LU81936A1 - PROCESS FOR PRODUCING 2-CETOGULONIC ACID FROM ITS ALKYL ESTERS AND SALTS - Google Patents

Description

OC 5ο.876

- "ΓΤ ~ Π— 2? GRAND DUCHY OF LUXEMBOURG

Patent N ° ...... I ..... Vf ....... y If of November 29, l97.9 Minister, 5¾¾¾¾ of the National Economy and the Middle Classes

Industrial Property Service

Jp (ôMp LUXEMBOURG

ÿl / j (η Μλ 'i ^ Invention Patent Application I. Request ...... La ... société.-dlt, es ..... P.EIZBR ~ INC - / .... .2.3.5 ..... Eas.t.-42nd..S.treet.f ..... to ...................... ......... (it ...... NEW-YORK, ..... State of Net * -York, ..... States of America, ..... reprë- .........................

....... seixtëe ..par ... Monsieur ... Jacques de ..Muyser, acting in .quality ............ (2)% ...... .from ... jnandataire ............................................ .................................................. .................................................. .................................................. ............................

deposit this .. twentyttr.neu. £ .... November. 19oo ..... s.oixanter.dixrne.uf ._______________ (3) at __________ 15 .___________ hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning: ........ ^ Process ... of ... production ... of acid ..... 2rcëtogulQnique # da ..... ses ____________________________ (4> .... ....... esters ..... alky.l ± ques ... and ..... de, ... ses ... salts "............ .................................................. .................................................. .......

* ............. * ........................ ..... ...... ............................... ............. ......... ... ...... .. ....

declares, assuming responsibility for this declaration, that the inventor (s) is (are): ....... Glenn. Colton -ÂNOEEWS .. #. .4.Jiigil ... Rldga .... Drive / .... Α ... ΪΐλΤΕΕΕΟ.ΒΟ .. / ...................... ......... (5) ....... Conté, from New .. London., ..... State. Of. ... Conne.c.tiout./...Etata-ünis.....d!Mir.ique 2. the delegation of power, dated NEW “.YORK / ..... NaY. · .. ....... on ..3.1 ..... Q.St.QbXe ..... l.9.7.9 ...

3. description in French ............ language ................................ of the invention in two copies; 4 ..... He ................ ... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on ........ 29 ..... November ..... 19.7.9 .......... .................................................. .................................................. .................................................. .........................................

claims for the above patent application the priority of one (s) request (s) of (6) ........................... ..patent ....................................... filed ^ / (7) .. .in ... United States ..... d. '. Âmë.rique ....................

the 1st. December. .19.78 ........... ÎN.o. " 9.6.5./..6.2.6.) And on March 26 19.7.9 ............................... ....

.................. (No ....... 0.2.4./. 2 84.) ............. .................................................. .................................................. .................................................. .................................................. ..

in the name of ..the inventor .......................................... .................................................. .................................................. .................................................. ..... (9) take up residence for him / her and, if designated, for their proxy, in Luxembourg ........................ ................

........ 35 ../ bld .. Royal .................................. .................................................. .................................................. .................................................. .................... <iO) requests the issuance of a patent for the subject described and represented in the abovementioned appendices, - with adjournment of this delivery at .................. 6 ........................... months.

· Vi-) £ '> W ·' -‘- w-- II. Depot Minutes

Y

The above application for a patent for invention has been filed with the Ministry of National Economy * and the Middle Classes, Industrial Property Service in Luxembourg, on: November 29, 1979 .. ·· ....... . · .. Pr. The Minister at ........... 15 .......... hours .β afe'Ss. d® National Economy and the Middle Classes, / r / * ·. -' He (/

, i ·. X * 1 V

I D. 5o.876

* V CLAIM OF PRIORITY

! of the patent application / jSjA / rfqtyèfè / pfiffig / W IN THE UNITED STATES OF AMERICA From December 1, 1978 From March 26, 1979 Brief Description filed in support of a request for

PATENT

4 to

Luxembourg on behalf of: PFIZER INC., For: "Process for the production of 2-ketogulonic acid, its alkyl esters and its salts".

i • 9 1.

The present invention relates to a process for producing * 2-ketogulonic acid, its alkyl esters and its salts by the selective reduction of 2,5-diketogluconic acid, its alkyl esters or its = · salts. 2-ketogulonic acid is useful as an intermediate for the production of ascorbic acid.

The total reduction of 2,5-diketogluconic acid with an excess of sodium borohydride has been reported as part of a structural analysis of the acid (see "Agr. Biol. Chem." 28, 819 (1964), "J. Biol. Chem." 204, 34 (1953) and Antonie Van Leeuwenhoeck 37, 185 (1971)). The catalytic reduction of 2,5-diketogluconic acid to hydrogen in the presence of a catalyst consisting of Raney nickel gives a low yield of a mixture of 2-ketogluconic acid and 2-ketogulonic acid, l 2-keto-gluconic acid being the dominant product ("Agr. Biol. Chem." 28, 819 (1964)). U.S. Patent 4,159,990 describes a 15 'reduction process of a 2,5-diketogluconate with an equivalent of an alkali metal borohydride to form a mixture of 2-ketogulonic acid and 2-ketogluconic acid.

It has just been discovered that 2,5-diketogluconate can be reduced with greater regioselectivity and greater stereoselectivity thereby giving greater yields of the desired 2-ketogulonic acid, which is then to be converted to ascorbic acid. , by the use of a reducing agent of the amino-borane type at a pH between approximately 2 and 7. Thus, for example, it is possible by this process to obtain yields of 2-ketogulonic acid and of 2-ketogluconic acid of 94% or more, the product mixture containing about 96% of the desired 2-ketogulonic acid. These high yields can be obtained without the reduction reaction having to be carried out in the presence of a boron complexing agent, as is necessary to obtain optimal yields in reduction using a metal borohydride alkaline. It has also been found that the 2-ketogulonic acid formed by this process is not exposed to further reduction, i.e. reduction of the 2-keto group, at a reasonable rate even in the presence an excess of reducing agent of the amino-borane type. However, the 2-keto group of 2-ketogulonic acid is rapidly reduced by an alkali metal borohydride, and this results in insufficient yields of 2-ketogulonic acid when this acid is formed by reduction by a metal borohydride alkali of 2,5-diketogluconate, and the inability to use an excess of alkali metal borohydride to increase the reduction rates and conversion rates of the starting 2,5-diketogluconate. In addition, 2,5-diketogluconate is very stable in both.

acid conditions used in the reduction by the action of an amino-borane according to the invention.

The present invention relates to a process for the production of a 2-ketogulonate, which process consists in reducing a 2,5-diketogluconate with an amino-borane of formula RjR ^ HN.BH ^ or with a pyridino-borane in solution * to a pH of approximately 2 to 7 at a temperature of approximately -20 to 70 ° C., and R2 each being chosen from hydrogen and a C 1 to C alkyl radical and the 2.5-diketogluconate being chosen from acid 2, 5-diketogluconic, an n-alkyl ester of said acid, in which the alkyl group comprises 1 to k carbon atoms, and a salt of said acid having a complementary ion chosen between an alkali metal, an alkaline earth metal, an ammonium ion and a tetraalkylammonium ion, each alkyl radical of which comprises 1 to 4 carbon atoms.

Preferred examples of amino borane reducing agents of the formula R ^ R2HN.BH ^ include ammonioborane, methyl-15 'aminoborane, dimethylaminoborane and tert-butylaminoborane. Pyridinoborane is also a popular aminoborane.

The reaction is preferably carried out at temperatures from 0 to 25 ° C, preferably at a pH of 4 to 6. Preferred 2,5-diketogluconates to be used as starting materials include 2,5-diketogluconic acid-20 e, sodium 2,5-diketogluconate, calcium 2,5-diketogluconate and methyl 2,5-diketogluconate.

The process of the invention allows the regioselective and stereoselective reduction of a 2,5-diketogluconate with an aminoborane. The reaction product is mainly a 2-ketogulonate, with the formation of a 2-25 ketogluconate in small quantities only, namely 2 to 12%. The reaction product is therefore advantageous to use for the preparation of ascorbic acid by means known in the art, for example by lactonization catalyzed by a base of the lower alkyl esters of 2-keto-gulonic acid. If desired, the small amounts of 2-ketogulonic acid present in the reaction product can be converted to erythorbic acid by similar methods, either separately or together with the conversion of 2-ketogulonate to ascorbic acid.

. The 2,5-diketogluconate used as a starting material in the process of the present invention can be 2,5-diketogluconic acid or salts of this acid. Suitable salts include the salts having for complementary ions an alkali metal, an alkaline earth metal, an ammonium ion or a tetraalkylammonium ion whose alkyl radicals contain 1 to k carbon atoms. It is also advantageous to use as t.

3.

starting materials for the process of the present invention normal alkyl esters of 2,5-diketogluconic acid, the alkyl group of which comprises 1 to carbon atoms. The terms "2,5-diketogluconate", "2- * ketogulonate" and "2-ketogluconate" used herein include free acids and their alkyl esters and their suitable salts, as defined above. 2,5-Diketogluconic acid and its salts can be produced by any means known in the art. Generally, 2,5-diketogluconate is produced in the form of the calcium salt in aqueous solution by fermentation, using methods well known in the fermentation industry, and can be used directly in this form as starting material for the process of the invention. 2,5-Diketogluconate can also be produced by fermentation in the presence of other ions such as sodium, and the resulting sodium 2,5-diketogluconate can likewise be used directly in the process of the invention. In a variant of the process, 2,5-diketogluconate is prepared in the conventional manner in the form of calcium 2,5-diketogluconate and converted to the desired compound by addition of a salt capable of precipitating calcium leaving the 2,5-diketogluconate in solution with the desired complementary ion. Thus, for example, sodium or ammonium 2,5-diketogluconate can be produced by adding sodium carbonate or ammonium carbonate respectively to a solution of calcium 2,5-diketogluconate produced by fermentation. The calcium is precipitated in the form of calcium carbonate, leaving 2,5-diketogluconate in solution with the complementary sodium or ammonium ions. The free acid can also be neutralized with a hydroxide or other suitable salt. If necessary, 2,5-diketogluconate can be isolated, purified and redissolved.

Normal alkyl esters of 2,5-diketogluconic acid in which the alkyl radical contains 1 to 4 carbon atoms can be prepared by heating a solution of 2,5-diketogluconic acid or a suitable salt. of this acid in the normal alkanol suitably chosen, at 50-100 ° C in the presence of a catalytic amount of a strong acid such as sulfuric acid, hydrochloric acid, paratoluenesulfonic acid or a similar acid. concentrated, to form the corresponding 5,5-dialkylacetal of 2,5-diketogluconate. Salts of 2,5-diketogluconic acid which are suitable for the preparation of esters by this process include the alkali metal, alkaline earth metal, ammonium and tetraalkylammonium salts, each alkyl radical of the ion tetraalkylammonium having 1 to 4 carbon atoms. The acetal is then hydrolyzed with an aqueous acid at a temperature ¢.

from about -10 to 30 ° C to form the desired alkyl ester of 2,5-diketogluconic acid. Suitable acids include aqueous hydrochloric acid, trifluoroacetic acid, sulfuric acid, ion exchange resins, sulfonic acid, etc.

When an alkali metal 2,5-diketogluconate is used as the starting material in the reduction process with an aminoborane of the invention, the sodium salt is preferable. A popular alkaline earth 2,5-diketogluconate is the calcium salt. When using tetraalkylammonium salts, preference is given to the tetramethylammonium salt. An advantageous alkyl ester to be used as the starting component is methyl 2,5-diketogluconate.

The reduction of 2,5-diketogluconate is carried out by contacting a solution of 2,5-diketogluconate with an effective amount of an aminoborane of formula R ^ R ^ HN.BH ^ in which Rj and R2 have the definitions 15 ' given above, or with pyridinoborane. Preferably, the reaction is carried out in an aqueous solution optionally containing organic cosolvents which comprise, without limitation, alkanols having 1 to ^ carbon atoms, alkanediols having 2 to 4 carbon atoms, etc. Methanol is a popular co-solvent. The concentration of 2,5-diketo-20 gluconate is not critical, but is preferably between about 5 and 20% by weight. The concentration of 2,5-diketogluconate formed by fermentation is generally within this range and there is thus an aqueous solution of the starting material advantageous to use in the process of the invention. When an alkyl ester is used as the starting material, the reaction can be carried out in anhydrous solvents such as alkanols, especially methanol. In any case, it is not necessary for all of the 2,5-diketogluconate to be dissolved in the solvent, provided that an appreciable part of the starting material is in solution.

Aminoboranes advantageous for use as reducing agents in the process of the invention are well known in the art and are generally commercially available (see, for example, CF Lane, "Aldrichimica" 6, 51 (1973)) . If necessary, they can be prepared by known methods, for example by reacting diborane with an amine, suitably chosen of formula R ^ R2NH to form the aminoborane RiR2HN.BH3, the reaction generally being carried out at temperatures of around 0 ° C or less.

• The amount of aminoborane that is used in the reduction reaction conditions the amount of starting 2,5-diketogluconate present 5.

in the reaction mixture which is converted to the desired reaction product. Preferably, a sufficient amount of aminoborane is used to transform all of the starting 2,5-diketogluconate present in the reaction mixture, since optimum yields are obtained in 2-5 ketogulonate desired which is suitable for the transformation subsequent ascorbic acid. However, if necessary, lower amounts of reducing aminoborane can be used to obtain lower concentrations, that is to say to reduce only part of the 2,5-diketogluconate present in the reaction mixture. The unreacted 2,5-diketogluconate can then be recycled and subjected to further reduction reactions. The present invention is intended to cover not only the above methods, but also other methods for carrying out the reduction, which are obvious to those skilled in the art, for example, without limitation, carrying out reduction discontinuously or continuously.

15 ’It should be noted that one mole of an aminoborane contains three equivalents of hydride ion. Consequently, high yields of the desired 2-ketogulonate can be obtained by using about 0.30 to about 0.40 mole, and preferably about 0.33 mole, of an aminoborane per mole of 2.5-diketogluconate present at the start. in the reaction mixture. However, since the 2-keto group of the 2-ketogulonate obtained as a product is only very slowly reduced by the excess of reducing aminoborane, in particular when R 1 and R 2 both represent something other than a hydrogen atom , higher rates of reduction of the 5-keto group can be obtained where appropriate by the use of relatively larger amounts of reducing agent, for example up to about 2 to 3 moles of aminoborane per mole of 2.5 - diketogluconate, and the use of such an excess ensures complete conversion of the starting 2,5-diketogluconate contained in the reaction mixture. The reducing aminoborane can be added to the 2,5-diketogluconate solution either in a single batch at the start of the reaction, or in portions during the reaction, and can be added either in solid form or in the form of a solution.

During the reduction of 2,5-diketogluconate with the amino-. borane, the pH of the solution should be kept at about 2 to 7 and preferably between about 4 and 6. To maintain the pH within the above range, an acid may be added to the reaction such as a mineral acid, for example hydrochloric acid, sulfuric acid, phosphoric acid, etc., or an organic acid such as a lower alkylcarboxylic acid, for example an alkylcarboxylic acid containing an alkyl group Cj to C ^. PH

6.

of an aqueous solution of sodium or calcium 2,5-diketogluconate produced by fermentation is usually less than 5 and such a solution can therefore be advantageously used in the reduction process of the invention.

The time required to complete the reduction depends on the temperature and the amounts of reagents used. However, reaction times are generally relatively short, the reaction being substantially completed in periods of from about 15 minutes to about 3 hours. When the selective reduction is complete, any unreacted 2,5-diketogluconate can be recycled for further reaction, or it can be efficiently separated from the reaction mixture by heating with an acid or a base, followed by filtration.

The 2-ketogulonate formed in the above process can be isolated, with lesser amounts of 2-ketogluconate, by filtration of the reaction mixture, by adjusting the pH of the filtrate to a value of about 1.5 to 2 by addition of an acid such as concentrated sulfuric acid and separating it by filtration and then throwing away any precipitate which has formed. The desired product can be collected by removing the water or the hydro-organic co-solvent, for example by lyophilization or heating under reduced pressure. The ratio of 2-ketogulonic acid to 2-ketogluconic acid in the mixture can be determined by gas and liquid chromatography of pertrimethylsilylated methyl esters using an "0V-210" column (Ohio Valley Specialty Co.) d '' about 1.5 m at 135 ° C. However, other methods of analysis can be used, such as liquid chromatography or thin layer chromatography. The 2-ketogulonic acid formed in the reduction process of the invention can be easily converted to ascorbic acid by means known in the art. The small amounts of 2-ketogluconate contained in the reaction mixture can be separated, for example by chromatography, and the 2-ketogulonate can be converted to ascorbic acid. However, the mixture of 2-ketogulonate and small amounts of 2-ketogluconate can be used directly in the subsequent reaction, the 2-ketogluconate being converted to erythorbic acid which can be separated from the ascorbic acid formed. So, for example, the mixture of 2-keto acids can. be converted to methyl esters by heating under reflux in methanol in the presence of an acid catalyst such as hydrochloric acid or a sulfonic ion exchange resin for about 3 to 24 hours. Other esters can be formed in this way, when the corresponding alcohol is used.

The esters are formed directly when an alkyl ester of 2,5-7 acid.

diketogluconic is the starting material for selective reduction.

The mixture of methyl esters can be separated and is then heated under reflux in methanol in the presence of a base such as sodium bicarbonate *, in an inert atmosphere. Upon cooling, ascorbate and sodium erythorbate separate by precipitation. The crude salts are collected by filtration, mixed with water and deionized with a cation exchange resin such as "Dowex 50" resin (Dow Chemical Co.). The water is removed and the ascorbic and erythorbic acids are recrystallized from a mixture of methanol and water to give ascorbic acid containing small amounts of erythorbic acid. If necessary, ascorbic acid can be obtained by recrystallization, for example in a methanol and water solution at ¢: 1. Other suitable solvents or co-solvents can be used if necessary. The methyl esters of 2-ketogulonic acid and 2-ketogluconic acid can optionally be separated and converted to ascorbic acid and erythorbic acid, respectively, under the same conditions as described above with regard to the mixture of 'esters. Ascorbic acid can also be selectively prepared from 2-ketogulonate containing small amounts of 2-ketogluconate, obtained by the reduction process of the invention by heating in a suitable organic solvent such as benzene, toluene, xylene, etc., at a temperature of about 50 to 130 ° C, preferably 60 to 90 ° C, in the presence of an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid and sulfonic ion exchange resins, although other similar acids can be used. Hydrochloric acid is a popular acid. After heating for a period of about 3 to 12 hours depending on the reaction used, the lactonization of the 2-ketogulonate to ascorbic acid is substantially complete. In this process, erythorbic acid is not produced from the small amounts of 2-ketogluconate present, and therefore this process constitutes a simple process for the selective formation of ascorbic acid from the product of the reduction reaction. with aminoborane according to the invention.

The present invention is illustrated by the following examples, given however without limitation.

EXAMPLE 1 ¢ 6 g (1.07 mole) of borane-dimethylamine complex is added to 100 ml of a 15% (w / v) aqueous solution of 2,5-diketogluconic acid. at a temperature of 6 to 8 ° C and at a pH of 3.0. After one hour, the high performance liquid chromatographic analysis s.

(resin "Aminex A-21" in formate form, ammonium formate buffer of pH 5.0) indicates that the reduction has taken place completely, then 30 ml of acetone are added and the solution is poured slowly into a 150 ml suspension * of "Dowex 50" ion exchange resin (hydrogen form). When the evolution of hydrogen has ceased, the resin is removed by filtration, the solvent is removed on a rotary evaporator and the residue is placed in 200 ml of anhydrous methanol. A catalyst consisting of ion exchange resin "Amberlyst 15" (20 ml, hydrogen form) is added and the azeotrope methanol / trimethylborate is distilled off at atmospheric pressure, with concomitant esterification of 2- acid. ketogulonic. The methanolic solution is filtered and reduced to a volume of 30 ml, then crystallization takes place, allowing the isolation of 6.9 g of methyl 2-ketogulonate (melting point 152-154 ° C; the literature indicates 153- 154 ° C). The mother liquor is evaporated in vacuo to a solid substance containing 3.5 g of methyl 2-ketogulonate and methyl 2-ketogluconate in a ratio of 77:23 (from analysis by gas chromatography and liquid of methylated esters persilylated on column "OV-210" from 1.5 m at 135 ° C), which corresponds to a stereoselectivity of overall reduction 2-ketogulonic acid: 2-ketogluconic acid of 92: 8.

EXAMPLE 2

The procedure of Example 1 is repeated while maintaining the pH at 3.5 by adding 6N hydrochloric acid. Analysis by high performance liquid chromatography (ion exchange resin "Dowex 50" under the calcium form, 0.01 M calcium chloride buffer, pH 8) after 3 hours at 0 ° C reveals the presence of 2-ketogulonate and 2-ketogluconate in a ratio of 94: 6. The reaction mixture is treated as described in Example 1, which gives, after esterification, a 96: 4 mixture (according to analysis by gas and liquid chromatography) of methyl 2-ketogulonate and 2 -methyl ketogluconate.

EXAMPLES 3 to 23. The reduction of sodium 2,5-diketogluconate was carried out with various aminoboranes, under different temperature and pH conditions, by the following procedure: the solid aminoborane is added in a single portion to a stirred solution of 10, 5% w / v of 2,5-sodium diketogluconate at the temperature and pH indicated. The reactions are followed to assess their degree of completion by chromatographic analysis.

high performance liquid phase graphics ("Aminex 25" resin in formate form, ammonium formate buffer, pH 5.3) and yields are determined by analysis by high performance liquid phase chromatography using an internal standard based on hydride equivalents. The ratios of 2-ketogulonic and 2-ketogluconic acids in Examples 3 to 20 were determined by conversion as described in Example 1 to corresponding methyl esters and by analysis by gas and liquid chromatography of their corresponding pertrimethylsilylated methyl esters (column "OV-210" from 1.5 m at 135 ° C). The ratios of 2-10 ketogulonic acid to 2-ketogluconic acid in Examples 21 to 23 were determined by conversion to ascorbic and erythorbic acids and analysis of their corresponding pertrimethylsilylated methyl esters by gas and liquid chromatography of the as described above.

The results obtained are summarized below.

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Claims (9)

1. Process for the production of a 2-ketogulonate, characterized in that it consists in reducing a 2-diketogluconate with an aminoborane chosen between * aminoboranes of formula RjR ^ HN.BH ^ and pyridinoborane in solution at 5 pH from about 2 to 7 and at a temperature of about -20 to 70 ° C, and R2 ′ being each chosen from hydrogen and alkyl radicals from to and 2.5-diketogluconate being chosen from acid 2.5 -diketogluconic, an n-alkyl ester of said acid, the alkyl group of which comprises 1 to carbon atoms, and a salt of said acid having a complementary ion chosen from an alkali metal, an alkaline earth metal, the ammonium ion and an ion tetraalkylammonium having 1 to 4 carbon atoms in each alkyl group. 2. Method according to claim 1, characterized in that the aminoborane corresponds to the formula Rj ^ HN.BH ^. 3. Method according to claim 2, characterized in that R ^ 15 "and R2 each represent a hydrogen atom. 4. Method according to claim 2, characterized in that Rj and R2 each represent a methyl group. 5. Method according to claim 2, characterized in that R ^ is a tert-butyl group and R2 is a hydrogen atom. 6. - Method according to claim 1, characterized in that the aminoborane is pyridinoborane. 7. Method according to claim 1, characterized in that the reduction is carried out in aqueous solution at a pH of 4 to 6 and at a temperature of 0 to 25 ° C. 25 S. - Process according to claim 7, characterized in that the 2.5-diketogluconate is sodium 2,5-diketogluconate, calcium 2,5-diketo-gluconate or methyl 2,5-diketogluconate, that l 'is used in an amount of 5 to 20% by weight of said solution. 9. Method according to claim 8, characterized in that the amount used of aminoborane is between 0.30 and 0.4 mole. 10. Method according to claim 9, characterized in that the aqueous solution contains a cosolvent chosen between an alkanol having 1 to 4 „carbon atoms and an alkanediol having 2 to 4 carbon atoms. h t