Title of Invention

A PROCESS FOR THE PRODUCTION OF 2-OXO-1,3-DIBENZYL-CIS-4,5-IMIDAZOLIDINE-DICARBOXYLIC ACID

Abstract

A process for the production of 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt comprises reacting reacting meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt with triphosgene in a two-phase solvent system consisting of an aqueous alkali hydroxide solution and an organic solvent at a temperature not exceeding about 50 and converting the 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt, which results wherefrom and which is present in the aqueous phase, into the desired 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid by acidification. The product is an important intermediate in the multi-stage process for the manufacture of biotin (vitamin H).

Full Text

The present invention is concerned with a process for the production of a cyclo acid, namely of 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, which is an important intermediate in the multi-stage process for the manufacture of biotin (vitamin H). The production of the aforementioned cyclo acid starting from meso-2,3-bis(benzylamino)-scenic acid in the form of its dialkali metal salt is known. Thus, for example, US Patent No. 5,151,525 describes such a process in which phosgene is used as the reagent in an alkaline aqueous/organic two-phase solvent system for the linkage of the two secondary nitrogen atoms via a carbonyl group with resulting ring formation. In this case anisole is employed as the essentially water-immiscible solvent for the reaction. However, as is known, the reagent phosgene is highly toxic and, moreover, potentially explosive under the influence of other gases or certain reaction liquids, so that its use is extremely dangerous when it is carelessly handled or supervised, and special precautions are required in its transport, storage and use, e.g. the employment of safety devices in the apparatus. The object of the present invention is to provide a process for the production of 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from meso-2,3-bis(benzylamino)-succinic acid in the form of its dialkali metal salt using an alternative reagent for the ring formation explained in more detail above, with the reagent not having the disadvantages of the use of phosgene or at least having them to a much lesser extent. This object is achieved surprisingly well by using as the alternative reagent carbonic acid bis(trichloromethyl ester), also known as "bus(trichloromethyl) carbonate" or - abbreviated and referred to repeatedly hereinafter - "triphosgene", and in other respects by carrying out the process under particular reaction conditions. Accordingly the present invention provides a process for the production of 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidine-dicarboxylic acid starting from meso-2,3-*bis(benzyl-amino)-succinic acid dialkali metal salt, which process comprises reacting meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt with triphosgene in a two-phase solvent system consisting of an aqueous alkali hydroxide solution and an organic solvent at a temperature not exceeding about 50*'C, and converting the resulting 2-oxo-l,3- The following reaction scheme is a structural representation of the process in accordance with the invention: In the above Reaction Scheme the alkali metal ion M is conveniently either the sodium ion or the potassium ion, preferably the potassium ion, so that the duodenum or dipotassium salt, preferably the latter, is conveniently used as the starting material for the process in accordance with the invention. The triphosgene used as the reagent in the process in accordance with the invention is a white, crystalline product in the pure state with a melting point of 78-80°C. It can be distilled without decomposition at the boiling point 203-206°C under atmospheric pressure (760 mm Hg/0.1013 Map). Its decomposition temperature is above 350°C. Triphosgene decomposes only slowly in air and can therefore be handled significantly better than phosgene in air. As is known, it can be produced in good yield and quality by the photo chlorination of dim ethyl carbonate and has also been commercially available in large amounts for many years. For the production of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt, the acid itself is conveniently suspended in water, preferably demonized water, and the resulting suspension is treated with alkali metal hydroxide solution, i.e. conveniently sodium or potassium hydroxide solution, preferably potassium hydroxide solution, generally at a pH value of about 9 to about 14, preferably at a pH value of about 12 to about 13. This gives a clear, alkaline aqueous solution of the desired dialkali metal salt. Suitable amounts of water and added alkali metal hydroxide solution are used in order conveniently to insure that the concentration of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt formed amounts to about 5 to about 20 weight percent, preferably about 10 to about 15 weight percent, based on the total weight of the resulting clear alkaline aqueous solution at pH about 9 to about 14. The concentration of the added alkali metal hydroxide solution is not critical, although it amounts to about 45-50 weight percent when commercial alkali metal hydroxide solution, e.g. potassium hydroxide solution, is used. The two-phase solvent system consisting of aqueous alkali metal hydroxide solution and an organic solvent, in which the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt and the triphosgene are reacted with one another in the process in accordance with the invention, is conveniently formed by combining the above-described clear alkaline aqueous solution of the first reaction participant with a solution of the triphosgene in the organic solvent. An paretic organic solvent, especially an aliphatic or cyclic ether, e.g. diethyl ether or, respectively, tetrahydrofuran or dioxin; an aliphatic or salicylic hydrocarbon, e.g. hexane, octane or, respectively, cyclopean; an aliphatic or cyclic ester, e.g. ethyl acetate or, respectively, y-butyrolactone; or an aromatic hydrocarbon, e.g. benzene or toluene, is conveniently used as the organic solvent. Tetrahydrofuran or toluene is preferably used as the organic solvent. The concentration of the solution of the triphosgene in the solvent can vary in a wide range, its upper limit depending, of course, on the employed solvent. This concentration is, however, not critical, although on ecological and economical grounds it is preferably as high as possible. In the combination of the alkaline aqueous solution of the meso-2,3-bis(benzyl-amino)-succinic acid dialkali metal salt with the solution of the triphosgene in the organic solvent, the former solution has conveniently already been heated to an elevated temperature in the range of about 30 to about 50°C, preferably in the temperature range of about 40 to about 45°C. If desired, the solution of the triphosgene can also previously be heated to the corresponding temperature. As a further possibility)% the heating can be effected for the first time during the course of the combination or thereafter. The combination can be carried out in optional sequence, i.e. the solution of the triphosgene can be added to the alkaline aqueous solution of the meso-2,3-bis(benzyl-amino)-succinic acid dialkali metal salt or the alkaline aqueous solution can be added to the solution of the triphosgene. The former addition variant is preferably effected. In this case, it has been found to be advantageous to add the solution of the triphosgene rather slowly and continuously, e.g. drop wise. In order to achieve a good intermixing during the combination, the mixture is suitably stirred or otherwise intermixed. With respect to the relative amounts of meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt and triphosgene after completion of the combination, the molar ratio triphosgene : meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt is suitably about 0.33 : 1 to about 10 : 1, preferably about 1.5 : 1 to about 5 : 1. The range of about 2 : 1 to about 4 : 1 is especially preferred. During the reaction of the triphosgene with the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt in the two-phase solvent system the pH value of the aqueous phase is conveniently held in the range of about 8.5 to about 13, preferably in the range of about 9.5 to about 10.5. In order to maintain this pH range, aqueous sodium or potassium hydroxide solution is conveniently added as required simultaneously with the combination of the reaction participants or after completion of the combination. The concentration of the sodium or potassium hydroxide solution is not critical, although it suitably amounts to about 5 to about 50 weight percent. It is especially suitable to use the same sodium or potassium hydroxide solution as that which was used for the production of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt. The reaction is effected at a temperature which does not exceed about 50°C, generally at temperatures in the range of about 30 to about 50°C, preferably at temperatures of about 40 to about 45°C. The pressure is not critical; the reaction is normally carried out under atmospheric or slightly elevated pressure. If desired, the process in accordance with the invention can be effected under an inert gas atmosphere. When an inert gas atmosphere is used, nitrogen or argon is especially suitable as the inert gas, nitrogen being preferred on an industrial scale. After the addition has been effected (combination of the two solutions), which usually takes about 2 to 4 hours, the reaction has normally also finished. The resulting two-phase mixture can then be worked up. The desired product, 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid in the form of its dialkali metal salt, is present mainly in the aqueous phase and is precipitated in the form of the free acid by acidification of this phase. Optionally, the previously separated aqueous phase or the entire two-phase mixture can be acidified, whereby in the latter case the resulting dicarboxylic acid migrates into the organic phase and must be isolated therefrom. As the acid for the acidification there is conveniently used a mineral acid, especially hydrochloric acid, hydrotropic acid or euphoric acid, preferably hydrochloric acid, the respective concentration and amount of which being so chosen that the aqueous phase from which the product precipitates finally has a pH value of about 0.5 to about 1.0; this expedites a good precipitation of the product. The sequence of the addition is also optional in the case of the acidification. Where the aqueous phase has previously been separated from the organic phase, this can be effected in a manner known per se, e.g. by separation of the lower (heavier) aqueous phase in a separating funnel, decantation or centrifugation. Alternatively, the product is isolated from the organic phase after separation of the acidified aqueous phase, which can also be carried out in a manner known per se; in this case the product can be isolated from the organic solvent for example by distillation. The thus-isolated 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarbox)'lic acid can in a manner known per se be washed, conveniently with water, dried and, if desired, purified further. The process in accordance with the invention is illustrated by the following Examples. Example 1 16.4 g (50 mmol) of meso-2,3-bis(benzylamino)-succinic acid (DBA; about 99% pure according to HPLC) were suspended in 160 ml of deionized water under an inert gas with stirring in a five-necked sulphonation flask fitted with a Dimorphs condenser, 250 ml dropping funnel with pressure balance, thermometer, mechanical stirrer and pH electrode. 12.0 ml of 48 wt.% potassium hydroxide solution (152.4 mmol KOH) were added while stirring and the resulting clear solution was warmed to an internal temperature of 40-45°C in an oil bath. The DBA passed into solution as the dipotassium salt with a slightly yellowish-brown co lour; the solution had a pH value of 13. 44.4 g (150 mmol) of triphosgene (98% pure according to HPLC) were dissolved in 120 ml of absolute tetrahydrofuran (THF) in a 250 ml dropping funnel having a pressure balance. In so doing, no heating or gas evolution was observed. About 150 ml of triphosgene/THF solution were obtained. The latter solution was added dropwise to the solution of the DBA dipotassium salt within 2.5 hours with vigorous stirring at an internal temperature of 40-45°C. Subsequently, the mixture was neutralized at a pH value between 9.8 and 10.3 with 48 wt.% potassium hydroxide solution using a Decimate and pH controller. The temperature was held at between 40 and 45°C with a water bath. After the addition of about 100 ml of triphosgene/THF solution the reaction mixture was present as a slightly brown colored emulsion. Then an additional 20 ml of deionized water were added. The entire amount of triphosgene/THF solution had been added dropwise after about 2.5 hours. For the neutralization, 140 ml of 48 potassium hydroxide solution (1.788 mol KOH) were added. The mixture was stirred for a further 5 minutes, during which time the pH of the solution remained at 10. 70 ml of deionized water were added to the batch in order to improve the separation of the aqueous phase from the organic phase. After brief stirring the batch was transferred into a 1000 ml separating funnel. Two phases were obtained: the upper phase (58 g) contained the major part of the THF as well as dark brown coloured, water- insoluble impurities, and after concentration under reduced pressure about 0.4 g of a solid, brown mass remained behind. The lower, aqueous phase contained 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid (CAC) and DBA as the dissolved dipotassium salt as well as further dissolved THF. This THF had to be distilled off prior to the working up. The aqueous phase was again transferred from the separating funnel into the apparatus, the apparatus was fitted with a rising distillation bridge and the still dissolved THF was distilled off up to a head temperature of 75 at an oil bath temperature of 85-90°C. About 33 g ofdistillate were obtained. The amount of reaction solution remaining amounted to 510 g or 470 ml. For the working up, the reaction solution was acidified to pH 0.90 with 65 ml of 36% hydrochloric acid (754 mmol HCl) at about 40 while stirring well within 2 hours. The CAC as well as untreated DBA separated first as a gum-like precipitate, which became fine grained after stirring at 40°C for about 30 minutes. Thereafter, the mixture was stirred in an ice bath for a further 30 minutes, filtered through a P4 internal glass frit and the frit residue was washed neutral with 340 ml of deionized water. The residue was dried to constant weight in a drying oven under a high vacuum and at 80°C and thereafter taken up in 150 ml of absolute acetone. The mixture was refluxed for 30 minutes and then filtered through the same frit as previously used and washed three times on the frit with 30 ml of absolute acetone each time. The CAC was present in the yellow-brown coloured acetone extracts; small amounts of DBA were detected on the frit. The acetone extracts were concentrated under reduced pressure at a bath temperature of 45°C and a pressure of about 110 mbar (11 kPa) and thereafter dried to constant weight in a drying oven under a high vacuum at 50°C. 17.0 g of pure CAC were obtained (96% yield). 0.12 g (0.7%) of DBA was isolated from the frit. (the THF phase contained 57.5 g of THF. The amount of distillate was 33.^s-ofTHF) Amount of potassium chloride in the aqueous filtrate: 144 g (corresponding to the neutralization of 1.930 mol of KOH with HCl) A maximum of 1% of DBA as well as 2-3% of unknown byproducts are still present in the aqueous filtrate according to analysis by thin-layer chromatography (tic). No CAC was present in the filtrate. The filtrate was discarded. Analysis CAC and DBA can be determined well by HPLC, and CAC, DBA as well as the brown byproducts can be detected qualitatively by means of tic. The following Rf values were determined using Merck Kieselgel 60 F254tlc plates, 50 toluene/50 glacial acetic acid/ 10 methanol (parts by volume in each case) as the elegant mixture and acetone as the solvent for the CAC and the brown byproducts and dilute hydrochloric acid as the solvent for the DBA: The elution time amounted to 45-50 minutes and the development was effected within 2 hours in an iodine tank, which gave brown flecks. In summary it can be said that DBA was converted almost completely into CAC with 3 equivalents of triphosgene dissolved in THF. The content of pure CAC amounted to 93.6% and the yield of pure CAC amounted to 90%. Example 2 16.6 g of DBA (98-99%; 50 mmol DBA 100%) were weighed into the prepared apparatus and suspended in 115 ml of deionized water, and the contents of the flask were heated to 45°C in an oil bath, and then 10.0 ml of potassium hydroxide solution (48 wt.%, 127 mmol) were added. After stirring for 10 minutes the DBA had dissolved to give a clear solution. The pH of the solution amounted to 12.4. The solution was neutralized to pH 9.9 with 0.5 ml of concentrated hydrochloric acid (6 mmol). 29.7 g of triphosgene (100 mmol) were weighed into a 250 ml dropping funnel and dissolved in 76 ml of absolute toluene. This solution was added dropwise while stirring well within one hour and 45 minutes at 45°C to the solution of the DBA dipotassium salt at pH 9.5 to 10.5. A brown emulsion was obtained. This was neutralized with 92 ml of 48 wt.% potassium hydroxide solution (1.168 mol KOH). The pH value amounted to 9.9. Because triphosgene dissolved in toluene reacts less rapidly with aqueous solutions, the mixture was stirred for a further 30 minutes. In so doing, the pH value fell to 9.7. The mixture was neutralized to pH 9.9 with 2.0 ml of 48 wt.% potassium hydroxide solution (25.4 mmol KOH). The pH value remained constant at pH 9.94. This signified that all of the triphosgene had reacted. The total time required for the conversion of DBA into CAC amounted to about 2.5 hours. Thereafter, the contents of the flask were transferred as completely as possible into a 1000 ml separating funnel. A good phase separation was obtained very rapidly. The impurities were present in the upper, dark brown coloured toluene phase. The amount of this phase was 62.6 g. The lower, slightly yellow coloured phase comprised the alkaline aqueous reaction solution. The volume amounted to about 300 ml. This solution was transferred into a 500 ml dropping funnel. For the working up (direct precipitation), 45 ml of concentrated hydrochloric acid (36 wt.%; 522 mmol) were placed in a 750 ml four-necked sulphonation flask fitted with a mechanical stirrer, thermometer and pH electrode, about 20 mg of crude CAC were added for seeding and the mixture was then heated to about 40*^C in an oil bath. Thereafter, the alkaline aqueous reaction solution was added dropwise by means of a dropping final to the concentrated hydrochloric acid while stirring vigorously. CAC crystals formed with the evolution of CO2 already after the addition of about 20 ml of this reaction solution. The velocity of the dropwise addition was adjusted to 5 ml/min. All had been added dropwise after 30 minutes. Crude CAC formed a fine crystalline precipitate. It was stirred at 40°C for 15 minutes, thereafter cooled and stirred in an ice bath at about +5°C for a further 30 minutes. The pH value of the aqueous solution amounted to 0.64. Thereafter, the batch was filtered through a P4 internal glass frit and the yellow-brown, crystalline residue was washed neutral three times with 40 ml of deionized water each time and dried to constant weight in a drying oven under a high vacuum at 80*^0. The amount of the toluene phase was 62.6 g. After concentration under reduced pressure about 0.7 g of brown, non-definable byproducts remained. This corresponded to 4.2% based on DBA used. 60 g of toluene distillate were obtained; this corresponded to about 69 ml of toluene or 90% of the amount of toluene solvent used (76 ml). 1.193 mol of potassium chloride were present in the aqueous filtrate. This corresponded to an amount of salt of 88.94 g of potassium chloride. Moreover, according to tic this filtrate still contained small amounts of CAC (max. 0.5-1%), DBA (max. 1%) as well as byproducts (about 2%) which were not investigated in more detail. The aqueous filtrate was discarded. WE CLAIM: 1. A process for the production of 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidine-dicarboxylic acid starting from meso-2,3-bis(benzyl-amino)-succinct acid digitalis metal salt, which process comprises reacting meso-2,3-bis(benzyl amino)-succinct acid digitalis metal salt with diphosgene in a two-phase solvent system consisting of an aqueous alkali hydroxide solution and an organic solvent at a temperature not exceeding about 50°C, and converting lie resulting 2-oxo-l,3- 2. The process as claimed in claim 1, wherein meso-2,3-bis(benzyl amino)-succinct acid disunion salt or dipotassium salt, preferably the latter, is used as the starting material. 3. The process as claimed in claim 1 or 2, wherein for the preparation of the meso-2,3-bis(benzyl amino)-succinct acid digitalis metal salt, the acid itself is suspended in water and the resulting suspension is treated with alma metal hydroxide solution, preferably potassium hydroxide solution, in order to obtain a clear, alkaline aqueous solution of the desired darkly metal salt. The process as claimed in claim 3, wherein the concentration of the meso-2,3-bis(bezylamino)-scenic acid dial kali metal salt formed in the clear, alkaline aqueous solution amounts to about 5 to about 20 weight percent, preferably about 10 to about 15 weight percent, based on the total weight of the solution at pH about 9 to about 14. The process as claimed in any one of claims 1 to 4, wherein an aortic organic solvent, especially an aliphatic or cyclic ether, e.g. diethyl ether or, respectively, tetrahydroftiran or dioxin; an aliphatic or salicylic hydrocarbon, e.g. hexane, octane or, respectively, cyclopean; an aliphatic or cyclic ester, e.g. ethyl acetate or, respectively, y-butyrolactone; or an aromatic hydrocarbon, e.g. benzene or toluene, preferably tetrahydrofuran or toluene, is used as the organic solvent. The process as claimed in any one of claims 1 to 5, wherein for the formation of the two-phase solvent system in which the meso-2,3-bis(benzyl amino)-scenic acid dial kali metal salt and the diphosgene react with one another, a clear alkaline aqueous solution of the meso-2,3-bis(benzyl amino)-scenic acid dial kali metal salt prepared in accordance with claim 3 is combined with a solution of the diphosgene in the organic solvent. The process as claimed in claim 6, wherein the clear alkaline aqueous solution and/or the solution of the diphosgene has/have been heated to an elevated temperature in the range of about 30 to about 50 , preferably in the temperature range of about 40 to about 45*C. The process as claimed in any one of claims 1 to 7, wherein the molar ratio triphosgene:meso-2,3'bis(benzyl amino)-succinct acid dial kali metal salt is about 0.33:1 to about 10:1, preferably about 1.5:1 to about 5:1, particularly about 2:1 to about 4:1. The process as claimed in any one of claims 1 to 8, wherein during the reaction in the two-face solvent system the pH value of the aqueous phase is held in the range of about 8.5 to about 13, preferably in the range of about 9.5 to about 10.5. The process as claimed in any one of claims 1 to 9, wherein the reaction is effected at a temperature in the range of about 30 to about 50®C, preferably in the temperature range of about 40 to about 45 The process as claimed in any one of claims 1 to 10, veering a mineral acid, especially hydrochloric acid, hydrotropic acid or euphoric acid, preferably hydrochloric acid, is used for the acidification of the resulting 2-oxo-l,3-dibenzyl-cis-4,5-imidazolidine-dicarbo:Kylic acid dial kali metal salt which is present in the aqueous phase. A process for the production of 2-oxo-l,3-dibenz)1-cis-4,5-imidazolidine-dicarboxylic acid substantially as herein described and exemplified.

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678-mas-2000-abstract.pdf

678-mas-2000-claims filed.pdf

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