DE707266C - Process for the extraction of connections with the action of the urine - Google Patents

Description

Process for the production of connections with the effect of the urine So far, no synthetically obtained substances have become known that show the effects of adermine (vitamin B6) in a biological test. The Adermin itself is one made of natural material in a very cumbersome way in only minor Substance that can be produced in quantities, for which Kuhn recently developed a probable constitutional formula (Reports of the German Chemical Society, Vol. 72 [1939], P. 31o). It has not yet been possible to obtain it synthetically.

According to the invention, compounds with the action of adermine can be prepared, starting from 2-methyl-3-nitro-5-cyano-6-chloro (or 6-bromo) pyridines, which are in position q. carry the radical CH2R (R = hydrogen, hydroxyl or a group that can be converted into OH). These substances are very easy to prepare from acetylacetone or its derivatives of the formula -CH3 - CO-CH2-CO-CH.R (R = OH or a radical that can be converted into OH), ammonia and a derivative of malonic acid or of a derivative of malonic acid suitable for pyridine ring closure Cyanoacetic acid (e.g. malonic acid amide with subsequent conversion of the acid amide group into the nitrile group or cyanoacetic acid ester or its amide, corresponding to known syntheses of the pyridine ring, cf. e.g. Chem. Zentralblatt 1899, 1, 289, and 193o, 1, a31 ). The reaction partners mentioned can be allowed to act on one another at the same time, or the monoimine of these compounds is first prepared from acetylacetone (or its derivatives) and ammonia and this is converted with the malonic acid derivative. In this way, compounds of the formula are obtained in good yield; 1 i, which can be obtained by nitration and chlorination (or CH., R CHORUS Chlorination N - C - - NO2 Ho- @ '- C H3 (bromination) Cl - @ @@ - C Hs N nitriding (Br) N (I) (1I) The invention consists in reducing these compounds under such conditions that the halogen is replaced by hydrogen and the cyano and nitro groups are reduced to the aminomethyl or amino group, for which purpose the catalytic reduction is preferred. The simplest and most important way to carry out the synthesis according to the invention is as follows: The 2,4-dimethyl-5-cyano-6-oxypyridine, which is easily obtained from the imino compound of acetylacetone and cvanacetic ester, is nitrated (with a mixture of concentrated sulfur and nitric acid) and chlorinated (, with thionyl chloride, phosgene, PO C13 and / or or P Cl,), with 2,4-dimethyl-3-nitro-5-cyano-6-chloropyridine being obtained.

Surprisingly, this substance can be zero in one operation reduce catalytically to 2,4-dimethyl-3-amiilo-5-aininonietliylpyridine. (The catalytic reduction of a Cvan group has hitherto been used in pyridine chemistry at all not yet carried out; one always has the reduction to very cumbersome Wise done with reducing chemicals and often only bad ones Can achieve results.) Finally, the aliphatically bound and the amino group attached to the pyridine core in a single operation Diazotize and boil in acidic solution to convert into hydroxy-I groups.

The obtained 2,4-diinethyl-3-oxy-5-oxymethylpyridine of melting point 25.I ° surprisingly shows the biological effect of the adermitis (vitamin B6). Bromination) can be converted into the desired starting material of the formula (II): is suitable. In the compound of the formula (III) thus obtained, the both amino groups are replaced by hydroxyl groups, what after the usual Process can be done by diazotizing and boiling. Examples 1. 5-Cyan-2, 4-dimethyl- (roxypyridine (cf.

G u a r e s c h i, Chemisches Zentralblatt 1899, I, 289) becomes 5-cyano-3-nitro-2, 4-diinethyl-6-oxypyridine with concentrated nitric acid and concentrated sulfuric acid nitrated. The 3-nitro derivative obtained is with a Mixture of P O Cl, and P CIS chlorinated. 5-cyano-3-nitro-6-chloro-2,4-diniethylpyridine is obtained of melting point 112 '.

j, 1 g of 6-chloro-3-rlitro-5-cyano-2, 4-dimethylpyridine are in 200 ccm 'Methanol with the addition of 15.6 ccm 2 n-H Cl in the presence of 5 g Pd-charcoal at room temperature shaken with Hz. After 40 hours, 6 moles of H = have been taken up, and the hydrogenation comes to a standstill. After filtering off the catalyst, the solvent becomes evaporated and the residue recrystallized from methanol -1- ether. The resulting 3-Amino-5-aminomethyl-2,4-dimethylpyridine crystallizes in the form of its dichlorohydrate in white, shiny leaflets with a decomposition point of 3 10 °. Yield 95 () / o der Theory. By extracting a concentrated alkaline solution with chloroform the free base can be isolated, which after recrystallization from methanol ether melts at 136 °.

2.24 g of 3-amino-5-aniinoniethyl-2,4-diniethylpyridinedichlorohydrate are dissolved in 10 cc of water and a solution of 1.5 g of sodium nitrite in 10 cc of water is added. For this purpose, i 5 cc of iN hydrochloric acid are allowed to flow in with stirring. The reaction solution is kept flat for about an hour at 60 ° until no more nitrite can be detected with iodine starch paper. The solution is then evaporated in vacuo and the well-dried residue is extracted several times with absolute alcohol. The one after the evaporation. the residue remaining from the alcohol is recrystallized from methanol + ether, the 3-oxy-5-oxymethyl-2,4-dimethylpyridine having a melting point of 254 ° crystallizing out as a hydrochloric acid salt.

In the vein test as a growth substance for lactic acid bacteria according to M ö 11 e r (magazine for physiological chemistry 1938, vol. 254, p.285) shows this substance perfectly positive effect, with the optimal concentration at a few y / ccm lies. So far, the outside of the natural vitamin B6 was not yet known in this test effective substance.

2.2 - methyl - 3 - nitro - 4. - methoxymethyl -5-cyano-6-chloropyridine is produced as follows: By condensation of methoxyacetylacetone with cyanoacetic ester in 25% ammonia at 60 °, 2-methyl-4-methoxymethyl-5-cyano-6-oxypyridine is obtained. This compound is first made using 86% nitric acid in acetic anhydride nitrated at no more than 60 ° C and then with phosphorus pentachloride and phosphorus oxychloride chlorinated by refluxing.

15 g of 2-methyl-3-nitro-4-methoxymethyl-5-cyano-6-chloropyridine become in - 6oo ccm of methanol with the addition of 31.5 ccm of 2N hydrochloric acid in the presence of io g io% palladium carbon shaken with hydrogen at room temperature. The recording of 3M01 hydrogen runs very quickly and generates heat. After 15 hours the hydrogenation comes to a standstill. after taking up a total of 6 moles of hydrogen have been. The catalyst is filtered off and most of the solvent is distilled from and ether is added, the resulting 2-methyl-3-amino-4-methoxymethyl-5-aminomethylpyridine as dichlorohydrate precipitates in white needles. Melts after dissolving from methanol it at 236 °. The yield is 90% of theory.

In a solution of 7.3 g of 2-methyl-3-amino-4-methoxymethyl -5 - aminomethylpyridine - dichlorohydrate in 5o ccm of water, a solution of 4.4 g of sodium nitrite in 5o ccm of water and 29 ccm of 2 n- Hydrochloric acid was added dropwise with stirring. The solution is kept at 6o to 7o ° for a further 30 minutes and then evaporated to dryness in vacuo at 40 °. By extracting the well-dried residue with absolute alcohol, the sodium chloride is separated off and the resulting solution is evaporated in vacuo. The residue can be redissolved from absolute alcohol and acetone. This gives 2-methyl-3-oxy-4-methoxymethyl-5-oxymethylpyridine as a monochlorohydrate of F. 182 '. Yield 5g.

The 4-methoxymethyl group of this compound is easily passed through Convert to the bromomethyl group by boiling with 66% hydrobromic acid. Since the Hydrobromic acid attacks the aliphatic hydroxyl, 2-methyl-3-oxy-4 is formed first, 5-di- (bromomethyl) pyridine, which is obtained by boiling in water and treating with silver chloride can be converted into 2-methyl-3-oxy-4,5-di (oxymethyl) pyridine.

3. 2.2 g-2-methyl-3-nitro-4-methoxymethyl-5-cyano-6-bromopyridine (prepared by treating the corresponding 6-chloro compound described in Example? with hydrobromic acid in acetic anhydride; recrystallized from isopropyl alcohol, Needles with a melting point of 88 °) are dissolved in 100 ccm of methanol and added. of 4 ccm of 2N hydrochloric acid in the presence of 2 g of 10% palladium carbon with hydrogen shaken. After several hours, the hydrogen uptake comes to a standstill, where exactly 6 moles of hydrogen are adsorbed. The solution freed from the catalyst is evaporated, the residue taken up in water, with freshly precipitated silver chloride treated and evaporated again. By recrystallization from methanol and ether the 2-methyl-3-amino-4-methoxymethyl-5 -, aminomethylpyridinedichlorohydrate is obtained with a melting point of 236 °. Yield 1.8 g = 89% of theory. This connection will processed according to example 2.

4. i g of 2-methyl-3-nitro-4-anethoxymethyl-5-cyano-6-chloropyridine (cf. Examples) are carried in 2.8 g of tin chloride (2 aq) and 3. g of concentrated hydrochloric acid (d = i, 19) so that the temperature does not exceed q.o ° C. Then you warm up 2 hours to 35 to 40 ° C, cool with ice and make alkaline with sodium hydroxide solution. Ethers are repeatedly extracted, the ether extract is dried with potash and decolorized with Animal charcoal and constricts. Crystallize when mixed with slightly boiling petroleum ether 0.6 g of 2-methyl-3-amino-4-methoxymethyl-5-cyano-6-chloropyridine in yellow-white crystals the end. Melting point 117 to 18 ° C. Yield 68% of theory. From the mother liquor 0.04 g of a somewhat impure product is obtained.

0.4 g of 2-methyl-3-amino-4-methoxymethyl-5-cyano-6-chloropyridine become in 50 cc of methanol with the addition of 1 cc of 2 n-H Cl in presence shaken from i g of 100% palladium carbon at room temperature with hydrogen gas. The hydrogenation comes to a standstill after 9 hours. The catalyst is filtered off, the methanolic solution. largely narrowed and mixed with plenty of ether ". The hydrogenation product precipitates in crystalline form. After dissolving from methanol / ether the dichlorohydrate of 2-methyl-3-amino -4-methoxymethyl -5-aminomethylpyridine melts at 236 ° C. Yield: 150 mg t = 94% of theory). This connection is according to example 2 further processed.

5.25 g of 2,4-dimethyl-3-nitro-5-cy an-6-chloropyridine (preparation cf. Example i) are in zoo cc alcohol with the addition of 50o cc dilute sulfuric acid heated to reflux on the steam bath. In the solution is over the course of 2 days Zinc dust added in portions until the solution has become colorless. After this the excess zinc is filtered off, the solution is made strongly alkaline and etherified. After drying the ether with sodium sulfate and distilling off remains 2,4-Dimethyl-3-amino-5-cyanopyridine as a crystalline residue. After recrystallization from 96% alcohol, the product melts at 195o. Yield 15g.

By introducing hydrochloric acid gas into an alcoholic solution of the 2nd 4-Dimethyl-3-amino-5-cyanopyridine can be converted into a chlorohydrate with a temperature of 275 °.

69 2,4-Dimethyl-3-amino-5-cyanopyridine are dissolved in fine spirits and treated with the stirrer with the amount of chromoacetate obtained from 100 g of potassium dichromate (by reduction with zinc and hydrochloric acid and subsequent precipitation with sodium acetate) A solution of 30 g of potassium hydroxide in a little water and fine spirits can be added dropwise for an hour. The reaction mixture is then kept at a gentle boil for 4 hours. During the whole time a stream of hydrogen is passed through the apparatus. After cooling, the precipitated chromium hydroxide is filtered off, the filtered solution is made strongly alkaline and extracted repeatedly with chloroform. After drying with sodium sulfate and distilling off the chloroform, the 2,4-dimethyl-3-amino-5-aminomethylpyridine is obtained in crystals which, recrystallized from fine spirits, melt at i36 °. Yield 2g.

Treatment of an alcoholic solution of 2,4-dimethyl-3-amino-5-aminomethylpyridine with hydrochloric acid gives the corresponding dichlorohydrate, which melts at 3109 with decomposition. The diazotization and boiling of this compound is carried out according to the instructions given in Example i.

Claims (1)

PATENT CLAIM: Process for the production of compounds with the action of adermins, characterized in that compounds of the formula (R is hydrogen, OH, or a group which can be converted into OH) to give compounds of the formula preferably catalytically reduced and in these compounds the two amino groups are converted into hydroxyl by diazotization and boiling.