C dihydrate 80 35 3.75% / 32 at 70 ° C dihydrate 98 37 3.97% / 32 at 60 ° C dihydrate

In carrying out the process according to the invention, it is possible to treat directly the ethanol solution of 4,10S-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13a. -yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained after acid deprotection of 4,10S-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9- oxo-19-nor-cyclopropa / g / tax-ll-en-13.alpha.-yl (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-oxazolidin-5-carboxylate.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2 g of crude 4,10B-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13a-yl- are introduced into a three neck flask. (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 20 cm ^{3 of} absolute ethanol. The solution obtained is stirred at a temperature of 50 ° C, then 20 cm ^{3 of} water are added over 45 minutes and the suspension obtained is cooled to a temperature in the region of 20 ° C. After filtration, the product on the filter is washed with 20 cm @ ^{3 of a} mixture of absolute ethanol and water (1: 1 by volume), then dried at 40 DEG C. under reduced pressure (5.3 kPa). There was obtained 1.64 g of 4,10E-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing (determined by ATG) 3.8% water (theoretical value of the water content of the dihydrate is 4.15%). Yield achieved: about 80%

The DPRX (powder X-ray) diagram shows that the product thus obtained has indeed dihydrate characteristics.

Powder X-ray was performed using a Philips PW 1700 cobalt anti-cathode lamp (lambda = 1.7889 A), scanning was performed at an initial scan angle of 5 ° 2-Θ, final scan 40 ° 2-Θ, step = 0.02 ° 2-θ, 1 sec per step, silicon lozenge.

Thermogravimetric analysis (ATG) was performed using a Perkin-Elmer TGA 7 thermal balance at a starting temperature of 25 ° C and a final temperature of 300 ° C with a temperature gradient of 10 ° C per minute.

Example 2

The nitrogen purged reactor was charged with 515 g of 4,10E-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl- ( 2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in crude form and 4 liters of absolute ethanol. The suspension obtained is heated to 35 to 40 ° C until the solids dissolve and the reactor is then brought to a reduced pressure mode of 8 kPa. About 8 liters of solvent are distilled off while maintaining a constant volume in the reactor by continuously feeding ethanol (8 liters) to the reactor. After the reactor has been brought to atmospheric pressure, the solution is clarified by passing through a filter equipped with a 0,45 μπι mesh filter cloth. After rinsing the filter with one liter of absolute ethanol, about 1.8 liters of water was added to the total liquid portion at 40 ° C over one hour. After initiation of crystallization of the solution by addition of 8 g of 4,10E-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate dihydrate (g) tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate was cooled to a temperature in the region of 20 ° C over 15 hours. The slurry was then heated to 40 ° C and 1.66 L of water was added over 4 hours. The mixture was cooled to a temperature in the region of 20 ° C and stirred for 17 hours. The suspension is filtered through a glass frit and the product is centrifuged and washed with 1.25 liters of a 50:50 alcohol / water mixture. The product is then dried in an oven at 35 ° C and 5.3 kPa for 72 hours in the presence of a water supply and then at 35 ° C and 2.7 kPa for 8 hours in the absence of a water supply and then again at at a temperature of 35 ° C and a pressure of 5.3 kPa over 16 hours and in the presence of a water supply.

There was thus obtained 4,10S-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13a-yl- (2R) (491 g). , 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing 4.0% water (Curry Fisher). The DPRX (powder X-ray) diagram shows that the product thus obtained is in the form of a dihydrate (theoretical water content of 4,10S-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor- cyclopropa (g) tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate accounts for 4.15%).

The powder X-ray was performed under the conditions described in Example 1.

Example 3

2 g of crude 4,10 E-diation-oxy-2-benzoyloxy-5 β, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa / g / tax 11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 20 cm ^{3 of} acetone. About 20 cm ^{3 of} water are added over 35 minutes to the solution obtained, which is stirred at a temperature in the region of 20 ° C. The resulting suspension is stirred for about 15 minutes. After filtration, the product is washed on the filter twice with 2 0 cm ³ of acetone: water at a volume ratio of 1: 1, then the product was dried at 40 DEG C. under reduced pressure (5.3 kPa). 1.28 g of 4,10B-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl are thus obtained. - (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.

The yield obtained is about 75%

The DPRX (powder X-ray) diagram shows that the product thus obtained has the characteristics of a dihydrate.

The powder X-ray was performed under the conditions described in Example 1.

Example 4

120 g of 4,10E-diacetoxy-2a-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13a-yl- are introduced into a nitrogen purged reactor. (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyloxazolidine-5-carboxylate and 1.08 liters of ethyl acetate. The suspension is stirred at a temperature in the region of 20 DEG C. and a solution of 3.25 cm @ ^{3 of} 36% hydrochloric acid in 17.6 cm @ ^{3 of} water is introduced into the reactor. After 3 hours and 30 minutes, a solution of 3.5 g of sodium bicarbonate in 350 cm ^{3 of} water is introduced into the reactor and stirred for 15 minutes. After decantation and removal of the aqueous phase, two washes of 350 cm @ ^{3 of} water are carried out. The organic phase is concentrated under reduced pressure at a temperature of about 25 ° C until a residual volume of 350 cm ³ is reached, followed by the addition of 350 cm ^{3 of} absolute ethanol. Distillation is carried out under reduced pressure at a temperature of about 30 DEG C. until ethyl acetate is exhausted, with 1.5 liters of absolute ethanol being introduced. The solution is heated to 40 ° C, then 470 cm ^{3 of} water are added over 15 minutes. Crystallization of the solution is initiated by the addition of a suspension of 1 g of 4,10E-diacetoxy-2a-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-ene-13β-. yl (2R, 3S) -3- tert -butoxycarbonylamino-2-hydroxy-3-phenylpropionate in a mixture of 40 cm ^{3 of} water and 40 cm ^{3 of} absolute ethanol. After 15 hours at a temperature of about 40 ° C, 410 cm ^{3 of} water are added over a period of 4 to 5 hours, then the suspension is cooled to 20 ° C. After filtration and washing of the product on the filter, the product is dried for 15 hours under reduced pressure (2.7 kPa) at 25 ° C and then for 24 hours at 35 ° C.

102 g of 4,10B-diacetoxy-2a-benzoyloxy-5B, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g) tax-11-en-13a-yl- (102 g) are thus obtained. 2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing 4.3% water (Curry Fisher). The product yield is about 93%.

The DPRX (powder X-ray) diagram shows that the product thus obtained has the characteristics of a dihydrate.

The powder X-ray was performed under the conditions described in Example 1.

Claims (6)

1. 4,10E-diacetoxy-2α-benzoyloxy-5α, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl- (2R, 3S) ) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 2. A process for the preparation of 4,10S-diacetoxy-2α-benzoyloxy-5S, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa dihydrate (g) tax-11-en-13a-yl- (2R, 2R, 3R, 4R). 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, characterized by crystallizing 4,10E-diacetoxy-2a-benzoyloxy-5B, 20-epoxy-1-hydroxy-9-oxo-19- nor-cyclopropa / g / tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 to 4 carbon atoms, that the product obtained is dried under reduced pressure and that it is optionally maintained at relative humidity conditions greater than or equal to 40%, or the product is dried directly under relative humidity conditions that is greater than or equal to 40%. The method of claim 2, wherein the final water / alcohol and water / ketone volume ratio is between 3: 1 and 1: 3. Method according to either of Claims 2 or 3, characterized in that ethanol is used as the aliphatic alcohol and acetone is used as the ketone. Process according to claim 2, characterized in that the drying or, optionally, maintaining the product in an environment with a relative humidity of greater than or equal to 40% is carried out at a temperature close to 40 ° C and a pressure close to 5 kPa and The product stabilizes under these conditions between 3 and 5%. The process according to claim 2, characterized in that it starts directly from an ethanolic solution of 4,10E-diacetoxy-2α-benzoyloxy-5E, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (g). tax-11-en-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained by acid deprotection 4,10B-diacetoxy-2a-benzoyloxy-5B, 20-epoxy- 1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl- (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyloxazolidine- 5-carboxylate.