CN1150423A - New taxoids, preparation thereof and pharmaceutical compositions containing them - Google Patents

New taxoids, preparation thereof and pharmaceutical compositions containing them Download PDF

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CN1150423A
CN1150423A CN95193482A CN95193482A CN1150423A CN 1150423 A CN1150423 A CN 1150423A CN 95193482 A CN95193482 A CN 95193482A CN 95193482 A CN95193482 A CN 95193482A CN 1150423 A CN1150423 A CN 1150423A
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H·布查德
J-D·伯扎特
A·科默康
C·特里尔
M·朱克
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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Abstract

New taxoids, preparation thereof and pharmaceutical compositions containing them are provided. In the general formula: Ra is hydrogen, hydroxy, alkoxy, acyloxy, alkoxyacetoxy, and Rb is hydrogen or Ra and Rb form together with the carbon atom to which they are linked a ketone function, Z is a hydrogen atom or a radical having general formula II wherein R1 is an optionally substituted benzoyl radical, a thenyl or furoyl radical or a radical R2-O-CO- wherein R2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl radical; R3 is an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphtyl or heterocyclic aromatic radical, and R4 and R5, similar or different, represent an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, aryl or heterocyclyl radical, with the condition that R5 does not represent a methyl radical. The new products having general formula I wherein Z is a radical having general formula II have remarkable antitumoral and antileukaemic properties.

Description

Novel taxoid, its preparation method and pharmaceutical composition thereof
The present invention relates to novel taxoid (taxoide) (I)
Figure A9519348200061
In the formula: R aRepresent hydrogen atom or hydroxyl, C 1-4Alkoxyl group, C 1-4Acyloxy or its moieties contain the alkoxy acetic acid base of 1-4 carbon atom, R aRepresent hydrogen atom or R aWith R bTogether with forming ketone jointly with its bonded carbon atom, Z represents hydrogen atom or group (II): In the formula: R 1Representative can be by one or more identical or different halogen atom and C of being selected from 1-4Alkyl, C 1-4The benzoyl that the atom of alkoxyl group or trifluoromethyl or group replace, thenoyl or furoyl, or radicals R 2-O-CO-, wherein R 2Representative :-C 1-8Alkyl, C 2-8Alkenyl, C 3-8Alkynyl, C 3-6Cycloalkyl, C 4-6Cycloalkenyl group, C 7-10Bicyclic alkyl, these groups can be selected from following substituent group and replace by one or more: halogen atom and hydroxyl, C 1-4Alkoxyl group, wherein each moieties all contain 1-4 carbon atom dialkyl amino, piperidino-(1-position only), morpholino, piperazine-1-base (can be by C in the 4-position 1-4Alkyl or wherein the moieties phenylalkyl that contains 1-4 carbon atom replace), C 3-6Cycloalkyl, C 4-6Cycloalkenyl group, phenyl (can be by one or more halogen atom and C of being selected from 1-4Alkyl or C 1-4The atom of alkoxyl group or group replace), cyano group, carboxyl or wherein moieties contain the carbalkoxy of 1-4 carbon atom ,-can be by the phenyl of one or more substituting groups replacements that are selected from following atom or group or α-or betanaphthyl: halogen atom and C 1-4Alkyl or C 1-4Alkoxyl group or preferred 5 Yuans aromatic heterocyclic radicals from furyl and thienyl ,-or can be by one or more C 1-4The C that alkyl replaces 4-6Saturated heterocyclyl, R 3Represent straight or branched C 1-8Alkyl, straight or branched C 2-8Alkenyl, straight or branched C 2-8Alkynyl, C 3-6Cycloalkyl; phenyl that can be replaced by one or more substituting groups that are selected from following atom or group or α-or betanaphthyl: halogen atom; alkyl; alkenyl; alkynyl; aryl; aralkyl; alkoxyl group; alkylthio; aryloxy; arylthio; hydroxyl; hydroxyalkyl; sulfydryl; formyl radical; acyl group; amido; aromatic acylamino; alkoxycarbonyl amido; amino; alkylamino; dialkyl amido; carboxyl; carbalkoxy; formamyl; alkyl-carbamoyl; the dialkyl amido formyl radical; cyano group; nitro and trifluoromethyl; or contain one or more nitrogen that are selected from; identical or different heteroatomic 5 Yuans aromatic heterocycles that can be replaced by one or more identical or different substituting groups that are selected from following groups of oxygen or sulphur: halogen atom and alkyl; aryl; amino; alkylamino; dialkyl amido; alkoxycarbonyl amido; acyl group; aryl carbonyl; cyano group; carboxyl; formamyl; alkyl-carbamoyl; dialkyl amido formyl or carbalkoxy; condition is at phenyl; α-or the substituting group of betanaphthyl and aromatic heterocyclic radical in; the moieties of alkyl and other group all contains 1-4 carbon atom and alkenyl and alkynyl, and to contain 2-8 carbon atom and aryl be phenyl or α-or betanaphthyl, R 4And R 5Identical or different, representative-straight or branched C 1-8Alkyl, straight or branched C 2-8Alkenyl, straight or branched C 2-8Alkynyl, C 3-6Cycloalkyl, C 4-6Cycloalkenyl group or C 7-11Bicyclic alkyl, these groups can be selected from following substituent group and replace by one or more: halogen atom and hydroxyl, C 1-4Alkoxyl group, wherein each moieties contain the 1-4 carbon atom dialkyl amido, piperidino-(1-position only), morpholino, piperazine-1-base (can be by C in the 4-position 1-4The phenylalkyl that alkyl or its moieties contain 1-4 carbon atom replaces), C 3-6Cycloalkyl, C 4-6Cycloalkenyl group; can substituted phenyl; cyano group; carboxyl or its moieties contain the carbalkoxy of 1-4 carbon atom;-or the aryl that can be replaced by one or more substituting groups that are selected from following atom or group: halogen atom and alkyl; alkenyl; alkynyl; aryl; aralkyl; alkoxyl group; alkylthio; aryloxy; arylthio; hydroxyl; hydroxyalkyl; sulfydryl; formyl radical; acyl group; amido; aromatic acylamino; alkoxycarbonyl amido; amino; alkylamino; dialkyl amido; carboxyl; carbalkoxy; formamyl; alkyl-carbamoyl; the dialkyl amido formyl radical; cyano group; nitro; azido-; trifluoromethyl or trifluoromethoxy, condition are R 5Must not be methyl or can be by one or more C 1-4Saturated or the unsaturated heterocycle base of 4-6 person that alkyl replaces, condition is that cycloalkyl, cycloalkenyl group or bicyclic alkyl can be by one or more C 1-4Alkyl replaces.
Preferably, can be by R 3, R 4And/or R 5The aryl of expression is the phenyl that can be replaced by one or more substituting groups that are selected from following atom or group or α-or betanaphthyl: halogen atom (fluorine; fluorine; bromine; iodine) and alkyl; alkenyl; alkynyl; aryl; aralkyl; alkoxyl group; alkylthio; aryloxy; arylthio; hydroxyl; hydroxyalkyl; sulfydryl; formyl radical; acyl group; amido; aromatic acylamino; alkoxycarbonyl amido; amino; alkylamino; dialkyl amido; carboxyl; carbalkoxy; formamyl; the dialkyl amido formyl radical; cyano group; nitro; azido-; trifluoromethyl and trifluoromethoxy; condition is that the alkyl in alkyl and other group contains 1-4 carbon atom; it is phenyl or α-or betanaphthyl that alkenyl and alkynyl contain 2-8 carbon atom and aryl, and R 5Represent methylidene not.
Preferably, can use R 3, R 4And/or R 5The heterocyclic radical of expression is to contain one or more identical or different atoms that are selected from nitrogen, oxygen or sulphur to be selected from 5 Yuans aromatic heterocyclic radicals that following one or more identical or different substituting group replaces: halogen atom (fluorine, chlorine, bromine, iodine) and C 1-4Alkyl, C 6-10Aryl, C 1-4Alkoxyl group, C 6-10Aryloxy, amino, C 1-4Alkylamino, wherein moieties contains the dialkyl amido of 1-4 carbon atom, wherein acyl moiety contains acyl amino, the C of 1-4 carbon atom 1-4Alkoxycarbonyl amido, C 1-4Acyl group, wherein aryl moiety contains aryl carbonyl, cyano group, carboxyl, the formamyl of 6-10 carbon atom, and wherein moieties contains the alkyl-carbamoyl of 1-4 carbon atom, wherein each moieties all contains the dialkyl amido formyl radical of 1-4 carbon atom or the carbalkoxy that its alkoxyl group partly contains 1-4 carbon atom.
More specifically, the present invention relates to compound shown in the general formula I, wherein R aRepresentation hydroxy, C 1-4Alkoxyl group, C 1-4Acyloxy or wherein moieties contain the alkoxy acetic acid base of 1-4 carbon atom, R bRepresent hydrogen atom; Z represents group, wherein R shown in hydrogen atom or the general formula I I 1Represent benzoyl or R wherein 2Represent the radicals R of the tertiary butyl 2-O-CO-, R 3Represent C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl, the phenyl that can be replaced by one or more identical or different substituting groups that are selected from following atom or group: halogen atom (fluorine, chlorine) and alkyl (methyl), alkoxyl group (methoxyl group), dialkyl amido (dimethylamino), amido (kharophen), alkoxycarbonyl amido (t-butoxycarbonyl amino) or trifluoromethyl or furans-2-base or furans-3-base, thiophene-2 or-3-base or thiazole-2,-4 or-the 5-base, R 4The phenyl that representative can be replaced by one or more identical or different substituting groups that are selected from following atom or group: halogen atom and alkyl, alkoxyl group, amino, alkylamino, dialkyl amido, acyl amino, alkoxycarbonyl amido, azido-, trifluoromethyl and trifluoromethoxy; or thiophene-2 or-3-base or furans-2 or-the 3-base, R 5Representative can substituted C 1-4Alkyl, condition are R 5Must not be methyl.
Further more specifically, the present invention relates to the compound shown in the general formula (I), wherein R aRepresent hydrogen atom or hydroxyl or acetoxyl or methoxyimino acetic acid base, R bRepresent hydrogen atom, Z represents group, wherein R shown in hydrogen atom or the general formula (II) 1Represent benzoyl or R wherein 2Represent the radicals R of the tertiary butyl 2-O-CO-, R 3Represent isobutyl-, isobutenyl, butenyl, cyclohexyl, phenyl, furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-, thiazol-2-yl, thiazole-4-base or thiazole-5-base, R 4Representative can be by the phenyl of a halogen atom replacement, R 5Represent C 2-4Alkyl.
Wherein Z represents that compound has significant antitumor and leukemia characteristic shown in the general formula I of group shown in the general formula (II).
According to the present invention, R wherein aRepresent hydrogen atom or alkoxyl group, acyloxy or alcoxyl acetoxyl, R bRepresent hydrogen atom, R 4, R 5With Z as defined above Compound I can pass through compound generation effect shown in alkali metal halide (NaCl, NaI, KF) or an alkali metal azide (sodiumazide) or quaternary ammonium salt or the alkali-metal phosphoric acid salt mutual-through type (III), substitute R with hydrogen atom if desired subsequently aThe protecting group that has prepares: Z, R in the formula 4With R 5Be defined as above R aRepresent hydrogen atom or alkoxyl group, acyloxy, alcoxyl acetoxyl or protected hydroxyl, R bBe hydrogen atom.
Usually, this is reflected in the organic solvent that is selected from ether (tetrahydrofuran (THF), diisopropyl ether, methyl tertiary butyl ether) and pure nitrile (acetonitrile) or its mixture and carries out to the boiling spread of reaction mixture at 20 ℃.
Wherein Z represents the compound shown in the general formula (III) of group shown in the general formula (II) can be by by acid shown in the logical formula V or this acid derivative compound esterification shown in the general formula I V being become ester shown in the general formula (VI), substitutes with hydrogen atom and use R subsequently 7And/or R 6And R 7The protecting group of representative and possible at R aRemove R with hydroxyl when representing acyloxy, alcoxyl acetoxyl or protected hydroxyl aProtecting group obtains:
Figure A9519348200102
R in the formula 4, R 5Be defined as above R aRepresent hydrogen atom or alkoxyl group, acyloxy, alcoxyl acetoxyl or protected hydroxyl, R bRepresent hydrogen atom,
Figure A9519348200103
R in the formula 1With R 3Be defined as above, or R 6Represent hydrogen atom, R 7The protecting group of representation hydroxy functional group, or R 6With R 75 or 6 Yuans saturated heterocyclics of common formation,
Figure A9519348200104
R in the formula a, R b, R 1, R 3, R 4, R 5, R 6And R 7As mentioned above.
Can in the presence of condensing agent (carbodiimide, activated carbon hydrochlorate) and activator (aminopyridine), in organic solvent (ether, ester, ketone, nitrile, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbons), under-10～90 ℃, finish by the esterification that acid shown in the logical formula V is carried out.
This esterification can also adopt acid shown in the general formula V that exists with the acid anhydride form carrying out under 0-90 ℃ in organic solvent (ether, ester, ketone, nitrile, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbons) in the presence of the activator (aminopyridine).
This esterification can also adopt acid shown in the general formula V that exists with halogenide or acid anhydride form and the aliphatic acid or the aromatic acid that can prepare immediately carrying out under 0-80 ℃ in organic solvent (ether, ester, ketone, nitrile, aliphatic hydrocrbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbons) in the presence of the alkali (aliphatic tertiary amine).
Work as R aDuring the protecting group of representation hydroxy functional group, R aBe preferably 2,2,2 ,-trichloro-ethoxycarbonyl oxygen.
Preferably, R 6Represent hydrogen atom, R 7The protecting group of representation hydroxy functional group or R 6With R 75 or 6 Yuans saturated heterocyclics of common formation.
Work as R 6When representing hydrogen atom, R 7Be preferably methoxyl methyl, 1-ethoxyethyl, benzyloxymethyl, trimethyl silyl, triethylsilyl, β-trimethylsilylethoxymethyl, carbobenzoxy-(Cbz) or THP trtrahydropyranyl.
Work as R 6With R 7When forming heterocycle jointly, it is preferably and can replaces De oxazolidine ring 2 coverlets replacements or together with Er.
Substitute protecting group R with hydrogen atom 7And/or R 6And R 7And replace R with hydroxyl possibly aProcess can carry out in the following manner according to its characteristic: 1) work as R 6Represent hydrogen atom, R 7The protecting group of representation hydroxy functional group, R aWhen representation alkoxy, acyloxy or alcoxyl acetoxyl; the process of hydrogen atom displacement protecting group carries out 2 by mineral acid that exists with pure state or form of mixtures (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic acid (acetate, methylsulfonic acid, trifluoromethanesulfonic acid, tosic acid) under-10～60 ℃ in the organic solvent that is selected from alcohol, ether, ester, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbons or nitrile) work as R 6Represent hydrogen atom, R 7Representation hydroxy protective group base, R aRepresent 2,2, during 2-trichloro-ethoxycarbonyl oxygen, protecting group R 7Replacement process 1) carry out R under the described condition aReplacement process handle by combining with the copper that optionally exists with zinc, in the presence of 30-60 ℃ of acetate or by inorganic or organic acid example hydrochloric acid or acetate and C 1-3The solution that Fatty Alcohol(C12-C14 and C12-C18) (methyl alcohol, ethanol, propyl alcohol, Virahol) or aliphatic ester (ethyl acetate, isopropyl acetate, n-butyl acetate) form can with copper bonded zinc in the presence of carry out 3) work as R 6With R 7Common form 5 or 6 Yuans saturated heterocyclics and more specifically general formula (during VII) Suo Shi oxazolidine ring,
Figure A9519348200121
R in the formula 1Be defined as above R 8With R 9Identical or different, represent hydrogen atom or C 1-4Alkyl, or wherein alkyl contain that 1-4 carbon atom, aryl moiety be preferably can be by one or more C 1 -4The aralkyl of the phenyl that alkoxyl group replaces, or be preferably can be by one or more C 1-4The aryl of the phenyl that alkoxyl group replaces, or R 8Be C 1-4Alkoxyl group or trihalomethyl group such as trichloromethyl or the phenyl that can be replaced by trihalomethyl group such as trichloromethyl, R 9Be hydrogen atom, or R 8With R 9Together with forming 4-7 person's ring, R jointly with its bonded carbon atom aBe acyloxy or alcoxyl acetoxyl or 2,2,2-trichloro-ethoxycarbonyl oxygen is replaced by R with hydrogen atom 6With R 7The protecting group that forms and replace R with hydroxyl aProcess can be according to R a, R 1, R 8And R 9Definition carry out in the following manner: a) work as R 1Be tertbutyloxycarbonyl, R 8With R 9Identical or different, represent alkyl or aralkyl (benzyl) or aryl (phenyl), or R 8The phenyl of representing trihalomethyl group or being replaced by trihalomethyl group, R 9Represent hydrogen atom, or R 8With R 9Common when forming 4-7 person and encircling, depend on the needs with inorganic or organic acid and to handle at organic solvent ester shown in pure mutual-through type (VI), obtain product shown in the following formula: Formula first R a, R b, R 3, R 4And R 5As above definition, this compound by benzene nucleus wherein can substituted Benzoyl chloride, compound acylation shown in thiophene chloride, furoyl chloride or the general formula (IX)
R 2R in-O-CO-X (IX) formula 2As above definition, X represents halogen atom (fluorine, chlorine) or residue-O-R 2Or-O-CO-OR 2, obtain compound shown in the general formula (X)
Figure A9519348200132
R in the formula a, R b, R 1, R 3, R 4And R 5As above limit, wherein protecting group R aWhen the protected hydroxyl of representative, under prerequisite, replaced by hydroxyl.
Preferably, product is handled through peroxyformic acid under about 20 ℃ shown in the general formula (VI).
Preferably; by phenyl wherein can substituted Benzoyl chloride, the process of compound (VIII) being carried out acidylate of compound shown in thiophene chloride or furoyl chloride or the general formula (IX) is being selected from ester such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbon such as methylene dichloride or 1, in the presence of mineral alkali such as sodium bicarbonate or organic bases such as triethylamine, carry out in the inert organic solvents of 2-ethylene dichloride.Temperature of reaction is 0-50 ℃, is good with about 20 ℃.
Preferably, at R aRepresent 2,2, during 2-trichlorine ethoxy carbonyl oxygen, R aThe replacement process in the above 2 of protecting group) carry out under the described condition.B) work as R 1Representative can substituted benzoyl, Thenoyl or furancarbonyl or R wherein 2The radicals R that is defined as above 2O-CO-, R 8Represent hydrogen atom or C 1-4Alkoxyl group or can be by one or more C 1-4Phenyl, R that alkoxyl group replaces 9When representing hydrogen atom, replace by R with hydrogen atom 6And R 7The process of the protecting group that forms be selected from the presence of at the mineral acid that exists with pure state or form of mixtures (hydrochloric acid, sulfuric acid) or organic acid (acetate, methylsulfonic acid, trifluoromethanesulfonic acid, tosic acid) in the organic solvent of alcohol, ether, ester, aliphatic hydrocrbon, halogenated aliphatic hydrocarbon and aromatic hydrocarbons with stoichiometry or catalytic amount-10～60 ℃, preferably carry out, and at R at 15-30 ℃ aRepresent 2,2, R during 2-trichloro-ethoxycarbonyl oxygen aProtecting group by hydrogen atom metathetical process in the above 2) carry out under the described condition.4) work as R aBe alcoxyl ethanoyl and R 6With R 7Such as above-mentioned 1) during qualification, at first by above-mentioned 1) operate with hydrogen atom displacement protecting group R under the described acidic conditions 7, depend on the needs subsequently by in alkaline medium, handle or under the condition of not touching the molecule other parts effect by zinc halide replace R by hydroxyl a, usually, by carrying out basic treatment in about 20 ℃ under the ammonia effect in the Diluted Alcohol medium.Usually, by zinc halide, preferably the zinc iodide treating processes of carrying out can be carried out in the methyl alcohol under about 20 ℃.5) work as R aBe alcoxyl acetoxyl, R 6With R 7As above-mentioned 2-a) during definition, by handle at alkaline medium or by zinc halide above-mentioned 3) condition under handle and carry out replacing R with hydroxyl aThe process of group, with aftertreatment at above-mentioned 2-a) go protect with acylation condition under the compound (VI) that obtains.6) work as R aRepresent the alcoxyl acetoxyl, R 6With R 7As top 2-b) as described in the time, replace R with hydroxyl aProcess by in the above 3) in alkaline medium, handle under the described condition or undertaken by handling with zinc halide, with aftertreatment 2-b in the above) resulting product under the described condition.
According to the present invention, R wherein 4With R 5Be defined as above, R aRepresent hydrogen atom or alkoxyl group, acyloxy or alcoxyl acetoxyl, R bRepresent hydrogen atom or R aWith R bObtain together with the effect that forms derivative compound shown in this sour acid anhydride or fluoroform sulfimide mutual-through type (XI) that compound shown in the general formula (III) that ketone and Z represent hydrogen atom can be by trifluoromethanesulfonic acid jointly with its bonded carbon atom:
Figure A9519348200141
R in the formula a, R b, R 4With R 5Be defined as above.
Usually, this is reflected in the inert organic solvents (can by halogenated aliphatic hydrocarbon, aromatic hydrocarbons) to exist down in organic bases such as aliphatic tertiary amine (triethylamine) or pyridine and carries out under-50～20 ℃.
R wherein 4With R 5Be defined as above, R aBe hydrogen atom or alkoxyl group, acyloxy or alcoxyl acetoxyl or protected hydroxyl, R bFor compound shown in the general formula (XI) of hydrogen atom can be by hydrofluoric acid or trifluoroacetic acid in alkali organic solvent as can be by one or more C 1-4The pyridine that alkyl replaces or can with inert organic solvents such as CH 2Cl 2Or obtain down in 20-80 ℃ among acetonitrile or the associating triethylamine of tetrahydrofuran (THF) with compound (XII) interaction: R in the formula 4With R 5Be defined as above R aRepresent hydrogen atom or alkoxyl group, acyloxy or alcoxyl acetoxyl or protected hydroxyl, R bRepresent hydrogen atom, G 1Be trialkylsilkl.
Compound (XII) can be by compound (XIII) R-Y (wherein R is the protecting group of alkyl, alkanoyl or alcoxyl ethanoyl or hydroxy functional group, and Y is a halogen atom) and R wherein 4, R 5With G 1The compound that is defined as above (XIV) interacts and obtains.
Figure A9519348200152
When R was alkyl or alcoxyl ethanoyl, particularly advantageous was at alkali organic solvent such as pyridine or at inert organic solvents such as CH 2Cl 2, chloroform or 1, in the presence of tertiary amine such as triethylamine or pyridine, operate in the 2-ethylene dichloride in about 0 ℃.
When R was alkyl, particularly advantageous was on 10 hydroxy functional group to be carried out metalized in advance by alkalimetal hydride (NaH) or metal alkyls (butyllithium).
Compound (XIV) and compound (XII) can be by R wherein under may situation 4Be defined as above and M is atoms metal, is preferably the Organometallic derivatives R of lithium or magnesium 4-M (XV) is with R wherein a, R b, R 5And G 1The compound that is defined as above (XVI) interacts and prepares.
Figure A9519348200161
Usually, this is reflected in organic solvent such as the ether (tetrahydrofuran (THF)) in below-50 ℃, carry out under preferred-78 ℃ the temperature approximately.
Compound (XVI) can be by by R wherein 5The sour R that is defined as above 5-COOH (XVIII) or derivative that should acid such as halogenide or acid anhydride be esterification R wherein in the presence of condensing agent or mineral alkali or organic bases a, R bAnd G 1The compound that is defined as above (XVII) obtains.
Figure A9519348200162
Compound (XVII) can pass through compound (XIII) and G wherein 1The compound that is defined as above (XIX) reacts under above-claimed cpd (XIII) and the interactional condition of compound (XIV) and prepares.
Compound (XIX) can be by phosgene or its a kind of derivative such as triphosgene and G wherein 1The compound that is defined as above (XX) in alkali organic solvent such as pyridine below-50 ℃, interacting under preferred-78 ℃ the temperature approximately obtains. Compound (XX) can be by halo trialkyl silane and G wherein 1The compound that is defined as above (XXI) interacts in alkali organic solvent and obtains.
Figure A9519348200173
Can be people such as D.G.I.Kingston, Journal of Nat.Prod.56 prepares compound (XXI) under 884 (1993) the described conditions.
R wherein aWith R bThe Compound I that is respectively hydrogen atom can be passed through wherein R of electrolytic reduction aFor the Compound I of hydroxyl or acyloxy or alcoxyl acetoxyl or obtaining under the condition described in the International Application PCT WO93/06093.
R wherein aWith R bCan be together with forming the Compound I of ketone jointly by R wherein with its bonded carbon atom aBe hydroxyl, R bFor the Compound I of hydrogen atom by, for example pyridinium chlorochromate, dichromic acid pyridine, potassium bichromate, ammonium dichromate or Manganse Dioxide are oxidized and obtain.
Can purify by implementing the novel cpd I that the inventive method obtains according to currently known methods such as crystallization or chromatography.
Wherein Z is that the Compound I of group shown in the general formula I I possesses important biological nature.
Can be by people's such as M.L.Shelanski Prot.Natl.Acad.Sci.USA, 70, the described method of 765-768 (1973) is carried out biological activity determination external to pig brain tubulin extract.To being the C.R.Acad.Sci.293 of the research of tubulin according to people such as G.Chauviere with microtubule depolymerization, the described method of serial II501-503 (1981) is carried out.Wherein Z is that the Compound I of group shown in the general formula I I shows the activity identical with taxol and taxotere at least.
In vivo in the test of carrying out, wherein to be that the Compound I of group shown in the general formula I I occurs by intraperitoneal administration table with the dosage of 1-10mg/kg in the mouse body of implanted melanoma b16 active for Z, and it also has curative effect to other liquid or solid tumour.
These novel cpds possess antitumor characteristic, more particularly to those to Taxol Or Taxotere The tumour that has developed immunity to drugs has antagonistic activity.This class tumour comprises the have gene mdrl colon tumor of high expression level of (multiple drug resistance gene).Multiple drug resistance is Essential Terms, means the resistance of tumour to the structure compound different with the mechanism of action.Taxoid is usually because experimental tumor such as P388/DOX (a kind of because to the resistance of the Zorubicin (DOX) that is expressed as mdr1 and selected clone) and widely understood.
The following example is used to describe the present invention.
Embodiment 1
To 0.193g 3-t-butoxycarbonyl amino-2-hydroxy-4-phenyl-(2R, 4S)-and propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene (Taxene)-13 α-ester and 2.5cm 3Acetonitrile and 0.250cm 3Add 0.096g powdery 4 molecular sieves, 0.290gNaCl in the solution of tetrahydrofuran (THF) successively.At about 75 ℃ reaction medium stirred 5 hours,, add 75cm subsequently at about 20 ℃ 3CH 2Cl 2And 50cm 3The NaCl saturated aqueous solution.The decant organic phase is with NaCl saturated aqueous solution 40cm 3Wash 2 times, use MgSO subsequently 4Drying, filtration also are concentrated into dried in 40 ℃ of decompressions (2.7Kpa).Obtain the 0.150g product, with chromatography (80g silica gel the 0.063-0.2mm) (scrub solution: CH of in diameter is the post of 1cm, purifying 2Cl 2-CH 3The OH:98/2 volume), obtain 10cm 3Cut.Wherein merge the fraction that only contains required compound, being depressurized (2.7Kpa) in 40 ℃ is concentrated into dried, obtain 0.08g 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 4S) propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-7 β, 8-methylene radical-19-falls-9-oxygen-4 α-Bing Suan base-11-Japanese yew alkene-13 α-ester, it is characterized in that:
-nuclear magnetic resonance spectrum 1H (400 MHz, CDCl 3, δ ppm): 1,24 (t, J=7.5Hz, 3H:CH 3Ethyl); 1,24 (s, 6H:CH 3); 1,27 (s, 9H:C (CH 3) 3); 1,42 (mt, 1H:H7); 1,68 and 2,24 (2mts, 1H:CH 219); 1,86 (s, 1H 0H 1); 1,86 (s, 3H:CH 3); 2,12 and 2,86 (d and dt, J=16 and J=16 and 5Hz, 1H:CH 26); 2,15～2,30 and 2,41 (mt and dd, J=16 and 9Hz, 1H:CH 214); 2,64 (mt, 2H:CH 2Ethyl); 3,26 (mt, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 4,07 (1H:H 3 for d, J=7Hz); 4,04 and 4,33 (2d, J=9Hz, 1H:CH 220); 4,22 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,62 (mt, 1H:H 2 '); 4,70 (1H:H 5 for d, J=4Hz); 5,28 (md, 2H:H 3 ' and CONH); 5,67 (d, J=7Hz, 1H:H2); 6,26 (t is wide, J=9Hz, 1H:H 13); 6,42 (s, 1H:H 10); 7,25～7,45 (mt, 5H: aromatics H3 '); 7,52 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,62 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,16 (d, J=7.5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 3-t-butoxycarbonyl amino-2-hydroxy-4-phenyl-(2R according to following manner, 4S)-and propionic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester:
With 0.760g 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-(2R, 4S, 5R) carboxylic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β-trifluoromethanesulfonic acid base-11-Japanese yew alkene-13 α-ester is at 6.6cm 30.1N the solution that forms in the alcohol hydrochloric acid solution stirred 22 hours down at about 0 ℃.Be concentrated into dried in 20 ℃ of decompressions (2.7Kpa).Reacting coarse product is dissolved in 80cm 3CH 2Cl 2And 80cm 3NaHCO 3Saturated aqueous solution.Decant separates organic phase, uses 50cm 3CH 2Cl 2Extract 2 times.Merge organic phase, use 50cm 3Distilled water wash is used MgSO 4Dry.Filter and be concentrated into dried in 20 ℃ of decompressions (2.7Kpa).Obtain the roasting albumen shape material of 0.9g white, in 150g silica gel (0.063-0.2mm) post (diameter is 3cm), carry out chromatogram purification (scrub solution: CH 2Cl 2-methyl alcohol: the 95-5 volume), obtain 15cm 3Cut.Merge and only contain the cut of required compound and be concentrated into dried in 20 ℃ of decompressions (2.7KPa).Obtain 0.456g purpose compound, its physical features is:
Nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 1,24 (s, 9H: CH 3And CH 3Ethyl); 1,34 (s, 9H:C (CH 3) 3); 1,74 (s, 1H:OH 1); 1,88 (s, 3H:CH 3); 2,05 (s is wide, 3H:CH 3); 2,24 and 2,86 (2mts, 1H:CH 26); 2,33 (d, J=9Hz, 2H:CH 214); 2,68 (mt, 2H:CH 2Ethyl); 3,30 (mt, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 3,93 (mt, 1H:H 3); 4,19 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,20 and 4,36 (2d, J=9Hz, 1H:CH 220); 4,64 (d is wide, J=5,5Hz, 1H:H2 '); 4,86 (d is wide, H=10Hz, 1H:H 5); 5,22 (mt, 1H:H 3 '); 5,30 (d, J=10Hz, 1H:CONH); 5,51 (dd, J=10 and 7,5Hz, 1H:H 7); 5,75 (1H:H 2 for d, J=7Hz); 6,20 (mt, 1H:H 13); 6,71 (s, 1H:H 10); 7,30～7,45 (mt, 5H:H fragrance H3 '); 7,52 (t, J=7.5Hz, 2H:OCOC 6H 5Position between H); 7,64 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,13 (d, J=7.5Hz, 2H:OCOC 6H 5The H ortho position)
Prepare 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1 according to following manner, 3-oxazolidine-5 (2R, 4S, 5R) carboxylic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester:
To by 0.590g 2 α-benzoyl oxygen-1 β, 13 alpha-dihydroxy-s-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene is at 10cm 3Add 0.463g 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1 in the solution that forms in the anhydrous ethyl acetate successively, and 3-oxazolidine-5 (2R, 4S, 5R)-carboxylic acid, 0.319g dicyclohexyl carbodiimide and 0.028g 4-Dimethylamino pyridine.In argon atmospher, reaction mixture stirred 15 hours, add 75cm subsequently at about 20 ℃ 3CH 2Cl 2And 50cm 3NH 4The Cl saturated aqueous solution. the decant organic phase, use 40cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 0.980g product that obtains carries out chromatogram purification (scrub solution, CH in 150g silica gel (0.063-0.2mm) post (diameter is 3cm) 2Cl 2-methyl alcohol: the 95-5 volume), obtain 15cm 3Fraction.Merge only contain the fraction of purpose compound and be concentrated in 40 ℃ of decompressions (2.7KPa) dried, 0.740g white is baked albumen shape purpose compound, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 1,06 (s, 12H:CH 3And C (CH 3) 3); 1,20 (s, 3H: CH 3); 1,27 (t, J=7,5Hz, 3H:CH 3Ethyl); 1,67 (s, 1H:OH1); 1,71 (s, 3H:CH 3); 1,83 (s, 3H:CH 3); 2,00～2,30 and 2,83 (2mt, 1H:CH 26); 2,00～2,30 (mt, 2H:CH 2Ethyl); 2,08 and 2,22 (2dd, J=16 and 9Hz, 1H:CH 214); 3,52 (s, 3H:OCH 3), 82 (s, 3H:ArOCH 3); 3,82 (mt, 1H:H 3); 4,12 and 4,29 (2d, J=9Hz, 1H:CH 220); 4,18 (AB is obvious, J=16 Hz, 2H:OCOCH 2O); 4,51 (d, J=5Hz, 1H:H 2 '); 4,80 (d is wide, J=10Hz, 1H:H5); 5,35～5,45 (mt, 1H:H 3 '); 5,43 (dd, J=10,5 and 7,5Hz, 1H:H 7); 5,68 (1H:H 2 for d, J=7Hz); 6,01 (mt, 1H:H 13); 6,38 (mt, 1H:H 5 '); 6,60 (s, 1H:H 10); 6,92 (2H: fragrant H is in OCH for d, J=8.5Hz 3The ortho position); 7,39 (d, J=8,5Hz, 2H: fragrant H is in OCH 3Between the position); 7,30～7,45 (mt, 5H: fragrant H 3 '); 7,50 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,65 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,03 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-1 β according to following method, 13 alpha-dihydroxy-s-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene:
To 0.660g 2 α-benzoyl oxygen-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene is in 6.6cm 3Anhydrous CH 2Cl 2And 0.338cm 3Form in the pyridine about 0 ℃ and be maintained in the solution in the argon atmospher and drip 0.354cm 3Trifluoromethanesulfanhydride anhydride.About 0 ℃ with the orange solution that obtains stir 10 minutes, stirred 30 minutes at about 20 ℃, add 3cm subsequently 3Water and 50cm 3CH 2Cl 2The decant organic phase is used 40cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 0.800g product that obtains is with 100g silica gel (0.063-0.2mm) post (diameter: 2cm) carry out chromatogram purify (eluant, CH 2Cl 2-methyl alcohol: the 95-5 volume), obtain 15cm 3Cut merges the fraction that only contains required compound and is concentrated into dried at 40 ℃ reduce pressure down (2.7KPa).Obtain the roasting albumen shape purpose compound of 0.591 gram white, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 1,05 (s, 3H:CH 3); 1,19 (s, 3H:CH 3); 1,23 (t, J=7,5Hz, 3H:CH 3Ethyl); 1,62 (s, 1H:OH 1); 1,89 (s, 3H:CH 3); 2,12 (1H:OH 13 for d, J=5Hz); 2,24 and 2,90 (2mts, 1H:CH 26); 2,25 (s, 3H:CH 3); 2,30 (AB is obvious, 2H:CH 214) 2,64 (mt, 2H:CH 2Ethyl); 3,52 (s, 3H:OCH 3); 4,02 (d, J ,=7Hz, 1H:H 3), 15 and 4,35 (2d, J=9Hz, 1H:CH 220); 4,20 (AB ethyl, J=16Hz, I:OCOCH 2O); 4,85 (mt, 1H:H 13); 4,91 (d is wide, J=10Hz, 1H:H 5); 5,57 (1H:H 7 for dd, J=10 and 7Hz); 5,69 (1H:H 2 for d, J=7Hz); 6,73 (s, 1H:H 10); 7,50 (t, J=7.5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,11 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position)
Prepare 2 α-benzoyl oxygen-5 β according to following manner, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene:
To 1.21g 2 α-benzoyl oxygen-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-11-Japanese yew alkene is in 15cm 3CH 2Cl 2Add 23cm in about 20 ℃ in the middle solution that forms 3Title complex triethylamine-hydrofluoric acid.At about 20 ℃ reaction mixture stirred 20 hours, add 50cm subsequently 3CH 2Cl 2And 100cm 3NaHCO 3Saturated aqueous solution.The decant organic phase is used 50cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the roasting albumen shape purpose product of 1.04g white, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 1,11 (s, 6H:CH 3); 1,25 (t, J=7,5Hz, 3H:CH 3Ethyl); 1,65 (s, 1H:OH 1); 1,70 (s, 3H:CH 3); 1,88 and 2,60 (2mts, 1H:CH 26); 2,08 (s, 3H:CH 3); 2,30 (AB is obvious, 2H:CH 214); 2,39 (1H:OH 7 for d, J=4Hz); 2,63 (mt, 2H:CH 2Ethyl); 3,55 (s, 3H:OCH 3); 3,90 (1H:H 3 for d, J=7Hz); 4,17 and 4,32 (2d, J=9Hz, 1H:CH 220); 4,25 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,51 (mt, 1H:H 7); 4,89 (mt, 1H:H 13); 4,95 (d is wide, J=10Hz, 1H:H 5); 5,64 (d, J=7Hz, 1H:H2); 6,43 (s, 1H:H 10); 7,48 (t, J=8Hz, 2H:OCOC 6H 5Position between H); 7,61 (t, J=8Hz, 1H:OCOC 6H 5The H contraposition); 8,13 (d, J=8Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-7 β according to following manner, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-11-Japanese yew alkene:
To 0.900g 2 α-benzoyl oxygen-1 β, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-propionyl oxygen-11-Japanese yew alkene is in 15cm 3Add 0.520cm in about 0 ℃ in the solution that forms in the pyridine 3The methoxy Acetyl Chloride 98Min..At about 20 ℃ reaction mixture stirred 2 hours, add 100cm subsequently 3CH 2Cl 2And 50cm 3NH 4The Cl saturated aqueous solution.The decant organic phase is used 40cm 3NH 4MgSO is used in Cl saturated aqueous solution washing 2 times subsequently 4Drying is filtered and reduce pressure under 40 ℃ (2.7KPa) are concentrated into dried.The 1.3g product that obtains is at 150g silica gel (0.063-0.2mm) post (diameter: carry out chromatogram 2.5cm) and purify (scrub solution: ethyl acetate-hexanaphthene: 25-75, volume), obtain cut 10cm 3Merge the gold-plating branch that only contains the purpose compound and be concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the roasting albumen shape purpose compound of 0.780g white, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 0,50～0,70 (mt, 12H:CH 2Ethyl; 0,92 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,00 (t, J=7.5Hz, 9H:CH 3Ethyl); 1,10 (s, 3H:CH 3); 1,17 (s, 3H:CH 3); 1,29 (t, J=7,5Hz, 3H:CH 3Ethyl 4); 1,61 (s, 1H:OH 1); 1,68 (s, 3H:CH 3); 1,84 and 2,51 (2mts, 1H:CH 216); 2,09 and 2,21 (2dd, J=16 and 9Hz, 1H:CH 214); 2,10 (s, 3H:CH 3); 2,60 (mt, 2H:CH 2Ethyl 4); 3,50 (s, 3H:OCH 3); 3,78 (1H:H 3 for d, J=7Hz); 4,12 and 4,30 (2d, J=9Hz, 1H:CH 220); 4,15 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,49 (1H:H 7 for dd, J=11 and 7Hz); 4,90 (mt, 2H:H 5 and H 13); 5,62 (1H:H 2 for d, J=7Hz); 6,52 (s, 1H:H 10); 7,45 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,58 (t, J=7.5Hz, 1H:OCOC 6H 5The H contraposition); 8,09 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-1 β according to following manner, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-propionyl oxygen-11-Japanese yew alkene:
To 1.105g 1 β, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-11-Japanese yew alkene is in 50cm 3Add 1.8cm in the solution that forms in the anhydrous tetrahydro furan 3The pact that the 1M phenyl lithium forms in tetrahydrofuran (THF)-78 ℃ solution.Stir this reaction mixture 15 minutes at about-78 ℃, add 10cm subsequently 3NH 4The Cl saturated aqueous solution.At about 20 ℃, add 20cm 3NH 4Cl saturated aqueous solution and 50cm 3CH 2Cl 2The decant organic phase is used 10cm 3MgSO is used in NaCl saturated aqueous solution liquid washing 2 times 4Drying is filtered, and is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 1.3g product that obtains is the enterprising circumstances in which people get things ready for a trip spectrum purifications of 150g silica gel (0.063-0.2mm) post (eluant: ethyl acetate-hexanaphthene: 10-90, volume) of 5cm at diameter, obtains 18cm 3Cut merges the cut only contain the purpose product, is concentrated into driedly in 40 ℃ of decompressions (2.7KPa), obtains 0.840g white and bakes albumen shape purpose compound, and its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 0,53 (mt, 6H:CH 2Ethyl); 0,65 (mt, 6H:CH 2Ethyl); 0,92 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,00 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,07 (s, 3H:CH 3); 1,14 (s, 3H:CH 3); 1,26 (t, J=7,5Hz, 3H:CH 3 Ethyl4); 1,40 (s, 1H:OH 1); 1,71 (s, 3H:CH 3); 1,88 and 2,45 (2mts, 1H:CH 26); 2,00 (s, 3H:CH 3); 2,06 and 2,18 (2 dd, J=16 and 9Hz, 1H:CH 214); 2,60 (q, J=7.5Hz, 2H:CH 2Ethyl 4) 3,84 (1H:H 3 for d, J=7Hz); 4,14 and 4,30 (2d, J=8,5Hz, 1H:CH 220); 4,26 (d, J=0,5Hz, 1H:OH 10); 4,40 (1H:H 7 for dd, J=11 and 7Hz); 4,90 (d is wide, J=10Hz, 1H:H 5); 4,94 (t is wide, J=9Hz, 1H:H 13); 5,12 (d, J=0,5Hz, 1H:H10); 5,58 (1H:H 2 for d, J=7Hz); 7,45 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,60 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,09 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 1 β according to following manner, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-11-Japanese yew alkene:
To 2.0g1 β, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl)-5 β, 20-epoxy-4 Alpha-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-11-Japanese yew alkene is at 90cm 3CH 2Cl 2Add 3.37g 4-Dimethylamino pyridine and 3.64cm in the middle solution that forms 3Third acid anhydride.About 42 ℃ with reaction mixture heating 8 hours.Add 50cm 3NaCl saturated aqueous solution and 50cm 3CH 2Cl 2The decant organic phase is used 40cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Dry.Filter, be concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the 2.6g product, at 100g silica gel (0.063-0.2mm) post (diameter: carry out chromatogram purification (eluant: ethyl acetate-hexanaphthene: 5-95, volume) 3cm) and obtain fraction 12cm 3, merge and only to contain the cut of purpose product and to be concentrated into driedly in 40 ℃ of decompressions (2.7KPa), obtain 1.97g white and bake albumen shape purpose compound, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 0,50～0,75 (mt, 12H:CH 2Ethyl); 0,94 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,03 (t, J=7,5Hz, 9H:CH 3Ethyl; 1,21 (mt, 6H:CH 3And CH 3Ethyl); 1,28 (s, 3H:CH 3); 1,75 (s, 3H:CH 3); 1,90 and 2,60 (2mts, 1H CH 26); 2,13 (s, 3H:CH 3); 2,15 and 2,38 (2dd, J=16 and 9Hz, 1H:CH 214); 2,43 (mt, 2H:CH 2Ethyl; 3,43 (d, J=5,5Hz, 1H:H 3); 3,51 (s, 3H:OCH 3); 4,18 (s, 2H:OCOCH 2O); 4,46 (1H:H 7 for dd, J=11 and 7Hz); 4,48 and 4,65 (2d, J=9Hz, 2H:CH 220); 4,51 (d, J=5,5Hz, 1H:H 2); 4,93 (d is wide, J=10Hz, 1H:H 5); 5,02 (1H:H 13 for t, J=9Hz); 6,51 (s, 1H:H 10).
Prepare 1 β according to following manner, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-4 Alpha-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-11-Japanese yew alkene:
To 4.12g1 β, 2 alpha-carbon acid esters-4 α, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-11 Japanese yew alkene is at 80cm 3Under stirring and about 0 ℃ of condition, add 2g mealy molecular sieve 4 and 2.86cm in the solution that forms in the pyridine 3The methoxy Acetyl Chloride 98Min..At about 0 ℃ reaction mixture stirred 15 minutes, make it slowly be warming up to about 20 ℃ subsequently.After 4 hours, add 50cm in about 20 ℃ of stirrings 3NH 4Cl saturated aqueous solution and 100cm 3CH 2Cl 2, the decant organic phase is used 40cm 3NH 4CuSO is used in Cl saturated aqueous solution washing 2 times 4Saturated aqueous solution 25cm 3Wash 2 times and use 25cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 5.3g product that obtains carries out chromatogram in diameter is 200g silica gel (0.063-2.2mm) post of 4cm purifies (eluant: ethyl acetate-hexanaphthene: 25-75, volume), obtains gold-plating and divides 12cm 3Merge and only to contain the cut of purpose product and to be concentrated into driedly in 40 ℃ of decompressions (2.7KPa), obtain 4.21g white and bake albumen shape purpose compound.Its physical features is:
-nuclear magnetic resonance spectrum. 1H (400 MHz, CDCl 3, δ ppm): 0,59 (mt, 6H:CH 2Ethyl); 0,73 (mt, 6H:CH 2Ethyl); 0,91 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,02 (t, J=7,5Hz, 9H:CH 3Ethyl; 1,15 (s, 3H:CH 3); 1,18 (s, 3H:CH 3); 1,65 (s, 3H:CH 3); 1,98 and 2,51 (2 mts, 1H:CH 26); 2,15 (s, 3H:CH 3); 2,54 and 2,72 (2dd, J=16 and 9Hz and J=16 and 3Hz, 1H:CH 214); 2,93 (s, 1H:OH 4); 3,03 (1H:H 3 for d, J=5Hz); 3,51 (s, 3H:OCH 3); 4,16 (mt, 1H:H 7); 4,17 (AB, J=18Hz, 2H:OCOCH 2O); 4,37 (1H:H 2 for d, J=5Hz); 4,54 (AB, J=9Hz, 2H:CH 220); 4,76 (d is wide, J=10Hz, 1H:H 5); 4,81 (1H:H 13 for dd, J=9 and 3Hz); 6,51 (s, 1H:H 10).
Prepare 1 β according to following manner, 2 alpha-carbon acid esters-4 α, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-11-Japanese yew alkene:
To 0.400g 7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-1 β, 2 α, 4 α, 10 β-tetrahydroxy-11-Japanese yew alkene is in 10cm 3CH 2Cl 2Add 1cm at about-78 ℃ while stirring in the middle solution that forms 3Pyridine and 0.560g triphosgene.Stirred 2 hours at about-78 ℃, slowly be warming up to about 20 ℃ subsequently.Add 30cm 3NH 4Cl saturated aqueous solution and 20cm 3CH 2Cl 2The decant organic phase is used 40cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The yellow roasting albumen shape thing of the 0.400g that obtains in diameter is 25g silica gel (0.063-0.2mm) post of 2cm, carry out chromatogram purify (eluant: ethyl acetate-hexanaphthene: 20-80, volume) obtain cut 10cm 3Merge and only contain the cut of purpose product and be concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the roasting albumen shape purpose compound of 0.330g white, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 0,54 (mt, 6H:CH 2Ethyl); 0,63 (mt, 6H:CH 2Ethyl); 0,92 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,03 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,11 (s, 3H:CH 3); 1,19 (s, 3H:CH 3); 1,72 (s, 3H:CH 3); 1,98 and 2,46 (2 mts, 1H:CH 26); 2,06 (s, 3H:CH 3); 2,55 and 2,66 (2 dd, J=16 and 9Hz and J=16 and 3Hz, 1H:CH 214); 3,00 (s, 1H:OH 4); 3,13 (1H:H 3 for d, J=5Hz); 4,06 (dd, J=11 and 7Hz, 1H:H7); 4,20 (d, J=2,5Hz, 1H:OH 10); 4,33 (1H:H 2 for d, J=5Hz); 4,55 (AB, J=9Hz, 2H:CH 220); 4,76 (d is wide, J=10Hz, 1H:H 5); 4,82 (1H:H 13 for dd, J=9 and 3Hz); 5,19 (d, J=2,5Hz, 1H:H 10).
Prepare 7 β according to following manner, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-1 β, 2 α, 4 α, 10 β-tetrahydroxy-11-Japanese yew alkene:
To 3.80g 5 β, 20-epoxy-9-oxygen-1 β, 2 α, 4 α, 10 β, 13 α-penta hydroxy group-7 β-triethyl-silicane Oxy-1 1-Japanese yew alkene is in 100cm 3CH 2Cl 2Add 1.20cm at about 0 ℃ while stirring in the middle solution that forms 3Pyridine and 2.48cm 3The chlorine triethyl silicane.Stirred 3 hours at about 0 ℃.Add 100cm 3The NaCl saturated aqueous solution.The decant organic phase is used 100cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the 5.34g orange oil, in diameter is 300g silica gel (0.063-0.2mm) post of 3cm, carry out the chromatogram (scrub solution: ethyl acetate-hexanaphthene: the 25-75 volume) obtain gold-plating and divide 40cm of purifying 3Merge the gold-plating only contain the purpose product and divide and be concentrated into driedly in 40 ℃ of decompressions (2.7KPa), obtain 4.18g white and bake albumen shape purpose product, it is characterized by:
-nuclear magnetic resonance spectrum. 1H (400 MHz, CDCl 3, δ ppm): 0,53 (mt, 6H:CH 2Ethyl); 0,75 (mt, 6H:CH 2Ethyl); 0,91 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,01 (s, 3H:CH 3); 1,03 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,09 (s, 3H:CH 3); 1,63 (s, 3H:CH 3); 1,97 (s, 3H:CH 3); 1,95～2,10 and 2,40 (2mts, 2H:CH 214 and CH 26); 3,17 (s, 1H:OH); 3,18 (d, J=5,5Hz, 1H:H 3); 3,43 (1H:OH 2 for d, J=10Hz); 3,76 (dd, J=10 and 5,5Hz, 1H:H 2); 3,96 (1H:H 7 for dd, J=11 and 6Hz); 4,10 (s, 1H:OH); 4,18 (1H:OH 10 for d, J=3Hz); 4,44 and 4,73 (2d, J=9Hz, 1H:CH 220); 4,64 (d is wide, J=10Hz, 1H:H 5); 4,74 (mt, 1H:H 13); 5,14 (1H:H 10 for d, J=3Hz).
Embodiment 2
To 20.5mg 3-t-butoxycarbonyl amino-2-carbonyl-3-phenyl-(2R, 3S)-and propionic acid 5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester is in 0.2cm 3Acetonitrile and 0.025cm 3Add a 45mg NaCl and a spatula active molecular sieve 4A in the solution that forms in the tetrahydrofuran (THF).Resulting reaction mixture was refluxed in argon atmospher 2 hours.After being cooled to about 20 ℃, desolventize, use 5cm in about 40 ℃ of decompressions (0.27KPa) steaming 3CH 2Cl 2The dissolving residual solid filters and uses 5cm on cotton 3Ethyl acetate-CH 2Cl 2(50-50, volume) mixture cleans, and concentrates organic phase in about 40 ℃ of decompressions (0.27KPa).Therefore obtain the yellow roasting albumen shape product of 17.1mg, with the thin layer preparative chromatography (2 Merck prepare plate, Kieselegel 60F 254, thickness 0.25mm is stored in CH with the solution form 2Cl 2In, eluant: methyl alcohol-CH 2Cl 2Mixture (6-94, volume)) purifies.Using methyl alcohol-CH 2Cl 2(10-90, volume) behind the mixture elution zone corresponding with principal product, filter with sintered glass, steam in about 40 ℃ of decompressions (0.27KPa) subsequently and desolventize, obtain 10.0mg white paint shape 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl (2R, 3S) propionic acid 5 β, 20-epoxy-1 beta-hydroxy-1 beta-methoxy-acetoxyl-7,8 β-methylene radical-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-19-falls-11-Japanese yew alkene-13 α-ester, and its feature is as follows:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 1,18 (t, J=7,5Hz, 3H:CH 3Ethyl); 1,22 (s, 6H:CH 3); 1,32 (s, 9H:C (CH 3) 3); 1,41 (mt, 1H:H 7); 1,69 and 2,23 (2mts, 1H:CH 219); 1,81 (s, 1H:0H 1); 1,85 (s, 3H:CH 3); 2,12 and 2,50 (d and dt, J=16 and J=16 and 4,5Hz, 1H:CH 26); 2,25 and 2,39 (2dd, J=16 and 9Hz, 1H:CH 214); 2,63 (mt, 2H:CH 2Ethyl); 3,23 (mt, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 4,03 (d, J=7Hz, 1H:H3); 4,12 and 4,44 (2d, J=9Hz, 1H:CH 220); 4,20 (the obvious J=16Hz of AB, 2H:OCOCH 2O); 4,62 (mt, 1H:H 2 '); 4,70 (1H:H 5 for d, J=4Hz); 5,22 (mt, 1H:H 3 '); 5,28 (d, J=10Hz, 1H:CONH); 5,58 (1H:H 2 for d, J=7Hz); 6,23 (t is wide, J=9Hz, 1H:H 13); 6,41 (s, 1H:H 10); 7,18 (dd, J=5 and 3,5Hz, 4 of 1H:H2-thenoyl); 7,30～7,50 (mt, 5H: the fragrant H 3 ' in side); 7,67 (d is wide, J=5Hz, 5 of 1H:H2-thenoyl); 7,96 (d is wide, J=3,5Hz, 5 of 1H:H2-thenoyl).
Prepare 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R according to following manner, 3S) propionic acid 5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α :-propionyloxy-2 α-(2-thenoyl oxygen)-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester:
75mg 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-(2R, 4S, 5R)-and carboxylic acid 5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α ester is in 0.77cm 30.1 the solution that forms in the alcohol hydrochloric acid solution is stirred 2 hours at about 5 ℃.Use 10cm subsequently 3CH 2Cl 2Diluted reaction mixture is used 1cm 3Distilled water wash 2 times.Using 1cm 3CH 2Cl 2After the aqueous phase extracted, merge organic phase, use MgSO 4Drying is filtered with sintered glass, concentrates in about 40 ℃ of decompressions (0.27KPa).Therefore obtain the yellow lacquer of 74.4mg shape thing, in diameter is 8g silica gel (0.063-0.2mm) post of 1.5cm, carry out the normal pressure chromatogram (scrub solution: ethyl acetate-CH of purifying 2Cl 2, 5-95 to 20-80, volume), obtain cut 8cm 3Merge and only to contain the cut of purpose product and to be concentrated into driedly in 40 ℃ of decompressions (0.27KPa), last 2 hours.Obtain the light yellow roasting albumen shape purpose compound of 56.3mg; Its feature is as follows
-nuclear magnetic resonance spectrum 1H (400 MHz, CDCl 3, δ Ppm): 1,20 (s, 6H:CH 3); 1,22 (t, J=7.5Hz, 3H:CH 3Ethyl); 1,36 (s, 9H:C (CH 3) 3); 1,71 (s, 1H: 0H 1); 1,89 (s, 3H:CH 3); 2,05 (s, 3H:CH 3); 2,25 and 2,86 (2mts, 1H:CH 26); 2,33 (d, J=9Hz, 2H:CH 214); 2,66 (mt, 2H:CH 2Ethyl); 3,28 (d, J=5Hz, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 3,90 (1H:H 3 for d, J=7Hz); 4,20 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,27 and 4,50 (2d, J=9Hz, 1H:CH 220); 4,61 (mt, 1H:H 2 '); 4,88 (d is wide, J=10Hz, 1H:H 5); 5,20 (the wide J=10Hz of d, 1H:H 3 '); 5,30 (d, J=10Hz, 1H:CONH); 5,50 (1H:H 7 for dd, J=10 and 7Hz); 5,65 (1H:H 2 for d, J=7Hz); 6,18 (t is wide, J=9Hz, 1H:H 13); 6,70 (s, 1H:H 10); 7,18 (dd, J=5 and 3,5Hz, 4 of 1H:H2-thenoyl); 7,30～7,50 (mt, 5H: fragrant H 3 '); 7,69 (dd, J=5 and 1,5Hz, 1H:H2-thiophene first
5 of acyl); 7,92 (dd, J=3,5 and 1,5Hz, 5 of 1H:H2-thenoyl).
Prepare 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1 according to following manner, 3-oxazolidine-5-(2R, 4S, 5R)-and carboxylic acid 5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α (2-thenoyl oxygen)-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester:
To 55.2mg 5 β, 20-epoxy-1 β, 13 alpha-dihydroxy-s-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene is in 0.1cm 3Add 41mg 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1 in the solution that forms in the dry toluene successively, 3-oxazolidine-5 (2R, 4S, 5R) carboxylic acid, 26mg dicyclohexyl carbodiimide and 3mg 4-N, N-Dimethylamino pyridine.This reaction mixture was stirred 2 hours at about 20 ℃ under argon atmospher, and being placed on diameter subsequently is the middle (scrub solution: ethyl acetate-CH of purifying of normal pressure chromatographic column (15g silica gel (0.063-0.2mm)) of 1.5cm 2Cl 25-95 to 10-90, volume) obtains cut 10cm 3Merge and only to contain gold-plating part of purpose product and to be concentrated into driedly in 40 ℃ of decompressions (0.27KPa), last 2 hours.Therefore obtain the roasting albumen shape purpose compound of 75.3mg white, it is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ Ppm): 1,04 (s, 9H:C (CH 3) 3); 1,04 (t, J=7.5Hz, 3H:CH 3Ethyl); 1,14 (s, 3H:CH 3); 1,16 (s, 3H:CH 3); 1,61 (s, 1H:0H 1); 1,68 (s, 3H:CH 3); 1,81 (s, 3H:CH 3); 2,00～2,30 (mt, 4H:CH 2Ethyl and CH 214); 2,03 and 2,80 (2mts, 1H:CH 26); 3,50 (s, 3H:OCH 3); 3,77 (1H:H 3 for d, J=7Hz); 3,81 (s, 3H:ArOCH 3); 4,13 (the obvious J=16Hz of AB, 2H:OCOCH 2O); 4,18 and 4,39 (2d, J=9Hz, 1H:CH 220); 4,48 (d, J=4Hz, 1H:H 2 '); 4,78 (d is wide, J=10Hz, 1H:H 5); 5,35～5,50 (mt, 2H:H 3 ' and H en 7); 5,55 (1H:H 2 for d, J=7Hz); 5,96 (the wide J=9Hz of t, 1H:H 13); 6,34 (mt, 1H:H 5 '); 6,56 (s, 1H:H 10); 6,88 (d, J=8Hz, 2H: fragrant H OCH 3The ortho position); 7,13 (dd, J=5 and 3,5Hz, 4 of 1H:H2-thenoyl); 7,30～7,45 (mt, 5H: fragrant H 3 '); 7,36 (d, J=8Hz, 2H:
Fragrance H OCH 3Between the position); 7,62 (d is wide, J=5Hz, 5 of 1H:H2-thenoyl); 7,80 (d is wide, J=3,5Hz, 5 of 1H:H2-thenoyl.
Prepare 5 β according to following manner, 20-epoxy-1 β, 13 alpha-dihydroxy-s-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene:
To 50mg 5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene is in 0.5cm 3Anhydrous CH 2Cl 2And 0.0255cm 7Drip down 0.0265cm in nitrogen atmosphere and about 0 ℃ in the solution that forms in the pyridine 3Trifluoromethanesulfanhydride anhydride.At about 0 ℃ resulting orange solution stirred 10 minutes, stirred 45 minutes, add 0.1cm subsequently at about 20 ℃ 3Methyl alcohol/CH 2Cl 2(5/95, volume) mixture.It is that the normal pressure chromatographic column (10g silica gel (0.063-0.2mm)) of 1.5cm is purified by (scrub solution: methyl alcohol-methylene dichloride: 2-98 to 5-95, volume) that this solution is placed diameter, obtains 8cm 3Cut merges and only to contain the cut of purpose compound and to be concentrated into driedly in 40 ℃ of decompressions (0.27KPa), lasts 2 hours.Therefore obtain the roasting albumen shape purpose compound of 55.2mg white.
Prepare 5 β according to following manner, 20-epoxy-1 β, 7 β, 13 α-trihydroxy--10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-11-Japanese yew alkene:
To 0.302g 5 β, 20-epoxy-1 beta-hydroxy-1 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-7 β, 13 α-two (silicoheptane alcoxyl base)-11-Japanese yew alkene is in 5cm 3CH 2Cl 2Add 6cm at about 20 ℃ in the middle solution that forms 3Title complex triethylamine-hydrofluoric acid (Et 3N3HF).At about 20 ℃ reaction mixture stirred 24 hours, add 50cm subsequently 3CH 2Cl 2And 100cm 3NaHCO 3Saturated aqueous solution.The decant organic phase is with NaCl saturated aqueous solution 40cm 3Wash 2 times, use MgSO subsequently 4Drying filters and is concentrated in 40 ℃ of decompressions (2.7KPa) dried, therefore obtains 0.24g white and bakes albumen shape purpose compound, it is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 1,07 (s, 3H:CH 3); 1,10 (s, 3H:CH 3); 1,22 (t, J=7,5Hz, 3H:CH 3Ethyl); 1,62 (s, 1H:OH 1); 1,69 (s, 3H:CH 3); 1,89 and 2,63 (2mts, 1H:CH 26); 2,03 (d, J=5,5Hz, 1H:OH 13); 2,07 (s, 3H:CH 3); 2,27 (d, J=9Hz, 2H:CH 214); 2,35 (d, J=4,5Hz, 1H:OH 7); 2,59 (mt, 2H:CH 2Ethyl); 3,52 (s, 3H:OCH 3); 3,84 (1H:H 3 for d, J=7Hz); 4,23 and 4,43 (2d, J=9Hz, 1H:CH 220); 4,25 (the obvious J=16Hz of AB, 2H:OCOCH 2O); 4,49 (mt, 1H:H7); 4,87 (mt, 1H:H 13); 4,95 (d is wide, J=10Hz, 1H:H 5); 5,53 (1H:H 2 for d, J=7Hz); 6,42 (s, 1H:H 10); 7,14 (dd, J=4,5 and 3,5Hz, 4 of 1H:H2-thenoyl); 7,61 (dd, J=4,5 and 1,5Hz, 5 of 1H:H2-thenoyl); 7,83 (dd, J=3,5 and 1,5Hz, 3 of 1H:H2-thenoyl).
Prepare 5 β according to following manner, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen base)-7 β, 13 α-two (silicoheptane alcoxyl base)-11-Japanese yew alkene:
To 0.5g 5 β, 20-epoxy-1 β, 10 beta-dihydroxyies-9-oxygen-4 α-propionyloxy-2 α-(2-thenoyl oxygen)-7 β, 13 α-two (silicoheptane alcoxyl base)-11-Japanese yew alkene is in 10cm 3Add 0.286cm in about 0 ℃ in the solution that forms in the pyridine 3The methoxy Acetyl Chloride 98Min..At about 20 ℃ reaction mixture stirred 10 hours, add 100cm subsequently 3CH 2Cl 2And 50cm 3Saturated NH 4The Cl aqueous solution.The decant organic phase is used NH 4Cl saturated aqueous solution 40cm 3Wash 2 times, use MgSO subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (0.27KPa).Resulting resistates (0.6g) is purified (eluant: ethyl acetate-hexanaphthene: 5-95, volume) by chromatogram by 50g silica gel (0.063-0.2mm) post (diameter 2cm), obtains 10cm 3The gold-plating branch merges the gold-plating branch that only contains the purpose product and is concentrated into dried in 40 ℃ of decompressions (0.27KPa).Obtain the roasting albumen shape purpose compound of 0.320g white, it is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz, CDCl 3, δ ppm): 0,50～0,70 (mt, 12H: CH 2Ethyl): 0,92 (t, J=7,5Hz, 9H:CH 3Ethyl); 0,98 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,09 (s, 3H:CH 3); 1,15 (s, 3H:CH 3); 1,27 (t, J=7,5Hz, 3H:CH 3Ethyl 4); 1,59 (s, 1H:OH 1); 1,65 (s, 3H:CH 3); 1,85 and 2,52 (2mts, 1HCH 26); 2,07 and 2,18 (2dd, J=16 and 9Hz, 1H:CH 214); 2,08 (s, 3H:CH 3); 2,58 (mt, 2H:CH 2Ethyl 4); 3,50 (s, 3H:OCH 3); 3,73 (1H:H 3 for d, J=7Hz); 4,13 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,20 and 4,41 (2d, J=9Hz, 1H:CH 220); 4,49 (1H:H 7 for dd, J=11 and 7Hz); 4,89 (t is wide, J=9Hz, 1H:H 13); 4,91 (d is wide, J=10Hz, 1H:H 5); 5,53 (d, J=7Hz, 1H:H2); 6,51 (s, 1H:H 10); 7,12 (dd, J=4,5 and 3Hz, 4 of 1H:H2-thenoyl); 7,61 (d, J=4,5Hz, 5 of 1H:H2-thenoyl); 7,83 (d, J=3Hz, 3 of 1H:H2-thenoyl).
Prepare 5 β according to following mode, 20-epoxy-1 β, 10 beta-dihydroxyies-9-oxygen-4 α-propionyl oxygen-2 α-(2-thenoyl oxygen)-7 β, 13 α-two (silicoheptane alcoxyl base)-11-Japanese yew alkene:
To 0.5g1 β, 2 alpha-carbon acyl dioxy-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-propionyl oxygen-7 β, 13 α-two (silicoheptane alcoxyl base)-11-Japanese yew alkene is in 20cm 3Add 1.5cm down in argon atmospher peace treaty-78 ℃ in the solution that forms in the tetrahydrofuran (THF) 3The solution of 1M2-thienyl lithium in tetrahydrofuran (THF).Reaction mixture in about-78 ℃ of stirrings 35 minutes, is added 1cm subsequently 3NH 4The Cl saturated aqueous solution.At about 20 ℃, add 10cm 3NH 4Cl saturated aqueous solution and 50cm 3CH 2Cl 2The decant organic phase is used 10cm 3NaCl saturated aqueous solution washing 2 times.Use MgSO subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 0.65g solid that obtains is at 90g silica gel (0.063-0.2mm) post (diameter: carry out chromatogram purification (scrub solution: ethyl acetate-hexanaphthene 1cm); The 10-90 volume), obtain 10cm 3Cut.Merge and only contain the cut of purpose compound and be concentrated into dried in 40 ℃ of decompressions (0.27KPa).Obtain the roasting albumen shape purpose compound of 0.511g white.Its physical features is:
-nuclear magnetic resonance spectrum 1H (600MHz, CDCl 3, δ ppm): 0,57 (mt, 6H:CH 2Ethyl); 0,68 (mt, 6H:CH 2Ethyl); 0,95 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,01 (t, J=7,5Hz, 9H:CH 3Ethyl); 1,07 (s, 3H:CH 3); 1,17 (s, 3H:CH 3); 1,27 (t, J=7,5Hz, 3H:CH 3Ethyl 4); 1,73 (s, 3H:CH 3); 1,90 and 2,47 (2mts, 1H:CH 26); 2,02 (s, 3H:CH 3); 2,09 and 2,18 (2dd, J=16 and 9Hz, 1H:CH 214); 2,60 (mt, 2H:CH2 ethyls 4); 3,82 (1H:H 3 for d, J=7Hz); 4,24 and 4,44 (2d, J=9Hz, 1H:CH 220); 4,26 (d, J=0,5Hz, 1H:OH 10); 4,42 (1H:H 7 for dd, J=11 and 7Hz); 4,93 (d is wide, J=10Hz, 1H:H 5); 4,97 (t is wide, J=9Hz, 1H:H13); 5,13 (d, J=0,5Hz, 1H:H 10); 5,53 (d, J=7Hz, 1H:H2); 7,15 (dd, J=4,5 and 3Hz, 4 of 1H:H2-thenoyl); 7,63 (d, J=4,5Hz, 5 of 1H:H2-thenoyl; 7,85 (d, J=3Hz, 3 of 1H:H2-thenoyl.
Embodiment 3
To 154mg 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S)-propionic acid 2 α-benzoyloxy-4 α-butyryl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester and 2cm 3Add 96mg powdery 4A molecular sieve, 225mg NaCl successively in the solution that acetonitrile and 200 μ l tetrahydrofuran (THF)s form.At about 75 ℃ reaction mixture stirred 5 hours,, add 15cm subsequently at about 20 ℃ 3CH 2Cl 2And 10cm 3The NaCl saturated aqueous solution.The decant organic phase is with NaCl saturated aqueous solution 20cm 3Wash 2 times, use MgSO subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the 133mg product, with chromatography (80g silica gel, the 0.063-0.2mm) (scrub solution: CH of in diameter is the post of 1cm, purifying 2Cl 2-CH 3The OH:98/2 volume), obtain 10cm 3Cut.The fraction that wherein only contains required compound is merged, be depressurized (2.7KPa) in 40 ℃ and be concentrated into the roasting albumen shape 3-t-butoxycarbonyl amino of the dried 63mg of obtaining white-2-hydroxyl-3-phenyl-(2R, 4S) propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-7 β, 8-methylene radical-19-falls-9-oxygen-4 α-butyryl acyloxy-11-Japanese yew alkene-13 α-ester, it is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz; CDCl 3δ ppm): 0,92 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,26 (s, 6H:CH 3); 1,31 (s, 9H:C (CH 3) 3); 1,42 (mt, 1H:H 7); 1,71 and 2,26 (2mts, 1H:CH 219); 1,60～1,85 (mt, 2H:CH 2Propyl group); 1,86 (s, 3H:CH 3); 1,88 (s, 1H:OH 1); 2,12 2,50 (the wide and mt of d, J=16Hz, 1H:CH 26); 2,23 and 2,39 (mt and dd, J=16 and 9Hz, 2H:CH 214); 2,49 and 2,65 (2mts, 1H:OCOCH 2Propyl group); 3,25 (mt, 1H:OH 2 '); 3,51 (s, 3H:OCH 3); 4,05 and 4,32 (2d, J=9Hz, 1H:CH 220); 4,10 (1H:H 3 for d, J=7Hz); 4,16 and 4,22 (2d, J=16Hz, 1H:OCOCH 2O); 4,62 (mt, 1H:H 2 '); 4,68 (d is wide, J=4,5Hz, 1H:H en 5); 5,25 (d is wide, J=10Hz, 1H:H en 3 '); 5,30 (d, J=10Hz, 1H:CONH); 5,65 (1H:H 2 for d, J=7Hz); 6,23 (t is wide, J=9Hz, 1H:H 13); 6,42 (s, 1H:H10); 7,25～7,45 (mt, 5H: fragrant H 3 '); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,62 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,16 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R according to following manner, 4S)-and propionic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester:
With 400mg 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-(2R, 4S, 5R) carboxylic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-7 β-trifluoromethanesulfonic acid base-11-Japanese yew alkene-13 α-ester is at 6.4cm 30.1N the solution that forms in the alcohol hydrochloric acid solution stirred 6 hours down at about 0 ℃, stirred 15 hours at about 20 ℃ subsequently.Be concentrated into dried in 20 ℃ of decompressions (2.7KPa).Reacting coarse product is dissolved in 20cm 3CH 2Cl 2And 10cm 3NaHCO 3Saturated aqueous solution.Decant separates organic phase, uses 20cm 3CH 2Cl 2Extract 2 times.Merge organic phase, use 30cm 3Distilled water wash is used MgSO 4Dry.Filter and be concentrated into dried in 20 ℃ of decompressions (2.7KPa).Obtain the 410mg product, in 60g silica gel (0.063-0.2mm) post (diameter is 1cm), carry out chromatogram purification (scrub solution: CH 2Cl 2-methyl alcohol: the 95.5-1.5 volume), obtain 10cm 3The gold-plating branch.Merge the gold-plating branch that only contains required compound and be concentrated into dried in 20 ℃ of decompressions (2.7KPa).Obtain the roasting albumen shape purpose compound of 307mg white, its physical features is:
-nuclear magnetic resonance spectrum 1H (400MHz; CDCl 3δ ppm): 0,93 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,22 (s, 3H:CH 3); 1,24 (s, 3H:CH 3); 1,35 (s, 9H:C (CH 3) 3); 1.65～1,85 (mt, 2H:CH 2Propyl group); 1,74 (s, 1H:OH 1); 1,88 (s, 3H:CH 3); 2,04 (s, 3H:CH 3); 2,25 and 2,86 (2mts, 1H:CH 26); 2,33 (d, J=9Hz, 2H:CH 214); 2,52 and 2,66 (2mts, J=14,5 and 6,5Hz, 1H:OCOCH 2
Propyl group); 3,33 (d, J=4Hz, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 3,94 (1H:H 3 for d, J=7Hz); 4,16 and 4,21 (2 d, J=16Hz, 1H:OCOCH 2O); 4,19 and 4,35 (2d, J=9Hz, 1H:CH 220); 4,62 (mt, 1H:H 2 '); 4,86 (d is wide, J=10Hz, 1H:H 5); 5,22 (d is wide, J=10Hz, 1H:H 3 '); 5,33 (d, J=10Hz, 1H:CONH); 5,50 (1H:H 7 for dd, J=11 and 8Hz); 5,73 (1H:H 2 for d, J=7Hz); 6,16 (t is wide, J=9Hz, 1H:H 13); 6,71 (s, 1H:H 10); 7,25～7,45 (mt, 5H: fragrant H 3 '); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,12 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position)
Prepare 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1 according to following manner, 3-oxazolidine-5 (2R, 4S, 5R) carboxylic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4-butyryl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene-13 α-ester:
To by 400mg 2 α-benzoyl oxygen-1 β, 13 alpha-dihydroxy-s-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene is at 10cm 3Add 247mg 3-tertbutyloxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1 in the solution that forms in the anhydrous ethyl acetate successively, and 3-oxazolidine-5 (2R, 4S, 5R)-carboxylic acid, 186mg dicyclohexyl carbodiimide and 12.5mg 4-Dimethylamino pyridine.In argon atmospher, reaction mixture being stirred 15 hours, be concentrated into dried in 40 ℃ of decompressions (2.7KPa) at about 20 ℃. the 1g product that obtains carries out chromatogram purification (scrub solution: CH in 100g silica gel (0.063-0.2mm) post (diameter is 3cm) 2Cl 2-methyl alcohol: the 95-5 volume), obtain 12cm 3Gold-plating part.Merge only contain the fraction of purpose compound and be concentrated in 40 ℃ of decompressions (2.7KPa) dried, 410mg white is baked albumen shape purpose compound, its physical features is:
Nuclear magnetic resonance spectrum 1H (400 MHz; CDCl 3δ ppm): 0,92 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,07 (s, 9H:C (CH 3) 3); 1,17 (s, 6H:CH 3); 1,55～1,70 (mt, 3H:CH 2Propyl group and OH 1); 1,64 (s, 3H:CH 3); 1,84 (s, 3H:CH 3); 2,08 and 2,15～2,30 (dd and mt, J=16 and 9Hz, 1H:CH 214) 2,15～2,30 and 2,82 (2mts, 1H:CH 26); 2,15～2,30 (mt, 2H:OCOCH 2Propyl group); 3,51 (s, 3H:OCH 3); 3,82 (s, 3H:ArOCH 3); 3,83 (d, J=7Hz, 1H:H3); 4,12 and 4,28 (2d, J=9Hz, 1H:CH 220); 4,14 and 4,22 (2d, J=16Hz, 1H:OCOCH 2O); 4,52 (d is wide, J=4,5Hz, 1H:Hen2 '); 4,79 (d is wide, J=10Hz, 1H:H en 5); 5,35～5,50 (mt, 1H:H en 3 '); 5,44 (1H:H 7 for dd, J=9 and 7Hz); 5,67 (1H:H 2 for d, J=7Hz); 5,99 (t is wide, J=9Hz, 1H:H 13); 6,40 (mf, 1H:H 5 '); 6,59 (s, 1H:H 10); 6,92 (d, J=8,5Hz, 2H: fragrant HOCH 3); 7,25～7,45 (mt, 5H: fragrant H 3 '); 7,37 (d, J=8,5Hz, 2H: fragrant H OCH 3Between the position); 7,48 (t, J=7,5Hz, 2H:OCOC 6H 5H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,11 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-1 β according to following method, 13 alpha-dihydroxy-s-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-7 β-fluoroform sulphonyl oxygen-11-Japanese yew alkene:
To 389mg 2 α-benzoyl oxygen-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene is in 6cm 3Anhydrous CH 2Cl 2With about 0 ℃ and be maintained at and drip 410 μ l trifluoromethanesulfanhydride anhydrides in the solution in the argon atmospher that forms in the 390 μ l pyridines.At about 0 ℃ the orange solution that obtains stirred 15 minutes, add 3cm subsequently 3Water and 50cm 3CH 2Cl 2The decant organic phase is used 40cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 510mg product that obtains is with 70g silica gel (0.063-0.2mm) post (diameter: 1cm) carry out the chromatogram (scrub solution: CH of purifying 2Cl 2-methyl alcohol: 95-5, volume), obtain 10cm 3Cut merges the gold-plating part that only contains required compound and is concentrated into dried at 40 ℃ reduce pressure down (2.7KPa).Obtain the roasting albumen shape purpose compound of 410mg white, its physical features is:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3δ ppm): 1,06 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,06 (s, 3H:CH 31,20 (s, 3H:CH 3); 1,63 (s, 1H:OH 1); 1,77 (mt, 2H:CH 2Propyl group); 1,87 (s, 3H:CH 3); 2,18 (1H:OH 13 for d, J=5Hz); 2,15～2,40 (AB is obvious, 2H:CH 214); 2,15～2,40 and 2,89 (2mts, 1H:CH 26); 2,25 (s, 3H:CH 3); 2,59 (AB is obvious, J=16 and 7,5Hz, 2H:OCOCH 2Propyl group); 3,51 (s, 3H:OCH 3); 4,03 (d, J=7Hz, 1H:H3); 4,16 and 4,24 (2d, J=16Hz, 1H:OCOCH 2O); 4,18 and 4,35 (2d, J=9Hz, 1H:CH 220); 4,85 (mt, 1H:H13); 4,92 (d is wide, J=10Hz, 1H:H5); 5,57 (dd, J=10,5 and 7Hz, 1H:H7); 5,68 (d, J=7Hz, 1H:H2); 6,73 (s, 1H:H10); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,10 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-5 β according to following manner, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene:
To 580mg 2 α-benzoyl oxygen-7 β, 13 α-two (silicoheptane alcoxyl)-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-11-Japanese yew alkene is in 5cm 3CH 2Cl 2Add 5.5cm in about 20 ℃ in the middle solution that forms 3Title complex triethylamine-hydrofluoric acid.At about 20 ℃ reaction mixture stirred 23 hours, add 50cm subsequently 3CH 2Cl 2And 100cm 3NaHCO 3Saturated aqueous solution.The decant organic phase is used 20cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 520mg product that obtains is by the chromatogram (scrub solution: MeOH-CH of purifying in 70g silica gel (0.063-0.2mm) post of 2cm at diameter 2Cl 2(5-95, volume)), obtain 10cm 3Cut.Merge and only contain the cut of purpose compound and be concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the roasting albumen shape purpose product of 389mg white, its physical features is:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 1,05 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,11 (s, 6H:CH 3); 1,67 (s, 3H:CH 3); 1,71 (s, 1H:OH 1); 1,75 (mt, 2H:CH 2Propyl group); 1,85 and 2,45～2,65 (2mts, 1H:CH 26); 2,05 (s, 3H:CH 3); 2,24 (d, J=5Hz, 1H:OH); 2,28 (AB is obvious, J=16 and 9Hz, 2H:CH 214); 2,40 (d, J=4Hz, 1H:OH); 2,56 (AB is obvious, 2H:OCOCH 2Propyl group); 3,51 (s, 3H:OCH 3); 3,88 (1H:H 3 for d, J=7Hz); 4,15 and 4,32 (2d, J=9Hz, 1H *: CH 220); 4,23 (AB is obvious, J=16Hz, 2HOCOCH 2O); 4,48 (mt, 1H:H 7); 4,86 (mt, 1H:H 13); 4,94 (d is wide, J=10Hz, 1H:H 5); 5,62 (1H:H 2 for d, J=7Hz); 6,43 (s, 1H:H 10); 7,49 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,62 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,12 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-7 β according to following manner, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-11-Japanese yew alkene:
To 906mg 2 α-benzoyl oxygen-1 β, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-butyryl oxygen-11-Japanese yew alkene is in 18cm 3Add 1.03cm in about 0 ℃ in the solution that forms in the pyridine 3The methoxy Acetyl Chloride 98Min..At about 20 ℃ reaction mixture stirred 14 hours, add 20cm subsequently 3CH 2Cl 2And 20cm 3NH 4The Cl saturated aqueous solution.The decant organic phase is used 20cm 3CuSO 4NH is used in saturated aqueous solution washing 4 times 4Cl saturated aqueous solution 40cm 3Wash 2 times, use MgSO subsequently 4Drying is filtered and reduce pressure under 40 ℃ (2.7KPa) are concentrated into dried.The 800mg product that obtains is at 100g silica gel (0.063-0.2mm) post (diameter: carry out chromatogram purification (scrub solution: MeOH-CH 2.5cm) 2Cl 2: 2-98, volume), obtain cut 15cm 3Merge and only contain the cut of purpose compound and be concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the roasting albumen shape purpose compound of 580mg white, its physical features is:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3δ ppm): 0,60 and 0,68 (2mts, 6H:CH 2Ethyl); 0,95 and 1,04 (2t.J=7,5Hz, 9H:CH 3Ethyl); 1,09 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,13 (s, 3H:CH 3); 1,18 (s, 3H:CH 3); 1,64 (s, 1H:OH 1); 1,68 (s, 3H:CH 3); 1,84 (mt, 2H:CH 2Propyl group); 1,89 and 2,50 (2mts, 1H:CH 26); 2,11 and 2,23 (2dd, J=16 and 9Hz, 1H:CH 214); 2,13 (s, 3H:CH 3); 2,55 (mt, 2H:OCOCH 2Propyl group); 3,53 (s, 3H:O CH 3); 3,82 (1H:H 3 for d, J=7Hz); 4,13 and 4,31 (2d, J=9Hz, 1H:CH 220); 4,16 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,52 (1H:H 7 for dd, J=11 and 7Hz); 4,91 (mt, 1H:H 13); 4,93 (d is wide, J=10Hz, 1H:H 5); 5,64 (1H:H 2 for d, J=7Hz); 6,54 (s, 1H:H 10); 7,47 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,61 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,11 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 2 α-benzoyl oxygen-1 β according to following manner, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-butyryl oxygen-11-Japanese yew alkene:
To 907mg1 β, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-11-Japanese yew alkene is in 50cm 3Add 2.34cm in the solution that forms in the anhydrous tetrahydro furan 3The pact that the 1M phenyl lithium forms in tetrahydrofuran (THF)-78 ℃ solution.Stirred 1 hour at about-78 ℃, add 10cm subsequently 3NH 4The Cl saturated aqueous solution.At about 20 ℃, add 20cm 3NH 4Cl saturated aqueous solution and 50cm 3CH 2Cl 2The decant organic phase is used 10cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times 4Drying is filtered, and is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 1.3g product that obtains is the enterprising circumstances in which people get things ready for a trip spectrum purifications of 150g silica gel (0.063-0.2mm) post (eluant: ethyl acetate-hexanaphthene: 10-90, volume) of 5cm at diameter, obtains 18cm 3Cut merges the cut only contain the purpose product, is concentrated into driedly in 40 ℃ of decompressions (2.7KPa), obtains 906mg white and bakes albumen shape purpose compound, and its physical features is:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3δ ppm): 0,56 and 0,67 (2mts, 6H:CH 2Ethyl); 0,95 and 1,03 (2t, J=7,5Hz, 9H:CH 3Ethyl); 1,08 (s, 3H:CH 3); 1,10 (t, J=7,5Hz, 3H:CH 3Propyl group); 1,18 (s, 3H:CH 3); 1,60 (s, 1H:OH 1); 1,73 (s, 3H:CH 3); 1,84 (mt, 2H:CH 2Propyl group); 1,91 and 2,48 (2rnts, 1H:CH 26); 2,03 (s, 3H:CH 3); 2,11 and 2,22 (2dd, J=16 and 9Hz, 1H:CH 214); 2,58 (mt, 2H:OCOCH 2Propyl group); 3,87 (1H:H 3 for d, J=7Hz); 4,18 and 4,32 (2d, J=9Hz, 1H:CH 220); 4,28 (1H:OH 10 for d, J=2Hz); 4,42 (dd, J=10,5 and 6,5Hz, 1H:H 7); 4,93 (d is wide, J=10Hz, 1H:H 5); 4,98 (1H:H 13 for t, J=9Hz); 5,17 (1H:H 10 for d, J=2Hz); 5,62 (1H:H 2 for d, J=7Hz); 7,49 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,61 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,12 (d, J=7,5Hz, 2H:OCOC 6H 5The ortho position).
Prepare 1 β according to following manner, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-butyryl oxygen-11-Japanese yew alkene:
To 870mg1 β, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl)-5 β, 20-epoxy-4 Alpha-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-11-Japanese yew alkene is at 15Cm 3CH 2Cl 2Add 1.46g 4-Dimethylamino pyridine and 3.90cm in the middle solution that forms 3Butanoic anhydride.About 42 ℃ with reaction mixture heating 45 hours.Add 50cm 3NaCl saturated aqueous solution and 50cm 3CH 2Cl 2The decant organic phase is used 40cm 3MgSO is used in NaCl saturated aqueous solution washing 2 times subsequently 4Dry.Filter, be concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain the 2.0g product, at 170g silica gel (0.063-0.2mm) post (diameter: carry out chromatogram 3cm) and purify (eluant: ethyl acetate-hexanaphthene: 5-95, volume), obtain gold-plating part 15cm 3, merge the gold-plating only contain the purpose product and divide and be concentrated into driedly in 40 ℃ of decompressions (2.7KPa), obtain 1.00g white and bake albumen shape purpose compound, its physical features is:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3: δ ppm): 0,50～0,70 (mt, 12H:CH 2Ethyl); 0,90～1,10 (mt, 21H:CH 3Ethyl and CH 3Propyl group); 1,18 (s, 3H:CH 3); 1,28 (s, 3H:CH 3); 1,73 (mt, 2H:CH 2Propyl group); 1,75 (s, 3H:CH 3); 1,92 and 2,59 (2mts, 1H:CH 26); 2,13 (s, 3H:CH 3); 2,14 and 2,35～2,45 (dd and mt, J=16 and 9Hz, 1H:CH 214); 2,35～2,45 (mt, 2H:OCOCH 2Propyl group); 3,42 (d, J=6,5Hz, 1H:H 3); 3,51 (s, 3H:OCH 3); 4,18 (s, 2H:OCOCH 2O); 4,46 (dd, J=10 and 6,5Hz, 1H:H 7); 4,50 and 4,63 (2d, J=9Hz, 1H:CH 220); 4,51 (d, J=6,5Hz, 1H:H 2); 4,93 (d is wide, J=10Hz, 1H:H 5); 5,02 (the wide J=9Hz of t, 1H:H 13); 6,51 (s, 1H:H 10).
Embodiment 4
Operate according to embodiment 3, with 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S) propionic acid 2 α-benzoyloxy-4 α-phenylacetic acid base-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is a raw material, obtain 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S) propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-7 β, 8-methylene radical-19-falls-9-oxygen-4 α-phenylacetic acid base-11-Japanese yew alkene-13 α-ester, it is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 1,24 (s, 15H:CH 3-CH 3And C (CH 3) 3); 1,40 (mt, 1H:H 7); 1,66 and 2,24 (2dd, J=6 and 5Hz and J=10 and 6Hz, 1H:CH 219); 1,92 (s, 1H:OH 1); 1,96 (s, 3H:CH 3); 2,07 and 2,46 (the wide and dt of d, J=16Hz and J=16 and 4,5Hz, 1H:CH 26); 2,32 and 2,54 (dd and dd are wide, J=16 and 9Hz, 1H:CH 214); 3,24 (mt, 1H:OH 2 '); 3,53 (s, 3H:OCH 3); 3,90 and 4,14 (2d, J=15Hz, 1H:OCOCH 2Ar); 4,00 and 4,16 (2d, J=9Hz, 1H:CH 220); 4,20 and 4,26 (2d, J=16Hz, 1H:OCOCH 2O); 4,23 (1H:H 3 for d, J=7Hz); 4,55 (d is wide, J=4, and 5Hz, 1H:H 5); 4,63 (mt, 1H:H 2 '); 5,31 (AB is obvious, 2H:H3 ' and CONH); 5,71 (1H:H 2 for d, J=7Hz); 6,34 (t is wide, J=9Hz, 1H:H13); 6,44 (s, 1H:H 10); 7,10～7,45 (mt, 10H: fragrant H and fragrant H3 '); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,16 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under operate, preparation 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S)-propionic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-phenylacetic acid base-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 1,24 (s, 6H:CH 3); 1,36 (s, 9H:C (CH 3) 3); 1,74 (s, 1H:OH 1); 1,87 (s, 3H:CH 3); 2,14 (s, 3H:CH 3); 2,19 and 2,83 (2mts, 1H:CH 26); 2,39 and 2,48 (2dd is wide, J=16 and 9Hz, 1H: CH 214); 3,38 (d, J=4,5Hz, 1H:OH 2 '); 3,53 (s, 3H:OCH 3); 3,90 and 4,14 (2d, J=15Hz, 1H:OCOCH 2Ar); 4,01 (1H:H 3 for d, J=7Hz); 4,11 and 4,20 (2d, J=9Hz, 1H:CH 220); 4,17 and 4,25 (2d, J=16Hz, 1H:OCOCH 2O); 4,65 (mt, 1H:H 2 '); 4,68 (d is wide, J=10Hz, 1H:H5); 5,28 (d is wide, J=10Hz, 1H:H 3 '); 5,35 (d, J=10Hz, 1H:CONH); 5,50 (1H:H 7 for dd, J=10 and 7 Hz); 5,77 (1H:H 2 for d, J=7Hz); 6,28 (t is wide, J=9Hz, 1H:H 13); 6,74 (s, 1H:H 10); 7,15～7,45 (mt, 10H: fragrant H and fragrant H 3 '); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,66 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,08 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under the preparation 3-tertbutyloxycarbonyl-2-(4-p-methoxy-phenyl)-4-phenyl-1,3-oxazolidine-5 (2R, 4S, 5R) carboxylic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-phenylacetic acid base-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3Temperature is 333 ° of K, δ ppm): 1,06 (s, 9H:C (CH 3) 3); 1,12 (s, 3H:CH 3); 1,24 (s, 3H:CH 3); 1,66 (s, 1H:OH1); 1,83 (s, 3H:CH 3); 1,86 (s, 3H:CH 3); 2,14 and 2,79 (2mts, 1H:CH 26); 2,24 and 2,30 (2dd, J=16 and 9Hz, 1H:CH 214); 3,45 and 3,58 (2d, J=15Hz, 1H:OCOCH 2Ar); 3,54 (s, 3H:OCH 3); 3,85 (s, 3H:ArOCH 3); 3,94 (1H:H 3 for d, J=7Hz); 4,08 and 4,17 (2d, J=9Hz, 1H:CH 220); 4,14 and 4,22 (2d, J=16Hz, 1H:OCOCH 2O); 4,59 (d is wide, J=10Hz, 1H:H 5); 4,63 (d, J=5,5Hz, 1H:H 2 '); 5,45 (d, J=5,5Hz, 1H:H3 '); 5,47 (mt, 1H:H7); 5,72 (d, J=7Hz, 1H:H2); 6,14 (t is wide, J=9Hz, 1H:H13); 6,34 (s, 1H:H 5 '); 6,65 (s, 1H:H 10); 6,94 (d, J=8,5Hz, 2H: fragrant HOCH 3The ortho position); 7,20～7,45 (mt, 12H: position and Haro fragrance H 3 ' between fragrant H and fragrant HOCH3); 7,48 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,64 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 7,98 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position)
With embodiment 3 operate under the also similar condition, obtain 2 α-benzoyl oxygen-1 β, 13 alpha-dihydroxy-s-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-phenylacetic acid base-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 1,07 (s, 3H:CH 3); 1,21 (s, 3H:CH 3); 1,64 (s, 1H:OH 1); 1,87 (s, 3H:CH 3); 2,18 (d, J=4,5Hz, 1H:OH13); 2,20 and 2,88 (2mts, 1H:CH 26); 2,30 (s, 3H:CH 3); 2,25～2,35 (mt, 2H:CH 214); 3,52 (s, 3H:OCH 3); 3,90 and 3,97 (2d, J=15Hz, 1H:OCOCH 2Ar); 4,08 (1H:H 3 for d, J=7Hz); 4,12 and 4,27 (2d, J=9Hz, 1H:CH 220); 4,16 and 4,24 (2d, J=16Hz, 1H:OCOCH 2O); 4,80 (d is wide, J=10Hz, 1H:H 5); 4,92 (mt, 1H:H 13); 5,55 (dd, J=10 and 6,5Hz, 1H:H7); 5,71 (1H:H 2 for d, J=7Hz); 6,74 (s, 1H:H 10); 7,25～7,45 (mt, 5H: fragrant H); 7,48 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,64 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,03 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under operate, obtain 2 α-benzoyl oxygen-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-phenylacetic acid base-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3: δ ppm): 1,12 (s, 3H:CH 3); 1,14 (s, 3H:CH 3); 1,66 (s, 1H:OH 1); 1,67 (s, 3H:CH 3); 1,84 and 2,56 (2mts, 1H:CH 26); 2,11 (s, 3H:CH 3); 2,20～2,45 (2mts, 1H:OH); 2,35 and 2,42 (2dd, J=16 and 9Hz, 1H:CH 214); 3,54 (s, 3H:OCH 3); 3,94 (AB is obvious, J=15Hz, 2H:OCOCH 2Ar); 3,94 (1H:H 3 for d, J=7Hz); 4,12 and 4,25 (2d, J=9Hz, 1H:CH 220); 4,26 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,50 (mt, 1H:H 7); 4,87 (d is wide, J=10Hz, 1H:H 5); 4,96 (mt, 1H:H 13); 5,66 (1H:H 2 for d, J=7Hz); 6,44 (s, 1H:H 10); 7,25～7,45 (mt, 5H: aromatics H); 7,47 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,62 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,04 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under the preparation 2 α-benzoyl oxygen-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-phenylacetic acid base-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 0,60 and 0,72 (2mts, 6H:CH 2Ethyl); 0,94 and 1,05 (2t, J=7,5Hz, 9H:CH 3Ethyl); 1,15 (s, 3H:CH 3); 1,22 (s, 3H:CH 3); 1,66 (s, 3H:CH 3); 1,69 (s is wide, 1H:OH1); 1,84 and 2,51 (2mts, 1H:CH 26); 2,20 (s, 3H:CH 3); 2,24 and 2,36 (2dd, J=16 and 9Hz, 1H:CH 2En 14); 3,54 (s, 3H:OCH 3); 3,82 and 3,96 (2d, J=15Hz, 1H:OCOCH 2Ar); 3,89 (1H:H 3 for d, J=7Hz); 4,06 and 4,16 (2d, J=9Hz, 1H:CH 220); 4,20 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,52 (1H:H 7 for dd, J=10 and 6Hz); 4,79 (d is wide, J=10Hz, 1H:H 5); 4,96 (t is wide, J=9Hz, 1H:H 13); 5,66 (1H:H 2 for d, J=7Hz); 6,58 (s, 1H:H10): 7,25～7,45 (mt, 7H: fragrant H and OCOC 6H 5Position between H); 7,61 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,00 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under the preparation 2 α-benzoyl oxygen-1 β, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-phenylacetic acid base-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (600 MHz; CDCl 3δ ppm): 0,53 and 0,72 (2mts, 6H:CH 2Ethyl); 0,94 and 1,05 (2t, J=7,5Hz, 9H:CH 3Ethyl); 1,10 (s, 3H:CH 3); 1,20 (s, 3H:CH 3); 1,64 (s, 1H:OH 1); 1,70 (s, 3H:CH 3); 1,86 and 2,45 (2mts, 1H:CH 26); 2,10 (s, 3H:CH 3); 2,20 and 2,32 (2dd, J=16 and 9Hz, 1H:CH 214), 3,80 and 3,96 (2d, J=16Hz, 1H:OCOCH 2Ar); 3,95 (1H:H 3 for d, J=7Hz); 4,07 and 4,17 (2d, J=9Hz, 1H:CH 220); 4,29 (s is wide, and 1H:OH 10); 4,43 (dd, J=11 and 7Hz, 1H:H7); 4,79 (d is wide, J=10Hz, 1H:H 5); 5,03 (t is wide, J=9Hz, 1H:H 13); 5,19 (s is wide, and 1H:H 10); 5,63 (1H:H 2 for d, J=7Hz); 7,25～7,45 (mt, 7H: fragrant H and OCOC 6H 5Position between H); 7,60 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,00 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Preparation 1 β under the condition similar to embodiment 3,2 alpha-carbon acid esters-7 β, 13 α-two (triethyl silicane oxygen base)-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-phenylacetic acid base-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3δ ppm): 0,61 and 0,74 (2mts, 6H:CH 2Ethyl); 0,92 and 1,05 (2t, J=7,5Hz, 9H:CH 3Ethyl); 1,20 (s, 3H:CH 3); 1,30 (s, 3H:CH 3); 1,73 (s, 3H:CH 3); 1,83 and 2,54 (2mts, 1H:CH 26); 2,18 (s, 3H:CH 3); 2,27 and 2,48 (2dd, J=16 and 9Hz, 1H:CH 214); 3,50 (d, J=6,5Hz, 1H:H 3); 3,53 (s, 3H:OCH 3); 3,65 (AB is obvious, J=14Hz, 2H:OCOCH 2Ar); 4,18 (AB is obvious, 2H:OCOCH 2O); 4,45 and 4,53 (2d, J=9Hz, 1H:CH 220); 4,46 (mt, 1H:H 7); 4,53 (d, J=6,5Hz, 1H:H 2); 4,68 (d is wide, J=10Hz, 1H:H 5); 5,06 (t is wide, J=9Hz, 1H:H 13); 6,53 (s, 1H:H 10); 7,25～7,45 (mt, 5H: fragrant H).
Embodiment 5
Operate according to embodiment 3, with 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S) propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is a raw material, obtain 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S) propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-4 α, 10 β-two (methoxyimino acetic acid base)-7 β, 8-methylene radical-19-falls-9-oxygen-11-Japanese yew alkene-13 α-ester, it is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCCl 3Temperature is 333 ° of K, δ ppm): 1,26 (s, 3H:CH 3); 1,29 (s, 3H:CH 3); 1,35 (s, 9H:C (CH 3) 3); 1,42 (mt, 1H:H 7); 1,71 and 2,29 (dd and mt, J=6,5 and 5Hz, 1H:CH 219); 1,81 (s, 1H:OH 1); 1,91 (s, 3H:CH 3); 2,15 and 2,54 (the wide and dt of d, J=16Hz and J=16 and 4,5Hz, 1H:CH 26); 2,32 (AB is obvious, 2H:CH 214); 3,50 and 3,53 (2s, 3H:OCH 3); 3,60 (mf, 1H:OH 2 '); 4,11 and (2d, J=16Hz, 1H:OCOCH 2O); 4,12 and 4,31 (2d, J=9Hz, 1H:CH 220); 4,17 (d, J=7Hz, 1H:H3); 4,19 and 4,24 (2d, J=16Hz, 1H:OCOCH 2O); 4,67 (mt, 1H:H 2 '); 4,78 (d, J=4,5Hz, 1H:H 5); 5,29 (d is wide, J=10Hz, 1H:H 3 '); 5,47 (d, J=10Hz, 1H:CONH); 5,70 (1H:H 2 for d, J=7Hz); 6,21 (t is wide, J=9Hz, 1H:H 13); 6,44 (s, 1H:H 10); 7,30 (t, J=7,5Hz, 1H:H aromatic ring contraposition 3 '); 7,39 (t, J=7,5Hz, position 3 between the 2H:H aromatic ring '); 7,45 (d, J=7,5Hz, 2H:H aromatic ring ortho position 3 '); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,61 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,12 (d, J=7,5 Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under operate, preparation 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S)-propionic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester, base is characterised in that:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3Temperature is 333 ° of K, δ ppm): 1,22 (s, 3H:CH 3); 1,27 (s, 3H:CH 3); 1,38 (s, 9H:C (CH 3) 3); 1,64 (s, 1H:OH 1); 1,92 (s, 3H:CH 3); 2,11 (s, 3H:CH 3); 2,25 and 2,92 (2mts, 1H:CH 26); 2,26 and 2,36 (2 dd, J=16 and 9Hz, 1H:CH 214); 3,47 and 3,52 (2s, 3H:OCH 3); 3,66 (s is wide, 1H:OH 2 '); 3,99 (d, J=7Hz, 1H:H3); 4,15 and 4,57 (2d, J=16Hz, 1H:OCOCH 2O); 4,19 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,24 and 4,35 (1H:CH2 20 for 2d, J=9Hz); 4,70 (mt, 1H:H2 '); 4,95 (d is wide, J=10Hz, 1H:H 5); 5,29 (d is wide, J=10Hz, 1H:H 3 '); 5,49 (d, J=10Hz, 1H:CONH); 5,53 (1H:H 7 for dd, J=11 and 8Hz); 5,76 (1H:H 2 for d, J=7Hz); 6,18 (t is wide, J=9Hz, 1H:H 13); 6,74 (s, 1H:H 10); 7,30 (t, J=7,5Hz, 1H:H aromatic ring contraposition 3 '); 7,38 (t, J=7,5Hz, position 3 between the 2H:H aromatic ring '); 7,45 (d, J=7,5Hz, 2H:H aromatic ring ortho position 3 '); 7,49 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,09 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under the preparation 3-tertbutyloxycarbonyl-2-(4-p-methoxy-phenyl)-4-phenyl-1,3-oxazolidine-5 (2R, 4S, 5R) carboxylic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3Temperature is 333 ° of K, δ ppm): 1,10 (s, 9H:C (CH 3) 3); 1,18 (s, 3H:CH 3); 1,20 (s, 3H:CH 3); 1,64 (s, 1H:OH 1); 1,75 (s, 3H:CH 3); 1,86 (s, 3H:CH 3); 2,12 and 2,26 (2dd, J=16 and 9Hz, 1H:CH 214); 2,24 and 2,86 (2mts, 1H:CH 26); 3,33 and 3,53 (2s, 3H:OCH 3); 3,65 and 4,10 (2d, J=16Hz, 1H:OCOCH 2O); 3,83 (s, 3H:ArOCH 3); 3,86 (1H:H 3 for d, J=7Hz); 4,14 and 4,20 (2d, J=16Hz, 1H:OCOCH 2O); 4,19 and 4,32 (2d, J=9Hz, 1H:CH 220); 4,72 (d is wide, J=4,5Hz, 1H:H 2 '); 4,89 (d is wide, J=10Hz, 1H:H 5); 5,46 (mt, 1H:H3 '); 5,45 (1H:H 7 for dd, J=11 and 8Hz); 5,69 (1H:H 2 for d, J=7Hz); 5,94 (t is wide, J=9Hz, 1H:H 13); 6,40 (s is wide, 1H:H 5 '); 6,63 (s, 1H:H 10); 6,93 (d, J=8,5Hz, 2H: fragrant HOCH 3The ortho position); 7,30 7,45 (mt, 5H: fragrant H 3 '); 7,38 (d, J=8,5Hz, 2H: fragrant H 3OCH 3Between the position); 7,48 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,08 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under operate, obtain 2 α-benzoyl oxygen-1 β, 13 alpha-dihydroxy-s-5 β, 20-epoxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 1,06 (s, 3H:CH 3); 1,20 (s, 3H:CH 3); 1,61 (s, 1H:OH 1); 1,89 (s, 3H:CH 3); 2,23 (d, J=5Hz, 1H:OH13); 2,20～2,35 and 2,92 (2mts, 1H:CH 26); 2,26 (s, 3H:CH 3); 2,32 (d, J=9Hz, 2H:CH 214); 3,52 and 3,58 (2s, 3H:OCH 3); 4,04 (1H:H 3 for d, J=7Hz); 4,19 et 4,32 (the obvious J=16Hz of 2AB, 2H:OCOCH 2O); 4,20 and 4,38 (2d, J=9Hz, 1H:CH 220); 4,82 (mt, 1H:H13); 4,99 (d is wide, J=10Hz, 1H:H 5); 5,55 (dd, J=10 and 7Hz, 1H:H7); 5,69 (1H:H 2 for d, J=7Hz); 6,73 (s, 1H:H 10); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,64 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,13 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under operate, obtain 2 α-benzoyl oxygen-5 β, 20-epoxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-1 β, 7 β, 13 α-trihydroxy--11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3δ ppm): 1,11 (s, 6H:CH 3); 1,63 (s, 1H:OH 1); 1,70 (s, 3H:CH 3); 1,92 and 2,63 (2mts, 1H:CH 26); 2,08 (s, 3H:CH 3); 2,20～2,30 (mt, 3H:CH 2With 14 and OH); 2,40 (d, J=4Hz, 1H:OH); 3,54 and 3,59 (2s, 3H:OCH 3); 3,92 (1H:H 3 for d, J=7Hz); 4,20 and 4,35 (2d, J=9Hz, 1H:CH 220); 4,24 and 4,28 (2AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,50 (mt, 1H:H 7); 4,86 (mt, 1H:H 13); 5,03 (d is wide, J=10Hz, 1H:H 5); 5,65 (1H:H 2 for d, J=7Hz); 6,44 (s, 1H:H 10); 7,49 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,14 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under the preparation 2 α-benzoyl oxygen-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-1 beta-hydroxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz; CDCl 3: δ ppm): 0,60 and 0,70 (2mts, 6H:CH 2Ethyl); 0,94 and 1,02 (2t, J=7,5Hz, 9H:CH 3The de ethyl); 1,12 (s, 3H:CH 3); 1,20 (s, 3H:CH 3); 1,64 (s, 1H:OH 1); 1,70 (s, 3H:CH 3); 1,91 and 2,57 (2mts, 1H:CH 26); 2,12 (s, 3H:CH 3); 2,13 and 2,23 (2dd, J=16 and 9Hz, 1H:CH 214); 3,53 and 3,57 (2s, 3H:OCH 3); 3,83 (1H:H 3 for d, J=7Hz); 4,15 and 4,40 (2d, J=16Hz, 2H:OCOCH 2O); 4,19 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,21 and 4,37 (2d, J=9Hz, 1H:CH 220); 4,51 (1H:H 7 for dd, J=11 and 7Hz); 4,93 (1H:H 13 for t, J=9Hz); 5,02 (the wide J=10Hz of d, 1H:H 5); 5,64 (1H:H 2 for d, J=7Hz); 6,56 (s, 1H:H10); 7,48 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,19 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under the preparation 2 α-benzoyl oxygen-1 β, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-methoxyacetic acid base-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz; CDCl 3δ ppm) 0,57 and 0,69 (2mts, 6H:CH 2Ethyl); 0,94 and 1,03 (2t, J=7,5Hz, 9H:CH 3Ethyl); 1,09 (s, 3H:CH 3); 1,17 (s, 3H:CH 3); 1,58 (s, 1H:OH 1); 1,75 (s, 3H:CH 3); 1,93 and 2,49 (2mts, 1H:CH 26); 2,03 (s, 3H:CH 3); 2,09 and 2,18 (2dd, J=16 and 9Hz, 1H:CH 214); 3,57 (s, 3H:OCH 3); 3,88 (1H:H 3 for d, J=7Hz); 4,16 and 4,40 (2d, J=16Hz, 1H:OCOCH 2O); 4,20 and 4,36 (2d, J=9Hz, 1H:CH 220); 4,28 (s is wide, and 1H:OH 10); 4,42 (mt, 1H:H7); 4,97 (1H:H 13 for t, J=9Hz); 5,01 (d is wide, J=10Hz, 1H:H en 5); 5,17 (s is wide, and 1H:H 10); 5,62 (1H:H 2 for d, J=7Hz); 7,47 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,61 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,18 (d, J=7,5 Hz, 2H:OCOC 6H 5The H ortho position).
Preparation 1 β under the condition similar to embodiment 3,2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-4 α, 10 β-two (methoxyimino acetic acid base)-9-oxygen-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum 1H (400 MHz; CDCl 3δ ppm): 0,60 and 0,68 (2mts, 6H:CH 2Ethyl); 0,92 and 1,01 (2t, J=7,5Hz, 9H:CH 3The de ethyl); 1,19 (s, 3H:CH 3); 1,27 (s, 3H:CH 3); 1,75 (s, 3H:CH 3); 1,91 and 2,63 (2mts, 1H: CH 26); 2,08 and 2,41 (2dd, J=16 and 9Hz, 1H:CH 214); 2,12 (s, 3H:CH 3); 3,44 (d, J=6,5Hz, 1H:H 3); 3,46 and 3,50 (2s, 3H:OCH 3); 4,06 and 4,14 (2d, J=16Hz, 1H:OCOCH 2O); 4,16 (s, 2H:OCOCH 2O); 4,46 (dd, J=10 and 7Hz, 1H:H en 7); 4,50 and 4,66 (2d, J=9Hz, 1H:CH 220); 4,51 (d, J=6,5Hz, 1H:H 2); 4,99 (mt, 1H:H 13); 5,00 (d is wide, J=10Hz, 1H:H 5); 6,51 (s, 1H:H 10).
Embodiment 6
Operate according to embodiment 3, with 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S) propionic acid 2 α-benzoyloxy-4 α-ring propionyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is a raw material, obtain 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3s) propionic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-7 β, 8-methylene radical-19-falls-9-oxygen-4 α-ring propionyloxy-11-Japanese yew alkene-13 α-ester, it is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400 MHz; CDCl 3The about 333 ° of K of temperature, δ ppm): de 0,80 à 1,40 (mt, 4H: the CH of cyclopropyl 2CH 2); 1,30 (s, 6H:CH 3); 1,35 (s, 9H:C (CH 3) 3); 1,30～1,40 (mt, 1H:H 7); 1,70 and 2,23 (2dd, J=6 and 5,5Hz and J=10 and 5,5Hz, 1H:CH 219); 1,80 (mt, 1H: the CH of cyclopropyl); 1,85 (s, 1H:OH 1); 1,86 (s, 3H:CH 3); 2,11 and 2,44 (the wide and dt of d, J=16Hz and J=16 and 4,5Hz, 1H:CH 26); 2,34 and 2,50 (2dd, J=16 and 9Hz, 1H:CH 214); 3,22 (d, J=4Hz, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 4,08 and 4,28 (2d, J=9Hz, 1H:CH 220); 4,13 (1H:H 3 for d, J=7Hz); 4,16 and 4,24 (2d, J=16Hz, 1H:OCOCH 2O); 4,62 (d, J=4,5Hz, 1H:H 5); 4,70 (d is wide, J=4Hz, 1H:H 2 '); 5,28 (AB is obvious, 2H:H3 ' and CONH); 5,70 (d, J=7Hz, 1H:H2); 6,23 (t is wide, J=9Hz, 1H:H 13); 6,42 (s, 1H:H 10); De 7,20～7,45 (mt, 5H:H fragrance H3 '); 7,52 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,61 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,14 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under operate, preparation 3-t-butoxycarbonyl amino-2-hydroxyl-3-phenyl-(2R, 3S)-propionic acid 2 α-benzoyl oxygen-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-ring propionyloxy-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is characterized in that:
-nuclear magnetic resonance spectrum. 1H (400MHz; CDCl 3δ ppm): 0,85 1,40 (mt, 4H: the CH of cyclopropyl 2CH 2); 1,22 (s, 3H:CH 3); 1,24 (s, 3H:CH 3); 1,39 (s, 9H:C (CH 3) 3); 1,70 (s, 1H:OH 1); 1,83 (mt, 1H: the CH of cyclopropyl); 1,88 (s, 3H:CH 3); 2,05 (s, 3H:CH 3); 2,23 and 2,84 (2mts, 1H:CH 26); 2,34 and 2,42 (2dd, J=16 and 9Hz, 1H:CH 214); 3,35 (d, J=5,5Hz, 1H:OH 2 '); 3,52 (s, 3H:OCH 3); 3,96 (d, J=7Hz, 1H:H en 3); 4,16 and 4,25 (2d, J=16Hz, 1H:OCOCH 2O); 4,17 and 4,28 (2d, J=9Hz, 1H:CH 220); 4,72 (mt, 1H:H 2 '); 4,81 (d is wide, J=10Hz, 1H:H 5); 5,28 (d is wide, J=10Hz, 1H:H 3 '); 5,36 (d, J=10Hz, 1H:CONH); 5,48 (dd, J=10,5 and 7Hz, 1H:H7); 5,72 (1H:H 2 for d, J=7Hz); 6,11 (mt, 1H:H 13); 6,71 (s, 1H:H 10); 7,25～7,45 (mt, 5H: fragrant H 3 '); 7,52 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,65 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,08 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
With embodiment 3 described similar conditions under the preparation 3-tertbutyloxycarbonyl-2-(4-p-methoxy-phenyl)-4-phenyl-1,3-oxazolidine-5 (2R, 4S, 5R) carboxylic acid 2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-ring propionyloxy-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene-13 α-ester is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz; CDCl 3δ ppm): 0,50～1,50 (mt, the CH of 5H:CH and cyclopropyl 21,04 (s, 9H:C (CH 3) 3); 1,17 (s, 3H:CH 3); 1,19 (s, 3H:CH 3); 1,65 (s, 1H:OH 1); 1,72 (s, 3H:CH 3); 1,84 (s, 3H:CH 3); 2,14 and 2,32 (2dd, J=16 and 9Hz, 1H:CH 214); 2,16 and 2,79 (2mts, 1H:CH 26); 3,52 (s, 3H:OCH 3); 3,82 (s, 3H:ArOCH 3); 3,86 (1H:H 3 for d, J=7Hz); 4,11 and 4,24 (2d, J=9Hz, 1H:CH 220); 4,15 and 4,22 (2d, J=16Hz, 1H:OCOCH, 4,60 (d, J=4,5Hz, 1H:H 2 '); 4,74 (d is wide, J=10Hz, 1H:H 5); 5,44 (dd, J=10,5 and 8Hz, 1H:H 7); 5,50 (mt, 1H:H 3 '); 5,67 (1H:H 2 for d, J=7Hz); 5,88 (mt, 1H:H 13); 6,41 (mf, 1H:H 5 '); 6,61 (s, 1H:H en 10); 6,92 (d, J=8,5Hz, 2H: fragrant HOCH 3The ortho position); 7,38 (d, J=8,5Hz, 2H: fragrant HOCH 3Between the position); 7,25～7,45 (mt, 5H:H fragrance H 3 '); 7,49 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,02 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position
With embodiment 3 described similar conditions under operate, obtain 2 α-benzoyl oxygen-1 β, 13 alpha-dihydroxy-s-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-ring propionyloxy-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum 1H (400MHz; CDCl 3Temperature is 333 ° of K, δ ppm): 0,90～1,40 (mt, 4H: the CH of cyclopropyl 2CH 2); 1,10 (s, 3H:CH 3); 1,22 (s, 3H:CH 3); 1,61 (s, 1H:OH 1); 1,70～1,85 (mt, 2H: the CH of cyclopropyl) yle and OH13); 1,90 (s, 3H:CH 3); 2,22 and 2,86 (2mts, 1H:CH 26); 2,26 (s, 3H:CH 3); 2,36 (d, J=9Hz, 2H:CH 214); 3,52 (s, 3H:OCH 3); 4,05 (1H:H 3 for d, J=7Hz); 4,14 and 4,22 (2d, J=16Hz, 1H:OCOCH 2O); 4,20 and 4,36 (2d, J=9Hz, 1H:CH 220); 4,84 (mt, 1H:H 13); 4,85 (d is wide, J=10Hz, 1H:H 5); 5,54 (1H:H 7 for dd, J=11 and 8Hz); 5,72 (d, J=7Hz, 1H:H2); 6,73 (s, 1H:H 10); 7,51 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,12 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position)
To embodiment 3 described similar conditions under operate, obtain 2 α-benzoyl oxygen-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-ring propionyloxy-1 β, 13 alpha-dihydroxy-s-7 β-trifluoro-methanesulfonyl oxy-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum, 1H (400 MHz; CDCl 3Temperature is 333 ° of K, δ ppm): 0,90～1,40 (mt, 4H: the CH of cyclopropyl 2CH 2); 1,10 (s, 3H:CH 3); 1,22 (s, 3H:CH 3); 1,61 (s, 1H:OH 1); 1,70～1,85 (mt, 2H: the CH OH13 of cyclopropyl); 1,90 (s, 3H:CH 3); 2,22 and 2,86 (2mts, 1H:CH 26); 2,26 (s, 3H:CH 3); 2,36 (d, J=9Hz, 2H:CH 214); 3,52 (s, 3H:OCH 3); 4,05 (1H:H 3 for d, J=7Hz); 4,14 and 4,22 (2d, J=16Hz, 1H:OCOCH 2O); 4,20 and 4,36 (2d, J=9Hz, 1H:CH 220); 4,84 (mt, 1H:H en 13); 4,85 (d is wide, J=10Hz, 1H:H 5); 5,54 (1H:H 7 for dd, J=11 and 8Hz); 5,72 (d, J=7Hz, 1H:H2); 6,73 (s, 1H:H 10); 7,51 (t, J=7,5H, 2H:OCOC 6H 5Position between H); 7,63 (t, J=7,5Hz, 1H:OCO C6H 5The H contraposition); 8,12 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position)
To embodiment 3 described similar conditions under the preparation 2 α-benzoyl oxygen-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-1 beta-hydroxy-10 beta-methoxy-acetoxyl-9-oxygen-4 α-ring propionyloxy-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum 1H (400 MHz; CDCl 3δ～ppm): 0,60 and 0,68 (2mts, 6H: the CH of ethyl 2); 0,90～1,35 (mt, 4H: the CH of cyclopropyl 2CH 2); 0,94 and 1,03 (2t, J=7,5Hz, 9H: the CH of ethyl 3); 1,14 (s, 3H:CH 3); 1,20 (s, 3H:CH 3); 1,64 (s, 1H:OH 1); 1,71 (s, 3H:CH 3); 1,73 (mt, 1H: the CH of cyclopropyl; 1,87 and 2,50 (the wide and mt of dd, J=14 and 11Hz, 1H:CH 26); 2,11 and 2,29 (2dd, J=16 and 9Hz, 1H:CH 214); 2,15 (s, 3H:CH 3); 3,53 (s, 3H:OCH 3); 3,86 (1H:H 3 for d, J=7Hz); 4,14 and 4,26 (2d, J=9Hz, 1H:CH 220); 4,19 (AB is obvious, J=16Hz, 2H:OCOCH 2O); 4,52 (1H:H 7 for dd, J=11 and 7Hz); 4,84 (d is wide, J=10Hz, 1H:H 5); 4,95 (t is wide, J=9Hz, 1H:H 13); 5,65 (1H:H 2 for d, J=7Hz); 6,56 (s, 1H:H10); 7,50 (t, J=7,5Hz, 2H:OCOC 6H 5Position between H); 7,62 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,09 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
To embodiment 3 described similar conditions under the preparation 2 α-benzoyl oxygen-1 β, 10 beta-dihydroxyies-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-9-oxygen-4 α-ring propionyloxy-11-Japanese yew alkene is characterized in that:
-nuclear magnetic resonance spectrum, 1H (400 MHz; CDCl 3δ ppm): 0,58 and 0,68 (2 mts, 6H: the CH of ethyl 2); 0,90～1,35 (mt, 4H: the CH of cyclopropyl 2CH 2); 0,94 and 1,03 (2t, J=7,5Hz, 9H: the CH of ethyl 3); 1,12 (s, 3H:CH 3); 1,22 (s, 3H:CH 3); 1,59 (s, 1H:OH 1); 1,67 (mt, 1H: the CH of cyclopropyl); 1,73 (s, 3H:CH 3); 1,90 and 2,44 (2mts, 1H:CH 26); 2,06 (s, 3H:CH 3); 2,10 and 2,25 (2dd, J=16 and 9Hz, 1H:CH 214); 3,91 (1H:H 3 for d, J=7Hz); 4,16 and 4,26 (2d, J=9Hz, 1H:CH 220); 4,28 (d, J=1,5Hz, 1H:OH10); 4,42 (1H:H 7 for dd, J=11 and 6Hz); 4,84 (d is wide, J=10Hz, 1H:H 5); 5,00 (1H:H 13 for t, J=9Hz); 5,16 (d, J=1,5Hz, 1H:H 10); 5,62 (1H:H 2 for d, J=7Hz); 7,50 (t, J=7,5Hz, 2H:OCOC 6H 5The position a) between H; 7,62 (t, J=7,5Hz, 1H:OCOC 6H 5The H contraposition); 8,09 (d, J=7,5Hz, 2H:OCOC 6H 5The H ortho position).
Prepare 1 β according to following manner, 2 alpha-carbon acid esters-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-4 α-ring propionyloxy-10 beta-methoxy-acetoxyl-9-oxygen-11-Japanese yew alkene:
To 100mg1 β, 2 alpha-carbon acid esters-4 Alpha-hydroxy-7 β, 13 α-two (silicoheptane alcoxyl base)-5 β, 20-epoxy-10 beta-methoxy-acetoxyl-9-oxygen-11-Japanese yew alkene is at 7cm 3Under about-30 ℃ of conditions, be added dropwise to 345 μ l 1M in the solution that forms in the tetrahydrofuran (THF) and be in hexamethyldisilazane lithium solution in the hexane.Under this temperature, reaction mixture was stirred 15 minutes, drip 39 μ l ring propionyl chloride subsequently.At about 0 ℃ reaction mixture stirred 30 minutes, by adding 1cm 3NH 4Cl saturated solution and 50cm 3CH 2Cl 2With its hydrolysis.The decant organic phase is with NaCl saturated aqueous solution 40cm 3Wash 2 times, use MgSO 4Drying, filtration also is concentrated into dried in 40 ℃ of decompressions (2.7KPa).The 120mg product that obtains carries out chromatogram in diameter is 70g silica gel (0.063-0.2mm) post of 2cm purifies by (scrub solution: ethyl acetate-hexanaphthene, 20-80, volume), obtains 10cm 3Cut merges the gold-plating branch that only contains the purpose compound and is concentrated into dried in 40 ℃ of decompressions (2.7KPa).Obtain 31mg purpose compound, its feature is as follows:
-nuclear magnetic resonance spectrum, 1H (400MHz; CDCl 3δ ppm): 0,60 and 0,66 (2mts, 6H: the CH of ethyl 2); 0,90～1,35 (mt, 4H: the CH of cyclopropyl 2CH 2); 0,92 and 1,02 (2t, J=7,5Hz, 9H: the CH of ethyl 3); 1,19 (s, 3H:CH 3); 1,29 (s, 3H:CH 3); 1,60 (s, 1H:OH 1); 1,62 (mt, 1H: the CH of cyclopropyl); 1,73 (s, 3H:CH 31,88 and 2,57 (the wide and mt of dd, J=15 and 10Hz, 1H:CH 26); 2,15 (s, 3H:CH 3); 2,19 and 2,37 (2dd, J=16 and 9Hz, 1H:CH 214); 3,48 (d, J=7Hz, 1H:H3); 3,51 (s, 3H:OCH 3); 4,16 (s, 2H:OCOCH 2O); 4,44 (mt, 1H:H 7); 4,45 and 4,54 (2d, J=9Hz, 1H:CH 220); 4,49 (1H:H 2 for d, J=7Hz); 4,85 (d is wide, J=10Hz, 1H:H 5); 5,02 (t is wide, J=9Hz, 1H:H 13); 6,52 (s, 1H:H 10).
Wherein on behalf of the novel cpd I of group shown in the general formula (II), Z possess the active of obvious suppression abnormal cellular proliferation and can produce therapeutic action to the illness patient relevant with abnormal cellular proliferation.These illnesss comprise the abnormal cellular proliferation of the malignant cell or the non-malignant cell of different tissues and/or organ, these organs and/or tissue include, but are not limited to muscle tissue, bone or reticular tissue, skin, brain, lung, sexual organ, lymphsystem or kidney, mammary cell or hemocyte, liver, digestion organs, suprarenal gland, pancreas and Tiroidina.These illnesss also comprise solid tumor, psoriasis, ovarian cancer, mammary cancer, the cancer of the brain, prostate cancer, intestinal cancer, cancer of the stomach, kidney or carcinoma of testis, Kaposi sarcoma, cholangiocarcinoma, choriocarcinoma or nerve metrocyte carcinoma, Wilms tumour, Hodgkin disease, melanoma, multiple myeloma, chronic lymphatic leukemia, acute or chronic granulosa cell lymphoma.Novel cpd of the present invention is specially adapted to treat ovarian cancer.The compounds of this invention can be used to prevent and treat or delay the appearance or the recurrence of these illnesss or be used for the treatment of these diseases.
Compound of the present invention can be according to the multi-form patient of being applied to who is applicable to selected route of administration, and these route of administration are good in the parenteral mode.The parenteral administration comprises intravenous administration, intraperitoneal administration, muscle or subcutaneous administration.More preferably intraperitoneal or intravenous administration.
The present invention also comprises and contains the pharmaceutical composition that at least a its quantity is enough to be applicable to the Compound I of human body or carcasses treatment.Said composition can adopt one or more medicine acceptable assistant, carrier or vehicle to prepare according to ordinary method.Suitable carrier comprises thinner, sterile aqueous media and innoxious solvent.Said composition preferably with the aqueous solution or suspension, can be existed by the form of injection solution, wherein contain emulsifying agent, tinting material, sanitas or stablizer.
Can be according to the solvability of product and chemical property, concrete route of administration and experienced medicament choice of practice auxiliary agent or vehicle.
For the parenteral administration, can use moisture or not aqueous solution or suspension.In order to prepare non-aqueous solution or suspension, can use crude vegetal such as sweet oil, sesame oil or paraffin oil or injectable organic ester such as ethyl oleate.Aseptic aqueous solution can be made of the aqueous solution of the acceptable salt of medicine.These aqueous solution are suitable for carrying out intravenous injection being suitable under the condition of regulating its pH value by for example capacity NaCl or glucose and realizing isotonicity.Can carry out sterilising treatment by heating or other any mode that does not change composition.
Certainly, all compounds that enter the present composition all should be pure state or be nontoxic to its consumption.
Said composition can contain at least 0.01% therapeutical active compound.The quantity of active compound meets the posology standard in the composition.Preferably, the preparation method of said composition causes parenteral administration unitary dose to contain about 0.01-1000mg active compound.
Therapeutic process can carry out jointly with other therapies that comprises anti-tumorigenesis pharmacotherapy, monoclonal antibody therapy, immunotherapy or radiotherapy or biological response modification therapy.Response properties-correcting agent includes, but are not limited to lymphokine and cytokine such as interleukin, Interferon, rabbit (α, β or δ) and TNF.Other chemotherapeutic that is suitable in the lysis that treatment causes owing to the undesired propagation of cell comprises, but be not limited to for example mustargen of alkylating agent such as nitrogen mustards, endoxan, melphalan and Chlorambucil, alkyl sulfonate esters such as busulfan, nitrous is for urea such as carmustine, lomustine, semustine and streptozocin, triazene such as Dacarbazine, metabolic antagonist such as folacin be methotrexate for example, pyrimidine analogue such as Fluracil and cytosine arabinoside, the analogue of purine such as mercaptopurine and Tioguanine, natural compounds such as catharanthus alkaloid such as vinealeucoblastine(VLB), vincristine(VCR) and Vendesine, epipodophyllotoxin such as etoposide and Vumon, microbiotic such as dactinomycin, daunorubicin, Zorubicin, bleomycin, Plicamycin and ametycin, enzyme such as Asparaginase, the title complex of other reagent such as platinum is cis-platinum for example, be substituted for example hydroxyurea of urea, methylhydrazine derivative such as Procarbazine, adrenal cortex inhibitor such as mitotane and aminoglutethimide, hormone and antagonist such as adrenocortical steroid such as prednisone, progestin such as hydroxcyprogesterone caproate, methoxy Progesterone acetic ester and megestrol acetic ester, oestrogenic hormon such as stilboestrol and Ethinylestradiol; Estrogen antagonist such as tamoxifen, male sex hormone such as testosterone propionate and Fluoxymesterone.
The dosage of implementing the inventive method can carry out prophylactic treatment or produce the maximum therapy response.Dosage is determined according to the concrete feature of form of medication, selected particular compound and object to be treated.Usually, its dosage has curative effect for the disease that causes owing to abnormal cellular proliferation.The compounds of this invention can be applied at any time so that produce required curative effect.Some patients can produce reaction rapidly to heavier or lighter dosage, need small amounts of medicament to keep drug effect subsequently or do not need this effect of keeping fully.Usually, adopt low dose at the treatment initial stage, in case of necessity, dosage is increasing, till producing optimum curative effect.For other patient, according to patient's physiological requirements can keep every day 1-8 medication, with 1-4 time for good, for some patient same possible be to be necessary medication every day 1-2 time.
The human body dosage is generally 0.01-200mg/kg.For the intraperitoneal administration, dosage is generally 0.1-100mg/kg, is good with 0.5-50mg/kg, with 1-10mg/kg for better.For intravenous administration, dosage is generally 0.1-50mg/kg, is good with 0.1-5mg/kg, with 1-2mg/kg for better.Certainly, for selecting dosage preferably, should consider route of administration, weight in patients, its general health, its age and all factors that can affect the treatment.
The following example is described the present composition.
Embodiment
The compound that 40mg embodiment 1 is obtained is dissolved in 1cm 3Emlphor EL 620 and 1cm 3In the ethanol, use 18cm subsequently 3Physiological saline dilutes this solution.
Among importing the physiology solute, said composition was poured into 1 hour.

Claims (7)

1. novel taxoid (taxoide) (I)
Figure A9519348200021
In the formula: R aRepresent hydrogen atom or hydroxyl, C 1-4Alkoxyl group, C 1-4Acyloxy or its moieties contain the alkoxy acetic acid base of 1-4 carbon atom, R bRepresent hydrogen atom or R aWith R bTogether with forming ketone jointly with its bonded carbon atom, Z represents hydrogen atom or group (II):
Figure A9519348200022
In the formula: R 1Representative can be by one or more identical or different halogen atom and C of being selected from 1-4Alkyl, C 1-4The benzoyl that the atom of alkoxyl group or trifluoromethyl or group replace, thenoyl or furoyl, or radicals R 2-O-CO-, wherein R 2Representative :-C 1-8Alkyl, C 2-8Alkenyl, C 3-8Alkynyl, C 3-6Cycloalkyl, C 4-6Cycloalkenyl group, C 7-10Bicyclic alkyl, these groups can be selected from following substituent group and replace by one or more: halogen atom and hydroxyl, C 1-4Alkoxyl group, wherein each moieties all contain 1-4 carbon atom dialkyl amino, piperidino-(1-position only), morpholino, piperazine-1-base (can be by C in the 4-position 1-4Alkyl or wherein the moieties phenylalkyl that contains 1-4 carbon atom replace), C 3-6Cycloalkyl, C 4-6Cycloalkenyl group, phenyl (can be by one or more halogen atom and C of being selected from 1-4Alkyl or C 1-4The atom of alkoxyl group or group replace), cyano group, carboxyl or wherein moieties contain the carbalkoxy of 1-4 carbon atom ,-can be by the phenyl of one or more substituting groups replacements that are selected from following atom or group or α-or betanaphthyl: halogen atom and C 1-4Alkyl or C 1-4Alkoxyl group or preferred 5 Yuans aromatic heterocyclic radicals from furyl and thienyl ,-or can be by one or more C 1-4The C that alkyl replaces 4-6Saturated heterocyclyl, R 3Represent straight or branched C 1-8Alkyl, straight or branched C 2-8Alkenyl, straight or branched C 2-8Alkynyl, C 3-6Cycloalkyl; phenyl that can be replaced by one or more substituting groups that are selected from following atom or group or α-or betanaphthyl: halogen atom; alkyl; alkenyl; alkynyl; aryl; aralkyl; alkoxyl group; alkylthio; aryloxy; arylthio; hydroxyl; hydroxyalkyl; sulfydryl; formyl radical; acyl group; amido; aromatic acylamino; alkoxycarbonyl amido; amino; alkylamino; dialkyl amido; carboxyl; carbalkoxy; formamyl; alkyl-carbamoyl; the dialkyl amido formyl radical; cyano group; nitro and trifluoromethyl; or contain one or more nitrogen that are selected from; identical or different heteroatomic 5 Yuans aromatic heterocycles that can be replaced by one or more identical or different substituting groups that are selected from following groups of oxygen or sulphur: halogen atom and alkyl; aryl; amino; alkylamino; dialkyl amido; alkoxycarbonyl amido; acyl group; aryl carbonyl; cyano group; carboxyl; formamyl; alkyl-carbamoyl; dialkyl amido formyl or carbalkoxy; condition is at phenyl; α-or the substituting group of betanaphthyl and aromatic heterocyclic radical in; the moieties of alkyl and other group contains 1-4 carbon atom and alkenyl and alkynyl, and to contain 2-8 carbon atom and aryl be phenyl or α-or betanaphthyl, R 4And R 5Identical or different, representative-straight or branched C 1-8Alkyl, straight or branched C 2-8Alkenyl, straight or branched C 2-8Alkynyl, C 3-6Cycloalkyl, C 4-6Cycloalkenyl group or C 7-11Bicyclic alkyl, these groups can be selected from following substituent group and replace by one or more: halogen atom and hydroxyl, C 1-4Alkoxyl group, wherein each moieties all contain the 1-4 carbon atom dialkyl amido, piperidino-(1-position only), morpholino, piperazine-1-base (can be by C in the 4-position 1-4The phenylalkyl that alkyl or its moieties contain 1-4 carbon atom replaces), C 3-6Cycloalkyl, C 4-6Cycloalkenyl group; can substituted phenyl; cyano group; carboxyl or its moieties contain the carbalkoxy of 1-4 carbon atom;-or the aryl that can be replaced by one or more substituting groups that are selected from following atom or group: halogen atom and alkyl; alkenyl; alkynyl; aryl; aralkyl; alkoxyl group; alkylthio; aryloxy; arylthio; hydroxyl; hydroxyalkyl; sulfydryl; formyl radical; acyl group; amido; aromatic acylamino; alkoxycarbonyl amido; amino; alkylamino; dialkyl amido; carboxyl; carbalkoxy; formamyl; alkyl-carbamoyl; the dialkyl amido formyl radical; cyano group; nitro; azido-; trifluoromethyl or trifluoromethoxy, condition are R 5Must not be methyl or can be by one or more C 1-4Saturated or the unsaturated heterocycle base of 4-6 person that alkyl replaces, condition is that cycloalkyl, cycloalkenyl group or bicyclic alkyl can be by one or more C 1-4Alkyl replaces.
2. according to the novel taxoid of claim 1, R wherein aRepresentation hydroxy, C 1-4Alkoxyl group, C 1-4Acyloxy or wherein moieties contain the alkoxy acetic acid base of 1-4 carbon atom, R bRepresent hydrogen atom; Z represents group, wherein R shown in hydrogen atom or the general formula I I 1Represent benzoyl or R wherein 2Represent the radicals R of the tertiary butyl 2-O-CO-, R 3Represent C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl, the phenyl that can be replaced by one or more identical or different substituting groups that are selected from following atom or group: halogen atom (fluorine, chlorine) and alkyl, alkoxyl group, dialkyl amido, amido, alkoxycarbonyl amido or trifluoromethyl or furans-2-base or furans-3-base, thiophene-2 or-3-base or thiazole-2,-4 or-the 5-base, R 4The phenyl that representative can be replaced by one or more identical or different substituting groups that are selected from following atom or group: halogen atom and alkyl, alkoxyl group, amino, alkylamino, dialkyl amido, acyl amino, alkoxycarbonyl amido, azido-, trifluoromethyl and trifluoromethoxy; or thiophene-2 or-3-base or furans-2 or-the 3-base, R 5Representative can substituted C 1-4Alkyl, condition are R 5Must not be methyl.
3. according to the novel taxoid of claim 1, R wherein aRepresent hydrogen atom or hydroxyl or acetoxyl or methoxyimino acetic acid base, R bRepresent hydrogen atom, Z represents group, wherein R shown in hydrogen atom or the general formula (II) 1Represent benzoyl or R wherein 2Represent the radicals R of the tertiary butyl 2-O-CO-, R 3Represent isobutyl-, isobutenyl, butenyl, cyclohexyl, phenyl, furans-2-base, furans-3-base, thiophene-2-base, thiene-3-yl-, thiazol-2-yl, thiazole-4-base or thiazole-5-base, R 4Representative can be by the phenyl of a halogen atom replacement, R 5Represent C 2-4Alkyl.
4. the preparation method of each compound among the claim 1-3 is characterized in that can passing through compound generation effect shown in alkali metal halide or an alkali metal azide or quaternary ammonium salt or the alkali-metal phosphoric acid salt mutual-through type (III), substituting R with hydrogen atom if desired subsequently aProtecting group prepares: Z, R in the formula 4With R 5Limit R as claim 1-3 aRepresent hydrogen atom or alkoxyl group, acyloxy, alcoxyl acetoxyl or protected hydroxyl, R bBe hydrogen atom.
5. the preparation method of each compound, wherein R among the claim 1-3 4With R 5Limit R as claim 1-3 aAnd R bBe respectively hydrogen atom, it is characterized in that the wherein R of claim 1-3 aFor the compound of hydroxyl, acyloxy or alcoxyl acetoxyl obtains reduction by electrolytic process.
6. the preparation method of each compound, wherein R among the claim 1-3 4With R 5Limit R as claim 1-3 aAnd R bTogether with forming ketone jointly, it is characterized in that the wherein R of claim 1-3 with its bonded carbon atom aBe hydroxyl and R bFor the compound of hydrogen atom oxidized.
7. pharmaceutical composition is characterized in that the wherein Z that contains at least a claim 1-3 represents group shown in the general formula I I, can accept compound bonded compound with one or more inertia or pharmacologically active medicine.
CN95193482A 1994-06-09 1995-06-07 New taxoids, preparation thereof and pharmaceutical compositions containing them Pending CN1150423A (en)

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US5919815A (en) * 1996-05-22 1999-07-06 Neuromedica, Inc. Taxane compounds and compositions
US5795909A (en) * 1996-05-22 1998-08-18 Neuromedica, Inc. DHA-pharmaceutical agent conjugates of taxanes
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US5773464A (en) * 1996-09-30 1998-06-30 Bristol-Myers Squibb Company C-10 epoxy taxanes
WO1998017656A1 (en) 1996-10-24 1998-04-30 Institute Armand-Frappier A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof
US6495579B1 (en) 1996-12-02 2002-12-17 Angiotech Pharmaceuticals, Inc. Method for treating multiple sclerosis
US6956124B2 (en) 2003-04-14 2005-10-18 Aventis Pharma S.A. Process for the preparation of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene
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