IE58625B1 - Process for preparing (3aS, 6aR) - and/or (3aR, 6aS)-1,3-dibenzylhexadydro-1h-furo[3,4-d]-imidazole-2,4-dione - Google Patents
Process for preparing (3aS, 6aR) - and/or (3aR, 6aS)-1,3-dibenzylhexadydro-1h-furo[3,4-d]-imidazole-2,4-dioneInfo
- Publication number
- IE58625B1 IE58625B1 IE208685A IE208685A IE58625B1 IE 58625 B1 IE58625 B1 IE 58625B1 IE 208685 A IE208685 A IE 208685A IE 208685 A IE208685 A IE 208685A IE 58625 B1 IE58625 B1 IE 58625B1
- Authority
- IE
- Ireland
- Prior art keywords
- dibenzyl
- acid
- optically active
- dione
- preparing
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
1. (+)-Dehydroabietylamine salts of (4S, 5R)- and (4R, 5S)-cis-1,3-dibenzyl-5-alkyloxycarbonyl- 2-oxo-imidazolidine-4-carboxylic acid, in which -alkyl- is alkyl having 1 to 6 C atoms, alkoxyalkyl having 2 to 8 C atoms, cycloalkyl having 3 to 5 C atoms, alkenyl having 2 to 6 C atoms, benzyl or 1- or 2-phenylethyl.
Description
The invention relates to a new process for preparing (3aS,6aR)and/or (3aR,6aS)-1,3-d i benzy1 hexahydro-1H-furo[3 ,4-d]-i mi dazo le-2z4-di one from 1z3-dibenzyl-5-alkoxycarbonyl-2-oxoimidazolidine-4-carboxylic aci dsz which is characterised in that a di astereoisomeric salt formed between an optically active amine and an optically active 1z3-dibenzyl5-a I koxycarbony l-2-oxoimidazoIidine-4-carboxy I ic acid is reduced.
(4SZ 5R)-1z3-dibenzyl-5-alkyloxycarbonyl-2-oxo10 imidazolidine-4-carboxylic acids are useful intermediates for preparing <3aSz 6aR)-1z3-dibenzy lt et rahy d ro-4H-f uro C3z4-d3-i midazole-2z4dH)-dionez a key product for the preparation of (+)-biotin.
The two enantiomers of cis-1,3-dibenzyl-515 alkoxycarbonyl-2-oxoimidazolidine-4-carboxylic acids have the formula Ia/b la lb
BZL-NXN-8Zl ηΛ-4-η
BZL-N^N-SZL h4—r-H
ROOC COOH HOOC COOR in which
BZL is alkyl having 1 to 6 C atoms, alkoxyalkyl having 2 to 8 C atoms, cycloalkyl having 3 to 5 C atoms, alkenyl having 2 to 6 C atoms, benzyl or 1- or 2-phenylethyl, is benzyl.
of the previously disclosed process for optically resolving racemic half-esters of th-e formula Ia/bz German Patent 2z058z234 describes the preparation of cyclohexyl half-esters and the separation of the resulting diastereoisomeric (+)-ephedrinium salts by fractional crystalli30 sation and the preparation of diastereoisomeric cholesterine half-esters and the separation of the triethylammonium salts obtained therefrom, by fractional crystallisation. However, the yields obtained with these processes are below 50% of theoretically obtainable pure isomers. The chiral auxiliary cholesterol, moreover, has the disadvantage of being very costly and, what is more, cannot be completely recovered.
European Offen legungsschrift 0,092,194 describes the optical resolution of the racemic methyl and ethyl half-esters by formation of the pairs of diastereoisomeric salts with an optically active 1,2-diphenyl ethylamine and their separation by crystallisation. A further method described is the spontaneous crystallisation of an enantiomer from the supersaturated solution of the racemate by seeding with the desired enantiomer. These methods likewise have the disadvantage of a low separating yield, which is only about 30% of theory. It is therefore the object of the present application to provide a process for the optical resolution of half-esters of the formula Ia/b, which permits their separation in high yield using an inexpensive resolving reagent.
It has now been found, surprisingly, that racemates of the formula Ia/b can be resolved into the enantiomers in high yields and great selectivity by means of ( + )25 dehydroabietylamine.
The invention accordingly provides the new ( + )dehydroabietylamine salts of (4S, 5R)- and (4R,. 5S)-cis1,3-dibenzyl-5-alkyloxycarbonyl-2-oxo-imidazolidine-4carboxylic acids, in which -alkyl- is alkyl having 1 to 6
C atoms, alkoxyalkyl having 2 to 8 C atoms, cycloalkyl having 3 to 5 C atoms, alkenyl having 2 to 6 C atoms, benzyl or 1- or 2-pheny lethyI.
Racemic half-esters are separated by standard methods which are known per se for the optical, resolution of racemates (for example
8.P.H. Boylez Quart.Rev. 25 (1971) 323 - 341). Racemates can be separated by chromatography on chirale phases, by seeding of supersaturated solutions or by mechanical sorting A further separating method consists in the formation, separation or decomposition of di astereoisomers. A preferred method is the separation of diastereoisomeric pairs of salts. A particularly preferred method for resolving the racemates of the formula Ia/b consists in dissolving the racemates together with a certain amount of (+)-dehydroabietylamine in a suitable organic solvent and subsequently recrystallising the (+)-dehydroabietylamine salt of an en15 antiomer. After the latter has been separated off by filtration or centrifugationz removal of the solvent from the remaining solution and if desired crystallisation of the residue produces the other enantiomer.
The amount of (+)-dehydroabietylamine used is 0.5 to 1 molz preferably 0.5 to 0.7 molz relative to 1 mol of racemate to be resolved. The solvent for the separation can be water or an inert organic solvent, preferably a watei—;mi sci bl e so Ivent, in particular an alcohol such as methanol, ethanol, isopropanol, n-butanol or tert.-butanol, an ether such as tetrahydrofuran, dioxane, ethylene glycol monomethyl or monoethyl ether (methy Ig lyco I.or ethy I g lyco I), ethylene glycol dimethyl ether (diglyme), a ketone such as acetone, butanon or isobutyl methyl ketone, a nitrile such as acetonitrile, or a nitro compound such as nitromethane.
Preferred solvents are alcohols, ketones and ethers, particularly preferably methanol, ethanol, isopropanol, acetone or tetrahydrofuran.
Also suitable are mixtures between these solvents. Preference is given to mixtures of these solvents with water in proportions of 0.5 to 50%, in particular 0.5 to 10% and particularly preferably 1 to 5%.
The temperatures used in carrying out this process are preferably between -20°C and the boiling point of the solvent used, but are advantageously below the crystallisation temperature of the pair of enantiomeric salts to be crystallised.
The optical resolution using . this process is particularly preferred for compounds of the formula Ia/b in which R is methyl or ethyl.
In a further preferred embodiment of this process, the diastereoisomeric mixture of pairs of salts is subjected to fractional crystallisation. For this purpose, the racemate of the halfesters of the formula Ia/b is first completely converted with the equivalent amount of (+)-dehydroabietylamine into the mixture of diastereoisomeric pairs of salts. The reaction of the racemic half-esters with the optically active amine is effected in the absence of solvent or in solution in an organic solvent, preferably in an apolar solvent, in particular chlorinated hydrocarbons such as methylene chloride, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride or hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene. Also suitable are mixtures between these solvents.
The salts isolated after removal of the solvent are crystallised for optical resolution in the solvents described above for separating the racemic half-esters.
this of embodi ment process process halfExamples of preferred consists in the optical resolution of the ( + )dehydroabietylamine salts of cis-1,3-dibenzyl-5-methoxycarbonyI-2-oxoimidazoIidine-4-carboxyIic acid and cis-1,3dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid.
The (+)-dehydroabietylamine salts of the optically active half-esters Ia or lb obtained by this can be converted back into the free ester acids by treatment with an acid or base, suitable bases are alkali metal and alkaline earth metal hydroxides, carbonates or bi carbonates , ammonia and strong organic bases. Preferred bases are alkali metal hydroxides and ammonia, in particular potassium hydroxide and sodium hydroxide.
Suitable acids are strong organic acids, for example formic acid or acetic acid, and inorganic acids, for example phosphoric acid, or nitric acid, preferably mineral acids such as hydrochloric acid or hydrobromic acid. Particular preference is given to sulphuric acid with which <+)-dehydroabietylamine forms a sparingly soluble hydrogensulphate which crystallises readily and is filtered off easily, thereby permitting recovery of the resolving agent in high yield.
The generally preferred agents for liberating the optically active half-esters of the formula Ia/b from their dehydroabietylamine salts are acids, since the half-esters have reduced stability to bases.
The amount of acid used can be varied within wide limits, but is at least 1 mol, preferably 1 to 1.5 mol, per mol of pair of diastereoisometric salts to be cleaved.
The half-ester is liberated by addition of the acid to a solution of the diastereoisomeric pair in a suitable solvent, preferably water. The liberated half-ester can then be extracted with an organic solvent, such as, for example, diethyl ether, toluene, ethyl acetate, dichloromethane or mixtures thereof. If desired after the extract has been washed the solvent is removed, leaving the desired optically active half-ester.
To recover the ( + )-dehydroabiety lamine used as a resolving reagent, the amine can be set free after alkalisation of the extracted solution by addition of a strong base, such as, for example, ammonia, sodium hydroxide solution or potassium hydroxide solution, and then be extracted in a manner analogous to that described for the isolation of the optically active half-ester. If sulphuric acid, referred to as particularly preferable, is used to decompose the pair of diastereoisomeric salts the ( + )dehydroabiety lamine is obtained in the form of the sparingly soluble hydrogensuIphate. After the latter has been separated off by filtration or centrifugation the free base can be obtained in the abovementioned manner by addition of strong hydroxide solutions and subsequent extraction.
The preparation of the racemic half-esters of the formula Ia/b which are required as starting material from, for example, cis-1,3-dibenzyl-2-oxoimidazolidine-4,5dicarboxylic anhydride is known for example from German Patent 2,058,234 or European Offenlegungsschrift 0,092,194 and is effected by reaction with the corresponding alcohol in an inert organic solvent, such as, for example, benzene, toluene or xylene, preferably at elevated temperature.
The optically active cis-1,3-dibenzyl-5-aIkyloxycarbony l-2-oxoimi dazo li di ne-4-ca rboxy lie acids thus obtained can be reduced to the optically active 1,3-di benzyI-tet rahydro-4H-furoC3,4-d3 imidazole-2,4 (1H)-dione using the method described for example in Gerecke et al. Helv.Chim.Acta 53 (1970) 991-999. This reduction can start from the free optically active halfester. However, it is similarly possible to use its diastereoisomeric (+)-dehydroabietylamine salt as the starting material for the reduction. A process of this kind offers particular advantages.
German Patent 2,058,248 already discloses a process for preparing (3aS,6aR)-lactone, in which cholesteryl and cycLohexyl half-esters of cis-1,3-dibenzyl-2-oxoimidazo I idine-4,5-dicarboxy I ic acid are separated into their enantiomers and the corresponding enantiomer is converted by reduction into the desired lactone. However, the yields obtained in this process are below 50% of theoretically obtainable pure isomers. The chiral auxiliary cholesterol is comparatively costly and cannot be completely recovered. Furthermorez in the claimed process the unwanted enantiomeric half-ester needs to be recyclised again.
An improvement to this process is known from European Offen Iegungsschrift 0,081,047. In this improvement, the carboxyl group of the unwanted half-ester is converted into the acid chloride. Subsequent reduction supplies the correct (3S,6R)-lactone. The low separation efficiency in the separation of the diastereoisomers and the high cost of the chiral auxiliaries mean that this process has no economic importance.
In German Patent 2,331,244 is to a process for preparing (3R,6S)- and (3S,6R)-lactones is claimed, in which c i s-1,3-di benzyIhexahydropyrrolo-C3,4-dTi midazole-2,4,6trione, obtained from c i s-1,3-di benzyl-2-oxoi midazolidine4,5-dicarboxylic acid and an optically active amine, is subjected to an asymmetric reduction, and the resulting amide alcohol is hydrolysed to give the desired lactone.
The disadvantages of this method are likewise the high cost of the optically active amine and the inadequate separation yield.
The diastereoisomeric separation of European Offen legungsschrift 84,892, which proceeds in high yields, likewise requires an optically active amine which is not easily accessible.
On the other hand, the salt formation of the enant i omeri c cis-1,3-dibenzyl-2-oxoimidazoli di ne-4,5dicarboxylic acids witn <+)-dehydroabietylamine represents an advantageous method for preparing the optically active half-esters of which each one can be converted into the desired optically active lactone as described, for example, in European Offenlegungsschrift 84,892.
In the above processes, the half-esters are freed before reduction from their diastereoisomeric pairs of salts formed with optically active amines by treatment with a strong acid and are isolated.
In the subsequent reduction step, which is carried out separately, first an equivalent of reducing agent is consumed for the reaction with the acidic hydrogen of the carboxyl group of the *ree half-ester and hence is lost to the reduction.
It was therefore the object to find a process for preparing optically active 1,3-dibenzyltetrahydro-4H-furoC3,4-dlimidazole-2,4-diones by reduction of corresponding cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid half-esters which permits better utilisation of the reducing agents combined with simplified procedure and the isolation of products of higher chemical and optical purity.
It has now been found, surprisingly, that diastereoisomeric salts between an optically active amine and an optically active 1,3-dibenzyl-5-aIkoxycarbonyl-2-oxoimidazoli-dine-4-carboxylic acid can be reduced in high chemical and optical yields without interference from the amine component.
The invention thus also provides a process for preparing (3aS,6aR)- and/or (3aR,6aS)-1,3-dibenzylhexahydro-1H-furoC3,4-d]imidazole-2,4-dione from 1,3-dibenzyl5-aIkoxycarbonyl-2-oxoi midazolidi ne-4-ca rboxylie acids, characterised in that a diastereoisomeric salt formed between an optically active amine and an optically active
1,3-dibenzyl-5-aIkoxycarbonyl-2-oxoi mi dazolidi ne-4-ca rboxylic acid is reduced.
The invention further relates to the use of an optically active 1,3-dibenzylhexahydro-1H-furoC3,4-d]imidazole-2,4-dione obtained by the process according to the invention, for preparing D-(+)-biotin.
The method used in the invention for reducing the diastereoisomeric salts of the optically active halfesters is in accordance with the methods known per se for reducing the free half-esters.
Depending on the choice of reducing agent, it is possible to obtain from salts in which the half-ester has a 4SZ5R- or 4R,5S-configuration not only the (3aR,6aS)but also the (3aS,6aR)-lactone.
If, for example, a salt of a 4S,5R-half-ester is reduced a.t the carboxyl group, the product is the 3aR,6aSlactone, while if the a Ikoxycarbony I group is reduced, a 3aS,6aR-lactone is obtained. The 4R,5S-half-ester is subject to the converse relationships.
Examples of reducing agents suitable for reducing the acid group are boron hydrides, such as diborane.
Suitable solvents are organic solvents which are inert towards the reducing agent, such as, for example, hydrocarbons such as benzene or toluene and ethers such as diethyl ether, ethylene glycol dialkyl ether, diethylene glycol dialkyl ether, tetrahydrofuran or dioxane. Particular preference is given to cyclic ethers such as tetrahydrofuran and dioxane. It is also possible to use mixtures of these solvents.
The temperature during the reduction is advantageously between -20 and +40°, preferably -10 to +30°, in particular between 0 and +20°. The amount of hydride used is between 0.8 and 3 equivalents of the theoretically required amount, preferably between 1 and 2 equivalents and in particular between 1 and 1.5 equivalents. For instance, the preferred amount in the case of diborane being used is 0.5 to 0.75 mol of B2H6 Per mo1· halfester salt.
Diborane can be used as such in the reduction, but it can also be prepared in situ by known methods, for example from NaBH^ and a Lewis acid such as boron trifluoride or its diethyl ether adduct, this in situ preparation being preferably carried out insolvents suitable for the reduction of the half-ester salts, so that the resulting solution of diborane can also be used as reaction medium for the subsequent reduction.
Examples of reducing agents suitable for reducing the aIkoxycarbony I group are complex boron hydrides, such
1 as lithium borohydride, sodium borohydride or calcium borohydride, and aluminium hydrides such as diisobutylaluminium hydride and diethylaluminium sodium hydride.
The reduction preferably takes place in a solvent which is inert towards the reducing agents under the reaction conditions and in which the reactants are at least partially soluble.
Examples of suitable solvents for reducing agents which can be used in an aqueous medium, such as sodium borohydride, are water, alcohols such as methanol, ethanol, isopropanol, ethylene glycol or diethylene glycol, and ethers such as tetrahydrofuran or dioxane. It is also possible to use mixtures of these solvents with one another or with water-immiscible solvents.
Suitable solvents for ‘reducing agents which react with water are not only ethers such as diethyl ether, ethylene glycol dialkyl ethers, diethylene glycol dialkyl ethers, tetrahydrofuran or dioxane, but also in particular hydrocarbons such as benzene and toluene. It is also possible to use mixtures of these solvents.
The reaction temperatures are between -70 and +100°. Aluminium-containing reducing agents are preferably used at -70 to +30°, in particular at -40 to +30°. Boron-containing reducing agents are preferably used at -10 to 100°z in particular between 0° and 80°.
The amount of reducing agent used is between 0.8 and 3 equivalents of the theoretically required amount, in particular between 1 and 2 equivalents and preferably between 1 and 1.5 equivalents. For instance, the preferred amount if sodium borohydride is used is 0.75 to 1.125 mol of NaBH^ per mol of half-ester salt.
In the diastereoisomeric 1,3-dibenzyl-5-aIkoxycarbony l-2-oxoi mi dazo li di ne-4-ca rboxy I i c acid salts used as starting materials -a IkoxycarbonyI- is to be understood as meaning -aIkyloxycarbonyI- having 1 to 6 C atoms, -aIkoxyaIkoxycarbonyI- having 2 to 8 C atoms,
-aIkenyloxy-carbonyI- having 2 to ό C atoms, -benzyloxycarbonyl- or 1- or 2-phenylethoxycarbony1-.
2
The reduction according to the process according to the invention is particularly preferably carried out using the salts of 1,3-dibenzyl-5-methoxy-, -5-ethoxy- and -5-benzyloxy-carbonyl-2-oxoimidazolidine-4-carboxyli c acids with optically active amines.
Suitable optically active amine salt components are all optically active amines suitable for separating the racemic half-estersz such as, for example, ephedrine as claimed in German Patent 2,058,248, the 1,2-diphenylethanamines mentioned in European Offenlegungsschrift 92,194 and in particular (+)-dehydroabietylamine. The use of di astereoisomeric ( + )-dehydroabietylamine salts constitutes a preferred embodiment of the process according to the invention.
The process is simple to carry out. The diastereoisomeric salts to be used as starting material are known or can be prepared by methods known per se, as indicated, for example, in European 0ffenlegungsschrift92,194. The reaction is carried out by mixing the components and heating or cooling the stirred reaction mixture to the temperature required for reaction, although it can be advantageous to add the diastereoisomeric salt, if desired in solution in a suitable solvent, gradually to the previously presented reducing agent. The reaction times are 0.5 to 40 hours, preferably 1 to 8 hours.
After the reaction has been carried out, the reaction mixture is acidified by addition of an acid, for example a mineral acid such as hydrochloric acid or sulphuric acid, and the reduction product is extracted in the form of the optically active lactone with a suitable solvent, such as, for example, diethyl ether, ethyl acetate, dich loromethane, chloroform or toluene.
After removal of the solvent used for the extraction, the desired lactone is usually left behind in the form of very pure crystals. If necessary it can be purified further by chromatography or crystallisation.
To recover the optically active amine, the amine can be freed by bringing the extracted solution to an
3 alkaline pH through the addition of a strong acid such as, for example, ammonia, sodium hydroxide solution or potassium hydroxide solution and can then be extracted analogously to the method described for the isolation of the optically active lactone.
Optically active (3aS, 6aR)-1,3-dibenzyl-tetrahydro-4H-furoC3,4-d]imidazole-2,4-(1H)-di one can be converted to D-(+)-biotin in known manner as described for example in German Patent 2,058,234 or German Patent 2,331,244
The present i n vent i on therefore provides a very advantageous process for a simple, economical way of reducing diastereoisomeric salts between an optically active amine and an optically active 1,3-dibenzyl-5-aIkoxycarbonyl-2-oxoimidazo I idine-4-carboxyIic acid to give optically active 1,3-dibenzylhexahydro-1H-furoC3,4-d3iraidazole-2,4-diones in high chemical and optical purity and hence for the preparation of D-( + )-biotin.
Example 1:
a) A suspension of 250 g <0.743 mol) of cis-1,320 dibenzyI-hexahydro-1H-furoC3,4-d] imidazole-2,4,6trione in 59.7 g <1.283 mol) of ethanol and 2 litres of benzene is refluxed for 2 hours, is then concentrated and is allowed to crystaLlise.
Yield: 256 g <90% of theory) of cis-1,3-dibenzyl25 2-oxoimidazolidine-5-ethoxycarbonyl-4-carboxylic acid; melting point 93°.
b) 57.4 g <0.15 mol) of racemic cis-1,3-dibenzy 1-5ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and 42.8 g (0.15 mol) of ( + )-dehydroabietyl30 amine are dissolved in 3«’5 ml of tetrahydrofuran, and 7.5 ml of water are added at room temperature. Lowering the temperature to -7° leads to the crystallisation of 47.7 g (95% of theory) of the dehydroabietylamine salt of <4R, 5S)-cis,1,31 1 di benzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4carboxylic acid; 0X3^^ = +47.1°. The addition of 400 ml of water or 500 ml of hexane to the mother
Liquor leads to the crysta11isaton of 49.8 g (98% of theory) of the dehydroabietylamine salt of (4SZ 5R)-ci s-1z3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazoIidine-4-carboxyIic acid; = +61-24°.
365
Example 2:
Equivalent amounts of racemic cis-1z3-dibenzy1-5ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and (+)-dehydroabiety lamine are dissolved in ethanol (4 to 5 litres per mol)z and, after the addition of 10% of water, are allowed to crystallise at -10°. The yield of dehydroabietylamine salt of (4RZ 5S)-cis-1z3-dibenzyl-5ethoxycarbonyl-2-oxoimidazoIidine-4-carboxyIic acid is 89% of theory; =
The mother liquor is reduced to about 2/3 of its volume and is diluted with the same amount of water, whereupon 92% of theory of dehydroabietylamine salt of <4SZ 5R)-cis-1z3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid can be isolated; = 63.6°.
On evaporation of the second mother liquor and treatment of the residue with 100 ml of diisopropyl ether a conglomerate of the diastereoisomeric (+)-dehydroabietylamine salts of (4RZ 5S)- and (4SZ 5R)-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazoIidine-4-carboxyIic acid is obtained in 9% of theory and can be used again for separating purposes .
Example 3;
A solution of 26.8 g (0.07 mol) of racemic cis-1z3dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and 20 g (0.07 mol) of ¢+)-dehydroabietylamine in ml of methylene chloride is evaporated to dryness.
Crystallisation from diisopropyl ether gives 45.6 t, (97.5% of theory) of a pair of diastereoisomeric ethyl half-ester acid dehydroabietylamine salts; 1X3 = +54.9°.
365
Example 4:
The separation of the mixture of the diastereoiso1 5 meric <+)-dehydroabietylamine salts of cis-1,3-dibenzyl5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxyli c acid obtained in Example 3 is possible by crystallisation from ethanol containing 10% of water.
The first salt to crystallise out has the (4R, 5S)configuration; 3^5+ 46.2°.
The mother liquor of the 1sl crystallisation gives on addition of water (about 50% relative to the volume of the organic solvents), diisopropyl ether or petroleum ether the crystallised salt having the (4S, 5R)-configuration;
CV:l365= + 63·6°·
Example 5:
The procedure described in Example 4 is repeated, except that ethanol is replaced by isopropanol containing 5% of water, affording an amount of the pair of <4RZ 5S)diastereoisomeric salts which corresponds to that obtained in Example 4.
Example 6:
The procedure described in Example 4 is repeated, except that ethanol is replaced by tetrahydrofuran containing 2% of water, affording a yield which corresponds to that obtained in Example 4.
Example 7;
The racemic cis-1,3-dibenzyl-5-methoxycarbony1-2oxoimidazolidine-4-carboxylic acids are separated analogously to Example 4, except that the amount of added water is reduced to 5%. The yields correspond to the yields obtained in Examples 4 to 7 for the separation of the corresponding ethyl half-esters.
(4S, 5R)-cis,1,3-dibenzyl-5-· methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid: = +39°.
(4R, 5S)-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazoIidine-4-carboxylic acid: 0x0^5 = +570 365
Example 8:
The procedure described in Example 7 is repeated, except that ethanol is replaced by isopropanol containing 3% of water, affording a yield which is comparable to that obtained in Example 7.
6
Example 9:
The procedure described in Example 7 is repeated, except that ethanol is replaced by tetrahydrofuran containing 1% of water, affording a yield on the same level as that obtained in Example 7.
Example 10:
The procedure described in Example 7 is repeated, except that ethanol is replaced by acetone containing 2% of water, affording a yield which is comparable to that obtained in Example 7.
Example 11:
177.8 g of racemic cis-1, 3-dibenzy1-5-benzy1 οxycarbοny1-2oxoimidazolidine-4-carboxy1ic acid (obtainable from cis-1,3dibenzyl-hexahydro-ΙΗ - f ur o_/3,4 — cJ / imidazole-2,4,6-trione and benzyl alcohol by repeating the procedure described in Example la) and 117.8 g of ( +)-Dehydroabietylamin are dissolved in 800 ml of toluene, and, after the addition of 40 ml of water, are allowed to crystallise at 0°. The yield of (4R,5S)-cis-1,3-dibenzy1-5-benzyloxycarbony1-220 oxoimidazolidine-4-carboxylic acid is 138.6 g (95% of theory); _/O4/25 = + 45.2°; optical purity: 99 %.
The mother liquor is evaporated to dryness. Treatment of the residue with 600 ml methyl tert. butylether and crystallisation a ambient temperature affords 135.8 g (93 % of theory) (4S,5R)25 cis-l,3-dibenzyl-5-benzyloxycarbonyl-2-oxoimidazolidine-4carboxylic acid; _/o£/2 5 = +54.2°; optical purity: — 99 %.
365
Example 12
a) 35 ml of 2N sulphuric acid are added with stirring to a suspension of 23.3 g of the dehydroabiety lamine salt of (4S, 5R)-cis1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxyIic acid in 200 ml of water and 200 ml of ethyl acetate. Filtration gives 12.18 g (90.6% of theory) of ( + )dehydroabietylamine hydrogen sulphate. In the filtrate, the organic phase is separated off and is washed with water. Drying, removal of the solvent and crystallisation from diisopropyl ether leaves
12.7 g (94.8% of theory) of (4S, 5R)-cis-1,3-dibenzyl5-ethoxycarbonyl-2-oxoimi dazoIi di ne-4-carboxyIi c acid; - -23.8°.
b) The 12.18 g of (+)-dehydroabietylamine hydrogen sulphate obtained in Example 12a are suspended in 200 ml of water, and the suspension is brought to pH 12 by addition of concentrated sodium hydroxide solution. The suspension is extracted twicewith 100 ml of toluene each time. Washing and drying of the combined extracts and evaporation to dryness gives 8.9 g (88.9% of theory) of (+)-dehydroabietylamine which is suitable for renewed resolution of racemate.
Example 1^:
The procedure of Example 12 is used to obtain:
(4S, 5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoi mi dazo li di ne-4-ca rboxy I i c acid: 0*325 _ .p 750 365 (4R, 5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoi mi dazo li di ne-4-ca rboxy I i c acid: C*2A = +18.2°.
Example 14:
The reduction of the optically active c i s-1,3dibenzyl-5-ethoxycarbonyl-2-oxoimidazo dine-4-carboxylic acids obtained in Example 12 to the corresponding optically active 1,3-dibenzyl-trahydro-4H-furoC3,4-d]imidazole-2,40H)-diones with lithium borohydride is carried out analogously to the method described by Gerecke et al., Helv. Chim.Acta 53 (1970) 991-999.
Yield of (3aS,6aR)-1,3-dibenzyl-tetrahydro-4HfuroC3,4-d]imi dazole-2,4(1H)-dione 88.5% of theory;
melting point 119.4°; OX]25,.= +240.6°. This lactone
65 can be converted in accordance with German Patent 2,058,234 or German Patent 2,331,244 into D-(+)-biotin.
Example 15 :
The method described in Example 14 is used to reduce the enantiomeric cis-1,3-dibenzyl-5-methoxycarbonyl2-oxoimidazolidine-5-carboxylic acid with lithium borohydride, affording:
(3aS, 6aR)-1,3-dibenzyl-tetrahydro-4H-furo C3,4-d3imidazole-2,4(1H)-di one; 97.4% of theory; '-cx^365 = +208° and (3aR, 6aS)-1,3-dibenzyl-tetrahydro-4H-furoC3,4-dlimidazoIidine-2,4(1H)-di one; yield quantitative;
^ 365= -206°·
Example 16 g of sodium borohydride are presented in 250 ml of tetrahydrofuran, and the suspension is heated to the reflux point. A solution of 60.8 g of (4S,5R)-1,3-dibenzyl
-ethoxycarbonyl-2-oxoimidazoline-4-carboxylic acid (+)dehydroabietylamine salt (obtained as described in Example 1b, 2, 3 or 4) in 150 ml of tetrahydrofuran is added dropwise to the NaBH^ suspension in the course of 4 hours, and the mixture is then stirred for 1 hour with further refluxing.
This is followed by cooling down to 20° and decomposition by dropwise addition of 300 ml of 3 N sulphuric acid.
9
The solvent is largely taken off under reduced pressure, and the resulting precipitate is filtered off with suction and washed with water.
The filter residue is taken up in ethanol and is dissolved by heating. Cooling is accompanied by crystallisation. Filtration and washing with ethanol gives 27.3 g (93% of theory) of (3aS, 6aR)-1,3-dibenzyItetrahydro-4H-furo C3^4-d3 imidazole-2,4(1H)-dione; melting point 119°, IX3365 = +208.7° (c = 1, benzene).
33.1 g of dehydroabietylamine hydrogen sulphate are recovered from the mother liquor by evaporating to dryness and treating with dich loromethane .
Example 17
A solution of 33.4 g of the (+)-dehydroabietylamine salt of (4R,5S)-1,3-dibenzyl-5-ethoxycarbony1-2oxoimidazolidi ne-4-ca rboxylic acid (prepared as described Example 1b, 2, 4, 5 or 6) is gradually added dropwise at 0° with stirring to 170 ml of 0.15 M diborane solution in tetrahydrofuran. After the addition is complete, stirring is continued at this temperature for a further 5 hours, which is followed by decomposition with dilute sulphuric acid and working up, both operations being carried out analogously to Example 16. This gives 14.6 g (91% of theory) of (3aS,6aR)-1,3-dibenzyltetrahydro-4HfuroC3,4-d3imidazole-2,4(1H)-di one; melting point: 118.8°, 0=k33^ +206.4° (c = 1, benzene).
Example 18
The method of Example 16 is used to reduce the d-1-phenyl-2-p-tolylethanamine salt of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-0xoimidazoline-4-carboxylic acid (prepared according to European Offenlegungsschrift 92,194) in tetrahydrofuran with sodium borohydride. This gives (3aS,6aR)-1,3-dibenzyltetrahydro-4H furoC3,4-d3imi dazole-2,4(1H)-di one in 89% of theory.
This lactone is converted in accordance with German Patent 2,058,234 or 2,331,244 into D-(+)-biotin. Example 19
A method analogous to Example 17 is used to reduce
Ο the d-1-phenyl-2-p-tolylethanamine salt of (4R,5S)-1,3dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (prepared according to European Offenlegungsschrift 92,194) in tetrahydrofuran with diborane. This gives (3aS,6aR)-1,3-dibenzyltetrahydro-4H-furoC3,4-d]imidazo le-2,4<1H)-di one in 92% of theory.
Claims (13)
1. < + )-Dehydroabiety land ne salts of (4S, 5R)- and (4R, 5S)-cis-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxoimldazo11 d1ne-4-carboxy lic acid, In which -alkyl- is 5 alkyl having 1 to 6 C atoms, alkoxyalkyl having 2 to 8 C atoms, cycloalkyl having 3 to 5 C atoms, alkenyl having 2 to 6 C atoms, benzyl br 1- or 2-phenylethyl.
2. ( + )-Dehydroabiety lamine salts of <4S, 5R)- and <4R, 5S)-ci s-1,3-di benzy1-5-methoxycarbony 1-2-oxo10 1 midazo11 d1 ne-4-carboxy11c acid.
3. <+)-DehydroabietyIamine salts of <4S, 5R)- and (4R, 5S)-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazo11 dine-4-carboxy11c acid.
4. Process for preparing (3aS, 6aR)- and/or (3aR, 15 6aS)-1,3-dibenzyl-hexahydro-lH-furo[3,4-d]-imidazole-2, 4-dione from 1,3-dibenzyl-5-alkoxycarbonyl-2-oxo-imidazolidine-4-carboxylic acids, characterized in that a diastereomeric salt formed between an optically active amine and an optically active l,3-dibenzyl-5-alkoxy20 carbonyl-2-oxoimidazole-4-carboxylic acid is reduced with complex hydrides.
5. . Process according to Claim 4 , characterised in that the d 1 astereoisomeric half-ester salt is reduced at the carboxyl group. 25
6. . Process according to Claim 4 / characterised in that the diastereOlsomeric half-ester salt is reduced at the a IkoxycarbonyI group. 2 2
7. . Process according to any one of Claims 4 to 6 , characterised In that the optically active amine Is ( + )dehydroabiety lamine.
8. -. Process for preparing (3aS z 6aR)-1 z 3-dibenzy l5 hexahydro-1H-furoC3 z 4-d]imidazole-2 z 4-dione according to any one of Claims 4 to 7, characterised In that the (+)-dehydroabietylamine salt of (4S Z 5R)-1 z 3-dibenzy1-5aethoxy- and/or -5-ethoxy- and/or -5-benzyloxy-carbony l2-oxoimldazo11 dine-4-carboxy11c acid 1s reduced with sodium 10 borohydride.
9. . Process for preparing (3a$) z 6aR)-1 z 3-dibenzy lhexahydro-lH-furoC3 z 4-d3imidazole-2 z 4-dione according to any one of Claims 4 to 7 Z characterised in that the (+)-dehydroab1etylamine salt of (4R Z 5S)-1 z 3-dibenzy 1-515 methoxy- and/or -5-ethoxy- and/or -5-benzyloxy-carbonyl2-oxoimidazolidine-4rcarboxylic acid is reduced with diborane.
10. Use of an optically active 1 z 3-d1benzyl-hexahydro1H-furoC3 z 4-d3imidazole-2 z 4-dione obtained according to 20 Claims 4 to 9, for preparing D-(+)-b1otin .
11. . A compound according to claim 1, substantially as hereinbefore described and exemplified.
12. A process according to claim 4 for preparing (3aS, 6aR)~ and/or (3aR, 6aS)-1, 3-dibenzyl-hexahydro-1H25 furo[3, 4-d]imidazole-2,4-dione, substantially as hereinbefore described and exemplified.
13. (3aS, 6aR)- and/or (3aR, 6aS)-1,3-Dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione, whenever prepared by a process claimed in a preceding claim.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843431294 DE3431294A1 (en) | 1984-08-25 | 1984-08-25 | Process for the separation of racemic hemiesters |
| DE19853522145 DE3522145A1 (en) | 1985-06-21 | 1985-06-21 | Process for the preparation of optically active lactones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE852086L IE852086L (en) | 1986-02-25 |
| IE58625B1 true IE58625B1 (en) | 1993-10-20 |
Family
ID=25824188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE208685A IE58625B1 (en) | 1984-08-25 | 1985-08-23 | Process for preparing (3aS, 6aR) - and/or (3aR, 6aS)-1,3-dibenzylhexadydro-1h-furo[3,4-d]-imidazole-2,4-dione |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0173185B1 (en) |
| JP (1) | JPH0625137B2 (en) |
| KR (1) | KR920007272B1 (en) |
| DE (1) | DE3575717D1 (en) |
| DK (1) | DK384285A (en) |
| ES (1) | ES8701166A1 (en) |
| IE (1) | IE58625B1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3541450A1 (en) * | 1985-11-23 | 1987-05-27 | Merck Patent Gmbh | METHOD FOR PRODUCING ENANTIOMERS |
| CH670644A5 (en) * | 1986-12-18 | 1989-06-30 | Lonza Ag | |
| CH671227A5 (en) * | 1986-12-02 | 1989-08-15 | Lonza Ag | |
| US5162540A (en) * | 1986-12-18 | 1992-11-10 | Lonza Ltd. | Process for the production of (+) biotin |
| FI95034C (en) * | 1989-03-15 | 1995-12-11 | Lonza Ag | Process for the preparation of 1,3-substituted tetrahydro-1H-thieno / 3,4-d / imidazole-2 (3H) -one-4-ylidene pentanoic acid ester |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD111577A5 (en) * | 1972-06-22 | 1975-02-20 | ||
| EP0081047B1 (en) * | 1981-12-07 | 1985-12-18 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Process for the preparation of an optically active lactone, and starting products for the process |
| DE3150723A1 (en) * | 1981-12-22 | 1983-06-30 | Basf Ag, 6700 Ludwigshafen | IMPROVED METHOD FOR PRODUCING 1,3-DISUBSTITUTED 4,5-CIS-DICARBOXY-2-IMIDAZOLIDONES |
| US4496739A (en) * | 1982-01-27 | 1985-01-29 | Sumitomo Chemical Company, Limited | Intermediates to optically active cis-1,3-dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4-dione |
| EP0092194B1 (en) * | 1982-04-16 | 1987-07-08 | Sumitomo Chemical Company, Limited | Method of obtaining optically active half esters |
| JPS5946282A (en) * | 1982-09-09 | 1984-03-15 | Sumitomo Chem Co Ltd | Preparation of optically active lactone |
| JPS5984888A (en) * | 1982-11-06 | 1984-05-16 | Sumitomo Chem Co Ltd | Preparation of optically active lactone |
-
1985
- 1985-08-16 DE DE8585110273T patent/DE3575717D1/en not_active Expired - Lifetime
- 1985-08-16 EP EP85110273A patent/EP0173185B1/en not_active Expired - Lifetime
- 1985-08-23 DK DK384285A patent/DK384285A/en not_active Application Discontinuation
- 1985-08-23 KR KR1019850006100A patent/KR920007272B1/en not_active IP Right Cessation
- 1985-08-23 ES ES546386A patent/ES8701166A1/en not_active Expired
- 1985-08-23 IE IE208685A patent/IE58625B1/en not_active IP Right Cessation
- 1985-08-23 JP JP60184356A patent/JPH0625137B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES546386A0 (en) | 1986-11-16 |
| JPS6157561A (en) | 1986-03-24 |
| KR920007272B1 (en) | 1992-08-29 |
| DK384285D0 (en) | 1985-08-23 |
| IE852086L (en) | 1986-02-25 |
| EP0173185B1 (en) | 1990-01-31 |
| JPH0625137B2 (en) | 1994-04-06 |
| EP0173185A1 (en) | 1986-03-05 |
| DK384285A (en) | 1986-02-26 |
| KR870002083A (en) | 1987-03-30 |
| ES8701166A1 (en) | 1986-11-16 |
| DE3575717D1 (en) | 1990-03-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2020201260B2 (en) | Process for preparing BTK inhibitors | |
| EP1772455A2 (en) | Industrial process for preparation a polmorph of clopidogrel hydrogen sulphate | |
| US3740416A (en) | (+)-cis - 1,3-dibenzyl-hexahydro-1h-thieno-(3,4-d)imidazoles - 2,4-dione, and process for tis preparation | |
| IE58625B1 (en) | Process for preparing (3aS, 6aR) - and/or (3aR, 6aS)-1,3-dibenzylhexadydro-1h-furo[3,4-d]-imidazole-2,4-dione | |
| CZ291387B6 (en) | Method for the preparation of a 2-azadihydroxybicyclo[2,2,l]heptane | |
| US5504230A (en) | Preparation of 9-(Z)-retinoic acid | |
| EP0092194B1 (en) | Method of obtaining optically active half esters | |
| EP0161580B1 (en) | Process for the preparation of a lacton | |
| EA007907B1 (en) | A process for the preparation of clopidogrel | |
| AU2009264395B2 (en) | Process for the preparation of clopidogrel hydrogen sulfate crystalline form I | |
| RU2588673C2 (en) | METHOD OF PRODUCING BENZYL-[(3aS, 4R, 6S, 6aR)-6-HYDROXY-2, 2-DIMETHYLTETRAHYDRO-3aN-CYCLOPENTA[d][1,3]DIOXOL-4-YL]CARBAMATE AND INTERMEDIATE COMPOUNDS IN SAID METHOD | |
| TWI511949B (en) | Diastereoselective preparation of bicyclo(2.2.2)octan-2-one compounds | |
| US6346649B1 (en) | Process for the recovery and recycle of D-tartaric acid | |
| CN1031461C (en) | Resolution process of racemic semi-ester | |
| US6013653A (en) | Processes for producing pyridoindole derivatives | |
| EP3383832A1 (en) | Process for the preparation of 3-substituted cannabinoid compounds | |
| US2701250A (en) | Process of producing indole-3-acetic acids | |
| EP0411074A1 (en) | Resolution process | |
| DE3522145A1 (en) | Process for the preparation of optically active lactones | |
| WO2004092119A2 (en) | Method for producing alpha-methylated cysteine and serine derivatives | |
| US20030149278A1 (en) | Method for preparing (+)-biotine | |
| IE913663A1 (en) | Ergoline derivatives | |
| DE3431294A1 (en) | Process for the separation of racemic hemiesters | |
| DE3134042A1 (en) | METHOD FOR SEPARATING THE RACEMAT S- (CARBOXYMETHYL) - (R, S) -CYSTEIN (A) | |
| JPH0225455A (en) | Production of optically active 1-methyl-3-phenylpropylamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |