IE852086L - Separating racemic half esters - Google Patents

Separating racemic half esters

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Publication number
IE852086L
IE852086L IE852086A IE208685A IE852086L IE 852086 L IE852086 L IE 852086L IE 852086 A IE852086 A IE 852086A IE 208685 A IE208685 A IE 208685A IE 852086 L IE852086 L IE 852086L
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IE
Ireland
Prior art keywords
dibenzyl
acid
optically active
dehydroabietylamine
hexahydro
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Application number
IE852086A
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IE58625B1 (en
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Merck Patent Gmbh
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Publication date
Priority claimed from DE19843431294 external-priority patent/DE3431294A1/en
Priority claimed from DE19853522145 external-priority patent/DE3522145A1/en
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Publication of IE852086L publication Critical patent/IE852086L/en
Publication of IE58625B1 publication Critical patent/IE58625B1/en

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    • 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

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  • 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. [EP0173185A1]

Description

.8625 t- 8 6 2 5 2 The invention relates to a new process for preparing (3aS,6aR)-and/or (3aR,6aS)-1,3-diben2ylhexahydro-1H-furo[3,4-d]-imida-zole-2,4-dione from 1,3-dibenzy l-5-a Ikoxycarbony l-2-oxo-imidazolidine-4-carboxylic acids, which is characterised 5 in that a diastereoisoraeric salt formed between an optically active amine and an optically active 1,3-dibenzyl-5-alkoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid is reduced. (4S, 5R)-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxo-10 imidazolidine-4-carboxylic acids are useful intermediates for preparing <3aS, 6aR)-1,3-dibenzy l-t et rahy d ro-4H-f uro C3, 4-d3-i mi dazole-2,4dH)-dione, a key product for the preparation of (+)-biotin.
The two enantiomers of cis-1,3-dibenzyl-5-15 alkoxycarbonyl-2-oxoimidazolidine-4-carboxylic acids have the formula Ia/b la lb 0 £ BZl-N^N-BZl BZL-N N-BZL H4-LH H-f-fH • • • • ROOC COOH HOOC COOR in which R is alkyl having 1 to 6 C atoms, 20 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, BZL is benzyl. 25 of the previously disclosed process for optically resolving racemic half-esters of th-e formula Ia/b/ German Patent 2,058,234 describes the preparation of cyclohexyl half-esters and the separation of the resulting diastereo-isomeric (+)-ephedrinium salts by fractional crystalli-30 sation and the preparation of diastereoisomeric cholesterine \ I 3 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 5 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 10 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 enanti-omer from the supersaturated solution of the racemate by 15 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, 20 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 <+)-dehydrqabi ety lami ne salts of <4S, 5R)- and <4R,. 5S)-cis-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acids, in which -alkyl- is alkyl having 1 to 6 30 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.
Raceraic half-esters are separated by standard methods which are known per se for the optical resolution of racemates (for example B.P.H. Boyle, Quart.Rev. 2J5 (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 diastereoisomers. 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 (+)-dehydro-abietylamine in a suitable organic solvent and subsequently recrystallising the (+)-dehydroabietylamine salt of an en-antiomer. After the latter has been separated off by filtration or centrifugation, removal of the solvent from the remaining solution and if desired crystallisation of the residue produces the other enantioraer.
The amount of (♦)-dehydroabietylamine used is 0.5 to 1 mol, preferably 0.5 to 0.7 mol, 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—:miscible solvent, in particular an alcohol such as 5 methanol/ ethanol, isopropano 1/ 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 5 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. 10 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 15 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 20 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 crystal-25 lisation. For this purpose, the racemate of the half- esters 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 30 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, trichloroethy lene, 1,2-dichloroethane or carbon tetrachloride or hydrocarbons such as hexane, 35 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 des 6 cribed above for separating the racemic half-esters. A preferred embodiment of this process consists in the optical resolution of the (+)- dehydroabietylamine salts of cis-1,3-dibenzyl-5-methoxy-5 carbonyl-2-oxoimidazo I idine-4-carboxyIic acid and cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid.
The <+)-dehydroabietylamine salts of the optically active half-esters la or lb obtained by this process 10 can be converted back into the free half- ester acids by treatment with an acid or base. Examples of suitable bases are alkali metal and alkaline earth metal hydroxides, carbonates or bicarbonates, ammonia and strong organic bases. Preferred bases are alkali metal 15 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 20 acids such as hydrochloric acid or hydrobromic acid. Particular preference is given to sulphuric acid with which <+)-dehydroabietylamine forms a sparingly soluble hydrogen-sulphate which crystallises readily and is filtered off easily, thereby permitting recovery of the resolving agent 25 inhigh 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. 30 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 35 solvent, preferably water. The liberated half-ester can then be extracted with an organic solvent, such as, for example, diethyl ether, toluene, ethyl acetate, dichloro-methane 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 (+)-dehydroabietylamine used as a resolving reagent, the amine can be set free after alkali-5 sation 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/ 10 referred to as particularly preferable/ is used to decompose the pair of diastereoisomeric salts the (+)-dehydroabietylamine is obtained in the form of the sparingly soluble hydrogensuIphate. After the latter has been separated off by filtration or centrifugation 15 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/ 20 for example/ cis-1/3-dibenzyl-2-oxoimidazolidine-4/5- dicarboxylic anhydride is "known for example from German Patent 2/058/234 or European Offen legungsschrift 0/092,194 and is effected by reaction with the corresponding alcohol in an inert organic solvent, such as/ for example/ benzene/ 25 toluene or xylene/ preferably at elevated temperature.
The optically active cis-1,3-dibenzyl-5-aIkyloxy-carbonyl-2-oxoimidazo lidine-4-carboxy I ic acids ' thus obtained can be reduced to the optically active 1,3-di benzyl-tetrahydro-4H-furoC3,4-dUimidazole-2,4 30 (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 half-ester. However/ it is similarly possible to use its diastereoi someri c (+)-dehydroabietylamine salt as the start-35 ing 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 8 cyclohexyl half-esters of cis-1,3-dibenzy l-2-oxoimida-zolidine-4,5-dicarboxylic acid are separated into their enantiomers and the corresponding enantiomer is converted by reduction into the desired lactone. However, the yields 5 obtained in this process are below 50% of theoretically obtainable pure isomers. The chiral auxiliary cholesterol is comparatively costly and cannot be completely recovered. Furthermore, in the claimed process the unwanted enantiomeric half-ester needs to be recyclised again. 10 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 15 - 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 20 cis-1,3-dibenzyIhexahydropyrrolo-C3,4-d3imi dazole-2,4,6- t ri one, obtained from c i s-1,3-di benzyl-2-oxoi midazolidine-4,5-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. 25 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 Offenlegungsschrift 84,892, which proceeds in high yields, 30 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-oxoimidazol i di ne-4,5-dicarboxylic acids witn < + )-dehydroabiety lamine represents 35 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. n 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. 5 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. 10 It was therefore the object to find a process for preparing optically active 1,3-dibenzy Itetrahydro-4H-furo-C3,4-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 15 reducing agents combined with simplified procedure and the isolation of products of higher chemical and optical purity.
It has now been found, surprisingly, that diastereoi someric salts between an optically active amine and an optically active 1,3-dibenzyl-5-alkoxycarbonyl-2-oxoimidazoli 20 -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-dibenzyIhexa-25 hydro-1H-furoC3,4-dDimidazole-2,4-dione from 1,3-dibenzyl-5-alkoxycarbonyl-2-oxoi mi dazolidi ne-4-carboxylie acids, characterised in that a diastereoisomeric salt formed between an optically active amine and an optically active 1,3-dibenzy1-5-aIkoxyca rbonyl-2-oxoi mi dazolidi ne-4-ca r-30 boxylic acid is reduced.
The invention further relates to the use of an optically active 1,3-dibenzylhexahydro-1H-furoC3,4-d]imi-dazole-2,4-dione obtained by the process according to the invention, for preparing D-(+)-biotin. 35 The method used in the invention for reducing the diastereoisomeric salts of the optically active half-esters is in accordance with the methods known per se for reducing the free half-esters. 10 Depending on the choice of reducing agent, it is possible to obtain from salts in which the half-ester has a 4S,5R- or 4R,5S-configuration not only the (3aR,6aS)-but also the (3aS,6aR)-lactone. 5 If, for example, a salt of a 4S,5R-haIf-ester is reduced a.t the carboxyl group, the product is the 3aR,6aS-lactone, while if the a Ikoxycarbony I group is reduced, a 3aS,6aR-lactone is obtained. The 4R,5S-haIf-ester is subject to the converse relationships. 10 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 15 as diethyl ether, ethylene glycol dialkyl ether, diethy-lene 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. 20 The temperature during the reduction is advan tageously 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 25 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 BjH^ per mol of half-ester salt.
Oiborane can be used as such in the reduction, but 30 it can also be prepared in situ by known methods, for example from NaBH^ and a Lewis acid such as boron tri-fluoride or its diethyl ether adduct, this in situ preparation being preferably carried out in solvents suitable for the reduction of the half-ester salts, so that the 35 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 as Lithium borohydride, sodium borohydride or calcium borohydride, and aluminium hydrides such as diisobutyl-aluminium hydride and diethylaluminium sodium hydride.
The reduction preferably takes place in a solvent 5 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 10 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. 15 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 20 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 25 used at -10 to 100°, 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 30 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-aIkoxy-carbonyl-2-oxoimidazolidine-4-carboxyIic acid salts used as starting materials -aIkoxycarbonyI- is to be under-35 stood as meaning -aIkyloxycarbonyI- having 1 to 6 C atoms, -a IkoxyaIkoxycarbonyI- having 2 to 8 C atoms, -aIkenyloxy-carbonyI- having 2 to 6 C atoms, -benzyl-oxycarbonyl- or 1- or 2-phenylethoxycarbony1-.
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 a L L optically active amines suitable for separating the racemic half-esters, such as, for example, ephedrine as claimed in German Patent 2,058,248, the 1,2-dipheny l-ethanamines mentioned in European Offenlegungsschrift 92,194 and in particular (+)-dehydroabietylamine. The use of diastereoisomeric (+)-dehydroabietylamine salts constitutes a preferred embodiment of the process according to the invention.
The process is simple to carry out. The diastereo-isomeric salts to be used as starting material are known or can be prepared by methods known per se, as indicated, for example, in European Offenlegungsschrift 92,194. 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 1 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-dibenzy l-tetra-hydro-4H-furoC3,4-d]imidazole-2,4-(lH)-dione 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 nvent 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-aIkoxy-carbonyl-2-oxoimidazo I idine-4-carboxyIic acid to give optically active 1,3-dibenzylhexahydro-1H-furoC3,4-d3-imidazole-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-1,3-dibenzyl-hexahydro-1H-furoC3,4-d3 imidazole-2,4,6-trione 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-dibenzyl-2-oxoim1dazolidine-5-ethoxycarbonyl-4-carboxylic acid; melting point 93°. b) 57.4 g <0.15 mol) of racemic cis-1,3-dibenzy1-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and 42.8 g <0.15 mol) of <+)-dehydroabietyl-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,1,3- 14 dibenzy 1-5-ethoxycarbony1-2-oxoimidazolidine-4-carboxylic acid; ^-^65' Tlie addition of 400 ml of water or 500 ml of hexane to the mother Liquor Leads to the crystaLLisaton of 49.8 g (98% 5 of theory) of the dehydroabietyLamine salt of (4S, 5R)-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo- i mi dazo L i di ne-4-ca rboxy L i c acid; = +61,24°. 365 Example 2: Equivalent amounts of racemic cis-1,3-dibenzy1-5-10 ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and (+)-dehydroabietyLamine are dissolved in ethanol (4 to 5 litres per mol), and, after the addition of 10% of water, are allowed to crystallise at -10°. The yieLd of dehydroabietyLamine salt of (4R, 5S)-cis-1,3-dibenzy 1-5-15 ethoxycarbonyl-2-oxoimidazoIidine-4-carboxyIic acid is 89% of theory; ^*^3^5= ^8.1°.
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 20 (4S, 5R)-cis-1,3-dibenzyl-5-ethoxycarbony1-2-oxoimidazoli-di ne-4-carboxy li c acid can be isolated; ^^5 = 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 25 salts of (4R, 5S)- and (4S, 5R)-cis-1,3-dibenzyl-5-ethoxy-carbonyl-2-oxo-imidazolidine-4-carboxylic acid is obtained in 9% of theory and can be used again for separating purposes.
Example 3: 30 A solution of 26.8 g (0.07 mol) of racemic cis-1,3- dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and 20 g (0.07 mol) of (+)-dehydroabietylamine in 80 ml of methylene chloride is evaporated to dryness.
Crystallisation from diisopropyl ether gives 45.6 t, (97.5% 35 of theory) of a pair of diastereoisomeric ethyl half-ester acid dehydroabi ety lami ne salts; C°<3^ = +54.9°. 365 Example 4: The separation of the mixture of the diastereoiso- 1 5 meric (+)-dehydroabietylamine salts of cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic 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 6 5 + The mother liquor of the 1sc 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 (4R, 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-methoxycarbony1-2-oxoimidazolidine-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-oxo- imidazolidine-4-carboxy li c acid: = +^9°. (4R, 5S)-cis-1,3-dibenzyl-5-methoxycarbony1-2-oxo- i mi dazo I i di ne-4-ca rboxy li c acid: 0x3^** = +67° 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. 1 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-benzy1oxycarbony1-2-oxoimidazolidine-4-carboxy1ic acid (obtainable from cis-1,3-dibenzyl-hexahydro-lH - furo/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-dibenzyl-5-benzyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid is 138.6 g (95% of theory); j_OC_/ 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 ambient temperature affords 135.8 g (93 % of theory) (4S,5R)- cis-l,3-dibenzyl-5-benzyloxycarbonyl-2-oxoimidazolidine-4- carboxylic acid; A*_/25 = +54.2°; optical purity: — 99 %. 365 1 ? Example 12 a) 35 ml of 2N sulphuric acid are added with stirring to a suspension of 23.3 g of the dehydroabiety l-amine salt of <4S, 5R)-cis1,3-dibenzyl-5-ethoxy-5 carbonyl-2-oxoimidazolidine-4-carboxyIic acid in 200 ml of water and 200 ml of ethyl acetate. Filtration gives 12.18 g <90.62 of theory) of (+)-dehydroabietylamine hydrogen sulphate. In the filtrate, the organic phase is separated off and is 10 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-dibenzyl-5-ethoxycarbonyl-2-oxoi mi dazoIi di ne-4-ca rboxyIi c acid; '-°^365= "23.8°. 15 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 twice- with 20 100 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 137; 25 The procedure of Example 12 is used to obtain: <4S, 5R)-1,3-dibenzyl-5-methoxycarbony1-2-oxo- imidazolidine-4-carboxyIic acid: D*D25 _ .15 750 "365 <4R, 5S)-1,3-dibenzyl-5-methoxycarbonyI-2-oxo-imidazolidine-4-carboxy lic acid: = +18.2°. 1 s Example 14; The reduction of the optically active c i s-1,3- dibenzyl-5-ethoxycarbonyl-2-oxoimidazo dine-4-carboxylic acids obtained in Example 12 to the corresponding 5 optically active 1,3-dibenzyl-trahydro-4H-furoC3,4-d!]- imidazole-2,4dH)-diones with lithium borohydride is carried out analogously to the method described by Gerecke et a I., He I v. Chim.Acta 53 (1970) 991-999.
Yield of (3aS,6aR)-1,3-dibenzyl-tetrahydro-4H- 10 furoC3,4-dlimidazole-2,4(1H)-dione 88.5% of theory; melting point 119.4°; 0>G25 = +240.6°. This lactone 365 can be converted in accordance with German Patent 2,058,234 or German Patent 2,331,244 into D-(+)-biotin.
Examp le 15 : 15 The method described in Example 1^ is used to re duce the enantiomeric cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-5-carboxylic acid with lithium borohydride, affording: (3aS, 6aR)-1,3-dibenzyl-tetrahydro-4H-furo C3,4-d3-20 i mi dazo le-2,4 (1 H)-di one; 97.4% of theory; ^■°<^Z65 = +208° and (3aR, 6aS)-1,3-dibenzyl-tet rahydro-4H-furoC3,4-dD-imidazolidine-2,4(1H)-dione; yield quantitative; ^365= "206°- 25 Example 16 4 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-di benzyl-5-ethoxycarbonyl-2-oxoimidazoline-4-carboxylic acid (+)-30 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. 35 This is followed by cooling down to 20° and decomposition by dropwise addition of 300 ml of 3 N sulphuric acid. 1 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 5 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-dibenzy Itetra-hyd ro-4H-fu ro C3^4-d3 imidazole-2,4(1H)-dione; melting point 119°, 0*1 $65 = +208.7° (c = 1, benzene). 10 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 ( + )-dehydroabiety l-15 amine salt of (4R,5S)-1,3-dibenzyl-5-ethoxycarbony 1-2- oxoimidazolidi ne-4-ca rboxylic acid (prepared as described in 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, 20 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-dibenzyItetrahydro-4H-25 furoC3,4-d]imidazole-2,4(1H)-dione; melting point: 118.8°, +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-di-30 benzyl-5-methoxycarbonyl-2-oxoimidazoIine-4-carboxy I ic acid (prepared according to European Offenlegungsschrift 92,194) in tetrahydrofuran with sodium borohydride. This gives (3aS,6aR)-1,3-dibenzyltetrahydro-4H furoC3,4-d3-imidazole-2,4(1H)-dione in 89% of theory. 35 This lactone is converted in accordance with German Patent 2,058,234 or 2,331,244 into D-(+)-biotin. Example 1^ A method analogous to Example 17 is used to reduce 2 0 the d-1-phenyl-2-p-toLylethanamine salt of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxyl acid (prepared according to European Offenlegungsschrift 92,194) in tetrahydrofuran with diborane. This gives (3aS,6aR)-1,3-dibenzyltetrahydro-4H-furoC3,4-dDimid-azo le-2,4(1H)-dione in 92X of theory.

Claims (13)

w 2 1 Clalms
1. < + )-Dehydroabiety lamine salts of (4S, 5R)- and (4R, 5S)-cis-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxo-i ml dazo 11 d 1 ne-4-ca rboxy U c add, in which -alkyl- 1s 5 alkyl having 1 to 6 C atoms, al.koxyalkyl having 2 to 8 C atoms, cycloalkyl having 3 to 5 C atoms, alkenyl having 2 to 6 C atoms, benzyl 5r 1- or 2-phenylethyl.
2. (+)-Dehydroabietylamine salts of (4S, 5R)- and <4R, 5S)-c1 s-1,3-d1benzyl-5-raethoxyca rbony t-2-oxo- 10 1 mldazo11 d1 ne-4-carboxy11c acid.
3. <+)-Dehydroab1etylamlne salts of <4S, 5R)- and <4R, 5S)-c1 s-1/3-d1benzyl-5-ethoxycarbonyl-2-oxo-1 mldazoll 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-imida-zolidine-4-carboxylic acids, characterized in that a diastereomeric salt formed between an optically active amine and an optically active 1,3-dibenzyl-5-alkoxy-20 carbonyl-2-oxoimidazole-4-carboxylic acid is reduced with complex hydrides.
5. . Process according to Claim 4 , characterised 1n that the diastereoisomeric half-ester salt 1s reduced at the carboxyl group. 25
6. . Process according to Claim 4 , characterised 1n that the diastereoisomeric half-ester salt 1s reduced at the a IkoxycarbonyI group.
7. ". Process according to any one of Claims 4 to 6, characterised in that the optically active amine is < + )-dehydroabietylamine.
8. -« Process for preparing <3aS,6aR)-1,3-d1benzy l- hexahydro-1H-furoC3,4-d3i«idazole-2,4-d1one according to any one of Claims 4 to 7, characterised in that the < + )-dehydroabietylamine salt of (4S/5R)-1,3-d1benzy 1-5-aethoxy- and/or -5-ethoxy- and/or -5-benzyloxy-carbonyl-2-oxo1midazo11d1ne-4-carboxy 11c acid is reduced with sodiu« borohydri de .
9. . Process for preparing <3aS),6aR)-1,3-d1benzyl- hexahydro-lH-furo C3,4-d3 i mi dazole-2,4-di one according to any one of Claims 4 to 7, characterised in that the (♦)-dehydroabietylamine salt of (4R,5S)-1,3-d1benzy1-5-aethoxy- and/or -5-ethoxy- and/or -5-benzyloxy-carbonyl-2-oxoiraidazolidine-47carboxylic add is reduced with diborane.
10. Use of an optically active 1,3-d1benzyl-hexahydro-1H-furoC3,4-d]im1dazole-2/4-dione obtained according to Claims 4 to 9, for preparing 0-(+)-b1ot1n.
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-1H-furo[3, 4-d]imidazole-2,4-dione, substantially as hereinbefore described and exemplified.
13. (3aS, 6aR)- and/or (3aR, 6aS)-1,3-Dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4-dione, whenever prepared by a process claimed in a preceding claim. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.
IE208685A 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 IE58625B1 (en)

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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

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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
EP0220435B1 (en) * 1982-04-16 1990-11-14 Sumitomo Chemical Company Limited A method for preparing optically active half esters
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