AU713086B2 - 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1- hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13alpha-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3- phenylpropionate dihydrate and its process of preparation - Google Patents
4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1- hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13alpha-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3- phenylpropionate dihydrate and its process of preparation Download PDFInfo
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- AU713086B2 AU713086B2 AU11013/97A AU1101397A AU713086B2 AU 713086 B2 AU713086 B2 AU 713086B2 AU 11013/97 A AU11013/97 A AU 11013/97A AU 1101397 A AU1101397 A AU 1101397A AU 713086 B2 AU713086 B2 AU 713086B2
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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Description
WO 97/21695 1 PCT/FR96/01957 4, 1OI-Diacetoxy-2ax-benzoyloxy-3, 20-epoxy-l-hydroxy-9oxo-19-norcycloproparaltax-11-en-3i-y1 (2R, 3S) -3-tertbutoxycarbonylamino- 2-hydroxy- 3-phenylpropionate dihydrate and its process of preparation The present invention relates to 4,1013diacetoxy-2ax-benzoyloxy-53, 20-epoxy-1-hydroxy-9-oxo-19norcyclopropa tax-l1-en-13ax-yl (2R, 3S) -3-tertbutoxycarbonylanino-2 -hydroxy-3 -phenyipropionate dihydrate and to its preparation.
4, 10j-Diacetoxy-2ax-benzoyloxy-503,20-epoxy-1hydroxy-9-oxo-19-norcyclopropa tax-11-en-13a-yl (2R, 3S) -3-tert-butoxycarbonylamino-2--hydroxy-3phenyipropionate exhibits notable anticancer and antileukaemic properties.
4, 1013-Diacetoxy-2cz-benzoyloxy-53, 2 0-epoxy-ihydroxy-9-oxo-19-norcyclopropa[g] tax-11-en-13cx-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3phenyipropionate is prepared according to the process which is described more particularly in International Application PCT WO 94/13654.
It has been found that 4,1013-diacetoxy-2vxbenzoyloxy-53, 20-epoxy-l-hydroxy-9-oxo-19norcyclopropa[g] tax-11-en-13cx-yl (2R, 3S) -3-tertbutoxycarbonylamino-2 -hydroxy-3 -phenyipropionate dihydrate exhibits a stability which is markedly superior to that of the anhydrous product.
According to the invention, 4,1013-diacetoxy- 2a-benzoyloxy-5P,20-epoxy-l-hydroxy-9-oxo-19norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate can be obtained by crystallization of 4,10pdiacetoxy-2a-benzoyloxy-50,20-epoxy-l-hydroxy-9-oxo-19norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate or by recrystallization of the dihydrate 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, followed by drying the isolated product under reduced pressure and by optionally maintaining in a relative humidity greater than or equal to 40 or by direct drying in an atmosphere with a relative humidity greater than or equal to 40 In order to carry out the process according to the invention, it may be particularly advantageous to dissolve 4,10p-diacetoxy-2a-benzoyloxy-5p,20epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13ayl (2R,3S)- 3 -tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate or its hydrate in an aliphatic alcohol containing 1 to 3 carbon atoms or in a ketone containing 3 to 4 carbon atoms, to treat the solution with water, to seed the solution with the dihydrate and then to treat again with water, to separate the crystals obtained, then to dry them under reduced pressure and then optionally to maintain them in an atmosphere with a relative humidity greater than or equal to 40 that is to say, by way of example for a relative humidity of 40 drying under a residual pressure of approximately 1.33 kPa for a temperature of 25 0 C and under a residual pressure of approximately 3.86 kPa for a temperature of 0
C,
or to dry them directly in an atmosphere with a relative humidity greater than or equal to 40 that is to say, by way of example for a relative humidity of drying under a residual pressure of approximately 1.33 kPa for a temperature of 25 0 C and under a residual pressure of approximately 3.86 kPa for a temperature of 45 0
C.
Generally, 4,10 -diacetoxy-2a-benzoyloxy- 5P,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11en-13-yl (2R,3S)- 3 -tert-butoxycarbonylamino-2-hydroxy- 3 -phenylpropionate or its hydrate is dissolved in an excess of aliphatic alcohol, preferably ethanol, or in an excess of a ketone, preferably acetone. Preferably, the amount of alcohol or ketone is between 4 and 16 parts by volume with respect to the weight of 4,10diacetoxy-2a-benzoyloxy-5p,20-epoxy-l-hydroxy-9-oxo-19norcyclopropa[g]tax-1l-en-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate used.
Generally, the water is added such that the water/alcohol or water/ketone final volume ratio is between 1/3 and 3/1.
The 4,100-diacetoxy-2a-benzoyloxy-50,20epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13ayl (2R,3S)- 3 -tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate dihydrate which crystallizes is separated, preferably by filtration or centrifuging.
The drying or the optional maintaining in an atmosphere with a relative humidity greater than or equal to 40 is carried out under reduced pressure, generally of between 0.5 and 30 kPa, preferably in the region of kPa, at a temperature of between 10 and 70 0
C,
preferably in the region of 400C.
The water activity isotherm of the product was studied. Thus, 4,10p-diacetoxy-2a-benzoyloxy-5p,20epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13ayl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate dihydrate samples, intentionally dehydrated by forced drying, were maintained in atmospheres of controlled relative humidity (HR) at 25 0 C. The water contents, determined by TGA, show that the products stabilize at contents in the region of 4 (between 3 and 5 when the relative humidity is greater than or equal to 40 (theoretical water content of 4.15 for a dihydrate).
I
N
Water activity isotherm at 25 0
C
Initial Initial Initial TGA RH Residence Loss by TGA Form by drying form by time XD conditions XD 0 18 days 0.8 34 to 1700C Dihydrate 31 days 0.99 33 to 55 0 C Dihydrate 55 days 1.69 32 to 630C Dihydrate 11 55 days 1.17'% 33 to 650C Dihydrate 20 19 days 1.96 33 to 680C Dihydrate 0 C, Dihydrate 1.6 32 to 31 days 2.06 34 to 610C Dihydrate 48 hours 710C 1.3 kPas 71 42 19 days 3.77 33 to 65 0 C Dihydrate Stability by 31 days 4.07 34 to 60 0 C Dihydrate weight from 71 58 19 days 3.30 34 to 630C Dihydrate to 2000C 31 days 3.59 34 to 650C Dihydrate 19 days 3.98% 34 to 630C Dihydrate 31 days 4.22 34 to 650C Dihydrate 98 19 days 4.61 34 to 68 0 C Dihydrate 31 days 4.63 34 to 650C Dihydrate 0 35 days 0.85% 31 to 60 0 C Dihydrate 11 37 days 0.90 31 to 60 0 C Dihydrate 35 days 0.95 32 to 54°C Dihydrate 600C, Dihydrate 0.76 32 to 42 35 days 3.51 32 to 60 0 C Dihydrate hours 1700C 58 35 days 2.35 32 to 600C Dihydrate 4.6 kPa 35 days 3.75 32 to 700C Dihydrate 98 37 days 3.97 32 to 600C Dihydrate In order to use the process according to the invention, it is possible to work directly on the ethanolic solution of 4,10p-diacetoxy-2a-benzoyloxy- 5P,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11en-13(-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy- 3-phenylpropionate obtained after deprotection in acid medium of 4,10p-diacetoxy-2a-benzoyloxy-5p,20-epoxy-lhydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4- The following examples illustrate the present invention.
EXAMPLE 1 2 g of crude 4,10p-diacetoxy-2a-benzoyloxy- 5p,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-l1en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy- 3-phenylpropionate and 20 cm 3 of absolute ethanol are introduced into a three-necked flask. 20 cm 3 of water are added over approximately 45 minutes to the stirred solution at 500C and the suspension obtained is then cooled to a temperature in the region of 20 0 C. After filtration, the product is washed on the filter with cm 3 of an absolute ethanol/water (1/1 by volume) mixture and the product is then dried at 400C under reduced pressure (5.3 kPa). 1.64 g of 4,10p-diacetoxy- 2a-benzoyloxy-50,20-epoxy-l-hydroxy-9-oxo-19- AMENDED SHEET 7 norcyclopropa[g]tax-11-en-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, containing 3.8 by TGA (Figure 5) of water (theoretical value of the water content of the dihydrate of 4.15 are obtained. The yield obtained is approximately 80 The XRPD (X-ray powder diagram) diagram represented by Figure 1 shows that the product thus obtained exhibits the characteristics of the dihydrate.
eb 9 9 9 9 9 9 9 9* 9* 9 99 The X-ray powder diagram is obtained using a Phillips PW 1700® device with a cobalt anti-cathode tube (A 1.7889 the sweeping being performed at an initial sweep angle of 50 2-8, final sweep angle of 2-8, with an increment of 0.02° 2-8, at a rate of 1 second per increment and using a silicon pastille.
Thermogravimetric analysis (TGA) is carried out using a Perkin-Elmer TGA 7® thermobalance at the initial temperature of 25 0 C and at the final temperature of 300°C with a temperature gradient of 10 0 C per minute.
9.
EXAMPLE 2 515 g of crude 4,10-diacetoxy-2a-benzoyloxy- 5p,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate dihydrate and 4 litres of absolute ethanol are introduced into a reactor purged with nitrogen. The suspension is heated at 35-40 0 C until dissolution is complete and the reactor is placed under a reduced pressure of 8 kPa. Approximately 8 litres of solvent are distilled off at constant volume, the reactor being continuously supplied with ethanol (8 litres). After returning the reactor to atmospheric pressure, the solution is clarified by passing through a filter equipped with a 0.45 gm filter cloth. After rinsing the filter with 1 litre of absolute ethanol, approximately 1.8 litres of water are added at 40 0
C
over 1 hour to the whole of the solution. After initiating with 8 g of 4,10 3 -diacetoxy-2a-benzoyloxy- 5P,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11en-13a-yl (2R,3S)- 3 -tert-butoxycarbonylamino-2-hydroxy- 3-phenylpropionate dihydrate, the mixture is cooled at a temperature in the region of 20 0 C for 15 hours. The suspension is then heated to 400C and then 1.66 litres of water are added over 4 hours. The mixture is cooled to a temperature in the region of 200C and left stirring for 17 hours. The suspension is filtered on sintered glass and the filtered product is washed with 1.25 litres of an alcohol/water (50/50 by volume) mixture. The product is dried in an oven at 35 0 C at 5.3 kPa for 72 hours in the presence of a stock of water and then at 350C at 2.7 kPa for 8 hours without a stock of water and again at 350C at 5.3 kPa for 16 hours in the presence of a stock of water. 491 g of 4,10p-diacetoxy-2(-benzoyloxy-5p, 2 0-epoxy-l-hydroxy-9- AMENDED SHEET oxo-19-norcyclopropa[g]tax-l1-en-13 -yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate containing 4.0 of water (Karl Fischer) are thus obtained. The XRPD (X-ray powder diagram) diagram represented by Figure 2 shows that the product thus obtained exists in the form of a dihydrate (theoretical value of the water content of 4,10 -diacetoxy-2abenzoyloxy-53,20-epoxy-l-hydroxy-9-oxo-19norcyclopropa[g]tax-ll-en-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate of 4.15 The X-ray powder diagram is obtained under the conditions described in Example 1.
EXAMPLE 3 2 g of crude 4,10-diacetoxy-2a-benzoyloxy- 5,20-epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate and 20 cm 3 of acetone are introduced into a three-necked round-bottomed flask. The solution obtained, which is stirred at a temperature in the region of 20 0 C, is treated with 20 cm 3 of water over approximately 35 minutes. The suspension obtained is stirred for approximately 15 minutes. After filtration, the product is washed twice on the filter with 20 cm 3 of an acetone/water (1/1 by volume) mixture and the product Sis then dried at 40 0 C under reduced pressure (5.3 kPa) 1.28 g of 4,10(-diacetoxy-2a-benzoyloxy-5p,20-epoxy-lhydroxy-9-oxo-19-norcyclopropa[g]tax-ll-en-13 -yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate dihydrate are thus obtained. The yield obtained is approximately 75 The XRPD (X-ray powder diagram) diagram represented by Figure 3 shows that the product thus obtained exhibits the characteristics of the dihydrate.
The X-ray powder diagram is obtained under the conditions described in Example 1.
S* EXAMPLE 4 9 120 g of 4,10p-diacetoxy-2a-benzoyloxy-53,20epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g]tax-l1-en-13 a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyloxazolidine-5-carboxylate and 1.08 litres of ethyl acetate are introduced into a reactor purged with 999* ;nitrogen. The suspension is stirred at a temperature in the region of 20 0 C and then a solution of 3.25 cm 3 of 36% hydrochloric acid in 17.6 cm 3 of water is introduced.
After maintaining for 3 hours 30 minutes, a solution of g of sodium hydrogencarbonate in 350 cm 3 of water is charged to the reactor and stirring is carried out for minutes. After separation by settling and drawing off the aqueous phase, washing is carried out twice in succession with 350 cm 3 of water. The organic phase is concentrated under reduced pressure at approximately 25 0
C
S until a residual volume of 350 cm 3 is reached and 11 then 350 cm 3 of absolute ethanol are introduced.
Distillation under reduced pressure is resumed at approximately 30 0 C until the ethyl acetate has been exhaustively removed, while supplying with 1.5 litres of absolute ethanol. The solution is heated to 40 0 C and then 470 cm 3 of water are added over 15 minutes. The solution is seeded with a suspension of 1 g of 4,10pdiacetoxy-2a-benzoyloxy-53,20-epoxy-l-hydroxy-9-oxo-19norcyclopropa[g]tax-11-en-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate in a mixture of 40 cm 3 of water and 40 cm 3 of absolute ethanol. After maintaining for 15 hours at approximately 40°C, 410 cm of water are added over hours and the suspension is then cooled to 20 0 C. After filtration and washing the product on the filter, the product is dried for 15 hours under reduced pressure (2.7 kPa) at 25 0 C and then for 24 hours at 35 0 C. 102 g of 4,10-diacetoxy-2a-benzoyloxy-53,20-epoxy-l-hydroxy-9oxo-19-norcyclopropa[g]tax-ll-en-13 c-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, containing 4.3 of water (Karl Fischer), are thus obtained with a yield of approximately 93 The XRPD (X-ray powder diagram) diagram represented by Figure 4 shows that the product thus obtained exhibits the characteristics of the dihydrate.
The X-ray powder diagram is obtained under the conditions described in Example 1.
Claims (8)
1. 4, 10-Diacetoxy-2a-benzoyloxy-53, hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13a-yl (2R, 3S)-3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate.
2. Process for the preparation of 4, 10p-Diacetoxy-2a- 20 -epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13a-yl (2R, 3S)-3-tert-butoxycarbonylamino-2- hydroxy-3-phenylpropionate dihydrate, characterized in that 4, 10p-diacetoxy-2a-benzoyloxy-5p,20-epoxy-l-hydroxy-9-oxo-19- norcyclopropa tax-ll-en-13a-yl (2R,3S) -3-tert- butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, characterized in that 4, 10p-diacetoxy-2a-benzoyloxy-50, 15 epoxy-l-hydroxy-9-oxo-19-norcyclopropa[g] tax-ll-en-13a-yl o* 3S)-3-tert-butoxycarbonylamino-2-hydroxy-3- phenylpropionate or its hydrate is crystallized from a mixture and an aliphatic alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 to 4 carbon 20 atoms, in that the product obtained is dried under reduced pressure and in that it is optionally maintained under relative humidity conditions greater than or equal to 40%, or in that the product is dried directly under relative humidity conditions greater than or equal to
3. Process according to claim 2, characterized in that the water/alcohol and water/ketone final ratio by volume is between 3/1 to 1/3.
4. Process according to either of claims 2 and 3, characterized in that the alcohol is ethanol and the ketone is acetone.
Process according to claim 2, characterized in that the drying or the optional maintaining under a relative humidity greater than or equal to 40% is carried out at a SA temperature in the region of 40 0 C under a pressure in the P:\OPER\PDB\1 1013-97.SPE 6/9/99 13 region of 5 kPa and that the product stabilized under these conditions between 3 and 5% of water.
6. Process according to claim 2, characterized in that the preparation is carried out directly from the ethanolic solution of 4, 1Oj3-diacetoxy-2cu-benizoyloxy-5 3, hydroxy-9-oxo--19-norcyclopropa [g]l tax-11-en-13cu-yl (2R,3S) -3- tert-butoxycarbonylamino-2 -hydroxy-3-phenylproionate obtained by deprotection in acid medium of the ester 4, 101-diacetoxy- 2c(-benzoyloxy-53, 20 -epoxy-1-hydroxy--9-oxo-19-norcyclopropa tax-11-en-13u-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4- methyoxyphenyl)
7. 4, 10l3-Diacetoxy-2cx-benzoyloxy-5p3, hydroxy-9-oxo-19-norcyclopropa~g] tax-11-en-13ca-yl (2R, 3S) -3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate from claim 1 when prepared according to a process according to any one of claims 2 to 6.
8. Process for the preparation of 4, 10r3-Diacetoxy-2x- benzoyloxy-53, 2 0-epoxy-1-hydroxy-9-oxo-19-norcyclopropa [g] tax-ii-en-i3cu-yl (2R, 3S) -3-tert-butoxycarbonylamino-2- hydroxy-3-phenylpropionate dihydrate substantially as *hereinbefore described with reference to the Examples. DATED this 6TH day of September, 1999 Rhone-Poulenc Rorer S.A. DAVIES COLLISON CAVE Patent Attorneys on behalf of the Applicant.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR95/14841 | 1995-12-14 | ||
| FR9514841A FR2742438B1 (en) | 1995-12-14 | 1995-12-14 | (2R, 3S) DIHYDRATE -3-TERT-BUTOXYCARBONYLAMINO-2-HYDROXY- 3-PHENYLPROPIONATE OF 4,10BETA-DIACETOXY-2ALPHA-BENZOYLOXY- 5BETA, 2O-EPOXY-1-HYDROX CYCLOPROPA (G) TAX-11- ENE-13ALPHA-YLE, AND PREPARATION METHOD THEREOF |
| PCT/FR1996/001957 WO1997021695A1 (en) | 1995-12-14 | 1996-12-09 | 4,10β-DIACETOXY-2α-BENZOYLOXY-5β,20-EPOXY-1-HYDROXY-9-OXO-19-NOR-CYCLOPROPA[G]TAX-11-ENE-13α-YL (2R,3S)-TERT-BUTOXYCARBONYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE DIHYDRATE, AND METHOD FOR PREPARING SAME |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU1101397A AU1101397A (en) | 1997-07-03 |
| AU713086B2 true AU713086B2 (en) | 1999-11-25 |
| AU713086C AU713086C (en) | 2002-09-19 |
Family
ID=9485512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11013/97A Ceased AU713086C (en) | 1995-12-14 | 1996-12-09 | 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1- hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13alpha-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3- phenylpropionate dihydrate and its process of preparation |
Country Status (37)
| Country | Link |
|---|---|
| EP (1) | EP0876361B1 (en) |
| JP (1) | JP4059351B2 (en) |
| KR (1) | KR100429330B1 (en) |
| CN (1) | CN101113143A (en) |
| AR (1) | AR004380A1 (en) |
| AT (1) | ATE204573T1 (en) |
| AU (1) | AU713086C (en) |
| BG (1) | BG63010B1 (en) |
| BR (1) | BR9611957A (en) |
| CA (1) | CA2236545C (en) |
| CO (1) | CO4810227A1 (en) |
| CZ (1) | CZ288998B6 (en) |
| DE (1) | DE69614716T2 (en) |
| DK (1) | DK0876361T3 (en) |
| DZ (1) | DZ2140A1 (en) |
| EA (1) | EA000668B1 (en) |
| ES (1) | ES2162123T3 (en) |
| FR (1) | FR2742438B1 (en) |
| GR (1) | GR3036437T3 (en) |
| HU (1) | HU224962B1 (en) |
| IL (1) | IL124766A (en) |
| IN (1) | IN185809B (en) |
| MY (1) | MY115886A (en) |
| NO (1) | NO317356B1 (en) |
| NZ (1) | NZ323964A (en) |
| OA (1) | OA11012A (en) |
| PL (1) | PL187613B1 (en) |
| PT (1) | PT876361E (en) |
| RO (1) | RO115880B1 (en) |
| SK (1) | SK282512B6 (en) |
| TN (1) | TNSN96157A1 (en) |
| TR (1) | TR199801087T2 (en) |
| TW (1) | TW358093B (en) |
| UA (1) | UA55401C2 (en) |
| UY (1) | UY24387A1 (en) |
| WO (1) | WO1997021695A1 (en) |
| ZA (1) | ZA9610200B (en) |
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| CN102851740A (en) * | 2011-06-30 | 2013-01-02 | 复旦大学 | Fluorinated docetaxel crystal and its preparation method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013654A1 (en) * | 1992-12-09 | 1994-06-23 | Rhone-Poulenc Rorer S.A. | Novel taxoids, preparation thereof and pharmaceutical compositions containing same |
-
1995
- 1995-12-14 FR FR9514841A patent/FR2742438B1/en not_active Expired - Fee Related
-
1996
- 1996-09-12 UA UA98063068A patent/UA55401C2/en unknown
- 1996-12-02 UY UY24387A patent/UY24387A1/en not_active IP Right Cessation
- 1996-12-04 ZA ZA9610200A patent/ZA9610200B/en unknown
- 1996-12-04 TW TW085114946A patent/TW358093B/en not_active IP Right Cessation
- 1996-12-09 CZ CZ19981830A patent/CZ288998B6/en not_active IP Right Cessation
- 1996-12-09 ES ES96941720T patent/ES2162123T3/en not_active Expired - Lifetime
- 1996-12-09 SK SK790-98A patent/SK282512B6/en not_active IP Right Cessation
- 1996-12-09 DZ DZ960185A patent/DZ2140A1/en active
- 1996-12-09 DE DE69614716T patent/DE69614716T2/en not_active Expired - Lifetime
- 1996-12-09 CA CA002236545A patent/CA2236545C/en not_active Expired - Fee Related
- 1996-12-09 CN CNA2007101024535A patent/CN101113143A/en active Pending
- 1996-12-09 HU HU9904048A patent/HU224962B1/en not_active IP Right Cessation
- 1996-12-09 BR BR9611957A patent/BR9611957A/en not_active IP Right Cessation
- 1996-12-09 PT PT96941720T patent/PT876361E/en unknown
- 1996-12-09 NZ NZ323964A patent/NZ323964A/en not_active IP Right Cessation
- 1996-12-09 PL PL96327451A patent/PL187613B1/en not_active IP Right Cessation
- 1996-12-09 EA EA199800452A patent/EA000668B1/en not_active IP Right Cessation
- 1996-12-09 WO PCT/FR1996/001957 patent/WO1997021695A1/en active IP Right Grant
- 1996-12-09 IL IL12476696A patent/IL124766A/en not_active IP Right Cessation
- 1996-12-09 KR KR10-1998-0704420A patent/KR100429330B1/en not_active IP Right Cessation
- 1996-12-09 EP EP96941720A patent/EP0876361B1/en not_active Expired - Lifetime
- 1996-12-09 AT AT96941720T patent/ATE204573T1/en active
- 1996-12-09 TR TR1998/01087T patent/TR199801087T2/en unknown
- 1996-12-09 AU AU11013/97A patent/AU713086C/en not_active Ceased
- 1996-12-09 JP JP52179097A patent/JP4059351B2/en not_active Expired - Fee Related
- 1996-12-09 DK DK96941720T patent/DK0876361T3/en active
- 1996-12-09 RO RO98-01069A patent/RO115880B1/en unknown
- 1996-12-12 IN IN2788DE1996 patent/IN185809B/en unknown
- 1996-12-13 AR ARP960105668A patent/AR004380A1/en active IP Right Grant
- 1996-12-13 CO CO96065734A patent/CO4810227A1/en unknown
- 1996-12-13 MY MYPI96005258A patent/MY115886A/en unknown
- 1996-12-13 TN TNTNSN96157A patent/TNSN96157A1/en unknown
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1998
- 1998-06-04 NO NO19982561A patent/NO317356B1/en not_active IP Right Cessation
- 1998-06-12 BG BG102535A patent/BG63010B1/en unknown
- 1998-06-15 OA OA9800085A patent/OA11012A/en unknown
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2001
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013654A1 (en) * | 1992-12-09 | 1994-06-23 | Rhone-Poulenc Rorer S.A. | Novel taxoids, preparation thereof and pharmaceutical compositions containing same |
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