DE2331969A1 - 3-(3,4,5-Trimethoxyphenyl) propionitrile - with antimicrobial activity - Google Patents

Abstract

3-(3,4,5-Trimethoxyphenyl)propionitrile (I) is a new cpd. with antifungal and antibacterial activity. It can be used as a medicament, an industrial chemical, and an inter. for other medicaments. (I) is pref. prepd. by diazotising 3,4,5-trimethoxyaniline, reacting the prodt. with acrylonitrile in the presence of a cuprous or cupric halide to give the corresp. 3-(3,4,5-trimethoxyphenyl)-2-halopropionitrile, and subjecting this to reductive dehalogenation.

Description

β- (3,4,5-trimethoxyphenyl) propionitrile The invention relates to B- (3,4,5-trimethoxyphenyl) propionitrile and a method for its production.

The new compound has the following formula: The compound (1) itself has antimicrobial activity and can also be used as an intermediate for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine, whose extraordinarily strong antibacterial activity is known ( U.S. Patents 2,658,897, 2,909,522, 3,049,544 and British Patents 734,801, 875,562, 920,412 and 957,797).

The compound (I) can thus be used directly as a medicament, as an intermediate medicament product and be regarded as an industrially recoverable chemical.

For the production of fl-Aryl-propionitrilen, which one or more Methoxy groups or hydroxyl groups carry arn aromatic nucleus is for example a process known in which the appropriately substituted methoxybenzene or the appropriately substituted hydroxybenzene can be reacted with acrylonitrile, whereby direct cyanoethylation of the starting benzene derivative is achieved (A. Chatterjee and B.G. Hazra; "Tetrahedron Letters" 73, 1969). Furthermore, the applicant has a Proposed method according to dn 3,4,5-trimethoxybenzaldehyde with cyanoacetic acid is converted to ß- (3,4,5-trimethoxyphenyl) acrylonitrile, which is then in the presence a palladium-carbon catalyst is hydrogenated (Japanese patent application 9783/1972).

The first-mentioned method of direct cyanoethylation of the substituted Benzene is not used in the production of ß- (3,4,5-trimethoxyphenyl) propionitrile suitable, since in this reaction there is a high probability that the cyanoethyl group is preferably installed in the ortho and para positions, so that when implementing 1,2,3-Trimethoxybenzene with acrylonitrile removes the cyanoethyl groups in undesired positions be introduced in the benzene ring of the starting material, so that, if at all, the desired compound of the formula (I) was obtained only in low yields will.

The second method mentioned is not necessarily also a economically advantageous process, since it is used as the starting material 3,4,5-trimethoxybenzaldehyde used is difficult to produce and also a Including catalytic hydrogenation, which is difficult to regulate on an industrial scale.

A new and peculiar one will be used to circumvent these difficulties Process for the preparation of ß- (3,4,5-trimethoxyphenyl) propionitrile proposed, that easily and commercially obtained with high yields of the desired Product can be carried out.

The process proposed according to the invention for the preparation of the nitrile of the formula (I) consists in that l-amino-3,4,5-trimethoxybenzene of the formula is diazotized in a known manner and the resulting diazonium salt of 3,4,5-trimethoxybenzene in the presence of KupEer (f) halide or copper (II) halide with acrylonitrile to form an α-halogen-β- (3,4, 5-trimethoxyphenyl) propionitrile of the general formula is reacted, in which X stands for the halogen originating from the copper salt, this nitrile of the formula (III) then being reductively dehalogenated before or after isolation from the reaction mixture.

When the l-amino-3,4,5-trimethoxybenzene is diazotized in the context of the process according to the invention, the diazonium salt of 3,4,5-trimethoxybenzene has the general formula formed, in which X is the acid residue of the mineral acid used in the diazotization. The reaction of the diazonium salt with the acrylonitrile is a MEERWEIN condensation in which the 1-amino group originally present in the starting material, 1-amino-3,4,5-trimethoxybenzene, can finally be exchanged for a 2-halo-2-cyanoethyl group . So far, the opinion has been that the efficiency of the MEERWEIN condensation with benzene derivatives that have a methoxy group on the core is lower than for benzene derivatives that contain an electron-sucking group, for example a nitro group or chlorine (Brunner and Perger, "MONTHSH" 79, P. 187, 1948). According to this doctrine, the preparation of ß-phenyl-propionitrile derivatives with 3 methoxy groups on the benzene ring using the SEA IN condensation has neither been attempted nor carried out. In view of this situation, it is all the more surprising that, contrary to expectations, the use of the diazollium salt of 3,4,5-trimethoxybenzene with acrylonitrile by the MEERWEIN process is high despite the presence of the three methoxy groups on the benzene ring of 3,4,5-trimethoxybenzene Yield runs smoothly, so that the α-halo-β- (3,4,5-trimethoxyphenyl) propionitrile can also be obtained with high yield and thus also the end product of the formula (I) with an extraordinarily high overall yield of the process.

The procedure is carried out in two stages, namely the first Stage of the MEERICIN condensation and the subsequent stage of reductive dehalogenation. For the MEERWEIN condensation, the l-amino-3,4,5-trimethoxybenzene is in a mineral acid, for example in hydrochloric acid, or in a mixture of mineral acids and organic Acids, for example in a mixture of hydrochloric acid and acetic acid, dissolved. In the solution obtained in this way becomes a lower nitrogen salt, for example sodium nitrite, added at 5 ° C or lower temperature, the diazotization of the l-amino-3,4,5-trimethoxybenzene goes smoothly. The reaction mixture of the diazotization is then with a Acrylonitrile solution and a copper salt in acetone at low temperature, preferably at a temperature below 0 ° C and preferably in an inert gas atmosphere, example page in a nitrogen atmosphere. The molar ratio of the acrylonitrile to the l-amino-3,4,5-trimethoxybenzene can preferably be 4: 1 to 5: 1. as Mineral acid can also be used besides hydrochloric acid, hydrobromic acid and others will. Copper (I) chloride, copper (II) chloride, copper (I) bromide, Copper (II) bromide and others in question. The diazotization is preferably carried out in the presence a small amount of alkali metal chloride, for example in the presence of a small amount Amount of lithium chloride.

The MEERMBIN condensation gives an α-halogen-ß- (3,4,5-trimethoxyphenyl) -propionitrile of the general formula (III), that of the reductive dehalogenation to the nitrile Formula (I) is subjected. The reductive halogenation can, for example be carried out in such a way that zinc powder or zinc granules can be directly inserted the reaction mixture obtained from the MEERWEIN condensation and the mixture then stirred at room temperature. This creates hydrogen in the reaction mixture released, which reductively dehalogenates the α-halogen compound (IE). Alternatively can the a-halogen «ß- (3,4,5-trimethoxyphenyl) propionitrile initially from the the reaction mixture obtained from the MEER9EIN condensation, for example by extraction with benzene and stripping off the solution under reduced pressure. The nitrile isolated in this way can then be dissolved in acetic acid and this solution with the metallic zinc in powder or granulate form are added. Here too will the hydrogen evolves, which reductively dehalogenates the nitrile.

The l-amino-3,4,5-trimethoxybenzene used as the starting product can can be obtained easily and in a simple manner by using trimethylgallamide subject to the H0FF reaction (C. Graebe and Moritzsuter, "Ann. Chem." 340, p. 222, (1905)) u The starting compound can also be prepared directly by adding nitromethane or sodium azide obtained with trimethylgallic acid in polyphosphoric acid solution will.

The β- (3,4,5-trimethoxyphenyl) propionitrile obtained as the end product of this process has, as already mentioned, antibacterial or antinicrobial activity on.

In Table 1 below are the minimum amounts of the compound (I), which prevent the growth of various bacteria and fungi.

Table 1 Antimicrobial activity of β- (3,4,5-trimethoxyphenyl) propionitrile tested microorganisms Minimum effective concentration (mcg / ml) Bacteria Shigella sonnei 320 Shigella flexneri 320 Salmonella typhi 160 Staphylococcus aureus 320 Fungi Trichophyton ment @ grophytes 80 The invention is described below on the basis of exemplary embodiments described in more detail.

Example 1 (1) 7.4 g of 1-amino-3,4,5-trimethoxylbenzene were in a Dissolved mixture of 8.6 ml of 35% hydrochloric acid, 15.6 ml of acetic acid and 42 ml of water. The solution was then at 0-5 ° C. in small portions with 2.8 sodium nitrite added to the diazotization. The diazonium salt solution thus obtained was then placed in a nitrogen atmosphere at -10 ° C dropwise to a solution of 0.5 g of copper (I) chloride, 0.3 g of lithium chloride and 20 g of acrylonitrile in 230 ml of acetone. After adding the diazonium salt solution the mixture became for 5 hours stirred at 0-5 OC. After standing the reaction mixture overnight was extracted with benzene. The benzene extract was washed several times with water and then with 2N aqueous sodium hydroxide solution and finally again with water and a saturated aqueous sodium chloride solution shaken. The benzene extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. There were 8.6 g of α-chloro-β- (3,4,5-trimethoxyphenyl) propionitrile obtained as a light yellow oil. The yield was 83.5%. After adding n-hexane the oil could be completely crystallized. The crystals had a melting point from 88 - 89 Oc. After recrystallization from a 1: 1 mixture of isopropyl alcohol and hexane, a crystalline product with the melting point of 89 ° C was obtained. The product had the following elemental analysis: Found: C 56.51% H 5.52% N 5.50 % Calculated for C12H14ClNO3: C 56.48% H 5.53% N 5.48% The NMR spectrum in CDCl3 as a solvent showed the following maxima: -CH2- 'g = 3.23 ppm (doublet) -CHOl-, g = 4.56 ppm (triplet).

(2) 6 g of a-chloro-B- (3,4,5-trimethoxyphenyl) propionitrile were in Dissolve 60 ml of acetic acid and add 12 g of metallic zinc powder. The mixture was stirred at room temperature for 3 hours. The reaction mixture thus obtained was the remaining zinc is filtered off and benzene and water are added to the filtrate. The mixture thus obtained was stirred and in a benzene and an aqueous phase separated.

The benzene phase was twice with 10% hydrochloric acid, then twice with 10% aqueous sodium hydroxide solution and finally with water and one saturated aqueous sodium chloride solution. Then it became like that benzene solution obtained dried over anhydrous magnesium sulfate and through Concentrated distillation under reduced pressure. 4.5 g of β- (3,4,5-trimethoxyphenyl) propionitrile were thereby obtained as a colorless oil in a yield of 86.6%. When left standing that became so obtained oil gradually solidified. The final product showed the following elemental analysis: Found: C 65.14% H 6.87% N 6.32% Calculated for C12H15N03: C 65.20% H 6.84 % N 6.33% Example 2 The method described in Example 1 under (1) was carried out with the amendment repeats that instead of 0.5 g copper (I) chloride 0.9 g copper (II) chloride dihydrate were used. 8.4 g of α-chloro-β- (3,4,5-trimethoxyphenyl) propionitrile were thereby obtained corresponding to a yield of 81.6% obtained in crystalline form.

The intermediate product thus obtained was prepared in the calibrated manner as in Example 1 described under (2), further processed to the desired end product of the formula (I).

Example 3 7.4 g of 1-amino-3,4,5-trimethoxybenzene were used in the same Way, as described in Example 1 under (1), diazotized.

The solution of the diazonium salt thus obtained was added dropwise to a solution von.O, 5 g of copper (I) chloride, 0.3 g of lithium chloride and 20 g of acrylonitrile given in 230 ml of acetone in a stream of nitrogen and while cooling the mixture to -10 ° C. After the addition, the mixture produced was stirred at 0-5 ° C. for a further 5 hours. The reaction mixture containing the -chloro-β- (3,4,5-trimethoxyphenyl) propionitrile obtained in this way was left to stand overnight and then 16 g of zinc powder were added. The mixture was stirred for 2 hours at room temperature, whereby the α-chloro-β- (3,4,5-trimethoxyphenyl) propionitrile was reductively dehalogenated. The reaction mixture was extracted with benzene. The extract obtained als.benzolische solution was several times with water, then with 2N aqueous sodium hydroxide solution and finally with water and a saturated aqueous solution Washed sodium chloride solution. The benzene solution so washed was over anhydrous sodium magnesium and then dried under reduced pressure constricted. As a result, 7.2 g of β- (3,4,5-trimethoxyphenyl) propionitrile were obtained in one yield of 80.7%, based on the 1-amino-3,4,5-trimethoxybenzene used, obtained as an oil.

Claims (2)

Patent claims 1. β- (3,4,5-trimethoxyphenyl) propionitrile. 2. Process for the preparation of B- (3,4,5-trimethoxyphenyl) propionitrile of the formula characterized in that one l-amino-3,4,5-trimethoxybenzene of the formula diazotized in a known manner and the resulting diazonium salt of 3,4,5-trimethoxybenzene then in the presence of a copper (I) halide or a copper (II) halide with acrylonitrile to form an α-halogen-β- (3,4 , 5-trimethoxyphenyl) propionitrile of the general formula @n which X denotes the halogen originating from the copper salt and that the compound of the formula (III) thus obtained is then reductively dehaloganated before or after being separated off from the reaction mixture.