MXPA97005460A - Procedure for the preparation of trihydrate (2r, 3s) -3-benzoylamino-2-hydroxy-3-phenylpropionate de4, 10-diacetoxy-2alfa-benzoiloxi-5beta; 20-epoxy-1, 7beta-dihidroxi-9-oxo-tax -11-en-13alfa- - Google Patents
Procedure for the preparation of trihydrate (2r, 3s) -3-benzoylamino-2-hydroxy-3-phenylpropionate de4, 10-diacetoxy-2alfa-benzoiloxi-5beta; 20-epoxy-1, 7beta-dihidroxi-9-oxo-tax -11-en-13alfa-Info
- Publication number
- MXPA97005460A MXPA97005460A MXPA/A/1997/005460A MX9705460A MXPA97005460A MX PA97005460 A MXPA97005460 A MX PA97005460A MX 9705460 A MX9705460 A MX 9705460A MX PA97005460 A MXPA97005460 A MX PA97005460A
- Authority
- MX
- Mexico
- Prior art keywords
- tax
- oxo
- epoxy
- diacetoxy
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- RRGNLQYIUYOTQC-LQFAMLORSA-N (2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoic acid trihydrate Chemical compound O.O.O.C(C1=CC=CC=C1)(=O)N[C@H]([C@H](C(=O)O)O)C1=CC=CC=C1 RRGNLQYIUYOTQC-LQFAMLORSA-N 0.000 title claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- HYJVYOWKYPNSTK-UONOGXRCSA-N (2r,3s)-3-benzamido-2-hydroxy-3-phenylpropanoic acid Chemical compound N([C@H]([C@@H](O)C(O)=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 HYJVYOWKYPNSTK-UONOGXRCSA-N 0.000 claims abstract description 14
- 150000004684 trihydrates Chemical class 0.000 claims abstract description 6
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000004593 Epoxy Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 claims description 2
- RZARFIRJROUVLM-GVHYBUMESA-N (3r)-3-amino-2-hydroxy-3-phenylpropanoic acid Chemical class OC(=O)C(O)[C@H](N)C1=CC=CC=C1 RZARFIRJROUVLM-GVHYBUMESA-N 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- RDVJYGYJBUIIOE-ZOAFEQKISA-N (4s,5r)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1N(C(=O)C=2C=CC=CC=2)[C@@H](C=2C=CC=CC=2)[C@H](C(O)=O)O1 RDVJYGYJBUIIOE-ZOAFEQKISA-N 0.000 description 1
- 102100022298 Divergent paired-related homeobox Human genes 0.000 description 1
- 101000902412 Homo sapiens Divergent paired-related homeobox Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
Abstract
The present invention relates to a process for the preparation of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate 4,10-diacetoxy-2alpha-benzoyloxy-5α, 20-epoxy-1,7a trihydrate -dihydroxy-9-oxo-tax-11-en-13alpha-yl, characterized in that the (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2alpha-benzoyloxy- is crystallized 5a, 20-epoxy-1,7α-d ihydroxy-9-oxo-tax-11-in 13alpha-yl, in a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, then the product is dried obtained under reduced pressure and then possibly maintained under conditions of relative humidity greater than 2
Description
PROCEDURE FOR THE PREPARATION OF TRIHYDRATE OF
(2R, 3S) -3-BENZ0ILAMIN0-2 -H IDR0XI-3 -FENILPR0PI0NAT0 OF 4, 10-DIACETOXY-2ALFA-BENZOI OXI-5BETA; 20-EPOXI-1, 7BETA-DIHI
DROXI-9-OXO-TAX-11-EN-13ALFA-ILO.
The present invention relates to a process for the preparation of (2R, 3S) -3-benzoylamino-2-hydroxyl-3-phenylpropionate 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l trihydrate. , 7β-dihydroxy-9-oxo-tax-11-en-13a-yl. The (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-1,7β-dihydroxy-9-oxo-tax-11- en-13a-yl (or paclitaxel) has remarkable anti-cancer and anti-leukemia properties The (2R, 3S) -3-benzoylaraine-2-hydroxyl-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy -1,7-dihydroxy-9-oxo-tax-11-en-13a-yl can be isolated either from the bark of the yew tree, or prepared from baccatine III or 10-desacetyl l-baccatine III according to the methods described more particularly in the European patent applications EP-0,336,840 or EP-0,400.97 or in the PCT international application WO94 / 07378 REF: 25022 It has been found that the trihydrate of
(2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate from
4, 10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl has a stability remarkably superior to that of the anhydrous product. According to the invention, the (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β-dihydroxy-9 -oxo-tax-11-en-13a-yl can be obtained after the crystallization of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl in a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, followed by drying the obtained product, under reduced pressure, and then kept at a relative humidity higher than 20% at a temperature close to 25 ° C. For carrying out the process according to the invention, it can be particularly advantageous to put in solution or in suspension 4,10-diacetoxy-2a-benzoyloxy (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate. -5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl in an aliphatic alcohol containing 1 to 3 carbon atoms, treat the solution of the suspension with water containing optionally a mineral base such as sodium acid carbonate, - separate the obtained crystals, then - dry under reduced pressure, then possibly maintain them in an atmosphere where the relative humidity is higher than 20% at a temperature close to 25 ° C. In general, the (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax- ll-en-13a-yl is dissolved in an excess of aliphatic alcohol, preferably methanol. Preferably, the amount of alcohol is between 6 and 12 parts by weight relative to the (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, -epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl put into operation. In general, the water is added in such a way that the weight ratio of water / alcohol is between 3/1 and 1/3. The added water may contain up to 10% (w / v) of a mineral base such as sodium hydrogen carbonate, from which the pH of the reaction mixture is greater than or equal to 7, preferably between 7 and 8, above of the separation of the crystals. The (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-ll -in-13a-yl which crystallizes is separated, preferably by filtration or centrifugation, and then dried. The drying is carried out under reduced pressure, comprised between 1/7 Pa, at a temperature close to 40 ° C and the product obtained is possibly maintained in an atmosphere where the relative humidity is higher than 20% and at a temperature comprised between 0 and 60 ° C, preferably close to 25 ° C. For putting the process into operation, it may be advantageous to carry out the crystallization in the presence of ascorbic acid, which is added after the dissolution or suspension of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate. of 4, 10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-1,7-dihydroxy-9-oxo-tax-11-en-13a-yl in alcohol. It is possible to use up to 1% by weight of ascorbic acid.
The (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-ll -en-13a-ilo has been studied by differential thermogravimetric and calorimetric analysis, and by X-ray diffraction. More particularly, the thermogravimetric analysis shows a mass loss between 25 and 140 ° C, close to 6%, which corresponds to three molecules of water per one molecule of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9- oxo-tax-ll-en-13a-ilo. For the operation of the process according to the invention, when the semisynthetic paclitaxel obtained according to the procedures described for example in the European patents EP-0,336,840 or EP-0,400,971 or in the PCT international application WO 94 / 07878 that lead intermediately to paclitaxel where the hydroxyl functional groups are protected, it is possible to operate directly on the solution or on the suspension of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpyrropionate of 4.10- diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl obtained after removal of the protective groups of the hydroxyl functional groups of the taxane cycle and of the side chain. For example, by operating under the conditions of the PCT international application 0 94/07878, (4S, 5R-3-benzoyl-2- (4-methoxy-phenyl) -4-phenyl-1,3-oxazolidine- is obtained intermediately. 5-carboxylic acid 4,10-diacete i-2a-benzoyloxy-5β, 20-epoxy-l-hydroxy-7β-triethylsilyloxy-9-oxo-tax-11-en-13a-yl where the protecting groups can be eliminated by Means of trifluoroacetic acid in methanol The following examples illustrate the present invention.
EXAMPLE 1
In a reactor protected from light, 5,014 g of (4S, 5R) -3-benzoyl-2- (4-methoxy-phenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate of 4 are introduced. 10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l-hydroxy-7β-triethylsilyloxy-9-oxo-tax-11-en-13a-yl where the titre is 98% (4.52 moles) and 50 cm3 of methanol To the stirred white suspension, 7 c of trifluoroacetic acid are rapidly added. The temperature rises to about 35 ° C. After cooling to a temperature close to 5 ° C, 110 cm3 of an aqueous solution of 6% sodium hydrogen carbonate is added
(p / v). The pH is equal to 7. The crystals are separated by filtration on calcined glass and washed with 4 15 cm3 portions of a mixture of rn.ta.i-water (30-70 by volume). After drying under reduced pressure at 35 ° C, 3.676 g of
(2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate from
4, 10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl whose title is 93.1% and which contains approximately 4.8% water. The product obtained is characterized by the X-ray powder diagram shown in Figure 1. The yield of the pure product is 89.3% in relation to the ester put into operation. Maintained in the conditions of relative humidity superior to 20%, the product stabilizes with a proportion of water close to 6%. The DPRX diagram (X-ray powder diagram), shown in Figure 2, shows that the product obtained in this way is prepared in the form of a trihydrate
(theoretical value of the water ratio of the (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate of 4,10-diacete i-2a-benzoyloxy-5β, 20-epoxy-1, 7β- d? hydroxy-9-oxo-tax-11-en-13a-Lio of 5.95%). The diagram according to the X-rays is made by means of a Philips PW 1700® device with a cobalt anti-cathode tube (? K "? = 1,7889 Á), being swept under an initial scanning angle of 5 ° 2-?, Of the final sweep of 40 ° 2- ?, with a step of 0.02 ° 2-? at a rate of 1 second per step and using a silicon wafer.
EXAMPLE 2
In a reactor protected from light, 3,006 g of (4S, 5R) -3-benzoyl-2- (4-methoxy-phenyl) -4-phenyl-1 are introduced., 3-oxazolidine-5-carboxylic acid 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l-hydroxy-7β-triethylsilyloxy-9-oxo-tax-11-en-13a-yl where the title is of 98% (2.70 mmol) and 30 cm3 of methanol. To the stirred white suspension, 6.3 cm 3 of 99% trifluoroacetic acid are added. After cooling to a temperature close to 5 ° C, 7.5 cm3 of demineralized water is added in 15 minutes. The crystals are separated by filtration on sintered glass and washed with 3 5 cm portions of a methanol-water mixture (80-20 by volume) at 5 ° C. After drying under reduced pressure at 35 ° C, 1989 g of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy are obtained. l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl with a titre of 97.8% and containing approximately 6.8% water. The yield of 84.3% in relation to the ester put into operation.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (7)
1. A process for the preparation of (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate 4,10-diacetoxy-2a-benzoyloxy-5β trihydrate, 20-epoxy-1,7-dihydroxy-9- oxo-tax-11-en-13a-yl, characterized in that the (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2a-benzoyloxy-5β, 20-epoxy is crystallized -l, 7β-dihydroxy-9-oxo-tax-11-en-13a-yl in a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms, then the product obtained is dried under reduced pressure and afterwards, it is kept in the conditions of relative humidity higher than 20%.
2. The process according to claim 1, characterized in that the water / alcohol weight ratio is between 3/1 and 1/3.
3. The process according to any of claims 1 or 2, characterized in that the alcohol is methanol.
4. The process according to claim 1, characterized in that the drying is carried out at a temperature close to 40 ° C under reduced pressure and because the product is stabilized towards 6% of water in an atmosphere in which the relative humidity is higher than 20 %.
5. The process according to claim 1, characterized in that the crystallization is carried out in the presence of ascorbic acid.
6. The process according to claim 1, characterized in that it is directly operated in itself on the ester resulting from the esterification of baccatine III where the hydroxyl functional group in position 13 is protected with a derivative of β-phenylisoserine, protected after of the removal of protective groups.
7. The (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionate trihydrate of 4,10-diacetoxy-2a-ben ~ - < Iloxy-5β, 20-epoxy-l, 7β-dihydroxy-9-oxo-tax-11-en-13a-1o.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9500816 | 1995-01-25 | ||
| FR95/00816 | 1995-01-25 | ||
| FR9500816A FR2729666A1 (en) | 1995-01-25 | 1995-01-25 | PROCESS FOR THE PREPARATION OF (2R, 3S) TRIHYDRATE - BENZOYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE OF 4,10-DIACETOXY- 2ALPHA-BENZOYLOXY-5BETA, 20-EPOXY-1,7BETA-DIHYDROXY-9-OX 11-EN-13ALPHA-YLE |
| PCT/FR1996/000104 WO1996022984A1 (en) | 1995-01-25 | 1996-01-23 | METHOD FOR PREPARING 4,10-DIACETOXY-2α-BENZOYLOXY-5β,20-EPOXY-1,7β-DIHYDROXY-9-OXO-TAX-11-EN-13α-YL (2R,3S)-3-BENZOYLAMINO-2-HYDROXY-3-PHENYLPROPIONATE TRIHYDRATE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9705460A MX9705460A (en) | 1997-10-31 |
| MXPA97005460A true MXPA97005460A (en) | 1998-07-03 |
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