DE923426C - Process for the production of ª ‡ -substituted ª ‰ -oxypropionic acids - Google Patents

Description

Process for the preparation of α-substituted, β-oxypropionic acids The invention relates to an improved process for the preparation of α-substituted β-oxypropionic acids of the general formula to which z. B. tropic acid and its derivatives, which are important intermediates in the synthesis of atropine and certain synthetic anticonvulsants, belongs.

In this formula, R represents an aromatic hydrocarbon group with one to two rings and fewer than 1ä carbon atoms, a thienyl group or a thienyl group substituted by low molecular weight alkyl radicals and R ' Hydrogen or an organic radical opposite to the reactants used is inert.

The process is carried out in such a way that formaldehyde is reacted with a salt of an acid of the general formula 1-Mg-C R R'-COOH (X means halogen) and the compound formed is hydrolyzed. The organometallic intermediate X-Mg-C R R'-COOH is prepared by reacting an acid R (R ') C HC OOH or a salt thereof with magnesium and an alkyl halide. The process can essentially be carried out in one operation and in the same reaction vessel without isolation of any of the intermediate products and proceeds according to the following equation: In these general formulas, -M is a cation, including hydrogen, a metal ion or the ammonium ion, R "is a low molecular weight alkyl group, X is halogen, such as chlorine, bromine or iodine, and R and R 'have the meanings given above. It should be mentioned that that is replaced with the use of the free acid as a starting material (M = H), the hydrogen atom of the carboxyl group by MgX in the formation of Grignardkomplexes I (M = Mg X). Therefore, it is preferable to operate with the salt of the acid (M = ammonium - or a metal ion), so that smaller amounts of magnesium and alkyl halide are required. The choice of the salt is immaterial, although the ammonium, alkali and alkaline earth metal salts and in particular the ammonium, sodium and calcium salts are preferred due to their easy accessibility the low molecular weight alkyl halide R "X, R" can be any alkyl group having from about z to 6 carbon atoms, although secondary alkyl halides and in particular Isopropyl chloride are preferred.

R, the meaning of which has already been defined in more detail above, preferably denotes Phenyl, naphthyl ,. Xenyl, 2-thienyl, 3-thienyl and by low molecular weight alkyl radicals substituted derivatives of these radicals. Besides hydrogen, R 'can be an organic radical be that towards the applied reactants, in this case towards the Grignard compound and the: formaldehyde, is inert. Such inert groups are z. B. alkyl and alkoxy groups with about r to 6 carbon atoms, 2- and 3-thienyl groups and aromatic hydrocarbon groups "optionally represented by hydroxyl or low molecular weight Alkyl radicals can be substituted, in which the aromatic hydrocarbon radical is the same as the definition for the group R.

The new method has certain advantages over the known ones. In the known processes, several stages and the isolation of intermediate products are necessary, while in contrast to this, the process according to the invention can be carried out in one operation. In one of the known methods for the synthesis of tropic acid, such as the USA. Patent 2,390,278, the preparation is carried out via an ester of a-oxy methylenphenylessigsäure, HIGH = C (C, H5) -COOR as an intermediate. This compound is not easily accessible and must be prepared by means of an acetoacetic ester synthesis from an ester of phenylacetic acid and an alkyl formate in the presence of a basic condensing agent. The double bond of the a-oxymethylene phenylacetic acid alkyl ester must then be reduced and the resulting alkyl ester of tropic acid saponified. So there are four stages in the production of tropic acid from phenylacetic acid by this method: z. Esterification, 2nd condensation with a formic acid ester, 3rd reduction and q .. saponification. In addition, this known method can obviously not be used for the preparation of α-disubstituted β-oxypropionic acids.

The process of the invention is expedient in the following manner carried out: Magnesium, generally in the form of chips, is made by the usual Methods for initiating Grignard reactions activated, e.g. B. by putting it with a small amount of an alkyl halide. Sometimes an iodine crystal helps to initiate implementation. The entire reaction is carried out in an anhydrous medium, preferably diethyl ether. When the implementation of the magnesium started the salt of arylacetic acid, R (R ') C H-C O O H, and then the alkyl halide, R "X, added, the mixture stirred and until the completion of the formation of the hydrocarbon R "H heated. If R 'has a meaning other than hydrogen, the yields can often by introducing additional Magnesium and alkyl halide at this stage, before adding the formaldehyde. The resulting Suspension or solution of the organometallic intermediate (I) is then for Implementation with formaldehyde done. Formaldehyde can be used as a gas by it is introduced into the reaction mixture over or with stirring. However, it is more expedient, the solid polymerized forms of formaldehyde, such as trioxane or Paraformaldehyde, which turns into gaseous monomer when heated decompose. The apparatus is expediently arranged so that a vessel with the polymer is heated at the appropriate time, so that gaseous formaldehyde with the reaction mixture comes into contact. In order to achieve good results, a large excess of Formaldehyde applied. After the reaction with formaldehyde, the reaction mixture becomes hydrolyzed by adding water and dilute acid, the desired substituted ß - oxypropionic acid (III) is set free. The essential Layer is separated from the aqueous layer and the latter extracted with ether. The combined ethereal fractions contain the acid (III). The acid (III) is best done by extracting the essential solution with sodium carbonate solution separated from neutral substances.

The following examples are intended to explain the invention in more detail without restricting it. Example i tropic acid. i2.2 g (0.5o mol) of magnesium were covered with dry ether in a thoroughly dried i-1 three-necked flask fitted with a condenser, dropping funnel and stirrer, and about i cc of ethyl bromide was then added. After the reaction had begun, about zoo cc of dry ether, 39.5 g (0.25 mol) of finely powdered sodium phenylacetate (which had been dried at 130 °) and 150 cc of ether were added in succession. The mixture was stirred and 39.3 g (0.5o mol) of isopropyl chloride dissolved in 125 cc of dry ether was added dropwise at such a rate that the mixture continued to reflux. After addition of the isopropyl chloride, the mixture was heated again with stirring and reflux until no more gas was evolved (about 2 to 21/2 hours), the mixture was cooled to 0 ° and the dropping funnel was replaced by a gas inlet tube. This tube should have a diameter of at least 1.27 cm and terminate approximately i, go cm above the surface of the liquid in the reaction flask. The tube was fused to the top of a 500 cc flask containing 60 grams of paraformaldehyde. This substance had to be dried over phosphorus pentoxide in a desiccator for at least two days. The mixture, which contained the organometallic intermediate, was stirred and the paraformaldehyde was evaporated by heating to 180 to 200 ° in an oil bath. A slow stream of dry nitrogen was passed through the flask containing the formaldehyde to facilitate its introduction into the reaction mixture. During the addition of the formaldehyde, the reaction mixture was kept at 10 ° with the aid of an ice bath. The introduction of the formaldehyde required about 21/2 to 3 hours. The mixture was cooled and water was added very slowly. After acidification, the ethereal layer was separated and the aqueous layer was extracted with ether. The combined ethereal layers were extracted with sodium carbonate solution. After acidifying the sodium carbonate solution, the tropic acid was extracted with ether. The extracts were dried over magnesium sulfate and the solvent removed. The crude tropic acid weighed 27.1 g (65.5 '/ 0); F. = I i I '. The product was recrystallized from 475 cc of benzene; Yield 24.0 g (59.511 / 9) of pure tropic acid, m.p. = 116 to 17 ".

Examples Tropic acid was prepared as in example i, but under Use of phenylacetic acid calcium instead of the sodium salt. This has so far a considerable practical advantage than the calcium salt as opposed to the sodium salt is not hygroscopic.

Example 3 Tropic acid was prepared according to Example i, but using phenylacetic acid ammonium instead of the sodium salt. From 115 g (0.75 mol) of ammonium salt, 879 (710/0) tropic acid were obtained. The ammonium salt of phenylacetic acid is also not hygroscopic.

Example [a- (2-Thienyl) -ß-oxypropionic acid was prepared by the method described in Example i from 12.2 g (0.5 mol) of magnesium, 41 g (0.25 mol) of sodium 2-thienyl acetic acid in 350 cc of ether and 39.3 g (0.5 mol) of isopropyl chloride dissolved in 125 cc of ether to which 45 g (1.5 mol) of paraformaldehyde were added. In this way, after recrystallization from benzene, 29.5 g (68.5%) of α- (2-thienyl) -β-oxypropionic acid with a melting point of 95 to 96 'were obtained.

Example s a- (p-xenyl) -ß-oxypropionic acid was prepared according to the method described in Example i from 18.5 g (0.76 mol) of magnesium, 8g g (0.38 mol) of sodium p-xenyl acetic acid, 6o g ( 0.76 mol) isopropyl chloride and 700 cc ether to which 68.4 g (2.28 mol) paraformaldehyde were added. In this way 71.4 g (77.60%) of a- (p-xenyl) -ß-oxypropionic acid were obtained which, after recrystallization from isopropyl alcohol, had a melting point of 207 to 2091 (decomposition). Neutralization number calculated for Cis H14 03: 242.3; found 241.2.

Example 6 a, a - Diphenyl - ß - oxypropionic acid. Red g (1.3 M01) of isopropyl chloride in 300 cc of ether were added to a mixture of 31.6 g (1.3 times) of magnesium, 117 ig (0.5 mol) of sodium diphenylacetic acid and 100 cc of ether. The mixture was refluxed for 3 hours, cooled to 0 °, 90 g (3.0 times) of paraformaldehyde were depolymerized and C H2 O was passed into the reaction mixture with a slow stream of nitrogen. After all of the formaldehyde had been passed in, the mixture was refluxed for 3 hours and then worked up as described in Example i. 109.5 g (90.50 / 0) of α, α-diphenyl-β-oxypropionic acid were obtained which, after recrystallization from isopropyl alcohol, had a melting point of 158 to 59 °.

Neutralization number calculated for Cis H14 03 ' 242.3; found: 242.1.

Example ? α-Benzyl-α-phenyl-β-oxypropionic acid. At 6.2 g (0.225 moles) Magnesium, 31.6 g (0.18 mol) of sodium benzylphenylacetate and 150 cc of ether in a 500 ccm flask 20 g (0.25 M01) isopropyl chloride dissolved in 50 cc ether was, slowly admitted. It was only 30% of the theoretical amount of propane gas, which formed during the reaction, so that more magnesium and isopropyl chloride (the same amounts as originally used) and zoo cc of ether were added. The total amount of propane gas reached 49% of the calculated amount. 45 g (1.5 moles) Paraformaldehyde was then depolymerized and the formaldehyde into the mixture initiated, which was then worked up as usual and 7.3 g (22%) of a-benzyl-a-phenyl-ß-oxypropionic acid revealed. Melting point after recrystallization from toluene 188 to z89 °.

Localization number calculated for Cio His 03, -: 256.3; found: 254.9.

Example 8 a-Phenyl-cc-phenoxy-ß-oxypropionic acid. 15.7 g (0.2 moles) Isopropyl chloride dissolved in 50 cc of ether became a mixture of 4.89 (0.2 mol) magnesium, 25 g (0.1 mol) sodium phenylphenoxyacetate and 150 cc Ether given. After the mixture had been refluxed for 4 hours, the same amounts of magnesium, isopropyl chloride and ether were added again. The mixture was refluxed for an additional 5 hours, cooled, 36 g (1.2 mol) of formaldehyde were added and worked up in the usual way. It was 6.8 g (: 26.30 / 0) a-phenyl-a-phenoxy-ß-oxypropionic acid, which after recrystallization from isopropyl alcohol showed a mp of 160 to 16 ° (decomposition).

Neutralization number calculated for Cis H14 04: 258.3; found: 26o.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of α-substituted β-oxypropionic acids of the general formula in which R is an aromatic hydrocarbon radical with one to two rings with fewer than 15 carbon atoms, a thienyl group or a thienyl group substituted by low molecular weight alkyl radicals, R 'is hydrogen, a low molecular weight alkyl or alkoxy group, a thienyl group, a thienyl group substituted by a low molecular weight alkyl radical or a aromatic hydrocarbon group, which can optionally also be substituted by hydroxyl or low molecular weight alkyl groups, the aromatic radical comprising one to two rings with less than 15 carbon atoms, characterized in that formaldehyde with a salt of an organometallic compound of the general formula is reacted, where X is halogen and R and R 'have the meaning given above, and that the compound obtained is hydrolyzed. 2. The method according to claim i, characterized in that the organometallic compound to be reacted with formaldehyde by reacting a compound of the general formula (M means a cation and R and R 'have the meanings given above) with magnesium and a low molecular weight alkyl halide. Referred publications: Journ. Amer. Chem.-Soc., Vol. 74, 1952, p. 253.