CN1012644B - Process for preparation of flavanone derivatives - Google Patents
Process for preparation of flavanone derivativesInfo
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- CN1012644B CN1012644B CN 85105079 CN85105079A CN1012644B CN 1012644 B CN1012644 B CN 1012644B CN 85105079 CN85105079 CN 85105079 CN 85105079 A CN85105079 A CN 85105079A CN 1012644 B CN1012644 B CN 1012644B
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- hydroxyl
- benzylidene
- flavanone
- methoxy
- group
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Abstract
A new flavanone derivant (formula I), phosphate and the salt thereof have an anti strain action, and Ar1 and Ar2 in the formula are respectively an unsubstituted or mono to tri-substituted phenyl group, and a substituent group of the phenyl is a hydroxyl group, an alkyl group, an alkoxyl group, an acylamino, a halogen carboxyl alkyl group and/or a hydroxyl group nitro alkyl group / or a carboxyl alkyl group which is substituted by a secondary methylenedioxy group, wherein the alkyl group, the alkoxyl group and the acyl group respectively have 1 to 7 carbon atoms, when one of the Ar1 and the Ar2 is the substituted phenyl group, then the hydroxyl group is in a 6-bit. The salt performance of the phosphate of the formula I and amino sugar antibiotic is extremely stable and has preferable release kinetic property.
Description
The present invention relates to new flavanone derivative suc as formula shown in the I
Ar wherein
1And Ar
2Respectively be phenyl, it can be unsubstituted or single the replacement to trisubstituted, and substituting group is OH, alkyl, alkoxyl group, amido, halogen, Coo alkyl and/or NO
2, and/or replaced by methylenedioxy group, alkyl, alkoxyl group and acyl group respectively have 1-7 carbon atom, if group Ar
1And Ar
2Have at least one be substituted-phenyl then the HO base only can be in the 6-position, and the salt of their phosphoric acid ester (" I-phosphoric acid ester ") and these compounds.
The present invention is based on and seek new compound, particularly can be used for preparing the purpose of the compound of medicine with valuable character.
The compound of discoverable type I and their phosphoric acid ester and the salt of these compounds have valuable pharmacological properties.For example, they show anti-allergic effect, and can be enough, as rat intravenous injection, confirm.The common method that confirms this effect is described in, and for example, european patent application 0,056 is in 475 documents of being quoted.
Particularly, the slightly soluble salt of some I-phosphoric acid ester is very much important, promptly is those salt from the Glucosaminitol antibiotic derivatives.These salt also show antibiotic effectiveness, slowly discharge but characteristic is an active compound.
The flavonoid phosphoric acid salt of Glucosaminitol antibiotic has mentioning of similar quality in the open communique 3,206,725 of Germany.Yet having not a particle of in this open communique of Germany is to be associated with the particularly advantageous salt of I-phosphoric acid ester of the present invention, and it is with remarkable stability and discharges favourable release dynamics and be celebrated.In addition, it contains a kind of acidic component, and this composition can more accurately be stipulated for particularly preferred hesperidine phosphoric acid ester than also referring to described in the reference material.
Formula I compound, the salt of their phosphoric acid ester and these compounds can be as medicinal compounds effective in medical treatment and veterinary science.Flavanone I itself and I-phosphoric acid ester also can be used as intermediate product, particularly are used for preparing described salt acids.
In the formula I, group Ar
1And Ar
2Preferably identical, yet, also can differ from one another.Best is monosubstituted phenyl, be preferably in one, but also can be at adjacent one or one; Yet they can be unsubstituted phenyl and di-substituted-phenyl also, are preferably in 3, the 4-position, but also 2,3-, 2,4-, 2,5-, 2,6-, or 3 ,-5 one, or trisubstituted.Be preferably in 3,4,5 one, but also 2,3,4 one, 2,3,5-, 2,3,6-, 2,4,5-or 2,4,6-position.
At group Ar
1And Ar
2On alkyl, alkoxyl group and acyl group respectively have 1-7, preferably respectively are 1-4, particularly 1 or 2, carbon atom.
At group Ar
1And Ar
2In particularly preferred alkyl be methyl and ethyl, also also have propyl group, sec.-propyl, butyl, isobutyl-, secondary monobutyl, uncle's monobutyl also has amyl group, isopentyl (being 3-first butyl), hexyl, isohexyl (being 4-first amyl group) and heptyl; Particularly preferred alkoxyl group is methoxyl group and oxyethyl group, also also has propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy, uncle-butoxy also has pentyloxy, isopentyloxy (being 3-first butoxy), hexyloxy, different hexyloxy (being 4-first pentyloxy) and heptan the oxygen base, particularly preferred amido is formamido group and kharophen, also also has propionamido, butyrylamino, isobutyryl is amino and also have valeryl amino, isovaleryl amino, trimethyl-acetyl, hexanamido, uncle's one fourth kharophen and heptanamido.Halogen is Cl preferably, also has F, Br or I; The COO alkyl is methoxycarbonyl or ethoxycarbonyl preferably, also also has the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc also has the second month in a season-butoxy carbonyl, uncle-butoxy carbonyl, penta oxygen carbonyl, own oxygen carbonyl or heptan the oxygen carbonyl.
Especially, Ar
1And/or Ar
2Preferably, also also have phenyl to a methoxyphenyl, adjacent-,-or right-hydroxyphenyl, adjacent-,-, or right-tolyl, adjacent-,-, or to the ethylbenzene base, adjacent-,-or right-propyl phenyl, adjacent-,-, or right-cumyl, neighbour-methoxyphenyl or-methoxyphenyl, adjacent-,-or right-phenelyl, adjacent-,-, or right-formamido group phenyl, adjacent-,-, or right-acetylamino phenyl, adjacent-,-, or right-fluoro phenyl, adjacent-, between-, or right-chlorophenyl, adjacent-,-, or right-bromo phenyl, adjacent-,-, or right-iodine substituted phenyl, adjacent-,-or right-methoxycarbonyl phenyl, adjacent-,-or right-carbethoxy phenyl, adjacent-,-or right-nitro-naphthalene phenyl, 2,3-methylenedioxy group phenyl or 3,4-methylenedioxy group phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-, Dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-person or 3, the 5-dichlorophenyl, 3,4,5-2,4,5-trimethoxyphenyl, 3-hydroxyl-4-methoxyphenyl or 3-methoxy-4-hydroxyphenyl.
Hydroxyl is preferably in the 6-position in the formula I, but it can also be at 5-, 7-or 8-position.
By this, The present invention be more particularly directed to the salt of some compounds of formula I and their phosphoric acid ester and these compounds, wherein one of described at least group has a preferred implication above-mentioned and/or is in one and is indicated as being on the preferred positions.The preferred group of some compounds can use with the corresponding following part formula of formula I I a to I
LRepresent that some of them do not have detailed indicated group to have in the implication shown in the formula I, but wherein:
At IaAr
1Be phenyl or for monosubstituted phenyl, substituting group is OH, alkyl, alkoxyl group or amido (the 1-4 carbon atom is respectively arranged), F, Cl, Br, I, alkyl are the COO alkyl that contains the 1-4 carbon atom, NO
2Or inferior methylenedioxy group, or be disubstituted phenyl, substituting group is the alkoxyl group that the 1-4 carbon atom is arranged, or Cl; Or alkoxy three substituents.
At IbAr
1Be phenyl, cumyl, methoxyphenyl, acetylamino phenyl, chloro-phenyl-, dichlorophenyl or trimethoxyphenyl;
At IcAr ' is phenyl or methoxyphenyl;
At IdAr ' is right-methoxyphenyl;
At IeAr
2Be phenyl or monosubstituted phenyl, substituting group is OH, and the alkyl of 1-4 carbon atom is respectively arranged, alkoxyl group or amido, and F, Cl, Br, I, alkyl contain the Coo alkyl of 1-4 carbon atom, NO
2Or inferior methylenedioxy group, or be alkoxyl group with 1-4 carbon atom or Cl or disubstituted, perhaps be that alkoxyl group is trisubstituted.
At IfAr
2Be phenyl, cumyl, methoxyphenyl, acetylamino phenyl, chloro-phenyl-, dichlorophenyl or 2,4,5-trimethoxyphenyl;
At IgAr
2Be phenyl or methoxyphenyl;
At IhAr
2It is right-methoxyphenyl;
At IiAr
1And Ar
2Respectively be phenyl or monosubstituted phenyl, substituting group is O ' H, and the alkyl of 1-4 carbon atom is respectively arranged, alkoxyl group or amido, and F, Cl, Br, I, alkyl contain the Coo alkyl of 1-4 carbon atom, NO
2Or inferior methylenedioxy group, or for the alkoxyl group or the disubstituted phenyl of chlorine of 1-4 carbon atom to be arranged, or be alkoxyl group three substituents.
At IjAr
1And Ar
2Respectively be phenyl, cumyl, methoxyphenyl, acetylamino phenyl, chloro-phenyl-, dichlorophenyl or 2,4,5-trimethoxyphenyl; With
At IkAr
1And Ar
2Respectively be phenyl or methoxyphenyl.At I
LMiddle Ar
1And Ar
2Respectively be-p-methoxyphenyl.
Particularly preferred compound is that those are formula Iaa to Ika person, and they are corresponding with formula Ia to Ik, but Ar wherein
1And Ar
2, also also have the compound of formula Iab to Ilb and Iaab to Ikab, they and formula Ia to I
LWith Iaa to Ik
aCorresponding, but wherein the HO base is in the 6-position of flavanone system.
At Ia to Ik, Iaa to Ika, the phosphoric acid ester of the compound of Iab to Ilb and Iaab to Ikab, the salt of these compounds, particularly the salt with Glucosaminitol antibiotic also is particularly preferred.
Formula I compound, the salt of their phosphoric acid salt and these compounds can be cis-configuration, also can be transconfiguration.Transconfiguration is preferred, unless there is any reverse situation to indicate below, the indication compound is trans-isomer(ide) normally.Yet cis-isomeride is also included within by in the general formula compound shown in the present; They can (method be seen organic chemistry magazine 35,2286(1970) obtains with illumination from trans-isomer(ide).Also comprise mixture of isomers by general formula compound shown in the present.
The present invention also relates to the preparation process by the formula I flavanone derivative of claim 1, it is characterized in that the flavanone with the formula II
Ar wherein
1Aldehyde reaction with the implication shown in the formula I and formula IV,
O＝CH-Ar
2Ⅶ
Ar wherein
2Has the implication shown in the formula I; Or the phenyl styryl ketone of or IV
Ⅳ
Ar wherein
2Has the implication shown in the formula I, with the aldehyde reaction of formula V
O＝CH-Ar
1
Ar wherein
1Have the implication shown in the formula I, and/or the hydroxyl dihydro anthoxanthin of a formula I with a kind of phosphorylation agent handle corresponding phosphoric acid ester, and/or the compound of formula I becomes its a kind of salt with alkaline purification.
Moreover the compound of formula I is with itself being the preparation of known method, has such as the example of described classic in the literature, and as this one dimension of lotus your " organic chemistry method ", George Sai Mo publishes, the Stuttgart; Or " organic reaction " John prestige is come and Subsidiary Company New York.Especially those known and suitable reaction conditionss to described reaction.May itself also be known variation method also in this respect, just not mention in detail here with some.
If desired, starting raw material also can generate in the original place, and mode is that they are not separated from reaction mixture, and further react immediately formula I compound.
Like this, the preferred preparation method of formula I compound is the dihydroxy acetophenone with the formula VI
With the aldehyde reaction of formula III or V, yellow ester ketone II of dihydro and/or phenyl styryl ketone VI generate as intermediate in process, but without separation, particularly, Ar in the formula I compound
1Be Ar
2And this method of the compound of Iaa to Ika, can obtain easily.
The formula II and to the starting raw material overwhelming majority of VI be known (for example seeing US Patent specification 3,450,717), if they are unknown, can itself be that known method prepares then with those.The starting raw material of this pattern II or IV can be used for obtaining from the aldehyde reaction of dihydroxy acetophenone (formula VI) with formula V or III.
Especially, II and III, the reaction of IV and V or VI and III or V is to deposit at inert solvent to carry out under being in or be not in, and this solvent has, and for example alcohols is as methyl alcohol, ethanol or Virahol, ethers is as tetrahydrofuran (THF) or dioxane, and ester is as ethyl acetate, or these solvents be mixed with each other and/or the mixed solution of water in, temperature of reaction is at about 0 ℃ to 150 ℃, preferably 15 to 100 ℃.
Even be not the sin qua non, also preferably will be reflected under the existence of acid or alkaline catalysts and carry out, catalyzer is for example, ore deposit acid is as hydrochloric acid, Hydrogen bromide, sulfuric acid or phosphoric acid, organic sulfonic acid such as methylsulfonic acid or right-toluenesulphonic acids, alkali metal hydroxide such as NaOH or KOH, amide such as NaNH
4Hydride such as NaH or amine is as the croak pyridine, triethylamine or pyridine.In indivedual examples, also available excessive catalyzer is as solvent.
The I phosphoric acid ester is preferably handled the hydroxyl dihydro anthoxanthin of formula I and is obtained with phosphorylation agent.If group Ar in starting raw material I
1And/or Ar
2On have one or more OH bases, they also can be by phosphorylation, so corresponding I-bisphosphate, I-triguaiacyl phosphate or the like just can obtain.
Except free phosphoric acid, phosphorylation agent at first has tetra-sodium, Tripyrophosphoric acid, five phosphorus oxide, phosphorous oxychloride, monochloro phosphoric acid (mixture of a kind of ortho-phosphoric acid and phosphorous oxychloride), mono phosphoric acid ester benzyl ester, phosphate dibenzyl ester muriate, phosphoric acid single (2-cyanoethyl ester) and di(2-ethylhexyl)phosphate morpholide-muriate.
The phosphorylation of formula I hydroxyl dihydro anthoxanthin is carried out existing or do not exist under the added solvent.The suitable solvent is, (if acid is arranged in reaction, as mauguinite, splitting) be organic bases preferably, as pyridine, and triethylamine, quinoline, xylidene(s) or diethyl-aniline.In other cases or additionally, may use inert organic solvents, such as, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), two _ alkane, chloroform, methylene dichloride, trichloroethane, dimethyl formamide, dimethyl sulfoxide (DMSO), benzene, toluene, dimethylbenzene naphthane or acetonitrile.Also can be with the mixed solution of above-mentioned alkali and/or solvent.Reaction also can be carried out in excessive phosphorylation agent.Temperature of reaction is at-80 ℃ to+200 ℃, preferably-10 ℃ to+100 ℃.
Process described in 1 of the common available He Ben-Wei Er, 143～210 page (1964) one book of X11/2 volume prepares I-phosphoric acid ester and their salt.
When preparation and their carboxylicesters, can form the intermediate product that has protecting group.These protecting groups can hydrolysis or hydrogenolysis remove.Particularly, the hydroxyl of having protected can with basic hydrolysis or modestly acid hydrolysis make hydroxyl free.Such protection hydroxyl may derive from that part of flavones, but most likely from the phosphate composition in the esterification.For example, as using mono phosphoric acid ester-(2-cyanoethyl ester), di(2-ethylhexyl)phosphate phenylester-muriate or di(2-ethylhexyl)phosphate morpholide-muriate carry out esterification, phosphodiester that generates or three esters or monoesters-diamide can be used, thus for example alkali metal hydroxide or solution of ammonium hydroxide or alkalescence or tart ion exchange resin split and obtain required flavones phosphoric acid ester.
Protecting group, preferably the benzyl in phosphoric acid ester can split with hydrogenolysis, for example catalytic hydrogenation; be preferably under the gentle condition, for example use palladium catalyst, such as the palladium charcoal; palladium lime carbonate or Strontium carbonate powder at room temperature and normal pressure, preferably just stop hydrogenation later at the hydrogen that has absorbed calculated amount.
The hydroxyl dihydro anthoxanthin of formula I and their phosphoric acid ester just can change into corresponding salt with alkaline purification.Suitable salt is the phenates of hydroxyl dihydro anthoxanthin, but primary be the salt of I-phosphoric acid ester.Preferably physiologically acceptable salt.Usually, salt is in room temperature preparation, and solvent for use is water particularly, alcohols.Such as methyl alcohol or ethanol, water and alcohol or be used for the mixed solution of the salifiable alkali of shape.Shi Yi alkali is the oxyhydroxide of alkali and alkaline-earth metal the most, and carbonate or alkoxide also have corresponding ammonium compound, sodium hydroxide preferably, yellow soda ash, sodium bicarbonate, sodium methylate and sodium ethylate, Virahol or sodium tert-butoxide, potassium hydroxide, salt of wormwood, saleratus, potassium methylate, potassium ethylate, Virahol or potassium tert.-butoxide, calcium hydroxide, lime carbonate, Calcium hydrogen carbonate, calcium methylate, calcium ethylate, Virahol or calcium tert-butoxide, magnesium hydroxide, magnesiumcarbonate, Magnesium hydrogen carbonate, magnesium methylate, magnesium ethylate, Virahol or uncle-butanols magnesium also has ammonium hydroxide, the ammonium hydroxide of volatile salt or bicarbonate of ammonia and replacement, and carbonate or supercarbonate.
Yet the salt of I-phosphoric acid ester and Glucosaminitol antibiotic has special importance.
Suitable Glucosaminitol antibiotic is that those contain a 2-deoxystreptamine unit, especially, and amikacin, dibekacin, gentamicin, Xin Meisu, paromycin, sagamicin, sisomycin, Streptomycin sulphate, tobramycin are particularly preferred, subsequently also be preferred, as allomycin, amicetin, apramycin, kanendomycin
2, betamicin, butyrosin, destomycins, everninomicin, ezomycin, flambamycin (flamlamycin), Promised Land mycin A and B.Soframycin, hikizimycin, homomycin, hybrimycin, Totomycin, kantlex class, kasugamycin, lividomycin, minot plug minomycin, myomycin, N-ethyl sisomicin, slight mycomycin (minosaminomycins), look sidelong at cryomycin A, ribostamycin, rimocidin, restomycin, ristomycin (ristosamin), Xi Er polymycin (sindomycin) sorbistin unwrapping wire shape is seen plain, streptothricin, tunicamycin and vernamycin, and if their enantiomorph and derivative they be alkaline.
Because several in these rhzomorphs, gentamicin for example, known is not single material, but represent that (for example gentamicin is the compound gentamicinC1 to mixture, the mixture of gentamicinC2 and gentamicinC la), the salt of I-phosphoric acid ester just is not to be one matter yet in indivedual examples, but mixture.Because many antibiotic of mentioning, for example all gentamicins have several basic nitrogen atoms, and again because of on the other hand, the I-phosphoric acid ester is a polyhydric acid, also might generate acidity, neutral and/or alkaline salt.Salt that all these are possible and mutual mixture all are included in " salt of formula I flavanone phosphoric acid ester and Glucosaminitol antibiotic " this definition.
Neutral salt is preferred with the mixture that contains the latter, for example in the example of gentamicin salt, one mol gentamicin, with 3 to 5 particularly the salt (mixture) formed of 4 mol I-phosphoric acid ester be highly preferred, particularly by a mol gentamicin and about 4 mol 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 '-salt that the methoxy flavanone-the 6-phosphoric acid ester is formed, use " G " to represent this salt below.Not existed in the salt, and available sodium ion or other physiologically acceptable ion neutralization by (acid) form of can dissociating of amino neutral acid proton in the antibiotic.
The salt of I-phosphoric acid ester and Glucosaminitol antibiotic can prepare with known mode itself, for example with the aqueous solution of water miscible antibiotic salt (for example gentamicin sulphate), merge with the aqueous solution of an I-phosphoric acid ester or its water-soluble salt (for example disodium salt), be preferably in room temperature and be 4 and stirred in 8 o'clock in the pH value.Also can add a kind of organic solvent, for example alcohol increases solubleness as methyl alcohol.The antibiotic salt that generates is slightly soluble in water, can filter to obtain, and washes with water and drying again.
Formula I compound and their phosphoric acid ester can have one or more asymmetric centers, thus, can obtain its raceme during preparation, are optically active as the starting raw material of using perhaps, and then product also is optically active.As compound two or more asymmetric centers are arranged, usually when synthetic, obtain the mixture of raceme, from mixture single racemization slowly physical efficiency separate pure product, for example can institute obtain from the inert solvent recrystallization.The raceme of gained if desired, can be analysed the light of getting them enantiomorph alive with known machinery own or chemical process.Preferably branch agent effect is analysed in raceme and a kind of light work and generate its diastereomer.Suitable analyse the branch agent, be used in particular for the optical active alkali of I-phosphoric acid ester, quinine for example, Quinidine, cinchonine, Cinchonidune, vauqueline, the dihydro rosin Amine D, Strychnine, morphine, or the D-of I-phenylethylamine and L-type, methyl oxyaniline or
Amine is perhaps used basic aminoacids, for example arginine or Methionin and their ester.Various forms of diastereomers can be with known mode itself separately, Steppecd crystallization for example, and optically active like this formula I compound or its phosphoric acid ester are disengaged from its diastereomer by known method itself.
The present invention also relates to application formula I compound, and the salt of their phosphoric acid ester and these compounds at first is that mention and salt Glucosaminitol antibiotic.Be used to prepare formula of medicine, use a kind of approach non-chemically especially.This can be with them and at least a solid, and the vehicle of liquid or half liquid or auxiliary become a kind of appropriate dosage form together to be realized, if suitable can also the combination with one or more active compound.
The present invention also relates to formula of medicine, and it contains some physiologically acceptable salt in the compound of at least a formula I and/or its phosphoric acid ester and/or these compounds.
These prescriptions can be used as medicine human or for animals.Suitable vehicle be some organic or inorganic things they be applicable to that enteron aisle (for example oral) and enteron aisle are outer and use or local use and the discord new compound reacts; Water for example, vegetables oil, benzylalcohol, macrogol, glyceryl diacetate, gelatin, carbohydrate, such as lactose or starch, magnesium stearate, talcum or Vaseline.Tablet, the look garment piece, capsule, syrup, elixir or drops are used in particular for oral, and suppository is used for rectum to be used, solution, suspension agent, emulsion or implant are used for enteron aisle to be used outward, ointment, frost or pulvis can locally use.Implant, as use silicone rubber, tricalcium phosphate or collagen are done being applicable to of substrate and are treated as infection of bone, are particularly importants, especially the antibiotic salt for being mentioned.Antibiotic can continue to discharge by implant, so antibiotic can be kept effective level in the vicinity of implant in long lasting period.Scleroproein-antibiotic gel at German prospectus 3,206, described in 725, also is suitable for treatment as.These new compounds also can lyophilize, and the lyophilize thing of generation can be used as, for example, and preparation injection prescription.Indicated prescription can sterilize and/maybe can contain auxiliary, such as lubricant, sanitas, stablizer and/or lubricant, emulsifying agent influences the salt of osmotic pressure, cushion, pigment, interior condiment and/or fragrant substance.If desired, they can also contain one or more other active compounds, the prescription that contains I phosphoric acid ester antibiotic salt, for example, can also additionally contain rapid solvability salt same or other antibiotic so that except the storage effect that produces by the I-phosphate ester salt, obtain the effect of system again.
The present invention also relates to formula I compound, the purposes of acceptable salt in fighting back the disease is used in particular for transformation reactions and/or infectation of bacteria on the physiology of their phosphoric acid ester and/or these chemicals, and they are in the purposes of the treatment mankind or animal.
In this respect, by the material among the present invention usually its taking method all with known, the commercial anti-allergy that gets or separate segmental bronchus/antiasthmatics, for example Cromoglycic Acid or its salt, or antibiotic is similar, preferably dosage is at about 5 to 1000 milligrams, especially between 10 and 500 milligrams, and every dose unit (next relevant) with the antibiotic active compound in the situation of antibiotic salt.Yet it is fixed that the dosage of each given patient is come by all factors very widely, for example, and the effectiveness of used specific compound.Patient age, body weight, general health situation and sex, and diet, Time of Administration and mode, excretion rate, drug combination and the seriousness that adopts the specified disease of this treatment.Local application is preferred.
Temperature is quoted formerly and in the article subsequently, degree centigrade.The absorption peak of the infrared spectra of its kbr tablet of IR=.
Embodiment 1
At-15.2 grams 2,5-dihydroxy acetophenone and 27.2 gram aubepines stir in 1.500 milliliters of alcoholic acid solution, feed HCl4 hour.3-is right-and ar-methoxy-benzylidene-6-hydroxyl-4-'-methoxy flavanone is settled out fusing point 199-201 °.6-hydroxyl-4 '-methoxy flavanone and 2,5-dihydroxy-right-ar-methoxy-benzylidene methyl phenyl ketone generates as intermediate.
Routine compound can obtain with similar methods with corresponding aldehyde down.
3-neighbour-hydroxyl benzylidene-6,2 '-the dihydroxy flavanone
Between 3--hydroxyl benzylidene-6,3 '-the dihydroxy flavanone
3-is right-hydroxyl benzylidene-6,4 '-the dihydroxy flavanone
3-is right-methyl benzylidene-6-hydroxyl-4 '-the methyl flavanone
3-is right-second benzylidene-6-hydroxyl-4 '-the ethyl flavanone
3-is right-ar-isopropyl benzylidene-6-hydroxyl-4 '-the sec.-propyl flavanone, fusing point 178-180 °
3-neighbour-ar-methoxy-benzylidene-6-hydroxyl-2 '-the methoxy flavanone
Between 3--ar-methoxy-benzylidene-6-hydroxyl-3 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-5-hydroxyl-4 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-7-hydroxyl-4 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-8-hydroxyl-4 '-the methoxy flavanone
3-(3,4-dimethoxy benzylidene)-6-hydroxyl-3 ' 4 '-the dimethoxy flavanone
3-(3,4,5-trimethoxy benzylidene)-6-hydroxyl-3 ', 4 ', 5 '-the trimethoxy flavanone, fusing point 168-170 °.
3-is right-kharophen benzylidene-6-hydroxyl-4 '-the kharophen flavanone, 205 ° of fusing points
3-is right-fluorine benzylidene-6-hydroxyl-4 '-the fluorine flavanone
3-is right-chlorine benzylidene-6-hydroxyl-4 '-the chlorine flavanone
3-(3, the 4-dichlorin benzylidene)-6-hydroxyl-3 ', 4 '-the dichloro-dihydro flavones, fusing point 228-230 °.
3-is right-bromine benzylidene-6-hydroxyl-4 '-the bromine flavanone
3-is right-iodine benzylidene-6-hydroxyl-4 '-the iodine flavanone
3-is right-methoxycarbonyl benzylidene-6-hydroxyl-4 '-methoxycarbonyl flavanone (methyl alcohol is as solvent)
3-is right-ethoxycarbonyl benzylidene-6-hydroxyl-4 '-the ethoxycarbonyl flavanone
3-neighbour-nitro benzylidene-6-hydroxyl-2 '-the nitro flavanone
Between 3--nitro benzylidene-6-hydroxyl-3 '-the nitro flavanone
3-is right-nitro benzylidene-6-hydroxyl-4 '-the nitro flavanone
3-(3,4-methylenedioxy group benzylidene)-6-hydroxyl-3 ', 4 '-inferior inferior dioxy base flavanone.
Embodiment 2
27 gram 6-hydroxyls-4 '-methoxy flavanone and 13.6 gram aubepines are saturated with HCl 1.400 milliliters of alcoholic acid hot solution, place made in 3 hours cooling, water separate out 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone, fusing point 199-201 °.
Compound shown in the example 1 also can obtain from corresponding 6-hydroxyl flavanone and corresponding aldehyde similarly.
Following compounds also can make similarly:
3-benzylidene-5-hydroxyl flavanone
3-benzylidene-7-hydroxyl flavanone
3-benzylidene-8-hydroxyl flavanone
3-is right-ar-methoxy-benzylidene-5-hydroxyl flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl flavanone
3-is right-ar-methoxy-benzylidene-7-hydroxyl flavanone
3-is right-ar-methoxy-benzylidene-8-hydroxyl flavanone
3-benzylidene-5-hydroxyl-4 '-the methoxy flavanone
3-benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-benzylidene-7-hydroxyl-4 '-the methoxy flavanone
3-benzylidene-8-hydroxyl-4 '-the methoxy flavanone
3-neighbour-hydroxyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
Between 3--hydroxyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-hydroxyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-(2,4-dihydroxy benzylidene)-6-hydroxyl-4 '-the methoxy flavanone
3-(3-methoxy-4-hydroxyl benzylidene)-6-hydroxyl-4 '-the methoxy flavanone
3-0-first benzylidene-6-hydroxyl-4 '-the methoxy flavanone
Between 3--first benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-first benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-ar-isopropyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-heptyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-neighbour-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone
Between 3--ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-ethoxy benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-heptan oxygen benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-(3,4-dimethoxy benzylidene)-6-hydroxyl-4 '-the methoxy flavanone
3-(3,4,5-trimethoxy benzylidene)-6-hydroxyl-4 '-the methoxy flavanone
3-is right-formamido group benzylidene-6-hydroxyl-4 '-the methoxy flavanone
The amino benzylidene of 3-o-acetyl--6-hydroxyl-4 '-the methoxy flavanone
Between 3--kharophen benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-kharophen benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-propionamido benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-butyrylamino benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-heptanamido benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-the amino benzylidene of benzoyl-6-hydroxyl-4 '-the methoxy flavanone
3-is right-fluorine benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-chlorine benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-(3,4 ,-dichlorin benzylidene)-6-hydroxyl-4 '-the methoxy flavanone
3-is right-bromine benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-iodine benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-methoxycarbonyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-ethoxycarbonyl benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-neighbour-nitro benzylidene-6-hydroxyl-4 '-the methoxy flavanone
Between 3--nitro benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-nitro benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-(3,4-methylenedioxy group benzylidene)-6-hydroxyl-4 '-the methoxy flavanone
Embodiment 3
2.7 gram 2.5-dihydroxy-right-ar-methoxy-benzylidene methyl phenyl ketone, the mixture of 1.36 gram aubepines and 5 milliliters of piperidines was 100 ° of heating one hour, and cooling adds water.3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone is settled out; Fusing point 199-201 °
Following compounds can obtain like corresponding aldehydes:
3-is right-ar-methoxy-benzylidene-6-hydroxyl flavanone
3-is right-ar-methoxy-benzylidene-6,2 '-the dihydroxy flavanone
3-is right-ar-methoxy-benzylidene-6,3 '-the dihydroxy flavanone
3-is right-ar-methoxy-benzylidene-6,4 '-the dihydroxy flavanone
3-is right-ar-methoxy-benzylidene-6,3 ' and, 4 '-three hydroxyl flavanones
3-is right-ar-methoxy-benzylidene-6,4 '-dihydroxy-3 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-2 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the sec.-propyl flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the heptyl flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-2 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 '-the methoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the ethoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-heptan the oxygen flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 ', 4 '-the dimethoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 ', 4 ', 5 '-the trimethoxy flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the formamido group flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-2 '-the kharophen flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 '-the kharophen flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the kharophen flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the propionamido flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the butyrylamino flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the heptanamido flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the amino flavanone of benzoyl
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the fluorine flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the chlorine flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 ', 4 '-the dichloro-dihydro flavones
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the bromine flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the iodine flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxycarbonyl flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the ethoxycarbonyl flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-2 '-the nitro flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 '-the nitro flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the nitro flavanone
3-is right-ar-methoxy-benzylidene-6-hydroxyl-3 ', 4 '-inferior methylenedioxy group flavanone
Embodiment 4
38.8 gram 3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-solution of methoxy flavanone in 300 milliliters of pyridines is 10 °～15 ° stirrings, drop to 100 milliliters of POCl in the solution of 500 milliliters of pyridines, mixture was 20 ° of restir two hours, then in the impouring 7 liter dilute hydrochloric acid, solution concentration and water and ethyl acetate are handled, add entry in the organic extract liquid again, the pH of mixed solution adjusts to 6 with NaOH, evaporate 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 '-disodium salt of methoxy flavanone-6-phosphoric acid ester.
NMR (Nuclear Magnetic Resonance) spectrum (dimethyl sulfoxide (DMSO) ten trifluoroacetic acids (diazonium)): 3.73(s), 3.81(s), 6.7(s), 6.9-7(m) and 8.01(s) ppm(s=is unimodal, the m=multimodal).
Following compounds can obtain similarly:
3-benzylidene-6-hydroxyl flavanone-6-phosphoric acid ester, 90～92 ° of fusing points.
3-is right-ar-isopropyl benzylidene-6-hydroxyl-4 '-different third flavanone-6-phosphoric acid ester
3-(3,4,5 ,-trimethoxy benzylidene)-6-hydroxyl-3 ', 4 ', 5 '-trimethoxy flavanone-6-phosphoric acid ester, fusing point 153-155 °
3-is right-kharophen benzylidene-6-hydroxyl-4 '-kharophen flavanone-6-phosphoric acid ester
3-(3, the 4-dichlorin benzylidene)-6-hydroxyl-3 ', 4 '-dichloro-dihydro flavones-6-phosphoric acid ester, fusing point 128-130 °
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-methoxy flavanone-6-phosphoric acid ester
3-benzylidene-6-hydroxyl-4 '-phosphoric acid ester of methoxy flavanone-6-phosphoric acid ester and all the other 3-benzylidene flavanones of being mentioned at example 1 to 3.
Embodiment 5
The 20 milliliter of 14 gram solution of phosphate dibenzyl ester muriate in ether-25 ° join 3.88 gram 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone is in the solution of 40 milliliters of pyridines, mixture stirred one hour and placed 16 hours at-5 ° at-25 °.Mixture is inclined on the ice cube, with hcl acidifying to pH4 and use ether extraction, extracting solution anhydrous sodium sulfate drying.The residue that obtains from diethyl ether solution is dissolved in 200 ml methanol, and to add 0.3 gram intensity at 20 ° be palladium/charcoal of 10%, and pressure is 1 crust hydrogenation down, till no longer inhaling hydrogen.Catalyzer removes by filter, filtrate evaporate 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 '-methoxy flavanone-6-phosphoric acid ester.
Embodiment 6
3.88 the gram 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 ' methoxy flavanone, 34 gram benzyl phosphoric acid ester muriates, the mixture of 19 gram dimethyl formamides and 150 milliliters of pyridines stirred 2 hours at 20 °, was added in 20 ° again and placed 16 hours, with the similar method operation of example 5, can get same product then.
Embodiment 7
2 milliliters of anhydrous phosphoric acids, the mixed solution of 17 milliliters of acetonitriles and 5 milliliters of triethylamines are cooled to-20 °, add the solution of 3.6 milliliters of Vinyl chloroformates in 4 milliliters of acetonitriles, and mixture stirred 15 minutes.Stir to add 3.88 gram 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 ' methoxy flavanone solution and 4.8 milliliters of triethylamines in 12 milliliters of acetonitriles, wait gas evolution to stop back mixture reheat and refluxed one hour, by example 5 operate similarly same product.
Embodiment 8
By 9.4 gram POCl
3With 10.2 the gram intensity be 85%H
3PO
4Act on the diethyl ether solution of resulting monochloro for phosphoric acid ,-10 ° join 3.88 gram 3-right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the methoxy flavanone is in the solution of 20 milliliters of pyridines.Place after 15 hours, mixture gets same product with the similar operation of embodiment 5.
Embodiment 9
17.6 the solution of garamycin sulfate in 200 ml waters, stirring joins, and presses embodiment 4 preparation, 3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the disodium salt solution of methoxy flavanone 6-phosphoric acid ester in.Its proximate composition of the salt of gained is 1 * gentamicin, 4 * 3-is right-ar-methoxy-benzylidene-6 hydroxyl-4 '-methoxy flavanone-6-phosphoric acid ester (" G ") leaches and dry.IR：1615，1520，1490，1270，1190，1180，1040cm
-1。
The gentamicin salt of the phosphoric acid ester that other are mentioned in example 4 also can obtain similarly, the salt IR:1670 of 3-benzylidene-6-hydroxyl-flavanone-6-phosphoric acid ester for example, 1620,1490,1070,980,920cm
-1; And 3-(3,4,5-trimethoxy benzylidene-6-hydroxyl-3 ', 4 ', 5 '-salt of trimethoxy flavanone-6-phosphoric acid ester, IR:1590,1510,1490,1250,1135cm.
Embodiment 10
3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-the following salt of methoxy flavanone-6-phosphoric acid ester, be and example 9 similar ground promptly to obtain from the vitriol of the corresponding antibiotic of calculated amount and the disodium salt of this compound.
A) and Xin Meisu;
B) and paromycin;
C) and sisomycin;
D) and amikacin;
E) and tobramycin;
F) and dibekacin;
G) and Streptomycin sulphate.
Following Example relates to the formula of medicine that contains The compounds of this invention:
The embodiment A tablet
1 kilogram of 3-is right-ar-methoxy-benzylidene-6-hydroxyl-4 '-single sodium salt of methoxy flavanone-6-phosphoric acid ester, 4 kilograms of lactose, 1.2 the kilogram yam starch, the mixture of 0.2 kilogram of talcum and 0.1 kilogram of Magnesium Stearate is pressed into tablet and makes every to contain 50 milliliters of active compounds by usual method.
The Embodiment B coated tablet
Tablet and embodiment A are pressed into similarly, use common mode dressing then, and dressing is by sucrose, yam starch, and talcum, tragacanth gum, pigment is formed.
The Embodiment C capsule
It is intrafascicular that 10 kilograms " G " fills in ebonite by common mode, makes the contained active substance of every capsule be equivalent to 165 milligrams of gentamicin bases.
Embodiment D ampoule
1 kilogram " G " is ground into superfine particulate and is suspended in 30 liters of sesame oil, and suspension is packed into ampoule, and at aseptic situation lower sealing.The contained active substance of per ampoule is equivalent to 10(40, and 80 or 120) milligram gentamicin base.
The embodiment E implant
1.05 gram is ground into " G " (being equivalent to 0.2 gram gentamicin) and 8.5 gram silicone rubber monomer (medical grade Silastic382 of particulate, Du, can be rather), adding 2 polymerizing catalysts, mix again, is that 20 millimeters thickness of circular disc diameter are 1 millimeter with mixture forming.Every circular disc contains 6 milligrams of gentamicin bases.
Embodiment F scleroproein-antibiotic gel
Taka-proteinase (article of commerce) 4NIH unit is dissolved in 1 milliliter of Trypsin inhibitor,Trasylol/calcium chloride (article of commerce, 3,000KIu/ milliliter Trypsin inhibitor,Trasylol is in 40 millimoles/rise in the calcium chloride) in the solution, solution is heated to 37 °, add " G " amount that is equivalent to 20 gram gentamicin bases, 37 ° " scleroproein-glutelin " of heating in advance of product and isodose mixes (article of commerce mutually, freezing precipitation preparation from blood donor's blood plasma, preserve in-18 ° or colder, 1 milliliter of this solution contains the Taka-proteinase one precipitable protein of 90 milligrams of average out to, and total albumin amount of this solution is about 10% by weight; Use precontract at needs thawed in 20-30 minute).Mixture solidifies in stainless copper bottle (6 millimeters of interior diameters, high 10 millimeters).The cylindrical gelatin that forms takes out in mould.
Embodiment G sucks capsule
5 kilograms of 3-are right-and ar-methoxy-benzylidene-6-hydroxyl-4 ' methoxy flavanone-6-phosphoric acid ester and 5 kilograms of lactose mix, and mixture is packed into and is inserted capsule and make each capsule contain 50 milligrams of active substances by mode commonly used.This capsule can be used with sucker.
Claims (1)
1,3-to ar-methoxy-benzylidene-6-hydroxyl-4 '-preparation method of the gentamicin salt of methoxy flavanone-6-phosphoric acid ester, it is characterized in that, make 6-hydroxyl-4 '-reaction of methoxyl group-flavanone and aubepine, the 3-that obtains to ar-methoxy-benzylidene-6-hydroxyl-4 '-methoxyl group-flavanone handles through a kind of phosphoric acid agent and changes into corresponding phosphoric acid ester, the phosphoric acid ester that obtains then or its a kind of salt and gentamicin or its a kind of reactant salt.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85105079 CN1012644B (en) | 1984-08-28 | 1985-07-03 | Process for preparation of flavanone derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843431534 DE3431534A1 (en) | 1984-08-28 | 1984-08-28 | FLAVANONE DERIVATIVES |
| CN 85105079 CN1012644B (en) | 1984-08-28 | 1985-07-03 | Process for preparation of flavanone derivatives |
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| CN85105079A CN85105079A (en) | 1987-01-28 |
| CN1012644B true CN1012644B (en) | 1991-05-22 |
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