DE1593190A1 - Oxalic acid monomethyl ester anhydride (methoxalic acid anhydride) and process for its preparation - Google Patents

Description

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Oxalic acid monomethyl ester anhydride (methoxalic acid anhydride) and its method of manufacture

Methoxalic acid ester of the general formula

R-OC-COOCH ₅

where R is an alcoholate residue other than OCH, Ms are now only little known / e.g. with R = OCpHp-: Liebigs Annalen der Chemie, Volume 253, page 290 (1889); with R s OCH (CH ₃ ) C ₆ H ₁ ^ i Journal of the Chemical Society (London), Volume 123 (1), Page 35 (1923); with R = OCpH.OHrReichte der Deutschen Chemischen Gesellschaft, Volume 64, Page 1758 (193117) and have so far not acquired any significance.

The preparation of such methoxalic acid esters by esterification of primary and secondary alcohols which are comparatively easy to acylate with the long-known methoxalyl chloride / CH ₅ OOC-COCl; Liebig's Annalen der Chemie, Volume 253, Page 289 (1889] [7i * i The presence of organic bases gives only moderate results because of the great aggressiveness of the acid chloride. Tertiary alcohols give no esters at all.

Another possibility for the preparation of methoxalic acid esters consisted theoretically in the use of the probable milder acting methoxalic anhydride of the formula

CH ₅ OOC-Co-O-CO-COOCH ₃

as acylating agent (Houben-Weyl, methods of organic Chemie, Georg Thieme Verlag, Stuttgart, 4th edition 1952, volume 8, page 547, 3rd line of text from the bottom).

BATH ORIGINAL

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Now methoxalic anhydride has not been produced up to now, probably out of the fear that as a result of it unusual constitution would not be able to exist, all the more so, as a previously described mixed anhydride of oxalic acid and acetic acid of the formula

Ch ₃ CO-O-CO-CO-O-COCH ₃

proved to be very unstable and for acylation purposes in practice as proved useless. It could be obtained from silver oxalate and acetyl chloride in a yield of only 9 # of theory / Journal of the American Chemical Society, Volume 75, Pages 3587 3589 (195317

Surprisingly, it has now been found that the anhydride of oxalic acid monomethyl ester - abbreviated as methoxalic anhydride, conveniently and cheaply in excellent, if certain conditions are met Yield (over 90 # of theory) can be produced without decomposition occurring.

Methoxalsäureanhydrid is up to 80 ⁰ C completely stable both in solid form and in benzene solution at temperatures. It can be in a high vacuum distillation (bp _{Q3 n} = 70 - 80 ^0C) and crystallized from benzene in plates at 65 - 67 ⁰ C melt. With water it is hydrolyzed to the oxalic acid monomethyl ester in a few seconds. Pyridine decomposes methoxalic anhydride very slowly at room temperature to products of unknown structure; with stronger organic bases, for example with triethylamine, this decomposition takes place more quickly.

Methoxalic anhydride is an extremely active carboxylic acid anhydride. It is suitable for acylating hydroxyl groups that are difficult to esterify, even those that were previously not considered esterifiable. This one Esterifications take place practically quantitatively, methoxalic anhydride can be used for the quantitative determination of hydroxyl groups

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use. Another possible use is manufacturing water-soluble derivatives of water-insoluble alcohols. Finally, methoxalic anhydride is a selective one Separation of alcohols from mixtures possible. Surprisingly, methoxalic anhydride does not react with keto groups.

Primary and secondary alcohols are produced by methoxalic anhydride in a dilute benzene solution (about 0.25 molar) at room temperature Quantitatively esterified in a few minutes, tertiary alcohols in an average of 2-3 days.

This esterification process cannot be used with some alcohols, however, because the very strong ΒψίΤβ oxalic acid monomethyl ester (K = 10 "°) released during the reaction causes dehydration (eg with linalool and with ß-dimethylnaphthylcarbinol).

It has also proven to be a general working instruction for esterification using methoxalic anhydride, working with the addition of pyridine. Although the Methoxalsäureanhydrid is decomposed by pyridine though, this decomposition, however, takes place at temperatures below 1O ⁰ C slowly that even under these conditions the accuracy of quantitative Hydroxylgruppenbestimmung hardly suffers.

Under Pyridinzusatz also tertiary alcohols are esterified quantitatively by Methoxalsäureanhydrid at temperatures between 0 and 10 ⁰ C under low heat in a few minutes. Even the sterically hindered 11β-hydroxyl group in steroids, such as in dihydrocortisone, is acylated quantitatively in less than 15 minutes under these conditions.

The acylation with methoxaü acid anhydride, which proceeds quantitatively and without side reactions, can be used to determine the hydroxyl group use in alcohols that are difficult to esterify (especially tertiary). The results obtained by determining the difference between

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The insert and blank obtained are within an error limit of 0.4 ^. In the case of hydroxyl groups that are difficult to esterify, including those in the 11ß-position in hydrocortisone, such a determination can be completed in less than 45 minutes. The acylation with formic acid-acetic acid takes a comparatively long time anhydride approx. 72 hours.

For the determination, the sample and a blank sample are "left ^{to stand for 15 minutes at 5 10 0} C with an excess of methoxalic anhydride in benzene and a little more pyridine than the amount of methoxalic anhydride used. the benzene phases are washed twice with a little water and the combined aqueous solutions are titrated with 0, in carbonate-free lye (phenolphthalein as indicator) until the red color remains at the top. The difference between sample and blank gives the hydroxyl number or the molecular weight. The resulting, in the benzene phase dissolved methoxalic acid esters can now be used in a variety of ways.

Once here, as with normal esters, the hydroxyl group is blocked, which leads to operations at other parts of the molecule be made possible without attacking the former. One example is the hydrocortisone family, where the 1Iß-hydroxyl group has hitherto been used only in an often non-quantitative way by formic acid or trifluoroacetic acid could be protected.

The esterification with common fatty acid anhydrides led here to esters that could no longer be hydrolyzed afterwards. The oxalic acid residue, on the other hand, is comparatively easy to split off.

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Next, neutral oxalic acid esters are compared to normal ones Fatty acid esters are saponified under alkaline conditions in an unusual manner, which has been observed in particular in the case of symmetrical oxalic acid esters / Monthly books for chemistry, Volume 38, page 159 (1917); Volume 39, pages 495, 697 and 765 (1918); Volume 41, page 339 (1920) /. For example, the rate of alkaline saponification of dimethyl oxalate is (compared to that of methyl acetate = 1):

Dimethyl ester monomethyl ^{ester salt oxalic} acid

This ratio is now shifted when there is a methyl group is replaced by a group that is more difficult to saponify. at Our own experiments have found that the alkaline saponification of methoxalic acid esters

with primary alcohols 0 - 60 # of theory, with secondary alcohols 60 - 98 $ of theory and in the case of tertiary alcohols, 93-98% of the theory of monoesters

results. Taking this and the above series of data into account, it is evident that methoxalic acid esters in particular are difficult to use saponifiable alcohol residues give the best yields of monoesters with partial alkaline saponification. The partial saponification can be done in several ways. Boiling the methoxalic acid esters for 3 to 5 hours has proven to be particularly advantageous Proven in aqueous acetone with triethylamine. The acetone and most of the triethylamine are then distilled off. After diluting the mostly very hydrotropic monooxalate solution Neutral parts, e.g. ketones, common fatty acid esters or phenols are removed by extraction with a lipoid solvent. the The aqueous phase now contains exclusively the oxalic acid monoester salts of alcohols, from which any by double reaction other "salts" can be prepared. Some of these salts can be used as water-soluble derivatives of alcohols Find. The oxalic acid monoester salts primary and secondary

However, alcohols are not very stable and hydrolyze after a while; however, those of tertiary alcohols are largely durable. Also the 11ß-oxalates of the hydrocortisone series are very stable and can therefore replace 21-esters, which can only be stored in solid form. Are under aggravated conditions but they are still hydrolyzable.

The total hydrolysis of such ester salts is comparatively gentle, since the hydrolysis of the second ester group is almost ten times as fast as with common fatty acid esters. In general, letting the solution stand for one day with about 2 to 5 ° alkali hydroxide is sufficient.

Incidentally, at this stage, by careful partial hydrolysis, primary and secondary alcohols can largely be removed tertiary separate. For example, the alkaline solution is simply shaken out at intervals with lipoid solvents. The easier Saponifiable esters of primary and secondary alcohols are hydrolyzed first.

It is surprisingly found that the method for determining or for the purification and / or separation of alcohols by means of methoxalic anhydride, especially in the case of otherwise difficult esterifiable alcohols can be used, i.e. in a body class in which such manipulations have so far mostly been used difficult or impossible to carry out on a preparative scale.

A particular advantage of the use of methoxalic anhydride for the separation and / or purification of alcohols should be emphasized, that all operations, as described above, are carried out in a weakly alkaline medium, in which alcohols usually are stable.

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Methoxalic anhydride is preferably prepared by reacting methoxalyl chloride with a salt of oxalic acid monomethyl ester. The use of the potassium salt is preferred, but the salt of an organic base, for example pyridinium methoxalate, can also be used. The reactants, of which the salt is expediently present in a slight excess, are boiled for a few hours in a non-polar solvent such as benzene or toluene. The reaction mixture is then filtered hot. Most of the aeine methoxalic anhydride crystallizes out of the piltrate on cooling.

In another procedural r s is Methoxalsäureanhydrid can be represented by hei low temperature, for example, can be, at -40 to -45 ⁰ C to a solution of toluene initially Methoxalylchlorid in pyridine and then added dropwise slowly Oxalsäuremonomethylester.

Finally, methoxalic anhydride is also obtained by adding the precisely calculated equimolar amount of pyridine or another weak organic base such as thiazole to an equimolar mixture of methoxalyl chloride and oxalic acid monomethyl ester at low temperature. The equimolar mixture of methoxalyl chloride and oxalic acid monomethyl ester is advantageously prepared by adding methoxalyl chloride to half the molar amount of water.

Methoxalic anhydride is therefore a versatile, valuable compound. It can be used, inter alia, for the preparation of esters which are difficult to esterify, with weak tertiary organic bases being advantageously added to the acylation mixture in a stoichiometric excess over the methoxalic anhydride. For the production of heavy Estersalzen esterifiable alcohols which Methoxalsäureester obtained with weak basic agents are partially hydrolyzed, preferably with triethylamine in aqueous acetone. To separate alcohols which are difficult to esterify from mixtures, the ester salt solutions obtained therefrom are extracted with lipoid solvents and then completely saponified with stronger alkali.

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example 1

In a 1 liter three-necked flask with stirrer, dropping funnel and descending cooler, 156 g of the potassium salt of oxalic acid monomethyl ester (1.1 mol) are suspended in 350 ml of benzene and 150 ml of benzene are then distilled off in an oil bath to remove moisture. Then the descending condenser is replaced by a reflux condenser fitted with a calcium chloride tube. After cooling the flask contents at 40 - 50 ⁰ C, a solution of 122 g Methoxalylchlorid (1 mole) in 150 ml of dry benzene for 15 minutes is added dropwise with continuous stirring. The reaction mixture is then refluxed for two hours with constant stirring. The mushy then reaction mass is allowed to approximately 50 ⁰ O cool, then filtered through a cloth and wash the group consisting of potassium chloride filter cake thoroughly with 200 ml warm benzene. Upon cooling to about 6 - 10 ⁰ C, the colorless filtrate suddenly solidified. In order to obtain large crystals, it is necessary to let the filtrate cool down slowly within 2-3 days and, if necessary, to add seed crystals. The yield of Methoxalsäureanhydrid is about $ 95> theory (based on Methoxalylchlorid). Mp. 65 - 67 ⁰ C.

Analysis: Calculated for CgHgO ^: C 37.9 # H 3.2 # 0 58.9 # Found C 37.7 Ί ° Η 3.3 S ^

Example 2

The procedure is as in Example 1, except that 190 g of pyridinium methoxalate (1.04 mol) are used instead of the potassium methoxalate. The yield of methoxalic anhydride is about 80 56 of theory (based on methoxalyl chloride). Inoculation is usually necessary for crystallization. However, the benzene solution is also directly suitable for most purposes. But the final product may also, after distilling off the benzene by high vacuum distillation (Kp _QQ 70 - 80 ⁰ C) to be cleaned.

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Example 3

122 g of methoxalyl chloride (1 mol) in 220 ml of toluene are placed in a 2-liter round-bottom flask equipped with a stirrer, dropping funnel and gas equalization tube with a calcium chloride seal, carefully excluding moisture. The flask is in a cold mixture, the temperature of which is kept at about -40 "to -45 ° 0. With vigorous stirring, a solution of 79 g of pure pyridine (1 mol) in 250 ml of toluene is added dropwise over the course of 30 minutes, and immediately thereafter a solution of 105 g (1 mol) of freshly distilled oxalic acid monomethyl ester (bp ₁₂ 1 ° ⁸ - ¹ ° 9 ° ^c ) ⁱⁿ 400 ml of toluene with continued vigorous stirring within 30 minutes. Stirring is continued for 30 minutes, then the cold mixture is removed and the reaction mixture slowly to +40 - heated 45 ⁰ C the reaction mixture is filtered and evaporated in vacuo the Piltrat is obtained in yields up to 90 Methoxalsäureanhydrid io of theory...

Example 4

In a 2 liter round bottom flask equipped with a stirrer and dropping funnel, 184 g of methoxalyl chloride (1.5 mol) are dissolved in 250 ml of anhydrous tetrahydrofuran and, while stirring and cooling with ice water, a mixture of 100 ml of tetrahydrofuran and 13.5 g of water (0.75 g Mol) was added dropwise over the course of 15 minutes. A solution of 118 g of pyridine (1.5 mol) in 300 ml of tetrahydrofuran is then added dropwise over the course of 30 minutes with vigorous stirring, the reaction flask still being cooled with ice water. After stirring for a further 30 minutes, the pasty reaction mixture is filtered off from the sparingly soluble pyridinium hydrochloride and the filter cake is washed thoroughly with 300 ml of tetrahydrofuran. The tetrahydrofuran is distilled off from the filtrate and the methoxalic anhydride is then distilled in vacuo (boiling point _{0 1} ^{85-90 0} C). The yield is about 83 fi of theory.

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Claims (5)

P at correspondence 1. Oxalic acid monomethyl ester anhydride (methoxalic acid anhydride) 2. Process for the preparation of methoxalic anhydride, thereby characterized in that one oxalic acid monomethyl ester or a salt of oxalic acid monomethyl ester with the equimolar amount Methoxalyl chloride converts. 3. The method according to claim 2, characterized in that the Ealiumsalz or the salt of oxalic acid monomethyl ester the salt of a tertiary organic base, preferably the pyridinium salt, is used. 4. The method according to claim 1, characterized in that oxalic acid monomethyl ester with a mixture of methoxalyl chloride and a tertiary organic base in a molar ratio of 1: 1: 1. 5. The method according to claim 1, characterized in that there is an equimolar mixture of oxalic acid monomethyl ester and Reacts methoxalyl chloride with the calculated amount of a weak tertiary organic base. 009818/1783 NeU6 documents (Art. 7 § I Aba. ·> No. 1 SM · 3 -ic « Amendment of 4. 9,196 ?!