CN100540544C

CN100540544C - Taxane intermediate and aziridine analogues semi-synthetic and to the conversion of the pure and mild Docetaxel of Pacific yew

Info

Publication number: CN100540544C
Application number: CNB2005800084129A
Authority: CN
Inventors: 拉吉娜·奈杜
Original assignee: Chatham Biotec Ltd
Current assignee: Chatham Biotec Ltd
Priority date: 2004-02-24
Filing date: 2005-02-24
Publication date: 2009-09-16
Anticipated expiration: 2025-02-24
Also published as: CN1942458A

Abstract

The invention provides the aziridine analogues and the Baccatine III intermediate that are used for partially synthetic taxinane intermediate, Cephalomannine, and this class intermediate and analogue are converted into the method for the pure and mild Docetaxel of Pacific yew.

Description

Taxane intermediate and aziridine analogues semi-synthetic and to the conversion of the pure and mild Docetaxel of Pacific yew

Background of invention

Invention field

The present invention relates to the semi-synthetic of taxane intermediate and aziridine analogues, particularly the aziridine analogues of Cephalomannine (cephalomannine) and Baccatine III intermediate is semi-synthetic, and they are to active antineoplastic agent, i.e. the conversion of the pure and mild Docetaxel of Pacific yew.

DESCRIPTION OF THE PRIOR ART

Semi-synthetic analogue Docetaxel (1, taxotere) (2, it is the most significant anticancer chemotherapy material of discovered in recent years that taxol has turned out to be to isolating diterpene mixture Paclitaxel and from the bark of Pacific yew tree (short leaf Taxus (Taxus brevifolia)).Though Paclitaxel can be from yew tree or semi-synthetic the acquisition, has only back one mode to can be used for forming non-natural Docetaxel at present.This important compound semi-synthetic usually by (2R, 3S) the protected form of the derivative of phenylisoserine side chain and 10-deacetylation baccatin III (also being present in the natural product that relatively enriches in the yew tree) is carried out esterification and finished.

Taxotere (1)

Taxol (2)

In No. the 4th, 814,470, the United States Patent (USP) of Colin, the activity of having reported Docetaxel is significantly greater than Paclitaxel.

Docetaxel and Paclitaxel can be as United States Patent (USP)s the 4th; 924; 011 and 4; 924; prepare from 10-deacetylation baccatin III or Baccatine III described in No. 012 semi-syntheticly; or, prepare by beta-lactam with by the 10-deacetylation baccatin III of due care or the reaction of baccatin III derivative described in No. 315 as United States Patent (USP) the 5th, 175 semi-syntheticly.10-deacetylation baccatin III (10-DAB; 3) can obtain from from the mixture of natural origin extraction, separating with Baccatine III (4); this natural origin for example is needle, stem, bark or the heartwood of numerous Japanese yew class species, and they have following structure:

Though; great majority pay close attention to Docetaxel and the semisynthetic research of Paclitaxel relates to 10-deacetylation baccatin III as starting raw material; but be present in other taxanes in the yew tree; be collected and identify as Cephalomannine (6) and the 9-dihydro-1 3-ethanoyl Baccatine III (9DHB, 5) that is present in the ground hemlock (add and take Ramulus et folium taxi cuspidatae (Taxus Canadensis)).

Cephalomannine (6)

As disclosed (this application is transferred to transferee of the present invention) in No. the 10/695th, 416, U.S. Patent application, Docetaxel and Paclitaxel also can prepare from 9-dihydro-13-acetyl Baccatine III semi-syntheticly.

Though existing many progress in this field are still needed badly and are used to prepare taxane intermediate and are translated into Docetaxel and new the improving one's methods of Paclitaxel.The present invention pays close attention to these demands and other associated advantages is provided.

Summary of the invention

In brief, the present invention relates to the semi-synthetic of new taxane intermediate and aziridine analogues, particularly the aziridine analogues of Cephalomannine and Baccatine III intermediate is semi-synthetic, and they are to active antineoplastic agent, i.e. the conversion of the pure and mild Docetaxel of Pacific yew.

In the first embodiment, the invention provides the method for preparing Taxan, this method may further comprise the steps: (1) is converted into Cephalomannine the taxane intermediate with following structure:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group, and (2) are converted into Paclitaxel or Docetaxel with this taxane intermediate.

In the more specifically embodiment of preceding method, the step that Cephalomannine is converted into described taxane intermediate comprises that further (1) is converted into Cephalomannine the Cephalomannine aziridine analogues with following structure:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group, and (2) are converted into described taxane intermediate with this Cephalomannine aziridine analogues.

In the selectable more specifically embodiment of preceding method, the step that Cephalomannine is converted into described taxane intermediate comprises Cephalomannine and formic acid reaction.

In another selectable more specifically embodiment, the step that Cephalomannine is converted into described taxane intermediate further comprises following reaction sequence:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group.

In another selectable more specifically embodiment, the step that Cephalomannine is converted into described taxane intermediate comprises that further (1) is converted into Cephalomannine the similar thing of Cephalomannine epoxide with following structure:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group, and (2) are converted into the similar thing of this Cephalomannine epoxide the Cephalomannine azido alcohol analogue with following structure:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group, and (3) are converted into described taxane intermediate with this Cephalomannine azido alcohol analogue.

In second embodiment, the invention provides the method for preparing Taxan, this method may further comprise the steps: (1) is converted into cinnamoyl halogenide in the cinnamoyl halogenide aziridine intermediate with following structure:

Wherein X is a halogen, and (2) react this cinnamoyl halogenide aziridine intermediate and protected Baccatine III so that the protected Baccatine III aziridine intermediate with following structure to be provided:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (3) are converted into the taxane intermediate with following structure with this protected Baccatine III aziridine intermediate:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (4) are converted into Paclitaxel or Docetaxel with this taxane intermediate.

In the more specifically embodiment of preceding method, X is a chlorine.

In the 3rd embodiment, the invention provides the method for preparing Taxan, this method may further comprise the steps: (1) is converted into cinnamoyl halogenide in the cinnamoyl halogenide aziridine intermediate with following structure:

Wherein X is a halogen, and (2) are converted into this cinnamoyl halogenide aziridine intermediate in the open chain cinnamoyl halogenide intermediate with following structure:

Wherein X is a halogen, and (3) react this open chain cinnamoyl halogenide intermediate and protected Baccatine III so that the protected Baccatine III intermediate with following structure to be provided:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (4) are converted into the taxane intermediate with following structure with this protected Baccatine III intermediate:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (5) are converted into Paclitaxel or Docetaxel with this taxane intermediate.

In the more specifically embodiment of preceding method, the step of described open chain cinnamoyl halogenide intermediate and the reaction of protected Baccatine III further comprises step: (1) is converted into the beta-lactam intermediate with following structure with this open chain cinnamoyl halogenide intermediate

And (2) react this beta-lactam intermediate and protected Baccatine III so that described protected Baccatine III intermediate to be provided.

More specifically in the embodiment, X is a chlorine at another of preceding method.

In the 4th embodiment, the invention provides the method for preparing Docetaxel from Cephalomannine, this method comprises reaction sequence:

By with reference to the accompanying drawings with following detailed description, these and other aspects of the invention can be apparent.

Brief Description Of Drawings

Fig. 1,2,3,4,5,6,7 and 8 has exemplarily described and of the present inventionly has been used to prepare taxane intermediate and aziridine analogues, and is translated into the chemical route of the pure and mild Docetaxel of Pacific yew.

Detailed description of the invention

As mentioned above, the present invention relates to narrowing of new taxane intermediate and aziridine analog Become the particularly aziridine analog of Cephalomannine and narrowing of baccatin III intermediate Become, and they are to active antitumor agent, i.e. the conversion of the pure and mild Docetaxel of Pacific yew.

Term used herein " hydroxyl protecting group " refers to that (oxygen OH) is combined with hydroxyl The group that disconnects easily. The example of hydroxyl protecting group include, but not limited to acetyl group (Ac), Benzyl (PhCH₂); 1-ethoxyethyl group (EE); methoxyl group methyl (MOM); (methoxyl group ethyoxyl) methyl (MEM); (p-methoxyphenyl) methoxyl group methyl (MPM); tert-butyl group dimethyl silane base (TBS); tert-butyl group diphenyl silane base (TBPS); tert-butoxycarbonyl (tBoc; t-Boc; tBOC; t-BOC); THP trtrahydropyranyl (THP); triphenyl methyl (Trityl; Tr); 2-methoxyl group-2-methyl propyl group; benzyloxy carbonyl (Cbz); tribromo-acetyl base (OCCCl₃), 2,2,2-three chloroethoxies Carbonyl (Troc), benzyloxy methyl (BOM), the tert-butyl group (t-Bu), silicohetane alkyl (TES), Trimethyl silyl (TMS) and triisopropyl silicyl (TIPS). Relational language is " protected Hydroxyl " refer to the hydroxyl of being combined with hydroxyl protecting group. The general example of protected hydroxyl comprises but not Be limited to-the O-alkyl ,-O-acyl group, acetal and-the O-ethoxyethyl group, some of them are specifically protected The hydroxyl that protects comprises formyloxy, acetoxyl group, propionyloxy, chloroethene acyloxy, acetyl bromide oxygen Base, dichloro acetoxyl group, tribromo-acetyl oxygen base, trifluoro acetoxyl group, methoxyl group acetoxyl group, Phenoxy group acetoxyl group, benzoyloxy, benzoyl formoxy, p-nitrophenyl formyloxy, Ethyoxyl ketonic oxygen base, methoxyl group ketonic oxygen base, propoxyl group ketonic oxygen base, 2,2,2-three chloroethoxies Ketonic oxygen base, benzyloxy ketonic oxygen base, tert-butoxycarbonyl oxygen base, 1-cyclopropyl ethyoxyl ketonic oxygen Base, phthalyl oxygen base, fourth acyloxy, isobutyl acyloxy, penta acyloxy, isoamyl acyloxy, Oxalyl oxygen base, amber acyloxy and new pentane acyloxy, phenylacetyl oxygen base, phenyl propionyloxy, Mesyloxy, chlorobenzoyl oxygen base, p-nitrophenyl formyloxy, to the tert-butyl benzene formyloxy, Hot acyloxy, propylene acyloxy, methylamino formyloxy, the amino formyloxy of phenyl, naphthyl Carbamyl oxygen base etc. Hydroxy-protective group and protected hydroxyl are such as C.B.Reese and E. Haslam, " Protective Groups in Organic Chemistry (blocking group in the organic chemistry) " J.G.W.McOmie, Ed., Plenum Press, New York, N.Y., the 1973, the 3 and the 4th chapter reaches T.W.Greene and P.G.M.Wuts, " Protective Groups in Organic Synthesis (has Blocking group during machine is synthetic) " Second Edition, John Wiley and Sons, New York, N.Y., in the 1991, the 2 and the 3rd chapter description is arranged all.

Following form is listed the chemical constitution of some blocking groups and is differentiated the life of these chemical constitutions The name principle.

Table 1

Term " alkyl " refers to hydrocarbon structure, and wherein carbon atom is with straight chain, and side chain or ring-type form (are wrapped Draw together their combining form) arrange. Low alkyl group refers to comprise the alkyl of 1 to 5 carbon atom, and is low The example of level alkyl comprises methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and uncle's fourth Base etc. " cycloalkyl " is the subset of alkyl, comprises the ring-type alkyl of 3 to 13 carbon atoms. The example of cycloalkyl comprise cyclopropyl, cyclobutyl, cyclopenta, norborneol alkyl (norbornyl), Adamantyl etc. When an alkyl residue with carbon atom of given number is named, All have the geometric isomer of identical carbon number to include wherein with it; Therefore, for example " butyl " Refer to comprise normal-butyl, sec-butyl, isobutyl group and the tert-butyl group; Propyl group comprises n-pro-pyl and isopropyl.

Term " thiazolinyl " refers to have at least one unsaturated position, i.e. the alkane of at least one two key Base.

Term " alkynyl " refers to have the alkyl of triple bond between at least one adjacent carbon atom.

Term " alkoxyl (alkoxy) " and " alkoxyl (alkoxyl) " refer to that all general formula is-the O-alkyl Part. Example comprise methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, Hexamethylene oxygen base etc. Rudimentary alkoxyl refers to contain the alkoxyl of one to four carbon. Similar art Language " aryloxy group " refers to that general formula is-part of O-aryl.

Term " acyl group " refer to general formula be-C (=O)-part of alkyl. As long as the tie point with parent Remain on the carbonyl, the one or more carbon in the acyl residue can be by nitrogen-atoms, oxygen atom or sulphur Atom replaces. Example comprises acetyl group, benzoyl, propiono, isobutyryl, uncle's fourth Oxygen base carbonyl, benzyloxy carbonyl etc. Rudimentary acyl group refers to contain the group of one to four carbon.

Term " aryl " refers to phenyl or naphthyl. The aryl that replaces refers to single the replacement or polysubstituted benzene Base or naphthyl. The substituting group example that is used for aryl comprises one or more halogens, hydroxyl, alcoxyl Base, aryloxy group, assorted aryloxy group, amino, alkyl amino, dialkyl group amino, sulfydryl, alkyl Sulfenyl, arylthio, assorted arylthio, cyano group, carboxyl, alkoxyl partly comprise 1 to 15 carbon Alkoxyl carbonyl, aryloxy group partly comprise aryloxy group carbonyl or the heteroaryl section of 6 to 20 carbon Divide the heteroaryl carbonyl that comprises 3 to 15 carbon atoms.

Term " heteroaryl " refers to comprise 1-3 heteroatomic 5-or 6-that is selected from O, N or S Unit's hetero-aromatic ring; Comprising 0-3 9-or 10-unit that is selected from heteroatomic two rings of O, N or S mixes Aromatic ring; Perhaps comprise 0-3 13-or 14-unit that is selected from heteroatomic three rings of O, N or S Hetero-aromatic ring. The example of virtue heterocycle comprise imidazoles, pyridine, indoles, thiophene, benzopyrone, Thiazole, furans, benzimidazole, quinoline, isoquinolin, quinoxaline, pyrimidine, pyrazine, tetrazolium And pyrazoles.

Term " halogen " refers to fluorine, chlorine, bromine or iodine.

In the first embodiment, the invention provides the method for preparing taxane, the method comprising the steps of: (1) is converted into Cephalomannine in the primary amine taxane intermediate with following structure:

Each R that wherein occurs is independently selected from hydrogen and hydroxyl protecting group, and (2) are with in this taxane Mesosome is converted into Paclitaxel or Docetaxel.

In a more particular embodiment, the two keys by in the C-13 side chain that replaces Cephalomannine with the aziridine ring are converted into Cephalomannine the Cephalomannine aziridine analog with following structure:

Each R that wherein occurs is independently selected from hydrogen and hydroxyl protecting group. This Cephalomannine aziridine Analog is hydrolyzed to obtain described primary amine taxane intermediate subsequently.

In selectable more specifically embodiment, directly be hydrolyzed Cephalomannine with formic acid, with Obtain described primary amine taxane intermediate.

In another selectable more specifically embodiment, according to following reaction order, by at AcOH:Ac₂Use N among the O with natrium nitrosum or in acetonitrile₂O ₄Carry out nitrosylation, with being hydrolyzed by lithium hydroxide and 30% hydrogen peroxide, then Raney-nickel reduction is converted into described primary amine taxane intermediate with Cephalomannine:

Each R that wherein occurs is independently selected from hydrogen and hydroxyl protecting group.

In another selectable more specifically embodiment, Cephalomannine is converted into the similar thing of Cephalomannine epoxides with following structure:

Each R that wherein occurs is independently selected from hydrogen and hydroxyl protecting group, then the similar thing of this Cephalomannine epoxides in 65 ℃ in methyl alcohol with reaction of sodium azide, the Cephalomannine azido alcohol analog that obtains having following structure:

Each R that wherein occurs is independently selected from hydrogen and hydroxyl protecting group, and this Cephalomannine is folded then Nitrogen alcohol analog is reduced to obtain described primary amine taxane intermediate.

In second embodiment, the invention provides the method for preparing taxane, the method comprising the steps of: (1) is converted into the Chinese cassia tree acyl halide in the Chinese cassia tree acyl halide aziridine intermediate with following structure:

Wherein X is halogen, and be combined this Chinese cassia tree acyl halide aziridine intermediate with NaH, DCM (2) with protected baccatin III, so that the protected baccatin III aziridine intermediate with following structure to be provided:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (3) are hydrolyzed to the taxane intermediate with following structure with this protected baccatin III aziridine intermediate:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (4) are converted into the Pacific Ocean with this taxane intermediate Taxol or Docetaxel.

In the more specifically embodiment of preceding method, X is chlorine.

In the 3rd embodiment, the invention provides the method for preparing taxane, the method comprising the steps of: (1) is converted into the Chinese cassia tree acyl halide in the Chinese cassia tree acyl halide aziridine intermediate with following structure:

Wherein X is halogen, and (2) are with this Chinese cassia tree acyl halide aziridine intermediate and acetic acid reaction, to obtain having the open chain Chinese cassia tree acyl halide intermediate of following structure:

Wherein X is halogen, and be combined this open chain Chinese cassia tree acyl halide intermediate with NaH, DCM (3) with the baccatin III of protection, so that the protected baccatin III intermediate with following structure to be provided:

Wherein R is selected from hydrogen and hydroxyl protecting group, and (4) are hydrolyzed to the taxane intermediate with following structure with this protected Baccatine III intermediate:

In the more specifically embodiment of preceding method, the step of this open chain cinnamoyl halogenide intermediate and protected Baccatine III reaction is also comprised following steps: (1) is converted into the beta-lactam intermediate with following structure with this open chain cinnamoyl halogenide intermediate:

And (2) this beta-lactam intermediate and the reaction of protected Baccatine III, so that described protected Baccatine III intermediate to be provided.

In the 4th embodiment; the invention provides the method for preparing Docetaxel from Cephalomannine; according to following reaction sequence; by on the secondary amine of protected Cephalomannine, introducing the t-BOC group; in THF, use the lithium hydroxide hydrolysis then, and prepare at 2 ', 7 and 10 deprotection:

Embodiment

Following examples disclose the concrete grammar that synthetic multiple aziridine analogues and they transform to the pure and mild Docetaxel of Pacific yew.The method of the disclosure can be used to obtain purifying and partially purified Taxan.Except as otherwise noted, all scientific terminology and technical terms are the implication that those skilled in the art understand.

Embodiment 1

The aziridineization of Cephalomannine

As shown in Figure 1, under room temperature and anhydrous condition, Cephalomannine (0.12mmol) is dissolved in exsiccant newly steams in the acetonitrile (1ml).Under vigorous stirring, in this solution, add chloramine-T (0.18mmol), add copper trifluoromethanesulfcomposite (0.12mmol) subsequently.Under (25 ℃) condition of heating a little, stir this mixture and all used up up to whole starting raw materials.This mixture is carried out aftertreatment, and utilize the mixture of methylene dichloride and ethyl acetate to pass through the column chromatography purifying, to obtain the white crystals of described Cephalomannine aziridine analogues.

The preparation of primary amine taxane intermediate

Method 1: in dry benzene (5ml) solution of above-mentioned Cephalomannine aziridine analogues (0.025mmol), add O-Phenylene Diamine (0.025mmol) and tosic acid (catalytic, 2mg).This mixture refluxed all used up (TLC) up to whole starting raw materials in 16 hours.This mixture is cooled to room temperature, also uses dilute hydrochloric acid (1N), water and salt water washing successively with the ethyl acetate dilution.Dry organic layer, and utilize the mixture of methylene dichloride and ethyl acetate to carry out purifying by column chromatography, obtain described primary amine taxane intermediate.

Method 2: the 1.0N lithium hydroxide solution that in the tetrahydrofuran solution (0.2M) of above-mentioned Cephalomannine aziridine analogues (3.51mmol), adds 10.54ml (10.54mmol).At room temperature stirred this solution 12 hours.After removing tetrahydrofuran (THF) in a vacuum, by adding the aqueous residue of 10% acidifying with acetic acid alkalescence, and extract with ether.Dry (MgSO ₄) and concentrate and to obtain thick material, the thick material of gained carries out purifying by column chromatography, obtains the white solid (attention: also available following mode: 10 normal LiOH, 20 normal 30%H of pure described primary amine taxane intermediate ₂O ₂, 3: 1 THF: H ₂O, time,

Na ₂SO ₃, 5 minutes, 0 ℃).

The primary amine taxane intermediate is to the conversion of Paclitaxel or Docetaxel

The sample (0.091mmol) of described primary amine taxane intermediate is dissolved in (9.1ml) in the ethyl acetate, and adds NaHCO ₃Saturated solution (9.1ml).In the mixture of this two-phase, add tert-Butyl dicarbonate (0.18mmol).At room temperature stirred this mixture 12 hours, TLC shows that described starting raw material exhausts fully.Adopt ordinary method that aftertreatment is carried out in this reaction, and utilize the mixture of methylene dichloride and ethyl acetate or acetone to carry out purifying, to obtain Docetaxel by column chromatography.Isolating material ¹H NMR, ¹³CNMR and mass-spectrometric data all with the report data consistent of Docetaxel.

Can use several different methods, for example at United States Patent (USP) the 5th, 808, disclosed method in No. 113 is converted into taxol with described primary amine, is incorporated herein by reference in its entirety.

Embodiment 2

The hydrolysis of Cephalomannine

As shown in Figure 2, under 0 ℃, Cephalomannine is dissolved in the formic acid, and under this temperature, stirred 12 hours, be poured on the trash ice then and adopt ordinary method to carry out aftertreatment.This thick resistates utilizes the mixture of methylene dichloride and ethyl acetate to carry out purifying by column chromatography, obtains pure described primary amine taxane intermediate.

Embodiment 3

The aziridineization of cinnamyl chloride

As shown in Figure 3, at room temperature, to the acetonitrile mixture adding phenyltrimethyammonium tribromide (PTAB) of cinnamyl chloride and anhydrous chloramine-T.After 12 hours vigorous stirring, concentrate this reaction mixture, filter by short silicagel column, and with the hexane wash-out that contains 10% ethyl acetate.Behind evaporating solvent, the gained solid obtains described cinnamyl chloride aziridine intermediate by column chromatography or recrystallization purifying.

Acid catalyzed ring opening

As shown in Figure 3, under 0 ℃, described cinnamyl chloride aziridine intermediate is dissolved in the water-containing acetic acid, and under this temperature, stirred 10 hours, adopt ordinary method to carry out aftertreatment then.Described crude mixture carries out purifying by column chromatography and crystallization, obtains described open chain cinnamyl chloride intermediate.

The preparation of beta-lactam intermediate

As shown in Figure 4, adopt known method in the document, above-mentioned open chain cinnamyl chloride intermediate is carried out cyclisation, to form described beta-lactam intermediate.

Embodiment 4

Association reaction

As shown in Figure 5, under argon gas atmosphere and room temperature, described open chain cinnamyl chloride intermediate and the protected Baccatine III of C7 are dissolved among the anhydrous THF of new steaming.The solution that stirs is cooled to 0 ℃, and under 0 ℃, this solution is added in the THF suspension of NaH.Solution slowly is warming up to room temperature, and under this temperature, kept 3 hours.Reaction mixture is cooled to 0 ℃, and should reaction with the salt solution cancellation.The reaction mixture dichloromethane extraction, the extraction liquid that is merged use anhydrous sodium sulfate drying, and concentrating under reduced pressure is to obtain crude product with the salt water washing for several times.This crude product carries out purifying with the mixture of hexane and ethyl acetate by column chromatography, obtains the protected Baccatine III intermediate of pure bonded, can be with this intermediate hydrolysis to obtain described primary amine taxane intermediate.Though this reaction is carried out exemplary illustration with sodium hydride in Fig. 5, but in other embodiment of the present invention, this association reaction can as the metal alkoxide of hexamethyldisilazane sodium salt (sodiumhexamethyldisalide) or lewis acidic in the presence of carry out.

Embodiment 5

Nitrosylation

As shown in Figure 6, in the Glacial acetic acid (2.5ml) of Cephalomannine (0.76mmol) and aceticanhydride (5ml) mixed solution, adding NaNO under 0 ℃ ₂(7.6mmol).0 ℃ down and in the argon gas with gained solution stirring 16 hours, be poured into then on ice, and extract with diethyl ether.With the organic extract liquid that merged water, 5%Na successively ₂CO ₃, water and saturated NaCl washing, and use MgSO ₄Dry.Filter institute's exsiccant extraction liquid, concentrate in a vacuum then, the gained crude product utilizes the mixture of hexane-ethyl acetate by the column chromatography purifying, obtains pure product.

Hydrolysis

The lithium hydroxide solution that in the tetrahydrofuran solution of above-mentioned product, adds 1.0N.At room temperature stirred this solution 12 hours.After under vacuum, removing tetrahydrofuran (THF), by adding the aqueous residue that 10% acidifying with acetic acid should alkalescence, and extract with ether.Dry (MgSO ₄) and concentrate after, obtain thick material, this thick material obtains the white solid of pure described primary amine taxane intermediate by the column chromatography purifying.(note: also available following mode: 10 normal LiOH, 20 normal 30%H ₂O ₂, 3: 1 THF: H ₂O, time,

Na ₂SO ₃, 5 minutes, 0 ℃)

Reduction

At room temperature the product with said hydrolyzed is dissolved in the ethanol and a Raney-nickel of adding in the solution of this stirring.Under this temperature, stir this reaction mixture and handle, used up fully up to whole starting raw materials with hydrogen.Filter this reaction mixture and evaporated filtrate.Resistates is dissolved in such as in the inert solvent of methylene dichloride and adopt ordinary method to carry out aftertreatment.Described crude product utilizes the mixture of methylene dichloride and ethyl acetate by the column chromatography purifying, to obtain described pure products.

Embodiment 6

The preparation of N-acyl derivative

As shown in Figure 7, in the dichloromethane solution of Cephalomannine (9.47mmol), add triethylamine (9.47mmol), tert-Butyl dicarbonate (18.94mmol) and 4-(dimethylamino) pyridine (DMAP) (9.47mmol).At room temperature, in argon gas atmosphere, with this solution stirring 12 hours.Remove volatile matter, the gained resistates is by the column chromatography purifying.Carry out wash-out with methylene dichloride and ethyl acetate, obtain Cephalomannine N-t-BOC derivative.

Perhaps, in the dry acetonitrile solution of the Cephalomannine (1.0mmol) that stirs, add DMAP (0.1mmol) and BOC successively ₂O (1.1mmol).After at room temperature stirring 10 hours, whole starting raw materials is all used up (TLC).At room temperature evaporate this reaction mixture, the gained resistates is distributed in ether and moisture KHSO ₄Between.Organic extract is used KHSO successively ₄The aqueous solution, NaHCO ₃The aqueous solution is used the salt solution thorough washing at last, and uses MgSO ₄Dry.Be evaporated to complete drying, remain faint yellow resistates, this resistates obtains described Cephalomannine N-t-BOC derivative by the column chromatography purifying.

Embodiment 7

The preparation of the similar thing of Cephalomannine epoxide

As shown in Figure 8, in the dichloromethane solution of Cephalomannine, adding NaHCO under-15 ℃ successively ₃And MCPBA.After starting raw material is used up, adopt ordinary method that aftertreatment is carried out in reaction, and the mixture that utilizes methylene dichloride and ethyl acetate obtain the pure similar thing of described Cephalomannine epoxide by the column chromatography purifying.

The preparation of Cephalomannine azido alcohol analogue

At room temperature, be dissolved in the similar thing of described Cephalomannine epoxide in the methyl alcohol and add NaN ₃The aqueous solution.With this solution 65 ℃ of time heating 12 hours.Reaction mixture is cooled to room temperature and adopts ordinary method to carry out aftertreatment, the mixture that utilizes methylene dichloride and ethyl acetate obtains pure described Cephalomannine azido alcohol analogue by the column chromatography purifying.

That mention in this specification sheets and/or list in the request for data table all above-mentioned United States Patent (USP)s, U.S. Patent application publication, U.S. Patent application, foreign patent, foreign patent application and non-patent publications are quoted its full content as a reference at this.

Though from preamble, be appreciated that and described specific embodiments of the present invention at this, can carry out various modifications in the spirit and scope of the present invention not departing from for exemplary illustration.Therefore, the scope of the invention is only defined by the appended claims.

Claims

1. the method for preparing Taxan, described method comprises the steps:

Cephalomannine is converted into taxane intermediate with following structure:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group; And

Described taxane intermediate is converted into Paclitaxel or Docetaxel,

The wherein said step that Cephalomannine is converted into described taxane intermediate further may further comprise the steps:

Cephalomannine is converted into Cephalomannine aziridine analogues with following structure:

Described Cephalomannine aziridine analogues is converted into described taxane intermediate.

2. the method for claim 1, wherein said taxane intermediate is converted into Paclitaxel.

3. the method for claim 1, wherein said taxane intermediate is converted into Docetaxel.

4. the method for preparing Taxan, described method comprises the steps:

Cephalomannine is converted into taxane intermediate with following structure:

Described taxane intermediate is converted into Paclitaxel or Docetaxel, and the wherein said step that Cephalomannine is converted into described taxane intermediate comprises Cephalomannine and formic acid reaction.

5. method as claimed in claim 4, wherein said taxane intermediate is converted into Paclitaxel.

6. method as claimed in claim 4, wherein said taxane intermediate is converted into Docetaxel.

7. the method for preparing Taxan, described method comprises the steps:

Cephalomannine is converted into taxane intermediate with following structure:

Described taxane intermediate is converted into Paclitaxel or Docetaxel, and the wherein said step that Cephalomannine is converted into described taxane intermediate further comprises following reaction sequence:

8. method as claimed in claim 7, wherein said taxane intermediate is converted into Paclitaxel.

9. method as claimed in claim 7, wherein said taxane intermediate is converted into Docetaxel.

10. the method for preparing Taxan, described method comprises the steps:

Cephalomannine is converted into taxane intermediate with following structure:

Described taxane intermediate is converted into Paclitaxel or Docetaxel, and the wherein said step that Cephalomannine is converted into described taxane intermediate further may further comprise the steps:

Cephalomannine is converted into the similar thing of Cephalomannine epoxide with following structure:

Wherein each R of Chu Xianing is independently selected from hydrogen and hydroxyl protecting group;

The similar thing of described Cephalomannine epoxide is converted into Cephalomannine azido alcohol analogue with following structure:

Described Cephalomannine azido alcohol analogue is converted into described taxane intermediate.

11. method as claimed in claim 10, wherein said taxane intermediate is converted into Paclitaxel.

12. method as claimed in claim 10, wherein said taxane intermediate is converted into Docetaxel.