DE1695006A1 - Process for the preparation of new amides of aliphatic carboxylic acids - Google Patents

Description

J. R. GEIGY / y.0. BAjSEL 21

Case 4-2332 * New complete application documents Process for the preparation of new amides aliphatic Carboxylic acids

The present invention relates to processes for the preparation of new amides of aliphatic carboxylic acids, these Amides as new substances as well as drugs containing them and their application.

Amides of the general formula I,

R ₁ -CO-N -j ^ jl (D

in which

Rn-CO- denotes the acyl radical of an alkanoic acid, alkenoic acid or

Alkapolyenoic acid having 6-14 carbon atoms, R ₂ a halogen atom, a lower alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkanoylamino or alkoxycarbonyl group, and

R ₃ denotes hydrogen or a lower alkyl radical have not yet become known.

As has now been found, surprisingly, such compounds and their addition salts with inorganic compounds and organic acids have valuable pharmacological properties,

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especially antiviral and anti-tumor effectiveness, with the favorable ratio of the significant effective at the maximum tolerated doses is remarkable. The antiviral effectiveness could e.g. '' subcutaneous and oral administration to herpes simplex virus, influenza A virus, in particular influenza A-PR 8 virus, Influenza B-Lee virus, Columbia SK virus and Louping ill virus (sheep cephalitis virus), and the anti-tumor effects im Animal experiment with subcutaneous and oral application on the transplanted Ehrlich carcinoma, on the induced one Methylcholanthrene sarcoma. Dirnethylbenzanthracene skin carcinoma and on spontaneous tumors in mice, as well as on transplanted Yoshida sarcoma and on induced Dimethylbenzanthracene mammary carcinoma in the rat. The animal experiments characterize the Compounds <ier general formula I as suitable for the treatment of viral diseases, such as herpes simplex, Herpes zoster, influenza, encephalitis and others, as well as for the treatment of neoplasias.

In the compounds I, R, -CO- is, for example, the acyl radical of a straight-chain alkanoic acid, such as

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Hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, Decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid uicr tetracanoic acid; a straight chain Alkene or alkapolyenoic acid, such as sorbic acid, 2-octenic acid, 2-conenic acid, 2-decenoic acid, 2-undecenoic acid, 10-undecenoic acid, 2-dodecenoic acid, 2-tridecenoic acid, ? -Tetradecenoic acid or 2,4,6,8-decatetraeric acid; a branched alkanoic acid, such as? -ethylbutyric acid, 3,3-Dirr: ethyl buttoric acid, 2-ethylpentanoic acid, ? -Aethyl-4-methyl-ppntanoic acid, 2-ethylhexanoic acid, 2,2-diethyl butyric acid, 3,3,5-triraethylhexanoic acid, 3, f>, i> -trimothyl-hexanoic acid,? -N-butylhexanoic acid, 2-ethyl-decane: acid or 2-ethyldodecanoic acid, odor of a branched alkenoic acid or alkapolyene acid, such as dor? -AlIyl-4-poir, «η acid, 3-ethyl-2-hexenoic acid, 2 »(l-ethyl-allyl) pentenoic acid, 3-Kethyl-2-nonenoic acid, 3-methyl-2-undecenoic acid or 3-methyl-2-tridecenoic acid.

The substituent Rp is e.g. chlorine, fluorine, Bromine, iodine, a methyl, ethyl, n-propyl-isopropyl, η-butyl, isobutyl, tert-butyl,

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Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Isobutoxy, n-hexoxy, allyloxy, (1-methyl-allyloxy), (2-methyl-allyloxy), methylthio, ethylthio, isopropylthio, n-butylthio, allylthio, formamido, acetamido, methoxycarbonyl, Ethoxy carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl group.

As lower alkyl radicals R >> For example, those listed as examples for Rg come into consideration. Under the general formula I. Urea adducts of compounds of the general formula I are also to be understood.

. For the preparation of the new amides of the general formula. 1 if an acid of the general formula II is used,

R ₁ - CO - OH (II)

in which R, -CO- has the meaning given above, or a reactive functional derivative of such an acid with a ring-substituted aminopyridine or ring-substituted one Alkylaminopyridine of the general formula III,

R ₂

H- N-J ^ l (III)

K ^N

in which R ₂ and R _{3 have} the meaning given above, or with a reactive functional derivative thereof. In carrying out this procedure, for example

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ORIGJNAL

wise an acid of the general formula II with a compound of the general formula III in the presence of a carbodiimide, such as dicyclohexyl-carbodiimide, in one inert solvents such as tetrahydrofuran, reacted. Lower alkyl esters, such as the methyl esters or ethyl esters, the acids of the general formula II, and also the When heated with compounds of the general formula III, amides give the corresponding substituted amides of the general formula Formula I.

'As further reactive functional derivatives of Acids of the general formula II are the halides and anhydrides, especially the mixed anhydrides Carbonated half-esters. These functional derivatives are preferably used with a compound of the general formula III Presence of an acid-binding agent, e.g. a strong tertiary organic base such as triethylamine, pyridine or s-collidine, which in excess also serve as a reaction medium can, or in the presence of an excess of the reaction component of the general formula III in the presence or absence an inert organic solvent such as benzene, tetrahydrofuran or dimethylformamide.

As a modification of the conversion of acid halides with compounds of the general formula III in the presence of acid-binding agents is the reaction of the acid halides with suitable, tertiary organic bases, in particular triethylamine, in an inert organic solvent,

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Filing off the hydrohalide formed and re τ. sung of the ketene or ketene dimerc present in the solution with the desired compound of the general formula ill £ - .. called.

Activated esters of acids of the general formula. II are, for example, their p-nitro-phenyl esters and cyanomethyl esters, which with compounds of the general formula III in inert ü * - Chemical solvents, if necessary with warming, ui. \ set will. Under similar conditions, dif 1-Im i da Zoll de of the acids mentioned with compounds egg r. generally Formula III implemented.

As reactive functional derivatives. Compounds of the general formula III, which are directly with acids the general formula II can be implemented, the caien of compounds of the general formula III with a hydrogen atom as R-, derived isocyanates and isothiocyanates called. These become more general with the acids! Formula II heated until the equimolar amount of carbon dioxide or carbon oxysulfide is released.

The reactions with isocyanates and isothiocyanates can be carried out in the presence or absence of an inert organic solvent with a sufficiently high boiling point or range. Instead of isocyanates it is also possible to use precursors of the same, ie in particular the azides of pyridinecarboxylic acids substituted according to the definition for R “with acids of the general formula II under Er-

. \ W>: H'-J WV = S

Warming can be implemented in suitable, inert organic solvents. Furthermore, for example N-chlorocarbonyl derivatives of compounds of the general formula III, in particular of those with a lower alkyl radical as R ₃ , are reacted with salts, for example alkali salts, of acids of the general formula II, in the presence or absence of inert organic solvents, and the Reaction mixtures are heated until the equimolar amount of carbon dioxide is released from the primarily formed carboxylic acid-carbamic acid anhydrides. " Sulfurous acid monoalkyl ester amides and phosphoryic acid o-phenylenediester amides can also be derived from compounds of the general formula III with a lower alkyl radical as R ^, which, when reacted with acids of the general formula II in organic solvents, such as, for example, »pyridine, Dioxane or dimethylformamide or benzene, the desired amides of the general formula I, provide.

Other reactive functional derivatives of compounds of general formula III are, for example, the N-trimethylsilyl derivatives obtainable by reacting these amines with trimethylsilyl chloride in inert, anhydrous organic solvents, including, for example, _{ethyl trimethylsilylaminopyridine carboxylate (R 2} = COOC ₂ H ₅ ), which are capable of reacting functional derivatives of the acids of the general formula II in inert organic solvents to give K-trimethyl

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implement silyl derivatives of amides of the general formula I, from which lower alkanols when decomposed with water vein the desired amides are formed.

Another type of reactive derivatives of compounds of general formula III are those in the two Pyridine rings substituted according to the definition of Rp Ν, Ν'-Dipyridyl-carbodiimide, which in turn, e.g. by heating the corresponding, substituted Ν, Ν'-dipyridyl-thioureas with lead (II) oxide in abs. Toluene can be obtained by gradually distilling off the solvent. When heating the said Carbodiimides with acids of the general formula II in a stream of carbon dioxide at temperatures around 200 ° form the desired ones Amides of the general formula I.

Instead of falling under the general formula II alkene or alkapolyenic acids with 6-14 carbon atoms or reactive functional derivatives thereof can, if desired the saturated bromine addition products of such acids or reactive functional derivatives thereof with ring-substituted aminopyrldines or ring-substituted ones Alkylaminopyridines of the general formula III or with react-

tionable derivatives of the same implemented and the directly obtained amides of polybromofatty acids having 6-14 carbon atoms and an even number of bromine atoms are debrominated in a manner known per se.

As reactive functional derivatives of both reaction components and as reaction conditions for amide formation essentially the ones above come for direct manufacture

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of compounds of the general formula I mentioned in question. Debromination takes place, for example, by boiling the Intermediate products with zinc in ethanol. This two-step process for the preparation of compounds of general Formula I appears more complicated than the first-mentioned, single-stage one. However, it can be advantageous if amides of such Alkene or alkapolyenoic acids are difficult to produce clean, e.g. to be separated from isomers and / or homologues. In such cases cleaning, e.g. Crystallization, at the stage of the bromine addition products Acids are carried out, or it can be the substituted pyridylamides obtained with such bromine addition products better cleaning of dibromo- or polybromic acids, e.g. Recrystallize, as the end products bromine-free in the acyl radical. If the latter applies, one can also use a cleaning operation according to the first-mentioned method obtained alkene or Älkapolyenamid of the general formula 1 add bromine, the addition product by crystallization or another common method of cleaning and then debroming.

Finally, amides of the general formula I, in which Rp is represented by a lower alkanoylamino group is also prepared by adding amides of the general formula IV,

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16951) 06

^ ~ Ci ^(IV)

R ₃

in which

R, -CO- and Ro have the meaning given under formula I, with a compound introducing a lower alkanayl radical. The alkanoylation, e.g. Etylation takes place after. known methods, for example by reacting ml ¹ : a lower alkanoic acid halide or anhydride at room temperature or moderately elevated temperatures. If necessary, the reaction is carried out in the presence of an acid-binding agent, such as, for example, pyridine as a simultaneous reaction medium, an alkali metal carbonate in an inert organic solvent or sodium hydroxide solution in a two-phase, organically aqueous system.

Starting materials of the general formula IV can be obtained, for example, by reducing corresponding nitropyridylaaiides. The latter in turn can be prepared, for example, by acylation of amino-nitro-pyridines, analogously to the first-mentioned preparation process for compounds of the general formula I. If a protective group customary in peptide synthesis is first introduced into the amino-nitro-pyridines mentioned, the nitro group is then reduced, the acyl radical R ₁ -CO- is introduced analogously to the first-mentioned production process for compounds of the general formula I and then the protective group is split off, so

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^Ba ü ORIGINAL

-IL-

obtained from the same amino-nitro-pyridines starting materials dor general formula IV with the position of Amide group and amino groups

The conversion of the preliminary compounds of the general formula I in the urea adducts already mentioned, for example, occurs through Adding a compound of the general formula-I with a solution of urea in methanoi and separation of the failed Adduct.

The conversion of Verbinuungeiν of the general formula IW into the acid addition salts already mentioned above can be carried out in the usual way. Suitable for salt formation acids may be mentioned are: hydrochloric acid, hydrogen bromide Saur ", sulfuric acid, phosphoric acid, methane, Aethandi sulf oic acid, P-Hydrixyä tt _t Ansul fön acid, acetic acid, lactic acid, oxalic acid, Ben: stone acid, fumaric acid, maleic acid, Aepfcrl, ^: iure, V.'ar'lure, citric acid ,. Benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.

The treatment of viral diseases and neoplasias g | suitable daily doses of Ami der, the general formula I and their salaries are in adults people of normal weight between 100 mg and 3000 mg and within this range, called parenteral application in generally lower than with oral application. The daily doses mentioned are expediently in unit sizes of 50 to 500 mg of active ingredient administered, but can also be appropriate

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Quantities of non-single-dose forms of application, such as syrups, sprays, aerosols, powders and ointments, are used.

Contains unit dose shapes for oral use as an active ingredient preferably between $ 10 and $ 90 of an amide general formula I or a pharmaceutically acceptable salt thereof. For their production, the active ingredient is mixed with, for example solid, powdery carriers such as lactose, sucrose, Sorbitol, mannitol j starches, such as potato starch, corn starch or Amylopectin, also laminaria powder or citrus pulp powder, Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or Polyethylene glycols of suitable molecular weights, and the mixture is pressed into tablets or dragee cores. "The latter is coated for example with concentrated sugar solutions, which e.g. still Arab gum, talc and / or 'titanium dioxide may contain, or With a lacquer dissolved in volatile organic solvents or solvent mixtures, these can be coated Dyes can be added, e.g. to mark different doses of active ingredients.

As unit dosage forms for rectal use, e.g. suppositories, which are made up of a combination of a Amides of the general formula I or a suitable one pharmaceutically acceptable salt thereof with a Neutral fat base, or gelatin rectal

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capsules containing a combination of the active ingredient or a suitable salt thereof with polyethylene glycols of suitable molecular weight.

Ampoules for parenteral, especially intravenous, intramuscular or subcutaneous administration contain a water soluble, pharmaceutically acceptable salt of an amide of the general formula I in a concentration of preferably 0.5-10 / o, optionally together with suitable stabilizers agents and buffer substances, in aqueous solution.

Further forms of application come, in particular for Treatment of viral infections of the respiratory tract, syrups as well Aerosols, and ointments Tjnä powder for the local treatment of viral diseases. All of these application forms can be using the usual carriers, diluents and additives.

The following examples illustrate the preparation of the new compounds of the general formula I, but are intended to do so in no way limit the scope of the invention. the Temperatures are given in degrees Celsius.

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Example Γ ·

7.6 g (0.05 mol) of 5-amino-2-propoxypyridine are in Dissolved 20 ml of pyridine. While stirring and cooling with egg water 10.15 g (0.05 mol) of 10-Uhdecenoylchlorid become within Added dropwise for 10 minutes and the mixture at room temperature more stirred for two hours. The reaction mixture is poured onto 200 ml of ice water, extracted three times with 100 ml of chloroform and the chloroform solutions washed neutral with water. The combined chloroform solutions are dried with sodium sulfate and evaporated to dryness. The residue is made from benzene petroleum ether recrystallized, the N- (6-propoxy-3-pyridyl) -10-undecenamide by Snip. 64 ° is obtained.

To prepare the hydrochloride, solve the above Amide in a little methanol, ethereal hydrochloric acid is added in excess and the precipitated hydrochloride is filtered off. After recrystallization from methanol-ether it melts at 159 °.

In an analogous way, for example, are produced:

a) N- (5-bromo-2-pyridyl) -10-undecenamide, melting point 74 °;

b) N- (5-chloro-2-pyridyl) -10-undecenamide, melting point 67 °;

c) N- (5-methyl-2-pyridyl) -10-undecenamide, melting point 67 °;

d) N- (6-allylthio-3-pyridyl) -10-undecenamide-

hydrochloride m.p.

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⁸ ^ original

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Example 2

7.0 g (0.0404 mol) of 2-AmIno-5-bromo-pyridine are in
bO ml of pyridine dissolved. While stirring and cooling with ice water, 8.21 g (G, G404 mol) of 10-undecenoyl chloride are within
Added dropwise for 10 minutes and the mixture was stirred at room temperature for a further two hours. The reaction mixture is poured onto 250 ml of ice water and the precipitated N- {5-bromo-2-pyridyD-10-undecenamide is recrystallized from methanol, melting point 74 °, in analogous Werse are prepared, for example;

a) N- ( ^f i-iodo-2-pyridyl) -10-undecenamide. Mp. 84 ° j

b) N- (6-ethoxy-3-pyridyl) -10-undecenamide melting point 67 °;

c) N- (6-butoxy-3-pyridyi) -10-uiidecenamide melting point 62 °;

d) N-io-allyloxy-S-pyridyD-10-undecenamide melting point 62 °;

e) N- (6-ethylthio-3-pyridyl) -IO-undecenamide melting point 64 °;

f) ri- (5-ethaxycarbonyl-2-pyriiiyl) ~ 10-undecenamide mp. 74 °;

g) U-Ce-Acetaniida-'S-pyridyD'-10-undeceiianiid mp. 152 ° / h) K- (6-propoxy-3-pyrldyl) -octanamide mp. 78 °; i) K- (6-Propoxy-3-pyrIdyl) -nonanaaiid Snip. 65 ^C ; j) N- (6-propoxy-3-pyriuyl) -decanamide mp. 70 °; k) N- (6-propoxy-3-pyridyl) undeciinate m.p. 77 °; 1) N- (5-chloro-2-pyridyl) -dedeeanamide £ mp. 91 °; m) N- (4-methyl-2-pyriayl) -doaeeanamide ftnp. 52 ^J ; n) N- (5-methyl-2-pyridyl) »doöeeananiid Sn.p. 79 °; o) N- (6-propoxy-3-pyridyl) -dödecananiid mp 83 ^C ; p) N-Ce-propoxy-S-pyridyD-tridecanaKiid m.p. 84 ^c ;

BAD OBtGlNAl.

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q) N- (6-Propoxy-3-pyridyl) -tetradecanamId Snip. 85 °;

r) · N- (5-ethoxycarbonyl-2-pyridyl) -tetradecanamide mp. 79 °

s) N- (6-propoxy-3-pyridyl) -2-nonenamide

t) N- (5-bromo-2-pyridyl) sorbamide

u) N- (5-methyl-2-pyridyl) sorbamide

v) N- (5-methyl-2-pyridyl) -2-allyl-3-methyl-4-

pentenaraid.hydrochloride
w) N- (e-Acetamido-S-pyridyl) -sorbamide x). N- (6-Allyloxy-3-pyridyl) -undecanamid y) N- (5-Aethoxycarbonyl-2-pyridyl) -sorbamid ζ ) N- (5-Aethoxycarbony1-2-pyridy1) -3,5,5-

trimethyl hexanamide

aa) N- (6-acetylamino-3-pyridyl-3-ethyl-2-hexenamide, melting point 162 °; bb) N- (5-chloro-2-pyridyl) -3-ethyl-2-hexenamid.Hy-

hydrochloride

cc) N- (5-methyl'-2-pyridyl) -2-ethyl-hexanamide dd) N- (6-acetylamino-3-pyridyl) -tridecanamide ee) N-methyl-N- (5-methyl-2- pyridyl) -10-undecenamide n ^ ¹ : 1.5095; ff) N- (4-methyl-2-pyridyl) sorbamide, mp 210 °

gg) N- (4-methyl-2-pyridyl) -3.5 | 5-trimethylhexanamide mp 53 °; hh) N- {4-methyl-2-pyridyl) -10-tinedecenamide m.p. 38 °.

M.p. 84 °; M.p. 154 ο; M.p. 151 ° \ M.p. 121 °; M.p. 238 °; M.p. 68 °; M.p. 162 °; M.p. 82 °:

M.p. 136 °; "22
ⁿ D ; 1.5185; M.p. 162 °;

OBiGlNAL 1098Q9 / 2178

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Example 3

7.6 g (0.05 mol) of 5-amino-2-propoxypyridine are dissolved in 20 ml of chloroform. With stirring and cooling with ice water, 5.48 g (0.025 mol) of dodeeanoyl chloride are added dropwise over the course of 10 minutes and the mixture is stirred at room temperature for a further two hours. The reaction mixture is poured onto 200 ml of ice water and extracted three times with 100 ml of chloroform. The combined chlorine solutions are washed neutral with water, dried with sodium sulfate and evaporated to dryness. The residue is recrystallized from methanol, the N- (6-propoxy-3 -pyridyl) dodecanamide having a melting point of 83 °. Example 4

3.69 g (0.02 mol) of 10-undecenoic acid and 2.02 g (0.02 mol) of triethylamine are dissolved in 100 ml of tetrahydrofuran and the solution is cooled to -15 °. 2.15 g (0.02 mol) of ethyl chloroformate, dissolved in 20 ml of tetrahydrofuran, are added dropwise with stirring, the temperature not exceeding -10 °. After stirring for 15 minutes at -10 °, a solution of 3.08 g (0.02 mol) of ethyl 6-aminonicotinate in 20 ml of tetrahydrofuran at -8 ° to - is added to the resulting solution of the mixed anhydride of 10-undecenoic acid and carbonic acid monoethyl ester. 12 ° added. The mixture is stirred for one hour at -10 ° and, after removal of the cooling, stirred for a further ½ hours at room temperature. The precipitated triethylamine hydrochloride is filtered off with suction, the filtrate is evaporated and the N- (5-ethoxyearbonyl-2-pyridyl) -10-undecenamide is recrystallized from methanol, melting point 74 °.

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Example 5

1.84 g (0.01 mol) of 10-undecenoic acid and 2.79 g (0.01 mol) 2-Amino-5-bromopyridine are dissolved in 50 ml of tetrahydrofuran. At -10 ° a solution of 2.08 g (0.01 mol) is stirred NjN'-dicyclohexyl-carbodiimide in 50 ml of tetrahydrofuran was added dropwise. After stirring for one hour at -10 ° and 4 hours at room temperature the precipitated N, N'-dicyclohexylurea slips off,

washed with tetrahydrofuran, the filtrate evaporated and the N- (5-bromo-2-pyridyl) -10-undecenamide recrystallized from methanol, mp. 74 °.
Example 6

2.14 g (0.01 mol) of ethyl 10-undecenoate are heated to 230 ° for 4 hours with 1.08 g (0.01 mol) of 6-amino-3-picoline under a stream of nitrogen and vigorous stirring. After cooling, the crude N- (5-methyl-2-pyridyl) -10-undecenatoid is recrystallized from methanol, melting point 66.5 °. Example 7

A solution of 2.08 is added at -10 ° with stirring to a solution of 1.84 g (0.01 mol) of 10-undecenoic acid and 1.4 g (0.01 mol) of p-nitrophenol in 50 ml of tetrahydrofuran g (0.01 mol) of NvN'-dicyclohexyl-carbodiimide in 50 ml of tetrahydrofuran were added dropwise. After stirring for one hour at -10 ° and 4 hours at room temperature, the precipitated N, N ^! -Dicyclohexyl urea removed and washed with tetrahydrofuran and the filtrate evaporated. 3.06 g (0.01 mol) of the 10-indenoic acid p-nitrophenyl ester remaining as residue are mixed with 10.8 g (0.1 mol)

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6-Amino-3-picoline was allowed to stand in 50 ml of chloroform for 4 days. After evaporation of the solvent, the crude product is purified by column chromatography. The product is identical to the N- (5-methyl-2-pyridyl) -xO-undeeenamid prepared according to Example 6.
B (MPPJeI 8

2,? 2 g (0.022 Hol) Xriäthylamin are in 50 ml of abs. Aether gc-lönL. While stirring and cooling with ice water 2 {; (0.01 mol) 10-undecenoyl chloride, dissolved in? 0 ml abs. φ Ether, added dropwise within 5 minutes. Then be 1.7 3 g (0.01 mol) of 2-amino-5-bromo-pyridine, dissolved in 50 ml Aothyl acetate, closed within 10 minutes. and the mixture stirred for a further 2 hours.

The precipitated triethylamine hydrachloride is thoroughly seen -ind washed with ethyl acetate. N- (5-brora-2-pyridyl) -10-undeceiiainide, Saip, is obtained from the filtrate by means of work-up as aiial of Example 1. V4 ".
Example 9 _

2.22 * (0.01 mol) of 2-amir: ^ - 5 -,: od-pyricine are dissolved in 30 ml of di: nethylfcrmamiü and 1.01 g (0.01 mol) of triethylamine. While stirring and cooling with ice water, 1.86 g (0.01 mol) of tri-ethyl-silyl-chloride, dissolved in 10 ml of dimethyl 1-forraamide, are added dropwise within 10 minutes and the mixture is added

"" Room temperature for a further 2 hours. To the received

ο -. ■

to solution of 2-TΓimethylsilylamino-5- ^ od-pyridine are under

OO -

Charge and cool with ice water, 1.11 g (0.011 mol) of irlethylamine κ, and then 2.0 g (0.01 mol) of lO-Undecenoylchloric,

-a dissolved in 10 ml of dimethylformamide, added dropwise and the mixture

getuhrt another 2 hours' JTAS ReäKttenegemisch is on

'IÖ9ÖUÜ6

300 ml of ice water are poured, the product which has precipitated is filtered off with suction, dried under high vacuum (4 hours at 40 °) and recrystallized from methanol. The resulting N- (5-iodo-2-pyridyl) -10-indecenamid melts at 84 °. See Example 2. Bei p iel 10

1.8.4 g (0.01 mol) of 10-undecenoic acid, in 25 ml of abs. Dissolved tetrahydrofuran, 1.62 g (0.01 mol) of 1,1'-carbonyldiimidazole are added at room temperature. After the evolution of carbon dioxide has ended, 1.56 g (0.01 mol) of 3-amino-6-ethylthio-pyriüin, which in 20 ml of abs. Tetrahydrofuran is dissolved, added and the reaction mixture heated under reflux for a further 10 minutes. The residue obtained after evaporation of the tetrahydrofuran is taken up in 50 ml of ether and extracted three times with 50 ml of water. The ethereal solution is evaporated and the? 1- (6-ethylthio-3-pyridyl) -10-undecenamide is recrystallized from methanol, melting point 64 °. Example 11

3.71 g (0.01 mol) of N- (6-amino-3-pyridyl) -10-undecenamide are dissolved in 20 ml of fyridine and 10 ml of acetic anhydride left to stand at room temperature for 12 hours. The reaction. mixture is poured onto 150 g of ice and the precipitated Crystals of N-ie-acetylamino-S-pyridyD-10-undecenamide suction filtered and recrystallized from methanol, m.p. 152 ° (see. Example 2g).

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Example 12

a) 1.52 g (0.01 mol) 6-amino-3-propoxypyridine and 1.1 g (0.011 mol) of triethylamine are dissolved in 50 ml of chloroform. While stirring and cooling with ice water, 3.63 g (0.01 mol) 10,11-dibromundecanoic acid chlorides dissolved in 35 ml of chloroform, was added dropwise over the course of 10 minutes and the mixture was stirred at room temperature for a further 2 hours. The chloroform solution will washed three times with water and evaporated to dryness and the N-6-propoxy-3-pyridyl) -10, ll-dibromundecanamide is removed Methanoi. Recrystallized. M.p. 83 °,

b) 4.78 g (0.01 mol) of N-6-propoxy-3-pyridyl) -10,1-dibromundecanamide are dissolved in 5 ml of abs, ethanol, 5 g of activated zinc dust are added under a nitrogen atmosphere and the mixture is heated to boiling under reflux for 1 hour. After cooling, "the zinc is separated off by filtration, the solution evaporated to dryness and the remaining N- (6-propoxy-3-pyridyl) -10-undecenamide from methanol recrystallized. M.p. 64 °.

Example 13

a) 2.75 g (0.01 mol) of N- (5-amino-2-pyridyl) -10-undecenamide are left to stand in 5 ml of pyridine and 5 ml of acetic anhydride at room temperature for 12 hours. The reaction product is made up to 100 g Poured ice and the precipitated crystals of N- (5-acetylamino-2-pyridyl) -10-undecenamide suction filtered and recrystallized from methanol. M.p. 149 °.

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b) N- (5-Amino-2-pyridyl) -lQ-undecenamide can be prepared as follows:

5.56 g (0.04 mol) of 2-amino-5-nitro-pyridine are in 30 ml Pyridine dissolved. Be with stirring and cooling (ice water) 8.12 g (0.04 mol) of 10-undecenoyl chloride were added dropwise and the mixture Stirred for 6 hours at room temperature. The reaction mixture is Poured onto 150 g of ice and the precipitated crystals of N- (5-nitro-2-pyridyl) -iO-undecenamide recrystallized from methanol. M.p. 74 °.

c) 3.05 g (0.01 mol) of N - (? - Nitro-2-pyridyl5-10-undecenamide) dissolved in a mixture of 30 ml of water, 6 ml of dioxane and 6 ml of methanol. 10 g iron powder are added and the mixture, stirred under a nitrogen atmosphere for 30 minutes at 90-93 °. The reaction mixture is filtered hot and the filtrate evaporated to dryness. The N- (5 ~ amino-2-pyridyl) -10 ~ undecenamide is recrystallized from methanol. M.p. 82 °.

109809 / 2Ί78

* AD OBiQf _NAL

Claims (4)

Claims 1. Process for the preparation of new amides aliphatic Carboxylic acids according to general formula I, R ₂ R - co - N-J ^ Ti (I) R ₃ in which R, -CO- denotes the acyl radical of an alkanoic acid, alkanoic acid or Alkapolycic acid with 6-14 carbon atoms, Rp is a Halogenatoia, a lower alkyl. Alkoxy--. Alkenoyl'ocy-, Alkylthio, alkenylthio, alkanoylamino or Alkoxycarbonyl group and Rj denotes hydrogen or a lower alkyl radical, and their additives salts with inorganic and organic Acids, characterized by being an acid of the general: Formula II R ₁ -CO-OH. (II) "■ ■ "'■' ■ Λ in which R ^ -CO- has the meaning given above, ocer a ™ reactive functional derivative of such an acid with a ring-substituted aminopyridine or ring-substituted alkylaminopyridine of the general formula III, (HD ^R 3 " 109809/2178 ORIGINAL 1695U06 in which R ^ and R _{3 have} the meaning given above, or reacts with a reactive functional derivative thereof, and if desired to an alkene or alkapolyo obtained. amide of the general formula I bromine is added, the addition product is purified by crystallization or another customary process and then debrominated, and / or, if desired, a compound of the general formula I obtained is converted into an addition salt with an inorganic or organic acid. 2. Modification of the method according to claim 1, characterized in that instead of one of those in claim 1 defined general formula II falling alkene or alkapolyenoic acid with 6-14 carbon atoms or one reactive functional derivative of such the saturated bromine addition product this acid or a reactive functional Derivatives of the same with a ring-substituted arainopyridine or ring-substituted alkylaminopyridine of im Claim 1 defined general formula III or reacts with a reactive functional derivative thereof and the immediately obtained amide of a polybromofatty acid with 6-14 Carbon atoms and an even number of bromine atoms in an debrominated in a known manner, and if desired a preserved one Compound of general formula I converted into an addition salt with an inorganic organic acid. 109809/2178 bath I68b006 3 «Modification of the method according to claim 1, thereby characterized in that an amide of the general formula IV, NH ₂ R, CO - N-μΠ (IV) ¹ ji * ^R 3 in which R-, -CO- and R _{3 have} the meaning given in claim 1, reacts with a compound introducing a lower alkanoyl radical and, if desired, converts a compound of the general formula I obtained into an addition salt with an inorganic or organic acid. 4. '' / bindings of the all & e & aln & ra fetter I CO - N- in which the aoyl radical of an alkane "sa? e, AlkemjKurs or Älkapolyensßure with 6-14 carbon atoms * οίη Kalogenatom, a Biedere AIk ^ l -, - Älko ^« », Alksnyl- * Alkyltnio-, Alksn ^ lthio-, Ällsanoylamino- or group ^ wiü
Wasssz ^s otoff öüqt means a lower universal residue. BAD ORlGJNAL