CN1031461C - Resolution process of racemic semi-ester - Google Patents
Resolution process of racemic semi-ester Download PDFInfo
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- CN1031461C CN1031461C CN 85106365 CN85106365A CN1031461C CN 1031461 C CN1031461 C CN 1031461C CN 85106365 CN85106365 CN 85106365 CN 85106365 A CN85106365 A CN 85106365A CN 1031461 C CN1031461 C CN 1031461C
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Abstract
The present invention relates to a resolution process of racemic half ester disclosed in the formulas of Ia and Ib, wherein in the formulas, R is alkyl of C1 to C6, naphthenic group of C3 to C5, alkenyl of C2 to C6, benzyl and 1 or 2-phenylethyl. The resolution method comprises the steps that the racemic half ester and (+)-dehydroabietic amine form salt; diastereomer salt is separated by a crystallization method; optically active cis-1, 3-dibenzyl-5-alkoxycarbonyl-2-oxo-imidazol-idinyl-4-carboxylic acid is an intermediate for preparing D (+)-biotin; optically active amine and active 1, 3-dibenzyl-5-alkoxycarbonyl-2-oxo-imidazol-idinyl-4-carboxylic acid form diastereoisomeric salt reduced into optically active 1, 3-dibenzyl hexahydro-1H-furanzo (3, 4-d) imidazolyl-2, 4-dione; the latter is an intermediate for preparing D(+)biotin; BZL is benzyl.
Description
The invention relates to the novel process of two enantiomorphs of suitable-1, the 3-dibenzyl-5-carbalkoxy shown in the preparation formula Ia/b-2-oxo-imidazole alkane-4-carboxylic acid,
Wherein,
R-the have alkyl of as many as six carbon atom,
The alkoxyalkyl of 2-8 carbon atoms,
The cycloalkyl of 3-5 carbon atoms,
The alkenyl of 2-6 carbon atoms,
Benzyl or 1-or 2-styroyl,
BZL-benzyl and by 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid preparation (3aS, 6aR) and/or (3aR, 6aS)-1, the novel process of 3-dibenzyl, six hydrogen-1H-furo (3,4-d) imidazoles-2,4-diketone, it is characterized in that: optically active amines and the formed diastereoisomeric salt of optical activity 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazolidine-4-carboxylic acid are reduced.
(4S, 5R)-1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid is preparation (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone useful as intermediates, the latter is the key intermediate of preparation (+)-vitamin H.
The existing optical resolution technology that discloses relevant suc as formula the racemic semi-ester shown in the Ia/b, wherein, German Patent 2,058,234 have narrated preparation cyclohexyl half ester and non-mapping foreign body object (+) ephedrine salt by the fractional crystallization resulting separation, and the cholesterol half ester of preparation diastereomer with separate the technology of resulting triethylamine salt thus with fractionation crystallization.Yet the productive rate of these technologies all is lower than 50%, and the ancillary compound of chirality-cholesterol price is expensive, also is difficult to reclaim fully.
Europe publication specification sheets 0,092,194 has been narrated the method for optical resolution of racemic methyl and ethyl half ester: the diastereoisomeric salt that separates half ester and the formation of optically active 1,2-phenpromethamine with crystallization process.Further method is to make in the supersaturated solution of enantiomorph by raceme that crystal seed makes required fractionation of enantiomorph to separate out automatically.This method also has the low shortcoming of the productive rate of fractionation, only is 30% of theoretical amount.So target of the present invention provides the cheap resolving agent of applied cost and splits the novel process of the half ester shown in the Ia/b with high yield.
Now find unexpectedly: (+) dehydroabietylamine can be split as enantiomorph with the racemic modification of formula Ia/b as resolving agent, and the productive rate height, and selectivity is good.
Therefore, the invention provides new compound: i.e. (4S, 5R)-and (4R, 5S)-and (+)-westvaco rosin amine salt of suitable-1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid, wherein " alkyl " is meant and has 6 carbon atoms of as many as, " alkoxyalkyl " has 2-8 carbon atoms, " cycloalkyl " has 3-5 carbon atoms, and " alkenyl " has 2-6 carbon atoms, benzyl or 1 or 2-styroyl.
The present invention also provides the resolution process of the racemic semi-ester shown in the formula Ia/b,
Wherein,
The alkyl of 6 carbon atoms of R-as many as,
The alkoxyalkyl of 2-8 carbon atoms,
The cycloalkyl of 3-5 carbon atoms,
The alkenyl of 2-6 carbon atoms,
Benzyl or 1 or 2-styroyl,
BZL-benzyl
This technology is: the raceme and the optically active amine salify that are split, separate formed diastereoisomeric salt then, and it is characterized in that: used optically active amines is (+) dehydroabietylamine.
The present invention further provides: according to this technology resulting optically active suitable-1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid can be used for preparing D (+)-vitamin H.
Racemic semi-ester of the present invention is to carry out isolating (for example, B.P.H.Boyte, Quart.Rev.25 (1971) 323-341) with the standard method of known racemic modification optical resolution.Racemic modification can split mutually with the chromatography chirality; Adding crystal seed way in the also available supersaturated solution perhaps splits with the way that machinery is picked.Further method for splitting is made up of the forming of diastereomer, separation and decomposition.Ideal method is based on the separation of diastereoisomeric salt.The best method for splitting of racemic modification shown in the formula Ia/b is to be dissolved in suitable organic solvent with raceme and a certain amount of (+)-dehydroabietylamine are same, then with the salt recrystallization of (+) dehydroabietylamine of its diastereomer.When by filter or centrifugal tell salt after, from surplus solution, remove and desolvate, make the residual solution recrystallization if necessary and another enantiomorph.
To the racemic modification that every mole of quilt splits, the amount of required (+)-dehydroabietylamine is 0.5-1 mole, and preferred amount is 0.5-0.7 mole.Used solvent can be water, or a kind of inert organic solvents, preferred solvent be a kind of can with water blended solvent, particularly alcohol, as methyl alcohol, ethanol, Virahol, propyl carbinol or uncle-butanols or the like, ether is as tetrahydrofuran (THF), dioxane, glycol monomethyl first or single ether, glycol dimethyl ether, ketone such as acetone, butanone or isobutyl methyl ketone also can be nitrile, as acetonitrile, or nitro-compound, as Nitromethane 99Min..
Preferred solvent is an alcohols, ketone and ethers, preferably methyl alcohol, ethanol, Virahol, propyl alcohol or tetrahydrofuran (THF).
The also mixture of available above-mentioned solvent.Preferably above-mentioned solvent and water is with the mixture of 0.5-50% ratio, and particularly 0.5-10%, be the best with 1-5%.
According to the present invention, the temperature that splits can be selected between the boiling point of-20 ℃ and solvent for use, but to be lower than by the Tc of crystalline enantiomorph salt for well.
Optical resolution technology of the present invention is specially adapted to that R is the compound of methyl or ethyl among the formula Ia/b.
In according to preferred embodiment of the present invention, used fractionation crystallization and separated the diastereomer salt mixture.For this reason, the racemic semi-ester shown in the formula Ia/b at first uses (+) dehydroabietylamine of equivalent to be converted into the diastereomer salt mixture.The reaction of racemic semi-ester and optically active amines can be solvent-free or carry out in the presence of organic solvent.Preferred solvent is non-polar solvent, particularly hydrochloric ether, as methylene dichloride, and chloroform, trichloroethane, 1,2-ethylene dichloride or tetracol phenixin, or hydrocarbon polymer, as hexane, sherwood oil, benzene, toluene or dimethylbenzene.Also available above-mentioned mixture.
Remove the salt of being told the back of desolvating and in above-mentioned solvent, carry out crystallization to carry out the optical resolution racemic semi-ester.In according to the preferred embodiments of the invention, narrated along 1, the optical resolution of (+)-salt that dehydroabietylamine generated of 3-dibenzyl-5-methoxycarbonyl-2-oxidation imidazolidine-4-carboxylic acid and suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid.
(+)-westvaco rosin amine salt that technology obtains the optically active half ester shown in the Ia/b according to the present invention can obtain the acid of free half ester again with acid or alkaline purification.The alkali that is fit to has: the oxyhydroxide of basic metal or alkaline-earth metal, the carbonate of basic metal or alkaline-earth metal or supercarbonate, ammonia and strong organic bases.Preferred alkali is alkali metal hydroxide and ammonia particularly sodium hydroxide and potassium hydroxide.
Suitable acid is strong organic acid, for example, formic acid or acetate, the example of mineral acid has phosphoric acid or nitric acid, and preferred mineral acid is hydrochloric acid or Hydrogen bromide.The best is sulfuric acid preferably because (+) dehydroabietylamine can with the hydrosulfate of its generation indissoluble, this salt is easy to crystallization, thereby is easily separated with filter method, thus with the used resolving agent of recovered in high yields.
For from their westvaco rosin amine salt middle reaches from going out suc as formula the optical activity half ester shown in the Ia/b, select acid usually for use, because half ester has reduction stability to alkali.
The amount of used acid can change in very wide scope, but every mole of split diastereoisomeric salt needs 1 equimolar acid at least, preferably adopts 1-1.5 moles.
Available appropriate solvent is dissolved diastereoisomeric salt, and preferred solvent is a water, then acid is added in this solution so that half ester is free.Can be used organic solvent extraction by the free half ester, for example use ether, toluene, ethyl acetate, methylene dichloride or their mixture.As needs, extracting solution washing back except that desolvating, is just drawn required optical activity half ester.
In order to reclaim resolution reagent (+)-dehydroabietylamine, can alkalize with highly basic in the solution after extraction, make resolving agent free.Available ammonia, sodium hydroxide solution or potassium hydroxide solution alkalization.Alkalization back organic solvent extraction, method is similar to the method for the active half ester of above-mentioned dissociated optical.
If the sulfuric acid with optimal selection decomposes diastereoisomeric salt, then (+)-dehydroabietylamine is separated out with the hydrosulfate form of indissoluble, with filtering or after centrifugal method told, available aforesaid method adds strong alkali solution made resolving agent free, then recyclable this resolving agent of solvent extraction.
The described initial substance of technology of the present invention, the preparation method of the racemic modification half ester shown in the formula Ia/b is known, for example, German Patent 2,058,234 or European publication specification sheets 0,092194 method, be to prepare by suitable-1,3-dibenzyl-2-oxo-imidazole alkane-4,5-dicarboxylic anhydride, can be with this acid anhydrides with corresponding pure in inert solvent, for example benzene reacts in toluene or the dimethylbenzene, and preferable reaction conditions is at high temperature to react.
The optical activity prepared suitable-1 according to the present invention, 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid, can use known method, people's method of reporting (Helv.Chem.Acta53 (1970) such as Gerecke for example, 991-999) be reduced to optically active 1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4 (1H)-diketone.Free optical activity half ester can be used as the initial substance of this reduction reaction.Yet also (+) of available its diastereomer-westvaco rosin amine salt is as initial substance.This class technological process has outstanding advantage.
German Patent 2,058,248 have narrated preparation (3aS, 6aR)-technology of lactone, with suitable-1,3-dibenzyl-2-oxo-imidazole alkane 4, the cholesterol ester of 5-dicarboxylic acid and cyclohexyl ester are split as its enantiomorph, and corresponding enantiomorph is converted into required lactone with reduction reaction.But this process yields is lower than 50% theoretical amount, and is somewhat expensive and can not reclaim fully as the cholesterol of chirality ancillary compound, and in the technology of this application patent, the half ester of unwanted enantiomorph need recycle once more.
Publication specification sheets 0,081,047 pair of above-mentioned technology in Europe has been done improvement.Improve in the technology at this, the carboxyl of unwanted half ester is converted into acyl chlorides earlier, reduce requiredly then (3S, 6R)-lactone.But because diastereo-isomerism spare separation efficiency is low, chirality ancillary compound price is expensive, and this technology does not have important economic worth.
At German Patent 2,331, narrated in 244 preparation (3R, 6S) and (3S, 6R)-technology of lactone.This technology will be by suitable-1,3-dibenzyl-2-oxo-imidazole alkane-4, suitable-1 of 5-dicarboxylic acid and a kind of optically active amine gained, 3-dibenzyl hexahydropyrrolo also (3,4-d) imidazoles-2,4,6-triketone carries out asymmetric reduction, subsequently with the acid amides alkylol cpd hydrolysis of gained and required lactone.
The shortcoming of this technology is that the optically active amines price is expensive and separation yield is not high equally.
Europe publication specification sheets 84 though 892 described diastereomeric separation yields are high, needs the difficult optically active amines that obtains equally.
On the other hand, suitable-1 of enantiomorph, 3-dibenzyl-2-oxo-imidazole-4,5-dicarboxylic acid is the good method that a class prepares the photolytic activity half ester with the salt-forming reaction of (+)-dehydroabietylamine, each optically active enantiomorph all can be by currently known methods, for example the method for being narrated at European publication specification sheets 84,892 is converted to required optically active lactone.
In above-mentioned technological process, before reduction reaction, half ester can be told through strong acid treatment from the diastereoisomeric salt that they and optically active amines are generated.
In the reduction reaction of proceed step by step subsequently, reductive agent can be earlier with free half ester in the acidic hydrogen effect of carboxyl, thereby consumed normal reductive agent, then reductive agent is to the effect of reduction unable to get up.
So find a kind of technological process, to reduce suitable accordingly-1,3-dibenzyl-2-oxo-imidazole alkane-4,5-dicarboxylic acid half ester prepares optically active 1,3-dibenzyl tetrahydrochysene-4H-furo (3,4-d) imidazoles-2,4-diketone, this technology should make reductive agent be able to than good utilisation and simple to operate, and it is high that the chemical purity of isolating product and optical purity are wanted.
Now find unexpectedly, optically active amines and optical activity 1,3-dibenzyl-5-carbalkoxy-formed diastereoisomeric salt of 2-oxo-imidazole alkane-4-carboxylic acid can be reduced, and chemical yield and optical yields are all high, and does not disturb with the component of amine.
Like this, the present invention also provides by 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid preparation (3aS, 6aR)-and/or (3aR, 6aS)-1,3-dibenzyl, six hydrogen-1H-furo (3,4-d) imidazoles-2, the technology of 4-diketone is characterized in that: the diastereomer that optically active amines and optical activity 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid forms can be reduced.
The invention further relates to optical activity 1,3-dibenzyl six hydrogen-1H-furo (3,4-d) imidazoles-2, the 4-diketone that utilizes prepared provided by the invention and prepare D (+)-vitamin H.
In the present invention and the method for the diastereoisomeric salt that reason optical activity half ester is generated is identical with the method for the free half ester of known reduction.
According to selected reductive agent, from having 4S, 5R-4R, the half ester salt of 5S-configuration can obtain not only that (3aR 6aS)-lactone, also can obtain (3aS, 6aR) lactone.
For example, as will (4S, 5R) carboxyl of half ester salt reduces, product be (3aR, 6aS) lactone, and when reducing its carbalkoxy, obtain (3aS, 6aR) lactone of configuration.Reduction (4R, 5S)-the configuration dependency of products therefrom during half ester salt, with above-mentioned opposite.
The appropriate reductant example of reduction carboxyl is: hydroborate, and as diborane.
Suitable solvent is that reductive agent is shown organic solvent inert, for example hydrocarbon polymer, for example benzene or toluene etc.; Ethers, ether for example, ethylene glycol bisthioglycolate alkyl oxide, diethylene glycol monoethyl ether, tetrahydrofuran (THF) Huo diox etc.Preferred solvent is: ring-type ethers, for example tetrahydrofuran (THF) and diox.Also available above mixture.
Reduction reaction temperature with between-20～+ 40 ℃ for well, preferably-10～+ 30, particularly between 0～20.Required reductive agent hydride amount is chosen between 0.8 and 3 equivalents of theoretical amount, preferentially selects 1-2 equivalents for use, particularly 1-1.5 equivalents.For example, when with diborane during as reductive agent, preferable consumption is: every mole of half ester salt is with 0.5-0.75 mole diborane.
Diborane can be used for reduction reaction, but it also uses currently known methods with preparation on the spot, for example available NaBH
4With Lewis acid such as boron trifluoride or its ether affixture, this preparation method on the spot preferably carries out in the solvent that adopts the half ester reduction reaction to be suitable for, and makes the diborane solution of gained can be used as the medium of reduction reaction subsequently.
The example of the reductive agent that the reduction carbalkoxy is suitable for is compound hydroborate, and as lithium borohydride, sodium borohydride or hydroboration calcium, and aluminum hydride compound are as diisobutylaluminium hydride and diethyl aluminium hydride sodium.
The used solvent of reduction reaction preferably will be the inert solvent to reductive agent under reaction conditions, reactant should be partially soluble in this solvent at least.
For the reductive agent that can in water-bearing media, use, be water as the suitable examples of solvents of this reductive agent, alcohols such as methyl alcohol, ethanol, Virahol, ethylene glycol or glycol ether, ethers such as tetrahydrofuran (THF) Huo diox.The also mixture of the mixture of available these solvents or they and the immiscible solvent of water.
For the reductive agent that can work with water, its suitable solvent is not only ethers, as ether, the ethylene glycol bisthioglycolate alkyl oxide, the glycol ether dialkyl ether, tetrahydrofuran (THF) or dioxane can use, and can use hydrocarbon polymer, particularly benzene and toluene and so on, the also mixture of available above-mentioned solvent.
Temperature of reaction can be selected between-70 ℃ to+100 ℃, is between-70 ℃ to+30 ℃ to the more excellent temperature of aluminiferous reductive agent, particularly-40 ℃ between+30 ℃.The temperature that the boracic reductive agent is preferentially selected for use is between-10 ℃ to+100 ℃, between special 0 ℃ to 80 ℃.
Required reduction dosage is to select between 0.8-3 equivalents of theoretical amount, particularly between 1-2 equivalents, preferably between 1-1.5 equivalents.For example, as use sodium borohydride, every mole of required sodium borohydride of half ester salt is preferentially selected 0.75-1.25 moles for use.
As used initial substance, 1 of diastereomer, in 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylate salt, " carbalkoxy " is meant the carbalkoxy with 6 carbon atoms of as many as, have 2-8 carbon atoms " alcoxyl carbalkoxy ", have 2-6 carbon atoms " chain ene keto carbonyl ", carbobenzoxy-(Cbz) or 1 or 2-benzene ethoxycarbonyl.
According to technological process of the present invention, preferentially select 1,3-dibenzyl-5-methoxycarbonyl for use, 5-ethoxycarbonyl and salt that 5-carbobenzoxy-(Cbz)-2-oxo-imidazole alkane-4-carboxylic acid is become with optically active amines raw material as reduction reaction.
Suitable optically active amines is meant all suitable optical activity amine salt components as the resolution of racemic half ester, for example, and Deutsches Reichs-Patent 2,058,248 described ephedrine, European publication specification sheets 92,194 described 1,2-phenpromethamines, and (+)-dehydroabietylamine particularly.The preferred example of technology has just been used the diastereomeric salt of (+)-dehydroabietylamine according to the present invention.
This technological operation is easy.Diastereoisomeric salt as initial substance is known, perhaps can be by currently known methods, as the method preparation of European publication specification sheets 92,194.Reactant is mixed, will heat under this reaction mixture stirring or be cooled to react required temperature, reaction be promptly carried out.But method is that diastereoisomeric salt (dissolving in appropriate solvent as needs) is slowly joined in the reductive agent preferably.Reaction times is 0.5-40 hours, is good with 1-8 hours.After reaction is finished, add acid and carry out acidifying, for example can add mineral acid, example hydrochloric acid or sulfuric acid extract the reduzate of optically active lactone form, solvent such as ether, ethyl acetate, methylene dichloride, chloroform or toluene then with appropriate solvent.
After solvent removed, can obtain the required lactone of very pure crystallized form generally speaking.If necessary, product can be further purified with chromatography or crystallization process.
In order to reclaim optically active amines, the solution alkalization after will extracting with highly basic for example, use ammonia, and sodium hydroxide solution or potassium hydroxide solution alkalization with above-mentioned dissociated optical activated lactone similar approach extraction, are told amine then.
Optically active (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo (3,4-d) imidazoles-2,4-(1H)-diketone can be converted into D (+)-vitamin H by currently known methods, for example, and at German Patent 2,058,234 or German Patent 2,331,244 in narrated these methods.
So the invention provides a technology simple, the half ester shown in the formula Ia/b is split the high and method completely of efficient, the route of a tool superiority further is provided for preparation D (+)-vitamin H.
Reduction optically active amines and optically active 1 have been the present invention further provides, the diastereomeric salt that 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid forms, preparation optical activity 1,3-dibenzyl-six hydrogen-1H-furo (3,4-d) imidazoles-2, the technology of 4 diketone, its chemistry and optical purity are all high, thereby the operational path of a superior simple economy is provided for preparation D (+)-vitamin H.
Example 1:
A) with 250 gram (0.743 moles) suitable-1,3-dibenzyl-six hydrogen-1H-furo (3,4-d)-imidazoles-2,4,6-triketone, the suspended substance of 59.7 gram (1.283 moles) ethanol and 2 liters of benzene refluxed 2 hours, concentrate then and make its crystallization, get suitable-1, the 3-dibenzyl-2-oxo-imidazole alkane-5-ethoxycarbonyl-4-carboxylic acid of 256 grams (90% theoretical value), 93 ℃ of fusing points
B) 57.4 gram (0.15 mole) racemic cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid and 42.8 gram (0.15 mole) (+)-dehydroabietylamines are dissolved in 375 milliliters of tetrahydrofuran (THF)s, at room temperature add 7.5 ml waters, this solution is cooled to-7 ℃, get (the 4R of 47.7 grams (95% theoretical value), 5S)-the westvaco rosin amine salt crystallization of suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, (a)
365 25=+47.1 °.In mother liquor, add 400 ml waters or 500 milliliters of hexanes get 49.8 grams (98% theoretical value) (4S, 5R)-suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, (a)
365 25=+61.24 °
Example 2:
The racemic cis of equivalent-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid and (+) dehydroabietylamine are dissolved in ethanol (every mole usefulness 4-5 liters), add 10% water again, being cooled to-10 ℃ makes it separate out crystallization, get (the 4R of 89% yield (theoretical value), 5S)-the westvaco rosin amine salt of suitable-1,3-dibenzyl-5-ethoxy carbonyl-2-oxo-imidazole alkane-4-carboxylic acid, (a)
365 25=48.1 °
Mother liquor is contracted to about 2/3 volume, with equal-volume water dilution, isolate (4S, 5R)-the westvaco rosin amine salt (92% yield) of suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, (a)
365 25=63.6 °.Mother liquor concentrates once more, raffinate is handled with 100 milliliters of diisopropyl ether, get (the 4R of 9% yield (theoretical value), 5S)-and (4S, 5R)-suitable-1, the mixture of (+)-dehydroabietylamine diastereoisomeric salt of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid can be used for separating once more.
Example 3:
The solution evaporation of (+)-dehydroabietylamine in 80 milliliters of methylene dichloride of 26.8 gram (0.07 mole) racemic cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acids and 20g (0.07 mole) extremely done.Get the ethyl half ester acid westvaco rosin amine salt of the diastereomer of 45.6 grams (97.5% theoretical value) from the diisopropyl ether crystallization, (a)
365 25=+54.9 °.
Example 4:
Gained suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid can split with crystallization method with the ethanol that contains 10% water with the mixture of the diastereomeric salt of (+) dehydroabietylamine in example 3.
The crystallization of at first separating out have (4R, 5S)-configuration, (a)
365 25=+46.2 °
Add entry (be equivalent to organic solvent volume 50%) diisopropyl ether or sherwood oil in the mother liquor after separating out crystallization first, can get the salt of crystallized form, its be configured as (4S, 5R), (a)
365 25=+63.6 °.
Example 5:
Repeat the operation described in the example 4, wherein, replace ethanol with the Virahol that contains 5% water, can with example 4 a great deal oves (4R, 5S)-diastereomeric salt.
Example 6:
Repeat the operation described in the example 4, and replace ethanol, output and example 4 gained suitable with the tetrahydrofuran (THF) that contains 2% water.
Example 7:
Racemic suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid can split with being similar to example 4 working method, but the amount that adds entry reduces to 5%.Gained is suitable in the example 4 to 7 of productive rate and the corresponding ethyl half ester of fractionation.
(4S, 5R)-suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, (a)
365 25=+39 °
(4R, 5S)-suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole-4-carboxylic acid, (a)
365 25=+67 °
Example 8:
Repeat the operation in the example 7, but replace ethanol with the Virahol that contains 3% water.The gained productive rate is suitable with example 7.
Example 9:
Repeat the operation of example 7, but replace ethanol with the tetrahydrofuran (THF) that contains 1% water, yield level is identical with example 7.
Example 10:
Repeat the operation of example 7, but replace ethanol to contain 2% water, its productive rate can be suitable with example 7.
Example 11:
With 177.8 gram racemic cis-1,3-dibenzyl-5-carbobenzoxy-(Cbz)-2-oxo-imidazole alkane-4-carboxylic acid is (from suitable-1,3-dibenzyl-six hydrogen-1H-furo (3,4-d)-imidazoles-2,4,6-triketone and phenylcarbinol make with example 1a method) and 117.8 gram (+)-dehydroabietylamines be dissolved in 800 milliliters of toluene, make it 0 ℃ of crystallization after adding 40 ml waters.138.6 grams (95% yield) (4R, 5S)-suitable-1,3-dibenzyl-5-carbobenzoxy-(Cbz)-2-oxo-imidazole alkane-4-carboxylic acid, (a)
365 25=+45.2 °, optical purity 99%.
Mother liquid evaporation is extremely done.Resistates is handled and crystallization at room temperature with methyl tertiary butyl ether, 135.8 grams (theoretical value 93%) (4S, 5R)-suitable-1,3-dibenzyl-5-benzyloxy carboxyl-2-oxo-imidazole alkane-4-carbonyl acid, (a)
365 25=+54.2 °, optical purity: 〉=99%.
Example 12:
A) 23.3 gram (4S, 5R)-suitable-1, the dehydroabietylamine salt suspension of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid is in 200 ml waters and 200 milliliters of ethyl acetate, under agitation add 35 milliliters of 2N sulphuric acid solns, filter, get 12.18 gram (90.6% yield) (+)-dehydroabietylamine hydrosulfates.The organic layer of filtrate is told, washing, drying is removed and to be desolvated, residue is with the diisopropyl ether crystallization, 12.7 grams (94.8% yield) (4S, 5R)-suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid; (a)
365 25=-23.8 °.
B) 12.18 (+) dehydroabietylamine hydrosulfates that restrain with example 12a gained are suspended in 200 ml waters, adding strong caustic makes this suspension be adjusted to PH12, with twice of each 100 milliliters of methylbenzene extraction, extracting solution merges, after washing, the drying, be evaporated to (+)-dehydroabietylamine of dried 8.9 grams (88.9% yield), this material can be reused the fractionation in racemic mixture.
Example 13:
The operating performance of application example 12 can obtain:
(4S, 5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid: (a)
365 25=-12.75 °
(4R, 5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid: (a)
365 25=+18.2 °.
Example 14:
With the optical activity of gained in the example 12 suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, be reduced to corresponding optical activity 1 with lithium borohydride, 3-dibenzyl-tetrahydrochysene-4H-furo (3,4-d) imidazoles-2,4 (1H)-diketone, working method is reported similar to people such as Gerecke: Helv, Chim, Acta53 (1970) 991-999
(3aS, 6aR)-productive rate of 1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d]-imidazoles-2,4-(1H)-diketone is 88.5%, 119.4 ℃ of fusing points; (a)
365 25=+240.6 °.According to German Patent 2,058,234 or German Patent 2,331,244, this lactone can be converted into D-(+)-vitamin H.
Example 15;
With the method for example 14, can with enantiotopic suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-5-carboxylic acid reduces with lithium borohydride, obtains:
(3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo (3,4-d)-imidazoles-2,4-(1H)-diketone; Yield 9 7.4%, (a)
365 25=+208 °
(3aR, 6aS)-1,3-dibenzyl-tetrahydrochysene-4H-furo (3,4-d)-imidazoles-2,4-(1H)-diketone, quantitative yield, (a)
365 25=-206 °
Example 16:
4 gram sodium borohydrides are suspended in 250 milliliters of tetrahydrofuran (THF)s and are heated to backflow, then with the 60.8 (4S that restrain, 5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (+)-westvaco rosin amine salt is (with example 1b, 2,3 or 4 narration methods make) solution in 150 milliliters of tetrahydrofuran (THF)s was added drop-wise in the suspension of above-mentioned sodium borohydride in 4 hours, finishes, with this reaction solution stirring and refluxing 1 hour.
Reactant is cooled to 20 ℃, is added drop-wise in the reactant with 300 milliliters of 3N sulphuric acid solns and decomposes.Under reduced pressure boil off most of solvent, the gained sedimentation and filtration washes with water.
Add ethanol in the filtrate and heating makes its dissolving, the cooling post crystallization is separated out, filter, washing with alcohol, 27.3 grams (93% yield) (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo (3,4-d)-imidazoles-2,4-(1H)-diketone; 119 ℃ of fusing points, (a)
25 365=+208.7 ° (C=1, benzene).
Mother liquor is concentrated into dried, handles recyclable 33.1 gram dehydroabietylamine sulfur hydrogen salts with methylene dichloride.
Example 17:
33.4 gram (4R, 5S)-1, (+) westvaco rosin amine salt of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid is (with example 1b, 2,4,5 or 6 methods preparations) solution under agitation slowly is added drop-wise in 170 milliliters 0.15 mole the diborane tetrahydrofuran solution in 0 ℃.Finish, continue to stir 5 hours at 0 ℃, decompose with dilution heat of sulfuric acid then, working method is similar to example 16.14.6 grams (91% yield) (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo (3,4-d) imidazoles-2,4-(1H)-diketone; Fusing point: 118.8 °, (a)
365 25=+206.4 ° (C=1, benzene)
Example 18
Method with example 16, with d-1-phenyl-2-to toluene ethamine with (4S, 5R)-1,3, the salt that-dibenzyl carbonyl-2-oxo-imidazole alkane-4-carboxylic acid became (by European publication specification sheets 92,194 described method preparations) is used sodium borohydride reduction in tetrahydrofuran (THF).89% yield (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo (3,4-d) imidazoles-2,4 (1H)-diketone.
This lactone compound can be by German Patent 2,058, and 234 or 2,331,244 described methods are converted into D-(+)-vitamin H.
Example 19:
With the method that is similar to example 17, in tetrahydrofuran (THF) with diborane with (4R, 5S)-1, d-1-the phenyl-2 of 3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid-toluene ethylamine salt (preparing with European publication specification sheets 92,194 described methods) is reduced can get (the 3aS of 92% yield, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo (3,4-d) imidazoles-2,4-(1H)-diketone.
Claims (5)
- By the preparation of 1,3-dibenzyl-5-alkoxy carbonyl-2-oxo-imidazole alkane-4-carboxylic acid (3aS, 6aR) or (3aR, 6aS) ,-1,3-dibenzyl, six hydrogen-1H-furo (3,4-d) imidazoles-2, the method of 4-diketone is characterized in that: with formula Ia/b1 of representative, 3-dibenzyl-5-alkoxy carbonyl-2-oxo-imidazole alkane-4-carboxylic acid, wherein, R is for containing the alkyl of 1-6 carbon atoms, the alkoxyalkyl that contains 2-8 carbon atoms, the cycloalkyl that contains 3-5 carbon atoms, the alkenyl that contains 2-6 carbon atoms, benzyl or 1-or 2-phenylethyl, BZL is a benzyl, with be selected from (+) dehydroabietylamine and the d-1-phenyl-2-diastereomeric salt of the optically active amines institute form of toluene ethamine and ephedrine is reduced with the borohydride reduction agent, decompose with mineral acid then.
- 2. the method according to claim 1 prepares (3aS, 6aR)-1,3-dibenzyl, six hydrogen-1H-furo (3,4-d) imidazoles-2, the method of 4-diketone, it is characterized in that: with sodium borohydride reduction (4S, 5R)-1,3-dibenzyl-5-methoxy or-5-ethoxy or-(+) westvaco rosin amine salt of 5-benzyloxy-carbonyl-2-oxo-imidazole alkane-4-carboxylic acid.
- 3. the method according to claim 1 prepares (3aS, 6aR)-1,3-dibenzyl, six hydrogen-1H-furo (3,4-d) imidazoles-2, the method of 4-diketone, it is characterized in that: with diborane reduction (4R, 5S)-1,3-dibenzyl-5-methoxy-or-5-ethoxy-or-(+) westvaco rosin amine salt of 5-benzyloxy-carbonyl-2-oxo-imidazole alkane-4-carboxylic acid.
- 4. according to the method for claim 1, it is characterized in that: (+) dehydroabietylamine amount that is used to form paired diastereomeric salt is for to add 0.5 to 1 mole to every mole of racemoid that will split.
- 5. according to the method for claim 4, it is characterized in that: (+) dehydroabietylamine amount that is used to form paired diastereomeric salt is for to add 0.5 to 0.7 mole to every mole of racemoid that will split.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85106365 CN1031461C (en) | 1985-08-24 | 1985-08-24 | Resolution process of racemic semi-ester |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85106365 CN1031461C (en) | 1985-08-24 | 1985-08-24 | Resolution process of racemic semi-ester |
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| CN85106365A CN85106365A (en) | 1987-03-18 |
| CN1031461C true CN1031461C (en) | 1996-04-03 |
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| CN110804062B (en) * | 2019-11-06 | 2021-03-30 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
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