CH629488A5 - Processes for preparing novel picolinic acid derivatives. - Google Patents

Description

This invention relates to a method for • valuable therapeutically active new Pìcclinsaurederi- \ aie. In particular, the new compounds as against acne are valuable.

Cevisse picolinic acid derivatives are already known as therapeutically active substances, but their structure already differs significantly from the compounds of the present invention, e.g. the picolinic acid derivatives according to the U.S. U.S. Patent 3,519,717 (antihypertensive agents) and U.S. Pat. Patent 3,585,206 (hypoglycemic agents).

These new picolinic acid derivatives are compounds of the general formula

(I)

and their pharmaceutically acceptable salts, wherein Ci is hydroxy or cyanomethoxy; Rs is hydrogen, a diphenylmethyl group of the general formula

R,

R,

(II)

a i or a triphenylmethyl group of the general formula

(III)

Low cycloalkyl groups: contain up to 6 carbon atoms.

The substituents Ri in a compound of formula 11} can be identical or different from one another, s The process for the preparation of a compound of formula (I), or its salt, in which Qi is hydroxy, is characterized in that a compound of general formula

15

Rr

R,

R.

(XVIII)

where R 1 is hydrogen, halogen, hydroxy, alkyl, cycloalkyl, alkoxy, cycloalkoxy, trifluoromethyl or phenyl and R9 is hydrogen, lower alkyl or lower cycloalkyl;

and when R5 is hydrogen, r3 and Ró are hydrogen and R4 is a diphenylmethyl group of the general formula (II) defined above;

and when Rs is diphenylmethyl group (II), R4 and Ró are hydrogen and R3 is hydrogen, lower alkyl, lower cycloalkyl or a diphenylmethyl group of the general formula (II) defined above;

and when Rs is the triphenylmethyl group (III), R3, R4 and Ró are hydrogen or one of the substituents R3, R4 and Rô is lower alkyl or lower cycloalkyl and the other two are hydrogen, the alkyl, cycloalkyl, alkoxy and Cycloalkoxy groups up to 12 carbon atoms and the lower alkyl and

20 wherein R3, R4, Rs and Ró are as defined above and Z is cyano, or the group -COQ, wherein Q is alkoxy, cycloalkoxy, cyanoalkoxy, cyanocycloalkoxy, 2,3-dihydroxy-prop-l-yl-oxy, -NR7R8 , -0-alkylene-NR7R8, -NR7-alkylene-OH, -0-cycloalkylene-NR7R8 or -NR7-cycloalkylene-OH 25;

R7 and Rs, which are the same or different from one another, are hydrogen, alkyl or cycloalkyl or R7 and Rs together with the amido nitrogen atom form a heterocyclic ring which consists of 5 to 7 ring members and 30 contains only the nitrogen atom mentioned or a second heteroatom contains which is oxygen or nitrogen;

said alkoxy, cycloalkoxy, alkylene, cycloalkylene, alkyl and cycloalkyl groups contain up to 12 carbon atoms; hydrolyzed and the resulting compound isolated in free form or in the form of its pharmaceutically acceptable salt. The compound thus obtained can, if desired, be converted into the corresponding cyano-methyl ester.

The term “alkyl” or 40 “alkoxy” used herein includes alkyl groups or alkoxy groups with straight and branched chains.

The alkyl, cycloalkyl, alkoxy and cycloalkoxy groups contain up to 12 carbon atoms. If these expressions are used in conjunction with the expression "low", the groups contain up to 6 carbon atoms. Examples of such groups are methyl, ethyl, propyl, n-butyl, t-butyl, octyl, dodecyl, isopropyl, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, porpyloxy, n-butyloxy, t-butyloxy, octyloxy, dodecyloxy , 50 isopropyloxy, cyclopropyloxy, cyclopentyloxy, cycloheptyloxy, cyclooctyloxy and the like, with the groups having up to 6 carbon atoms being preferred.

The groups -0-alkylene-NR7Rs and -O-cycloalkylene-NR7R8, in their place also the expression «aminoalkyloxy» 55 (alkylene refers to a straight-chain and branched-chain alkylene group) contains up to 12 carbon atoms, preferably up to 6 Carbon atoms. Preferred groups include:

Aminoethoxy, aminopropyloxy, aminovaleryloxy, 60 mono- and dialkylaminoethoxy, mono- and dialkylamino-valeryloxy, piperidinoethoxy, morpholinoethoxy, piperazino-ethoxy, pyrrolidinoethoxy, morpholinopropyloxy, morphololinovaleryloxy and piperazoxy.

Examples of the NR7Rs group are amino, mono- and 65-dialkylamino, morpholino, pyrrolidino, piperidino and piperazino.

The terms “NR7-alkylene-OH” and “O-alkylene-CN” (cyanoalkoxy) are to be understood analogously.

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Examples of salts of the picolinic acids of the formula (I) (compounds in which Q is hydroxy) are those which are reacted with alkali and alkaline earth metals (for example with their hydroxides, carbonates or bicarbonates) and non-toxic organic bases such as, for example, amines (for example triethylamine, N. -Methylglycamin) and alcohol amines (eg diethanolamine) are formed.

Compounds of general formula (I) in which Q is hydroxy and the other substituents are as defined above can be prepared by hydrolysis of the corresponding nitriles (V).

R-

R

R.

s-r ^ V3

(v)

6

(This formula corresponds to Formula XVIII, in which Z is cyano.)

The nitrii can be converted directly into the acid (I) via an alkali metal salt. The cleaning can be carried out in a known manner by salt formation and hydrolysis. Preferably the nitrii is in an organic solvent such as glycols e.g. Ethylene glycol or propylene glycol, reacted with an aqueous solution of potassium hydroxide. The reaction can be carried out at elevated temperature, e.g. at reflux temperature for a long time (for example 80 hours).

The starting material for the preparation of a compound (I) in which Rs is a triphenylmethyl group (III) as defined above can be prepared as follows:

Reaction scheme I R4

shark

CuCN

(V)

(IV)

In formulas (IV) and (V), R3, R4 and Re are as defined above, R5 is the triphenylmethyl group (III) and hai is halogen (preferably chlorine or bromine). The halopyridines (IV) can be prepared according to Journal of the American Chemical Society 71, s 387-390 (1949). The nitrite (V) can be prepared by known methods, such as by heating the compound (IV) and copper-I-cyanide, preferably in the presence of an inert organic solvent, for about 2 to 10 hours. For example, the reaction can be carried out by refluxing in dimethylformamide for about 4 to 6 hours. The nitrii (V) can be isolated by known extraction methods after the reaction mixture has been quenched. Solvents immiscible with water, e.g. Benzene, toluene, ethyl ether and the like. The crude nitrii (V) can be used directly in Process A described above.

The compounds of this invention which have a lower alkyl group in position 3 can be prepared as follows:

a 2-amino-3-lower alkyl pyridine (e.g. 2-amino-β-picolin) is reacted with nitrous acid to the corresponding 3-lower alkyl pyridone. The latter compound can be converted into the corresponding 3-lower alkyl-5-triphenylmethylpicolinic acid by the process described above.

The preferred reaction sequence for the preparation of compounds which have a diphenylmethyl group (III) in position 5 begins with the reaction of a benzhydrol (VI) 30 with a 2-hydroxypyridine (VII) to produce a substituted diphenylmethylpyridone (VIII). This condensation is carried out by heating a mixture of equimolar amounts of the reactants in a temperature range of about 225-275 ° C, preferably about 35-245 ° C, in the presence of a strong acid such as sulfuric acid. The pyridone (VIII) is treated with a phosphorus oxyhalide, e.g. Phenylphosphonic acid dichloride, converted at elevated temperature to the corresponding 2-halopyridine (IX). The 2-halo compound, preferably a 2-chloro or 2-bromo compound, is converted into the analog 2-cyano compound (X) by known methods, as described, for example, above. The 2-cyano compound is then hydrolyzed to the corresponding substituted 45 diphenylmethylpicolinic acid as described above. These reactions are illustrated by the following reaction scheme.

Reaction scheme II

H2SO4.

OH

(VI)

(VII)

5

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(X)

(IX)

Rj, R3 and R9 are defined in these formulas as for formula I.

In the preferred process for the preparation of the compounds (I), wherein R3 and Rs are a diphenylmethyl group (II), a 2-hydroxypyridine is reacted with a benzhydrol, using essentially the same reaction conditions as for the preparation of the compounds ( VIII) have been described in reaction scheme II, with the difference that the reaction is carried out at approximately 150 ° -200 ° C. in order to favor the condensation of the benzhydrol in position 1 (ie on the nitrogen atom of the pyridine radical). When the second mole of the substituted benzhydrol is subsequently condensed with the first condensation product (XI), the reaction 25 is carried out in a temperature range of approximately 225 ° -275 ° C. This reaction leads to the migration of the first benzhydryl group and the simultaneous condensation of the second benzhydryl group, whereby the correspondingly substituted 3,5- [bis- (diphenylmethyl)] - 2-hydroxypyridine (XII) is obtained. The product is converted into the corresponding 3,5- [bis- (diphenylmethyl)] picoic acid, as is essentially shown in reaction scheme 2.

Reaction scheme III explains this implementation

30th

R1

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Ri and R9 are defined as above.

To prepare the cyanomethyl ester of the compound (I), the compound (I) in which Qi is hydroxy can be treated at elevated temperature with a haloacetonitrile in the presence of an acid acceptor such as triethylamine. This reaction is preferably carried out in an inert organic solvent, such as, for example, acetone, methyl ethyl ketone or the like. The reaction takes about 5-20 hours, after which the reaction mixture is cooled and filtered, the filtrates are concentrated to a residue which is triturated with water to give the cyanomethyl ester.

Compounds of formula (I) in which Qi is hydroxy can, as mentioned above, also be prepared by hydrolysis of compounds of formula (XVIII) in which Z is the group -COQ, where Q is as defined above, preferably from compounds in which Q is NR7R8, preferably NH2.

The hydrolysis is preferably carried out under acidic conditions. The starting compounds can be prepared by processes known per se, for example from compounds of the formula (I) in which Qi is hydroxy or their cyanomethyl ester. These compounds can also be prepared by methods other than those described above.

Compounds of general formula (XVIII), wherein Q s is NH2 and the other substituents are as defined above, can be prepared by hydrolysis of the corresponding nitrile (V) under mild conditions (nitrii (V) is defined in the description of the above procedure and described its manufacture). This hydrolysis is preferably carried out by heating the nitrii (V) with potassium hydroxide in a mixture of water and an organic solvent, such as, for example, methanol, ethanol, propanol and isopropanol.

Compounds of formula (XVIII) wherein R4 is a diphe-isnylmethyl group (II) as defined above and Q is NH2 and the other substituents are as defined above can be prepared by using a corresponding 4-benzhydrylpyridine sulfate (XIII ) or 4-BenzhydryIpyridin in the presence of sulfuric acid with formamide in the presence of iron (II) sulfate and a peroxide, preferably t-butyl hydroperoxide, and thus forms the corresponding 4-benzhydrylpicolinamide (XIV).

XIII

Reaction scheme IV

NH2, t-butyl hydroperoxide

1 — Ri

FeS04

C0NH2 XIV

K.HgSO ^

Ri and R9 are defined as above.

To prepare compounds of this invention in which R9 is a lower alkyl group, it is preferred to first alkylate a 4-diphenylmethyl pyridine and then carry out the reactions shown in Reaction Scheme IV. The alkylation can be carried out according to known methods by alkylating in an inert solvent with a lower alkyl halide in the presence of sodium amide and an excess of ammonia and a catalytic amount of ferrin nitrate.

Compounds of the formula (XVIII) in which Q is glyceryloxy can be obtained by hydrolysis of an alkylidenedioxypropyl ester of a picolinic acid of the general formula (XV)

C00CH2 - CH - CH2

0 0 \ /

wherein R3, R4, Rs and Rö are as defined above and Rio and Ri 1 are lower alkyl (up to 6 carbon atoms).

45 The hydrolysis of the compound (XV) to the desired glyceryl ester is carried out according to methods known per se, for example by heating the starting material in the presence of an acid, for example in the presence of dilute acetic acid and isolating the ester.

50

The alkylidene dioxypropyl ester (XV) is generally prepared by reaction, a reactive alkyl ester of appropriately substituted picolinic acid, such as a cyanomethyl ester, being reacted with a cyclic acetal of glycerol. The reaction is generally carried out by heating the reactive ester with the cyclic acetal in the presence of a catalytic amount of a tertiary amine, for example triethylamine, 60 the temperature being in the range of 80 ° -200 ° C., preferably 100 ° C. It is advantageous to use a large excess of the cyclic acetal in order to complete the reaction.

(XV),

65

R10 Rll

Compounds of the formula (I) in which Qi is hydroxy can also be obtained by oxidation of a correspondingly substituted 2-methylpyridine of the formula (XVI)

7

629488

(XVI),

wherein Ri, R4, Rs and Re are as defined above. The oxidation is preferably carried out with selenium dioxide. The reaction takes place in an organic solvent, such as pyridine, which contains water, at the reflux temperature of the reaction mixture. The oxidation can also be carried out with potassium permanganate, provided that Rs is the triphenylmethyl group (III) and Rj, R4 and Rö are hydrogen. This reaction is preferably carried out in water. Another possibility for the preparation of the compound (I), in which Qi is hydroxy, consists in the oxidation of a correspondingly substituted 2-styrylpyridine 20 of the formula (XVII)

(XVII),

25th

30th

wherein R3, R4, Rs and Ró are as defined above. The oxidation is preferably carried out with potassium permanganate in acetone at acetone at temperatures of approximately -5 ° C. to 35 ° -15 ° C. or with selenium dioxide.

Compounds of formula (I) in which Qi is hydroxy,

can be converted into compounds (XVIII)

wherein Q is alkoxy, cyanoalkoxy, cycloalkoxy, cyanocycloalkoxy, glyceriloxy, -O-alkylene-NRvRs or -O-cycloalkylene-40 NR7R8. Cyanoalkyl and cyanocycloalkyl esters can be prepared analogously to the cyanomethyl ester. A compound of formula (XVIII) wherein Q is cyanoalkoxy or cyanocycloalkoxy (the alkoxy or cyanoalkoxy group contains up to 6 carbon atoms) wherein the cyano group 45 is attached to the carbon atom of the 1-position

CN

(i.e.-O-CH alkyl),

50

preferably cyanomethoxy, can be converted and / or amidated into a compound of the formula (XVIII),

where Q is alkoxy, cycloalkoxy, NR7R8, -0-alkylene-NR7R8, -0-cycloalkylene-NR7R8, -NR.7-alkylene-OH or -NR7- gs cycloalkylene-OH.

For example, the cyanomethyl ester can be subjected to a customary, base-catalyzed alcoholysis, whereby the analog alkyl ester is obtained. In a similar manner, the cyanomethyl ester can be treated with dialkylamine at elevated temperature and the corresponding dialkylamide can be prepared in this way. In cases where you want to produce an amine with reactive hydrogen, the amine groups must be protected before the reaction (e.g. by conventional benzylation) and the protective groups (e.g. benzyl) must be split off after the transesterification fs. If Q represents a hydroxyalkylamine, the terminal hydroxyl group is initially protected analogously, for example by ether. The protective group is removed after the transesterification. A compound (I) in which Qi is hydroxy can be converted into the corresponding compound (XVIII) in which Q is alkoxv or -NR.7R8 by esterification and amidation.

If desired, a compound of formula (I) thus obtained can be converted into its salts, in particular by reacting the acid with an excess of the base in a suitable solvent.

Acne is a common inflammatory disease in areas where the sebaceous glands are the largest, most common, and most active. It is characterized by the appearance of comedones, pustules, leaves, inflamed nodules and, in extreme cases, infected sac-like extensions. In more inflamed types of acne, Corynebacterium acnes and Staphylococcus albus are usually among the infecting organisms. These organisms are believed to exacerbate existing inflammation by triggering enzymes (lipase) that break down the lipid in sebum while releasing irritating fatty acids. Therefore, an effective remedy for acne should prevent or significantly reduce the breakdown of lipid in sebum, which would have an anti-inflammatory effect on the skin. Preferably, the agent should be topically effective to substantially reduce the occurrence of undesirable side effects that can occur with systemic treatment. For example, it is believed that the drugs commonly used against acne, such as tetracyclines, are causally related to the side effects that are usually required with prolonged systemic treatment of acne. These side effects include irritation, photosensitive reactions, dizziness, nausea and vomiting. There is therefore a need for an effective, externally applicable remedy for acne. The compounds according to the invention meet this need.

By in vitro investigations, in a slightly modified form according to A. Shalita and V. Wheatley, in J. Invest, Dermatol. 54, 413 (1970), it could be shown that compounds of this invention substantially inhibit the formation of free fatty acids from triglycerides by bacterial lipases, including those formed by Corynebacterium acnes. The free fatty acids formed were determined by the automated colorimetric method of C. Dalton and C. Kowalski (Clinical Chem. 13, 744 (1967). The test results clearly show that the antilipase effect of the compounds of this invention investigated is significantly greater than that of Furthermore, in contrast to the compounds of this invention, neither hexachlorophene nor tetracycline show substantial in vivo topical activity. Furthermore, the compounds according to the invention do not lead to visible irritation of the skin even when repeated topical administration. They also have only low systemic toxicity repeated topical, oral or intraperitoneal administration.

The compounds according to the invention are also antibacterial agents, in particular against Corneybacterium acnes and S. albus, and against other gram-positive organisms, and are active against Trichomonas, in particular against T. vaginalis. These compounds can therefore also be used in the customary manner for the treatment of gram-positive infections and infections by Trichomonas. Activity studies and preparations for such uses are carried out according to known methods.

For the treatment of acne, the inventive

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compounds administered topically in pharmaceutical preparations containing conventional excipients. The preparations can be in the form of lotions, creams, aerosols and ointments. The preparations contain about 0.5 to 10% by weight, preferably 1.5-5% by weight, of the active compound and are used about 2 to 5 times a day.

As with most groups of compounds suitable for certain purposes, it has also been found in the present case that some members of the group are superior to others. In this case, studies indicate that the compounds of the formula (I) are preferred in which Rs is hydrogen, the diphenylmethyl group (II) or the triphenylmethyl group (III), in which Ri is hydrogen, chlorine or phenyl and R9 is hydrogen, methyl or Is ethyl; and when Rs is hydrogen, R3 and Ré are hydrogen and R4 is the diphenylmethyl group (II) defined above; and when Rs is the diphenylmethyl group (II), R4 and Ro are hydrogen and R3 is hydrogen or the diphenylmethyl group (II);

and, if Rs is the triphenylmethyl group (III), r3, R4 and Re are hydrogen or one of the substituents R3, R4 and Rô is lower alkyl, in particular methyl, and the other two are hydrogen, in particular compounds,

where Ri is hydrogen or chlorine.

Of these compounds, those of particular interest are those in which Q is hydroxy, Rs is diphenylmethyl group (II) or triphenylmethyl group (III), wherein Ri and R9 are hydrogen, and when Rs is diphenylmethyl group, R4 and Rö are hydrogen and R3 represents hydrogen or the diphenylmethyl group (II) and, when Rs is the triphenylmethyl group (III), R3, R4 and Rô are hydrogen.

The most preferred compounds are 5-diphenylmethyl-picolinic acid, 3,5-bis- (diphenylmethyl) -picolinic acid, in particular 5-tritylpieolinic acid, 5- [a- (4-chlorophenyl) -benzyl] -picolinic acid, 5-triphenylmethylpicolinic acid cyanomethyl ester and salts of the compounds which are capable of salt formation, in particular their diethanolamine salts.

The preparation of the compounds of the formula (I) is illustrated by the following examples:

example 1

5- (triphenylmethyl) -picolinic acid

A. 2-bromo-5- (triphenylmethyl) pyridine

A mixture of 50.6 g of 5- (triphenylmethyl) -2-pyridone and 171 g of phosphorus oxybromide is heated under reflux for 3 hours. The mixture is poured onto ice and stirred on a steam bath to decompose the excess of phosphorus oxybromide, filtered, the solid is dried, the product is triturated with benzene and ethanol and the product is obtained with a melting point of 273-276 ° C.

B. 5- (triphenylmethyl) picolinic acid

A mixture of 46.9 g of 2-bromo-5- (triphenylmethyl) pyridine and 21.5 g of copper-I-cyanide in 450 ml of dimethylformamide is heated under reflux for 5 1/2 hours. Then pour the reaction mixture onto a mixture of ice and 200 ml of ethylenediamine, extracted with benzene, dry the extracts and concentrate them. The crude, viscous 2-cyano-5- (triphenylmethyl) pyridine can be purified by recrystallization from acetonitrile to give the product with a melting point of approximately 176 ° -179 ° C. or the compound is added directly to the acid via the potassium salt to reflux with 20 g of potassium hydroxide in 120 ml of water and 400 ml of ethylene glycol for 15 hours. The hot solution is filtered, the filtrate is cooled, causing the potassium salt of the acid to precipitate, the salt is filtered, washed with ethylene glycol, suspended in water, acidified and heated for one hour, the acid is filtered off, dried and recrystallized from acetonitrile. Melting point 215-217 ° C. Additional acid is obtained by concentrating and acidifying the ethylene glycol filtrate of the potassium salt.

In an analogous manner, an equivalent amount of the following compounds, which can be prepared according to stage A of this example, can be reacted using the above-described process.

2-bromo-3-methyl-5- (triphenylmethyl) pyridine, 2-bromo-5 - [(4-biphenyl) diphenylmethyl] pyridine, 2-bromo-5 - [(4-chlorophenyl) diphenylmethyl] pyridine, 15 2-bromo-5- [tris (4-chlorophenylmethyl)] pyridine, 2-bromo-5 - [(4-methylphenyl) diphenylmethyl] pyridine, 2-bromo-5- [bis- (4-fluorophenyl) phenyimethyl] pyridine, 2-bromo-5 - [(4-methoxyphenyl) diphenylmethyl] pyridine, 2-bromo-5 - [(4-trifluoromethylphenyl) diphenylmethyl] pyridine, 20 2-bromo-3-methyl-5- [(4-trifluoromethylphenyl) diphenylmethyl] pyridine,

2-bromo-5 - [(3-bromophenyl) diphenylmethyl] pyridine, 2-bromo-5- [tris (3-fluorophenyl) methyl] pyridine, 2-bromo-5 - [(3-ethylphenyl) diphenylmethyl] pyridine, 25 2-bromo-5- [bis (3-fiuophenyl) phenylmethyl] pyridine, 2-bromo-5 - [(3-propoxyphenyl) diphenylmethyl] pyridine, 2-bromo-5- [tris- (3rd trifluoromethylphenyl) methyl pyridine, 2-bromo-3-ethyl-5 - [(3-methylphenyl) diphenylmethyl] pyridine,

30 2-Bromo-5 - [(2-chlorophenyl) diphenylmethyl] pyridine, 2-bromo-5 - [(2-isopropylphenyl) diphenylmethyl] pyridine, 2-bromo-5- [bis- (2-fluorophenyl) phenylmethyl ] pyridine, 2-bromo-5- [tris- (2-methylphenyl) pyridine, 2-bromo-5 - [(2-ethoxyphenyl) diphenylmethyl] pyridine, 35 2-bromo-5 - [(2-trifluoromethylphenyl ) diphenylmethyl] pyridine, and

2-bromo-5 [(2-chlorophenyl) phenylmethyl] pyridine to thereby obtain the corresponding substituted picolinic acids, such as 40 3-methyl-5- (triphenylmethyl) picolinic acid,

(Melting point 195-196.5 ° C), 5 - [(4-biphenyl) diphenylmethyI] -picolinic acid,

(Melting point 213-214.5 ° C), 5 - [(2-chlorophenyl) phenylmethyl] -picolinic acid 45 (melting point 197-200 ° C)

Example 2

5- (diphenylmethyl) -picolinic acid

A. 5- (Diphenylmethyl) -2-pyridine so To a mixture heated to 180 ° C of 92.1 g (0.5 mol) of benzhydrol and 142.7 g (1.5 mol) of 2-hydroxypyridine is added with stirring 1.5 ml concentrated sulfuric acid. The mixture is heated for 2 hours at 250-255 ° C with removal of water. The cooled reaction mixture is poured into water, stirred, extracted with chloroform, the chloroform extracts concentrated to a residue which contains 5- (diphenylmethyl) -2-pyridone. The residue is triturated with ethyl acetate and the solid is filtered, yielding 5- (diphenylmethyl) -2-pyridone with other 60 isomers. The product of this example, melting point 174 ° -176 ° C., is obtained by recrystallization from acetonitrile.

B. 2-chloro-5- (diphenylmethyl) pyridine

6s 55 g of the crude 5- (diphenylmethyl) -2-pyridone and 110 ml of phenylphosphonic dichloride are heated at 200 ° -210 ° C for 6 hours with stirring. The cooled reaction mixture is poured onto ice and made with ammonium hydroxide

9

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basic, extracted with ethyl ether, dries the ether extracts and concentrates to dryness. The residue is distilled at 160 ° -175 ° C./0.15 mm, the distillate is recrystallized from hexane and 2-chloro-5- (diphenylmethyl) pyridine is obtained, melting point 69.5-71 ° C.

C. 5- (Diphenylmethyl) picolinic acid

A mixture of 16.5 g (0.059 mol) of 2-chloro-5- (diphenylmethyl) pyridine and 10.6 g (0.059 mol) of copper-I-cyanide in 120 ml of hexamethylphosphoramide is heated with stirring at 210 ° -220 ° C for 7 hours. The cooled reaction mixture is poured into a solution of 200 ml of ethylene diamine in 500 ml of water and extracted with benzene. The benzene extracts are washed with 10% aqueous sodium cyanide, then with water, dried, treated with activated carbon, filtered, concentrated and 2-cyan-5- (diphenylmethyl) pyridine is thus obtained. This compound is converted directly into the title compound by refluxing with 13 g of potassium hydroxide in 100 ml of water and 200 ml of ethylene glycol for 15 hours. The ethylene glycol and water are removed under reduced pressure, the residue is dissolved in water, acidified with concentrated hydrochloric acid and extracted with chloroform. The chloroform extracts are dried, the dried extracts are concentrated to a solid and triturated with isopropyl ether. The solid is filtered off, dried and recrystallized from ethanol, giving 5- (diphenylmethyl) -picolinic acid, melting point 189-191 ° C.

In an analogous manner, an equivalent amount of the following substituted pyridines, which can be prepared according to stages A and B of this example, can be converted into the corresponding substituted picolinic acid by the process described above:

2-chloro-5- (2-chlorophenylphenylmethyl) pyridine,

2-chloro-5- [bis- (4-fluorophenyl) methyl] pyridine,

2-chloro-5- (4-biphenylphenylmethyl) pyridine,

2-chloro-5 - [(4-trifluoromethyl) phenylphenylmethyl] pyridine,

2-chloro-5- (3-methoxyphenylphenylmethyl) pyridine,

2-chloro-5- [bis- (4-methylphenyl) methyl] pyridine, and

2-chloro-5- (diphenylmethyl) -3-methylpyridine.

Example 3

5- (4-chlorophenyl-phenylmethyl) -picolinic acid

A. 5- (4-chlorophenylphenylmethyl) -2-pyridone

109.3 g (0.5 mol) of 4-chlorobenzhydroI are combined with 142.7 g (1.5 mol) of 2-hydroxypyridine and the mixture is heated to 150 ° C. while stirring to the melt. About 2 ml of concentrated sulfuric acid are added and the mixture is heated further to 240-250 ° C., water being removed from the reaction mixture. The mixture is left to react for 2 hours, then the mixture is cooled to about 25 ° C., the solid obtained is treated with ethyl acetate and water and filtered to remove the undesired 3- (4-chlorophenylphenylmethyl) -2-pyridone. The organic layer is separated and washed several times with water, dried over potassium carbonate and filtered off. The filtrate is concentrated to half the volume, filtered to remove the remaining 3-substituted-2-pyridone, the filtrate is evaporated and the residue is dissolved in ethyl ether. 5- (4-Chlorophenyl-phenylmethyl) -2-pyridone crystallizes overnight, yield 60 g, melting point 164-169 ° C.

B. 2-Chloro-5- (4-chlorophenylphenylmethyl) pyridine

50 g (0.174 mol) of 5-substituted 2-pyridone of stage A are combined with 125 ml of phenylphosphonic dichloride and the mixture is heated to 210 ° -220 ° C. for about 7 hours

Stir. The reaction mixture is left to stand overnight and then poured onto ice, made basic with ammonium hydroxide and extracted with ethyl ether. The ether solution is dried and concentrated to dryness, the residue is distilled and the fractions are combined with a boiling point of 205 ° -215 ° C. at 0.55 mm (49 g).

C. 5- (4-Chlorophenyl-phenylmethyl) -picolinic acid

55 g of the product of stage B are dissolved in 200 ml of dry hexamethylphosphoramide and 32 g (0.36 mol) of copper I-cyanide are added. The reaction mixture is heated to 210-220 ° C for 7 hours, the reaction mixture is poured into approximately 500 ml of ice water containing 200 ml of ethylenediamine and extracted with benzene. The benzene extracts are washed with 10% sodium cyanide solution, then with water. The benzene solution is treated with activated carbon and filtered, the filtrates are evaporated to dryness, the residue is dissolved in 300 ml of ethylene glycol and 20 g of potassium hydroxide, dissolved in 100 ml of water, are added. The reaction mixture is heated under reflux overnight and the solvent is removed in vacuo. The residue is dissolved in water, treated with activated carbon and filtered. The filtrate is acidified with hydrochloric acid, the precipitate thus formed is extracted with chloroform and the extract is evaporated to dryness. The residue is triturated with acetonitrile to give the product of this example, melting point 200 ° -203 ° C.

Example 4

3,5-bis (diphenylmethyl) picolinic acid

A. N-Diphenylmethyl-2-pyridone

92.1 g (0.5 mol) of benzhydrol are combined with 142.7 g (1.5 mol) of 2-hydroxypyridine and the mixture is heated to 190 ° C. with stirring. 1.5 ml of concentrated sulfuric acid are added and the procedure is continued according to Example 3, stage A, whereby the product of this example is obtained, yield 68 g, melting point 142 ° -145 ° C.

B. 3,5-bis (diphenylmethyl) -2-pyridone

Combine 46 g (0.18 mol) of N-substituted 2-pyridone with 33.2 g (0.18 mol) of benzhydrol and heat to 230 ° C. About 1 ml of concentrated sulfuric acid is added and the mixture is heated to 250-260 ° C for 2 hours, the reaction mixture is cooled to about 25 ° C, the solid reaction product is stirred with hot acetonitrile, filtered, washed and dried to give the product of this reaction step , Yield 49 g, melting point about 240 ° C.

C. 2-Chloro-3,5-bis (diphenylmethyl) pyridine

49.5 g (0.11 mol) of 3,5-bis- (diphenylmethyl) -2-pyridone (prepared as described in stage B) are combined with 105 ml of phenylphosphonic dichloride and the reaction mixture is heated with stirring at 200 ° for 6 hours. 210 ° C. The reaction mixture is poured onto ice and made alkaline with ammonium hydroxide. It is extracted with ethyl ether, the extract is dried, evaporated, the solid residue is crystallized from ethanol and the product of this reaction stage is thus obtained, yield 40 g, melting point 131 ° -133 ° C.

D. 3,5-bis (diphenyimethyl) picolinic acid

38.4 g (0.086 mol) of 2-chloro-3,5-bis (diphenylmethyl) pyridine (prepared according to step C) are combined with 15.3 g (0.17 mol) of copper-I-cyanide in 180 ml dry hexamethylphosphoramide. The reaction mixture is heated at 210 ° -220 ° C. for 7 hours, the reaction mixture is poured into aqueous ethylenediamine, extracted with benzene, the benzene extracts are washed with 10% sodium cyanide and then with

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Water and dry over potassium carbonate. It is filtered and the filtrates are concentrated to a residue. The residue is dissolved in 300 ml of ethylene glycol, a solution of 15 g of potassium hydroxide in 90 ml of water is added and the mixture is heated under reflux for 22 hours. Concentrate the reaction mixture in vacuo to a residue, acidify the residue with dilute hydrochloric acid, extract with benzene, concentrate the solution to a residue containing the compound of this example, purify it via the formation of the diethanolamine salt followed by restoration of the free acid , Melting point 172 ° -175 ° C.

Similarly, an equivalent amount of the following 2-chloro-3,5-bis (Ri-substituted diphenylmethyl) pyridines (which can be prepared by steps A through C of this example) can be added to the following procedure implement the corresponding 3,5-bis- (Ri-diphenyl-methyl) -picolinic acids:

2-chloro-3,5-bis- (4-chlorophenylphenylmethyl) pyridine,

2-chloro-3,5-bis- [bis- (4-chlorophenyl) methyl] pyridine,

2-chloro-3,5-bis (2-chlorophenylphenylmethyl) pyridine,

2-chloro-3,5-bis- [bis- (4-fluorophenyl) methyl] pyridine,

2-chloro-3,5-bis (4-biphenylphenylmethyl) pyridine,

2-chloro-3,5-bis- [4-trifluoromethylphenylphenylmethyl] -

pyridine,

2-chloro-3,5-bis- (3-methoxyphenylphenylmethyl) pyridine and 2-chloro-3,5-bis- [bis- (4-methylphenyl) methyl] pyridine.

Example 5

5- [bis- (4-chlorophenyl) methyl] picoic acid

A. 5- [bis- (4-chlorophenyl) methyl] -2-pyridone

50.6 g (0.2 mol) of 4,4'-dichlorobenzhydrol are combined with 57.1 g (0.6 mol) of 2-hydroxypyridine, the mixture is heated to 200 ° C. with stirring and 1.0 ml of concentrated sulfuric acid is added dropwise . The temperature of the reaction is raised to 240 ° -250 ° C and maintained at this temperature while collecting the escaping water. The reaction mixture is cooled, a mixture of ethyl acetate and water is added with stirring, the liquid phases are separated, the organic phase is dried, the volume of the ethyl acetate is reduced, the mixture is cooled and the crude product is precipitated, yield 43 g. Recrystallization from ethanol gives the product of this reaction stage with a melting point of 211 ° -215 ° C.

B. 2-chloro-5- [bis- (4-chlorophenyl) methyl] pyridine

Add to a mixture of 35.2 g (0.11 mol) of 5- [bis- (4-chlorophenyl) methyl] -2-pyridine and 11.8 g (0.11 mol) of 2,4-lutidine 50.6 g (0.33 mol) of phosphorus oxychloride are added dropwise while the reaction mixture is heated at 80 ° C. The reaction mixture is then heated at 120 ° C. for 6 hours. The reaction mixture is poured onto ice, made alkaline with ammonium hydroxide, extracted with benzene, the benzene and the remaining 2,4-lutidine are removed by distillation, the residue is distilled at approximately 195-210 ° C. (0.01 mm) and is thus obtained about 30 g of the product of this reaction step in the form of a yellowish viscous oil.

C. 5- [bis- (4-chlorophenyl) methyl] picolinic acid

The product of stage B is dissolved in approximately 150 ml of dry hexamethylphosphoramide, 15.4 g (0.172 mol) of copper I-cyanide are added and the procedure of Example 4, stage D is continued and the product of this example is obtained.

Example 6

5- (triphenylmethyl) picolinamide

5 g of 5- (triphenylmethyl) -2-cyanopyridine are dissolved in one

Mixture of 50 ml of water and 1.0 liter of methanol. 4 g of potassium hydroxide are added and the mixture is heated under reflux for 15 hours. The methanol is removed under reduced pressure, the residue is triturated with water and the solid obtained in this way is dried. The product is crystallized from acetonitrile and the product of this example is obtained with a melting point of 239 ° -240 ° C.

Example 7

4- (diphenylmethyl) -picolinic acid

A. 4- (Diphenylmethyl) picolinamide

20 g (0.082 mol) of 4-benzhydrylpyridine are dissolved in 200 ml of formamide, and 4.35 ml (0.082 mol) of sulfuric acid are added with external cooling. The reaction temperature is adjusted to 5 ° -10 ° C, while 21.6 g (0.24 mol) of t-butyl hydroperoxide and 67 g (0.24 mol) of iron (II) sulfate are added over 30 minutes. The iron salts are removed by filtration, the precipitate is washed with chloroform and water and the two liquid phases are separated. The aqueous phase is extracted with chloroform, the combined chloroform phases are washed with water and dried. The extract is concentrated to a residue, the residue is dissolved in ether, filtered and the product of this reaction stage is obtained in a yield of 3.5 g, melting point 165 ° -170 ° C. Additional product can be obtained by extracting the iron salts with chloroform under reflux.

B. 4- (Diphenylmethyl) picolinic acid

5.3 g of 4- (diphenylmethyl) -picolinamide (prepared according to stage A) are dissolved in 80 ml of concentrated hydrochloric acid and heated under reflux. Heating at reflux is continued overnight, then 50 ml of the solvent is removed by distillation in vacuo, the residue is treated with ice and made alkaline with an excess of 10% sodium hydroxide. 300 ml of water are added and the solution is extracted with 50 ml of ethyl ether, the pH of the aqueous phase is adjusted to approximately 5, the precipitate is collected by filtration and dried. This gives the product of this example with a melting point of 172 ° -177 ° C. It is crystallized from 75 ml of acetonitrile and the product is obtained in a yield of 3.8 g, melting point 176 ° -178 ° C.

In an analogous manner, an equivalent amount of the following 4- (Ri-diphenylmethyl) -picolinamides (producible according to step A of this example) can be converted into the corresponding 4- (Ri-diphenylmethyl) -picolinic acids: 4- (4-chlorophenylphenylmethyl) -picolinamide, 4- [bis- (4-chlorophenyl) methyl] -picolinamide, 4- (2-chlorophenyl-phenylmethyl) -picolinamide, 4- [bis- (4-chlorophenyl) -methyl] -picolinamide, 4- ( 4-biphenylphenylmethyl) picolinamide, 4- (4-trifluoromethylphenylphenylmethyl) picolinamide, 4- (3-methoxyphenylphenylmethyl) picolinamide and 4- [bis- (4-methylphenyl) methyl] picolinamide.

Example 8 4- (1,1-diphenylpropyl) -picolinic acid A. 4- (1,1 -diphenylpropyl) -pyridine 2.5 g of sodium are dissolved in 500 ml of liquid ammonia in the presence of a catalytic amount of ferric nitrate. A solution of 24.5 g of 4-diphenylmethyl-pyridine in 600 ml of ether is added dropwise to the suspension obtained over the course of 20 minutes. The dark red mixture thus obtained is stirred for a further 20 minutes, then 13 g of ethyl bromide are added dropwise. More are added

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Add 500 ml of ammonia, stir overnight and add the 3- ■ = »n; Add ether and then 150 ml of water. They are called 'Ji <î rlii-Sigkeiisschicnten, washed without ether layer with water; bn su neutrality, dry and remove the solvent under reduced pressure until a residue is obtained. The residue is distilled at 192 ° -200 ° C./1.6 to 2 mm and the product of this reaction stage is thus obtained in the form of an orange oil (14.7 g).

B. 4- (1,1-Diphenylpropyl) picolinamide

The 4- (1,1-diphenylpropyl) pyridine obtained according to stage A is treated in accordance with example 7, stage A, and 13.9 g of a yellow oil are obtained, which can be crystallized from acetonitrile and the product of this reaction stage is thus obtained , with a melting point of 144 ° -147 ° C.

C. 4- (1,1-diphenylpropyl) piconic acid

3.8 g of 4- (1,1-diphenylpropyl) -picolinamide are dissolved in 50 ml of ethanol, 100 ml of 10% aqueous potassium hydroxide are added and the mixture obtained is heated under reflux overnight. The ethanol is removed under reduced pressure, water is added to the residue and the pH is adjusted to about 5 with 10% aqueous hydrochloric acid. The solid obtained is filtered and recrystallized from ethanol, giving the product of this example, yield 1.6 g. Melting point 191 ° -193 ° C.

Example 9

Glyceryl (5-triphenylmethyl) picolinate

A. p-y-isopropylidenedioxypropyl- (5-triphenylmethyl) -picolinate

While stirring, a mixture of 4 g of cyanomethyl-5- (triphenylmethyl) picolinate, 50 ml of 2,2-dimethyl-1, 3-dioxolane-4-methanol and 2 ml of triethylamine is heated on a steam bath for 1 hour. The reaction mixture is treated with water, cooled and filtered, and the product of this reaction stage is thus obtained.

B. Glyceryl 5- (triphenylmethyl) picolinate

While stirring, a mixture of 4.5 g of β-y-isopropylidene-dioxypropyl-5- (triphenylmethyl) -picolinate and 90 ml of 75% acetic acid is heated on a steam bath for one hour. The reaction mixture is poured onto ice, filtered and the solid obtained is dissolved in ethyl acetate. It is washed twice with water, dried over magnesium sulfate and concentrated, recrystallized from acetonitrile, and the product of this example is thus obtained with a melting point of 183 ° -186 ° C.

Example 10

5- (triphenylmethyl) -picolinic acid diethanolamine salt

Combine 5.5 g of 5- (triphenylmethyl) -picolinic acid and 1.6 g of diethanolamine in 200 ml of ethanol and heat to prepare a solution, then cool to precipitate the salt. It is recrystallized from ethanol and the product of this example is obtained with a melting point of 206 ° -209 ° C.

Example 11

5- (4-Chlorophenyl-phenylmethyl) -picolinsäuredietätol-amine salt

0.97 g of 5- (4-chlorophenyl) -phenylmethyl) -picolinic acid (see Example 3C) is combined with 0.4 g of diethanolamine in 100 ml of ethyl acetate. The reaction mixture is heated and the solvent is decanted from the brown insoluble residue. After a few hours, the product of this example precipitates out of the ethyl acetate solution, melting point 108 ° -115 ° C.

Example 12

5- [bis- (4- € h-orphenyl? -Roethyl] picolinic acid piperazine salt. 19.8 g <0.055 mol) of 5- [bis- (4-chlorophenyl) methyl] picolinic acid are combined with 4.7 g of piperazine in hot methanol. 5 volumes of ether are added and the precipitate is filtered off. The precipitate is recrystallized from ethanol, giving the product of this example, melting point 240 ° -255 ° C.

Example 13

Cyanomethyl-5- (triphenylmethyl) picolinate 4.5 g of chloroacetonitrile are added to a stirred mixture of 5 g of 5- (triphenylmethyl) picolinic acid and 6.1 g of triethylamine in 150 ml of acetone. The mixture obtained is heated under reflux for 15 hours, cooled, filtered, the filtrate is concentrated to a residue and the residue is triturated with water and dried. It is recrystallized twice from isopropyl ether-ethanol and the product of this example is obtained, melting point 173 ° -175 ° C.

Example 14

Cyanomethyl-5- (diphenylmethyl) -picolinate 4.3 g (0.015 mol) of 5- (diphenylmethyl) -picolinic acid are suspended in 100 ml of acetone with stirring and 2.3 g (0.023 mol) of triethylamine are added. 1.7 g (0.023 mol) of chloroacetonitrile are added dropwise to the solution obtained, the reaction mixture is stirred at room temperature (25 ° C.) for 15 minutes and then under reflux for 4 hours. The mixture is cooled, the reaction mixture is filtered, the filtrate is concentrated in vacuo to a residue and the residue is triturated with hot isopropyl ether. This gives the product of this example, yield 3.5 g, melting point 95 ° -98 ° C.

Example 15 Methyl 5- (triphenylmethyl) picolinate 4 g (0.01 mol) of cyanomethyl 5- (triphenylmethyl) picolinate and 2 ml of triethylamine in 50 ml of methanol are heated under reflux for 4 hours. The methanol is removed under reduced pressure, the solid residue is triturated with water and recrystallized from ethyl acetate-isopropyl ether, giving the product of this example, melting point 160 ° -164 ° C.

In an analogous manner, by replacing methanol with other alcohols, such as, for example, ethanol, propanol, isopropanol, n-butanol or alcohols of the general formula HO-alkylene-NR7R8, the corresponding esters can be prepared by the process of Example 15 (e.g. 5- (triphenylmethyl) isopropyl picolinate, melting point 170 ° -182 ° C.

Example 16

N, N-diethyl-5- (triphenylmethyl) -picolinamide. A mixture of 0.1 mol of cyanomethyl-5- (triphenylmethyl) -picolinate and 0.5 mol of diethylamine is heated under reflux for 6 hours. The reaction mixture is cooled, poured into water and extracted with chloroform, the chloroform layer is dried over anhydrous sodium sulfate and evaporated to give the product of this example.

In an analogous manner, by using an equivalent amount of another mono- or dialkylamine or mono- or dialcoholamine or heterocyclic amine, such as, for example, methylamine, ethylamine, octylamine, dodecylamine, ethanolamine, diethanolamine, piperazine, morpholine, pyrrolidine, piperidine , according to this example 16 produce the corresponding mono- or dialkylamides.

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Example 17

5- (triphenylmethyl) picolinic acid

A. 5- (triphenylmethyl) -5-cyanopentanone-2

0.5 ml of a 2-normal methanolic solution of sodium methoxide is added to a solution of 28.3 g (0.1 mol) of triphenylmethylacetonitrile in 50 ml of methanol. 3.5 g (0.05 mol) of methyl vinyl ketone are added to the stirred, cooled solution and the mixture is left to stand at room temperature overnight. Then 100 ml of ether are added and the ether solution is washed successively with 10% acetic acid, water, 5% sodium bicarbonate solution and water. The ether layer is dried and concentrated. The excess of triphenylmethylacetonitrile is removed to give the product of this example as a viscous oil.

B. 2-Methyl-5-triphenylmethylpiperidine

In a mixture of 10 g of 5- (triphenylmethyl) -5-cyano-pentanone-2,100 ml of ethanol and 2 g of Raney nickel, the theoretically absorbable amount of hydrogen is passed at 75 ° -80 ° C and 800 p.s.i. a. The reaction mixture is filtered and concentrated in vacuo to obtain the product of this example as a crystallized solid.

C. 5- (Triphenylmethyl) -2-methylpyridine

10 g of 5% palladium-charcoal catalyst are added to a solution of 12 g of 5-triphenylmethyl-2-methyl-piperidine and 100 ml of p-cymene. The mixture is heated under reflux for 12 hours, cooled, filtered and the p-cymene removed in vacuo. The residue is crystallized by trituration with hexane.

D. 5- (triphenylmethyl) -picolinic acid

3.3 g of 5-triphenyl-methyl-2-methylpyridine in 30 ml of pyridine are added to a solution of 1.4 g of selenium dioxide in 15 ml of pyridine, which contains 4% water. The reaction mixture is heated under reflux for 4 hours, filtered hot and the product of this example is crystallized by cooling, melting point 215 ° -217 ° C.

Example 18

5- (Diphenylmethyl) -picolinic acid A. 6,6-Diphenyl-5-cyano-hexan-2-one Add to a solution of 20.7 g (0.1 mol) of 3,3-diphenylpropionitrile in 50 ml of methanol 0.5 ml of a 2 normal methanolic solution of sodium methoxide. 3.5 g (0.05 mol) of methyl vinyl ketone are added to the stirred, cooled solution and the mixture is left to stand at room temperature overnight. Then 100 ml of ether are added and the ethereal solution is washed successively with 10% acetic acid, water, 5% sodium bicarbonate solution and water. The ether layer is dried and concentrated, the excess of 3,3-diphenylpropionitrile is removed, giving the product of this example as a viscous oil.

B. 2-methyl-5- (diphenylmethyl) piperidine

The theoretically absorbable amount of hydrogen at 75 ° -80 ° C. and 800 psi is passed into a mixture of 10 g of 6,6-diphenyl-5-cyanohexan-2-one, 100 ml of ethanol and 2 g of Raney nickel, and the reaction mixture is filtered one concentrated off in vacuo and thus obtained the product of this example as a solid.

C. 2-methyl-5- (diphenylmethyl) pyridine can be prepared according to Example 17, Step C from the product of Example 18, Step B described above, or by the following process:

A mixture of 65 g of 3- (diphenylmethyl) pyridine (which can be prepared according to British Patent No. 1,175,693), 70 g of W-5 Raney nickel and 700 ml of dodecanol are heated to 200 ° C. for 20 hours, during which time a stir well and separate the water. The hot solution is filtered, the Raney nickel is washed with dodecanol, the dode-canol solution is diluted with an equal volume of ether, the organic solution is extracted three times with 10% aqueous hydrochloric acid, the acidic extracts are made alkaline with sodium hydroxide and extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried and concentrated to obtain the product of this example.

D. 5- (Diphenylmethyl) picolinic acid

2.6 g of 2-methyl-5- (diphenylmethyl) pyridine in 30 ml of pyridine are added to a solution of 1.4 g of selenium dioxide in 15 ml of pyridine, which contains 4% water. The reaction mixture is heated under reflux for 4 hours, filtered hot and the crystallized product of this example is obtained by cooling, melting point 189 ° -191 ° C.

Example 19

5- (DiphenylmethyI) -picolinic acid

A. 3- (Diphenylmethyl) pyridine N-oxide

14 ml of 30% hydrogen peroxide are added to a solution of 22 g (0.09 mol) of 3- (diphenylmethyl) pyridine in 70 ml of acetic acid. The solution is heated to 70 ° -80 ° C. for 15 hours, the amount of acetic acid is reduced in vacuo to approximately Vi, water is added, the solution is made alkaline with sodium hydroxide, extracted with methylene chloride, dried and concentrated, so as to obtain the product to obtain this example as a solid.

B. 3- (Diphenylmethyl) -1-methoxypyridinium methyl sulfate

To a solution of 25 g of 3- (diphenylmethyl) pyridine-N-

oxide in 160 ml of benzene is added dropwise 11.4 g of dimethyl sulfate. The solution is heated under reflux for 4 hours, cooled, the benzene decanted from the product of this reaction, which separates out as an oil.

C. 2-Cyano-5- (diphenylmethyl) pyridine

A solution of the crude product of the above reaction step in 80 ml of water is added dropwise to a solution of 13.2 g of sodium cyanide in 80 ml of water, which is kept at 0 ° C. The mixture is stirred for one hour, the aqueous solution is decanted from the semi-solid residue, water is added to this residue and the mixture is extracted with chloroform. The chloroform solution is dried and concentrated to give a solid which is a mixture of isomers. The desired product of this example is obtained by fractional crystallization.

D. 5- (DiphenylmethyI) -picolinic acid can be prepared from the product of reaction step C above according to Example 1, step B, melting point 189 ° -19PC.

Example 20

5- (triphenylmethyl) -picolinic acid

A. 3-Tritylpyridine-l-oxide

26.0 g (0.081 mol) of 3-tritylpyridine are dissolved in 200 ml of glacial acetic acid and treated with 20 ml of 30% hydrogen peroxide. The solution is heated under reflux for 16 hours, cooled and diluted with water, the white crystalline solid is separated off and dissolved in chloro5

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The chloroform solution is shaken with dilute sodium hydroxide, washed with water, dried and concentrated to a white solid. The pure 1-oxide, melting point 290 ° -292 ° C., is obtained by recrystallization from absolute ethanol.

B. 1-methoxy-3-tritylpyridinium methyl sulfate

22.0 g of 3-tritylpyridine-1-oxide are dissolved in 350 ml of toluene and treated with 9.0 g of dimethyl sulfate. The solution is heated under reflux for 2.5 hours, during which time an oil separates which crystallizes out after cooling, melting point 162 ° -165 ° C. The pure methyl sulfate, melting point 169 ° -171 ° C., is obtained by recrystallization from acetonitrile / ether.

C. 2-Cyano-5-trityipyridine

25.0 g of l-methoxy-3-tritylpyridinium methyl sulfate is dissolved in 800 ml of water and added dropwise with stirring to an ice-cooled solution of 13.5 g of sodium cyanide in 100 ml of water while passing a vigorous stream of nitrogen through the mixture. The mixture is left to stand at room temperature for 4 hours and then the white solid is filtered off. Recrystallization of the product from methanol gives a pure 2-cyano-5-tritylpyridine, melting point 180 ° -182 ° C.

D. 5- (triphenylmethyl) -picolinic acid can be prepared according to Example 1, stage B from the product of reaction stage C above, melting point 215 ° -217 ° C.

Example 21

5- (triphenylmethyl) -picolinic acid

A mixture of 8.2 g of 2-styryl-5- (triphenylmethyl) pyridine and 120 ml of acetone is cooled to -10 ° C. and 6.66 g of fine potassium permanganate are slowly added in portions over a period of time, with vigorous stirring from 1 '/ •> hours, keeping the temperature below - 5 ° C. The mixture is left to stand at -5 ° C. for 15 hours, filtered and the solid is washed with chloroform, extracted three times with 150 ml of boiling water. The aqueous extracts are acidified with hydrochloric acid, extracted with ether, the ether extracts are discarded, the aqueous phase is adjusted to a pH of 2.5, and the precipitated acid is filtered off and dried, which is recrystallized from benzene, giving the product this example with a melting point of 215 ° -217 ° C.

Example 22

5- (triphenylmethyl) -picolinic acid 20 A mixture of 18 g of 2-methyl-5- (triphenyl-methyl) -pyridine, 1 liter of water and 9 g of potassium permanganate is heated on a steam bath for about 3 hours until the reaction mixture is colorless. 9 g of potassium permanganate, 200 ml of water are added and the reaction mixture is further heated for about 5 hours until the mixture is colorless. It is filtered, washed carefully with hot water (70 ° -90 ° C.), the filtrate and the washing water are combined, cooled to about 25 ° C., acidified with hydrochloric acid and the product of this example is separated off by filtration, melting point 30 215 ° -217 ° C.

B

Claims (3)

629488 2. The method according to claim 1, characterized in that hydrolyzing a compound of formula XVIII, in which Z is the cyano group. 30 3. The method according to claim 1, characterized in that hydrolyzing a compound of formula XVIII, in which Z is the group -conh2. 4. The method according to any one of claims 1 to 3, characterized in that hydrolyzing a compound of formula 35 XVIII, wherein Rs is hydrogen, the diphenylmethyl group (II) or the triphenylmethyl group (III), wherein Ri is hydrogen, chlorine or phenyl and R9 is hydrogen, methyl or ethyl; and when Rs is diphenylmethyl group (II), R4 and Re 40 are hydrogen and R3 is hydrogen or diphenylmethyl group (II); and when Rs is the triphenylmethyl group (III), R3, R4 and Rö are hydrogen or one of the substituents r3, R4 and Rs is methyl and the other two are hydrogen. 45 5. The method according to any one of claims 1-4, characterized in that a compound of formula XVIII is hydrolyzed, wherein Rs is the diphenylmethyl group (II) or the triphenylmethyl group (III), wherein Ri and R9 are hydrogen, 50 and, when Rs is the diphenylmethyl group (II), R4 and Rö are hydrogen and R3 is hydrogen or the diphenylmethyl group (II), and when Rs is the triphenylmethyl group (III), r3, R4 and Rß are hydrogen. 55 6. The method according to any one of claims 1 to 4, characterized in that a compound of formula XVIII is hydrolyzed, wherein Rs is triphenylmethyl or a- (4-chlorophenyl) benzyl and R3, R4 and Rß are hydrogen. 7. A process for the preparation of the cyanomethyl ester of a 60 compound of the formula I which is as defined in claim 1, characterized in that the compound of the formula I is prepared by the process of claim 1 and this is carried out at elevated temperature with a haloacetonitrile in the presence of a Implement acid acceptor. 65 8. The method according to claim 7, characterized in that one reacts a compound of formula I in which Rs is triphenylmethyl and r3, R4 and Rö are hydrogen. 2nd PATENT CLAIMS 1. Process for the preparation of new picolinic acid derivatives of the general formula (I) C - (II) or a triphenylmethyl group of the general formula R. (HI) R, R, (XVII.I) and their pharmaceutically acceptable salts, wherein Qi is hydroxy; R.5 is hydrogen, a diphenylmethyl group of the general formula R " where R 1 is hydrogen, halogen, hydroxy, alkyl, cycloalkyl, alkoxy, cycloalkoxy, trifluoromethyl or phenyl and R9 is hydrogen, lower alkyl or lower cycloalkyl; and when Rs is hydrogen, R3 and Re are hydrogen and R4 is a diphenylmethyl group of the general formula (II) defined above; and when Rs is diphenylmethyl group (II), r4 and Rô are hydrogen and R3 is hydrogen, lower alkyl, lower cycloalkyl or a diphenylmethyl group of the general formula (II) defined above; and when Rs is the triphenylmethyl group (III) r3, R4 and Re are hydrogen or one of the substituents r3, R4 and Rs is lower alkyl or lower cycloalkyl and the other two are hydrogen, said alkyl, cycloalkyl, alkoxy and cycloalkoxy groups containing up to 12 carbon atoms and said lower alkyl and lower cycloalkyl groups containing up to 6 carbon atoms; characterized in that a compound of the general formula 10th in which R3, R4, Rs and Re are as defined above and Z is cyano, or the group COQ, in which Q is alkoxy, cycloalkoxy, cyanoalkoxy, cyanocycloalkoxy, 2,3-dihydroxy-prop-1-yl-oxy, -NR7R8, - Represents 0-alkylene-NR7R8, NR7-alkylene-OH, is -O-cycloalkylene-NRzRs or-NR.7-cycloalkylene-OH; R7 and R8, which are identical or different from one another, are hydrogen, alkyl or cycloalkyl or R7 and Rs together with the amido nitrogen atom form a heterocyclic ring which consists of 5 to 7 ring members and 20 contains only the nitrogen atom mentioned or a second heteroatom contains which is oxygen or nitrogen; said alkoxy, cycloalkoxy, alkylene, cycloalkylene, alkyl and cycloalkyl groups contain up to 12 carbon atoms; hydrolyzed and the compound thus obtained isolated in free form or in the form of its pharmaceutically acceptable salt. 3rd 629488