DE1470022A1 - Process for the production of chemical compounds - Google Patents

Description

Description Process for the preparation of chemical compounds For The priorities of May 15, 1961 and January 16, 1962 were made the n U.S. patent applications Serial No. 109 853 and 166 688 used @@@ The present invention relates to the preparation of pyridine compounds. In particular eie relates to a process for the preparation of 2-methyl-3-hydroxypyridines.

@@@ 2-Methyl-3-hydroxypyridines are valuable compounds that contribute to the synthesis of compounds such as vitamin B6 and its derivatives, usable and the so far for the production of vitamin B6 and don usable starting materials or intermediates available for this purpose Methods included multi-step procedures that were difficult on an industrial scale are to be carried out.

An object of the present invention is to provide an improved method for the production of 2-methyl-3-hydroxypyridines.

Another goal is to create methods of making 2-methyl-3-hydroxypyridines, which have 4 and 5 substituents in the lungs, which can be easily converted to hydroxymethylene substituents. Another @ goal The invention is to provide a convenient method of making Vitamin H6, Other objects and objects of the invention are from the following @@@ going description.

It has now been found that 2-methyl-3-hydroxypyridines are easily and conveniently prepared by reacting 4-methyloxazoles, d @@ in the 5-position, an oxy group substituted by a hydrocarbon radical (hereinafter referred to as hydrocarbonoxy radical), with an ethylenic compound can be. This use set is particularly suitable for the production of 4,5-disubstituted derivatives of 2-methyl-3-hydroxypyridina by reacting 1,2-disubstituted ethylenic compounds with the O @@ z @@. The reaction to produce similar substituted derivatives can be shown structurally as follows In accordance with the direct scheme, the oxazole is reacted with the ethylenic compound to form the corresponding 4,5-disubstituted 2-methyl-3-hydroxypyridine.

In the reactions described above, the substituent represents R of the oxazole is a carbon hydrogen group.

The process according to the invention can be carried out with various 4-methyl-5-hydrocarbonoxyoxazoles are generally carried out, but oxazoles are / preferably used, which have a hydrocarbon group with 1-10 carbon atoms, as these compounds are easiest to manufacture and produce high yields under optimal conditions lead to the desired 2-methyl-3-hydroxypyridine compounds.

Thus represent oxazole, in which the hydrocarbon substituent an alkyl radical here with 1-10 carbon atoms, such as methyl, Ethyl, isopropyl, butyl, isobutyl, amyl and octyl, a heterocyclic alkyl radical, such as tetrahydrofurfuryl, an aralkyl radical, such as for example Benzyl, phenylethyl and phenylpropyl, or an aryl radical, such as phenyl, Kr @@ yl un @ @@@., Tet, preferred oxazoles of those used in the process according to the invention can be used.

The ethylenic compounds ate with the oxazole to form the desired pyridine compounds are implemented, can be those in which & and B in the above formula represent a substituted carbon atom such as wine COOH, CHO, 00) 11 (2, COOH, COX, 0E20R1, CN, Ch2X, CH2NH2, CH2OH and CH2NHR1, mean, wherein R1 is a hydrocarbon substituent, preferably one having 1-10 Carbon atoms, and X represents a halogen atom.

A and B can also be in a heterocyclic ring by oxygen, Sulfur or nitrogen can be combined with one another.

According to one embodiment of the invention, an ethylenic Compound such as maleic acid or fumaric acid or a derivative thereof, such as an ester or an anhydride, with the oxazole to the corresponding 4,5-disubstituted 2-methyl-3 - hydroxypyridine implemented. For example, if maleic anhydride, Maleic acid or fumaric acid reacted with the oxazole, so is 2-methyl-3-hydroxy-4,5-dicarboxypyridine obtain. This product can be converted into vitamin B6 using known methods. alternatively, the oxazole is combined with a mono- or diester of maleic or fumaric acid implemented, the corresponding ester of 4,5-dioarboxy-2-methyl-3-hydroxypyridine is used obtained, which can also be converted into Vitasin B6 by known methods can.

Likewise, other derivatives of fumaric acid or maleic acid, such as for example fumaronitrile or fumaric chloride, maleonitrile and the like., in the appropriate Way with the Oxasol to form the corresponding 2-methyl-3-hydroxypyridine, which has substituents in positions 4 and 5, reacted; the so obtained Compounds are also used as intermediates in the manufacture of Vitasin and like pyridine compounds are valuable.

It has been found that 2,5-dihydrofuran also reacts with 4-methyl-5-hydrocarbonoxyoxazole can be converted to form the inner ether of vitamin B6; that then can be converted into vitamin B6 according to known methods. This represents a represents another particular embodiment of the invention.

According to a further embodiment of the invention, butenediol with ' 4-methyl-5-hydrocarbon oxazole with direct formation of vitamin B6 implemented.

The reaction between the oxazole and the ethylenic compound is carried out by keeping a mixture of the reaction components in intimate contact until the reaction is complete. the reaction of the ethylenic compound and the oxazole can be completed by letting the reaction components stand at room temperature or by heating the reaction axially to a temperature of up to about 2000C to accelerate the formation of the desired pyridine compound. If the reaction is carried out with an active dienophile such as maleic anhydride, it can generally be carried out at room temperature. If non-activated dionophiles, such as, for example, dihydrofuran, butenediol and the like, are used, the reaction does not take place at a noticeable rate unless the temperature is raised to 150-200.degree. The formation of the substituted pyridine can be carried out in the presence of a suitable solvent for the reaction components, such as, for example, methanol, benzene and the like, but the presence of such a solvent is not necessary for carrying out the process according to the invention -3-hydroxypyridine compounds is the initial product formed by the reaction of @@@ zols and some ethylene compounds under ge - @@@@ en conditions, probably an adduct of the formula in which R, A and B have the meanings given above. This adduct appears to be formed as a reaction product when certain ethylenic compounds, such as maleic anhydride, are reacted with the oxazole at low temperatures, and it is cleaved to form the desired 2-methyl-3-hydroxypyridines when the reaction product is treated with acid weather. If the condensation of the ethylenic compound with the oxazole is carried out at elevated temperatures, 100 ° C. or above, 80 the adduct appears to be thermally cleaved under the reaction conditions.

It is evident that this explanation of the course of the reaction is included the adduct intermediates based on mutual knowledge of the reaction, and that these theoretical explanations do not exclude the possibility customs, baae of the adduct may also have a different structure than the one specified owns.

The present invention is therefore not intended to be based on these theoretical ones Considerations be limited. Rather, the explanations are only used as aids given for a better understanding of the invention. the following examples explain the invention without limiting it.

Example 1 1 * 27 g (0.01 mol) of 4-methyl1-5-ethoxyoxazole are mixed, 0t98 g (0.01 mol) of maleic anhydride and 2.5 11 dry benzene, with a yellow Color occurs @ and lice is released, the cooling required maoht. To 3-4 minutes the heat development stops, and the color before. pale. The mixture is then refluxed for about 18 hours. Then the solvent decanted off and the residue treated with a small amount of water. The received Mixture is dried by adding ethanol and benzene and the result is Mixture is dried by azeotropic Deetillatlon.

To the residue, 40 ml of ethanol are added and the solution is then saturated with gaseous HCl. The acidic solution is refluxed for 3 1/2 hours heated. After cooling down, the solvent is evaporated, and in some cases it is crystalline Residue, the 2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid diethyl ester hydrochloride contains, will diarch reaction with aqueous sodium bicarbonate converted into the free base, the solution obtained is extracted with boron, and the ether extracts are dried over magnesium sulfate.

The 2-methyl-3-hydroxypyridn-4,, 5-dicarboxylic acid diethyl ester containing Ether solution is treated with 0.5 lithium aluminum hydride, with a violent reaction entry. The resulting mixture is stirred for 2 hours and then left to stand over power calmly. Then the excess hydride by adding ethanol and then replaced by water. The ethereal layer is removed and the watery one o; ht saturated with carbon dioryd. After filtering, the solution is evaporated to dryness. The residue obtained is extracted three times with hot ethanol * and gaseous HCl is introduced into the ethanol extracts. After 2 to 3 hours of 8tehenlaasen the acidified, ethanol solution separate sioh @ crystals of vitamin B6.HCl, obtained by filtration. The infrared and ultraviolet spectra as well the melting point are with those of an authentic sample of vitamin B6.HCl identical.

Example 2 A mixture of 1.27 g (0.01 mol) of 4-methyl-5-ethoxyoxazole, 0.98 g (0.01 mol) of maleic anhydride and 2.5 ml of dry benzene react, with the temperature is kept below about 3000 until the reaction has ended in about 20 minutes is. The resulting reaction mixture contains the adduct, which is hygroscopic, Das Infrared spectrum, the low volatility and the lack of UV absorption about over 220 m µ show that no starting material is present in any appreciable amount0 95 ml of ethanol are added to the resulting reaction mixture containing the adduct added. This solution is ge @ @ saturated with gaseous dry HCi, and the acidified The solution is then refluxed for about 15 1/2 hours. After cooling, it is the solvent is removed by evaporation and the residue is removed by adding a aqueous sodium bicarbonate solution neutralized. The solution obtained is three times extracted with ethyl ether. The aqueous part is acidified to Congo red with HCl.

Crystals of a monoethyl ester of 2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid separate on standing from, diN can be obtained by filtration. F = 252 ° C (dec.) 0 the Ether extracts become naobic; Dry over magnesium sulphate and filter partially crystalline residue evaporated. The crystalline separated off by filtration Part consists of 2-methyl-3-hydroxypyridine - @ - carboxylic acid ethyl ester.

The oily residue obtained after removing the crystalline portion is distilled at a pressure of 0.15 mm at 105-120 ° C and thus provides the diethyl ester des 2-methyl-3-hydroxy-4,5-dicarboxypyridines. , This product is made by dissolving in a mixture of ethyl ether and ethanol and introduction of gaseous HCl Ln the hydrochloride transferred. The product melts after recrystallization from ethanol-ethyl ether at 140-144 ° C.

After mild hydrolysis with dilute aqueous sodium hydroxide during 5 minutes and subsequent acidification, a monoethyl ester of 2-methyl-3-hydroxy-4,5-carboxypyridine crystallizes from F = 203-205 ° C (decomp.), which is different from that obtained as described above Is the diethyl ester hydrochloride with aqueous sodium hydroxide 15 minutes heated for a long time on a steam bath and the resulting reaction mixture cooled and acidified against Congo red, the dicarboxylic acid, 2-methyl-3-hydroxy-4,5-dicarboxypyridine, crystallizes, from, and obtained by filtration.

Treatment of the diethyl ester hydrochloride with lithium aluminum hydride in a manner known per se leads to vitamin B6 hydrochloride with an temperature of 203.5 - 203 ° C (Decomposition).

I Example 3 A mixture of 1.27 g (0.01 mol) of 4-methyl-5-ethoxyoxazole and 3.5 1 (0.02 mol) diethyl maleate is heated at 50-60 ° C for 2 hours. After cooling down 10 ml of ethanol and 2 ml of ethanolic 9m HCl are added to every 000, and the solvents are removed under reduced pressure. -Dor residue obtained, which is the diethyl ester des 2-methyl-3-hydroxy-4,5-dicarboxypyridine is suspended in 25 ml of ether and filtered; the filter cake is washed twice with 10 ml of ether each time. tor eo obtained diethyl ester of 2-methyl-3-hydroxy-4,5-dicarboxypyridine hydrochloride Schmilst at 132-138 ° C.

Example 4 Diethyl fumarate is added with 4-methyl-5-ethoxyoxazole according to the method described in Example 3 to obtain the diethyl ester of 2-methyl-3-hydroxy-4,5-dicarboxypyridine [HCl.

Example 5 A small portion of a mixture of 0.254 g of 4-methyl-5-ethoxyoxazole, 2.804 g of 2,5-dihydrofuren and 0.01 g of hydroquinone are placed in a sealed glass tube 6 stuaben heated at 150 ° C. After cooling, the tube is opened and the contents washed out with a small amount of ethanol. Part of this solution is on a Spotted paper strips and immersed in chloroform for 15 minutes; Formamide chromatographed, where the chloroform is the mobile phase and the formamide is the stationary phase.

The paper chromatogram is dried at 90 ° C under reduced pressure, and brr UV absorbing stain is eluted with 4.00 ml of 0.1N HCl. the UV spectrum the solution obtained corresponds exactly to that of the inner ether of the vitamin B6. The product can also be obtained by cooling the reaction tube and filtering off the precipitated product can be isolated.

Example 6 To 0.88 $ (0.01 mol) of 2-butene-1,4-diol, 1.27 g (0.01 Mol) 4-methyl-5-ethoxyoxazole added, and the resulting mixture is 15 hours left to stand at room temperature. The reaction mixture is under a nitrogen atmosphere on Heated to 199 ° O and then allowed to cool. The infrared spectrum of a sample of the reaction mixture shows that the 6.01 µ µ oxazole band will be attenuated dead. At this point in time 20 oom Xthanol was added to the mixture, and the resulting solution was with gaseous HCl saturated. After refluxing the solution for 15 minutes, the ethanol becomes evaporates. A small amount of ethanol is added and then evaporated, to remove excess HCl. gvoh How repetition of this procedure becomes the The residue is dissolved in 5 ml of water, and oin part of the solution is used to determine and Separation of vitamin B6 by paper chromatography in the n-butanol vs. aqueous phosphate of pH 7 subjected. The part of the paper chromatogram corresponding to the Vitamin B6 control stain is eluted with water. The ultraviolet spectrum the aqueous solution obtained corresponds to both acidic and basic Solution to the spectrum known for vitamin B6.

Example 7 A mixture of 1.27 g (0.01 mol) of 4-methyl-5-ethoxyoxazole, 0.97 6 (0.011 mol) 2-butene-1,4-dol and a trace (»<1 mg) hydroquinone heated and 2 hours @@ ter nitrogen atmosphere at about 200 ° C held. The reaction mixture obtained immediately is as described in Example 6 Process worked up. The aqueous solution contains vitamin B6 like the biological one Test shows, W t Gemi.ch, of 1.27 <(0.01 mol) 4-methyl-5- @ thoxyexazole, @, 97 g (0.011 mol) of 2-butene-1,4-diol, a trace (<1 mg) of hydroquinone and 58 ml of 1,2-dimethoxyethane is heated for about 5 days at 100 ° C under a pressure of 10200 at (145000 pei). The reaction mixture obtained is filtered and evaporated. Bas infrared spectrum the residue shows a noticeable decrease in the 6.01 @ oxazole band. The residue is then dissolved in 15 ml of 0.1N HCl, and the solution obtained is on for 30 minutes heated in a steam bath. Then the solution is adjusted to pH 7.5 with sodium carbonate, and a portion of the solution is subjected to paper chromatography according to that described in Example 6 Procedure.

By eluting the stain that corresponds to the vitamin B6 control, With 0.1N HCl solution, you get a solution that contains vitamin B6, as with the UV spectrum is determined and confirmed by biological testing.

Example 9 1.016 g (0.008 mol) of 4-methyl-5-ethoxyoxazole and 1,2'16 g (0.016 mol) of 2,5-dihydrofuran are placed in a 22 ml pair of peroxide bombs and heated for 3 hours at 175 ° C.

After cooling down, the bomb is opened and the crystalline inner Xther of vitamin B6 obtained by filtration.

The filtered product is washed with 5 ml of cold 2,5-dihydrofuran and dried in a vacuum oven at 800C.

Example 10 41.0 g (0.53 moles) of fumaronitrile and 52.5 ml of anhydrous Methanol are poured into a 500 ml four-necked round bottom flask fitted with a thermometer, a A reflux condenser, a dropping funnel and a stirrer are introduced.

66.8 are added to the methanolic nitrile slurry with stirring g (0.53 mol) of 4-methyl-5-ethoxyoxazole were added from the dropping funnel. The smell is heated under reflux and held at this temperature for 45 minutes.

Then 131.3 ml of cold anhydrous methanol are added, and that The mixture is cooled to 3 ° C. in an ice bath while stirring. Become this mixture Pass 21.0 ml of concentrated hydrochloric acid through the dropping funnel at such a rate added that the temperature of the reaction mixture does not rise above 20 ° C. Of the after cooling formed light yellow lower base is aged for 1 hour.

The precipitate is filtered off and the slurry with once 50 al. washed cold anhydrous methanol.

The precipitate is dried in a cold, vacuum oven.

The product thus obtained contains 83.1% of 2-methyl-3-hydroxy-4,5-dicyanopyridine hydrochloride, as the UV test shows.

Example 11 A portion of a mixture of 0.127 5 4-methyl-5-ethoxyoxazole, 3.44 g of 1,4-diaoetoltybutene- (2) and a trace of hydroquinone are placed in a glass capillary tube enclosed and heated in an oil bath for 1 1/2 hours at 175 ° C. The pipe will cooled and broken up and the contents dissolved out with 95% ethanol. The solvent is stripped off and the residue is taken up in water, alkaline with sodium carbnate to pH 11. done and on a steam bath for 30 minutes heated to hydrolyze the ester groups. The cooled solution is then concentrated with Salassic acid neutralizes. A measured portion is dabbed on pilter paper and as described in Example 6 in the n-butanol vs. aqueous phosphate system chromatographed from pH 7. “He part of the chromatogram that corresponds to the vitamin B6 control stain corresponds to, is eluted with 0.1N HCl. The ultraviolet spectrum of this solution corresponds exactly the spectrum known for vitamin B6.

Example 12 A mixture of 0.25 g of 1,4-dimethoxybutene- (2), 0.72 g 4-methyl-5-ethoxyoxazole and a trace of hydroquinone are heated at 1000C for 120 hours. Unreacted starting materials are in vacuo at 30 mm Hg up to one Temperature of 60 ° C distilled off. The residue is taken up in 20 ml of methanol, treated with anhydrous hydrogen chloride gas, warmed briefly and cooled in vacuo freed from solvent 0 The residue is recrystallized from isopropyl alcohol. This gave 2-methyl-3-hydroxy-4,5-dimethoxymethylpyridine hydrochloride, which after the IR absorption and the Rf value in the paper strip chromatography with a authentic sample produced in an indubitable way is identical; F = 144-145 ° C.

Example 13 Min mixture of 0.127 g of 4-methyl-5-ethoxyoxazl, 0.128 g γ-acetoxycrotonaldehyde and a trace of hydroquinone is used for 18 hours Maintained room temperature. The mixture is taken up in ethanol, with 5 ml of 3% Ethanolic sodium ethylate made basic and heated under reflux for 2 hours. The solution is cooled, neutralized with concentrated hydrochloric acid and in vacuo freed from solvents. A sample of the residue gives the same R-value at of paper strip chromatography and the same UV absorption spectrum as one authentic sample of pyridoxal hydrochloride (2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine hydrochloride). The remainder of the residue is treated with lithium aluminum hydride in ethylene glycol dimethyl ether to vitamin B6 hydrochloride (as indicated by the Rf value in paper strip chromatography and the UV absorption shown).

Example 14 A portion of a mixture of 2980 g of 2,5-dihydrofuran, 0.23 g of 4-methyl-5-methoxyoxazole and a trace of hydroquinone is placed in a glass capillary tube sealed and heated in an oil bath at 17500 for 2 hours. The pipe is cooled down and the contents are dissolved out with 95% ethanol. Part of this solution is spotted on filter paper and chromatographed in the chloroform-formamide system. The fluorescent band (UV light) with the same Rf value as the inner ether of vitamin t6 is eluted with 0.1n-HCl and shows the same UV absorption spectrum like an authentic sample.

Example 15 A portion of a mixture of 0.28 g of 4-methyl-5-isopropoxyoxazole, 2.80 g of 2,5-dihydrofuran, a trace of hydroquinone and 0.10 g of trichloroacetic acid is in enclosed in a glass capillary tube and heated in an oil bath for 2 strokes at 175 ° C. The tube is cooled, the contents are dissolved out with 95% ethanol, and a portion of this solution is dabbed on filter, paper and in the chloroform-formamide system chromatographed, the fluorescent (in UV light) band with the same $ f value as the inner Xther of vitamin B6 is eluted with 0.1N HCl and shows the same UV absorption spectrum like an authentic sample.

Those used as starting materials in the previous examples Oxyzole compounds can be prepared according to the procedure of the patent ........... (patent application by the same applicant on the same day with the same title) by formylation of the appropriate α-alaninate ester acid salt and reaction of the formyl derivative obtained or an enol ether derivative thereof with a dehydrating agent, such as phosphorus pentoxide, with the formation of the corresponding 4-methyl-5-hydrocarbyl oxyoxyzene will. The ethoxyoxyzene can thus be prepared as follows: To 35 g of ethyl α-alaninate hydrochloride 10 g of formula are added, and the resulting mixture is slowly insidehal @ heated to 105 ° C for 30-45 minutes. After 10 minutes heating at 1050C about 75 ml of toluene were added. According to eta Standing for 1 hour will do that Cteii'iech then refluxed for about 6 hours. After cooling, the formed Removed ammonium chloride and the solution obtained to remove the solvent evaporated. The ethyl N-formyl-α-alaninate is distilled at 10,000 obtained at 0.9 mm »jerk.

To a mixture of 25 ml of alcohol-free chloroform and 1136 g of P2O5 a solution of 5 g of ethyl N-formyl-α-alaninate is obtained within 20 minutes added in 15 ml of alcohol-free chloroform at about 30 ° C. The reaction mixture obtained is refluxed for 1 hour and cooled, and the solvent is decanted. The remaining hard mass is crushed and long with a Solution of 27 g of potassium hydroxide in 27 ml of water and 34 ml of methanol are added, with the temperature is kept at 10-20 ° C.

The resulting solution is refluxed for 1 hour, cooled and extracted ten times with 15 ml of methylene chloride since 4-methyl-5-ethoxyoxazole is used after removing the solvent by distillation at 75-80 ° C at 10 mm pressure won.

I, n in the same way are other oxazoles by using the appropriate Alaninate ester produced.

Claims (1)

Patent claims P a t e n t a n s p r ü c h e (D Method for manufacturing of 3-Uydroxy-2-methylpyridinen, characterized in that one is a 4-methyl-5-hydrocarbonoxyoxazole with @ @ t @ ethylenic compound to the corresponding 3-hydroxy-2-methylpyridine implements. 2. Process for the preparation of a compound of the formula characterized in that a 4-methyl-5-hydrocarbonoxyoxazole is reacted with maleic anhydride. 3. Process for the preparation of a pyridine compound, characterized in that a 4-methyl-5-hydrocarbonoxyoxazole is mixed with 2,5-dihydrofuran to give a compound of the formula implements. 4. Process for the preparation of pyridine compounds, characterized in that a 4-methyl-5-hydrocarbonoxyoxazole is mixed with an ethylenic compound of the formula A-HC-CH-B in which A and B each from the group CHO, COOH, COOR1, COX , CH2OR, CN, CH2X, CH2NH2, CH2OH and CH2NHRa are selected, where R1 is a hydrocarbon radical and X is a haloene atom, with the formation of the corresponding pyrine @ yne compound of the formula implements. 5. A process for the preparation of pyridino bonds, characterized in that ian a 4-methyl-5-hydrocarbonoxyoxazole with a compound of the formula HOOC-HC = CH-COOH to form a compound of the formula implements. 6. The method according to claim 5, characterized in that one dic implementation with maleic acid. 7. The method according to claim 5, characterized in that the implementation with fumaric acid. 8. A process for the preparation of pyridine compounds, characterized in that a 4-methyl-5-hydrocarbonoxyoxazole with a compound of the formula ROOC-CH = CH-COOR in which R is a hydrocarbon radical, gives a compound of the formula implements. 9. The method according to claim 8, characterized in that the Implementation with a lower alkyl ester of maleic acid. 10, the method according to claim 8, characterized in that one the Implementation with a lower a yl ester of fumaric acid. 11. Experience the preparation of a pyribine compound, characterized in that a 4-methyl-5-carbon @assoxidoxyoxazole with a compound of the formula NC-CH = CH-CN to form a compound of the formula implements 12c Process for the preparation of pyridine compounds, characterized in that a 4-methyl-5-hydrocarbonoxyoxazole with e is a compound of the formula XH2C-CH = CH-CH2X in which X is a halogen atom, u a compound of the formula implements. 13. A method for the production of vitamin B6, characterized in that that a 4-methyl-5-hydrocarbonoxyoxazole with a compound of the formula HOH2C-CH = CH-CH2OH converts. 14. A process for the preparation of a pyridine compound, characterized in that a 4-methyl-5-koh @enwasserstoffoxyoxazole with a compound of the formula H2NH2C-CH = CH-CH2NH2 to form a compound of the formula implements.