CN1020596C - Process for preparing epipodophyllotoxin intermediates - Google Patents

Abstract

There is provided a novel and efficient stereoselective total synthesis of epipodophyllotoxin and related epipodophyllotoxin compounds of the general formula wherein R1 and R2 each are independently hydrogen or (lower)alkoxy, or R1 and R2, taken together, is methylenedioxy; R4 and R6 each are independently hydrogen or (lower)alkoxy; and R5 is hydrogen or a phenol-protecting group; or an acid addition salt thereof. The present invention also provides novel intermediates and processes for the preparation of said intermediates, which are then converted into known antineoplastic agents.

Description

Process for preparing epipodophyllotoxin intermediates

The present invention relates to change into the intermediate of difference to podophyllotoxin and relevant antineoplastic agent thereof.Particularly be related to difference new effectively complete synthesis to podophyllotoxin, then, difference can easily be transformed into known antineoplastic by known program to podophyllotoxin.In addition, the present invention also provides the technology for preparing these intermediates, and these intermediates are transformed into the technology of difference to podophyllotoxin and related compound.

Difference is the 4-hydroxyl epimer of podophyllotoxin (II) to podophyllotoxin (I), and it is a kind of xylan lactone of separating from several podophyllotoxins, has very strong cytotoxicity.Simultaneously, known many other of people has the related compound of the aryl-tetrahydro naphthalene ring structure of feature, they have plenty of naturally occurring, has plenty of to derive out from some naturally occurring compounds.Some of them have anti-tumor activity, and other then can change into has this active compound.Difference is as follows to the structure of podophyllotoxin (I) and podophyllotoxin (II):

Difference is to podophyllotoxin (I)

Podophyllotoxin (II)

The above-mentioned chemical compound lot that comprises podophyllotoxin all prepares by complete synthesis now.

At J.Org.Chem., 31,4004-4008(1966)-Wen in, W.J.Gensler and C.D.Gatsonis have described the complete synthesis of the podophyllotoxin (II) realized by the epimerization of the adjacent tetrahydropyran derivatives that uses enolate quenching picropodophyllin., this epimerization reaction is not exclusively, still needs and separates the mixture of podophyllotoxin (II) and picropodophyllin (III), and parents' ratio is about 45: 55.Picropodophyllin (III) is the interior ester isomer of the cis of podophyllotoxin (II).Structural formula is as follows:

～picropodophyllin (III)

At J.Am.Chem.Soc., 82,1714-1727(1960) in the literary composition, people such as W.J.Gensler have reported the complete synthesis of picropodophyllin (III), and response procedures reached for 13 steps, and total recovery is on the low side.People such as the present invention and Gensler report different have fully been avoided the preparation of picropodophyllin (III).

At J.Org.Chem., 46,2826-2828(1981)-Wen in, people such as A.S.Kende have reported and have a kind ofly improvedly prepared the total synthesis method of picropodophyllin (II) by piperonylaldehyde that in totally 12 steps, its total recovery is 4.5%.It is similar that but the synthetic and above-mentioned Gensler of Kende synthesizes, and still need synthesize picropodophyllin (III), and then epimerization.

At J.C.S.Perkin I, 271-276(1982)-Wen in, W.S.Murphy and S.Watlanasin have narrated the building-up process of improved aryl tetralone (IV), its structural formula is as follows:

Aryl tetralone (IV)

Aryl tetralone (IV) is the intermediate of a synthetic picropodophyllin (III), the aryl tetralone is once at above-mentioned J.Am, Chem.Soc., 82-1714-1727(1960)-being introduced among the Wen, the present invention also utilizes aryl tetralone (IV) as the complete synthesis super beginning raw material of podophyllotoxin (I).

D.Rajepaksa and R.R.odrigo are at J.Am.Chem.Soc., 103,6208-6209(1981)-Wen in, R.Rodrigo is at J.Org.Chem., 45,4538-4540(1980)-Wen in, all reported podophyllotoxin (II) and difference novel synthesis to podophyllotoxin (I), it can be when picropodophyllin (III) transfers into podophyllotoxin (II) to, avoid using the thermodynamics grid described in people's such as people such as above-mentioned Gensler and Kende document, the synthetic precursor (compound 9 in document in 1980) that then requires a dicycloization of preparation of Rodrigo only could obtain the yield of a satisfaction when cyclisation again.

The present invention has also avoided intermediate picropodophyllin (III), and provides one to utilize the new effective main body of cheap chemical to select synthetic method, so that novel process has commercial possibility.

On August 18th, 1970, in the United States Patent (USP) 3,524,844 that people such as Keller-Juslen propose, narrated that 4 ' piptonychia basis replaces to podophyllotoxin-β-D() preparation method of glucoside,

Its structural formula is as follows:

R is a methyl in the formula, promptly obtains etoposide (antitumour drug) from 4-piptonychia basis to podophyllotoxin (V), or R ' is the 2-thienyl, promptly obtains Vumon (antitumour drug) from 4-piptonychia basis to podophyllotoxin (V).The structural formula of (V) is as follows:

4-piptonychia basis is to podophyllotoxin (V)

It makes from podophyllotoxin (II).4 '-the piptonychia basis replaces to podophyllotoxin-β-D() glucose, particularly etoposide (R '=methyl) and Vumon (R '=the 2-thienyl) be anti-tumor agents, can be used for treating the mankind's cancer, particularly carcinoma of testis.

The invention provides the method for a kind of effective stereoselective total synthesis difference to podophyllotoxin (I) and related compound thereof, these compounds are easy to be transformed into known anti-tumor agents, and the general formula of the new intermediate that is provided lists in graphic 1:

Graphic 1

Among Fig. 1, the R of each structural formula ¹And R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹With R ²Be the methylene radical dioxy base that connects together; R ³Be hydrogen or carboxyl-protecting group; R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group; R ⁵Be hydrogen or phenol protecting group; R ⁷Be hydrogen, halogen, (rudimentary) carbalkoxy, carboxyl, cyano group, trimethyl silyl, benzenesulfonyl or carbobenzoxy, R ⁷Phenyl ring on can have one or two substituting group, be respectively (rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl etc.; R ⁸Be cyano group, amino methyl, formyl radical or formamyl; Or the salt of acid.

Another aspect of the present invention provides a new intermediate X IV from can optionally being separated, effectively the improving one's methods of synthesizing aryl tetralone, and the general formula of all cpds lists in graphic 2:

Graphic 2

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶As previously mentioned; R ⁹Be phenyl or (rudimentary) alkyl, they can be replaced by one or more halogen atom-fluorine, chlorine and bromine atoms.

The invention provides in difference in podophyllotoxin and related derivatives thereof complete synthesis the stereoselective process of preparation intermediate.The use of these intermediates of the present invention and technology have been avoided the difficulty that run in the former document, provide one can commercial feasible method synthesize useful anti-tumor agents, as etoposide and Vumon.

" (rudimentary) alkyl " and " (rudimentary) alkoxyl group " (unless in context, indicating in addition) that reaches in the claim herein to be carried, what all refer to contain 1 to 6 carbon atom has side chain or unbranched alkyl or alkoxyl group, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, tertiary butyl, amyl group, a hexyl etc.These groups preferably contain 1 to 2 carbon atom to contain 1 to 4 carbon atom for well.Except that explanation in particular example, reach said in the claim " halogen " speech herein and all refer to chlorine, fluorine, bromine and iodine." hydrochlorate " speech is meant the nontoxic carboxylic acid and the salt of phenol, for example, nontoxic metal-salt-sodium, potassium, calcium and magnesium salts, ammonium salt and nontoxic amine salt can be in order to the salt of the amine of the salt that forms carboxylic acid or phenol as trialkylamine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, pyridine, N-methylmorpholine, N-methyl piperidine and other.

Because compound of the present invention has one or more asymmetric carbon atoms, thus the present invention includes all graphic 1 and 2, and the possible enantiomorph and the diastereomer of the compound of listed general formula in the claim.These isomer mixtures can be by known method, for example fractional crystallization, and chromatographic adsorption, or other separation method that is suitable for is divided into each isomer.The racemoid of gained can be divided into diastereoisomeric salt with this mixture again by introducing the mixture that suitable salt forming agent forms diastereoisomeric salt, and various salt are changed into the method for free cpds, and it is divided into enantiomorph.Various possible enantiomorphs also can separate by optically active high pressure liquid chromatography post.

If plan poor natural (-) isomer of preparation, institute's synthetic of the present invention (±) isomer can be produced by the currently known methods of technology maturation to podophyllotoxin.In addition, can use an intermediate above-mentioned, that can form optically active salt, analyze at the synthetic initial stage by same general method and obtain the difference of needed optical activity (+) or (-) to the podophyllotoxin isomer.People such as W.J.Gensler are at J.Am Chem.Soc., 82,1714-1727(1960)-Wen in, analyse the branch example as above-mentioned this generalization compound, narrated by forming and separating corresponding optically active quinine salt, isolated the process of the α-A Piao Podophyllinic acid of natural optically active from DL-α-A Piao Podophyllinic acid.

In the present invention; in order to stop or protect the functionallization of carboxyl; the carboxyl-protecting group that is adopted all be people known, technical be sophisticated, comprising being with substituent phenyl (rudimentary) alkyl, methoxy toluene, benzyloxymethyl, allyl group, diphenyl methyl etc. on (rudimentary) alkyl, phenyl (rudimentary) alkyl, the phenyl ring.In the present invention; in order to stop or protect the functionallization of phenol; the phenol protecting group that is adopted also is that people are known, and technical is sophisticated, comprising (rudimentary) alkyl, phenyl (rudimentary) alkyl; be with substituent phenyl (rudimentary) alkyl, carbobenzoxy-(Cbz) on the phenyl ring; 2,2, the 2-trichloro-ethoxycarbonyl; methoxyl methyl, allyl group etc.Visible " protecting group in the organic synthesis " (" Protective Groups in Orgami Synthesis ") book of other protecting group that is suitable for, Theodora W.Greene(John Wiley ﹠amp; Sons, 1981), about phenol, see the 3rd chapter, about carboxylic acid, see the 5th chapter, they can be used as reference.

As one aspect of the present invention, the general formula of the compound that is provided is as follows:

VIII-trans, IX-cis

Wherein, R ¹And R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene-dioxy that connects together; R ³Be hydrogen or carboxyl-protecting group; R ⁴And R ⁶, be respectively hydrogen or (rudimentary) alkoxyl group, R ⁵Be hydrogen or phenol protecting group; Or its sour salt.

Among the desirable embodiment, compound has following general formula:

Ⅷa

Wherein, R ³Be hydrogen or carboxyl-protecting group, R ⁵Be hydrogen or phenol protecting group, or its sour salt.Compound has following general formula among another desirable embodiment:

Ⅸa

Wherein, R ³Be hydrogen or carboxyl-protecting group, R ⁵Be hydrogen or phenol protecting group; Or its sour salt.

At general formula is in the compound of VIII a and IX a, R ³Generally be to be with substituent phenyl (rudimentary) alkyl or diphenyl methyl on hydrogen, (rudimentary) alkyl, phenyl (rudimentary) alkyl, the phenyl ring, preferably (rudimentary) alkyl or diphenyl methyl.R ⁵Generally be to be with substituent phenyl (rudimentary) alkyl, carbobenzoxy-(Cbz) or 2,2,2-trichloro-ethoxycarbonyl, preferably methyl or benzyl on hydrogen, (rudimentary) alkyl, phenyl (rudimentary) alkyl, the phenyl ring.R ³And R ⁵Phenyl ring on can have one or two substituting group-be selected from respectively (rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl.

The compound of general formula VIII can be from corresponding aryl tetralone IV, and by the reduction of the ketone group among compound VI or the VI a, the pure VII of gained or VII a are dewatered with the method for technology maturation makes then, as shown in Figure 3:

Graphic 3

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned.

Starting raw material, general formula are the aryl tetralone of VI, wherein R ¹And R ²Be the methylene radical dioxy base that connects together, R ³Be hydrogen, methyl or ethyl, R ⁴And R ⁶Be methoxyl group, R ⁵Be methyl, can be according to J.Am.Chem.Soc., 82,1714-1727(1960)-Wen in, the described usual way of people such as W.J.Gensler is produced.The starting raw material of general formula VI also can be according to J.C.S.Perkin I, 271-276(1982)-Wen in, described the improving one's methods of W.S.Murphy and S.Wattanasin produced, R in the VI formula ¹Be methoxyl group, R ²Be hydrogen, or R ¹And R ²Be the methylene radical dioxy base that connects together, R ³Be hydrogen and ethyl, R ⁴And R ⁶Be hydrogen, or R ⁴And R ⁶Be methoxyl group, R ⁵Be methyl.In addition, the starting raw material of general formula VI can also be produced by new the improving one's methods that embodiments of the invention are narrated in more detail.

According to a reaction scheme, need to change R ³, promptly during carboxyl-protecting group, aryl tetralone VI at first uses conventional methods, for example acidity or alkaline hydrolysis, and preferably alkaline hydrolysis for example is hydrolyzed with potassium hydroxide.The sour VI a of gained is reduced to pure VII a with ketone group under the selective reduction condition then.Reduction can adopt the method for shortening to finish.Used hydrogenation catalyst has palladium, platinum, Lan Shi nickel or ruthenium, and selected conventional carrier has charcoal, diatomite, is reflected at the inert solvent of no reductibility, and for example water, methyl alcohol, ethanol or vinyl acetic monomer carry out.Hydrogenation is preferably under normal temperature, normal pressure or the high slightly pressure and carries out.Aryl tetralone VI a in a kind of appropriate solvent, selects for use a kind of optionally reductive agent to reduce mostly, and used reductive agent has sodium borohydride, sodium cyanoborohydride, zinc borohydride, sulfurized sodium borohydride (Na BH ₂S ₃), lithium borohydride, diisoamyl borine (disiamylborane), ammonia borine, 3-sec-butyl lithium borohydride, or other can not reduce the similar reductive agent of carboxyl.The pure VIII a of gained, under the dehydration conditions of standard, with a small amount of organic acid or mineral acid, for example the dehydration of tosic acid or sulfuric acid generates trans alkene VIII, wherein R ³Be hydrogen, react suitable inert solvent, for example in toluene, benzene, ether or the methylene dichloride, at siccative, Na for example ₂SO ₄, MgSO ₄, carry out under the existence such as molecular sieve, perhaps, be more preferably the water that reaction is produced and take away with fourth-Rodney Stark trap or similar instrument azeotropic.Then, adopt a suitable carboxyl-protecting group, preferably diphenyl-methyl is incited somebody to action wherein R with usual method ³Trans alkene VIII esterification for hydrogen.

Be worth those be familiar with this field people accepted is, pure VII a can form corresponding lactone X V in dehydration reaction, the hydroxyl among the pure VII a that the generation of lactone X V will be depended in the dehydration reaction to be adopted and the three-dimensional chemical configuration of carboxyl.

R ³Be the trans alkene VIII of carboxyl-protecting group, can be by with a kind of alcohol, diphenyl-methyl alcohol for example is added in the lactone X V that dehydration reaction generates and directly makes.

In one embodiment, R ¹And R ²Be the methylene-dioxy that connects together, R ⁴And R ⁶Be methoxyl group, R ⁵For the pure VII b of methyl can be dehydrated, generate trans alkene VIII a with the diphenyl-carbinol esterification then.

In another example, lactone X V a can separate from the dehydration reaction of corresponding pure VII b and obtains.The lactone of gained is handled under the acidic conditions of standard with diphenyl-carbinol, generates desirable trans alkene VIII a, following graphic shown in.

In another reaction scheme, when hope keeps same R ³During carboxy protective group; the selective reduction of aryl tetralone VI can be finished by shortening; selected hydrogenation catalyst has palladium, platinum, Lan Shi nickel or ruthenium; selected conventional carrier has charcoal, diatomite etc.; at the inert solvent of irreducibility, for example carry out in methyl alcohol, ethanol or the vinyl acetic monomer.Hydrogenation be preferably under normal temperature, normal pressure or the high slightly pressure carry out, the reduction of aryl tetralone VI preferably selects for use a kind of selective reduction agent to carry out in appropriate solvent.Used reductive agent: sodium borohydride, sodium cyanoborohydride, hydrosilation zinc, sulfuration sodium borohydride (Na BH ₂S ₃), diisoamyl borine, 3-sec-butyl lithium borohydride, or other can not reduce the similar reductive agent of carboxylic acid ester groups.Then with the pure VII that produced under the dehydration conditions of standard, with a small amount of organic acid or mineral acid, for example toluenesulphonic acids or sulfuric acid dehydration generates trans alkene VIII, wherein R ³Be carboxyl-protecting group.Be reflected in the suitable inert organic solvents, for example in toluene, benzene, ether or the methylene dichloride, at siccative, Na for example ₂SO ₄, MgSO ₄Carry out under the existence such as molecular sieve, or be more preferably the hydromining that reaction is produced and take away with fourth-Rodney Stark trap or similar instrument.

Can realize by the epimerization of carboxylic acid ester groups by of the transformation of trans alkene VIII to cis alkene IX.This epimerization is usually at inert organic solvents, for example in the tetrahydrochysene ketone (THF) ,-78 ℃ to～-20 ℃ low temperature, preferably approximately-78 ℃, and in the presence of a kind of highly basic, carry out.Used highly basic has lithium hydride, two (TMS) ammonification potassium, two sec.-propyl lithamide or two (trimethyl silyl) lithamide.Then, the negatively charged ion of gained is with sour, and for example cooling such as mineral acid-hydrochloric acid, sulfuric acid can solid selectively generate cis alkene IX.

Another aspect of the present invention provides the VI of the compound X with following structure:

ⅩⅥ

R wherein ¹And R ²Be respectively hydrogen, (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene radical dioxy base that connects together; R ³Be hydrogen or carboxyl-protecting group; R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group; R ⁵Be hydrogen or phenol protecting group; Or the salt of acid.

In a desirable embodiment, the compound that provides has general formula X VI a:

ⅩⅥa

R wherein ³Be hydrogen or carboxyl-protecting group; R ⁵Be hydrogen or phenol protecting group; Or the salt of acid.

In a preferable embodiment, the compound that is provided has general formula X VI a, wherein R ³Be (rudimentary) alkyl or diphenyl methyl, R ⁵Be methyl or benzyl.

Cis aryl tetralone with general formula X VI can be produced by the epimerization of corresponding trans aryl tetralone.Then, with compound reduction, the dehydration generation cis alkene of general formula X VI, general formula is an IX, and reaction scheme is as follows:

The initial aryl naphthalenone VI that has the ester group of relative transconfiguration can be approximately-70 ℃ to-20 ℃ low temperature, and preferably approximately-78 ℃, poly-cold with enol, epimerization changes into cis aryl tetralone X VI.This is reflected at inert organic solvents, for example in the tetrahydrochysene ketone (THF), use a highly basic, for example lithium hydride, two (trimethyl silyl) lithamide, two sec.-propyl lithamide or two (trimethyl silyl) lithamide earlier, add a kind of mineral acid then, for example hydrochloric acid is finished.

The cis aryl tetralone X VI of gained can be under the condition of selective reduction be reduced into ketone group pure X VII, wherein R ³Be carboxyl-protecting group.Reduction can adopt the method for shortening to finish, and the hydrogenation catalyst of employing has palladium, platinum, Raney Ni or ruthenium, and the conventional carrier of selecting for use has charcoal, diatomite etc.Be reflected at the inert solvent of irreducibility, for example carry out in water, methyl alcohol, ethanol or the vinyl acetic monomer.Hydrogenation is preferably under normal temperature, normal pressure or the high slightly pressure and carries out.Aryl tetralone X VI is preferably carried out in the appropriate solvent that has a selective reduction agent.Reductive agent has sodium borohydride, sodium cyanoborohydride, zinc borohydride, sulfurized sodium borohydride (Na BH ₂S ₃), diisoamyl borine, diboron hexahydride base, ammonia borine, tertiary butyl amino borane, pyridine borine, 3-sec-butyl lithium borohydride, or other can reduction, the similar reductive agent of hydrolysis or epimerization carboxylic acid ester groups.Then with the pure X VII that produced under the dehydration conditions of standard, with a spot of organic acid or mineral acid, for example p-methyl benzenesulfonic acid or sulfuric acid dehydration generates cis alkene IX, wherein R is a carboxyl-protecting group.Be reflected at suitable inert organic solvents, for example, in toluene, benzene, ether or the ethylene dichloride, at siccative, Na for example ₂SO ₄, MgSO ₄, carry out under the existence such as molecular sieve, or be more preferably the water that reaction is produced and take away with fourth-Rodney Stark trap or similar instrument azeotropic.

According to another reaction scheme, cis aryl tetralone X VI can have the selective reduction agent, preferably is reduced into pure XII a in the appropriate solvent of lithium borohydride and/or has lactone with general formula X VIII structure

Be worth those be familiar with this field people accepted is that pure XII a can form corresponding lactone X VIII in reduction reaction.From reaction the quantity of isolating lactone X VIII depend on the hydroxyl of the pure XII a that in reaction, produces and the relative three-dimensional chemical configuration of carboxyl.In special example, R ¹And R ²Be the methylene radical dioxy base that connects together, R ⁴And R ⁶Be methoxyl group, R ⁵For the lactone X VIII a of methyl is the main products of preferentially separating from reaction mixture.

The lactone X VIII a of gained according to the top lactone X V a time institute accepted standard acidic dehydration condition of talking about, handles with alcohol, and preferably diphenyl-carbinol can generate desirable cis alkene IX, wherein R ³Be carboxyl-protecting group.

According to another aspect of the present invention, provide compound with following general formula:

R wherein ¹And R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene radical dioxy base that connects together; R ³Be hydrogen or carboxyl-protecting group; R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group; R ⁵Be hydrogen or phenol protecting group; R ⁷For hydrogen, halogen, (rudimentary) carbalkoxy, carboxyl, cyano group, trimethyl silyl, benzenesulfonyl or carbobenzoxy, at R ⁷Phenyl ring can have one or two substituting group-(rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl respectively.

The compound that is provided in a desirable embodiment has following general formula X:

Ⅹ

R wherein ³Be hydrogen or carboxyl-protecting group; R ⁵Be hydrogen or phenol protecting group; R ⁷Be hydrogen; Halogen, (rudimentary) carbalkoxy, carboxyl, cyano group, trimethyl silyl, benzenesulfonyl or carbobenzoxy, R ⁷Phenyl ring on have one or two substituting group-(rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl respectively.

The compound that preferable example provided has wherein R of general formula X a ³Be hydrogen, (rudimentary) alkyl or diphenyl methyl; R ⁵Be methyl or benzyl; R ⁷Be bromine or chlorine.

Compound with general formula X can make through [3+2] cycloaddition reaction from having the cis alkene of general formula IX accordingly, shown in graphic 5:

Graphic 5:

Cis alkene IX is approximately-20 ℃ to reflux temperature, in inert solvent (water or organic solvent, or the mixture of water and organic solvent), for example water, C ₁-C ₆Alcohol, the ethanol ethyl ester, dioxane, in tetrahydrofuran (THF), acetone, Nitromethane 99Min., methylene dichloride or the chloroform, with at least one normal replacement itrile oxides XX, reaction generates different azoles adducts X.Though the solvent and the temperature of reaction are not strict, work as R ⁷During for halogen, reaction is preferably near carrying out under the reflux temperature of solvent, solvent for use has acetone or ethyl acetate.

Above-mentioned 1, in the dipolar cycloaddition reaction of 3-, preferably use excessive itrile oxides XX, normally excessive 3 equivalents.Itrile oxides is gone up reaction in position and is made usually from corresponding formoxime.Reaction is at mineral alkali, for example a KHCO ₃, or Na ₂CO ₃, or one three replacement amine, as carrying out under the existence of triethylamine or pyridine.Formula as follows:

In order to prepare R ⁷Be the compound XX a of bromine, can be by document Tetrahedron letters 21, the 229-230(1980) method described in, or preferably according to the improvement program of the example 20 described steps A of this explanation, from R ⁷For the dibromo formoxime X IX of bromine makes the bromination itrile oxides.General formula is other itrile oxides of XX, R ⁷Be hydrogen; Ethoxycarbonyl, carboxyl and cyano group; Trimethyl silyl; And benzenesulfonyl, can make by the described general procedure of following document, reference has Terahedron letters, and 24,1815-1816(1983); J.Org.Chem.48,366-372(1983); Synthesis, 719(1982) and J.Org.Chem.48,1796-1800(1983).

In the specific examples of compound X, R ¹And R ²Be the methylene-dioxy that connects together; R ⁴And R ⁶Be methoxyl group; R ⁵Be methyl; R ⁷Be bromine; R ³Be diphenyl methyl,, in Nitromethane 99Min., be used for being easy to generate crystalline isoxazole acid X c after the protecting group that HCl takes off carboxyl, wherein R at inert organic solvents ³Be hydrogen, R ⁷Be chlorine.The special protection process of going of this compound X has caused the replacement of halogen, the R on the Zai isoxazole ring ⁷, bromine is originally replaced by chlorine.When hope keeps R ⁷During for bromine,, preferably go provide protection with trifluoroacetic acid as what demonstrated at the different azoles acid of preparation X d.

In selection by non-antipodal faces, the Stereoselective structure that the itrile oxides XX that replaces is connected in ， isoxazole ring in the compound X that the β face of cis alkene IX produced be easy to by ¹The H nuclear magnetic resonance spectrum is measured.For regiospecific of the present invention and stereoselective additional evidence are provided, use cis alkene VIII b to repeat [3+2] cycloaddition reaction, formula as follows:

In the process that connects different azoles ring, the separation that contains opposite stereochemical compound X XI proves, the technology of preparation compound X described herein is the three-dimensional technology of selecting of a kind of height that produces desirable regiospecific, and it is needed to podophyllotoxin and relevant derivative thereof that regiospecific is synthetic effectively difference.

As the more deep one side of the present invention, provide compound with general formula XI:

Ⅺ

R wherein ¹, R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene radical dioxy base that connects together; R ³Be hydrogen or carboxyl-protecting group; R ⁴And R ⁶Hydrogen, or (rudimentary) alkoxyl group respectively; R ⁵Be hydrogen or sour protecting group; R ⁸Be cyano group, aminomethyl, acyl group or formamyl; Or the salt of acid.

The general formula of the compound that another embodiment provided is:

Ⅺa

R wherein ³Be hydrogen or carboxyl-protecting group; R ⁵Be hydrogen or phenol protecting group; Or the salt of acid.

The general formula of a compound that more desirable embodiment provided is XI a, wherein R ³Be hydrogen, (rudimentary) alkyl or diphenyl methyl, R ⁵Be methyl or benzyl; Or the salt of acid.

The general formula of the compound that another embodiment provided is:

Ⅺb

R wherein ³Be hydrogen or carboxyl-protecting group; R ⁵Be hydrogen or phenol protecting group; Or the salt of acid.

The general formula of a compound that more desirable embodiment provided is XI b, wherein R ³Be hydrogen, (rudimentary) alkyl or diphenyl methyl, R ⁵Be methyl or benzyl; Or the salt of acid.

General formula is that the difference of XII can be produced from corresponding isoxazole compound X according to the order shown in 6 to podophyllotoxin and relevant derivative thereof.

Graphic 6

The compound X can cause N-0 key heterolytic fission under various conditions.The condition of isoxazole ring open loop depends on R usually ⁷Substituting group, R herein ³Be hydrogen or carboxyl-protecting group, for example R ⁷During for trimethyl silyl, according at Heterocycles, 20, the 511-518(1983) general procedure described in the literary composition, the thermal rearrangement after hydrolysis will produce compound XI c.Work as R ⁷During for carbalkoxy, benzoyl or cyano group, be hydrolyzed into R earlier ⁷For the compound X of carboxyl, then according to J.Org.Chem., 48,366-372(1983) the general procedure decarboxylation described in the literary composition also will produce compound XI c.Work as R ⁷Be benzenesulfonyl, R ³During for hydrogen or carboxyl-protecting group, with sodium borohydride or 2% sodium amalgam, according to J.Org.Chem., 49,123-125(1984) with J.Am Chem.Soc., 101, the 1319(1979) general procedure described in, selective reduction also produces compound XI c.In addition, if use a stronger reductive agent, for example lithium aluminum hydride, then R ³For the reducible one-tenth of the compound of hydrogen has the cyano compound of general formula XI c, do not have under the isolating situation, can further reduce and generate general formula is the amino methyl compound of XI d.And have been found that R ⁷For bromine De isoxazole X can be at radical initiator, for example 2,2 '-existence of azobis isobutyronitrile under, be reduced into compound XI cR with tri-butyl tin hydride ⁷Be the compound X of chlorine or bromine, preferably adopt the shortening method to reduce.The reduction be preferably in the about 40-50 pound of hydrogen initial pressure/cun ²,, for example in the presence of the Raney Ni on charcoal or the nickel borides, platinum oxide, palladium,, for example carry out in alcohol, vinyl acetic monomer, water or their mixture at the solvent of irreducibility at catalyzer.Work as R ³Be not the compound X of hydrogen when reducing, can be by adding a suitable buffer reagent, for example boric acid or other similarly gentle buffering acid are regulated the pH of solvent, with prevent carboxyl epimerization may appear, as used compound X, R ³During for hydrogen, reduce lowlyer to the susceptibility of reaction conditions, buffered soln can save.

The compound of general formula XI c, R ³Be hydrogen or carboxyl-protecting group, but selective reduction cyano group and be transformed into aminocompound, and general formula is the compound of XI d, works as R ³During for carboxyl-protecting group, can carry out catalytic hydrogenating reduction, catalyst system therefor has platinum oxide or Raney Ni, is reflected at the inert solvent of irreducibility, for example water, methyl alcohol, ethanol or vinyl acetic monomer, or carry out in their mixture.Hydrogenation preferably carries out under normal temperature, normal pressure or high slightly pressure.In addition, reduction also can be adopted the selective reduction agent, and for example the diboron hexahydride in tetrahydrofuran (THF) or other neither can reduce carboxylic acid ester groups, also can not make it the similar reductive agent of epimerization.The compound XI d of gained, R ³Be carboxyl-protecting group, can be under the condition of non-epimerization, for example tell when hydrogenolysis or hydrolysis.

At R ³Among the compound XI c for hydrogen, the reduction of cyano group generally adopts the shortening method for well.Used hydrogenation catalyst has platinum oxide or Raney Ni.Be reflected at the inert solvent of irreducibility, for example carry out in methyl alcohol, ethanol, ethyl acetate, methylene dichloride or its mixture, hydrogenation should or carry out under the high pressure slightly at normal temperature, normal pressure.The reduction preferably adopt lithium aluminum hydride, in appropriate solvent, for example carry out in the tetrahydrofuran (THF).If necessary, the compound XI d that is produced, R ³Be hydrogen, can an additive salt, for example the isolated in form of acetate is come out.

R ³For the methyl compound XI d of hydrogen can pass through the cyclisation of primary amine diazotization, preferably in acidic aqueous media, for example aqueous acetic acid or trifluoroacetic acid aqueous solution, with Sodium Nitrite or the reaction of isoamyl nitric ether.Cyclisation directly obtains desired lactone XII, and it has accurate poor relative three-dimensional chemical property to mortar poison and podophyllotoxin.

If necessary, general formula XI c compound can change into the compound that general formula is an XI, wherein R selectively by the method for having known ⁸Be formyl radical.Method therefor has the shortening method of using Raney Ni.Be reflected in the aqueous acetic acid, Sodium Pyrosulfite exists down, or in acetic acid, zinc carries out under existing.R then ⁸Be formyl radical, R ³Be the compound XI of hydrogen, can become pure formula Podophyllinic acid through selective reduction, the latter can be by J.Am.Chem.Soc., and 103,6208-6209(1981) method described in the literary composition changes into difference to podophyllotoxin.

If desired, compound XI c can optionally change into compound XI, wherein R with hydrogen peroxide ⁸Be formamyl.R then ⁸Be formamyl, R ³For the compound XI of hydrogen can be with lithium aluminum hydride through selective reduction generation compound XI d, wherein R ³Be hydrogen, this compound can change into difference to podophyllotoxin and related compound thereof by methods described herein.

In a more desirable reaction scheme, compound XI b need not to separate, and can further react to generate desirable difference to podophyllotoxin (I) and allied compound.For example, compound XI a, R ⁵Be methyl, R ³Be hydrogen, at first handle with the reductive agent lithium aluminum hydride, with cyano reduction, treat solvent evaporation after, the thick product XI b of gained handles with sodium nitrite solution again, diazotization, lactonizing then generates desirable difference to podophyllotoxin (I), is shown below:

Compared with the above case in a more desirable reaction scheme, compound XI a need not to separate with XI b, can further react to generate desirable difference to podophyllotoxin (I), for example, R ⁵Be methyl, R ³Be hydrogen, R ⁷Be the compound X a of chlorine, room temperature, hydrogen pressure be about 40-50 pound/cun ²Condition under, use nickel borides, handle with platinum oxide then, the thick product XI b of gained promptly uses diazo reagent, preferably Sodium Nitrite without further separating and purifying, at acidic medium, for example handle in the aqueous acetic acid, generate desirable difference to podophyllotoxin (I).

In another aspect of this invention, provide compound with general formula X IV:

ⅩⅣ

R wherein ¹, R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene radical dioxy base that connects together; R ³Be hydrogen or carboxyl-protecting group; R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group, R ⁵Be hydrogen or phenol protecting group; R ⁹For selecting to be substituted with phenyl or (rudimentary) alkyl of one or more halogen atom one fluorine, chlorine and bromine arbitrarily.

The compound X IV a that is provided in a desirable embodiment is:

ⅩⅣa

R wherein ³Be hydrogen or carboxyl-protecting group; R ⁵Be hydrogen or phenol protecting group; R ⁹For selecting to be substituted with phenyl or (rudimentary) alkyl of one or more halogen atom one fluorine, chlorine and bromine arbitrarily.

The compound X IV a that in more desirable another example, is provided, wherein R ³Be diphenyl methyl; R ⁵Be methyl or benzyl, R ⁹Be methyl.

Compound X IV can be passed through effective, an improved cyclization process, prepares from corresponding compounds X III.Cyclopropane compound X III itself is easy to make from the phenyl styryl ketone X XII that can get.The synthetic order of preparation compound X IV with used the same of preparation aryl tetralone VI, lists in graphic 7.

Graphic 7

Starting raw material X XII is easy to from known ketone and aromatic aldehyde, and at Synrhesis, 647-650(1980) universal method described in the literary composition makes according to S.Watlanasin and W.S.Murphy.

The phenyl styryl ketone X XII of carrying out Cyclopropanated in order to prepare cyclopropyl ketone, can use known cyclopropanation agent, ethoxycarbonyl trimethylammonium sulfonium compound for example, adopt W.S.Murphy and S.Wattasin at J.C.S.Perkin I, 271-276(1982) general method described in the literary composition goes to carry out,, the method for Murphy and Watlanasin can run into two poor isomer of compound X III, α-COOR ³With β COOR ³, mixture, its ratio is about 1: 1.People such as Murphy think that alpha-isomer is prior isomer for later cyclization, because β-isomer is under the condition of lewis acid, can change into alpha-isomer by epimerization in ten minutes.

Have been found that now when cyclopropanization reaction in dimethyl sulfoxide (DMSO), with corresponding phenyl styryl ketone X XII a-R wherein ¹And R ²Be the methylene radical dioxy base that connects together, R ⁴And R ⁶Be methoxyl group; R ⁵Be methyl, R ³Be ethyl, but specificity ground generates α-COOR of cyclopropanone XII a ³Isomer, yield are 96%.

By the lewis acid catalyzed reaction, some cyclopropane base ketone X III are directly changed into trans aryl tetralone VI, by W.S.Murphy and S.Wattanasin at J.C.S.Perkin I, write up 271-276(1982) and in the relevant document, people such as Murphy have narrated compound X III a, wherein R ¹And R ²Be the methylene radical dioxy base that connects together; R ⁴And R ⁶Be methoxyl group; R ⁵Be methyl and R ³Be ethyl, can successfully be cyclized into corresponding important Gensler ketone VI b, the cyclisation feature is to use the noticeable effect of Nitromethane 99Min. as solvent, and in benzene and methylene dichloride, all can not successfully realize this rearrangement under various conditions.[W.S.Murphy and S.Wattanasin, J.C.S.chem.Comm., 262-263(1980)]., by people's such as Murphy method, the reaction that compound X III a is rearranged into aryl tetralone VI b is carried out quite slowly, and has generated the mixture of various products, and optimum program is the BF that utilizes in Nitromethane 99Min. ₃(C ₂H ₅) ₂O, through 15 days reaction, it can obtain a product mixture, separated through freshly prepd thin-layer chromatography, can obtain the compound VI b of 57% yield at most, shown in graphic 8.

Graphic 8

The purpose that the present invention is specialized prepares the new significant improvement of being done in the process of aryl tetralone VI in order to be described in through novel enolization compound X IV.

The compound of general formula X III is handled with about 0.5 normal lewis acid and 1 normal acid anhydrides in room temperature, inert organic solvents at least, can generate the enolization compound of general formula X IV, and used lewis acid has Sncl ₄, BF ₄(C ₂H ₅) ₂O, ZnCl ₂Deng, acid anhydrides has acetic anhydride or trifluoro acid anhydrides, and inert organic solvents has Nitromethane 99Min., methylene dichloride, benzene, tetrahydrofuran (THF), vinyl acetic monomer, toluene, chloroform, dioxane etc.Used in this example solvent is not strict.General use 1 normal lewis acid and 1 equivalent, or preferably use 2 normal acid anhydrides, molecular formula is

, R in the formula ⁹As mentioned above.When using lewis acid BF ₃(C ₂H ₅) ₂During O, be preferably within about 5 minutes and make the stopping of reaction., if in reaction, used more weak lewis acid, for example ZnCl ₂Before separating corresponding enolization compound X IV, reaction was continued 24 hours so.

When needs produced aryl tetralone VI, the cyclisation of corresponding cyclopropyl ketone X III should be with recited above, carry out under the identical condition during preparation enolization compound X IV, but this reaction can change into except the situation of aryl tetralone VI always fully.In addition, have been found that cyclization can be at catalytic amount, carry out under about 0.1 normal acid anhydrides exists.In general, finished reaction and obtained purer product in about 1 to 2 hour, cyclization is at 1 equivalent acid anhydrides, or preferably 2 equivalent acid anhydrides carry out under existing.Using weak lewis acid, for example ZnCl ₂During with 2 equivalent aceticanhydrides, preferably allow reaction carry out more than 24 hours, be appreciated that, just need the longer reaction times can finish reaction if use is less than 1 to 2 normal acid anhydrides in cyclization.

In an example of the present invention that is shown below, compound X III a is with 1 normal BF ₃(C ₂H ₅) ₂O and 2 normal aceticanhydrides are handled, at about 1 hour, through obtaining the aryl tetralone VI b of 96% yield behind the enol intermediate X IV b.In another embodiment, compound X III a handles with 1 normal ZnCl and 2 normal aceticanhydrides, through about 24 hours, can obtain the enolization compound X VI b greater than 90% yield.Above-mentioned example clearly, excitingly has illustrated general applicability of the present invention and superiority with other example that utilizes a kind of acid anhydrides.

According to the present invention, it is the technology of the compound of XII that the preparation general formula also is provided,

Ⅻ

R wherein ¹And R ²Be respectively hydrogen, or (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene radical dioxy base that connects together; R ⁴And R ⁵Be respectively hydrogen or (rudimentary) alkoxyl group; R ⁵Be hydrogen or phenol protecting group, or pharmaceutically receptible alkali, technological process comprises:

(a) general formula is that the cis alkene and the general formula of IX are the itrile oxides of XX, reacts in inert solvent, and producing general formula is the different azoles of X.In the cis alkene IX, R ³Be hydrogen or carboxylic acid protecting group; R ¹

Ⅸ

R ², R ³, R ⁴And R ⁶All as previously mentioned, itrile oxides R ⁷-C three In, R ⁷Be hydrogen, halogen, (rudimentary) carbalkoxy, carboxyl, cyano group, trimethyl silyl, benzenesulfonyl or carbobenzoxy, R ⁷Phenyl ring on can have one or two substituting group-take from respectively (rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl; In the isoxazole X, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷All as previously mentioned.

Ⅹ

(b) cracking compound X De isoxazole ring, producing general formula is the compound of XI c.

Ⅺc

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned.

(c) nitrile of general formula XI c produces compound XI d, wherein R through selective reduction ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned.

Ⅺd

Or alkali; If R ³Be carboxyl-protecting group, remove said carboxyl-protecting group, promptly produce R ³Compound XI d for hydrogen.

(d) by amino diazotization, make compound XI d cyclisation, lactonizing then produces the compound XII.

Ⅻ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned.

An example of the present invention is the technology of preparation difference to podophyllotoxin chemical compounds I a, and wherein R is hydrogen or phenol protecting group.Technological process is as follows:

Ⅰa

(a) cis alkene IX a and itrile oxides XX are reacted in inert solvent and are generated different azoles X a, among the cis alkene IX a, and R ³Be hydrogen or carboxylic acid protecting group, R ⁵Be hydrogen or phenol protecting group.Nitrile oxygen

Ⅸa

Change in the thing XX R ⁷Be hydrogen, halogen, (rudimentary) carbalkoxy, carboxyl, cyano group, TMS, benzenesulfonyl or carbobenzoxy, R ⁷Phenyl ring on can have one or two substituting group-be selected from respectively (rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl.Among the isoxazole X a, R ³, R ⁵And R ⁷All as previously mentioned.

(b) the different azoles ring of cracking compound X a produces compound XI a:

Ⅺa

R wherein ⁴And R ⁵All as previously mentioned.

(c) nitrile XI a generates compound XI b through selective reduction:

Ⅺb

R wherein ³And R ⁵All as previously mentioned, or be alkali, if R ³Be carboxyl-protecting group, remove said carboxyl-protecting group and promptly produce the compound that general formula is XI b, wherein R ³Be hydrogen.

(d) by amino diazotization, make compound XI b cyclisation, lactonizing then, it is poor to podophyllotoxin chemical compounds I a to produce:

Ⅰa

R wherein ⁵As previously mentioned.

Another example of the present invention is the technology of preparation cis alkene IX.

Ⅸ

R wherein ¹And R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹And R ²Be the methylene radical dioxy base that connects together, R ³Be hydrogen or carboxyl-protecting group, R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group, R ⁵Be hydrogen or phenol protecting group, its technological process is as follows:

(a) pure VII is dewatered in the presence of acid and is produced trans alkene VIII, in the pure VII, and R ³Be carboxyl-protecting group,

Ⅶ

R ¹, R ², R ⁴And R ⁶All as previously mentioned, in the trans alkene VIII,

Ⅷ

R ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned,

(b) in the trans alkene VIII, in the presence of low temperature, inert organic solvents, handle, use sour quenching then, produce cis alkene IX with highly basic:

Ⅸ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above, optionally go protecting group, promptly produce the compound IX, wherein R ³Be hydrogen and R ⁵Be the phenol protecting group, or R ⁵Be hydrogen and R ³Be carboxyl-protecting group.

Another example of the present invention is the stereospecific synthesis technology of the different azole compounds X a of preparation:

Ⅹa

R wherein ³Be hydrogen or carboxyl-protecting group, R ⁵Be hydrogen or phenol protecting group, R ⁷Be hydrogen, halogen, (rudimentary) carbalkoxy, carboxyl, cyano group, trimethyl silyl, benzenesulfonyl or carbobenzoxy, R ⁷Phenyl ring on can have one or two substituting group-be selected from (rudimentary) alkyl, halogen, (rudimentary) alkoxyl group and trifluoromethyl respectively, its technological process comprises: cis alkene IX a, R ³Hand R ⁵All as previously mentioned, with itrile oxides XX, R ⁷As previously mentioned, at a kind of inert water or organic

Solvent, or in the mixed solvent of water and organic solvent, making an appointment with-20 ℃ to the reflux temperature of solvent; Stereoselective produces said different azole compounds X a; and with compound X a, wherein R is a carboxyl-protecting group, optionally goes protecting group to obtain compound X b:

(b) the different azoles ring of cracking compound X, producing general formula is the compound of XI c.

Ⅹb

R wherein ⁵And R ⁷All as previously mentioned.

Another example of the present invention is the technology of preparation difference to podophyllotoxin I a.

Ⅰa

R wherein ⁵Be hydrogen or phenol protecting group, its technological process is as follows:

(a) cracking compound X b De isoxazole ring, wherein R ⁵Be hydrogen, or the phenol protecting group, R ⁷

Ⅹb

Be chlorine or bromine, produce nitrile XI e, wherein R ⁵Be hydrogen or phenol protecting group.

Ⅺe

(b) nitrile XI e generates compound XI f through selective reduction,

Ⅺf

R wherein ⁵Be hydrogen or phenol protecting group.

(c) make compound XI f cyclisation by amino diazotization, lactonizing then produces a difference to podophyllotoxin chemical compounds I a:

Ⅰa

R wherein ⁵Be hydrogen or phenol protecting group.

For the above-mentioned various technologies that prepare the compound XII comprise: under hydrolysising condition, the hydrolysis of the carboxylic acid ester groups of the selective reduction of trans aryl tetralone VI or trans aryl tetralone VI, the sour VI a of selective reduction gained produces compound VII a then.Compound VII a in the presence of hydrolysising condition and acid, produces trans lactone X V again,

ⅩⅤ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above.Compound X V is at acid and pure, R ³OH exists down, and dehydration produces trans alkene VIII, R ³Be carboxyl-protecting group.Trans then alkene VIII is by the enolate quenching, and epimerization produces cis alkene IX.The compound IX is reacted with the itrile oxides XX again, and the isoxazole compound X that is produced is cracked into nitrile XI a successively, is reduced into amine XI b, changes into desirable compound XII by above-mentioned technology diazonium again.

The preparation difference comprises that to the further improvement of the above-mentioned technology of podophyllotoxin and related compound XII thereof trans aryl tetralone VI produces cis aryl tetralone X VI by enol quenching epimerization.

XⅥ

R wherein ¹, R ², R ⁴, R ⁵, R ³And R ⁶All as previously mentioned.Compound X VI generates compound X VII through selective reduction then:

ⅩⅦ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned.Compound X VII is in the presence of acid, and the water that produces is removed on the limit, and the limit dehydration produces cis alkene IX:

Ⅸ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above.Cis alkene IX, then with itrile oxides, the XX reaction, the different azoles X that is produced is cracked into nitrile XI a successively, is reduced into amine XI b, changes into desirable compound XII according to above-mentioned technology diazonium then.

The further improvement of the above-mentioned technology of preparation compound XII comprises that trans aryl tetralone VI produces cis aryl tetralone X VI by enolate quenching epimerization:

ⅩⅥ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above.Then, compound X VI is under hydrolysising condition, and selective reduction, or carry out selective reduction after the hydrolysis again produces compound X VIII:

ⅩⅧ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above.Compound X VIII is in the presence of acid and alcohol, and dehydration produces cis alkene IX:

Ⅸ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above.Cis alkene IX, with the reaction of itrile oxides XX, the isoxazole compound X that is generated is cracked into nitrile XI a successively, is reduced into amine XI b, changes into desirable compound XII by above-mentioned technology diazonium then again.

Another aspect of the present invention provides the technology for preparing compound X IV.

ⅩⅣ

R wherein ¹And R ²Be respectively hydrogen or (rudimentary) alkoxyl group or R ¹And R ²Be the methylene radical dioxy base that connects together; R ³For hydrogen is exhaled the carboxyl-protecting group of vomitting; R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group; R ⁵Be hydrogen or phenol protecting group, its technological process comprises cyclopropyl compounds XII, wherein R ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above, in inert solvent, through at least 0.5 normal lewis acid and at least 1 normal acid anhydrides,

ⅩⅢ

(R ⁹-C-) ₂O handles and cyclisation, until compound X IV base

This generation, in the X IV, R ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned, R ⁹Be phenyl or (rudimentary) alkyl, can have one or more halogen atom one fluorine chlorine and bromines on it.

ⅩⅣ

Another aspect of the present invention provides the technology for preparing the compound VI.

Ⅵ

R wherein ¹And R ²Be respectively hydrogen or (rudimentary) alkoxyl group, or R ¹And R ²For connecting methylene radical dioxy base together; R ³Be hydrogen or carboxyl-protecting group, R ⁴And R ⁶Be respectively hydrogen or (rudimentary) alkoxyl group, R ⁵Be hydrogen or phenol protecting group, technological process comprises: cyclopropyl compounds X III:

ⅩⅢ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as previously mentioned, in inert organic solvents, with at least 0.5 normal lewis acid and be at least catalytic amount acid anhydrides (

) ₂O handles, and cyclisation generates substantially until trans aryl tetralone VI, in the VI, and R ¹, R ², R ³

Ⅵ

R ³, R ⁴, R ⁵, R ⁶All as previously mentioned, R in the acid anhydrides ⁹For having phenyl or (rudimentary) alkyl that one or more halogen atoms one are selected from fluorine chlorine and bromine.

A desirable example of the present invention is the technology of the trans aryl tetralone VI c of preparation.

Ⅵc

Among the VI c, R ³Be hydrogen or carboxyl-protecting group, R ⁵Be hydrogen or phenol protecting group, its technological process comprises: cyclopropyl compounds X III b, wherein R ³Be carboxyl-protecting group, R ⁵Be the phenol protecting group,

ⅩⅢb

In inert organic solvents, through about 1 normal lewis acid and 1 to 2 normal acid anhydrides,

, to handle, cyclisation is until generating trans aryl tetralone VI c basically.

Ⅵc

R wherein ³And R ⁵All as previously mentioned, in the acid anhydrides, R ⁹For having one or more halogen atoms-be selected from (rudimentary) alkyl of fluorine chlorine and bromine, compound VI c goes protecting group through selectivity, produces compound VI c, wherein R ³Be hydrogen and R ⁵Be the phenol protecting group, or R ⁵Be hydrogen and R ³Be carboxyl-protecting group.

In following examples, all temperature all adopt ceslius scale (℃).Fusing point is measured record by thomas-Hu Fo (Thomas-Hoover) capillary melting point determination instrument, and the fusing point of surveying need not be proofreaied and correct. ¹HNMR spectrum (nuclear magnetic resonance spectrum) Bruker WM360 type spectrometer record.Use solvent to be deuterochloroform (CDCl).Chemical shift δ unit record, coupling constant is unit record with hertz (Hz).Separating (branch) phantom remembers by following provisions: S, singlet (unimodal); Doublet; T, triplet; Q, quartet; M, multiple; Bp, broad peak; Dd, quartet.Infrared spectra is with Beckman (Beckman) 4240 type spectrophotometric determinations, with centimetre inverse (cm) be unit record.Thin-layer chromatography (TLC) uses ultraviolet lamp and/or iodine vapor to show observation, carries out on precoating silica-gel plate (60F-254).Flash distillation chromatography (gas chromatography) carries out with Woehn silica gel (32-63 μ m) and indication solvent.The evaporation of all solvents is all measured and is under reduced pressure carried out.Here employed " Skellysolve B " is that to contain the normal hexane boiling point in fact be a kind of petroleum solvent cut of 60-80 ℃, and employed " ether " is often referred to ether (diethyl ether) if no special instructions.

Embodiment 1

Ethyl 2-(3,4-methylene protocatechuoyl)-3-(3,4, the 5-trimethoxy-benzene)-(the X III is a) for cyclopropanecarboxylcompound

At the device agitator that is magnetic, dropping funnel is placed sodium hydride (8.2 grams, 0.17 mole, 50% disperse phase) in one liter the three neck round-bottomed flasks of a nitrogen inlet and a diaphragm plate.Wash this separation phase with sherwood oil (2 * 100 milliliters), use nitrogen drying.Add then trimethylammonium oxyiodination blunderbuss (37.7g, 0.17moles).In the time more than 30 minutes, drip dried methyl-sulphoxide (45 milliliters) again with syringe.At room temperature this emulsion was stirred one and a half hours, under continuous stirring condition, add ethoxycarbonyl methyl dimethoxy base bromination system (41.2g, 0.18moles) methyl-sulphoxide (60ml) solution then with the time more than ten minutes.Further this white emulsion was stirred one and a half hours under the room temperature.In the time more than five minutes, add 3 with stable a fluid stream, 4,5-trimethoxy-3 ', 4 '-methylene-dioxy phenyl styryl ketone X XI a(55.9 gram, 0.16 mole) [according to S.Wattanasin and W.S.Murphy.Synthesis, the method preparation of 647(1980) being narrated] and the formed emulsion of methyl-sulphoxide (185 milliliters), at room temperature this reaction mixture was stirred 17 hours then.Pour reaction mixture into cold 0.1NHCl(700 milliliter) in, the consequent adhesive and the aqueous solution are separated.Extract this aqueous solution with ether (2 * 500 milliliters).Come together to dissolve gummous substance with combining extraction liquid and the ether (500 milliliters) that replenishes.Use sodium bicarbonate aqueous solution (500 milliliters, 5%) and water washing more successively, dry (Na ₂SO ₄And MgSO ₄), reconcentration is made the alpha-isomer (68.0 gram) of yellowish glass title compound.Its ¹HNMR spectroscopic data and W.S.Murphy and S.Wattanasin, J.C.S.Perkin I, 271(1082) Bao Dao alpha-isomer spectroscopic data unanimity.

In similarly testing, save trimethylammonium oxyiodination sulfonium used in the top process, reaction also can obtain the alpha-isomer of the title compound of high yield.In the experiment, (2.98g 1.2mM), adds 19 milliliters of methyl-sulphoxides again to add ethoxycarbonyl methyl dimethoxy base bromination sulfonium in 10 milliliters of anhydrous dimethyl sulfoxide solution of past sodium hydride (0.67 gram, 1.4mM, 50% disperse phase).After about 75 minutes, with the phenyl styryl ketone X XII a(3.4g in 21 milliliters of tetrahydrofuran (THF)s, 1.0mM) solution with 4 milliliters of methyl-sulphoxides compositions slowly added in the time more than 35 minutes.Press top this reaction mixture of method processing again, thereby obtain α-(with dividing) isomer of title compound, productive rate is 96%.

Embodiment 2

Trans-ethyl 1,2,3,4-tetrahydrochysene-6,7-methylene-dioxy-4-oxygen-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylic ester ester (VI b)

Toward cyclopropyl ketone X III a(0.8g, add BF in methylene dichloride 1.8mM) (40ml) solution ₃Et ₂O(0.24ml, 19mM), add again acetic anhydride (0.36ml, 3.8mM).With solution stirring two and a half hours, dope sodium hydroxide solution (50ml) and the methylene dichloride (50ml) of 0.2N then under the room temperature.Organic layer is told washing (H ₂O), dry (MgSO ₄) and be condensed into oily solid (0.72g).With dehydrated alcohol recrystallization, activated carbon treatment, make the white crystalline solid (0.46 gram) of title compound; The m.p.(fusing point): 157-159 ℃.Its ¹HNMR spectroscopic data and W.S.Murphy and S.Wattanasin, J.C.S.Perkin I, 271(1082) data consistent of being reported.

Embodiment 3

Trans-ethyl 1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-oxygen-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (VI b)

Using 50mg(0.12mM) cyclopropyl ketone X III a repeats example 2, used methylene dichloride before only will replacing with Nitromethane 99Min., make the title compound of 45mg with this, thin-layer chromatography TLC[silica gel/ether: Skellysolve B(3: 2)] draw Rf=0.26.Its ¹The HNMR spectroscopic data is consistent with the result of embodiment 2.

Embodiment 4

Trans-ethyl 1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-oxygen-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (VI b)

(a) in methylene dichloride, use 50mg(0.12mM) cyclopropanone X III a repeat the experimental procedure of embodiment 2, just to use SnCl ₄Used BF before replacing ₃Et ₂O, thus prepare title compound, productive rate about 90%.

(b) replace used methylene dichloride with Nitromethane 99Min., repetitive process (a) then, thus prepare title compound, productive rate about 90%.

(c) replace used methylene dichloride repetitive process (a) again with benzene, thereby prepare title compound.

Its thin-layer chromatography TLC[silica/ether: Skellysolve B(3: 2)] all draw Rf=0.26, they ¹The HNMR spectroscopic data is identical with the data of the product of embodiment 2.

Embodiment 5

Trans-ethyl 1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-oxygen-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (VI b)

Use 428mg(1.0mM) cyclopropyl ketone X III a and 204mg(2.0mM) acetic anhydride repeats example 3 processes in the 5ml Nitromethane 99Min., be will wherein used BF ₃Et ₂The consumption of O is restrained by 1() equivalent is kept to 0.5(gram) (71mg 0.5mM), thereby prepares title compound to equivalent.Its ¹The HNMR spectroscopic data is identical with the data of embodiment 3 products.

Embodiment 6

Trans-ethyl 1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-oxygen-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (VI b)

Toward cyclopropanone X III a(428mg, (10.2mg 0.1mM), is adding BF 1.0mM) to add an amount of acetic anhydride that plays katalysis in the solution of forming with the 5ml Nitromethane 99Min. ₃Et ₂O(142mg, 1.0mM).Stirring reaction liquid under the room temperature is carrying out highly pressurised liquid chromatograph chromatography.After about 100 hours, the sodium hydroxide solution reaction mixture with 10ml0.2N dopes the 5ml methylene dichloride again.Isolating organic phase carries out drying, reduction vaporization (solvent) and obtains title compound.Except some impurity are arranged, its ¹HNMR spectrum is identical with embodiment 2 products.

Embodiment 7

Trans-ethyl 1,2-dihydro-6,7-methylenedioxy group-4-acetoxy group-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (X IV b)

To cyclopropanone X III a(1.40g, (0.61ml 6.47mM), adds BF again to add acetic anhydride in methylene dichloride 3.24mM) (50ml) solution ₃Et ₂O(0.40ml, 3.25mM).With solution stirring 5 minutes, use the sodium hydroxide solution (35ml) of 0.5N to handle then.Isolate organic layer and wash (H ₂O), dry (MgSO ₄) and be condensed into pulpous state (1.53g).Thin-layer chromatography TLC[vinyl acetic monomer: methylene dichloride (5: 95)] demonstrate the Rf=0.36 of two main mottle Rf ' S=0.47 and the initial thing of 0.27().Vinyl acetic monomer methylene dichloride with 3% obtains these two kinds by silica gel column chromatography and analyzes purifying compounds as elutriant.

124-129 ℃ of the component (0.52g Rf=0.47) is considered to title compound, the m.p.(fusing point) that elder generation's wash-out comes out.

To C ₂₅H ₂₆O ₉

Analytical Calculation: C, 63.82; H, 5.57

Experiment is found: C, 63.52; H, 5.74

¹HNMR（CDCl ₃，δ）：

1.18（t，3H，7.2Hz），2.31（s，3H），3.62（t，1H，5.5Hz），3.8（s，9H），4.10（q，2H），4.49（d，1H，5.5Hz），5.55（d，1H，5.7Hz），5.92（s，2H），6.52（s，3H），6.68（s，1H）。

(0.40g Rf=0.27) is identified as tetralone VI b to the component that back wash-out comes out, and is identical with the compound that obtains among the embodiment 2.

Embodiment 8

Trans-ethyl 1,2-dihydro-6,7-methylenedioxy group-4-acetoxy group-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (X IV b)

With zinc chloride (Zn.Cl ₂) replace used BF among the embodiment 7 ₃Et ₂O repeats embodiment 7 steps then, and reaction is 24 hours under the room temperature, makes title compound, its productive rate＞90%; TLC[vinyl acetic monomer: methylene dichloride (5: 95)] Rf=0.47 that provides.Its ¹The HNMR spectroscopic data is identical with the data of embodiment 7 products.

Embodiment 9

Cis-ethyl 1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-oxygen-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (X VI b)

Toward nitrogen envelope ,-78 ℃ 1.7M n-Butyl Lithium (in the hexane) (10.6ml, 1.80mM) add lentamente in tetrahydrofuran (THF) (10ml) solution di-iso-amylamine (2.52ml, 18.0mM).Stir after 20 minutes, with the time more than 30 minutes, temperature-78 ℃ drips trans-tetralone VI b(1.93g, 4.51mM) tetrahydrofuran (THF) (40 milliliters) solution.After adding, this orange mixed solution slowly is warmed up to-40 ℃ with the time more than 1 hour, further stirred 30 minutes.With (3.5ml) once (with a collection of form) adding of tetrahydrofuran (THF) (3.5ml) solution of dense hydrogenchloride (HCl), obtain-yellow solution then.It is raised to room temperature,, extracts with vinyl acetic monomer with the dilution of 50ml water.Merge organic extract liquid and carry out drying (MgSO ₄), concentrate, purifying with 95% alcohol crystal obtains the 2.1g product.Carry out recrystallization with dehydrated alcohol, its slow cool to room temperature obtained the crystalline solid of title compound, the m.p.(fusing point) 136.5-137.5 ℃.

¹HNMR（CDCl ₃，δ）：

1.24（t，3H，8Hz），2.88（m，2H），3.52（m，1H），3.76（s，6H），3.84（s，3H），4.16（q，2H，8Hz），4.72（d，1H，6Hz），6.10（s，2H），6.24（s，2H），6.68（s，1H），7.64（s，1H）。

Embodiment 10

Ethyl 1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-hydroxyl-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (VII d)

Toward tetralone VI b(6.25g, 14.6mM), cold sodium borohydride (0.42g, 11.1mM) water (5ml) solution of adding in 95% ethanol (100ml) and methylene dichloride (50ml) solution.With solution stirring 3 hours, rise to 40 ℃ under the room temperature, under this temperature, stirred 30 minutes again.Water (50ml) dilutes this solution then, at 35 ℃ it is condensed into solid residue.This residue is distributed among methylene dichloride (100ml) and the water (100ml).With the further aqueous layer extracted of methylene dichloride (100ml), merge organic extract liquid then, and dry (MgSO ₄), be condensed into solid deposits (5.95g).Obtain the crystalline solid of title compound with 95% ethyl alcohol recrystallization, m.p.151-15 ℃.About C ₂₈H ₂₆O ₈

Analytical calculation: C, 64.18; H, 6.09

Experimental result: C, 64.03; H, 6.02

¹HNMR（CDCl ₃，δ）：

1.15（t，3H，7.2Hz），2.06（m，1H），2.35（m，1H），2.46（d，1H，8.6Hz），2.95（m，1H），3.78（s，6H），3.82（s，3H），4.06（q，2H，7.2Hz），4.31（d，1H，7.7Hz），4.83（m，1H），5.91（2H），6.24（s，2H），7.07（s，1H）。

IR（KBr），ν _max，cm ^-1：3290，1730，1725，1590，1235，1122。

Embodiment 11

Trans-ethyl 1,2-dihydro-6,7-methylenedioxy group-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylicesters (VIII b)

With the curved water pipe (or collector) of Deam-Stark with pure VII d(0.43g, 1.0mM) with contain the suspension reflux 1 hour that tosic acid hydrate (4mg) toluene (15ml) forms.Thin-layer chromatography TLC[ethyl acetate: Skellysolve B(1: 1)] show that all parent materials (Rf=0.40) all are converted into a kind of new compound (Rf=0.69).With this solution cooling, sodium bicarbonate aqueous solution and water with 5% wash, and concentrating under reduced pressure becomes the oily settling again., as elutriant the oily settling is purified by silica gel (20g) column chromatography for separation with the ethyl acetate-methylene dichloride of methylene dichloride and 3%, obtain the white amorphous solid of title compound (Rf=0.69), m.p.129.5-130.5 ℃.

Relevant C ₂₃H ₂₄O ₇

Analytical calculation: C, 66.98; H, 5.87

Experimental result: C, 66.83; H, 5.87

¹HNMR（CDCl ₃，δ）：

1.14（t，3H，7.3Hz），3.58（m，2H），3.80（s，6H），3.83（s，3H），4.07（q，2H，7.3Hz），4.40（d，1H，9.4Hz），5.82（dd，1H，3.9Hz，9.6Hz），5.89（t，2H），6.39（s，1H），6.42（s，2H），6.49（dd，1H，2.0Hz，9.6Hz），6.63（s，1H）。

IR（KBr），ν _max，cm ^-1：1726，1580，1240，1125。

Embodiment 12

1,2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-hydroxyl-1-(3,4,5-trimethoxy-benzene) naphthalene-2-carboxylic acid (VII b)

According to W.S.Murphy and S.Wattanasin, J.C.S.Perkin I, 271(1982) the described method tetralone VI b hydrolysis that embodiment 2 is prepared, 1 of hydrolysis generation, 2,3,4-tetrahydrochysene-6,7-methylenedioxy group-4-oxygen-1-(3,4, the 5-trimethoxyphenyl) naphthalene-2-carboxylic acid (VI d) is according to people such as W.J.Gensler, J.Am.Chem.Soc., 82,1714(1960) described general method is handled with sodium borohydride (NaBH), prepare title compound crystalline solid thus, m.p.191.5-193 ℃.

(m.p. of relevant report is 181.4-182 ℃).

Embodiment 13

Anti-form-1,2-dihydro-6,7-methylenedioxy group-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylic acid (VIII c)

With pure VII b(400mg, 0.99mM) the suspension liquid reflux of forming with the toluene (20ml) that contains tosic acid hydrate (10mg) is 2 hours with the curved water pipe of Deam-Stark.With the reaction solution cooling, water (15ml) washs then, dry (MgSO ₄) and the concentrated white solid (365mg) that obtains.Use recrystallizing methanol, activated carbon treatment obtains the crystalline solid of title compound, m.p.177-180 ℃.

To C ₂₁H ₂₀O ₇

Analytical calculation value: C, 65.62; H, 5.24

Experimental result: C, 65.61; H, 5.26

¹HNMR（CDCl ₃，δ）：

3.60（m，1H），3.78（s，6H），3.82（s，3H），4.40（d，1H，7.8Hz），5.83（dd，1H，4.6Hz，9.6Hz），5.91（d，2H），6.39（s，2H），6.41（s，2H），6.53（dd，1H，1.8Hz，9.7Hz），6.64（s，1H）。

IR（KBr），ν _max，cm ^-1：1745，1710，1590，1510，1485，1250，1130。

Embodiment 14

Trans-diphenyl-methyl 1,2-dihydro-6,7-methylenedioxy group-1-(3,4,5-trimethoxyphenyl) naphthalene-(VIII is a) for the 2-carboxylicesters

With the curved water pipe of Deam-Stark with sour VIII c(1.63g, 4.24mM), diphenyl-methyl alcohol (0.79g, 4.29mM), toluene (100ml) vlil of tosic acid hydrate (37mg) 2 hours.Ethyl acetate-methylene dichloride by TLC(2%) monitors the degree that reaction is carried out.After the reaction, solution is cooled to room temperature, the sodium bicarbonate aqueous solution with 5% (90ml), water (50ml) washing, and dry (MgSO ₄), be condensed into pale brown look oily matter (2.43g), further separate the amorphous solid of purifying this oily matter and obtaining title compound, m.p.149-156 ℃ with column chromatography (silica gel).

To C ₃₄H ₃₀O ₇

Analytical calculation value: C, 74.17; H, 5.49

Experimental result: C, 74.13; H, 5.62

¹HNMR（CDCl ₃，δ）：

3.72（s，6H），3.73（m，1H），3.83（s，3H），4.41（d，1H，9.6Hz），5.84（dd，1H，4.2Hz，9.6Hz），5.89（t，2H），6.35（s，1H），6.38（s，2H），6.52（dd，1H，2.0Hz，9.6Hz），6.65（s，1H），6.67（s，1H），7.37-7.07（m，10H）。

Embodiment 15

Dl-8,9-dihydro-9-(3,4,5-trimethoxyphenyl)-5,8-methylene radical-1, (4,5-h) (2) benzo-xepin-7(5H)-(the X V is a) for ketone (5 β, 8 β, 9 α) for 3-Dloxole base

With pure VIII b(42.9g, the 1 liter of toluene suspension liquid that contains tosic acid hydrate (500mg) 0.107moles) heated under reflux temperature about 2 and a half hours with the curved water pipe of Deam-Stark.(19.6g 0.107mole) with 100 milliliters of O for toluene reaction mixtures that add, and refluxed 3 hours again to use benzhydrol then.Yellow soda ash (Na with 5% ₂CO ₃) aqueous solution and saturated sodium-chloride (NaCl) solution washing reaction mixture, and dry (MgSO ₄), be concentrated to 49.0 the gram.

Ethyl acetate/dichloromethane with 0～5% obtains title compound as elutriant by silica gel (350g) column chromatography for separation purification raffinate.Get a sample with 95% ethyl alcohol recrystallization and carry out activated carbon treatment, make title crystal, fusing point 191.5-193 ℃.

To C ₂₁H ₂₀O ₇

Analytical calculation value: C, 65.79; H, 5.26

Experimental result: C, 65.32; H, 5.30

¹HNMR（CDCl ₃，δ）：

2.43（m，2H），2.98（d，1H，5.0Hz），3.78（s，6H），3.84（s，3H），4.40（bs，1H），5.25（d，1H，4.8Hz），5.97（m，2H），6.29（s，2H），6.49（s，1H），6.75（s，1H）。

In similarly testing, diphenyl-methyl alcohol is saved from reaction, repeat said process then, thereby prepare desired lactone X V a.

Embodiment 16

Trans-diphenyl-methyl 1,2-dihydro-6,7-methylenedioxy group-1-(3,4,5-trimethoxyphenyl) naphthalene-(VIII is a) for the 2-carboxylicesters

With the curved water pipe of Deam-Stark with lactone X V a(3.9g, 10.2mM) and diphenyl-methyl alcohol (1.87g, 10.2mM) mixture in 100 milliliters of toluene that contain tosic acid hydrate (200mg) heats about two and one-half-hours at reflux temperature.The water yield of collecting reaches after the theoretical value (0.2ml), with saturated sodium bicarbonate (NaHCO ₃) solution and saturated sodium-chloride (NaCl) solution washing reaction mixture, and dry (MgSO ₄), be condensed into oily, filter the dichloromethane solution of this oily matter with a silica-gel plate (15g), again with methylene dichloride (75ml) flushing of adding.Reduction vaporization filtrate, thus the 4.06 oily products that restrain obtained.Pass through column chromatography (aluminium oxide Al with 0～2% ethyl acetate-methylene dichloride as elutriant ₂O ₃) obtaining a title compound amorphous solid sample, this sample is identical with embodiment 14 products, fusing point: m.p.149-156 ℃.

Embodiment 17

Cis-ethyl 1,2-dihydro-6,7-methylenedioxy group-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylicesters (IX b)

Under-78 ℃ and nitrogen envelope, toward the hexane of 1.7M n-Butyl Lithium (7.3ml, 12.4mM) drip in tetrahydrofuran (THF) (20ml) solution di-iso-amylamine (1.75ml, 12.5mM).Stir after 5 minutes, drip trans-alkene VIII b(2.06g, 5.0mM) tetrahydrofuran (THF) (10 milliliters) solution by syringe with the time more than 20 minutes.After adding, reaction mixture is being warming up to-40 ℃ and stirred 30 minutes in the time more than 30 minutes under this temperature.Add dense HCl(2.2ml in the liquid toward stirring) cold tetrahydrofuran (THF) (2.5ml) solution.Remove and do an ice acetone bath, make reaction mixture rise to room temperature.Tetrahydrofuran (THF) is removed in decompression, and surplus residual thing is distributed in water (100ml) and the methylene dichloride (100ml).With the further aqueous layer extracted of methylene dichloride, merge organic extract liquid then, water (100ml) washing, and dry (MgSO ₄), be condensed into an oily matter (2.1g).Pass through the further separation and purification oily matter of silica gel column chromatography with 5% ethyl acetate-methylene dichloride as elutriant, obtain the amorphous solid (1.74g) of title compound.Get a point with ethyl alcohol recrystallization and to analyse sample, fusing point: 112-113 ℃.

To C ₂₃H ₂₄O ₇

Analytical calculation value: C, 66.98; H, 5.87

Experimental result: C, 66.87; H, 5.82

¹HNMR（CDCl ₃，δ）：

1.12（t，3H，7.2Hz），3.75（s，6H），3.76（s，3H），4.07-3.95（m，3H），4.30（d，1H，7.7Hz），6.11（m，2H），6.45（s，2H），6.50（dd，1H，3.0Hz，9.7Hz），6.61（s，1H），6.65（s，1H）。

IR（KBr），ν _max，cm ^-1：1730，1592，1508，1490，1250，1130。

Embodiment 18

Cis-diphenyl-methyl 1,2-dihydro-6,7-methylenedioxy group-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylicesters (IX c)

Replace trans-alkene VIII b to repeat embodiment 17 processes with trans-alkene VIII a, thereby obtain the waxy solid of title compound.

To C ₃₁H ₃₀O ₇

Analytical calculation value: C, 74.17; H, 5.49

Experimental result: C, 74.17; H, 5.76

¹HNMR（CDCl ₃，δ）：

3.51（s，6H），3.73（s，3H），4.38（dt，1H，7.4Hz，2.9Hz），4.38（d，1H，7.5Hz），5.91（2H），6.19（dd，1H，2.7Hz，9.7Hz），6.40（s，2H），6.51（dd，1H），2.9Hz，9.8Hz），6.65（s，2H），6.75（s，1H），7.11-7.37（m，10H）。

Embodiment 19

Dl-8,9-dihydro-9-(3,4,5-trimethoxyphenyl)-5,8-methylene radical-1, (the X VIII is a) for 3-dioxane amyl group (4,5-h) (2) benzo-xepin-7(5H)-one(5 α, 8 α, 9 α)

Stick ketone X VI b(124mg toward cis-aryl, 0.29mM) add the LiBH of 0.29ml2.0M in dry tetrahydrofuran (10ml) solution ₄Tetrahydrofuran (THF) (0.58mM) solution.Stir under the room temperature after 17 hours with the saturated NH of 7ml ₄Cl solution-treated reaction mixture is isolated solvent layer.(3 * 5ml) further aqueous layer extracted are with the organic extract liquid drying (MgSO that merges with ether ₄), be condensed into yellow oil.Methyl alcohol-methylene dichloride with 5% is further purified this oily matter as scrub solution by the preparation of lamina chromatography.Collect near the suitable combination of Rf=0.53, and filter, concentrate, produce the oily title compound, thin-layer chromatography TLC[silicon-dioxide/methyl alcohol: methylene dichloride (5: 95)] must Rf=0.53.

¹HNMR（CDCl ₃，δ）：

2.33（d，1H，11.5Hz），2.82（m，1H），3.03（t，1H，4.9Hz），3.79（s，6H），3.85（s，3H），4.36（d，1H，4.5Hz），5.24（d，1H，5.2Hz），5.94（bd，2H），6.30（s，2H），6.48（s，1H），6.75（s，1H）。

Embodiment 20

Dl-[3a β, 4 α, 5 α, 10b β]-ethyl 3a, 4,5,10b-tetrahydrochysene-3-bromo-5-(3,4,5-trimethoxyphenyl)-1, (2,1-d) isoxazole-(X is a) for the 4-carboxylicesters for 3-Dloxole base (6,7) naphthalene

A. dibromo formoxime

Put gyloxylic acid oxime hydrate (12g, 112mM) in water (60ml), constantly stir and the condition of ice bath (0～4 ℃) under, adding methylene dichloride (130ml) and sodium bicarbonate (18.83g, 224mM).(continuously stirring 7 hours (at 0 ℃) at room temperature stirred 13 hours again for 35.84g, methylene dichloride 488mM) (50ml) liquid to add bromine again in this two-phase mixture.Eliminate excessive bromine by careful adding Sulfothiorine solid.Isolate organic layer, with methylene dichloride (2 * 100ml) further aqueous layer extracted.With the organic extract liquid drying (Na that merges ₂SO ₄), evaporation and obtain the white solid (11.4g, 50.13% productive rate) of title compound.Its a part of getting a point with Skellysolve B recrystallization is analysed sample, fusing point: 65-68 ℃.

IR(KBr): 3000-3600,1580 and 980cm.

To CHNOBr ₂

Analytical calculation value: C, 5.91; H, 0.49; N, 6.90

Measured value: C, 5.40; H, 0.20; N, 6.95

B.dl-[3a β, 4 α, 5 α, 10b β]-ethyl 3a, 4,5,10b-tetrahydrochysene-3-bromo-5-(3,4,5-trimethoxyphenyl)-1, (2,1-d) isoxazole-(X is a) for the 4-carboxylicesters for 3-Dloxole base (6,7) naphthalene

Toward cis-alkene IX b(0.10g, (146mg 0.72mM) [prepares in steps A], adds KHCO again to add the dibromo formoxime in acetone soln 0.24mM) ₃(145mg, 1.45mM).Solution refluxed 3 hours at 56 ℃.Thin-layer chromatography TLC[ether: Skellysslve B(1: 1)] indicate almost whole parent materials (Rf=0.30) all to transform, the product spot of Rf=0.19 occurs.With the solution cooling, behind the filtering solid particulate, use washed with dichloromethane, be condensed into the yellow oily solid.Ethyl acetate-methylene dichloride with 4% obtains straight product (72mg) as elutriant by silica gel column chromatography.Get the title compound crystal with ethyl alcohol recrystallization, fusing point: 212-214 ℃ (dec).

To C ₂₄H ₂₄NO ₈Br

Analytical calculation value: C, 53.95; H, 4.53; N, 2.62

Measured value: C, 53.64; H, 4.52; N, 2.91

¹HNMR（CDCl ₃，δ）：

1.19（t，3H，7.2Hz），3.14（dd，1H，4.9Hz，10.7Hz），3.76（s，6H），3.81（s，3H），3.93（t，1H，10.3Hz），4.10（q，2H），4.37（d，1H，4.9Hz），5.71（d，1H，9.7Hz），5.98（s，2H），6.08（s，2H），6.57（s，1H），7.02（s，1H）。

IR（KBr），ν _max，cm：1732，1590，1495，1482，1235，1120。

Embodiment 21

Dl-[3a β, 4 α, 5 α, 10b β]-diphenyl-methyl 3a, 4,5,10b-tetrahydrochysene-3-bromo-5-(3,4,5-trimethoxyphenyl)-1,3-Dloxole base (6,7) naphthalene (2,1-d) different azoles-4-carboxylicesters (X b)

Toward cis-alkene IX c(0.85g, (0.94g 4.63mM), adds KHCO again to add the dibromo formoxime in ethyl acetate 1.54mM) (40ml) solution ₃(0.47g, 4.69mM).With this suspension liquid reflux 3 hours.Thin-layer chromatography [ether: Skellysslve B(1: 1)] shows to react has finished about 60%.Therefore, in reaction mixture, add dibromo formoxime (0.47g) and saleratus KHCO ₃(0.24g), this solution was further refluxed 2 and a half hours.With its cooling and be condensed into an oily matter, oily matter is distributed among methylene dichloride and the water then.With the further aqueous layer extracted of methylene dichloride, then with the organic extract liquid drying (MgSO that merges ₄), be condensed into an oily solid.Do the silica gel column chromatography of above-mentioned oily matter with 1-3% ethyl acetate-methylene dichloride as elutriant, obtain the title compound solid (0.61g, Rf=0.25).Get a point with ethanol development (recrystallization) and to analyse sample, 164.5-168 ℃ of m.p. fusing point.

To C ₃₅H ₃₀NO ₈Br

Analytical calculation value: C, 62.50; H, 4.50; N, 2.08; Br, 11.88

Measured value: C, 62.12; H, 4.45; N, 2.08; Br, 10.75

¹HNMR（CDCl ₃，δ）：

3.30（dd，1H，4.7Hz，9.4Hz），3.44（s，6H），3.76（s，3H），3.96（t，1H，9.7Hz），4.34（d，1H，4.7Hz），5.69（d，1H，10.1Hz），5.95（s，2H，）5.98（d，2H），6.57（s，1H），6.93（s，1H），7.01（s，1H），7.39-7.12（m，10H）。

IR（KBr），ν _max，cm：1750，1590，1502，1483，1240，1130.

Embodiment 22

Dl-[3a β, 4 α, 5 α, 10b β]-ethyl 3a, 4,5,10b-tetrahydrochysene-3-bromo-5-(3,4,5-trimethoxyphenyl)-1,3-Dloxole base (6,7) naphthalene (2,1-d) isoxazole-4-carboxylicesters (X XI)

Toward trans-alkene VIII b(100mg, (148mg 0.73mM), adds KHCO again to add the dibromo formoxime in ethyl acetate 0.24mM) (5ml) solution ₃(145mg, 1.45mM) and water (2).Under the room temperature reaction mixture was stirred 18 hours.Thin-layer chromatography TLC[5% ethyl acetate-methylene dichloride] show whole parent materials (Rf=0.71) reaction consumes, two new spots have appearred, respectively at Rf ' s=0.57 and 0.90 place.Reaction mixture is filtered, and with ethyl acetate rinse solid precipitate.Filtrate is carried out drying (MgSO ₄), be concentrated to residue shape solid.Obtain the amorphous solid (80mg) of desired product (Rf=0.57), fusing point 208-209 ℃ (dec.) as elutriant by silica gel column chromatography with the ethyl acetate of methylene dichloride and 10%.Ethyl alcohol recrystallization with 95% gets the analysis sample of title compound, fusing point 212-214 ℃ (dec.).

To C ₂₄H ₂₄NO ₈Br

Analytical calculation value: C, 53.95; H, 4.53; N, 2.62

Measured value: C, 53.95; H, 4.48; N, 2.58

¹HNMR（CDCl ₃，δ）：

1.04（t，3H，7.2Hz），3.12（t，1H，8.1Hz），3.80（s，6H），3.84（s，3H），4.08-3.92（m，3H），4.17（d，1H，8.1Hz），5.62（d，1H，10.1Hz），5.97（s，2H），6.31（s，2H），6.37（s，1H），6.95（s，1H）。

IR（KBr），ν _max，cm ^-1：1735，1585，1498，1480，1245，1120。

Embodiment 23

Dl-[3a β, 4 α, 5 α, 10b β]-3a, 4,5,10b-tetrahydrochysene-3-chloro-5-(3,4,5-trimethoxyphenyl)-1,3-Dloxole base (6,7) naphthalene (2,1-d) different azoles-4-carboxylicesters (X c)

Under the room temperature,, add 1NHCl(3.5ml in Nitromethane 99Min. 0.61mM) (12ml) solution toward ester X b(0.41g) Nitromethane 99Min. solution.With solution at room temperature stir 3 hours, under the ice bath temperature, stirred 30 minutes.This cold soln is filtered, collect the white crystal (175mg) of title compound, fusing point, 238.5 ℃

To C ₃₂H ₂₀NO ₈Cl

Analytical calculation value: C, 57.21; H, 4.36; N, 3.03

Measured value: C, 57.13; H, 4.39; N, 3.18

¹HNMR（CDCl ₃，δ）：

3.24（dd，1H，4.9Hz，11.0Hz），3.74（s，6H），3.80（s，3H），3.86（t，1H，10.7Hz），4.42（d，1H，4.7Hz），5.76（d，1H，9.8Hz），5.98（s，2H），6.12（s，2H），6.58（s，1H），7.02（s，1H）。

IR（KBr），ν _max，cm ^-1：2800-3100，1715，1520，1485，1230，1125，1035。

Embodiment 24

Dl-[3a β, 4 α, 5 α, 10b β]-3a, 4,5,10b-tetrahydrochysene-3-bromo-5-(3,4,5-trimethoxyphenyl)-1,3-Dloxole base (6,7) naphthalene (2,1-d) different azoles-4-carboxylicesters (X d)

With ester X b(134mg, 0.2mM) cold soln in the 1.3ml trifluoracetic acid (0 ℃) rises to room temperature.Stir after 2 hours, at about 35 ℃, trifluoracetic acid is removed in decompression.Use the water treatment residue then, filter title compound.Methyl alcohol-methylene dichloride with 10% separates a part of solid of purifying as elutriant by silica gel column chromatography, obtains title crystal, and fusing point 225-229 ℃, the heavy 42mg of this crystal.

Embodiment 25

Dl-[1 α, 2 α, 3 β, 4 β] 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylic acid (XI g)

Toward Lv Dai isoxazole acid X c(2.00g, 0.43mM) add skeleton nickel (Ruan comes nickel) (about 0.5cc) in the suspension liquid in methyl alcohol (100ml), be placed under 42 pounds/inch the hydrogen pressure, jolting is 4 hours on the Parr instrument.Add hydrogenation platinum (50mg) then, jolting 2 and a half hours on hydrogenator again.With diatomite plate filter Chu catalyzer, filtrate is concentrated into solid (2g).Thin-layer chromatography (20% methyl alcohol-methylene dichloride) shows in this solid that except initial acid (Rf=0.53), it is main to have increased by two composition Rf=0.30() and Rf=0.09(less).Isolate the white solid (0.9g) of the main component of Rf=0.30 by silica gel column chromatography as elutriant with methyl alcohol-methylene dichloride (1: 5).Get the analysis sample of a title compound, fusing point 245-246.5 ℃ (dec.) with recrystallizing methanol.

To C ₂₂H ₂₁NO ₈Br

Analytical calculation value: C, 61.82; H, 4.95; N, 3.28

Measured value: C, 61.67; H, 4.94; N, 3.27

¹HNMR（CDCl ₃δ）：

3.35（dd，1H，3.4Hz，12.4Hz），3.71（dd，1H，12.5Hz，5.8Hz），3.74（s，6H），3.78（s，3H），4.55（d，1H，5.7Hz），4.98（d，1H，3.2Hz），5.94（m，2H），6.11（s，2H），6.41（s，1H），6.86（s，1H）。

IR（KBr），ν _max，cm ^-1：3490，2920，2240，1750，1590，1500，1485，1240，1130，1035。

Embodiment 26

Dl-[1 α, 2 α, 3 β, 4 β] 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylic acid (XI g)

For isoxazole acid X c(1.40g, 3.23mM) adding skeleton nickel (about 1.0cc) in the suspension liquid in methyl alcohol (200ml) toward chlorine, is hydrogenation 2 hours on 50 pounds/inch the Parr instrument at initial hydrogen pressure.Use the diatomite filtration catalizer, remove solvent under reduced pressure, use the 6NHCl acidified aqueous solution, and with this solution of methyl alcohol-dichloromethane extraction of 10%.Then with the organic extract liquid drying (MgSO that merges ₄), evaporate the amorphous solid (0.8g, 60%) of title compound, its ¹HNMR spectrum is identical with the spectrum of embodiment 25 products.

Embodiment 27

Dl-[1 α, 2 α, 3 β, 4 β]-ethyl 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylicesters (XI h)

Toward ester X a(0.106g, (36mg 0.6mM), adds skeleton nickel (about 0.1cc) again 0.2mM) to add boric acid in the suspension liquid in the saturated ethyl acetate of water (20ml) and methyl alcohol (5ml).In the Parr of 40 pounds of/inch hydrogen pressures instrument with this suspension liquid hydrogenation 6 hours.Thin-layer chromatography (ethyl acetate-methylene dichloride of 5%) shows, except that parent material ester X a(Rf=0.61), a new constituent Rf=0.15 appears.Filtration catalizer is condensed into solid with filtrate.Ethyl acetate-methylene dichloride with 59% and 10% carries out this solid silica gel column chromatography as elutriant, obtains the amorphous solid (54mg) of compound (Rf=0.15).Ethyl alcohol recrystallization with 95% gets title compound, fusing point 215-216 ℃.

To C ₂₄H ₂₅NO ₈Br

Analytical calculation value: C, 63.29; H, 5.53; N, 3.08

Measured value: C, 63.16; H, 5.59; N, 3.02

¹HNMR（CDCl ₃δ）：

1.17（t，3H，7.3Hz），2.62（d，1H，4.4Hz），3.44（dd，1H，3.3Hz，12.4Hz），3.74（m，1H），3.74（s，6H），3.80（s.3H），4.06（q，2H，7.1Hz），4.53（d，1H，5.9Hz），5.07（t，1H，3.8Hz），5.97（dd，2H），6.03（s，2H），6.42（s，1H），6.85（s，1H）。

IR（KBr），ν _max，cm ^-1：3560，2245，1725，1590，1235，1128。

Embodiment 28

Dl-[1 α, 2 α, 3 β, 4 β]-ethyl 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylicesters (XI h)

A nitrogen depress with tri-butyl tin hydride (0.12ml, 0.45mM) and Diisopropyl azodicarboxylate (2mg) processing ester X a(64mg, the 0.12mM) solution in the dried benzene of 5ml., at room temperature stir then and spend the night mixture heating up 6 hours at reflux temperature.The reduction vaporization reaction mixture.Ethyl acetate-methylene dichloride with 5% and 15% is as elutriant, by the silica gel column chromatography separating purification evaporation residue.Collect close suitable component, reduction vaporization and obtain title compound again, its ¹HNMR spectrum is identical with the product spectrum of example 27.

Embodiment 29

Dl-[1 α, 2 α, 3 β, 4 β]-ethyl 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylicesters (XI h)

Depress ester X a(106mg at 1 hydrogen atmosphere, 0.2mM) at the 10%pd/c(55% of dense HCl that contains 0.08ml and 10mg by the weight in water) the aqueous methanol of 10ml90% in suspension liquid hydrogenation 24 hours, placed then 5 days.Use the diatomite filtration catalizer, use saturated NaHCO ₃Solution is neutralized to about pH=7 with solution, removes solvent again under reduced pressure.Ethyl acetate-methylene dichloride with 20% steams excess as elutriant by purification by silica gel column chromatography.Obtain the 40mg title compound, this thing is identical with the product of example 27.

Embodiment 30

Dl-[1 α, 2 α, 3 β, 4 β]-ethyl 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylic acid (XI g)

Toward Lv Dai isoxazole acid X c(92mg, 0.2mM) in the solution in the 50ml solvent (comprising 36ml methyl alcohol, the water of 10ml methylene dichloride and 4ml), add the 30mg nickel borides.It at initial hydrogen pressure this mixture of hydrogenation 16 hours on 40 pounds/inch the Parr instrument.Use the diatomite filtration catalizer, remove solvent under reduced pressure, obtain the 90mg title compound, this thing is identical with the product of example 25.

Embodiment 31

Dl-[1 α, 2 α, 3 β, 4 β] 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylic acid (XI i)

Under 0 ℃, the condition of nitrogen envelope, with hydroxyl nitrile XI g(0.50g, dry tetrahydrofuran 1.2mM) (15ml) solution adds the lithium aluminum hydride that stirs, and (0.16g is 4.2mM) in tetrahydrofuran (THF) (20ml) suspension liquid.Reaction is after 16 hours under the room temperature, successively water (0.16ml), 15% sodium hydroxide solution (0.16ml) and the excessive lithium aluminum hydride of water (0.48ml) processing.The filtering solid particulate removes tetrahydrofuran (THF) under reduced pressure then.With 0.1NHCl this acidified aqueous solution is extracted with methylene dichloride to pH=6 again.With the organic extract liquid drying (MgSO that merges ₄), the evaporation, thereby make title compound (0.12g, 24%).In methyl alcohol-methylene dichloride (1: 4), make its inflow-silicon dichloride solid phase collection carry the filter column casing a part of sample dissolution, wash this post with methyl alcohol (4ml) with the amino acid of 10% acetate methyl alcohol (2ml) elution.The solid that evaporating solvent is obtained remains under 78 ℃ and the high vacuum and carries out drying, thereby obtains the acetate of title compound.

To C ₂₂H ₂₅NO ₈CH ₃COOHH ₂O

Calculated value: C, 56.57; H, 6.13; N, 2.75

Measured value: C, 56.85; H, 6.28; N, 2.68

¹HNMR（CDCl ₃，δ）：

6.84（s，1H），6.32（s，1H），6.05（s，2H），5.88（d，2H），4.86（bp，1H），4.10（bp，1H），3.79（s，3H），3.73（s，6H），3.26（bp，2H），3.13（m，1H），2.60（m，1H），2.30（m，1H）。

Embodiment 32

The dl-difference is to podophyllotoxin (I)

Toward Lv Dai isoxazole acid X c(200mg, 0.43mM) at 100mlCHOH/HO/CHCl(7: 1: 3) in solution in add nickel borides (60mg, 0.86mM).This suspension liquid is placed the hydrogenation 18 hours under 40 pounds/inch hydrogen pressure of Parr instrument, add then platinum oxide (200mg, 0.88mM), hydrogenation 2 hours again under 40 pounds/inch.Methyl alcohol-methylene dichloride of TLC(5%) shows that initial acid (Rf=0.48) disappears (all transforming), a high polar component (Rf=0.07) occurs.With diatomite plate filtration catalizer, filtrate is condensed into the paste shape.Its acetic acid (7ml) with 5% is dissolved, (200mg, 2.9mM) water (8ml) solution stir them after 4 hours under the room temperature to add Sodium Nitrite again, the careful saturated sodium bicarbonate aqueous solution (20ml) that adds is with methylene dichloride (5 * 30ml) extractive reaction solution.With the organic extract liquid drying (Na that merges ₂SO ₄), filter, concentrate, make the solid (84mg) of flaxen title compound.

¹HNMR（CDCl ₃，δ）：

2.86（m，1H），3.29（dd，1H，5.1Hz），14.1Hz），3.75（s，3H），3.81（s，3H），4.38（m，2H），4.63（d，1H，5.1Hz），4.88（t，1H，3.4Hz），6.00（d，2H），6.29（s，2H），6.56（s，1H），6.89（s，1H）。

Above spectroscopic data and J.Med.Chem.22, the difference of being reported in 215(1979) is to the data consistent of podophyllotoxin.

Embodiment 33

The dl-difference is to podophyllotoxin (I)

With hydroxyl nitrile XI g(0.25g, dry tetrahydrofuran 0.59mM) (7ml) solution adds the lithium aluminum hydride that is cooled, and (0.08g is 2mM) in tetrahydrofuran (THF) (20ml) solution under the nitrogen envelope.Under the room temperature reaction mixture was stirred 16 hours.By adding 1: acetic acid 1(V/V), water (10ml) termination reaction, tetrahydrofuran (THF) is removed in decompression.(200mg, water 2.9mM) (1ml) solution at room temperature stirred 1 hour to add Sodium Nitrite again.With the saturated NaHCl aqueous solution this acidic solution that neutralizes, use this mixture of dichloromethane extraction then.With the organic extract liquid drying (MgSO that merges ₄), evaporate, make the foamed Etoposide of light brown yellow (I) (0.21g, 87%), its ¹The difference of preparation is identical to the spectrum of podophyllotoxin in HNMR spectrum and the example 32.

Embodiment 34

Repeat embodiment 1,20,10,11,17,20,23 and 32 successively, just with the initial thing 3,4 that uses among the embodiment 1,5-trimethoxy-3 ', 4 '-methylenedioxy group phenyl styryl ketone X XII a is with the compound replacement with following structure of equimolar amount,

Substituting group is as showing in the formula:

Compound R ¹R ²R ⁴R ⁵R ⁶

ⅩⅫb H OCH ₃H CH ₃H

ⅩⅫc H OCH ₃OCH ₃CH ₃H

ⅩⅫd OCH ₃OCH ₃H CH ₃H

ⅩⅫe OCH ₃OCH ₃OCH ₃CH ₃H

ⅩⅫf -OCH ₂O- OCH ₃CH ₃H

ⅩⅫg OCH ₃H H CH ₃H

[all using Synthesis, 647-650(1980) the general method preparation described in], therefore preparation has the compound of following structural formula

The following following table of each compound substituent wherein:

Compound R ¹R ²R ⁴R ⁵R ⁶

ⅩⅪb H OCH ₃H CH ₃H

ⅩⅪc H OCH ₃OCH ₃CH ₃H

ⅩⅪd OCH ₃OCH ₃H CH ₃H

ⅩⅪe OCH ₃OCH ₃OCH ₃CH ₃H

ⅩⅪf OCH ₃CH ₃H

ⅩⅪg OCH ₃H H CH ₃H

Embodiment 35

DL-(1 α, 2 α, 3 β, 4 β) 1,2,3,4-tetrahydrochysene-3-cyano group-4-hydroxyl-1-(3,4,5-trimethoxyphenyl) naphthalene-2-carboxylic acid (XI g)

Adopt anhydrous tetrahydro furan (8 milliliters) under nitrogen strip of paper used for sealing spare, handle by solid Xiu Dai isoxazole acid (X d) (160mg, 0.3mM) and anhydrous sodium hydride (39.2mg, 1.22mM) mixture of Zu Chenging.Suspension at room temperature need stir 10 minutes, needed down to stir 2 minutes at 60 ℃, after this was cooled to-78 ℃.By a syringe in 1 minute time, add lentamente n-Butyl Lithium (in hexane) 1.6 gram (0.22ml, 0.35mM).So just obtained a kind of red solution, and this solution turns yellow when adding above-mentioned substance.This mixture stirred 5 minutes down at-78 ℃, after this removed ice bath, and its temperature was gone up in 3～5 minutes to 0 ℃, and stirred 3 minutes down at 0 ℃.And then it is cooled to-78 ℃, and with its impouring by 6% aqueous ammonium chloride solution, in 5% hydrochloric acid (20ml) and the formed aqueous solution of ethyl acetate (40ml).Organic phase water (30ml) wherein and saturated brine (30ml) flushing, and use the MgSO drying.Behind the rotary evaporation at the silica gel (CH that 5-15% is arranged in ETOAC ₃OH) carry out the flash distillation chromatography on again, so just obtained title compound (124mg), its ¹The data consistent of report among HNMR spectroscopic data and the embodiment 25.

Claims (1)

1, the preparation method of following formula structural compounds,

Wherein,

R ¹And R ²All be hydrogen or (rudimentary) alkoxyl group, perhaps R ¹And R ²The formation methylenedioxy group connects together;

R ³Be hydrogen or carboxy protective group;

R ⁴And R ⁶All be hydrogen or (rudimentary) alkoxyl group;

R ⁵It is hydrogen or phenol protection group;

This method comprises the following steps:

(A) pure VII is dewatered in the presence of acid and is produced trans alkene VIII, in the pure VII, and R ³Be carboxyl-protecting group; R ⁵Be phenol protecting group or hydrogen;

Ⅶ

E ¹, R ², R ⁴And R ⁶All as described above, in the trans alkene VIII,

Ⅷ

R ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above; If preparation cis alkene is short, then have

(B) trans alkene VIII in the presence of low temperature, inert organic solvents, is handled with highly basic, uses sour quenching then, produces suction formula IX:

Ⅸ

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶All as described above, optionally go protecting group, promptly produce the compound IX, wherein R ³Be hydrogen and R ⁵Be the phenol protecting group.Or R ⁵Be hydrogen and R ³Be carboxyl-protecting group.