1. Field of the Invention
The invention relates to the preparation of ortho-amides (alkoxy-aminomethanes), which include the two groups of the dialkoxy-dialkylaminomethanes (DMF acetals) and alkoxy-bis(dialkylamino)-methanes (aminal esters); to prepare them, highly active alcoholate suspensions are employed. DMF acetals and aminal esters are reactive C.sub.1 units for the aminomethylenation of C-H-acidic compounds. These aminomethylenated substances represent valuable intermediates for the synthesis of heterocycles such as indoles, pyrimidines, pyridines and quinolonecarboxylic acids.
2. Description of the Related Art
To prepare ortho-amides, alkoxy groups can be replaced in a stepwise manner with amino groups on an acid catalyst by reaction of ortho-esters with secondary amines. However, the equilibrium is slanted towards the ortho-esters, a targeted exchange of one or two alkoxy groups is difficult, so that this method is mostly used for synthesising trisaminomethanes (DE-OS (German Published Specification) 2,214,497).
The use of chloroform instead of the ortho-esters (Rec. Trav. Chem. Pays-Bas 88 (1969), 289; DE-AS (German Published Specification) 1,161,285) has not proved to be very appropriate.
A selective preparation of DMF acetals and aminal esters is furthermore possible by reacting alkoxyiminomethylene salts or formamidiniumsalts with alcoholares (Chem. Bet. 101 (1968), 41). The yields in the case of five different aminal esters are between 62 and 72%, and in the case of one aminal ester 79%; in the case of 14 different amide acetals they are between 42 and 63%, while DMF dimethyl acetal is said to be obtainable in 75-87% of the theoretical yield. However, DMF dimethyl acetal is reported, in DD 94,359, to be obtainable in not more than 50-55% by this process because of decomposition. According to the description in Helv. Chim. Acta 48 (1965), 1746, this method gives the DMF dimethyl acetal in a yield of only 37% of the theoretical yield.
DE-AS (German Published Specification) 1,205,548 describes the preparation of a range of aminal esters. Yields of 62-77% are obtained using a 10% excess of expensive, alcohol-free alcoholate. It was impossible to confirm the statement that, starting from raw formamidinium salt which contains one equivalent of methanol for production reasons, the methyl aminal ester is obtained in 68% of the theoretical yield. When the synthesis was reproduced, the result was a 1.8:1 amide acetal/aminal ester mixture in 65% of the theoretical yield.
Following U.S. Pat. No. 3,239,534 and without using a solvent, 19.1% of the theoretical yield of DMF acetal was obtained from dimethylformamide, dimethyl sulphate and alcoholate, and 25.6% of aminal ester with the additional use of dimethylamine.
The reaction of bis (dialkylamino)-acetonitriles with alcoholares (Chem. Bet. 105 (1972 ), 1340 ) is described as an elegant, homogeneously proceeding reaction. The yields of aminal esters are around 76-84%, however, the preparation of the acetonitriles used is only possible in 53% of the theoretical yield starting from the formamidinium salts (Chem. Ber. 104 (1971 ), 924 ).
Synthesis of DMF acetal is also possible by reacting two equivalents of alcoholate with amide chlorides (Angew. Chem. 72 (1969), 836; BE 598,238). However, when they are prepared from dialkylformamides using chlorinating agents such as POCl.sub.3, SOCl.sub.2 and others, the carcinogenic carbamide chlorides are always formed as by-products.
Besides the varying yields of 40-75%, which are relatively low for industrial syntheses, working-up as is known from the literature is not suitable for an industrial process. If, after the reaction to give the orthoamide, first the solvent and then the desired product is removed from the salt residue by distillation, the result is, according to DD 94,359, decomposition reactions and yield losses. This is why this Patent Specification attempts to increase the yield to 85% by entraining the product using methanol. However, this process entails large amounts of solvent to be distilled twice. Furthermore, separation of methanol and DMF dimethyl acetal by distillation is difficult. Moreover, when the synthesis was reproduced, the high yield indicated could not be obtained.
The previous removal of the salts is also problematic. On the one hand, methylsulphates are partially soluble in polar media such as, for example, alcohols, on the other hand, they are obtained in gel-like, lumpy or very finely crystalline form, depending on solvent and how the reaction is carried out, which makes filtration very difficult.
Aqueous working-up is impossible because of the sensitivity of the ortho-amides to hydrolysis.
USPTO Backgrounds
USPTO Backgrounds