TW387885B - New taxoids, their preparation and pharmaceutical compositions containing them - Google Patents

Description

Patent Application No. 8411 1246 Revised Chinese Manual (October 88) V. Description of Invention (A7 B7

0 Λ 鹗 The present invention provides a novel cyanoid 7 having the following formula: wherein: -Ra represents a hydroxyl group or an ethoxyl group & Rb vapah hydrogen atom, and z represents a group of the formula: -V Please read the back Attention 呗 *-裳-1Write this page j

R R, NH 〇 (Π)

OH-Ding- 'is printed in the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs where: R1 represents a fluorenyl group, or an alkyl group of the formula R2-O-CO- to an alkyl group of 8 carbon atoms, and K · 3 represents benzene Or β-or / S-theophyl, R * 4 represents an unbranched or branched alkyl or phenyl group having 1 to 8 carbon atoms, and R5 represents an unbranched or branched alkyl group having 1 to 8 carbon atoms . More particularly, the invention provides paclitaxel like formula (1), wherein Ra represents a hydroxyl or ethoxyl group and Rb represents a hydrogen atom, Z represents a group of formula (II), wherein Ri represents a benzamidine group or a group r2-〇_C〇-, where r2 represents the third butyl 'R · 3 represents phenyl' R_4 represents phenyl, and R5 represents 1 to 4 carbon atoms, which represents 1 to 4 -4-This paper size applies Chinese National Standard (CNS) A4 Specification (210X297 mm) No. 8411 1246 Patent Application Chinese Specification Revision Page (October 88) V. Description of Invention (A7 B7

0 Λ 鹗 The present invention provides a novel cyanoid 7 having the following formula: wherein: -Ra represents a hydroxyl group or an ethoxyl group & Rb vapah hydrogen atom, and z represents a group of the formula: -V Please read the back Attention 呗 *-裳-1Write this page j

R R, NH 〇 (Π)

OH-Ding- 'is printed in the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs where: R1 represents a fluorenyl group, or an alkyl group of the formula R2-O-CO- to an alkyl group of 8 carbon atoms, and K · 3 represents benzene Or β-or / S-theophyl, R * 4 represents an unbranched or branched alkyl or phenyl group having 1 to 8 carbon atoms, and R5 represents an unbranched or branched alkyl group having 1 to 8 carbon atoms . More particularly, the invention provides paclitaxel like formula (1), wherein Ra represents a hydroxyl or ethoxyl group and Rb represents a hydrogen atom, Z represents a group of formula (II), wherein Ri represents a benzamidine group or a group r2-〇_C〇-, where r2 represents the third butyl 'R · 3 represents phenyl' R_4 represents phenyl, and R5 represents 1 to 4 carbon atoms, which represents 1 to 4 -4-This paper size applies Chinese National Standard (CNS) A4 Specification (210X297 mm) No. 84111246 Patent Application Chinese Specification Revision Page (October 88) Five 'Invention Description (2) A7 B7 Alkyl Supplement without Paclitaxel Like Formula (I) , Where Z represents a group of formula (π), exhibiting significant antitumor and antileukemia properties. Paclitaxel of formula I, in which 2 represents a hydrogen atom, can be used as an intermediate to prepare paclitaxel of formula〗 by a known esterification method, wherein Z represents a base of formula II. According to the present invention, paclitaxel of formula (I), in which RaR represents ethoxyl, .. Rb represents a hydrogen atom, and Chi 5 and Z are as defined above can be obtained from an alkali metal halide (eg, gasification) Sodium, sodium iodide or potassium fluoride) or alkali metal azides (such as sodium azide) or quaternary ammonium salts or alkali metal phosphates on compounds of the formula T: — — ΙΊΙJ --- pack- {Please read the note on the back before filling in this page】

(III) Order the cooperation of shellfish consumer cooperation between the Central and Standard Bureau of the Ministry of Economic Affairs, ¾.¾ αν) where 2〗 represents the hydrogen atom or the basis of formula (Π), where R 丨 and ruler 3 are as defined above or the following formula Basic difficulties:

Ri, n′6o, ΛΛ 0-R, where R 丨 and R3 are as defined above, and r6 represents a hydrogen atom and r7 represents a group for protecting the function of a hydroxyl group, or r6 and r7 together form a saturated pyrazolidinyl group, -5 -The paper size of the table is applicable to the Chinese National Standard (CNS) Congwei (2 丨 〇297297) Patent Application No. 84111246 Patent Specification Revised Page (October 88) Five 'Invention Note (2) Alkyl version of A7 B7 Paclitaxel like formula (I), where Z represents a group of formula (π), exhibits significant antitumor and anti-leukemia properties. Paclitaxel like formula I, where 2 represents a hydrogen atom, can be used as an intermediate, by A known esterification method is used to prepare paclitaxel of the formula, wherein Z represents the base of formula II. According to the present invention, paclitaxel of the formula (I), wherein RaR represents ethoxyl, .. Rb represents a hydrogen atom, and 5 and Z are as defined above and can be obtained from an alkali metal halide (such as sodium gaseous, sodium iodide or potassium fluoride) or an alkali metal azide (such as sodium azide) or a quaternary ammonium salt or Alkali metal phosphate acts on compounds of the formula T: — — ΙΊΙJ --- pack-{Please read first Note the cold items on the back, then fill out this page]

(III) Order the cooperation of shellfish consumer cooperation between the Central and Standard Bureau of the Ministry of Economic Affairs, ¾.¾ αν) where 2〗 represents the hydrogen atom or the basis of formula (Π), where R 丨 and ruler 3 are as defined above or the following formula Basic difficulties:

Ri, n′6o, ΛΛ 0-R, where R 丨 and R3 are as defined above, and r6 represents a hydrogen atom and r7 represents a group for protecting the function of a hydroxyl group, or r6 and r7 together form a saturated pyrazolidinyl group, -5 -The paper size of the table is applicable to the Chinese National Standard (CNS) Congwei (2 丨 〇χ297) No. 841U246 Patent Application Chinese Specification Correction Page (October 88) V. Description of Invention (15) A7 B7

0 (XXVI) where G 丨 is as defined above, under the condition that the compound of formula (xv) above acts on the compound of formula. The product of the formula (XXVI) can be obtained from the function of a trialkylsilane on the compound of the formula (XXV) under the conditions described above for a trialkylsilane on a compound of the formula (XXIX). The product of formula (XXV) can be obtained under the conditions described by d.G.I. Kingston et al., Tetrahedron Letters, ϋ, 6839 (1992). Taxols of formula s 9 9 (I) obtained by carrying out the method according to the invention can be purified by known methods such as crystallization and chromatography. Paclitaxel of formula (I), where Z represents a group of formula („), exhibits significant biological properties. In a test tube, the bioactivity was measured on microtubulin extracted from pig brain by M_L. Sheianski et al. People, Proc. Natl Acad, Sci USA, conducted by the method of printing 765-768 (1973) by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The research on depolymerization of microtubules into microfibers was based on G. ChauWere et al., CR Acad% 'sequence η 501 was performed in accordance with (Chen) method. In this study, paclitaxel such as formula ，, in which Z represents a group of formula (II), has been shown to be at least as effective as T_re). I … ㈣ and yew in the body, formula ⑴ like paclitaxel 'where z represents the formula called the group Jing-18-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 public; t— 5. Description of the invention ( 3) A7 B7 114 and 115 are as defined above, RaR represents an ethoxy group or a hydroxyl-protecting group, preferably 2,2,2-trichloroethoxycarbonyloxy, and Rb represents a hydrogen atom, The product of the following formula is obtained:

0 (V) II «^ ϋ»--HI an— 1 n (Please read the notes on the back before filling out this page) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Among which Zl, Ruler 4, Ruler 5, Ra And Rb are as defined above, and then, when necessary, the protecting group represented by Ra is replaced by a Ra or the protecting group represented by a ruler 7 and / or by a ruler 6 and 1 ^ is replaced by a hydrogen atom. In general, the reaction is selected from ethers (such as tetrahydrofuran, diisopropyl ether, fluorenyl, or tertiary butyl ether) and nitriles (such as acetonitrile) in an organic solvent, either alone or in a mixture at 20 ° C to The reaction is carried out at a temperature between the boiling points of the reaction mixture. The product of formula (V), where Zι represents a hydrogen atom or a group of formula (Π), Ra represents an ethoxy group and Rb represents a hydrogen atom, which are exactly the same as those of formula (I), where Z, Ra, Rb , R4 and R5 have corresponding counterparts. In formula (V), when Zl represents a radical of formula (IV) and when 6 represents a hydrogen atom, R? Preferably represents methoxymethyl, 1-ethoxyethyl, and methoxymethyl. Group, trimethylsilyl group, triethylsilyl group, trimethylsilylethoxymethyl group, benzyloxycarbonyl group, or tetrahydropiperanyl group, or alternatively, when formed together with R 6 and R? P bite ring, replace single or double in position 2 as appropriate -6 Good paper size applies to China National Standard (CNS) A4 (210X297 mm)

1. 1T Patent No. 84111246, Chinese Patent Application, Revised Page (October 1988) A7 ___B7 V. Description of the Invention (16) The supplement shows that it is effective at the dosage of 1 to 10 mg / kg intraperitoneally. B 1 6 melanoma transplanted mice, and against other liquid or solid tumors. These novel taxoids have valuable antitumor properties and are more effective against tumors that are resistant to Taxol® or Taxotere®. Such tumors include colon tumors, which have mdr 1 High expression of genes (multidrug resistance genes). Multidrug resistance is a conventional term for tumors that are resistant to different products of different structures and mechanisms of action. Paclitaxel is generally known to be strongly recognized by experimental tumors such as P388 / DOX, which is a cell line that has been selected to be resistant to doxorubicin (DOX), which overexpresses mdr 1. The following examples illustrate the invention. Example 1 Shellfish consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs. Printed by the agency «. 40 mg of 2α-fluorenol, 10 cold-dihydroxy_5 Ling, 20-epoxy_4 cz -methoxy-7 8-Methyl-19-nor-9-oxy-11-taxane-13α-yl (2R, 4S, 5R) -3-third butoxycarbonyl-2- (4-methoxy Phenyl) -4-phenyl-1,3-pyrazolidine-5-carboxylic acid ester in 450 microliters of 0.1 equivalent concentration of hydrogenated gaseous solution in ethanol solution kept stirring at a temperature in the region of 0 ° C 3 hour. The reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C. The resulting crude product was dissolved in 10 ml of dichloromethane and 10 ml of a saturated aqueous sodium hydrogen peroxide solution. The organic layer was separated after sedimentation, washed twice with 0 ml of a saturated aqueous sodium chloride solution, then dehydrated in magnesium sulfate, filtered, and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). 59 mg of the product was obtained, which was purified by preparative chromatography on a 0.5 mm thick silica plate and eluted with a cyclohexane / ethyl acetate (60:40 volume ratio) mixture. Thus, 12 mg of 2α-fluorenyl-1, 10 cold-two-base, 5/3, 20- -19, was obtained as a white foam. SS Jiapi (CNS) A4 * US · (2 丨 GX297 mm) ~ ~ V. Description of the invention (4) A7 B7 generation. The replacement of the protecting groups R7 and / or feet 6 and R7 by hydrogen atoms, and the replacement of Ra by peptidyl when appropriate, can be carried out according to its nature in the following manner: 1) When R6 represents a fluorene atom and R7 represents a hydroxyl protecting function When Ra is an ethoxyl group, the protecting group is replaced by a hydrogen atom. The inorganic acid (such as hydrochloric acid, sulfuric acid, or hydrofluoric acid) or an organic acid (such as acetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid) is substituted. Or p-toluenesulfonic acid), used alone or in a mixture, in an organic solvent, selected from the group consisting of alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, or nitriles, between -10 and 60 ° C. Performed at temperature, 2) when R6 represents a hydrogen atom and R7 represents a base diagram for protecting a hydroxyl function, and R represents 2,2,2-trifluoroethoxycarbonyloxy, the substitution of the protecting group is in 1) above Under the conditions and replacement of Ra by combining with zinc, as appropriate, and copper, in the presence of acetic acid at a temperature of 30 to 60 ° C, or by inorganic or organic acids such as hydrochloric acid or acetic acid in the range of 1 to 3 carbon atom aliphatic alcohol (such as methanol, ethanol, propanol or isopropanol) or an aliphatic ester (such as ethyl acetate , Isopropyl acetate or n-butyl acetate) solution, in the presence of copper, optionally combined with copper, 3) when R_6 and R? Together form a 5- or 6-membered saturated heterocyclic ring, and more particularly Underground pyrazolidine ring: (Please read the precautions on the back before filling out this page) -Packing-* 11 Printed by the Employees' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs

The ruler 丨 is defined in the above and ruler 8 and |? _9, which may be the same or different, representing

.- I Is— I —'7 ~ (CNS) Α4Α (210X297 ^ 17 -ny .1 · No. 84111246 Patent Application Chinese Specification Revision Page (October 88) A7 B7 V. Explanation of the Invention (40) Revision Supplement Printed by Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5.25 (s, 1H: Η is in position 1 〇); 5.54 (d, J = 6, 1H:: is in position 2); 7.42 (t, J = 7.5, 2Η: OCOC6H5 Η is in the intermediate position); 7.55 (t, J = 7.5, 1H: OCOC6H5 H is in the opposite position); 8.11 (d, J = 7.5, 2H: OCOC6H5 H is in the adjacent position). 2α -Hydroxy 1 Ling-Hydroxy_i〇 Ling-Ethyloxy_5 cold, 20-epoxy_ 4 α · ethoxy-4α-ethoxy-7 / 5, 8-methylene-9-oxo -11-Taxane-13 α-yl- (2R, 3S) -3-third-butoxycarbonylamino-2-hydroxy-4-phenylpropanoic acid can be prepared by the following method, 100 mg of powder 4A molecular sieve and 390 mg of sodium azide, added 260 mg of 2α-fluorenyloxy-1zol-hydroxy-ι-β-ethoxyl-5, 20-epoxy-4α-ethoxy- 7 o'clock-trifluoromethanesulfonic acid-9-oxo-Π-taxane -13 0: -yl- (2R, 3S) -3 -third-butoxycarbonylamino_2 · meridyl-4 -Phenylpropionic acid at 3.4 mmol Acetonitrile and a solution formed in 0.340 ml of tetrahydrofuran. The reaction mixture was stirred at about 75 ° C for 3 hours. The reaction mixture was then slowly cooled to about 20 ° C and then at 40eC under reduced pressure (2.7 kPa). Concentrated to dryness. The obtained product was purified by chromatographic analysis. The chromatographic analysis was performed on 100 g of silicide (0.063 to 0.2 mm) using a 70 cm column of cyclohexane and ethyl acetate in a 1 cm diameter column. 30 volumes of the mixture was used as an eluent 'and 8 ml of the split solution was collected. The split solutions containing only the desired product were pooled and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). 13 g of a white foam was obtained Forms of 2α-Germanyloxy-1 call-Jingji · 10point_Ethyl. Oxy-5 cold, 20-epoxy-4α-ethoxy-7 call, 8-methylene_9_ The oxo_11-taxane-13-yl- (2R, 3S) -3-tertiary-butoxy condensylamino-2-hydroxy-4_phenylpropionic acid has the following physical properties: Proton NMR Spectrum (300 MHz, CDC13 in ppm); from 120 to 43- This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back # & q uot; write this page) -LI.-binding and ordering Γ line A7 ---------- 5. Description of the invention (5)-Hydrogen atom or alkyl or arane with 1 to 4 carbon atoms Group in which the alkyl portion has 1 to 4 carbon atoms and the aryl portion preferably represents phenyl, optionally substituted with 1 or more alkoxy groups having 1 to 4 carbon atoms, or preferably represents benzene An aryl group, as the case may be, is substituted with 1 or more alkoxy groups having 1 to 4 carbon atoms, or alternatively R8 represents an alkoxy group having 1 to 4 carbon atoms or, for example, trimethyl A dentate methyl group or a phenyl group substituted with a tridentate methyl group such as a trifluoromethyl group and a ruler 9 represent a hydrogen atom, or alternatively 118 and 119 together with the carbon atom to which they are attached form a 4- to 7-membered ring, And% represents fluorenyl or alkoxyethenyloxy or 2,2,2-trifluoroethoxycarbonyloxy, the protecting group formed by 6 and 1 ^ is replaced by a hydrogen atom and Ra is replaced by a hydroxyl group According to the meaning of Ra, Ri, feet 8 and feet 9 in the following ways: a) When feet 丨 represents the second butoxy carboxyl group and feet 9 which may be the same or different, and represents alkyl or aralkyl ( (Such as fluorenyl) or aryl (such as phenyl), or alternatively Alternatively, when R8 represents a trimethyl group or a phenyl group substituted with a trimethyl group and represents a hydrogen atom 'or alternatively r8 and-form a 4- to 7-membered ring, the ester of formula (V) is inorganic Or organic acid treatment, when appropriate, in an organic solvent such as alcohol, the product of the following formula: n ^ — i ml ^^^ 1 HI. An— .., τ (Please read the precautions on the back before filling in this Page} Central Government Bureau of the Ministry of Economic Affairs

(VII) ο

Revised Page of Chinese Specification for Patent Application No. 841 1 1246 (October 88) A7 B7 V. Description of Invention (40b) 1Η: Η3 ·); 5.66 (d, J = 7Hz, 1H: H2); 6.05 (mt, 1H: H13); 6.38 (s, 1H: H5 '); 6.91 (d, J = 8.5Hz, 2H: H aromaticity is adjacent to OCH3); from 7.30 to 7.50 (mt, 7H: H aromaticity is in position 3, and position between OCOC6H5 H); 7.41 (d, J = 8.5Hz, 2Η: Η Aromaticity is between OCH3); 7.85 (t, J = 7.5Hz, 1H: OCOC6H5 H position); 7.96 (d , J = 7.5Hz, 2H: oCOC6H5 H adjacent position) "A novel paclitaxel of formula (I), in which Z represents the base of formula (II), showing a significant inhibitory activity of abnormal cell proliferation i, and has medical properties, Allows treatment of patients with conditions associated with abnormal cell proliferation. Such disorders include a variety of abnormal cell proliferation of tissues and / or organs, malignant or non-malignant, including but not intentionally limited to muscle, bone, and connective tissue, skin, brain, lung, sexual organs, lymph and kidney system, breast and Blood cells, liver 'digestive system, pancreas and thyroid or adrenal glands. Such conditions include dry addiction, solid tumors, ovarian cancer, breast cancer, brain cancer, prostate cancer, colon cancer, gastric cancer, kidney cancer or testicular cancer, pigmented dry skin disease, bile duct tumor, villous adenoma, neuroblastoma, Embryonic carcinosarcoma, malignant granuloma, heteromas, multiple myeloma, chronic lymphocytic leukemia, and acute or chronic granulocytic lymphoma. The paclitaxel of the present invention is particularly useful in the treatment of ovarian tumor β, which can be used to prevent or delay the appearance or recurrence of conditions, or to treat such conditions. Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -Shang-(Please read the -.ii notice on the back > Shan' write this page) Order Γ According to the present invention, paclitaxel can be suitable for different application routes. The dosage form is administered to the patient, preferably by a parenteral route. Parenteral routes include intravenous, intraperitoneal, intramuscular or subcutaneous administration. Intraperitoneal or intravenous administration is particularly preferred. The present invention provides pharmaceutical compositions that have at least one paclitaxel of formula (i) in an amount sufficient for human or veterinary use. These compositions can be prepared according to conventional methods. Use 1 or more in medicine Acceptable adjuvant,

• Rb

0

Rb, Ri, R_3, R_4, and R5 are as defined above. When they represent the base for protecting hydroxyl groups, they are printed by the Consumer Cooperatives of the China Economic and Social Development Bureau of the Ministry of Basic Economics when necessary. A7 B7 V. Inventions Note (6) wherein Ra, Rb, R3, Chi 4 and R5 are as defined above, and they are fluorinated with benzyl hydrazone, pyrimidine hydrazone, furan hydrazone or compounds of the formula : R2-0-C0-X (VIII) where R2 is as defined above and X represents an _ atom (such as fluorine or chlorine) or a radical 圏 o-r2 or -o-co-o-r2 to obtain the formula Product: (IX) where Ra is protected by Ra. Preferably, the product of formula (V) is formic acid at 20. (: Treatment at a temperature in the region. Preferably, the product of formula (IX) and the product of formula (IX) in which the phenyl group is optionally substituted are ytterbium gas, methaneformium gas, furan gas, or the product of formula (νπι) The reaction is carried out in an inert organic solvent, selected from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, and from aliphatic hydrocarbons such as digas methane or 12-digas ethane, in the absence of alkali such as carbonic acid In the presence of sodium hydrogen or an organic base such as triethylamine. The reaction is carried out at a temperature between 0 and 50 ° C, and preferably at 20. (: area. (Please read the precautions on the back before (Fill in this page).

V. Explanation of the invention (7) A7 B7 Preferably, the substitution of the protective group Ra is performed under the conditions described in 2) above when it represents 2,2,2-trifluoroethoxycarbonyloxy. b) When Ri represents optionally substituted fluorenyl, p-thiophene or furanyl or R20-C0- 'where R2 is as defined above' Rg represents a hydrogen atom or has 1 to 4 carbons When an atomic alkoxy group or a phenyl group substituted with 1 or more alkoxy groups having 1 to 4 carbon atoms and R9 represents a hydrogen atom, the protecting group formed by rule 6 and 1? _7 is replaced by a hydrogen atom. In the presence of an inorganic acid (such as hydrochloric acid or sulfuric acid) or an organic acid (such as acetamidine, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid), 'single or mixed with stoichiometric catalysts in organic In the solvent, a temperature selected from the group consisting of alcohols, ethers, esters, aliphatic hydrocarbons, aliphatic hydrocarbons and aromatic hydrocarbons, between -10 and 60 ° C, and preferably between 15 and 30 ° C The next treatment and the replacement of the protective group Ra, when it represents 2,2,2-trifluoroethoxycarbonyloxy, is performed by a hydrogen atom under the conditions in 2) above. Compounds of formula (in), where ζ〗 represents the formula (called a base diagram or a group of formula (IV) can be obtained by esterification of a compound of the following formula: (Please read the precautions on the back before filling out this page) -T1 .11 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(X) where R4M5 is bounded as above ^, and ~ represents an ethyl alcohol group or a protecting group, and Rb represents a hydrogen atom, an acid of the following formula: -10- Private paper scales are applicable to Chinese national standards (CNS ) A4 specifications (210X297 public A7 B7 V. Description of invention (8)

Rl> ^ 60 X (XI) ό-R, where ^ and ruler 3 are as defined above, and Rg is substituted for `` hydrogen atom and R7 represents a group that protects the function of the derivatizing group '' or ~ and ruler? Together form a saturated 5_ or 6_ member heterocyclic ring, or a derivative of this acid, to obtain an ester of the following formula: (Please read the precautions on the back before filling this page) • 11 packs.

'Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where Ra, Rb, Ri, R3, r4, r5, r ^ r7 are bounded as above' and then represented by R? And / or r6 and R7 when needed Where the protecting group is replaced by a hydrogen atom, and Ra is, when appropriate, a hydroxyl group, when it represents an ethoxy group or a hydroxyl-protecting group 囷, under the condition that the above-mentioned protective group of the product of the formula (V) is substituted, Wherein Z represents the base of formula (IV), the esterification reaction of the acid of formula (XI) can be carried out in a condensing agent (for example, carbodiimide or reactive carbonate) and an activator (for example, amine pipido) In the presence of organic solvents (such as ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at temperatures between -10 and 90 ° C. The esterification reaction can also be carried out using an acid of formula (XI) in the form of an acid anhydride. For the paper size, the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 is used.

V. Description of the invention (9) In the presence of a chemical agent (such as aminopyridine), in an organic solvent (such as an ether, an ester, a ketone, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, or an aromatic hydrocarbon), from 0 to 9 Processed at a temperature between 00 ° C. The brewing reaction may also use an acid of formula (XI) in the form of a dentate or with an aliphatic or aromatic anhydride, optionally prepared in situ, in the presence of a base (such as a tertiary aliphatic amine), in In organic solvents (such as ethers, esters, ketones, nitriles, aliphatic fes, halogenated aliphatic or aromatic hydrocarbons), from 0 to 80. Under the 〇 spillover degree. According to a feature of the present invention, the compound of formula (m), wherein the neutralization is as defined above, Ra represents an ethoxyl group, Rb represents a hydrogen atom, and Zι represents a hydrogen atom. Phenyltrifluoromethyleneimine is obtained by the action of a compound of the formula:

HO

(ΧΠΙ) (Please read the precautions on the back before filling out this page) .1H Pack., Π Printed by Zhengong Consumer Cooperatives, Central Samples Bureau, Ministry of Economic Affairs where Ra, Rb, R4 and R5 are as defined above. Generally, the reaction is in an organic solvent such as an aliphatic hydrocarbon, optionally halogenated, or an aromatic hydrocarbon, in the presence of an organic base such as a tertiary aliphatic amine (such as triethylamine) or pyridine. Down, at -5-0 to +20. (: The product of formula (XIII) is carried out at a temperature between, where r_4 and rs are as defined above, Ra represents an ethyl alcohol group or a hydroxyl-protecting group and Rb represents a hydrogen atom, and can be hydrofluoric acid or -12- This paper size is applicable to Chinese National Standard (CNS) M specification (21 () > < 297 male thin, 1 I II-V. Description of the invention (1〇) A7 B7 difluoroacetic acid in alkaline organic solvents such as video Qing Shen is combined with one or more alkyl substituted pyridines with four to four carbon atoms, or triethyl.amine, as appropriate, in combination with an inert organic cereal such as digasmethane or acetonitrile or tetrahydrool, At a temperature between 20 and 80 ° C, acting on a compound of the formula:

0 (XIV) wherein R4 and R5 are as defined above, Ra represents an ethoxy group or a hydroxyl-protecting group, represents a hydrogen atom, and the symbol G 1, which are all the same and represent a trialkylsilyl group. * Compounds of the formula (XIV), where 113 represents an ethoxy group or a hydroxyl-protecting group and Rb represents a hydrogen atom, and can be a compound of the formula: R_Y (XV) where R represents an ethano group and Y represents a south atom, below The compound of the formula is obtained:

0 (XVI) Jing first read the note on the back-then fill in the gutter on this page. 13-This paper size is applicable to the national standard (CNS) A4 specification (210X297 mm) A7 B7 5. Description of the invention (11) of which R4, R5 * Gi are as defined above. When R represents ethenyl, 'particularly advantageous is in a basic organic solvent such as p-pyridine or in an inert organic solvent such as dichloromethane, aeroform or 1 > 2-gas diethanol, in tertiary amines such as In the presence of triethylamine or pyridine. 〇 Processing at a temperature within the zone. The product of formula (XVI) and where appropriate the product of formula (XIV) can be derived from organometallic derivatives of the formula: R4-M (XVII) where R 4 is as defined above and M represents a metal atom, preferably lithium or Town atom, obtained by acting on the compound of the following formula: (Please read the precautions on the back before filling this page)

Rb

.π. Wc Industrial and Consumer Cooperation of the Central Government Bureau of the Ministry of Economic Affairs Du Yindong

P

〇 Wherein Ra, Rb, R5 and Gi are as defined above. Generally, the reaction is in an organic solvent such as a bond (such as tetrazine) at a temperature of less than -50 ° C, preferably at -7. Performed at a temperature of 8 ° C. The product of formula (XVIII) can be obtained by etherification of a compound of the following formula:%, (XIX) -14- This paper size applies to China National Standards (CNS > A4 ^ # (210X297 & |) A7 B7 V. Description of the invention (Η) where Ra, Rb, and Gi are as defined above, using the following compounds:

Rs-Hal (XX) where R5 is as defined above and Hal stands for atom. Particularly advantageous is that the compound of formula (XIX) is treated with a compound of formula (XX) before, by the action of an alkali metal hydride or an amidate such as sodium amide or monoisopropyl aminated compound. Functional metallization. Generally, the reaction is carried out in a polar organic solvent such as dimethyl methylamine at a temperature between 0 and 50 / C. The product of formula (XIX) can be obtained from the compound of formula (XV) on the compound of the following formula: (Please read the note f on the back before filling this page) 11 packs.

, 1T

0 Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives (XXI) where G! Is as defined above, under the conditions described above for compounds of formula (XV) to act on compounds of formula (XVI). The product of formula (XXI) can be phosgene, or one of its derivatives, such as triphosgene, in the following 15- Chinese paper standard (CNS) A4 specifications (210X297 mm) are applicable to each paper size. 5. Description of the invention (13) Preparation: A7 B7

0 (χ > αΐ) wherein 〇 丨 is as defined above, and is treated in a basic organic solvent such as pyridine at a temperature lower than -50 ° C, preferably in a temperature range of -78 ° C. The product of formula (XXII) can be prepared by the action of a tristrialkylsilane on a compound of the formula

0 (XXIII) ----: ---: --- (install-(Please read the notes on the back before filling out this page) Ordered by the Central Standards Bureau of the Ministry of Economic Affairs, Paiger Consumer Cooperatives 11 where G 1 is as above As defined, treated in a basic organic solvent. The product of formula (XXIII) can be prepared under conditions described by DGI Kingston et al., J. Nat. Prod., Inverse, 884 (1993). Product, in which R4 represents phenyl, and the rule 5 is as defined above; Ra represents a hydroxyl group or an ethoxyl group or a protected hydroxyl group; and Rb represents a hydrogen atom, which can be obtained by a compound of formula (XX) acting on a compound of the following formula ： -16 This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇 < 297 mm) A7 B7 V. Description of the invention (14) ο

ο lb (XXIV) where Ra and Rb are as defined above, as defined above, under the condition that the compound of formula (XX) above acts on a compound of formula (XIX). The product of formula (XXIV), where Ra represents a group protecting the hydroxyl function, which is exactly the same as Gi and Rb represents a hydrogen atom: the product can be obtained by the action of a halotrialkylsilane on a compound of the formula: (Please read the (Please fill in this page again)

0 (XXV) Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where Gi is as defined above. This reaction is preferably carried out in an organic solvent such as dimethylformamide in the presence of acetone. The product of formula (XXIV), in which Ra represents an ethoxyl group, a hydrogen atom, and 0 is as defined above, can be obtained by the compound of formula (xv) acting on a compound of the following formula: 17- This paper is from the national standard of a suitable country (CNS) M Specification ⑺GX297 Gong No. 841U246 Patent Application Chinese Specification Revised Page (October 88) V. Description of Invention (15) A7 B7

0 (XXVI) where G 丨 is as defined above, under the condition that the compound of formula (xv) above acts on the compound of formula. The product of the formula (XXVI) can be obtained from the function of a trialkylsilane on the compound of the formula (XXV) under the conditions described above for a trialkylsilane on a compound of the formula (XXIX). The product of formula (XXV) can be obtained under the conditions described by d.G.I. Kingston et al., Tetrahedron Letters, ϋ, 6839 (1992). Taxols of formula s 9 9 (I) obtained by carrying out the method according to the invention can be purified by known methods such as crystallization and chromatography. Paclitaxel of formula (I), where Z represents a group of formula („), exhibits significant biological properties. In a test tube, the bioactivity was measured on microtubulin extracted from pig brain by M_L. Sheianski et al. People, Proc. Natl Acad, Sci USA, conducted by the method of printing 765-768 (1973) by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The research on depolymerization of microtubules into microfibers was based on G. ChauWere et al., CR Acad% 'sequence η 501 was performed in accordance with (Chen) method. In this study, paclitaxel such as formula ，, in which Z represents a group of formula (II), has been shown to be at least as effective as T_re). I … ㈣ and yew in the body, formula ⑴ like paclitaxel 'where z represents the formula called the group -18-This paper size applies to China National Standard (CNS) A4 specifications (210X297 public; t-84111246 patent t Please amend the Chinese instruction sheet (October 1988) A7 _B7 V. Description of the invention (16) The supplement especially shows that it is effective for B 1 6 melanoma transplantation at a dosage of 1 to 10 mg / kg intraperitoneally. Mice, and fight against other liquid or solid tumors. These novel paclitaxel-like Valuable antitumor properties and more effective against tumors resistant to Taxol® or Taxotere®. Such tumors include colon tumors, which have the mdr 1 gene (multidrug resistance Genes). Multidrug resistance is a conventional term for tumors that are resistant to different products of different structures and mechanisms of action. Paclitaxel is generally known to be strongly recognized by experimental tumors such as P388 / DOX, which is recognized by Select a cell line that is resistant to doxorubicin (DOX), which overexpresses mdr 1. The following examples illustrate the present invention. Example 1 Shellfish Consumer Cooperation, Central Bureau of Standards, Ministry of Economic Affairs. 40 mg of 2α-fluorenol, 10-cold-dihydroxy_5, 20-epoxy_4 cz-methoxy-7, 8-methyl-9-nor-9-oxy- 11-Taxene-13α- (2R, 4S, 5R) -3-Third-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-pyrazolidine The solution of -5-carboxylic acid ester in 450 µl of 0.1 equivalent concentration hydrogenated gas in ethanol solution was kept stirred for 3 hours at a temperature in the range of 0 ° C. The reaction mixture was under reduced pressure (2.7 kPa) at 20 ° C It was concentrated to dryness. The obtained crude product was dissolved in 10 ml of dichloromethane and 10 ml of a saturated aqueous sodium hydrogen peroxide solution. After the sedimentation occurred, the organic layer was separated and washed twice with 0 ml of a saturated sodium chloride aqueous solution. , Then dehydrated in magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 59 mg of the product was obtained, which was prepared by preparative chromatography on a 0.5 mm thick silica plate Purify and elute with a cyclohexane / ethyl acetate (60:40 volume ratio) mixture. Thus, 12 mg of 2α-fluorenyl-1, 10 cold-two-base, 5/3, 20- -19, was obtained as a white foam. SS Jiapi (CNS) A4 * US · (2 丨 GX297 mm) ~ ~ A7 _____B7_ V. Description of the invention (17) Epoxy-4α-methoxy-7 / 5, 8-methyl-9-nor-9-oxy-11-purple The physical characteristics of taxane-13 α-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are as follows:-Proton NMR spectrum (440 MHz CDC13; β at ppm; fit constant j at Hz); 1,20 (s, 6H: CH3); 1.35 (s, 9H: C (CH3) 3; from 1.35 to 1.60 (mt, 1H: Η in position 7); 1.73 (s, 1H: OH in position 1); 1.81 and 2.27 (2mts, each m: CH2 in position 19); 1.90 (s, 3 ,: <:113); 2.07 and 2.26 (211 ^, each 111: (: 112 at position 6); 2.35 and 2.87 (2mts, each 1H: CH2 at position 14 ″); 3.24 (mt, 1H: OH at position 2 '); 3.46 (s, 3H: 〇CH3); 3 .? 0 (d, J = 7, 1H: Η is in position 3); 3_97 and 4.39 (2 (1, 1 = 9, each 111: (: 1 € 2 in position 20); 4.24 (Canton 5, 11, · !: OH is at position 10); 4.62 (mt, 1Η: Η is at position 2 '); 4.90 (wide d, J = 4, 1H: Η Position 5): 4.98 (s, 1H: Η is in position 10); 5.36 (mt, 1H: Η is in position 3,); 5.48 (d, J = 10, 1H: CONH); 5.69 (d, J = 7, 111: 11 at position 2); 6.24 (11 ^, 111: 11 at position 13); from 7.25 to 7.50 (mt, 5H: aromatic H at position 3 '); 7.49 (t, J = 7.5, 2H: OCOC6 H5 H is in the middle position); 7.57 (t, j = 75, m · COCO6% h is in the opposite position); 8.12 (d, J = 7.5, 2H: OCOC6H5 H is in the adjacent position). Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative (please read the precautions on the back before filling out this page) 2α- 芊 芊, ι〇θ-dihydroxy_5 / 5, 2〇_epoxy_4 methoxy-7 Lu, 8-Methyl-19-nor-9-oxy-1 1-taxane · 13 oxo (2R, 4S, 5R) -3-Third-butoxycarbonyl-2- (4-methoxy Phenyl) -4-phenyl · 1,3-, isozoridin-5-carboxylic acid ester can be prepared in the following way: 100 mg powder of 4 angstrom molecular sieve and 100 mg of sodium azide are continuously added 112 mg fluorenyloxyl 1 rou, 10 /? _ Dihydroxy_5 / 5,2〇_epoxy_ -20-This paper size applies to China National Standard (CNS) A4 (210X297 mm) Central Ministry of Economic Affairs Rate round A7 B7 printed by the consumer cooperative V. Description of the invention (18) 4α-methoxy-9-oxy-7 /?-Trifluoromethane oxy_ιι · taxane_13 α _ group (2R, 4S, 5R) -3-Third-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-Sakisho-yodo-5-Amino acid brewed in 1 ml acetonitrile and 1 ml tetra Hydrogen squeaking solution. The reaction mixture was kept stirring at a temperature in the region of 75 ° C for 3 hours, and then 50¾ liters of a saturated gasified sodium hydroxide solution was added at a temperature in the range of 20 ° C. The organic layer was disclosed after settling, and washed twice with 40 ml of a saturated aqueous solution of sodium vaporization, and then dehydrated in magnesium sulfate, filtered, and concentrated to dryness at 40 ° C under derating (2.7 kPa). 77 mg of product was obtained, which was purified by preparative chromatography on a 2 mm thick silica plate and eluted with a mixed solution of dimethane / methanol (90:10, volume ratio). Thus was obtained 45 mg of 2 α-benzyloxy-1 / 3, 10々-diacryl-5, 20-epoxy-4 α-fluorenyl-7, 8-methylene, as a white foam. -19-nor-9-oxy-11-taxane- 13-yl (2R, 4S, 5R) -3-third butoxycarbonyl-2- (4-methoxyphenyl) -4- The physical characteristics of phenyl-1,3-pyrazolidine-5 · chitoate are as follows:-Proton NMR spectrum (400 MHz; CDC13; at 330k; at ppm; coupling constant J at Hz) ; 1.10 〇, 9H: C (CH3) 3); 1.20 (s, 3H: CH3); 1.22 (s, 3H: CH3); 1.29 (mt, 1H: Η in position 7); 1.68 (s, 3Η: CH3 ); 1.78 and from 2.25 to 2.35 (2mts, each 1Η: CH2 is in position 19); 1_99 and 2.24 (dt and guang, respectively J = .17 and 4 and J = 17, each 1H: CH2 in position 6) From 2.25 to 2.35 and 2.56 (mt and dd, respectively (J = 15 and 7); each 1H: CH2 at position 14); 3.06 (5, 3 ^ 1: 0 (: 113); 3.67 (d, J = 7, 1H: Η is at position 3); 3.80 (s, 3H: ArOCH3); 3.96 and 4.26 (2 (1, 1 = 9, each 111: (: 112 is at position 20)), 4.17 (Guang 5,111 : 〇 only at position 10); 4.66 (d, J = 5, 1H: Η at position 2,); 4.78 (wide d, J = 4, -21-this paper ruler Degree applies to Chinese national standard (CNS) A4 specification (2lOX29? Mm) {Please read the precautions on the back before filling this page)

Printed by the Central Standards Bureau of the Ministry of Economy, Shellfish Consumer Cooperative A7 B7 V. Description of the invention (19) 1H: Η is in position 5); 4.92 (Canton, 1H: Η is in position 10); 5.48 (mt, 1H: Η At position 3,); 5.66 (d, J = 7, 1H: Η is at position 2); 6.05 (mt, 1H: Η is at position 13); 6.38 (s, 1H: Η is at position 51); 6.91 (d, ] = 8.5, 211: Aromatic 11 is in the neighboring position related to 00: 113); from 7.30 to 7.50 (mt, 7H: Aromatic H is in position 3 'and OCOC6H5 H is in position); 7.41 (d, JT = 8.5, 2H: aromatic Η is related to OCH3 i); 7.58 (t, J = 7.5,: OCOC6 H5 Η is in the opposite position), · 7 _ 9 6 (d, J = 7.5, 2H: OCOC6H5 Η next door). 2α-benzylfluorenyl dihydroxy_5, 20-epoxy-4α_methoxy-9-oxo-trifluoromethanesulfonyloxy-zulu-1 1 -taxane_3 α, radical (2R, 4S, 5R) -3-Third-butoxycarbonyl-2- (4-methoxyphenyl) -4 · phenyl-1,3-oxazolidine-5-carboxylic acid ester can be as follows Prepared by: 70 mg (2R, 4S, 5R) -3 · Third-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-pyrazolidine-5 -Carboxylic acid, 50 mg of dicyclohexylcarbonyldiimide and 6 mg of 4- (methylamino) pyridine were continuously added at a temperature in the 20 X: region of 100 mg of 2π-pentoxy-50,000, 20- Epoxy-methoxy-9-oxy_ 7 A -trifluoromethylphenoxy-1 / 9, 10 1, 13α-trisyl-11-taxane solution in 4 ml of anhydrous ethyl acetate . The reaction mixture was stirred under argon pressure at a temperature in the region of 20 ° C for 3 hours and 30 minutes. 30 ml of ethyl acetate and 20 ml of a saturated aqueous solution of ammonium vapor were added. The organic layer was separated 'after the settling occurred, washed twice with 20 ml of water and then dehydrated in magnesium sulfate. After filtration and concentration under reduced pressure (2.7 kPa) at 40 ° C to dryness, 200 mg of the product was obtained, which was chromatographically contained in a 15-cm column with a diameter of 1 cm in diameter (0.063-0.2 mm), purified with cyclohexane / ethyl acetate-22-This paper is suitable for paper towels (CNS) iron grid (21GX297 mm) '--- (Please read the note on the back first Matters refill this page}

A7 ___B7 V. Description of the invention (20) (80:20, volume ratio) The mixed solution was lysed out, and 8 ml of the separation solution was collected. The differentiation containing only the desired product was concentrated and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). Thus, 1 1 2 mg of 2 α-benzyloxy-1 Lu was obtained in the form of a white foam, 10 /?-Dihydroxy-5 cold, 20-epoxy-4 α-methoxy-9-oxy_7 /? _Trifluoromethanesulfonyloxy-11-taxane-13α-yl (2R, 4S, 5R) -3-third butoxycarbonyl-2- (4-methoxyphenyl) -4-benzene -1,3-oxazolidine-5-carboxylic acid ester, its physical characteristics are as follows: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) -Quality NMR spectrum Figure (400 MHz; CDC13; at 333K; d at ppm; coupling constant J at Hz); 1.-10 (s, 9H: C (CH3) 3); 1.13 (s, 3Η: CH3) ; 1.18 (s, 3H: CH ^; 1.77 (s, 3H: CH3); 1.87 (s, 3H: CH3); 2.33 and 2.76 (2dd, J = 15 and 11Hz and J = 15 and 7, each 1H: CH2 At position 14); 2.36 and 2.68 (2mts, 1H each: CH2 at position 6); 3.19 (s, 3H · · OCH3); 3.44 (d, J = 6, 1H · · H at position 3); 3.83 (3,311 : Enter 1: 0 (: 113); 3.95 (Guang 3, 111: 〇11 at position 10); 4.19 and 4.34 (2d, J = 9, each 1H: CH2 at position 20); 4.66 (d, J = 5.5 , 1H: -11 at position 2 |); from 4.85 to 4.95 (11 ^, 214: 11 at position 7 and 1 ^ in position 5), 5.32 (W, 1H: H in position 10); 5.49 (d, J = 5.5, 1H: H in position 3,); 5.60 (d, J = 6, 1H: H in Position 2); 5,95 (mt, 1H: H at position 13); 6.38 (s, 1H: H at position 5 '); 6.94 (d, J = 8.5, 2H: aromatic 11 is related to 〇 (: Neighbor position 113); from 7.30 to 7.50 (11 ^, 711: aromatic H is in position 3_ and OCOC6H5 H is in intermediate position); 7.40 (d, J = 8.5, 2H: aromatic H is related to OCH3 Between positions); 7.60 (t, J = 7.5, 1H: OCOC6H5 H is in the opposite position); 7.97 (d, J = 7.5, 2H: 〇COC6H5 H is in the adjacent position). -23-This paper size applies Chinese national standards ( CNS) A4 specifications (210X297 mm) _ Α7 Β7 Printed by the Male Workers Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (21) 2 α-Hydroxy-5, 20 · epoxy · 4 Λ _ A Oxy_9_oxy · 7y3 -trifluoromethanesulfonyloxy-1々, 10 / ?, 13α-trihydroxytaxene can be prepared in the following manner:

25 microliters of difluorophosphonium sulfonic anhydride was added to 516 mg of 2 β _fluorenyl-5 /? At a temperature in the region of 0 ° C, 20-epoxy_4.α_methoxy_9_oxygen point j, 7 / ?, 10θ, 13 α-tetrahydroxytaxane in ml of digas methane and in microliters of pyridoxine solution "The reaction mixture was stirred at a temperature within the range of« C for 20 minutes and Then 15 ml of dioxane and 3 ml of water were added. The organic layer was separated after settling, washed twice with a saturated aqueous solution of 100 ml and then dehydrated in magnesium sulfate. After filtration and concentration under reduced pressure (27 kpa) at 20 ° C. to dryness, 72 mg of the product was obtained. The product was purified by chromatography on a 2 mm thick silica plate with digas methane / methanol (9 〇: 10, volume ratio) The mixed solution was eluted. Thus 8 mg of 2 α-fluorenyloxy · 5 Lu, 20-epoxy-4α_methoxy-l々, white cold, 13 α-trichloroyl-9_oxy-7 / were obtained as a white foam. The physical characteristics of? -Difluoromethane-oxyl-11-taxane are as follows: • Proton NMR spectrum (400 MHz; CDC13; β at ppm; coupling constant J at Hz); 1'06 (s, 3H: CH3); 1.10 (s, 3H: CH3); 1.86 (s, 3H: CH3); 2.13 (s, 3H: CH3); 2.41 and 2.74 (2mts, each 1H: 0: 112 in position 6); 2.47 And 2.59 (2 (1 (1, > 16 and 10 and 1) = 16 and 4, each 111: CH2 is at position 14): 2.96 (wide d, J = 10, 1H: OH at position 13); 3.66 (s 3H: OCH3); 3.79 (d, J = 6, 1H: Η is in position 3); 3.95 (wide s, 111: 〇11 in position 10); 4.30 and 4.49 (2 (1, 1 = 9, 111 for each) : 〇112. At position 2 0); 4.57 (mt, 1Η: Η at position 13); 4.98 (dd, J = 12 and 6, 1H: Η at position 7); 5.04 (dd, J = 10 and 3, 1H: Η in position 5); 5.42 -24- Applicable to the standard of the paper method (CNS) A4 specification (2 丨 0 × 297mm) Calling -------- Order ------ 1 ^ ---- (Please read the notes on the back before filling out this page) 5. Description of the invention (22 ) (W, s, 1H: H in position 10); 5.61 (d, J = 6, 1H: Η in position 2); 7.59 (t, J = 7.5, 2Η: OCOC6H5 in position); 7.63 (t, J = 7.5, 1Η: 〇COC6H5 Η in the opposite position); 8.00 (d, J = 7.5, 2H: 〇COC6H5 Η in the adjacent position). Printed by the Consumer Goods Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the note on the back first) Matters need to be refilled on this page} 2 α-Yeastoxy-5 Lu, 20-Epoxy-4.α -Methoxy-9-oxy-1 Lu, 7 / ?, 10 / ?, 13α -Tetrahydroxy- 11-Taxene can be prepared as follows: 7.5 ml of triethylamine · hydrofluoric acid complex at a temperature in the region of 20 ° C by adding 3 3 8 mg 2 α-benzylpyridyl-1 0,1 〇 /? _ Dihydroxy · 70,000, 13α · bis (triethylsilyloxy) -5 / ?, 2 0-epoxy-4α-methoxy-9-oxy-ll_ taxane in 5 ml three The reaction mixture of "Pyridoxane-zun" reaction mixture was stirred at a temperature of 20 eC for 2 hours and then 50 ml of digas methane and 50 ml of a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated after settling, washed with 50 ml of a saturated sodium gaseous aqueous solution twice and then dehydrated in sulfuric acid. After filtration and concentration under reduced pressure (2.7 kPa) at 4 ° C to dryness, 420 mg of product was obtained, which was chromatographed in 60 g of precious stones (0.063- 0.2 mm), and lysed with a mixture of two-gas solution / methanol (95: 5, volume ratio), and collected 10 ml of fractions. The fractions containing only the desired product were concentrated and under reduced pressure (2.7 kPa) Concentrated to dryness at 4 ° C. Thus, 184 mg of 2α-octyloxy-5 Lu, 20-epoxy-4α-methoxy-9 · oxy-1 Lu, 70,000, -4 were obtained as a white foam. The physical characteristics of quinol-1 1 -taxene are as follows:-proton NMR spectrum (400 MHz; CDC13; at ppm; the coupling constant j at Hz); 1.05 (s, 3H: CH3); 1'10 (s, 3H: CH3); 1.72 (s 3H: CH3); 1.99 and from 2.40 to 2.55 (2mts, each 1H: CH2 at position -25- This paper size applies to China National Standards (CNS) to specifications (210X297) (%) A7 -_____ B7_ V. Description of the invention (23) " '^ ———— 6); 2.09 (3,311 < only 3); 2.48 and 2..69 (24 (1, 1 = 16 and 10 and 1) = 16 and 4, each 1H: CH2 is at position 14); 3.15 (Wd, J = ll > 1H: 0H at Position 13); 3.65 (s, 3H: 〇CH3); 3.74 (d, J = 6, 1H: Η is in position 3); 3.78 (dd, J = 12 and 6, 1Η: Η is in position 7); 4.13 ( S, 1Η: 〇Η in position 10); 4.31 and 4.45 (21 > 9.5, 111 .: (: 112 in position 20); 454 (rat, 1H: Η in position 13); 5.00 (dd, J = 10 and 3, 1H: Η is in position 5); 5.27 (Guang s, 1Η: Η is in position 10); 5.61 (d, J = 6, 1Η: Η is in position 2); 7.48 (t, J = 7.5, 2Η : OCOC6H5 Η in the intermediate position); 7 62 (t > 7.5, 1H: OCOC6H5 Η in the opposite position); 8.03 (d, J = 7.5, 2H: 〇COC6H5 Η in the adjacent position). 2 λ-卞 fermentoxy -1 / ?, 10 Lu-di-unradical_7 Lu, 13 β-bis (triethylsilyloxy) -5A, 20-epoxy-4 α-methoxy-9-oxy-U-violet Sugizu can be prepared in the following way: Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first and then fill in this page) 2.22 ml of 1 equivalent concentration of phenyl lithium in tetrahydrofuran At a temperature in the range of -78 ° C, 940 mg of 1 Lu, 2α-carbonyldioxy-7 points, 13α-bis (triethylsilyloxy) -5 / ?, 20-epoxy-4 α- Methoxy-10 /?-Methoxy B brewing group -9-- solution of 45 ml of anhydrous tetrahydro-thiopyran-oxy -11- yew squeak in Xi. The reaction solution was dialed off at a temperature in the region of -78 C for 2 hours and 30 minutes, and then 20 ml of a saturated aqueous solution of ammonium vapor was added. At a temperature of 20 ° C, 50 ml of water and 100 ml of ethyl acetate were added. The organic layer was separated after settling, and was dehydrated twice with 50 ml of a saturated sodium gaseous aqueous solution and then with magnesium sulfate. It was filtered and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa) to obtain 1.2 mg of the product, which was chromatographically contained in a 100-gram column of 3 cm diameter stone syrup by chromatography. (0.063-0.2 cm), purified with ethyl acetate-26- This paper is scaled to the Chinese national standard (cns) from the specifications (2ωχ29? Mm). A7 B7 printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Note (24) Ester / cyclohexane (15:85 'volume ratio) mixed solution dissolution' Collect 10 ml of fractions. The differentiation containing only the desired product was concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 7 3 4 mg of 2 α-benzylacetoxy-1β, 10/3 · dihydroxy-7々, 13 bis (triethylsilyloxy) -5 lu, 20-epoxy-4α were obtained as a white foam. -Methoxy-9 · oxy-11-taxane, its physical characteristics are as follows: ^-Proton NMR spectrum (400 MHz; CDC13; β at ppm; coupling constant J at Hz); 0_55 (mt, 6H: Ethyl CH2); 0.70 (q, J = 7.5, 6H: ethyl CH2), 0.93 (t, J = 7.5, 9H: ethyl CH3); 1.05 (t, J = 7.5, 9H: ethyl CH3) ; 1_09 (s, 3H: CH3). ^ 1.14 (s, 3H: CH3); 1.55 (s, 111: 〇 only in position 1); 1.71 (5,31!: (: ^ 13); 2.02 and 2.33 ( 211 ^, each 1? 1: (31'12 in position 6); 2.07 (5, 31 !: (: 113); 2.12 and 2.74 (24 (1, J = 15 and 9Hz and J = 15 and 7.5, each 1H: CH2 is in position 1 4); 3.43 (s, 3H: OCH3); 3.47 (d, J = 7, 1H: H is in position 3); 3.85 (dd, J = ll and 6, 111: 117); 4.17 And 4.29 (2 (1,) = 8.5, each 111 :(: 11220); 4.27 (d, J = 2, 1H: OH in position 1 0); 4.95 (mt, 1H: H in position 1 3); 5_00 (dd, J = 10 and 3, 1H: H is in position 5); 5.14 (d, J = 2, 1H: H is in position 1 0); 5.59 (d, J = 7, 1H: H is in position 2); 7.45 (t , J = 7.5, 2H: OCOC6H5 H is in the middle position); 7.57 (t, J = 7.5, 1H: OCOC6H5 H is in the opposite position); 8.07 (d, J = 7.5, 2H: OCOC6H5 H is in the adjacent position)., 2α -Carbodioxy-7 Lu, Γ3 α -Bis (triethylsilyloxy) _5 points, 20 -Epoxy_4α -Methoxy-10yS -Methoxyacetoxy_9 -Oxygen-11 -Yew tree can be prepared in the following way: 0.3 grams of 4 angstrom molecular sieves, 12 milliliters of methyl bromide, and 90. milligrams of hydrogenated steel at 20 27-b paper size applicable to China National Standard (CNS) A4 specifications (210 × 297 mm) ) --------------- Order ------ rt. (Please read the notes on the back before filling out this page) Yin Chang, Shellfish Consumer Cooperative of Central Procurement Bureau, Ministry of Economic Affairs A7 __; ______B7_ V. Description of the invention (51) At a temperature in the region of 25 ° C and under argon pressure, 51 mg of 1 point, 2α_carbonyldioxy-7 / ?, 13α-bis (triethylsilyloxy) are added. A solution of -5 ', 20-epoxy-4 α-hydroxy-10 / 5 -methoxyethoxyl-9-9-oxy-η-taxene in 6 ml of dimethylformamide. The reaction medium was stirred at a temperature of 2 ° C for 3 hours. 10 ml of a saturated ammonium chloride aqueous solution and 30 ml of digas methane were added. After the sedimentation occurred, the organic layer was separated and saturated twice with 10 ml The gasified aqueous sodium solution was washed and then dehydrated in magnesium sulfate. It was filtered and concentrated to dryness at 4 ° C under reduced pressure (2.7 kPa) to give 7 1 5 mg of the product by chromatography within 50 g. Purified from silica (〇063_ 0.2 mm) contained in a 1 cm diameter column, dissolved in a mixed solution of ethyl acetate y cyclohexane (25:75, volume ratio), and collected 10 ml of the separation solution. The differentiation of the product was concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus 494 mg of 1-naphthalene, 2α-carbonyldioxy-7 lu, 13α-bis (tris) were obtained as a white foam. Ethylsilyloxy) -5々, 20 -epoxy-4α_methoxy-10y3 -methoxyethoxy-9-oxy-1 1 -taxene, its physical characteristics are as follows:-proton NMR spectrum (400 MHz; CDC13; β at ppm; coupling constant J at Hz); 0_60 (q, J = 7_5, 6H: ethyl CH2); 0.68 (q, J = 7.5, 6H: ethyl CH2); 0.92 ( t, J = 7.5, 9H: ethyl CH3); 1.03 (t, J = 7.5, 9H: ethyl CH3); 1.19 (s, 3H: CH3); 1.23 (s, 3H: CH3); 1.44 (3, 11!: 〇11 in position 1); 1.71 (5,311: (: 113); 1.99 and 2.47 (21 ^, each output: (: 112 in position 6); 2.15 (3,311: <:113); 2.32 and 2.93 (2dd, J = 15 and 9 and J = 15 and 6.5, each 1H: CH2 at position 14); 2.89 (d, J = 5, 1H: H at position 3); 3.45 and 3.51 (2s, each 3H: OCH3 ); 4 · 10 (dd, J = 10.5 and 7, 1H: H is at position 7); 4.17 (Pug 28-28- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)) (Please (Read the notes on the back before filling out this page)

A7 B7 Five 'invention description (26) AB, J = 16, 2H: 0C0CH20); 441 (d, J = 5, 1H: Η is in position 2); 4 43 and 4.79 (2d, J = 10, 1H each : CH2 is at position 20); 4.93 ㈣, 1H: Η is at position 1 3); 5,10 (Gd, J = i〇, 1Η: Η is at position 5); 6.51 (s, 1H: Η is at position 1 〇 ). Example 2 Printed by the Shellfish Consumer Cooperative of the Central Samples Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

, 1T 15¾ g powder of 4 angstrom molecular sieves and 27 mg sodium hydride 18 mg 2 «-Methoxy_ly ?, 10 Lu-dihydroxy_5 Lu, 20-epoxy-4 α-epoxy -9-oxy-7 /?-Trifluoroethanesulfonyloxy · η-taxane-13 α-yl (2R, 3S) -3-third butoxycarbonylamino_2_hydroxy_3 A solution of phenylpropionate in 233 microliters of acetonitrile and 23 microliters of tetrahydrolan. Reaction medium at 75. 〇 Keep stirring at the temperature in the zone for 3 hours, and then add 15 ml of digas methane and 15 ml of a saturated sodium vaporized aqueous solution at a temperature of 20 ° C. After sedimentation, the organic layer was separated, washed twice with 10 ml of saturated gasified molten steel, and then dehydrated in magnesium sulfate, filtered, and concentrated under reduced pressure (2.7kpa) at 40 ° C. To dry up. 22 mg of the product was obtained, which was purified by preparative chromatography on a silica plate of 0.25 mm thickness and eluted with a mixed solution of dioxane / methanol (95: 5, volume ratio). Thus was obtained 10 mg of 2α-benzyloxy-fluorene as a white foam, 10 lu-diacryl-5々, 20-epoxyethoxy-7々, 8-methylend-19-曱 -9-oxy-11-taxane · 13 α _ (3S) -3-Second-butoxylanylamino-2-lightyl-3-phenylpropionate, its physical characteristics The system is as follows: '-Proton NMR spectrum (400 MHz; CDC13; β at ppm; coupling constant! At Hz); 1.21 (s, 3H: CH3); 1.28 (s, 3H: CH3); 丄 37 (s 9H: C (CH3) 3); 1.35 (mt, 1H ·· H7) ·, 1.47 (t, J = 7, 3H: -29- This paper size applies to China National String (CNS) A4 specification (2 丨 OX29 " 7 (Mm) A7 B7 printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. The CH3 of invention description (27) is in position 4); 1.72 (s, 1H: 0H is in position 1); 1.84 and 2.32 (t and dd, J = 6 and J = 10 and 6, respectively 1H: CH2 is at position 19); 1.89 (s 3H: CH3); 2.03 and 2.22 (dt and Guang d, respectively J = 16 and 4 and J = 16, 1H each: CH2 at position 6); 2.20 and 2_90 (dd and guang dd, respectively J = i6 and 9, each 1H: CH2 at position 14); 3.22 (unresolved component, 1H: OH at position 2 ') ; 3.47 And 3.68 (211 ^, each 111: (: 2115 ^ (: 112 in position 4); 3.65 (1) = 7, 11! .1 in position 3); 4.02 and 4.39 (21) = 9, each 111: { : 112 in position 20); 4.26 (wide s, 1H: OH in position 1 0); 4.61 (mt, 1H: Η in position 2); 4.87 (mt, 1H: Η in position 5); 4.95 (wide s ， 1H: Η is in position 10); 5.33 (Guang d,】 = 1 standing 1Η: Η is in position 3_); 5.42 (d, J = 10, 1H: C0NH); 5.67 (d, J = 7, 1H: Η At position 2); 6.28 (Guang t, J = 9, 1H: Η at position 13); from 7.30 to 7_45 (mt, 5H: aromatic Η at position 3 '); 7.49 (t, J = 7.5, 2Η: OCOC6H5 is in the intermediate position); 7.60 (t, J = 7_5, 1H: OCOC6H5 Η is in the opposite position); 8.11 (d, J = 7.5, 2H: OCOC6H5 Η is in the adjacent position). Methoxy-l々, i〇々-dihydroxy · 5 / ?, 20-epoxy-4α-ethoxy-9-oxy-7々-trifluoromethanesulfonyloxy_ιι · taxane The 13α-yl (2R, 3S) -3-second butoxyepiaminoamino-2-triyl-3-phenylpropionate can be prepared in the following manner: 66 mg of 2α-fluorenyloxy- 10,10 Lu-dihydroxy-5 Lu, 20-epoxy-4 〇 ^ ethoxy-9.-oxy-7 / 3-trifluoromethanesulfonyloxy_1butaxene_13 £ ^- (2R, 4S, 5R) -3-Third-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-hydrazone丨. 5 ml ο · 〖Equivalent concentration solution of hydrogenated gas in ethanol solution at 0. (: Keep stirring for 19 hours at the temperature of the area. Reaction -30- This paper size applies to the Chinese national standard (CNS > A4 size (210X297 mm)) ---------- "Raid-- ί Please read the notes on the back before filling out this page),? Τ A7

V. Description of the invention (28) The mixed solution was concentrated to dryness under reduced pressure (2.7kPa) at 20 ° C. 82 mg of product was obtained. The product was purified by preparative chromatography in a 0.25 mm thick silica plate. Two gas sintered / methanol (95: 5, volume ratio) mixed solution was eluted, thus obtaining 20 mg of 2α-fluorenyloxy-1β, ΐ〇; 9-dihydroxy-5nitro, 20-cyclo Oxy-4α -ethoxy-9 -oxy-7 / 5-trifluoromethanesulfonyloxy-11-taxane-13 «-yl (2R, 3S) -3-third butoxycarbonylamino The physical characteristics of 2-hydroxy-3-phenylpropionate are as follows:-Proton NMR spectrum (600MHz; CDC13; at ppm; coupling constant J at Hz): 1.13 (s, 3H: CH3); 1.25 ( s, 3H: CH3); 1.40 (s, 9H .: Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) C (CH3) 3); 1.47 (t, J = 7, 3H: CH3 of ς ^ 5 is at position 4); 1.58 (s, 1H: OH is at position 1); 1.90 and 2.25 (mt and dd, respectively J = i6 and 9, each 1H: CH2 at position 14 ); 1.92 (s, 3H: CH3); 1.94 (s, 3H: CH3); 2.40 and 2.70 (2mts, each 1H: CH2 in position 6); 3.18 (wide s, 1H: OH is at position 2,); 3.43 (d, J = 6.5, 1H: H is at position 3); 3,75 and 3.82 (2mts, each 1H: C2H5 CH2 is at position 4) ); 4.05 (wide, 1H: OH at position 10); 4.28 and 4.46 (2d, J = 9, each 1H: CH2 at position 20); 4.63 (mt, 1H: H at position 2 ·); 4.92 (dd , J = ll and 7, ih: H is at position 7); 5.03 (dd, J = 10 and 2, 1H: H is at position 5); 5.32 1H: H is at position 3 '); 5.33 (wide s, 1H: H at position 10); 5.45 (d, J = 10, 1H: CONH); 5.65 (d, J = 6.5, 1H: H at position 2); 6 2〇

(Guang T, J = 9, 1H: H is at position 13); from 7.30 to 7.55 (mt, 5H: Aromatic H at position 3_); 7.49 (t, J = 7_5, 2H: OCOC6H5 H at position); 7 61 (t J = 7.5 1H: OCOC6H5 Η is in the opposite position); 8.02 (d, J = 7.5, 2H: OCOC6H5 H is in the adjacent position). -31-This paper size uses the Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) " — A7 B7 Printed by the Male Workers Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (4) 2 «-芊Oxygen-1 Lu, ίο? -Dihydroxy_5, 2_epoxy_4 < 1? _Ethoxy-9-oxy-7 /?-Trifluoromethane oxo-1 1 Taxus Alkenyl 13 α- (2R 4S, 3) -tertiary butoxycarbonyl_2_ (4_methoxyphenyl) _4 • phenylpyridine-5-carboxylic acid ester can be prepared according to one of the following formulas : 60 mg of (2R, 4S, 5R) -3-third butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-humazidine-5-carboxylic acid , 42 mg of dicyclohexylcarbonyldiimide and 5 mg of 4- (dimethylamino) pyridine were continuously added at a temperature in the 20 eC region to 90 mg of 2α-benzyloxy-5 cold, 20-epoxy -4α -ethoxy_9_oxy-7cold-trifluorosulfonylsulfonyloxyl 1 RUB, 0 / g, 1S α -trihydroxy_u_taxane, dissolved in 4 ml of anhydrous ethyl acetate Then, the reaction mixture was stirred under argon pressure at a temperature in the region of 20 ° C for 6 hours. 30 ml of ethyl acetate and 20 ml of saturated gasification were added. After the sedimentation occurred, the layers were separated, washed twice with 20 ml of water, and then dehydrated in magnesium sulfate, filtered and rolled to dryness at 40 ° C under reduced pressure (2.7 kPa). 140 mg of the product was obtained, and the product was purified by chromatography in 30 g of a column containing 1 cm diameter; Xi Xi Shi (0.063-0.2 mm), and cyclohexyl acetate / ethyl acetate (70 : 30, volume ratio) The mixed solution was eluted, and 8 ml of the separation solution was collected. The differentiation containing only the desired product was concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° F. Thus, 110 mg of 2α-benzyloxy-1々, 10 / J-diazonyl-5,20-epoxy-4α-ethoxy-9-oxy-70000-trifluoromethyl was obtained as a white foam. Benzyloxy · ιι · Taxane-13λτ -yl (2R, 4S, 5R) -3-Third-butoxylanyl-2- (4-methoxyphenyl) -4-phenyl-1 , 3-Hemazolidine-5 -carboxylic acid ester, its physical characteristics are as follows:-Proton NMR spectrum (400MHz; CDC13; "in ppm; (CNS) A4 specification (2! 0X297 mm) [Please read the precautions on the back before filling this page) Order the Central Government Standards Bureau of the Ministry of Economic Affairs to eliminate the stamp of the cooperative A7 _____B7____ 5. Description of the invention (30)

Hz): 1.10 (s, 15H: C (CH3) 3-CH3 and C2H5 tCH3 in position 4); 1.19 (s, 3H: CH3); 1.51 (s, 1H: OH in position 1); 1.64 (s, 311 : 0: 113); 1.85 (3,311 :(: 113); from 2.25 to 2.40 and 2.66 (21 ^, each 1H: CH2 is at position 6); from 2.25 to 2.40 and 2.88 (mt and dd, respectively J = 16 and 8, each 1H: CH2 at position 14); 3,35 (d, J = 6.5, 1H: Η at position 3); 3.52 and 3_62 (2mts, each 1 各: CH2 of C2H5 at position 4); 3 , 84 (s, 3H: ArOCH3); 4.01 (d, J = 1, 1H: OH at position 10); 4, 20 and 4.34 (2 (1, 1 = 9, each 111: 0 ^ at position 20); 4.64 ((1,1 = 4, 1H: Η is in position 2_); 4.85 (dd, -J = 11.5 and 6_5, 1H: Η is in position 7); 4.92 (wide d, J = 10.5 '1Η: Η is in position 5); 5.26 (d, J = 1, 1Η: Η is at position 10); 5.55 (dispersing unresolved components at position 3 ′); 5_59 (d, J = 6.5, 1H: Η is at position 2) 5.91 (mt, 1H: Η is at position 13); 6.40 (dispersing unresolved components, η is at position 5 ·); 6.94 (d, J = 8.5, 2H: H is at the Zheng position related to OCH3); From 7.30 to 7.50 (mt, 9H: aromatic Η is in position 3 ·, Η is in a position related to 0CH3 and C〇C6H5 Η in the middle position); 7_63 (t, J = 7.5, 1H: 0C0C6H5 Η in the opposite position); 7.95 (d, J = 7_5, 2H: OCOC6H5 邻 in the adjacent position). 2α-芊 醯 oxy- 5; 5,20-epoxy_4〇 < -ethoxy_9_oxy-7 /? _ Trifluoromethyl donkeyoxy-1 / 5, 10/5, 13π-tricyclic radical i Sugimoto system was prepared as follows: 200 microliters of trifluorophosphonium sulfonic anhydride was added at a temperature in the region of 0 ° C by adding 260 mg of 2 α-Zinoxy-5 Lu, 20-Epoxy-4 α- Ethoxy_9_Oxygen-'1 Lu 7 Na, 10 Lu, 13 α-tetrahydroxy-11-taxane in 10 ml of digas methane and 145 μl ** of the disease. The mixed solution is disturbed at the temperature * degree in the 0 C area -33- This paper size is applicable to the Chinese National Standard (CNS) Α4 size (210X297 mm)-(Please read the precautions on the back before filling this page)

Ti, · ιτ Printed by the Central Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperatives A7 _____B7 V. Description of the invention (31) Mix 45 minutes ’and then add 15 ml of digas methane and 10 ml of water. After the sedimentation occurred, the organic layer was separated 'washed twice with 10 ml of a saturated sodium bicarbonate aqueous solution', and then dehydrated in osmium sulfate, filtered and concentrated to dryness at 20 C under reduced pressure (2.7 kPa). 3.08 mg of the product was obtained, which was purified by chromatography in 60 g of silica (0 6302 mm) contained in a 1 cm diameter column. 'Ethyl acetate / cyclohexane (40: 60, volume ratio) Dissolve the mixed solution and collect 10 ml of the differentiation solution 6. The separation containing only the desired product is concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 90 mg of 2 λ + Linoxy-5 / 5, 2Ό-epoxy-4 α-ethoxy_1 Lu, ιο, 13 α-trihydroxy-9-oxy-7 Lu was obtained as a white foam. -Lan · methanesulfonyloxy] ^ taxene, its physical characteristics are as follows:-Proton NMR spectrum (300MHz; CDC13; β at ppm; coupling constant j at Hz): 1.07 (s, 3H: CH3) ; 1.12 (s, 3H: CH3); 1.47 (t, J = 7, 3H: CH3 from C2H5 is in position 4); 1.87 (s, 3H: CH3); 2.05 (s, 1H: OH is in position 1); 2.15 (s, 3H: CH3); 2.38 and 2.75 (2mts, each 111: (1; 112 in position 6); 2.49 and 2.65 (2 (1 < 1, 1 = 16 and 9 and) = 16 and 3 5, 1H each: CH2 at position 14); 2.89 (d, J = 10, 1H: 0H at position 13); 3.72 (d, J = 6.5, 1H: H at position 3); from 3.80 to 3.95 (mt, 2H: CH2 from C2H5 is at position 4); 3.97 (d, J = 1, 1H: 〇H is at position 10); 4.30 and 4.48 (2 (!,) = 9, each 汨: (: 112 At position 20); 4.57 (W1, J = 10, · 1Η: H at position 1 3); from 4.95 to 5.15 (mt, 2H: H at position 5 and Η at position 7); 5.42 (d, J = l, 1Η: Η is in position 10); 5 63 ⑷ J = 6.5, 1Η: Η is in position 2) ; 7.48 (t, J = 7.5, 2Η: 〇C〇C6H5 Η in the middle position); 7.63 (t, J = 7.5, 1Η: OCOC6H5 Η in the opposite position); 〇〇 (d, -34- this paper size Applicable to Chinese national standards (CNS > A4 specification (210 X297 mm) " '--y ^-(Please read the notes on the back before filling out this page) * • 11 A7 __B7______ V. Description of the invention (32) J = 7.5, 2H: OCOC6H5 Η is in the adjacent position) 2α -benzyloxy-5々, 20-epoxy-4α -ethoxy-9-oxy_1 /? 7 points, 10/3, 13α- Tetrahydroxy-11-taxane can be prepared in the following way: 10 ml of triethylamine-hydrofluoric acid complex is added at a temperature in the region of 20 ° C by adding 524 mg of 2α-fluorenyl-5 /? , 20-epoxy-4α-ethoxy_1) 5-hydroxy-9-oxy-7lu, 10 / ?, 13α-tris (triethylsilyloxy) -li_taxane in 8 ml di Gas methane solution. The reaction mixture was stirred at a temperature in the range of 20 ° C for 7 hours, and then 100 ml of dioxane and 200 ml of a saturated aqueous sodium hydrogen carbonate solution were added. After sedimentation, the organic layer was separated, washed twice with 50 ml of a saturated gasified aqueous A solution, then dehydrated in magnesium sulfate, filtered, and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). Thus, 260 mg of white foam-like 2 «-_ ye brewyloxy-5yS, 20-epoxy-4α-ethoxy-9-oxyl-1, 7々, 10/9, 13〇?- Tetrahydroxy-11-yew, its physical characteristics are as follows:-Proton NMR spectrum (400MHz; CDC13; β at ppm; coupling constant J at Hz): 1.06 (s, 3H: CH3); 1.12 (s, 3H : CH3); 1.46 (t, J = 7, printed by the Consumers ’Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the back of the page first, and pay attention to this page before filling out this page) 3H: CH2 of C2H5 is in position 4); 1.72 (s , 3H: CH3); 1.99 and 2.50 (2mts, each 1H: CH2 in position 6); 2,04 (s, 1H: OH in position 1); 2.10 (s, 3H: CH3); from 2.45 to 2_55 (mt , 1H: OH at position 7); 2.50 and 2.65 (mt and dd, respectively J = 16 and 3.5, each 1H: CH2 at position 14); 3.06 (d, J = ll, 1H: OH at position 13); 3.70 (d, J = 6.5, 1H: H is in position 3); 3.84 (mt, 1H: H is in position 7); 3.89 and 3.96 (2mts, each 1H: C2H5 CH2 is in position 4); 4.15 (Wide, 1H: OH is at position 10); 4_31 and 4.44 (2d, J = 9Hz, each 1H: CH2 is at position 20); -35- This paper size applies Chinese national standards CNS) A4 specification (210X297 mm) ~: --- Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 _B7_ V. Description of the invention (33) 4.54 (Guang t, J = 10, 1H: H13); 4.93 (dd , J = 10 and 3.5, 1H: Η is in position 5); 5.28 (s, 1Η: Η is in position 10); 5.63 (d, J = 6.5, 1Η: H2); 7_48 (t, J = 7.5, 2H: OCOC6H5 Η in the intermediate position); 7.61 (t, J = 7.5, 1H: 〇COC6H5 对 in the opposite position); 8.02 (d, J = 7.5, 2H: OCOC6H5 Η in the adjacent position) 〇2 «-benzyloxy- 5 / ?, 20-epoxy-4 «-ethoxy-1々-hydroxy-9-oxy · 7 Lu, 10/9, 13 ο; -tris (triethylsilyloxy) _Π · taxus Ethylene can be prepared according to one of the following methods: 1) 320 microliters of a 1 molar solution of phenyl lithium in tetrahydrofuran at -78. 〇 After the temperature in the region is added, 253, gram 1 point, 2 «-· condensed dioxy_5 / ?, 20-epoxy-4 ethoxy-9-oxy-7々, 10 Lu, 13α -Tris (triethylsilyloxy) _ 11-Taxus solution in 1 3 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at a temperature in the range of -78 ° C for 1 hour and 30 minutes, and then 10 mL of a saturated aqueous solution of ammonium vapor was added. At a temperature in the region of 20 ° C, 10 ml of water and 50 ml of ethyl acetate were added. The organic layer was separated after settling, washed twice with 20 ml of a saturated sodium gaseous aqueous solution, then dehydrated in magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) at 40 Torr. 500 mg of product was obtained. The product was purified by chromatography in 50 g of dream stone (0.063-0.2 mm) contained in a 3 cm diameter column. Ethyl acetate / cyclohexane (15:85 'volume ratio) ) The mixed solution was eluted, and 10 ml of a fractionation solution was collected. The differentiation containing only the desired product was concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° F. Thus, 260 mg of -fluorenyloxy-5,20-epoxy-4 α-ethoxy-1 /?-Acryl-9-oxy · 7/5, ιmol, 3α-triol were obtained as a white foam. (Triethylsiloxo) -11-Yew tree, its physical characteristics are as follows: -36- This paper size is applicable to China National Standard (CNS) Α4 size (210X297 mm) ~ --- (please first Please read the notes on the back of the page and fill in this page) -1 ^ 裟. 、 1Τ Α7 Β7 V. Description of the invention (34)-Proton NMR spectrum (400MHz; CDC13; at ppm; coupling constant J at Hz): from 0.55 to 0.75 (mt, 18H: CH2 of C2H5); from 0.90 to 1.10 (mt, 27H: C2H5tCH3); 1.15 (s, 3H: CH3); 1.22 (s, 3H: CH3); 1.38 (t, J = 7, 3H: C2H5 (: 113 in position 4); 1.50 (s, 1H: OH in position 1); 1.65 (s, 3H: CH3); 2.00 and 2.39 (2mts, each 1H: CH2 in position 6); 2.02 ( (s, 3H: CH3); 2.05 and 2.85 (2dd, and 9 and J = i6 and 8. · 5, respectively 1H ·· CH2 is at position 14); 3.43 (d, J = 6.5, 1H: H3); 3.44 and 3.90 (2mt, each 1H: CH2 of C2H5 in position 4); 3.91 (1! ^, 111: 11 in position 7); 4.20 and 4.30 (2 £ 1, BU 9, each 1H: CH2 in position 20) 4.93 (Station, J = 10 and 3_5, 1H: Η is in position 5); 4.97 (Guang t, J = 9, 1Η: Η is in position 13); 5.17 (s, 1Η: Η is in position 10); 5.60 ( d, J = 6.5, 1Η: Η2); 7.45 (t, J = 7.5, 2Η: 〇COC6H5 Η in the middle position); 7.57 (t, J = 7.5 1H: OCOC6H5 Η in the opposite position); 8.06 (d, J = 7.5, 2H: OCOC6H5 H is in the adjacent position) 1/9, 2α · carbonyldioxy-5 points, 20-epoxy-4 α-ethoxy-9 -oxy-7 / 5, 10 / M3 from -Tris (triethylsilyloxy) · ι! • Taxane can be prepared in the following way: Printed by the Shellfish Consumer Cooperative of the Central Rubbing Bureau of the Ministry of Economic Affairs 〇_3 of 4 angstrom molecular sieves, 4.2 ml of ethyl iodide and 68 mg of 80% sodium hydride at a temperature in the region of 20 ° C and under argon pressure by adding 353 mg of 1 Lu, 2 carbonyldioxy-5 Lu 20-epoxy-4 α-hydroxy-9-oxy-7 / ?, 10 lu, 13 α-tris (triethylsilyloxy) -11 · taxene in 21 ml of dimethylformamide . The reaction mixture was stirred at a temperature in the region of 20 ° C for 1 hour. After adding 10 ml of saturated gasified ammonium hydroxide aqueous solution and 30 ml of digas methane β organic layer, they were separated after settling, and 2 times of 10 ml of saturated gasified sodium hydroxide aqueous solution was used. -37- This paper applies Chinese national standard (CNS) Α4 Specification (2ΙΟ × 297 公 楚) Printed by A7 B7, Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the Invention (35) Wash, then dehydrate in magnesium sulfate, filter and decompress (2.7kPa) at 40 ° C Concentrated to dryness. 500 mg of product was obtained, which was purified by chromatography in 25 g of silica (0 063_0 2 mm) contained in a one-cm diameter column with ethyl acetate / cyclohexane (10:90, volume Ratio), the mixed solution was lysed, and 10 ml of a fractionation solution was collected. The differentiation containing only the desired product was concentrated and concentrated to dryness at 40 9C under reduced pressure (2.7 kPa). As a result, 253 mg of 1 cold, 2-cardiocarbonyldioxy-5 lu, 20-fluorenoxy-4 α-ethoxy-9-oxy-7 lu, 10 lu, 13 α-tri (three Ethylsilyloxy) -11-taxane, its physical characteristics are as follows:-Proton NMR spectrum (400MHz; CIJC13; d at ppm; coupling constant j at Hz): from 0.55 to 0.75 (mt, 18H: C2H5tCH2 ); From 0.90 to 1.ΐ〇 (mt, 27Η: CH3 of C2H5); 1.17 (s, 3Η: CH3); 1.25 (s, 3Η: CH3); 1.25 (t, J = 7, 3H: CH2 of C2H5) At position 4); 1.68 (s, 3H: CH3); 1.98 and 2.47 (2mts, each 1H: CH2 at position 6); 1.98 (s, 3H: CH3); 2.26 and 3.07 (2dd, J = 16 and 9 and J = 16 and 7, respectively 1H: CH2 is in position 14); 2.87 (d, J = 5Hz, 1H: Η is in position 3); 3.71 and 3.82 (2mts, each 1Η: C2H5iCH2 is in position 4); 4.05 (dd, J = i〇 and 7, 1H: Η is in position 7); 4,39 (d, J = 5, 1H: Η is in position 2); 4.45 and 4.77 (2d, J = 9, each 1Η: CH2 is at position 20); 4.97 (mt, 1Η: Η is at position 13); 5.03 (Gd, J = 10, 1Η: Η is at position 5); 5.15 (s, 1Η: Η is at position 1 0). Ly5, 2a-Chlorodioxy-5 /? , 20-epoxy-4 α-superyl-9-oxy-7々, 10 / ?, i3 'α-tris (triethyl tomb dream entertainment * .oxy) -11-yew association can be according to the following Preparation method: The temperature of 51 mg of imidazole and 50 microliters of triethylsilane in the 20 X region -38- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ --- ---- ---- 11 packs-(Please read the back-notes on the back first and then fill out this page) Order five. Description of the invention (36) Α7 Β7 Add 98 mg under the print and argon pressure of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 7々, 13 α-bis (triethylsilyloxy) -1, 2 α-carbonyldioxy_4α, 10々-dihydroxy_5, 20-epoxy-9 · oxy-1, yew taxane A solution in 1 ml of dimethylformamide. The reaction mixture was stirred at a temperature in the region of 20 ° C for 72 hours. 10 ml of water and 20 ml of ethyl acetate were added. The organic layer was separated after settling, washed twice with 10 ml of a saturated aqueous solution of sodium vaporization, then washed with water in magnesium sulfate, filtered, and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). 190 mg of the product was obtained. The product was purified by preparative chromatography on a 2 mm thick layer and eluted with a cyclohexane / ethyl acetate (75:25, volume ratio) mixture. Thus, 58 mg of 1 lu, 2α-carbonyldioxy, 20-epoxy-4α-hydroxy-9-oxy-7-point, 10 / ?, 13α-tris (triethylsilapoxy) was obtained as a white foam. )]] [! _ Taxane, its physical characteristics are as follows: '-Hikoko NMR spectrum (400MHz; CDC13; ¢ 51 at ppm; fit constant j at Hz): from 0.50 to 0.70 and 0.74 (2mts, 12H And 6H, respectively: CH2 of c2H5); from 0.90 to 1.10 (mt, 27H: CH3 of C2H5); 1.14 (s, 3H: CH3); 1.19 (s, 3H: CH3); 1.63 (s, 3H: CH3); 1.98 ^ 2.50 (2mts, each 1H: CH2 at position 6); 1.98 (s, 3H: CH3); 2.55 and 2.67 (J = 16 and 9 and J = 16 and 3.5, respectively ih: CH2 at Position 14); 3 〇a (s 1H: OH is at position 4); 311 (d, J = 5, 1H: H is at position 3); 4 14 (dd, J = 10 and 7, 1H: H is at position 7); 4.33 (d, J = 5, 1H: H2); 4.54 (restricted AB, J = 9, 2H: CH2 is in position 20); 4.73 (wide d, J = 9, 1H: H is in position 13) ); 4.77 (W, d, J = 10, 1H: H is at position 5); 5.23 (s, 1H: H is at position 1 0). 7 o'clock, 13α · bis (triethylsilyloxy) -1 / 5,2cardiocarbonyldioxy · 4α, ι〇 ^ -39-

(Please read the > i notice on the back before filling in this page)

* 1T

• —----II

ϊ I— II Shellfish consumer cooperation with the Central Bureau of Standards, Ministry of Economic Affairs, Du printed A7 __________ B7 V. Description of the invention (37)-Dijiji 50,000, 2_epoxy-9-oxy-11-taxane IA was prepared as follows: 0.3 g of 4 angstrom molecular sieves and 470 mg of zinc iodide were added at a temperature in the region of 20 τ and under argon pressure by adding 108 mg of 7 8, 13α-bis ( Triethylsilyloxy) 1,2 or -carbonyldioxy_5 / ?, 20-epoxy, 4 α-hydroxy-10 /?-Methoxyethoxyl-9-oxy-11- A solution of taxene in 3.5 ml of methanol <. The reaction mixture was stirred at a temperature in the region of 20 ° C for 72 hours. Add ml of water and 20 ml of ethyl acetate. After sedimentation, the organic layer was separated, washed twice with 10 ml of a saturated aqueous solution of sodium vaporization, and then dehydrated in magnesium sulfate, and then reduced to dryness under reduced pressure (2.7 kPa) at 40T. The milligram of the product was purified by preparative chromatography on a thin layer of 2 mm thick and dissolved in a cyclohexane / ethyl acetate (75:25, volume ratio) mixture. Thus 56 mg of white foam, 13 α-bis (triethylsilyloxy) -1 / ?, 2α-carbonyldioxy-4 ?, 10 /?-Dihydroxy-5 lu, 20-ring The physical characteristics of oxygen-9-oxy-11-taxane are as follows:-Proton NMR spectrum (400MHz; CDC13; at ppm; coupling constant j at Hz): 0.54 and 0.74 (2mts, each 6H: CH2 of C2H5) ); 〇.91 and! 〇3 (2t, J = 7.5 Hz, each 9H: CH3 of C2H5); 1.12 (s, 3H: CH3); 1.20 (s, 3H: CH3); 1.72 (s, 3H: CH3); 1.98 and 2.46 (2mts, each 1H: CH2 at position 6); 2_04 (s, 3H: CH3); 2.55 and 2.67 (2dd) = 16 and 9 and 1 = 16 and 3.5, respectively 111: (1; 112 at position 14) ;); 300001H: 0H is in position 4); 3.14 (d, J = 5, 1H: H is in position 3); 4,07 (d J = 110 and 7, 1H: H is in position 7) ); 4,19 (d, J = 2, 1H: 0h at position 10); 4.33 (d, J = 5, 1H: H at position 2); 4.54 (limiting ab, J = i0-40- This paper size applies to China National Standard (CNS) A4 specification (210X: 297 mm) " ---- -------- ('Pack II (Please read the precautions on the back before filling this page) ) Order A7 B7 V. Description of the invention (38) 2H · · CH2 is at position 20); 4.76 (Guang d, J = 9, 1H: Η is at position 1 3); 4.82 (Guang d, J = 10, 1Η : η in position 5); 5.18 (d, J = 2, 1Η: Η in position 1 0). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 2). 3 grams of 4 angstrom molecular sieves, 1 ml of ethyl iodide, and 34 mg 50% sodium hydride was added at a temperature in the region of 20 ° C and under argon pressure. 200 mg of 2 α _ benzyloxy-1 / ?, 4α-dihydroxy-5 / ?, 20-epoxy-9- Oxygen-7 cold, 10 / ?, ΐ3α-tris (triethylsilyloxy) _U_taxene in 6 ml of dimethylformamide. The reaction mixture was at 20 ° C. (: The temperature in the area was stirred for 1 hour. 10 ml of a saturated aqueous solution of ammonium hydroxide and 30 ml of ethyl acetate were added. After the sedimentation occurred, the organic layer was separated and washed twice with 0 ml of a saturated aqueous solution of sodium gasification. Dehydrated in magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 eC. 32 mg were obtained. The product was chromatographed at 100 g in a 1 cm diameter column. Purified in silica (0.063-0.2 mm), lysed with a mixed solution of ethyl acetate / ring fired (10:90, volume ratio), and collected 10 ml of fractions. The fractions containing only the desired product were concentrated and reduced. Concentrated to dryness at 40 ° C under pressure (2.7kPa) to obtain 3 8 mg of 2 methoxy-4α-ethoxy-5 Lu, 20-epoxy.-1 fluorene. The physical characteristics of -9-oxy-7 / 9, 10yS, 1.3 or-tris (triethylsilyloxy) -11-taxene are exactly the same as those of the product mentioned above. 2α-Benzyloxy-1 / 3,4α-dihydroxy-50,20-epoxy-9-oxy-7 / ?, 10 / ?, 13α · tris (triethylsilyloxy) -11-taxane can be prepared in the following manner : 4.6 g of imidazole and 2.35 g of three Ethylsilane gas at a temperature in the region of 20 ° C and under argon pressure was added 4.2 g of 2 α-fluorenyl-5 Lu, 20-epoxy-9-oxyl 10,000, 4 -41 _ this Paper size applies Chinese National Standard (CNS) A4 is now (21 × 297 mm) A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (39) α, 10/3, 13π-tetrahydroxy- 7 Cold-triethylsilyloxy-11-taxene, prepared according to DG Kingston et al. Tetrahedron Letters. 35, 6839 (1994), in 50 ml of diamidinofluoramide solution. The reaction mixture was at 20 ° (: The temperature in the area was stirred for 72 hours. 30 ml of water and 100 ml of ethyl acetate were added. After the sedimentation occurred, the organic layer was separated, washed twice with 30 ml of a saturated aqueous solution of tritium trioxide, and then sulfuric acid Dehydrated in magnesium, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 12 g of product were obtained, which was chromatographed at 100 g of silica contained in a 3 cm diameter column ( 0.063-0.2 mm), and lysed with a mixed solution of ethyl acetate / cyclohexane (10:90, volume ratio), and collected 20 ml of differentiation liquid The differentiation of the desired product was concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus 3.6 g of 2α-fluorenyloxyl-1, 4α-dihydroxy-5 / were obtained as a white foam. ?, 20-epoxy-9-oxy-7 cold, 10 / ?, 13α-tris (triethylsilyloxy) -11 · taxene, its physical characteristics are as follows: _Proton NMR spectrum (300MHz; CDCl3; (y at ppm; coupling constant J at Hz): 0.57 and from 0.60 to 0.85 (2mts, 6Η and 12Η, respectively, CH2 of C2H5); from 0.90 to 1.10 (mt, 30H: CH3 and CH3 of C2H5); 1.21 (s, 3H: CH3); 1.53 (s, 3H: CH3); 1.63 (s, 1H: OH in position 1); 1.96 (s, 3H: CH3); 1.97 and 2.45 (2mts, each 1H: CH2 in Position 6); 2.32 and 2.60 (2 (1 (1, Bu 16 and 9 and) = 16 and 2.5, respectively: (: 112 in position 14); 3.61 (d, J = 6, 1H: Η in Position 3); 3.80 (W, 1H: ΟΗ is in position 4); 4.05 (dd, J = 11.5 and 6, 1Η: Η is in position 7); 4_23 and 4.27 (limit ΑΒ, J = 9, 2Η: CH2 is in Position 20); 4.64 (Guang d, J = 9, 1H: Η is in position 1 3); 4.71 (dd, J = 10 and 4, 1H: Η is in position 5); -42- Wood paper scale applies to China Home Standard (CNS) Α4 Specification (210X297 mm) {Please read the precautions on the back before filling this page) Pack. Order the revised Chinese manual of Patent Application No. 84111246 (October 88) A7 B7 V. Description of the invention (40) Amendment to print 5.25 (s, 1H: Η is in position 1 〇); 5.54 (d, J = 6, 1H: Η is in position 2); 7.42 (t, J = 7.5, 2Η: OCOC6H5 Η is in the middle position); 7.55 (t, J = 7.5, 1H: OCOC6H5 H is in the opposite position); 8.11 (d, J = 7.5, 2H: OCOC6H5 H is in the adjacent position). 2α-fluorenyloxy-1 Ling-hydroxy_i〇ling-ethoxyl-5 cold, 20-epoxy-4 α · ethoxy-4α-ethoxy-7 / 5, 8- Methyl-9-oxo-11-taxane-13 α-yl- (2R, 3S) -3-third-butoxycarbonylamino-2-hydroxy-4-phenylpropanoic acid can be obtained in the following ways To prepare, add 100 mg of powdered 4A molecular sieve and 390 mg of sodium azide, and add 260 mg of 2α-fluorenyloxy-1zol-hydroxy-ιοβ-ethoxyl-5zol, 20-epoxy -4α-ethoxy-7-point-trifluoromethanesulfonic acid-9-oxo-Π-taxane-13-13 ::-yl- (2R, 3S) -3-third-butoxycarbonylamino _2. A solution of meridyl-4-phenylpropionic acid in 3.4 ml of acetonitrile and 0.340 ml of tetrahydrofuran. The reaction mixture was stirred at about 7 5 ° C for 3 hours. The reaction mixture was then slowly cooled to about 20 ° C and then concentrated to dryness at 40eC under reduced pressure (2.7 kPa). The obtained product was purified by chromatographic analysis. The chromatographic analysis was performed on 100 g of silicide (0.063 to 0.2 mm) using a 70/30 volume mixture of cyclohexane and ethyl acetate in a 1 cm diameter column. Eluent 'and collect 8 ml of pipette solution. The fractions containing only the desired product were pooled and concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). Obtained 13 grams of 2α-elastyloxy-1Hole-Cyclo-1 / 10-Ethyl. White Oxy-5, 20-Epoxy-4α-Ethoxy-7, 8 -Methylene_9_oxo_11-taxane-13-yl- (2R, 3S) -3 -third-butoxycoagulylamino-2 -hydroxy-4_phenylpropionic acid, Its physical characteristics are as follows: Proton NMR spectrum (300 MHz, CDC13 in ppm); from 120 to 43- This paper size is applicable to China National Standards (CNS) A4 specification (210X297 mm) (Please read the notes on the back first # " Write this page) -LI.-Binding and ordering Γ Thread No. 841 1 1246 Chinese Patent Specification Correction Page (October 88) A7 B7 V. Description of Invention (40b) 1Η: Η3 ·); 5.66 (d, J = 7Hz, 1H: H2); 6.05 (mt, 1H: H13); 6.38 (s, 1H: H5 '); 6.91 (d, J = 8.5Hz, 2H: H aromaticity is adjacent to OCH3 ); From 7.30 to 7.50 (mt, 7H: H aromaticity in position 3, and OCOC6H5 H position); 7.41 (d, J = 8.5Hz, 2Η: Η aromaticity in OCH3); 7.85 (t, J = 7.5Hz, 1H: OCOC6H5 H pair position); 7.96 (d, J = 7.5Hz, 2H: oCOC6H5 H ortho position) "A novel paclitaxel of formula (I), where Z represents (II) the group granary, show significant growth inhibitory activity of abnormal cell i, and with medical properties, allowing the treatment of patients with proliferative related disorders of the abnormal cell. Such disorders include a variety of abnormal cell proliferation of tissues and / or organs, malignant or non-malignant, including but not intentionally limited to muscle, bone, and connective tissue, skin, brain, lung, sexual organs, lymph and kidney system, breast and Blood cells, liver 'digestive system, pancreas and thyroid or adrenal glands. Such conditions include dry addiction, solid tumors, ovarian cancer, breast cancer, brain cancer, prostate cancer, colon cancer, gastric cancer, kidney cancer or testicular cancer, pigmented dry skin disease, bile duct tumor, villous adenoma, neuroblastoma, Embryonic carcinosarcoma, malignant granuloma, heteromas, multiple myeloma, chronic lymphocytic leukemia, and acute or chronic granulocytic lymphoma. The paclitaxel of the present invention is particularly useful in the treatment of ovarian tumor β, which can be used to prevent or delay the appearance or recurrence of conditions, or to treat such conditions. Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -Shang-(Please read the -.ii notice on the back > Shan' write this page) Order The dosage form is administered to the patient, preferably by a parenteral route. Parenteral routes include intravenous, intraperitoneal, intramuscular or subcutaneous administration. Intraperitoneal or intravenous administration is particularly preferred. The present invention provides pharmaceutical compositions that have at least one paclitaxel of formula (i) in an amount sufficient for human or veterinary use. These compositions can be prepared according to conventional methods. Use 1 or more in medicine Acceptable adjuvant,

Printed by the staff of the Central Procurement Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (41) Carrier or excipient. Suitable carriers include diluents, sterile aqueous vehicles, and various non-toxic effervescent agents. Preferably, these compositions are in the form of aqueous solutions and suspensions, injections, which may contain emulsifiers, colorants, preservatives or stabilizers. The choice of adjuvant or excipient can be determined by the solubility and chemical properties of the product, the particular method of administration and good pharmaceutical practice; for administration outside the intestine, sterile aqueous or non-aqueous solutions or suspensions can be used. Non-aqueous solutions or suspensions, natural vegetable oils such as olive oil, sesame oil or liquid petroleum, or injectable organic esters such as ethyl oleate can be used. Sterile water drops can include medically acceptable solutions of salts in water. The pH of the aqueous solution suitable for intravenous administration is appropriately adjusted and the solution is made isotonic, for example with a sufficient amount of sodium gas or glucose. The bactericidal action can be performed by heat or by any other means which does not adversely affect the composition. It is to be noted that all products involved in the composition according to the invention must be pure and non-toxic in the amounts used. These compositions may contain at least 0.01% of a therapeutically effective product. The amount of active product in the composition must be such that a suitable dosage can be administered. Preferably, these compositions are prepared so that a single amount of the active product is from about 0.01 to 1000 milligrams for parenteral administration. This medical treatment can be performed in conjunction with other medical treatments, including anti-neoplastic drugs, monoclonal antibodies, immunotherapy or radiation therapy, or biological response modifiers. Such biological response modifiers include, but are not intended to be limited to, lymphokines and cytokines such as interleukins, interferon Θ or TNF. Other chemotherapeutic agents, which can be used to treat disorders caused by abnormal cell colonization, including but not intended to be limited to the appearance of 44 · dagger paper standards applicable to Chinese National Standards (CNS) μ specifications (2 丨 〇 > < 297 mm) ( (Please read the notes on the back before filling out this page)

387885 A7 ------—__ B7 V. Description of the invention (42) Chemical agents, for example, mustards such as nitrogen mustard, cyclophosphamide, amphetamine and amines, alkyl sulfonates such as dimethylsulfonate Succinate, nitrosourea such as urea nitrogen, lomustine, semustine, and streptavidin, diazenes such as dacarbazine, and antimetabolites such as folic acid Analogs, such as methotrexate's pyrimidine analogs such as fluorouracil and thymabine's throat analogs such as hydrothiopurine and thioguanine, natural products such as vinca alkaloids such as vinblastine, vincristine, and Vindesine, epipodophyllotoxins such as etoposide: y: (etoposide) and tenyposide, antibiotics such as actinomycin 0, daunorubicin, Doxorubicin, bleomycin, plicamycin and mitomycin 'enzymes such as B-asparaginase, different isoforms such as cisplatin (cisplatin) ), Substituted urea such as hydroxyurea 'methyl hydrazine derivative such as procarbazine, adrenal cortex Inhibitors such as mitotane and glutamine, hormones and antagonists such as adrenal corticosteroids such as dehydrocortisone, feminine hormones such as caproate and progesterone acetate, methoxylutein acetate Ketoesters and pregnancy esters of acetate, estrus hormones such as diethylstilbestrol and ethinyl estradiol, antiestrus hormones such as tamoxifen and male hormones such as stearyl propionate and fluoxandrol. Dosages for use with taxanes such as the present invention are those that allow preventative treatment or maximum medical response. These agents vary according to the form of application, the particular product selected, and the individual characteristics of the individual to be treated. Generally speaking, the doses are those which are medically effective for treating disorders caused by abnormal cell proliferation. The products according to the present invention can be frequently administered as necessary to obtain the desired medical effect. Some patients can respond quickly to relatively high or low doses, and then need to -45- 'This paper size is suitable for financial and family care (CNS) Α4 ^ (21〇 × 297 public) — ~~~~ Central Standards of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives 387885 a? ______B7 V. Invention Description (^ — Low or zero maintenance dose. Generally speaking, a low dose will be used at the beginning of treatment, and when needed, a stronger dose will be applied until Get the best results. For other patients, a maintenance dose must be administered 1 to 8 times, and preferably 1 to 4 times, depending on the physiological needs of the patient in question. It is also possible that some patients only need 1 to 2 times each In humans, the dosage is usually between 0.01 and 200 mg / kg. For intraperitoneal administration, the dosage will usually be between OjSiOO mg / kg, preferably 0-5 to 50 mg Between 1 and 10 mg / kg and more particularly between 1 and 10 mg / kg. For intravenous administration, the dosage is usually between 0 and 50 mg / kg, preferably between 0.1 and 5 mg / kg. And county is more particularly between! To 2 mg / kg. Of course, to choose the most suitable application The amount, the route of administration, the weight of the patient, the general state and age of health, and all factors that can affect the effectiveness of treatment should be considered. The following examples illustrate the composition according to the invention. Examples are in Example 1 The 40 mg of the product obtained was dissolved in 1 ml of Emulphor EL 620 and 1 ml of ethanol, and the solution was then diluted by adding is ml of physiological saline. The composition was administered by infusion for 1 hour after introduction of physiological solution. (Please read the back -Notes please fill out this page)

, 1T

T k · -46-This paper size is applicable to China National Standard (CNS) A4 (210X297)

Claims (1)

387835 No. 84111246 patent application A8 Chinese patent application scope amendment (October 88) Zhe D8 patent application scope 1. A paclitaxel of the following formula 丨 Bulletin 0 (I) Where: Ra represents a hydroxyl group or an ethoxyl group and Rb represents an argon atom. Z represents a group of the following formula: (Please read the following on the reverse side: 5 £ Matters before filling out this page}. • R R. NH 0 (Π) where Η is printed on the consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Ri represents benzamidine, or a radical of formula R2_〇_C〇_ is an alkyl group having 1 to 8 carbon atoms, and R > 3 represents Phenyl or CT- or N-theyl, and Chi 4 represents an unbranched or branched alkyl group having 1 to 8 carbon atoms or phenyl and Rs represents an unbranched or branched alkyl group having 1 to 8 carbon atoms. 2. Paclitaxel according to item 1 of the applied patent, wherein R a represents antelope or ethyl alcohol and Rb represents hydrogen atom one, z represents a group of formula (π), and Ri represents a benzamidine group or a group. R2_0_C0-, where R2 represents the third butyl group and R3 represents the phenyl group, R4 represents the phenyl group, and Rs represents the number of carbon atoms to 4 carbons, where the ruler 2 represents the T-line. The paper scale is applicable to the Chinese bacterial country (CNS) A4 ^ ( 210X297 ^ '387835 No. 84111246 Patent Application A8 Chinese Patent Application Scope Amendment (October 88) Zhe D8 Application Patent Scope 1. A purple formula like the following Taxol 丨 Bulletin 0 (I) Where: Ra represents a hydroxyl group or an ethoxyl group and Rb represents an argon atom. Z represents a group of the following formula: (Please read the following on the reverse side: 5 £ Matters before filling out this page}. • R R. NH 0 (Π) where Η is printed on the consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Ri represents benzamidine, or a radical of formula R2_〇_C〇_ is an alkyl group having 1 to 8 carbon atoms, and R > 3 represents Phenyl or CT- or N-theyl, and Chi 4 represents an unbranched or branched alkyl group having 1 to 8 carbon atoms or phenyl and Rs represents an unbranched or branched alkyl group having 1 to 8 carbon atoms. 2. Paclitaxel according to item 1 of the applied patent, wherein R a represents antelope or ethyl alcohol and Rb represents hydrogen atom one, z represents a group of formula (π), and Ri represents a benzamidine group or a group. R2_0_C0-, where R2 represents the third butyl group and R3 represents the phenyl group, R4 represents the phenyl group, and Rs represents the number of carbon atoms to 4 carbons, where the ruler 2 represents the T-line. The paper scale is applicable to the Chinese bacterial country (CNS) A4 ^ ( 210X297 ^ '3S7885—, patent application scope A8 B8 C8 D8 4. In < alkyl. : According to the patent, the scope of patents, such as paclitaxel, is a 2-cardiac extension T1 ″ -dihydroxyepoxydi: 1/19 · nor_9-oxy · η_taxane 13 ^- Hydrazone, 'dibutoxycarbonylamino_2.hydroxy_3_phenylpropionate.' No .: According to the patent scope of the first item paclitaxel, which is 2 α 4 ferric oxygen H0 dihydroxy _M, 20_ epoxy · ethoxy "dyne f_19-nor_9 · oxy-η-yew association 3S) 3 the second butyl rolling carbonylamino group 2_hydroxy_3_phenylpropyl Acid ester. A method of preparing a paclitaxel according to item 1 or 2 of the scope of the patent application ', which comprises compound of the formula: (ΙΠ) Central Ministry of Economic Affairs It represents the group of formula (11), and its center and heart are the groups defined by the following formula 1 or 2 of the patent application park or the group of the following formula: Rl, hTR6o «ΛΑ State 0-R, 'where R 丨 and As defined above, and R6 stands for hydrogen atom and R7 stands for ____- 2- This paper size applies to China's Standards (CNS) A4 specification (21〇) < 297 mm) 387885 A8 B8 C8 D8 Patent scope protection The hydroxyl-functional group, or feet 6 and feet 7 together form saturation. 3_Hemazolyl 'R4 and R5 are as defined above. Ra represents ethoxyl or a hydroxyl-protecting group, preferably 2, 2,2-three gas ethoxycarbonyloxy, and Rb represents the nitrogen atom 'as a mechanical metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal scale salt. Treatment' gives the product of the formula: lb D (V) where Z 丨, R_4, R5, Ra, and Rb are as defined above, and when necessary, the protective group carried by Ra is replaced by hydrogen or the hydrogen atom is replaced by the ruler and / or represented by R6 and R7 Protection group. A pharmaceutical composition useful for treating abnormal cell proliferation, comprising at least one paclitaxel according to any one of claims 1 to 4, wherein Z represents a group of formula (II). (Please read the precautions on the back and fill in this form first) Packing. 、 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T and 3T printed sheet ^ Grid (210 > < 297 mm)