HU206190B - Process for producing 4-amino-3,5-dimethoxybenzoic acid and its derivatives - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF CARBOXYLIC ACIDS AND ESTERS The invention relates to the preparation of carboxylic acids and alkyl esters of the general Formula I (I) (wherein R1 and R2 are identical and stand for lower alkyl; R3 and R4 are identical and stand for hydrogen or lower alkyl and R5 represents hydrogen or lower alkyl) by subjecting a compound of the general Formula II (II) to ammonolysis with aqueous ammonium hydroxide in the presence of a strong inorganic base and a cupric(II)compound and, if desired, N-dialkylating the 4-amino-compound of the general Formula III (III) thus obtained. The advantage of the process resides in the fact that inexpensive, readily available starting materials can be used and the process can be performed economically on industrial scale too. The compounds of the general Formula I are known pharmaceutical intermediates.

Description

This invention relates (I) carboxylic acids and alkyl esters of formula (wherein R ¹ and R ² is methyl;

R ² and R ^{4 are the} same and are hydrogen or methyl, and

R- is hydrogen or methyl).

The 4-amino-3,5-dimethoxy- compound of the formula (I)

4- (N, N-dimethylamino) -3,5-dimethoxybenzoic acids and their methyl esters are valuable pharmaceutical intermediates, such as the antibacterial and sulfonamide potentiating agent Aditoprim [2,4-diamino-5]. - (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine]. For the preparation of this commercially available compound of formula I, 4- (dimethylamino) -3,5-dimethoxybenzoic acid and its methyl ester are appropriate intermediates. This compound is known to be prepared by N-alkylation of the corresponding 4-amino-3,5-dimethoxybenzoic acid or its methyl ester. In this respect, 20-4-amino-3,5-dimethoxybenzoic acid is considered a key intermediate.

Several methods are known in the art for the preparation of 4-amino-3,5-dimethoxybenzoic acid or its methyl ester. Kompis I. and Wick A. [Helv. 25 Chim. Acta 60 (8) 3025-34 (1977)] 2,6-dimethoxytherephthalic acid dimethyl ester is subject to regioselective Lossen degradation. The reaction is carried out with hydroxylamine in a solvent for polyphosphoric acid. However, due to the very expensive and inaccessible starting material, this process can only be carried out on a laboratory scale and is not suitable for industrial production.

No. 2,443,682. In U.S. Patent No. 4,600,600, 4-acetamido-3,5-dimethoxytoluene is oxidized with pyridine-water with potassium permanganate to the corresponding benzoic acid derivative 35, then the acid is esterified and the acetamido group is converted to the amino group. The disadvantage of the process is that due to the oxidation of potassium permanganate it is not economically viable on an industrial scale. The patent specification 40 does not otherwise disclose yield data.

No. 4,515,948. U.S. Pat. No. 4,123,115 discloses a very complex six-step synthesis for the preparation of 4-dimethylamino-3,5-dialkoxybenzoic acid methyl ester. The starting material used in this procedure is 3-hydroxy-5-keto-3-cyclohexanecarboxylic acid, which is first azo-coupled, followed by the resulting 4-phenylazo-3-hydroxy-5-keto-3-cyclohexanecarboxylic acid with methanol. the resulting methyl ester is aromatized by treatment with acetamide and bromine, the resulting 4-phenylazo-3,5-dihydroxybenzoic acid methyl ester is methylated, and the resulting 4-phenylazo-3,5-dimethoxybenzoic acid methyl ester is reduced to 4-amino-3,5-dimethoxybenzoic acid methyl ester by reduction and finally the amino group is alkylated. In addition to the complexity of the process and the number of reaction steps, the additional disadvantage is that the starting material is expensive and difficult to access. This process is not suitable for industrial production.

It is an object of the present invention to provide a process for the production of valuable intermediates of formula (I) economically on readily available starting materials, on an industrial scale.

It has been found that this object is achieved by reacting a compound of formula II (wherein R _b R ₂ and R ₅ are as defined above) with aqueous ammonia in the presence of a strong inorganic base and a copper (II) compound R is hydrogen atom _is replaced by _s, the acid being a narrower group of the compounds of formula (I) (III) (wherein R, and _R2 are as defined above), purifying or a methyl group R ₅ in place in a known manner, if desired, known resulting salt manner Esterifying the compound of formula (I); then optionally methylating the compound of formula (III) (wherein R 1, R ₂ and R ₅ are as defined above) in a manner known per se, and optionally obtaining an ester of formula (I) containing R ₅ ; converting it into a suitable carboxylic acid of formula I wherein R ₅ is hydrogen.

The present invention is based on the discovery that the 4-bromo-3,5-dimethoxybenzoic acids of formula II and their alkyl esters are obtained in excellent yield with 4-amino-3,5-dimethoxyethyl compound of formula III in excellent yield with aqueous ammonium hydroxide. can be converted to benzoic acids. This recognition is surprising. It is known that compounds of formula II cannot be converted to the corresponding 4-dialkylamino derivatives by reaction with dialkylamines. While reacting the compound of formula II with aqueous dimethylamine, the bromide cleavage occurs in the range of 75-100%, however, many side reactions occur, leading to the formation of many by-products and consequently the desired 4-dimethylamino compound is not traces are formed.

In view of the foregoing, one of ordinary skill in the art would not have expected that the compounds of formula (II) would provide 4-amino-3,5-dimethoxybenzoic acid (III) of sufficient purity with aqueous ammonia.

Ammonolysis of the starting material (II) is carried out at a temperature of 110 to 140 ° C, preferably 118 to 128 ° C. The reaction is carried out in the presence of a strong inorganic base. For this purpose, alkali metal hydroxides (e.g., sodium or potassium hydroxide), alkali metal carbonates (e.g., sodium or potassium carbonate) or alkali metal bicarbonates (e.g., sodium bicarbonate or potassium bicarbonate) are preferably used. ). In a particularly preferred embodiment of the process, sodium hydroxide or potassium hydroxide is used. The strong inorganic base may preferably be used in a stoichiometric amount of ± 10% relative to the starting material of formula (II).

The reaction is carried out as a catalyst in the presence of a copper (II) compound. Both inorganic and organic copper (II) compounds can be used for this purpose. Thus, copper (II) sulfate or copper (II) oxide is preferably used. The

In a particularly preferred embodiment of the process, copper (II) can be used as copper (II). The copper (II) compound may be used in an amount of 5-20 mol%, preferably 8-12 mol%.

The reaction is preferably carried out with aqueous ammonium hydroxide at a concentration of at least 20% by weight, especially at least 30% by weight. A 5% by weight aqueous solution of ammonium hydroxide is particularly preferred.

In one embodiment of the process of the present invention, anhydrous 4-bromodimethoxybenzoic acid (II) or methyl ester (II) is used. In this case, an aqueous solution of ammonium hydroxide of at least 20% by weight, preferably at least 30% by weight, may be added. The process involves starting with a wet compound of formula II, which is dissolved in water and introduced into the aqueous solution with ammonia gas.

The reaction time is usually 7-15 hours, preferably 8-11 hours.

A reaction mixture containing carboxylic acid of formula ₅ wherein R is hydrogen, (III) salt of the copper salt was removed, and after dilution, the carboxylic acid salt is liberated by acidification. A. Acidification can be carried out with mineral acids. The resulting (ΠΙ) wherein _R5 is appropriate carboxylic acid is separated from hydrogen, and washed by means of appropriate purity can be directly used in the methylation reaction.

Carboxylic acid of formula ₅ wherein R is a hydrogen atom, (III) is esterified with the corresponding alkyl esters, if desired, in known manner.

Thus obtained, _R5 is hydrogen or optionally appropriate compound containing a methyl group (III) can then be converted to the compound of Formula by methylation with a methyl group (I), the corresponding R ₃ and R ₄ in place. Otherwise, compounds of formula (III) are a subgroup of compounds of formula (I) wherein R ₃ and R _{4 are} hydrogen. Alkylation can be carried out by known methods. The methylating agent used is dimethyl sulfate or methyl halide. Preferably, the 4-amino compound of formula (III) is reacted with a dialkyl sulfate in an organic solvent such as methanol in the presence of an alkali metal hydroxide, carbonate or bicarbonate.

Alternatively, the 4-amino compound of formula (III) may be alkylated with methanol in the presence of anhydrous mineral acid, preferably hydrochloric acid. The reaction is carried out while heating under confinement. The reaction temperature is generally 120 to 180 ° C, preferably 130 to 150 ° C. The reaction is complete within a few hours, with a preferred reaction time of 7-15 hours, especially 8-9 hours.

The starting material 4-bromo-3,5-dimethoxybenzoic acid and its methyl ester (Π) can be obtained from 3,5-dihydroxybenzoic acid or its esters in a known manner in a very good yield of 80-90%.

The process according to the invention has the advantage that the valuable intermediates of formula I are prepared using inexpensive and readily available starting materials, in appropriate purity and economically on an industrial scale.

Further details of the process are set forth in the following examples, without limiting the invention to the examples.

Example 1 25 liters of crystalline copper (II) sulphate, 275 g of anhydrous 4-bromo-3,5-dimethyl-oxybenzoic acid methyl ester or 261 g of anhydrous 4-bromo-3,5-dimethoxy-benzoic acid are added to a 1 liter stainless steel tubular reactor. 40 g of sodium hydroxide are weighed. The tube reactor was cooled to 0 ° C in a salted ice bath and 800 g of 25% aqueous solution or 58 g of 35% aqueous ammonium hydroxide solution were added. The tube 15 reactor was sealed and heated to 118-128 ° C in an oil bath for 45 minutes. The reaction mixture was maintained at this temperature for 8-11 hours, and after completion of the ammonolysis, the ammonia was removed from the tubular reactor, the pH was adjusted to 7 ± 0.5, and the precipitated copper (II) dimethoxybenzoate was filtered off. In this way, 20% of the product formed is precipitated as copper. The copper compound isolated in this manner can be used as a catalyst instead of copper (II) sulfate in the process.

The material was diluted with 1500 mL of water and adjusted to pH 4-5 with dilute hydrochloric acid. The precipitated crude 4-amino-3,5-dimethoxybenzoic acid was filtered off and washed to yield 63-70%. The crude product has an active ingredient content of 100-110 g.

The crude 4-amino-3,5-dimethoxybenzoic acid thus obtained can be used directly for the methylation reaction. The product may, if desired, be purified by dissolving it in dilute hydrochloric acid, treating it with celite and charcoal, and adjusting the pH to 4-5. Clean

4-amino-3,5-dimethoxybenzoic acid is obtained, m.p. 210212 ° C.

Example 2

The crude product containing 100-110 g of 4-amino-3,5-dimethoxybenzoic acid was dissolved in 1100 ml of methanol at room temperature. To the solution was added 230 g of sodium bicarbonate and 210 g of dimethyl sulfate were added at 40-45 ° C over 30-40 minutes. The reaction mixture was refluxed for half an hour after the gas evolution had ceased, then clarified and filtered with celite and activated carbon. 90-105 g of methyl 4- (N, N-dimethylamino) -3,5-dimethoxybenzoic acid are obtained in a yield of 17-55% after two steps. 71-72 ° C. Literary Op. 7150-72 ° C (German Patent Application No. 2443682, Example 11).

Isolation of the 3,4,5-trimethoxybenzoic acid methyl ester, if desired, can be carried out in a known manner and, if desired, converted to 3,4,5-trimethoxy-benzoic acid by saponification.

Example 3

The procedure described in Example 1 was performed except that 460 g of 40% moisture

Or methyl 4-bromo-3,5-dimethoxybenzoic acid

HU 206 190 Β

435 g of 40% moisture, 4-bromo-3,5-dimethoxybenzoic acid were used, with 40 g of sodium hydroxide and 25 g of crystalline copper (II) sulfate unchanged. Instead of aqueous ammonium hydroxide, 230 g of water were added and 225 g of ammonia gas was swallowed. 90-105 g of 4- (N, N-dimethylamino) -3,5-dimethoxybenzoic acid methyl ester are obtained. Yield: 57-66%. 71-72 ° C.

Example 4 Into a reactor certified to bar pressure, 105 g of 4-amino-3,5-dimethoxybenzoic acid prepared in Example 1 were charged, followed by the addition of 800 g of alcohol containing 3.3 moles of hydrochloric acid per liter. The reaction mixture is heated at 130 ° C for 8-9 hours and the methyl chloride formed is sucked off. The solution is mixed with 2.2 liters of water at 0-5 ° C and washed with 130-150 ml of toluene. The aqueous solution was adjusted to pH 7 with ammonia, and the precipitated product was filtered, washed and dried in vacuo. 95-110 g of 4- (N, N-dimethylamino) -3,5-dimethoxybenzoic acid methyl ester are obtained. Yield 49-57% after two steps. M.p. 71-72 ° C.

Example 5

7.5 g (0.038 mol) of 4-amino-3,5-dimethoxybenzoic acid were mixed with 120 ml of 2.5-3.0 mol / L hydrochloric acid methanol and allowed to stand at room temperature for 68 hours. The methanolic solution of the ester was added, after addition of 1 g of clarifying carbon and 1 g of Perfil filter aid, and neutralized with ice-water sodium bicarbonate. It was crystallized at + 5 ° C for 2 hours, filtered, washed with methanol (+ 5 ° C) (2 x 5 ml) and dried under infrared light. 6.9 g (86%) of 4-amino-3,5-dimethoxybenzoic acid are obtained. Mp 116 ° C. Literary Op. 115-116 ° C (German Patent Application No. 2443682, Example 2).

Claims (9)

PATENT CLAIMS A process for the preparation of the carboxylic acids and alkyl esters of the formula (I) R ¹ and R ² is methyl; R ³ and R ^{4 are the} same and are hydrogen or methyl, and R ⁵ is hydrogen or methyl), characterized in that a compound of formula II (wherein R 1, R ₂ and R ₅ are as defined above) is reacted with aqueous ammonia in the presence of a strong inorganic base and a copper (II) compound and then releasing the acid of formula (III) (wherein R 1 and R ₂ are as defined above), which is a narrower group of compounds of formula I, wherein R ₅ is hydrogen, and is optionally purified by conventional means or R Esterifying the compound of formula (I) wherein ₅ is methyl; then optionally N-methylating the compound of formula (III) (wherein R 1, R 1, and R ₅ are as defined above) in a manner known per se, and optionally obtaining one. Ester of formula (I), _R5 is a methyl group in the appropriate customary manner. R ₅ is converted to a carboxylic acid of formula I containing hydrogen. Process according to claim 1, characterized in that the copper (II) chemical compound is used in an amount of 5-20 mol%, preferably 812 mol%. The process according to claim 1 or 2, wherein the copper (II) compound is copper (II) sulfate. copper (II) oxide or copper (II) -4-bromo-3,5-dimethoxybenzoate. 4. Process according to any one of claims 1 to 3, characterized in that the strong inorganic base is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide. The process according to claim 4, wherein the strong inorganic base is used in an approximately equimolar amount, preferably ± 10% relative to the equimolar, relative to the starting material of formula (II). 6. Process according to any one of claims 1 to 3, characterized in that the compound of the formula (II) is reacted with at least 20%, preferably at least 30% by weight of aqueous ammonium hydroxide. 7. A process according to claim 6 wherein the aqueous solution is ammonium hydroxide at 35% by weight. 8. Process according to any one of claims 1 to 4, characterized in that the compound of the formula II is reacted with aqueous ammonia at a temperature of 110 to 140 ° C, preferably 118 to 128 ° C. 9. A process according to any one of claims 1 to 3, wherein the compound of formula (II) is reacted with aqueous ammonia for 7-15 hours.