IL22830A - Sulphur-containing derivatives of vitamin b6 and process for their preparation - Google Patents

Description

PATENTS FORM NO. 5 £ΰΙ3ΗιΕΒ¾ SPECIFICATION Sulphur-containing derivatives of vitamin and process for their preparation.

We, E. IERGK AKTIENGESELLSCHAFT, a German Body Corporate, of 250 Frankfurterstrasse , Darmstadt, Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement ·- This invention relates to sulphur-containing derivatives of vitamin Bg and to processes for their preparation.

Bis- [ -hydroxymethy1-5-hydroxy-6-methy1-pyrid 1 (3)-methyl] disulphide of the formula:- has become known by the name of pyrithioxine and has proved to be very useful for the treatment of geriatric disorders. It is also suitable for the treatment of cerebral functional disorder^ .and associated illnesses.

Previously pyrithioxine has been produced by reacting a salt of 3 ,4-bis-bromomethyl-5-hydroxy-6-methyl-pyridine with an alkali metal xanthogenate and then converting v e reaction product to pyrithioxine by treatment with a weak base.

Alternatively, an acid addition salt of 3}4~bis- has been bromomethyl-5-hydroxy-6-methyl-pyridine 9isay-¾e/reacted with a water-soluble inorganic disulphide in the presence of water and/or water-miscible organic solvent ''to give pyrithioxine.

The first of these processes has the disadvantage that; traces of a .yiolet coloured dye of unknown composition are formed as a by-product and before the drug can be used it is necessary to separate out the dye in order to satisfy the required purity standards.

This purification is a time-consuming procedure ■ ain■d' ° always results in the loss of material.

The pyrithioxine obtained by the second of the two processes is cheaper than that produced by the first Although no violet dye is formed in the process, small -quantities of a trisulphide are. Although the trisulphide is present only in traces it can be detected by thin-layer chroma ography. Repeated treatment with concentrated hydrochloric acid is required to obtain the required degree of purity in the drug.

It is thought that the sulphur function of the starting materials is probably responsible for the formation of the undesired by-products, but we have found that they are not formed when the starting material used is a mercapto-vitamin Bg derivative whose hydroxyl •groups are present in a functionally modified form.

That the formation of the undesired by-products was controlled by the free hydroxyl groups of the vitamin Bg molecule was a surprising and unpredictable discovery and we are not yet aware of- any explanation for this phenomenon.

According to the present invention we provide a process for the preparation of bis-[4-hydroxymethyl-5-hydroxy-6-methyl-pyridyl-(3)-methyl]-disulphide which comprises the steps of oxidising a compound of the formula:- where and Bg, which may be the same or different, are acyl groups containing from 1 to 6 carbon atoms or together form a group of the formula:- G R_ / \ where and R^, which may be the same or different, are H or alkyl groups containing from 1 to 5 carbon atoms or where and R^ together with the carbon atom to which they are attached form a saturated carbocyclic ring containing and then converting the compound of Formula III into the bis-/, 4-hydroxymethyl-5-hydroxy-6^methyl-pyridyl-( 3)-methy¾~ disulphide by reacting it with dilute acid.

Alternatively, a compound of the formula:- where ^ and R≥ are as previously defined and X is chlorine, bromine or iodine, is reacted with a water-soluble inorganic disulphide, preferably sodium disulphide, in the presence of water and/or water-miscible organic solvent to form a compound of Formula III, which is then reacted with dilute acid to give the desired product.

In the oxidation process a salt of the compound of Formula II may be used instead of the free base as a starting material.

The preferred oxidizing agents for the oxidation step are air, hydrogen peroxide or iodine.

The compounds of Formula III are novel per se and, as such, are provided by the invention. . used for the preparation of pyrithioxine is that the starting material used was 3 ,4~bis-bromomethyl~5-hydroxy-6~methyl-pyridine which is accessible in economic yields practically only by treatment of vitamin Bg or its 4-methylether with concentrated hydrobromic acid. This bromination process produces gaseous hydrobromic acid in high concentration which attacks the material of the reaction vessel and hence the apparatus used is subject to very considerable wear.

Against this, the present invention permits of the use of halogen methyl pyridine compounds of Formula IV for starting material and these compounds can be prepared from the basic hydroxyl compounds by treatment with thionyl halide. This halogenation process is much less corrosive because low temperatures can be used while in addition gaseous hydrogen halide is formed only to a minor degree. The corrosion occurring on the apparatus used is therefore greatly reduced.

Although the processes of the present invention may not give pyrithioxine in a better yield, they do give it in a form free from dye and trisulphide by-products.

In the starting materials of Formula II and Formula IV, R^ and B.^, may in particular denote acetyl, propionyl or butyryl groups, R^ and/or R^ may denote not only hydrogen but also methyl, ethyl, n-propyl, isopropyl or butyl, -s-o-ihai. the and R2 radicals e& jointly , ethylene, n-propylidene , isopropylidene or butylidene groups, with the carbon atom to which they are attached The radicals R^ and R^ may together form particularly a cyclopentane or cyclohexane ring.

Piles 129OI 12.I.I .

In detail, the starting material used may, for example, be the following compounds of Formula II (only the free mercapto form is mentioned in each case, although it is also possible to use the salt)t-5-acetoxy- -acetoxymethyl-3-mercaptomethyl-6-methyl-pyridine, 3-mercaptomethyl-6-methyl-5-propionyloxy-4-propionylo ysmethyl-pyridine, 5-butyryloxy-¾-butyryloxy-methyl-3-mercaptomethyl-6-methyl-pyridine, 5-me ea tornethyl-2,2,8-trimethyl- and 2-ethyl-5-raerca tomethyl-2,8-dimethyl-and 5-mercaptomethyl-8-methyl-2-propyl- and -2-isopropyl-5-mercaptomethyl-8-methyl- and 2-ethyl-5-mercaptomethyl-8-me»thyl- and 5-mercaptomethyl-2,8-dimethyl- and 5 mercaptomethyl-8-methyl- and 2, 2-diethyl-5-mercaptomethyl-8-methyl-4H-m-dloxino 5, 5-c pyridine; and mercaptomethyl-8-methyl-4H-ni~dioxxno Jkt 5-c/ pyridine-2-spiro-cyclohexane and -2-spiro-cyclopentane.

Formula IV halogen methyl derivatives used are preferably those compounds of Formula IV in which X denotes chlorine or bromine, for example, 5-acetoxy-¾-acetoxymethyl-3-bromomethyl-6-methyl-pyridine, 3*chloromethyl-5-propionyloxy-U-propionyloxymethyl-6-methyl-pyridine a»eV 3-chloromethyl-5-butyryloxy-¾-butyryloxy-methyl-6-methyl-pyridine, 5-Chloromethyl- 2,2,8-trimethyl- and 5-Chloromethyl-2-ethyl-2,8-dimethyl-and 5-Chloromethyl-2,2-diethyl-8-methyl- and 5-Chloromethyl- 8-methyl-2-propyl- and 5-Chloromethyl-2-lsopropyl-8-methyl- ai 5-Chloromethyl-2-ethyl-8-methyl- and 5-Chlororaethyl- 2,8-dlmethyl- and 5-Chloromethyl-8-methyl-¾H-m-dioxino pyridine; and 5~Chloromethyl-8-methyl-¾H-m- P.A. 22830 File» 12 01 (η_ 3«Ϊ|Ι»1969.

The Formula XI mercapto compounds may be present in the form of their metal salts* for example in the form of their alkali-metal salts* preferably their sodium salts, when alkaline solutions are used* Ammoniacal .................. corresponding ammonium salt may be present as an Λ " intermediate.

Any oxidation agents which may be employed for the preparation of organic disulphides from the basic-SH compounds can be used for the oxidative conversion of the mercapto compounds of Formula II to the disulphides of Formula III. In the present case it is particularly advantageous to use atmospheric oxygen for the oxidation* For example, a Formula II mercapto compound in an ammoniacal or alkaline aqueous-alcoholic solution can be converted to the corresponding Formula III disulphide in good yield by simply being left to stand in contact with the atmosphere. Preferably, the solution should be agitated. The atmospheric oxygen thus acts, as the oxidation agent. Oxidation is advantageously carried out in the presence of a solvent, for example water, ethyl alcohol, methyl alcohol, isopropyl alcohol, dioxan or dimethylformamide . If required, catalysts may be added for. oxidation purposes, for example iron, gold, platinum, copper and mercury salts, for example FeCl^, AuCl^, ( H )2[PtCl63 , GuS0 , H Cl^ As a rule it is not necessary to heat the reaction mixture and room ,temperature may be sufficiently high. As an alternative to atmospheric oxygen, the oxidising agent may be 'hydrogen peroxide, preferably in the form of a 30% . . aqueous solution, or elementary iodine. In the latter case it is advantageous to eliminate the excess iodine after reaction by treatment with sulphurous acid.

Other oxidising agents which may be used are as follows:- bromine, hypoiodides, 3?eCl¾, potassium , chloride (see Houben-Weyl, Hethoden der organischen Chemie, Volume 9 (1955)? pages 59 t. seq . ) and electrolytic oxidation on platinum anodes.

The mercapto compound used as starting material need not be isolated for use. in the reaction. On the contrary, the mercapto compound can be produced directly before oxidation and be used in situ. For example, a Formula IV halogen compound can be used as starting material and be reacted with thiourea, alkali- or ammonium-xanthogenate , -dithiocarbamate , -thioacetate or -thiosulphate , without it being necessary to isolate the primary sulphur compounds. The reaction of the halogen compound with thiourea is advantageously carried out in the presence of a solvent, for example methanol j ethanol or isopropanol, The reaction mixture is preferably heated to the boiling point of the solvent whereupon the solution may suitably be left to stand for some time. The corresponding isothiouronium compound forms in these conditions (Formula II, instead of -SH the radical is —S-C The resultant isothio-uronium salt maybe split by oxidation by treatment with say, 50% hydrogen peroxide 'solution without the intermediate mercapto compound of Formula II being isolated. In this way the required Formula III disulphide is obtained directly.

A Formula IV halide may also be reacted with alkali- or ammonium-alkyl-xanthogenate or -dithiocarbamate. The xanthogenate used for this reason is preferably potassium ethyl xanthogenate (usually referred to sinply as potassium xanthogenate), or ammonium dithiocarbamate.

T aqueous-alcoholic solution, and it is preferable to do it at room temperature. Preferably, the reaction solution is then left to stand for some time, for example about 3 hours, and, under these conditions the corresponding dithiocarbamate or xanthogenate (Formula II, radical -S-CS-NH2 or -S-CS-OR instead of the '-SH group, R = lower alkyl) forms. Treatment with alcoholic ammonia solution results 'in a splitting of the xanthogenate to form the mercapto compound of Formula II which need not be isolated.

Oxidation to form the Formula III disulphide may then take place immediately as a result of the atmospheric oxygen contained in the alcoholic ammonia solution.

The solution may be agitated in air to accelerate the oxidation.

The mercapto compound of Formula II may also be formed in situ by reacting a Formula IV halide with alkali- or ammonium-thiosulphate , preferably sodium thiosulphate, to form the corresponding thiosulphate sodium compound (Formula II, radical -S-SO^Na instead of the -SH group) . The reaction is preferably carried out in aqueous-alcoholic solution at temperatures between room temperature and 70°C. After the reaction the reaction solution is inspissated, and after the solution has been left to stand the required thiosulphate sodium compound crystallises out. This compound can be split by treatment with alcoholic iodine solution or by the action of HgC^ and at the same time the intermediate Formula II mercapto derivative can be converted directly to the Formula III disulphide. The latter precipitates to stand and it can "be isolated by filtration.

The Formula II mereapto compound can also be produced in situ by treatment of a Formula IV halogen compound with a thioacetate. The reaction is advantageously performed in an alcoholic solution and the thioacetate used is preferably potassium thioacetate. The reaction may suitably be carried out at room temperature and completed by refluxing. Inspissation of the reaction solution gives the required acetylthio compound (Formula II, -S-CO-CHj radical instead of the -SH group). The acetylthio compound is saponified by alkali, preferably dilute sodium hydroxide, and the resultant -SH compound (Formula II) which is present in the form of its sodium salt, can then be converted to the required Formula III disulphide by oxidation without the need to isolate the intermediate. If a Formula IV halide is reacted with sodium hydrogen sulphide in aqueous, alcoholic or aqueous-alcoholic solution, the Formula II mercapto compound is obtained after concentration of the solvent if the pH of the solution is equal to · Conversion of a Formula IV halide to the associated Formula III disulphide by treatment with a water-soluble inorganic disulphide can be carried out in the presence of water and/or a water-miscible organic solvent. The solvents used may, for example, be as follows:- lower aliphatic alcohols, such as methanol, ethanol or isopropanol, acetone, dioxan, tetrahydrofuran, glycerin or glycol, Dimethylformamide (also in the presence of water) can also be used. A mixture of water out in the presence of water, the proportion of water * . to water-miscible organic solvent in the mixture is preferably 2:1.

The alkali metal disulphides are the preferred water-soluble disulphides and the use of sodium disulphide ( &^&^) is very advantageous.

The Formula III disulphides can readily be split to form pyrithioxine by treatment with dilute aqueous or alcoholic acids, more particularly by the action of mineral acids, for example hydrochloric acid. In addition to mineral acids the following organic acids may also be used for example:- succinic acid, citric acid, oxalic acid, malonic acid, acetic acid, fumaric acid, benzoic acid, ascorbic acid, propionic acid, methanesulphonic acid, amino sulphonic acid.

Pyrithioxine can be used in human medicine in admixture with physiologically acceptable carriers.

The carrier may be an organic or inorganic substance or substances which are suitable for parenteral, enteral or topical application and which do not react with the pyrithioxine, for example water, vegetable oils, polyethylene glycols, gelatin, lactose, starch, magnesium stearate, talc, vaseline or cholesterol.

Solutions, more particularly oily or aqueous solutions, and suspensions, emulsions or implants may be used for parenteral application. For enteral application it is possible to use tablets or pills, and for topical application ointments or creams which may or may not be sterilised or mixed with additives, such as preservatives, stabilisers or wetting agents, or salts for influencing The pyrithloxine is preferably given in a dosage unit of 20 to 500 iag.

In order that the invention may be more fully understood, the following Examples are given by way of illustration only.

Example 1 (a) 6,3. g of 5-acetoxy-4~acetoxymethyl-6-methyl-pyridyl~(3)-methyl-thiosulphate sodium were dissolved in 50 ml of water. Alcoholic iodine solution was added dropwise until the yellow-brown colour persisted. The 3-acetoxy- -acetoxymethyl-3-mercaptomethyl-6-methyl-pyridine which forms immediately was not isolated. The excess iodine was removed by adding a few drops of sulphurous acid until the solution lost its colour.

The pH of the solution was then adjusted to 7· The precipitate was filtered off by suction, to give bis-C5-acetoxy- -acetoxymethyl--6-methyl-pyridyl~(3)-methyl]-disulphide , melting point 134-°C. (b) 2 g of the compound obtained in accordance with Example 1(a) were boiled under reflux for half an hour in 30 ml of 2N aqueous hydrochloric acid. The resultant solution was inspissated under reduced pressure.

Bis-[ 5-hydroxy- -hyd oxymethy 1-6-me hy 1-pyridyl-( 3 ) -methyl]-disulphide was obtained in the form of the . dihydrochloride hydrate with a melting point of 133-134-°C. (melting point 100°0) were dissolved in 100 ml of alcohol. The solut on was coo e o an . g o γ % aqueous hydrogen peroxide were added dropwise at this temperature. The reaction mixture was then left at room temperature for 4 days. The intermediate A 5- ercaptoraethyl-2,258-trimethyl- H-m-dioxino T „ nyridin< . ( -4-Lr·?L-ieΘp.?epyli «-R-€^-5-¾^ thyr=-3=-- disulphide was obtained, melting point 132°C (alcohol/ water) . (b) 4.5 g of the disulphide obtained in accordance with Example 2(a) were heated for a quarter of an hour at 50-55°C in 40 ml of IN aqueous hydrochloric acid.

The solution was then inspissated under reduced pressure Pyrithioxine-dihydrochloride-hydrate having a melting point of 133-13 °C was obtained.

Example 3 ^ (a) 0.67 ml of 30% hydrogen peroxide was added to in 10 ml of alcohol at 0°0. The primary Formula II mercapto compound which was formed was not isolated but instead the reaction mixture was left for days and yellowish oil, obtained in accordance with Example 3(a) was heated at or m nu es n m o aqueous yroc or c acid. The reaction mixture was then inspissated under reduced pressure and the residue rubbed with acetone.

This gave pyrithioxine dihydrochloride hydrate having a melting point of 153-134°C. . were boiled with 18 ml of 2N aqueous caustic soda solution until dissolved (about 20 minutes). Alcoholio iodine solution was then added to the reaction mixture until a yellow colour persisted. The Formula II mercapto derivative obtained as an intermediate product (the compound is present in the form of a sodium salt in the solution) was not isolated. The reaction solution was left at room temperature for some time, cooled, and the precipitated disulphide then suction-filtered. point of 132-133°G was obtained. (b) The disulphide obtained according to Example 4(a) was converted to pyrithioxine-dihydrochloride-hydrate of a melting point of 134°C as described in Example 2(b). pyridine were left to stand at room temperature for 4 z [ orm ng as n erme a e pro uc n ese con ons · was not isolated. The reaction mixture was left at room temperature for 4- days. The alcohol was then evaporated under reduced pressure and the precipitated off by suction and dried. (b) 1 g of the disulphide obtained in accordance with Example 5(a) was heated at 55°C for 15 minutes in 15 ml of IN aqueous hydrochloric acid. The reaction mixture was then cooled and the cyclohexanone forming during the process was extracted with ether. The reaction mixture was then inspissated under reduced pressure. Pyrithioxine dihydrochloride hydrate was obtained with a melting point of 133-134-°C.

Example 6 (a) 1,8 g of 3-isothio-ureidomethyl-6-methyl-5- propionyl- -propionyloxymethyl-pyridine were dissolved in 50 ml of alcohol, cooled to 0°C, and 0.28 g of 30% hydrogen peroxide were added dropwise. After being left for 4- days the solution was inspissated in vacuo and the residue treated with alcoholic hydrochloric acid and ether. The. precipitated bis-[6-methyl-5-propionyloxy- -propionyloxymethyl-pyridyl-(3)--nethyl]-disulphide- dihydrochloride was filtered off by suction and recrystallised from alcohol/ether. Melting point 170°C (decomposition). (b) 2 g of the bis-C5-piOpionyloxy- -propionyloxy- methyl-6-.methyl-pyridyl-(3)-methyl]-disulphide- dihydrochloride obtained in accordance with Example 6(a) were boiled for half an hour with 30 ml of 2XT aqueous under reduced pressure. Pure pyrithioxine dihydrochloride hydrate was obtained with a melting point of 133-13 °C. Example ψ (a) 2.6 g of 3-chloromethyl-5-acetoxy- -acetoxymethyl-6-methyl-pyridine were dissolved in 40 ml of absolute ethanol, 0„5 g of disodium disulphide in 8 ml of water was then added to this solution, which was left overnight. The precipitated bis-C5-acetoxy-4-acetoxy-methyl-6~methyl-pyridyl-(3)-methyl]-disulphide was then filtered off by suction and recrystallised from ethyl acetate. Melting point 134°C. (b) 2 g of the compound obtained in accordance with Example 7(a) were refluxed for half an hour in 30 ml of 2N aqueous hydrochloric acid. The resultant solution was inspissated under reduced pressure to give a residue. Bis-[5-hyd oxy-4-h droxymethy1-6-me h 1-pyridyl-(3)-methyl]-disulphide was obtained as a dihydrochloride hydrate with a melting point of 133-134°C. Example g $ (a) A solution of 6 g of 3-chloromethyl-5-p opionyloxy- -propionyl0xymethyl-6-methyl-pyridine in 25 ml of alcohol was added dropwise to a solution of 1,1 g of sodium disulphide in 20 ml of water. The reaction mixture was then left overnight at room temperature.

The oil was then treated with alcoholic hydrochloric acid and the precipitated bis-[6~methyl- -propionyloxy- -propionyloxymethyl-pyridyl-(3)-methyl3-disulphide-dihydrochloride was recrystallised from alcohol/ether.

Melting point 170°C (decomposition). (b) ' 2 g of the bis--[6-methyl-5-propionyloxy-A- in accordance with Example 8(a) were boiled for half an ! hour with 30 ml of 2N aqueous hydrochloric acid. The solution was then inspissated under reduced pressure.

Pure pyrithioxine was obtained as a dihydrochloride hydrate of a melting point of 133-14-°0. hydrexyme hyl~6-m€^h^ thy-1-3^ijEml hi&e-- was recrystallised from alcohol/water. Melting point 132°C. (b) 4,5 g of the disulphide obtained in accordance with Example 9(a) were heated at 50-55°C for a quarter of an hour in 0 ml of IN aqueous hydrochloric acid.

The reaction solution was then inspissated under reduced pressure, Pyrithioxine Preparation of starting compounds Example A. s 65 g of 5-acetoxy~ -acetoxymethyl-3-hydroxymethyl- 6-methyl-pyridine were dissolved in 400 ml of chloroform, 80 g of thionyl chloride were added to the solution, ether was added after cooling. 3-chloromethyl-5-acetoxy- -acetoxymethyl-6-methyl-p3n?idine-hydrochloride precipitated out and filtered off by suction and recrystallised from alcohol,, Melting point 1 8°C.

Melting point of free "base 72°C (hexane) , Example B (a) 10 g of 3-hydroxymethyl-6-methyl-5-propionyloxy- ~propionyloxy-methyl-pyridine-hydrochloride were boiled under reflux for half an hour in 0 ml of chloroform with 15 g of thionyl chloride. After the solution had cooled, ether was added and the 3-chloromethyl-5- propionyloxy- -propionyloxymethyl-6-methyl-pyridine- hydrochloride which precipitated out was filtered - off by suction and recrystallised from alcohol ether, ' Melting point 139*0. Melting point of free base 62°C. (b) 1.8 g of the free base were refluxed for half an hour in 20 ml of alcohol with 0.5 g of thiourea and ether was added thereto after cooling. 3-iso-thio-ureidomethyl- 6-methy1- -propiony1oxy-4-propiony1oxy-methyl-pyridine- hydrochloride precipitated out and was filtered off by suction and then recrystallised from alcohol/ether.

Melting point 1 7°C Example C (a) 6 g of pyridoxol-hydrochloride were suspended in 125 ml of isobutyraldehyde and 20 g of hydrochloric acid were added with agitation and ice cooling. The . oil which separates out after standing overnight was - - point 184-185°C 2.7 g of the compound obtained in this way were refluxed for half an hour in 20 ml of chloroform with 2.4 g of thionyl chloride and ether was added after hydTX tB Ti&e- was filtered off by suction and then recrystallised from chloroform/ether. Melting point 204°C. (b) 2 g of this substance were refluxed for half an out and was recrystallised from alcohol/ether. Meltin " point 163 °0.

Example D (a) 30 g of pyridoxol hydrochloride was added in portions to a mixture of 500 ml of cyclohexanone and 45 ml of concentrated sulphuric acid, with ice cooling and agitation. After agitation for 1.5 hours at room temperature the reaction mixture was added to 250 g of 32% caustic soda solution with cooling. The precipitate was filtered off by suction and the filtrate extracted . with ethyl acetate. The solution was dried over sodium sulphate, filtered and hydrochloric acid was then added to the filtrate with ice cooling until an acid reaction -Hydroxy methyl-8-methyl-!H-m-dioxino was obtained. ^L,^l^_¾^iekexylidene-;5-^^ & ' pyridine-2-spiro-cyclohexane-hydrochloride dihydroxymethy1-6»me h l~pyridine-hyd ochloride forms as a precipitate which was filtered off by suction and - - . .

Melting point of free base 130-131°C (ethyl acetate). 8<, 6 g of the hydrochloride were suspended in 50 ml of chloroform, 8 g of thidnyl chloride was added and the mixture was refluxed for half an hour. Ether was precipitate was filtered off by suction and recrystallised from chloroform/ether. Melting point 226PC. (b) 6 g of the compound obtained in this way were added to a solution of 4.4 g of ammonium dithiocarbamate ' precipitated out after 3 hours, was filtered off by suction and recrystallised from methanol. Melting point 159-160°C.

Jayfeoi-cy" Example P.

Potassium fchioacetate prepared from 4, 2 g of thioacetic acid and 3. 12 g of potassium hydroxide was suspended in 30 ml of alcohol and a suspension of 7 g of -chloromethyl-2 , 2. , 8-trimethyl- H-m-dioxino J<»5>-Q) pyridine-dydro chloride -iii th l-6-ae h l-pyri4^^ ml of alcohol which separates as a precipitate was f ltered off by suction and recrystallised from isopropyl alcohol.

Melting point 180°C, Example G 6 (a) 120 g of 5-hydroxy- - ydroxymethyl-^-methyl- bromometh i pyridine - yri^iy-t--(-$-)--me-fehylb-?e-aid« were slowly added to 800 ml of acetyl chloride with ice cooling and intensive bromide hydrochloride precipitated out and was filtered off by suction and then dissolved in water. The aqueous solution was then adjusted to a pH of 7 with dilute sodium hydroxide. 5-acetoxy- -acetoxymethyl-6-methyl- pyridy¾~( )T ethylbgomidc which separates as a precipitate was filtered off by suction and recrystallised from' isopropyl ether. Melting point 90°C. (b) 9.15 g of the compound obtained in this way were suspended in 50 ml of alcohol and a solution of 7.2 g of sodium thiosulphate in 10 ml of water was added with agitation. The mixture was heated at 60Λ0 for one hour, then filtered and 20 ml of ether added. -acetoxy- -ace oxymethyl-6-methyl-pyridyl-(3)-niethyl- thiosulphate sodium separated in the form of a

Claims (1)

1. WHAT IS CLAIMED IS» 1. A process for preparing compounds of the general N wherein R and R either designate -H or an acyl group, containing from 1 to 6 carbon atoms, or which together form a group of the formula: where R and R. which may be the same or different, are 3 k II , or an alkyl group containing rom 1 to 5 carbon atoms or where R and R, form together with the carbon atom, 3 to which they are attached a saturated carbocyclic ring oontalning 5 or 6 carbon atoms, which comprises the steps of oxidising a compound of the formula! N where ^ and Rg are as defined above and do not designate hydrogen, or reacting a compound of the formula! 2h where and are as defined above, and do not designate hydrogen, and X is chlorine, bromine or iodine, with a water-soluble inorganic disulfide in the presence of water and/or a water-miscible organic solvent to form of the formula in this Claim a compound/wherein the two substituents and R2are as defined above, and do not designate hydrogen, which compound may be hydrolyzed, if desired, to form bis 4-hydroxy-methyl-5-hydroxy-6-methyl-pyridyl-(3)-methvT7hi π- disulphide. 2. , A process for the preparation of bis«-,5» hydroxyroethyl-5-hydroxy-6-methy1-pyridy1- (3)-methyl/-disulphide, which comprises the steps of oxidising a compound of the formula «- where ^ and R^ are cyl groups containing from 1 to 6 carbon atoms or which together form a group of the formulat- where and which may be the same or different are K, or an alkyl group containing from 1 to 5 carbon atoms, or where ^ and R^ form together with the carbon atom to whic they are attached a saturated carbocyclic ring containing 5 or 6, carbon atoms, to result in a compound of the formul where R^ and R2 are as defined in this claim and then reacting this compound with dilute acid to form bis-^-hydroxy-methyl-5-hydroxy-6-methyl-pyridyl- (3)-methyldisulph de. 3. A modification of the process according to claim 2 in which the compound of the formula»- File: 12901 4. 18. I.1968. where R^ and R^ are as defined in Claim 2, is used in the form of its salt. A process according to Claim 3» in which the salt is a sodium salt of said compound. 5. * A process according to any of Claims 1 to k in which the oxidation is effected by atmospheric oxygen. 6. A process according to any of Claims 1 to in which the oxidation is effected by hydrogen peroxide or iodine. 7. A process as claimed in any of Claims 1 to 6, wherein third a compound of the first- formula in Claim 1 , but which contains instead of the raercapto group an iothioureido, a xanthogenate, a dithiocarbamyl, an acetylthio or a thiosulfate group, is hydrolyzed or respectively result in oxidized in situ so as to /a compound as defined by the first formula in Claim 1, and the reaction is continued as claimed in the preceding claims. 8. A process according to any of Claims 1 to 7 substantially as herein described with reference to any of Examples 1 to 11. 9. A process for the preparation of bis- ^-hydroxymethyl- 5-hydroxy-6-methyl-pyridyl-(3)-methyl^ - disulphide, which comprises the steps of reacting a compound of the formulat- where R., and R are as defined in Claim 2, and X 6» is chlorine , bromine or iodine , with a water-soluble inorganic disulphide in the presence of water -and/or a water-miscible organic solvent to form a compound of the formula:- R,-0-CH CHp-O-R, where R^ and R2 are as defined in claim 1, and then reaoting this compound with dilute acid to form bis-[— hydroxymethyl-5-hydrox -6-methyl-pyridyl-(3)-methyl]-disulphide. 10. A process according to claim in which the inorganic disulphide is sodium disulphide". \ ^ A process according to claim & or IPin which X is chlorine or bromine. ^VIl, A process according to any of claims S6 to 10 in which the compound of the formula:- R1-0-CH2 2 where ^ and R2 are as defined in claim and X is as defined in claim 8 is reacted with a water-soluble inorganic disulphide in the presence of a mixture of water and a water-miscible organic solvent, the proportions of the water and the water-misoible organic A process according to any of claims 9 to 13 substantially herein described with reference to any of Examples 1 to 11. A compound of the formula where R and are as defined in claim 2. 1 2 16. Bis-|jj-acetoxy-¾-acetoxymethyl-6-methyl-pyridyl- (3)-methylj -disulphide, 20. Bis B--^8"-raethyl-2-spiro-cyclohexane-^H-m-dioxino^, 5-c^