HU182767B - Process for producing compounds containing amino-methylene-carbonyl-groups - Google Patents

Abstract

The present invention relates to a novel process for the preparation of aminomethylene carbonyl derivatives of formula (I), wherein R1 and R2 together represent -O-CH2jm-O- wherein m is 1 or 2 R3 and R4 are -CN, -COCH3 or -COOC2H5 - , wherein R1 and R2 are as defined above, such that an amine of formula II wherein R * and R2 are as defined above are condensed with an equimolar amount of orthoethyl formate at a temperature of from 90 to 110C. in the presence of an amount of acid, preferably acetic acid, followed by formimino ether of formula III, wherein R1 and R2 are as defined above, preferably without isolation of a compound of formula IV wherein B is (V) or (VI). in which R 'is added to an ethoxy or methyl group for the carbanion addition of the compounds of formula VII wherein R3 and R4 are as defined above. arbonyl derivative is formed at pH 11-14 in the presence of a catalytic amount of auxiliary base. According to the process, the compounds of formula (I) can be produced more economically, with lower yields, with lower yields than with the methods known to date. 'V V / V / l. -1-

Description

The present invention relates to a novel process for the preparation of aminoethylene carbonyl derivatives of the formula I wherein

2

R and R together represent -O- / CII ₂ / _m -O-, in which m represents 1 or 2, zn

R Ea R -GM, -COCH ^ or HCJ -C00C ₂ group, and

Formula II - wherein;

R ¹ and R ² are as defined above for an amine of formula II

- where. ₂

R ¹ and R ^ is as defined above is condensed with an equimolar amount ortoetil formate interest ⁹ catalytic amount of acid, preferably in the presence of eoetsav and III thus obtained - wherein

R ¹ and R ² are the above formylmino ether, preferably of the formula IV without isolation

- where R · ³

B is V is added to the anion which is added from the carbonyl derivative of formula VII where R < ⁴ > and R < ⁴ > are as defined above in the presence of a catalytic amount of auxiliary base at pH 11-14. Embodiment VII is provided. . 2,

As the interpretation of R ^x - IC, n and m remains unchanged in this specification, the list of possible meanings is omitted below.

The compounds of the present invention are valuable intermediates for the synthesis of various organic chemicals; in particular the production of quinoline derivatives which are useful as medicaments.

Several processes for the preparation of some of the target compounds of the present invention have been described. For example, 3,4-methylenedioxyaniline and ethoxymethylenemalonic acid diethyl ester are reacted for 3 hours at 100 ° C. French Patent No. 5,968,011, entitled Preparation of the corresponding diethyl esters of aminomethylene malonic acid. The product is purified by crystallization from ligroin.

These methods utilize the ethoxymethylenemalonic acid diethyl ester as an intermediate, which has also been reported in several processes. Thus, an oxycarbonyl compound, e.g. and malonic acid diethyl ester / and orthoethyl formate were reacted in the presence of Lewis acid and carboxylic anhydride J. Org. Chem., 11, 1946, 194, No. 2,426,964. Patent in the USSR. Also known is the reaction of diethyl malonic acid and orthoethyl formate with acetic acid at 150-210 ° C with continuous distillation of the ethanol formed. United States Patent Number /.

A disadvantage of these methods is that the orthoethyl formate used must be used in a significant amount below the carboxylic anhydride present and the resulting carboxylic acid. / The ethanol leaving the reaction esterifies the carboxylic acid and the water thus released attacks the orthoethyl formate. / Even so, the yields still do not exceed 75%. The purification of the product by fractional distillation is difficult due to the large number of by-products with nearly the same boiling point.

-2182.767

According to a further known method, J. Med.Chem.1968.11/1/160/ 3,4-methylenedioxyaniline and ethoxymethylenemalonic acid dlethyl ester are reacted for 3 hours at atmospheric pressure and then at 10-15 mmHg over a steam bath.

However, the disadvantage of this procedure is the same as mentioned above.

One of the bases of the present invention is the discovery that if the Formimino III general Formula III is of Formula VII. Reaction of the compounds of formula (VII) with the appropriate pH and in the presence of a suitable catalytic amount of auxiliary base, the highly reactive carbanion of formula (VII) (and not the enol) is added to the formiminoether derivative.

One of the foundations of our invention is the realization that post-addition elimination can be accelerated by acid catalysis. In this way, the whole process can be carried out at 125 ° C and, as the main reactions accelerate, the side reactions are suppressed.

We have found that the pH ranges from 11 to 14 correspond to the formation of carbanions of general formula IV from compounds of formula VII. For example, a suitable pH value for the diethyl ester of malonic acid is 13.5.

One advantage of our process is that it is not necessary to isolate the formimino ether of formula III. Because of the lower temperature, in this case, the undesirable diethoxymethyl malonate derivative may not be formed in advance.

For the formation of the formimino ether derivative, it has been found to be advantageous to use a catalytic amount of acid which is consumed at the completion of the reaction.

The process according to the present invention provides the following advantages over the synthesis via ethoxymethylenemalonate derivatives »

- orthoethyl formate need not be used in excess,

- the major part of the amine used is converted into its product form after it is not absorbed by the acid,

reactions can be conducted at lower temperatures, '

- the addition is made to the highly reactive carbanion which leads to a good yield.

- acid catalysis of the elimination step allows a low reaction temperature, the formimino ether derivative is further reacted without isolation,

- starting materials have a lower specific material consumption. Thus, according to our process, the compounds of the formula I can be obtained more economically, in a better yield, with a lower specific material consumption, than by the processes known hitherto.

In carrying out the process of the invention, the amine of the formula II and the orthoethyl formate are preferably reacted in molar equivalents, preferably at a temperature of 90 to 1100 ° C. in the presence of a catalytic amount of acid.

Preferably, the reaction is carried out using a reflux condenser, and only after the reaction is complete, the alcohol formed is distilled off, thus preventing a difficult to separate ethyl alcohol orthoethyl formate mixture from leaving the system, which would cause a loss. Yeah

To compound III182,767, compound VII, as well as buffer or auxiliary base for adjusting the pH, is added so that the reaction is carried out at a maximum of 125 ° C in a short time (1.5-2 hours).

Puffs are a mixture of a weak acid and a salt of a weak acid, preferably one of the following; acetic acid + sodium lumacetate, ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid, tributylbenzylammonium hydroxide + acetic acid. The salt component of the buffer mixture also serves as an auxiliary base. -. Among the compounds of formula VII, preference may be given to the use of ethyl cyanoacetic acid ester, methyl cyanoacetic acid or malonic acid dinitrile to form the carbanion at pH 11-14. When a malonic acid diethyl ester is used, a pH of about 13.5 is preferred. The compound of formula VII is preferably added in an excess of 10-40% by weight.

The following examples illustrate our process:

Example 1 5.4 g of methylene dioxylaniline, 90 g of orthoethyl formate and 3 ml of acetic acid were heated at reflux for 1.5 hours, then 45-50 ml of ethanol formed in the reaction using a Vigreux half-meal and a reflux condenser. distilled out.

To the residue containing N- (3,4-methylenedioxyphenyl) -formiminoethyl ether were added 105 g of malonic acid dlethyl ester, 3 g of anhydrous sodium acetate and 7 ml of acetic acid, and the reaction mixture was further heated to an internal temperature below 130 ° C. and the ethanol formed is continuously distilled off. Methanol (200 mL) was then added to the melt cooled below 100 ° C and stirred at room temperature for 2 hours and at 0 ° C for 3 hours.

The suspension is filtered, the crystals remaining on the filter are washed with chilled methanol, then suspended in 320 ml of water containing 1% acetic acid and stirred for 2 hours at room temperature. The crystalline material is then filtered off, washed with water and methanol and dried under infrared light to constant weight.

The product is 142 g of diethyl 3, 3- ^z- L-nitro-dioxyaniline-methylenemalonic acid. Mp: 105 ° C.

The product is 99 * 5% pure by UV spectrum. From the methanolic mother liquor, fractional distillate was used to recover 8-10 g of ethyl ortho formic acid and 7-θ g of malonic acid dlethyl ester.

Yield: 83% for 3,4-methylenedioxyaniline, 96-97% for ethyl ester of ortho formic acid and 85-89% for diethyl ester of malonic acid.

Example 2

Example 1 was repeated except that 5 g of Complexon III was used in place of sodium lumacetate. 140-143 g of 3,4-methylenedioxyanilomethylene malonic acid diethyl ester are obtained. 105 °

3 · Example

The procedure of Example 1 was followed except that 3 g of ethylenediaminetetraacetic acid was used in place of soda ash and acetic acid. 140 g of 3,4-methylenedioxyanilomethylenemalonic acid diethyl ester are obtained. Mp: 105 °

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Example 4

S-3,4-methylenedioxyaniline, 66 g of orthoethyl formate, g of malonic acid diethyl acetate, 3 g of glacial sodium acetate and 12 ml of acetic acid were spun into a thread. The mixture containing the N- (3,4-methylenedioxyphenyl) -formiminoethyl ether is then distilled off on a settling condenser to approx. 70 ml of ethanol, while the internal temperature was gradually raised to 140-145 ° C. The mixture is cooled to 90 DEG C. and 200 ml of absolute methanol are added. After filtration at 0 ° C, the precipitate was washed with methanol and then sealed. The product is diethyl ester of 3,4-methylenedioxyanilomethylene malonate. 105-106 ° C.

5 · Example

5,4-Methylenedioxyaniline, 66 g of orthoethyl formate, g of cyanoacetic acid ethyl ester, 4 g of glacial sodium acetate and 12 ml of acetic acid are refluxed for 1 hour. Subsequently, 70 ml of ethanol is distilled off from the mixture containing N- (3,4-methylenedioxyphenyl) -formin-o-ethyl ethyl acetate and evaporated at 80 [deg.] C., while maintaining the internal temperature at 145 [deg.] C. °. The mixture was cooled to 90 Οθ and 200 mL of methanol was added. After heating for 15 minutes, cool to 0 ° C, filter and wash with methanol. 93-99 g of ethyl 3,4-methylenedioxyanilomethylene cyanoacetate are obtained. Mp: 140142 ° C.

Example 6

Example 1 except that 2 g of trihutylbenzylammonium hydroxide was used instead of sodium acetate. The product is 140-144 g of 3,4-methylenedioxyanilomethylenemalonic acid dlethyl ester. 105 °.

7 · example

Example 1 was repeated except that 75 S ethyl acetate was used in place of the malonic acid diethyl ester. 135-157 g of 3,4-methylenedioxyanileacetacetic acid ethyl ester. M.p. 113-115 ° C.

Claims (6)

A process for the preparation of aminomethylene carbonyl derivatives of formula I wherein: 1 2 R and R together are -O-ZdIg / O, wherein m is 1 or 2, R 4 and R ⁴ represent -CN, - COCH 2 - or -COC 6 H 2 - using an amine of formula II, orthoethyl formate and carbonyls of formula VII, wherein R 1 and R 2 are as defined above, to catalyze condensation of an amine of formula II, wherein R ¹ and R ² are as defined above, with an equimolar amount of orthoethyl formate at 90-110 ° C. preferably acetic acid, followed by hydrolysis of the general formula III - aholRl and R ² are as defined above - formlmino ether, preferably without isolation of the formula IV - wherein B is a group of Formula V or VI group of the formula in which -5182.767 R ⁵ is ethoxy, or methyl-carbanion additions náltatunk by the general Formula VII - wherein R3 and R4 are as defined above - prepared catalyst karbonilszármazékból pH 11-14 · rheumatic amount of a weak acid and weak acid salt buffer mixture or in the presence of an auxiliary base. 2. The method of claim 1, wherein the condensation and addition is carried out without spatial separation. 3) A process according to claims 1 and 2 wherein the compound of formula VII is a diethyl ether of malonic acid, which forms a corresponding carbanion at a pH of about 13.6 and is added thereto. 4. The process of claim 1, wherein the compound of formula VII, wherein R * and B 4 are as defined above, is cyanoacetic acid ethyl ester, cyanoacetic acid methyl ether or malonic acid dinitrile, from which the carbanion is formed at pH 11-14. . 5 · Refer to Figures 1-4. A process according to any one of claims 1 to 4, wherein the carbanion is formed in the presence of one of the following bi mixtures: acetic acid + sodium acetate, disodium salt of ethylenediaminetetraacetic acid (Complexon III), ethylenediaminetetraacetic acid, quaternary ammonium base (e.g. tributylbenzylammonium hydroxide / + acetic acid. 6. A process according to any one of claims 1 to 3, wherein an equimolar amount of orthoethyl formate is condensed in a catalytic amount by condensation of the amine of formula II, wherein R ¹ and r 2 are as defined above, at 90-110 ° C. in the presence of acetic acid at a pH of about 13.6, 10-40% excess malonic acid diethyl ester is added to the reaction mixture.