DE1159928B - Process for the preparation of ªÏ, ªÏ-dialkoxycarboxylic acid esters - Google Patents

Description

GERMAN

PATENT OFFICE

M 44740 IVb / 12 ο

REGISTRATION DATE: MARCH 22, 1960

NOTICE THE REGISTRATION AND ISSUE OF EDITORIAL: DECEMBER 27, 1963

are ω-formylcarboxylic acids and ω-formyl alcohols important intermediates in the synthesis of various natural products, such as B. biotin, lipoic acid or actithiazinic acid. So far, they have been reproduced by reducing the corresponding acid chlorides Rosenmund here. The acid chlorides of the dicarboxylic acid half-esters used as starting material however, they are difficult to access.

The invention was therefore based on the object of finding a method that allows simple, economically feasible way to obtain the above intermediates.

It has been found that, starting from compounds of the general formula

OR Process for the production of ω, ω-dialkoxycarboxylic acid esters

Applicant:

E. Merck Aktiengesellschaft, Darmstadt, Frankfurter Str. 250

in which R is an alkyl or - CO - alkyl group and η is a number from 1 to 4, by ozonization, catalytic hydrogenation and acetalization without isolation of the intermediates ω, ω-dialkoxycarboxylic acid esters of the general formula

O - alkyl

(CHo) _n /

\ / ^CH \

ORi

in which η has the meaning given and

OR Dipl.-Chem. Dr. Ulrich Schmidt

and Dipl.-Chem. Paul Grafen, Freiburg (Breisgau), have been named as the inventor

Means methyl or ethyl, can produce. These can be obtained in good yields in a manner known per se by reduction and / or hydrolysis into the abovementioned ω-formylcarboxylic acids or -Convert alcohol.

The ozone breakdown of etherified or esterified enols has not yet been known.

The process of the invention proceeds according to the following reaction scheme:

OR

+ O ₃

/ Ο - alkyl

C = O
(CH ₂ ) ,, / ORi

X / ^CH \
^ ^{7 X} ORi

IV

Acetalization

III

In detail one proceeds so that one first a cycloalkenyl ether or ester of general formula I in a suitable solvent, e.g. B. in alcohol, dissolves and through treatment

309 770/466

converted with ozone into the corresponding ozonide (II). The case to be maintained temperature is advantageously at 0 to -2O ⁰ C, but also lower temperatures may be used. Without prior isolation, the ozonide is mixed with a hydrogenation catalyst, for example with a palladium-barium carbonate or a palladium-calcium carbonate catalyst, and hydrogenated in the customary manner under normal pressure. After the hydrogenation has ended, the catalyst is filtered off and the solvent is removed in vacuo. The residue is dissolved in alcohol, refluxed with acetalizing agents such as orthoformic acid ester, alcohol-acid or diethyl sulfite and the ω, ω-dialkoxyalkanecarboxylic acid ester (IV) formed is distilled in vacuo.

If a cycloalkenyl ether is used as the starting material, an ω, ω-dialkoxycarboxylic acid ester is also obtained as in the implementation of a cycloalkenyl ester, since the acetalization results in an ester of the formula (R = CO - alkyl) mixed anhydride formed as an intermediate is cleaved; the acetalizing agent then immediately esterifies the resulting carboxyl group.

The compounds obtained by the process according to the invention can be stored easily without any signs of decomposition or condensation.

Cycloalkenyl ethers and esters which are easy to use are preferably used as the starting material accessible cyclic ketones are based. Examples are cyclohexanone and cycloheptanone or cyclooctanone. The cycloalkenyl ethers and esters can be derived from these ketones, for example according to information in the "Journal of American Chemical Society", vol. 80, p. 6044, or "Chemical Abstracts", Vol. 49, p. 2470, produce in excellent yield.

As already mentioned, the acetal esters obtained should be used as intermediates in the synthesis of therapeutically valuable natural substances. You can z. B. easily and in good yield in a conventional manner, e.g. B. using lithium aluminum hydride or sodium and alcohol according to the Bouveault-Blanc method to the corresponding ω, ω - reduce dialkoxy alcohols. The corresponding cu-formyl alcohols can be prepared therefrom in a manner known per se by treatment with acids.

Since the acetal group of the acetal esters obtained according to the invention can easily be split off by acids is, by the action of acids on the ω, ω-dialkoxycarboxylic acid esters, the corresponding cü-Formylcarbonsäureester or after subsequent Saponification also produce the co-formylcarboxylic acids in good yield.

example 1
ω, ω-diethoxyoctanoic acid ethyl ester

a) from cyclooctenyl ether

17.1 g of cyclooctenyl ether ( ^x / io mol of an approximately 90% strength product) are dissolved in 100 ml of acid-free absolute alcohol and ozonated at 0 ° C. The solution of the ozonide is mixed with the alcoholic suspension of 1.5 g of a freshly reduced 5% palladium-calcium carbonate catalyst and initially hydrogenated at normal pressure while cooling with ice. The uptake of hydrogen is over after about 2 hours. The catalyst is filtered off and the solvent is removed in vacuo. The residue is mixed with 20 ml of absolute alcohol, 20 g of diethyl sulfite and a drop of concentrated sulfuric acid and refluxed until the evolution of SO2 has ceased. After neutralization of the catalyst with sodium carbonate or sodium ethylate solution, the volatile components of the reaction mixture are removed in vacuo and the residue is distilled in vacuo. The ω, ω-diethoxy-octansäureäthylester distilled at 0.5 Torr 100-103 ⁰ C. Yield: 16 g (= 62% of theory); η = 1.4357; Dinitrophenylhydrazone, m.p. = 70 to 71 ° C.

b) from cyclooctenyl-1-acetate

15 g cyclooctenyl-1-acetate in 50 cc of absolute ozonated Essigester at 0 ⁰ C. After adding 50 ecm of dry ethanol and 1.5 g of a freshly reduced Pd - BaCOa catalyst, the solution of the ozonide is hydrogenated at normal pressure with ice cooling. After the solvent has been distilled off in vacuo, the residue is taken up in absolute ethanol, refluxed with 30 g of diethyl sulfite and a drop of sulfuric acid for 24 hours and then evaporated in vacuo. The residue is taken up in ether, the ethereal solution is washed with soda solution and water, dried and then distilled in vacuo. Yield: 12.1 g (= 52% of theory). ω, ω-diethoxyoctanoic acid ethyl ester with a boiling point of 0.1 = 75 to 85 ° C.

Example 2
ω, ω-diethoxyhexanoic acid ethyl ester

12.6 g (Vio mol) Cyclohexenyläther are dissolved in 100 ml of absolute alcohol and acid-free ozonized at 0 ⁰ C. The solution of the ozonide is hydrogenated with 1.5 g of a freshly reduced 5% Pd - BaCO3 catalyst with initial ice cooling at normal pressure. The hydrogenation is over after about 2 hours (check for ozonide with an acidic KJ-starch solution). The catalyst is filtered off, the solvent is distilled off in vacuo and the residue is refluxed for 1 hour with 20 ml of alcohol, 20 g of ethyl orthoformate and a drop of concentrated sulfuric acid. The solution is then neutralized and distilled in vacuo. The ω, ω-diethoxyhexanoic acid ethyl ester distills at 15 torr between 128 and 132 ° C. Yield: 14 g (= 60.3% of theory) 2,4-dinitrophenylhydrazone; F. = 75 to 76 ° C.

Claims (1)

PATENT CLAIM: Process for the preparation of ω, ω-dialkoxycarboxylic acid esters the general formula / O - alkyl C = O
(CH ₈ ) * / ORi X / ^CH \
^ ^X ORi in which η is a number from 1 to 4 and Ri is methyl or ethyl, characterized in that 5 6 that one is a compound of the general in which R is an alkyl or - CO - alkyl group Formula OR ^unc * ⁿ ^ ^ε ° bige meaning on each other then with ozone, hydrogen and an acetalizing agent without isolating Zwi-5 products. © 309 770/466 12.63