SU633475A3 - Method of obtaining pyridine derivatives or salts thereof - Google Patents

Description

This invention relates to a process for the preparation of new pyridine derivatives which have high biological activity and can be used in the pharmaceutical industry. The use of the reaction of the interaction of amides of acids with phosphorous phosphorus known in organic chemistry with the formation of the corresponding thioamides l for the pyridine amides allowed us to obtain new pyridonic derivatives of the general formula d. 1 where RR and Re are the same or different and represent hydrogen, trnfluoromethyl alkyp, aralkyl or arip, any of the co-coils of the cushet can be mixed with alkyl by an apkoxyl group, halogen by a nitro group or by fluoromethyl or B and R together are one-branched alkylene containing 3- 5 carbon atoms; R is one or more substituents which represent hydrogen, alkyl, aralkyl K2 and aryl are mixed, moreover, when R and those are unbranched alkylene, the resulting ring can also be substituted by one or more radicals Rg, Rj and R are the same or different and represent hydrogen, alkyl, aralkyl or aryl, any of which may be substituted by alkyl, alkoxy, halogen, nitro or trifluoromethyl: t 1,2 or 3; as well as their suns with high biological activity. The proposed method for the preparation of pyridine derivatives of general formula 1 is that the amide of general formula II. G. K-R, (. (M.). V., CONKjR

hee R, have values, interact with five-grained phosphorus when heated, preferably at boiling points of the reaction mass, in a medium of organic solvent, such as pyridine, and when R is hydrogen or apkip, and R, is hydrogen, the process is preferably carried out in the presence of hydrogen sulfide; the resulting compound ipi is isolated in free form or as a salt, or if R and R are hydrogen, is subjected to alkylation with an amine

 ,

A 8

where Rf is hydrogen, alkyl, RO is alkyl, when heated, preferably at a temperature of 120 ° C in a sealed vessel, in the middle of an organic solvent, for example alcohol, in the presence of hydrogen sulfide.

It has been established that decomposition to nitrip may occur. jioraa amide, corresponding to the formula 1, in which Rj and RX is hydrogen, is treated with five-grained phosphorus.

Nitrile can either be separated, for example by chromatography, or the mixture can be treated with hydrogen sulfide to convert the nitrile, into a by-product, into the corresponding thioamide.

PRI me R 1. A) 2-phenyl-5,6,7,8-tetrahydroquinoline.

2- (3-Phenip-3-oxopropyl) cyclohexon non is obtained by heating a mixture of P-dimethylaminopropiophenone (27 g) and cyclohexanone (37.5 g) under reflux for 5 hours under a nitrogen atmosphere and the solvent is removed in vacuo. The residual oil is distilled with a yield of 2- (3-phenyl-Zuksopropip) cyclohexanone 14 g, which is cycled to the desired compound by dissolving 12 g of diketone in 65 mp of ethanol, treatment with hydroxylamine hydrochloride (9 g) and refluxing for 1 hour. the reaction mixture was poured into water (30% ml), extracted with ether (2x50 ml) and the extracts discarded. The aqueous solution is alkalinized with extraction with ether (3 × 50 ml). The combined ether extracts were dried and the solvent was removed in vacuo. The residual oil is distilled and the desired compound is obtained as a colorless oil with a yield of 7 g and so on. 134-138 C / 15 mm Hg. Art.

Found,%: C 85.4O; H 7.5; N6.9. .

Calculated,%: C 86.00; H 7.2; N 6.7

c) Methyl-2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.

A solution of 2-phenyl-5,6,7,8-tetrahydroquinoline (2O g) in ether (5O ml) is added dropwise over 30 minutes to a previously prepared ethereal solution of phenyplitis prepared from bromobenzene (40 g) and lithium (2.78 g) in dry ether (160 ml). The reaction mixture is stirred for 1 hour at room temperature and treated with dry carbon dioxide until decolorized. The solvent is removed in vacuo, the residue is dissolved in ethanol (25 O ml), saturated with dry hydrogen chloride, the solid is filtered and crystallized from water to yield 2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylic acid hydrochloride (12 d). The product is dissolved in methanol (20 O ml) and the solution is treated with dry hydrogen chloride at reflux for 4 hours. The solvent is removed in vacuum and the residue is dissolved in water (50 ml), then the solution is alkalinized with 2N sodium hydroxide and extracted with chloroform (3 × 10 ml). The combined extracts are evaporated to dryness and the residue is crystallized from petrolley ether to yield the title compound as colorless needle crystals (I g), mp. 75 ° C.

Found,%: C 76.8; H 6.5; N 5.14.

C 7H 7 Calculated,%: C 76.4; H 6.4; N5,2

J

Approx. 2. 2-phenyl-5,6,7,8-tetrahydroquinolin-8-carboxamide.

Methyl 2-c}) enyl-5,6,7,8-tetrahydroquinoline-8-carboxypate (4 g) is dissolved in methanol, previously saturated with ammonia (90 ml), and heated in a bomb for 4 days. After removal of the solvent in vacuo, an oily solid residue is obtained, after recrystallization of which from ethyl acetate, the desired compound is obtained as colorless needle-like crystals (1.5 g) with m.p. .

Found,%: C 76.4; H 6.5; N11.1.

Calculated,%: C 76.2; H 6.4; N 11.1

Example 3. 2-phenyl-5,6,7,8-tetrahydroquinoline-in-thiocarboxamide.

2-phenyl-5,6,7,8 tetrahydroquinoline-8-carboxamide (8 g) is dissolved in pyridine (2 O ml), treated with five-grained phosphorus (5.2 g) and the mixture is heated with an o6paTHbrkf forage B for 30 min.  The solvent is removed in a vacuum, the residual oil is dissolved in dilute carrier and washed with ether (2 x 5 O mp).  The aqueous solution is alkalinized, extracted with chloroform (3 X 5O ml) and the combined extracts are dried and evaporated to dryness.  The residual maspo is chromatographed on silica gel by washing with chloroform to yield 8 cyano-2-. -C | Yunil-5,6,7,8-etrahydroquinoline 1.2 g in the form of colorless needle-like crystals from ether with t, nn.  .  Found,%: C 82.0; And 6.2; N 11.7.  16 "2 Calculated,%: C 82.0; H 6.0; N 11.9. With further chloroform leaching, 1.1 g of the expected product are obtained in the form of colorless needle-like crystals from ether with m, pl.  154C.  Found,%: C 71.8; H 6.1; N10.2.  C, H ,.  Calculated,%: C 71.6; H 6.0; M 1O, 4 P p and m p 4, N, M-dimethyl-2-phenyl-5, 6,7,8 gtetrahydrohi nolin-8-carboxamnd.  2-Phenyl-5,6,7,8-tetrahydroquinopnn-8-carboxamide (b g) is dissolved in hexamethylphosphoric acid (24 ml) and the solution is heated at 220 ° C for 2 hours.  The cooled reaction mixture was poured into water (50 ml), extracted with chloroform (3 x 1 ml) and the combined extracts were washed with water (3 x 100 ml), dried and evaporated to dryness.  The residual oil is chromatographed on sipicagel by washing with chloroform to yield 2-phenyl-8-cyano-g -5,6,7,8-tetrahydroquinoline 2.5 g, recrystallized from ether as colorless needle-like crystals with m, pl.  10О С.  Upon further leaching with chloroform, 1.1 g of N, N dimethyl L-5,6,7,8-tetrahydroquino LIN-8-K of arboxamide is obtained, which is crystallized from the ether in the form of colorless needle-shaped crystals. t.  Found,,%: C 77.17; H 7.22; N 1O, 2 Calculated,%: C 77.11; H 7.19; N 9.99.  Note 5.  A) 5,6,7 8-tetrahydroquinoline.  5-Oxo-5H-6,7,8-tetrahydroquinolc is obtained by adding propyl aldehyde (16 g) to a solution of 3-amino-cyclohexo-p-oav (31 g) in dimethylformamide (l5O mp) for 5 minutes.  After the termination of the exothermic reaction, the reaction mixture is heated to 1OO C and distilled off under vacuum of 15 mm Hg, Art., Solvent.  The temperature is then raised to 16 ° -17 ° C, the distillate is collected, which is pacTBOpsnoT in diluted HCC (75.  ml) and extracted with ether (2x50 MP) ether and extracts discarded.  The aqueous solution is alkalinized and extracted with ether, (3 × 15 O ml), the combined ether extracts are dried and evaporated in vacuo.  The remaining oil is distilled and 21 g of 5-oxo-5H-6,7,8-tetrahydroquinoline are obtained with t.  kip  133-4 C / 15 mmHg  Art. which is dissolved in diethylene glycol (19 O ml) and treated with gddraznnehydride (14 g) and sodium hydroxide (l4 g).  The reaction mixture is heated to reflux. for 30 minutes and then 3.5 hours in a Dean-Stark water separator.  The cooled reaction mixture is poured onto water (10 ml), extracted with ether (3 x 10 ml) and the combined extracts are dried and evaporated in vacuo.  The residual oil is distilled to give the South of the title compound as a colorless oil with m.  Kip, 10O5715 mm Hg, Art.  c) Methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate. A solution of 5,6,7,8-tetrahydroquinoline (14 g) in dry ether (OO ml) is added dropwise in half an hour to the ether solution. phenyllithium obtained from bromobenzene (42 g) and lithium (3.7 g) with ether (300 ml), and the reaction mixture is stirred at room temperature for another 1 h.  The cooled reaction mixture is saturated with dry carbon dioxide, evaporated in vacuo, the residue is treated with methanol, previously saturated with dry hydrogen chloride (5OOmp), and the solution is heated under reflux for 12 hours.  The solvent is removed in vacuo, and the residue is dissolved. in water (50 ml), extracted with ether (3 × x x 10 ml) and the extracts are discarded.  The aqueous solution is alkalinized and extracted with ether (3 X X OO ml).  The combined ether extracts are dried, evaporated in vacuo, and the residual oil is distilled with a methyl 5,6,7,8-tetragyroquinoline-in-carboxylate c-yield as a colorless oil, 13 g, etc. kip  , O5 mm Hg.  Art.  Hydrochloride is obtained by saturating the ethereal solution with dry hydrogen chloride by crystallization of the solid residue from methanol-ether to yield the desired compound hydrochloride as colorless needle-like crystals with m.  square  173 ° C.  Found,%: C 58.2; H 6.3; N 6.3. NOaCalculated,%: C 58.0; H 6.2; N6,2 EXAMPLE 6.  5,6,7,8-Tetrahydroquinopin-8-carboxamide.  5,6,7,8-Tetrahydroquinolin-8-carboxyl "at (9 g) pacTBopsDOT in methanol, preliminarily saturated with ammonia (270 ml) and heated in a bomb at iOO ° C for 5 days.  The solvent is removed and the residual oil is dissolved in hot petroleum ether at 40-60 ° C. The solid is filtered and crystallized from ethyl acetate and 5 g of the desired product are obtained as colorless needle-like crystals with m.  square  .  Found,%: C 67.7; H 7.1; N16.0.  C. oi N OCalculated,%:. C 68.1; H 6.9; N 15.9 EXAMPLE 7.  5,6,7,8-Tetrahydrokhnnolin-8-thiocarboxamide.  A solution of 5,6,7,8-tetrahydroquinoline-9-carboxamide (1.2 g) in pyridine (15 mp) is treated with phosphorous fuzzy (0.8 g) and the mixture is heated under reflux for 30 minutes.  The solvent is removed in vacuo and the residual oil is treated with 2N.  with caustic soda (5 ml), saturated with solid potash and extracted with chloroform (3 x 50 mp).  The combined extracts are present and the solvent is removed in vacuo.  The residual oil is dissolved in pyridine (4 ml and triethylamine (1 ml), the solution is saturated with hydrogen sulfide (bh) and left overnight. After removing the solvent, a solid residue (850 mg) is obtained, which is crystallized from methanol to give the desired compound as quarter hydrate.  Colorless needle-shaped crystals with t.  square  Found,%: C 59.8; H 6.2; N14.0.  C oH a -V HaO Calculated,%: C 59.6; H 6.4; N 13.9.  PRI me R 8.  A) 2-tert, Butyl-5,6 7,8-tetrahydroquinoline.  .  : 5-Dimethylamide n-2,2-dimethylpentan-3-one hydrochloride (GO g), dissolved in water (bO ml) and using 1C) n. caustic soda set pH 12.0: the solution is extracted with ether (3x50 ml).  The combined ether extracts are dried, evaporated in vacuo to / the residual oil is dissolved in cyclohexanone (30 ml).  The mixture is boiled for 2 hours.  The solvent is removed in vacuo and the residual oil is dissolved in ether (iQO mp).  The ethereal solution is washed with diluted HC6 (G X 20 ml) and discarded.  The aqueous solution is alkalinized 2n.  caustic soda and extracted with ether (W x 50 ml); the combined extracts are dried and evaporated in vacuo.  The residual oil is distilled and the title compound is obtained as a colorless oil with m.  kip   mm Hg  Art. (yield 47 g, 67%).  c) 2-thirds  Butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide.  Methyl 2-tert.  butyl 5,6,7,8-tetrahydroquinoline-8-carboxylate is prepared from 2-tert.  butyl-5,6,7,8-tetrahydroquinoline (18.9 g O, 1 mm) and phenyl lithium (O, 1 m) using the general method described in example 1 B, and isolated as a pale yellow oil (9 g) .  kip  106 C /.  / 0.4 mmHg  Art.  The desired compound is obtained from methyl 2-tert.  butyl 5,6,7,8-tetrahydroquinols 1-8 carboxylate (8 g) according to the general method described in example 2, and isolated as colorless needle-like crystals (W g) after crystallization from hexane, m.  square  131 ° C  Found,%: С 72, О; H 8.71; N11.62.  C, H, N, 0, Calculated,%: C 72.38; H 8.68; N 12.06.  PRI me R 9.  2-thirds  butyl 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide.  The desired compound is obtained from 2-tert.  butyl-5,6,7,8-tetrahydroquinoline-8-carboxamnd (4 g) and p-sulphate phosphorus (W g), as described in example 7.  and isolated as cream needle-like crystals after recrystallization from hexane, t.  square   (650 mg).  Found,%: C 68.18; H 8.25; li, 14.  C “2oNiS, Calculated,%: C, 67.7; H 8.12; N 11.23.  Example 10  5,6,7,8-Tetrahydroquinoline.  3-methoxyacrolein is obtained from 1D, 3, d-tetramethoxypropane and converted to 3-amino-acrolein.  5,6,7,8-Tetrahydroquinolone derived from 3-amino-acrolein.  A mixture of 3-amino-acrolein (7.3 g O, 1 mop and aiclohexanone (12 g, 0.12 mol) is treated with triethylamine (5 ml) and piperidine acetic acid (0.1 g), after which it is heated in an oil bath for 24 h at.  The cooled reaction mixture was dissolved in ether (10 O ml), washed with water and 2N.  Hydrochloric acid (2 X X 20 MP), acidic water, HsnoT, are alkalized with sodium carbonate and extracted with ether.  The combined extracts are dried, the evaporated p residue is distilled and 4.5 g (35%) of the title compound are obtained as a pale yellow oil (4.5 g, 35%) with t.  kil.   / 15 mmHg  Art.  Example 11.  2-Methyl-5,6,7,8-those rag idrohinol ign.  4-Diethylaminopropanedione, derived from acetone and diethylamine, is reacted with cyclohexanone to form 2- (3-methyl-3-oxopropyl) nicolexanone as a colorless oil with m. kip  15O / 2O mm Hg  Art.  The target compound is obtained from 2- (3 -methyl-3-oxopropyl) cyclohexanone by the general method described in examples 1 and 8 A, and is isolated as a colorless oil with m.  kip  I6-2O / 18 mmHg  Art.  (yield 60%).    Example 12 2-type-5,6,7,8-tet rahidrokhinolin-8-carboxamide.  The reaction of 2-methyl-5,6,7,8-tetrahydro, quinoline with phenyl lithium and carbon dioxide followed by esterification by the method of examples 1B and 5B gives an inseparable mixture of methyl 2-methyl-5,6,7,8- tetra hydroquinoline-B-carboxylate to methyl 5, 6,7,8-tetrahyroquinna-2-acetate, which is converted without purification into a mixture of 2-methyl-5,6,7,8-tetrahydrochi no lino-8-boxamide and 5,6,7,8-tetrahydroquinolin-2-ylutamide by reaction with ammonia according to the method of example 2.  By fractional crystallization from diisopropyl ether, the title compound is obtained as colorless needle-like crystals with m.  square   (total yield of 30%).  Found,%: G 69.31; H 7.45} N14.7 ,, 0.  Incl.%: C 68.45; H 7.42; N 14. 72.  Example 13  2-Methyl-5,6,7,8-tet rahidrokhinolin-8-thiocarboxamide.  2-Metip-5,6,7,8-tetrahydroquinoline-8-carboxamide is treated with five p-phosphorus to obtain 2-methyl-8-cyano-5, 6,7,8-tetrahydroquinoline, which is treated with hydrogen sulfide (both reactions are conducted / pcs according to the method described in example 7).  Obtain the desired compound after 1-distillation from ethyl acetate as colorless needle-like crystals (28%), t.  square  .  Found,%: C 64.04; H 6.93; N 13.52.  . .  Calculated,%: C 64.01; H 6.84; N 13.58.  Example 14  3-Methyl-5,6,7, in-trag cd rokhino l and N.  The desired compound is obtained from Z-amine-2-methylacrolein and cyclohexlnone and isolated in the very same oil with t.  kip  12O / 15 mmHg, Art.  yield 30%.  Example 15  Methyl-3-methyl-5, 6,7,8-tetrahydroquinolin-8-carboxy lat.  The title compound is prepared from 3-mbuty-5, 6,7,8 tetrahydroquinoline as described in Example 1B and baked as a pale yellow oil with m.  kip  25 mmHg  Art.  yield 8O%.  The hydrochloride is prepared in the usual way (cf. Example 5B) and crystallized as colorless needle-like crystals from ethanol: Fir and t.  square  14 C.  Found,%: C 59.9; H 6.7; N 6, Oh.  C 2 W 92- C Calculated,%: C 59.6; H 6.7; N 5, and Example 16.  3-Methyl-5,6,7,8 etrahydrohgyaln-8-carboxamide.  The desired compound is obtained from methyl 3-metip-5, 6, 7, 8-tetramhehydroquinoline-8 carboxylate according to the method described in reamer 2, and is obtained after recrystallization from hexane in the form of colorless gloomy crystals with m. square  Ц8 ° С, output of ОО%.  Found,%: C 69.60; H 7.5; N 14.8.  ". .  Calculated,%; C, 69.5; H 7.4; N 14.7.  P n. m r 17.  3-Methyl-5,6,7,8-teTagidrokhinolin-8-thiocarboxamide.  3-Methyl-5,6,7,8-tetra-agidroquino l in-8 carboxamide is treated with five-nosphoric osphor to obtain 3-methyl-8-cyan5, 6,7,8-tetrahydroquinoline, which is coated with hydrogen sulfide, as described in romer 7, and get the target compound after recrystallization from benzene to idel colorless needle-like crystals t.  square  151 ° С, yield 5О%.   Found,%: C 63.71; H 6.85; N 13.38.  С Н N SCalculated,%: С 64.04; H 6.84; N13.58.  Hydrochloride is obtained by dissolving the spruce compound in the minimum amount of isopropane and adding ether, on | Я5 | schwnnnogo dry hydrogen chloride, Gndrochloride precipitates in the form of bestoeTHbix syngates crystals, t.  pp  .  Found,%: C 54.33; And 6.23; N 11.42.   it with 54.42; H 6.23; Calculated N 11. 54.  Example 18, metip-3-methyl-5,6, 7,8-tetrahydroquinoline-8-carboxylate.  E-Butyl bromide {285 ml) in dry ether (50 O ml) is added to a clean drink wire (42 g, 6 moles in dry ether (11 ml) under nitrogen atmosphere at such a rate that the internal temperature is kept at -15 ° C.  After the addition is complete, the reaction mixture is stirred until the temperature increases to (approximately 2 hours).  Concentrated butyl lithium is calculated using standardization against O, 1H.  hydrochloric acid and set the amount of 3-methyl-5,6, 7,8-tetrahydroquinoline, necessary in the next stage, with excess of 1-, 2 mol of butyl lithium.  A stirred solution of 3-methyl-5,6 7,8-tetrahydroquinoline (147 g, 1 mol) and dry ether (7OO ml) is treated with a freshly prepared solution of butyl lithium (86 O ml, 1.4 m solution, t. e, 1.2 m) B nitrogen atmosphere.  The reaction mixture is stirred for 15 minutes and then slowly, dry carbon dioxide is passed through the reaction mixture until decolorization.  The reaction mixture is diluted with 1.2 L of water, filtered, the aqueous phase is separated and extracted with ether (3 x X 500 ml).  The combined ethereal extracts are treated to obtain reconstituted 3-fly-5,6,7,8-tetrahydroquinopine (40 g), t, kip, 116–20 ° / 15 mm Hg, st.  The aqueous phase is evaporated to dryness, the solid residue is treated with a solution of methanol, sat. dry hydrogen chloride (1.5 liters) and left at room temperature for 12 hours.  The volatile fractions are removed in vacuo.  The residual oil is redissolved in 1 l of water, extracted with ether (3 X 250 ml) and the extracts are discarded.  The aqueous solution is adjusted to pH 9.0 with soda and extracted with ether (4 X 25 O ml). The combined extracts are dried and the solvent is removed in vacuo.  Obtain the target median in the form of a pedro-yellow mask (85 g, 42%).  Example 19  Methyl-3-metip-5, 6,7,8-tetrahydroquinoline-8-carboxylate.  C-Metip-5,6,7,8 etrahydroquinoline (5 g, O, O34 mol) in dry ether (5 O ml) is treated in portions with a solution of a bottle of hexane (0, O4 mop) under nitrogen atmosphere and the mixture is left at room temperature temperature for 30 minutes  A slow stream of carbon dioxide is then passed through the mixture until it becomes discolored.  A further 0.02 mole of butylply in hexane solution is added.  The mixture is allowed to stand for 30 minutes and then treated with dry carbon dioxide, as described.  The reaction mixture is diluted with water (20 ml) and the aqueous phase is extracted with ether (.  OO ml) and the combined extracts were allowed to recover unreacted 3-methyl-5, 6,7,8-tetrahydroquinoline.  The aqueous phase is evaporated in vacuo to dryness.  The solid residue is treated with methanol, previously saturated with dry hydrogen chloride (50 ml), and left at room temperature for 3 hours, the Solvent is removed and the residual oil is dissolved in water (2 O ml), extracted with ether (3 X 25 ml) and extracts cast away.  The aqueous phase is adjusted to pH 9.0 with soda, extracted with ether (3 X 5O ml).  The combined extracts are dried and evaporated in vacuo to yield the title compound as an endowed oil, 4.3 g (BO%).  PRI me R 2O, 3-Methyl-5,6,7,8-tetrahydroquino l-8-carbox MID.  A mixture of methyl 3-methyl-5,6,7, & tetra-1 hydro-quinoline-8-carboxylate (25 g,. 0.13 mol), formamide (11.6 g, O, 26 mol) and sodium methoxide (out of 2.99 g, 0.13 mol) are heated with stirring in an oil bath for 1 hour.  Next, the reaction mixture is heated at a temperature of 1OO ° C for 3 h at a pressure of 15 mm Hg.  Art.  The cooled reaction mixture is diluted with 2N acid for an acidic solution, which is extracted with an ethyl atom (2 x 50 ml) and the combined extracts are discarded.  With the help of solid soda in an aqueous solution, the pH is adjusted to 9.0, the thief pacTv is saturated with sodium chloride and extracted with chloroform (3 X 1OO ppm). The combined extracts are dried and evaporated and a pale yellow oil is obtained, which. hardens when rubbed with hexane.  Crystallization of ethyl acetate gives the desired compound in the form of colorless cubic crystals (18.6 g, 88% t.  square  11 о с.  Found,%: C 69.6; H 7.4; N 14.1.  C H, Calculated,%: C 69.5; H 7.4; N14.7 Example21.  3-Methyl-5,6,7,8-those rahidrohinolin-8-carboxamide.  A mixture of metip-3-methyl-5,6,7,8-tetrahydroquinol-8-carboxylate (25 g, 0.13 mol), formamide (ll, 6 g, 0.26 mol) and sodium methoxide (2.99 g , 0.13 mol of sodium) is heated on a steam bath by passing nitrogen through the mixture for 1 hour to blow off the methyl formate resulting in the reaction.  The cooled reaction mixture is diluted with 2N hydrochloric acid, treated as indicated in Example 2O, and the desired product is obtained in a yield of 90%, Example 18.  3-Methyl-5,6,7,8-te ragi / foquinoline-8-thiocarboxamide.  A solution of 3-methyl-5,6,7,8-tetragndroquinoline-8-carboxamide (27 g, O, 14 mol) in dry pyridine (ZOO ml, saturated with hydrogen sulfide, is treated with sodium phosphorus (26 g, About 14 mol) and heated under reflux for 45 minutes with slow prolusion through a mixture of hydrogen sulfide.  The reaction mixture is evaporated in vacuo to dry, cooled to, basified with a 1O% sodium hydroxide solution, and the solution is extracted with chloroform (3 x 10 ml).  The combined extracts are washed with brine, dried and evaporated in vacuo. The residual pacTBOpsooT oil in benzene and the solid residue is filtered and crystallized from benzene to give the desired compound as pale yellow needle-like crystals with m, pl.   (21, 8 g, 87%).  Hydrochloride was prepared in the same manner as described in Example 17, and isolated as colorless needle-like crystals with m.  square  219 C, Example 23, Methyl-3-methyl-5,6 7,8-tetrahydroquinolin-8- “ar6oxylate, 3-ethyl-5,6,7,8-tetrahydroquinoline {45 g, 0.29 mo l) and ether (4OO ml).  With stirring, a solution of phenyl lithium (ZZO ml of a 1 M solution in ether) is added at a rate that ensures low boiling, which is maintained for 2 hours.  The mixture is cooled in an ice bath and carbon dioxide is passed through the solution until the reaction stops.  Water (70 ml) is added to dissolve the solid.  The aqueous phase is separated, washed with ether (3 times / and evaporated to dryness in a vacuum. 1 L of a saturated solution of hydrogen chloride in methanol is added to the residue and left at room temperature overnight.  It is evaporated in vacuo to dryness and the residue is dissolved in water.  The aqueous solution is extracted with ether (3 times), alkalinized with solid sodium carbonate and extracted with ether.  The residue is a heavy white solid, but this does not interfere; extraction.  The ether phase is washed with water, then with brine, it is dissolved and evaporated.  Yield 25 g (44%).  Example 24, Methyl-3-methyl-5, e, 7,8-tetrahydroquinoline-8-carboxylate.  A solution of 15% n-butyl lithium in hexane (51 ml, about 0.12 mol) is added in portions to a solution of 3-methyl-5,6,7, B-tetrahydroquinoline (i4.7 g, O, 1 mol) in ether (10 ml) and the mixture is allowed to stand at room temperature for 1 h. Then added dropwise to a cooled displaced solution of methyl chloroformate (9.45 g, O, 1 mol) in ether (100 ml). stirred for 1 h at which point, then diluted with water (2 ml) and then treated with 2 and hydrochloric acid until the solution turned acidic.  The ether solution is separated and washed with 2N hydrochloric acid (2 x X 25 ml).  The combined aqueous phases are extracted with ether and the ether extracts are discarded. The aqueous solution is adjusted to pH 9.0 with soda and extracted with chloroform (3 x 5 ml), and the combined extracts are dried and evaporated with a yield of pale yellow oil (16 g), which according to GC - mixture unreacted tetrahydroquinoline (45%), the desired compound (23%) and 8,8-dicarboxyl ether (2%).  The mixture is treated with a 1O% sodium hydroxide solution (75 ml) and heated under reflux with stirring for 4 hours.  Cool and extract with ether (3 X 5O ml).  The combined ether extracts are dried, evaporated and the unreacted 3-methyl is distilled off: - - 5,6,7,8-tetrahydroquinopine (7 g) at boiling point in mm Hg.  Art.  With concentrated hydrochloric acid, the basic solution was adjusted to pH 8.5-9.0, precipitated (dried to dryness, the residue was treated with meganol saturated with dry hydrogen chloride (5 O ml), and left at room temperature for 5 hours.  The solvent was removed, the residue was dissolved in water (2 O ml) and extracted with ether (2 x 50 ml).  Using soda, the aqueous solution is adjusted to pH 9.0 and extracted with chloroform (3 × 25 ml) and the combined extracts dried and evaporated.  Get the target connection with the release of 3 hours  Example 25  3-Metip-5,6,7,8 tetrahydroquinopnn-8-hyocarboxeswitching.  Crystalline form A, Y-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (1 g), prepared as described in example 17, is dissolved in boiling isopropyl alcohol (25 ml), filtered and cooled to 4 ° C, An excess ethereal solution of hydrogen chloride is added, and then an ether in an amount sufficient to cloud the reaction mixture. After cooling, the desired compound is isolated in the form of fine colorless needle-like crystals (o, 95 g) with m, pl.  Found:% C 54.3j H 6.2; N 11.4.  H ,, Calculated ,,%: C 54.4; H 6.2; N 11.5 Infrared spectrum V jf ZZOO (lateral), 3230 (wide), ZO6O (wide), 2540 (wide), 1650 (bright), 16O5, 1555 This IR spectrum is identical to the spectrum of the product obtained according to example 18, Crystal Form B (l) 3 -Methi L-5,6,7,8-teGragidrokhinolin-8-thiocarboxamide (1 g) obtained in Example 17 is dissolved in boiling isopropyl alcohol (15 ml) and a slight excess of ethereal solution is added hydrogen chloride without cooling.  The desired compound is obtained in the form of thin colorless needle-like crystals (950 mg) with t, pl.  Found:% C 54.58; H 6.29; N 11.34.  .  Calculated,%: C 54.42; H 6.23; N 11.54.

The crystalline form B (fi) 3-metip-, 6,7,8-tetrahydroquinopin-8-thiocarboxamide (0.5 g) is dissolved in

but"

ml /, is treated with methanol, saturated with hydrogen chloride (l mp), and the solution is heated to boiling. Then, simultaneously with evaporation of methane, ethyl ethyl acetate is added until dimmed. After cooling, the desired compound is isolated in the form of colorless needle-like crystals (0.4 g) with mp, 6

- ("

.

Calculated,%: C 69.5OJ H 7.40; "14,70,„ ",

Infrared spectrum V at „ak 3395, 328O, 3185, 1680 (bright), 1605.1595 1560, 900 (bright), 575 (bright)

Claims (1)

The crystalline forms A and B can be transformed one into the other with a non-recrystallization using suitable solvents. So, during the crystallization of form A from ethnyl acetate, the form B is obtained, and during the crystallization of form B from di-nopropyl ether, form A is obtained, 516 Found: C 54.11} H H 6.18; N 11.31. C f N S-HCe Calculated,%: C 54.42; H 6.23; N 11.54. Crystalline form A cannot be converted into crystalline form B by crystallization from isopropyl alcohol, ether, methanol or ethyl acetate; Ostalein for 2-3 days crystalline form A is converted into form B, Form A can also be converted into form B by heating at for 6 h in vacuum. Example 26. 3-metip-5,6,7,8-tetrahydroquinoline-8-carboxamide. Crystalline form A, 3-Methyl-5,6,7,8-tetrahydroquino lin-8-carboxamide (l g) prepared in Example 16 is dissolved in boiling diisopropyl ether (80 ml) filter |: coziness and left cool down The coeminant that is separated out is isolated in the form of colorless 1 biic crystals (O, 85 g) with m, pl. Found:% C 69.6 j H 7.5; N 14.8, C H,. Calculated,%: C 69.5; H 7.4; N 14.7, Infrared spectrum V 3395, 3195, 1650 (bright), 162O, 16O5 (lateral), 1595, 156O, 1235, 875 (bright), 62O (RCA) see The IR spectrum is identical to that of Example 16, Crystalline Form B, 3-Metip-5,6,7,8-tetrahydroquinoline-8-carboxamide (l g), prepared as described in Example 16, was dissolved in boiling ethyl acetate ( 2 ml), filtered and allowed to cool. The desired compound is isolated in the form of colorless rhombic crystals (O, 8O g) with m.p. , Nayeno,%: C 68.81; H 7.40; N 14.45. Example 27. 3-Metip-5,6,7,8-tet rahidrokhinolin-8- (N-metnl) -thiocarboxamide. Metip-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamnd (5 g) is dissolved in 33% methylamine in ethanopa (so MP) and the solution is heated at 15 ° C for 24 hours in a bomb from of stainless steel. The solvent is removed under vacuum and the residual solution is left to crystallize. Crystallization from 2-propanol-N-hexane gives 3-methyl-5,6,7,8-tetrahydroquinolin-8- (N-methyl) carboxamide in the form of colorless needle-like crystals (4 g, 85%). Hydrochloride is obtained by treating the main solution in ethanol with ether, saturated with hydrogen chloride, and isolated as colorless needle-like crystals with m.p. 185 C. Found,%: C 59.81; H 7.11; N 11.34 C, 2 i6 20-HCt. Calculated,%: C 59.87; H 7.12; N 11.64. A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8- (N -methyl) -carboxamnd (1.2 g) in pyridine (9 ml) is treated with pentaaceous phosphorus (1.2 g) and the mixture The mixture is heated under reflux for 3 hours. The solvent is evaporated in a vacuum and the residue is treated with a 1O% aqueous solution of caustic soda until it is alkaline. The solution is extracted with chloroformum (Zx50kt), the combined extracts are washed with aqueous brine (2 x X 20 ml), dried and brewed. The solid oily residue is crystallized from benzene, and the desired compound is obtained in the form of colorless needle-like crystals (0.9 g 65%) with m.p. Found,%: C 65,12; H 7.26; N 12.56. 42 16 Calculated,%: C 65.41; H 7.32; N 12.72. Example 28. 3-Methyl-5.6,7,8-those rahidrohinolin-8- (N, N-dimethyl) thiocarboxamide, 3-Methyl-5,6,7,8-tetrahydroquinolin-8-thiocarboxamide (l g) solution 33% dimethylamine in ethanol (50 ml) and the mixture is heated to 6oivf6e stainless steel for 3 days. The volatile products are removed in vacuo and the solid residue is crystallized from ethyl acetate. Obtain the target compound in the form of a pedoidal yellow needle-like crystals (0.5 g 44%) with T. pl. . Found,%: C 66.5; H 7.82; N 11.75. C, H ,. Calculated,%; C, 66.62; H 7.74; N 11.95. PRI me R 29 Simm. Octahydroacridnn-4-thiocarboxamide. Simm octahydroacridine is obtained by converting cyclohexanone to di- (2-oxocyclohex-1-yl) methane and then reacting it with hydroxylamine. It is isolated as a colorless oil with m.p. 11О-115 С / О, 5 mm Hg. Art. with a total yield of 4O%. Solution SIMM. Octagydroacrcdine (5 g, O, O26 mol) in dry ether (30 ml) is treated dropwise with a solution of butyl lithium in hexane (I ml, O, O26 mol) and the mixture is stirred at room temperature for 15 minutes under a nitrogen atmosphere . Nitrogen is replaced by carbon dioxide, which is passed through the reaction mixture until it becomes discolored. The reaction mixture is diluted with water (50 ml), the organic layer is separated, and the aqueous phase is extracted with ether (2 x 5 Om). The combined extracts are left to recover SIMM. octahydroacridine. The aqueous phase is evaporated to dryness, the residue is treated with methanol, previously saturated with dry HCl (5 O ml), and the solution is left in a vacuum; the residue is diluted with water (2Q m) and extraction |: that with ether. The aqueous phase is adjusted to pH 1O with soda and extracted with ether (3 x 2O ml). The combined extracts are washed with brine, dried, evaporated, and 1 g (15%) of metip-syroct oacacidine-4-carboxylate is obtained. A solution of methyl-mm-octagidro-acridine 4-carboxylate (5 g) in methanol, pre-loaded with ammonia (80 m), is heated in a stainless steel bomb for 3 days at 140. The solvent is removed and the solid octate is crystallized from diisopropyl ether with SIMM. octahydroacridine-4-carboxamide in the form of colorless needle-like crystals (2.6 g, 57%) with m. 15 9 C. Found,%: C 72.98; H 8, O4; N 12.01. . Calculated,%: C 73, O1; H 7.88; N 12.17. Solution SIMM. Octahydroacridine-4-boxamide (1.8 g) in pyridine (17 mp) is treated with hydrogen sulfide for 5 minutes. The reaction mixture is treated with n-grained phosphorus (1.4 g) and heated under reflux for 45 minutes while passing a mediated current of hydrogen sulfide through the mixture. The cooled reaction mixture is evaporated, the residue is treated with 10% solution of sodium hydroxide. The aqueous solution is extracted with chloroform (3 × 50 ml), the combined extracts are washed with brine, dried, evaporated and the solid residue is crystallized from diisopropyl ether. Obtain the target compound in the form of a fine yellow powder (O, 3 g, 16%) with m. Pl. 104-b C (solidifies and re-melts. Melts at), Found,%: C 68.69; H 7.54; N 1O 98. c.nife Calculated,%: C 68.26; H 7.36; N 11.37. Zo example. 3-Methyl-5,6,7,8-tet rahidroh sharn-8-thiocarboxamidoxapate. To a solution of 3-methyl-5,6,7,8-tetrahyd roquinoline-8-thiocarboxamide (l g) in a hot ethapope (10 ml) is added a solution of digvdrata-shavely acid (65O mg in hot ethanol (6.6 mp) The solution is filtered and allowed to cool to form an oxalate. The oxalate is filtered off, washed with ether and dried. Yield 1 g T. 186-188PC, Found,%: C 52.71; H 5.63; N 9,19.C "H bM504Vychispeno,%: C 52.7O; H 5.44; N 9.46. Example i31. H-Methyl-5,6,7,8-tetrahydroquinolin-8-thiocarboxamide tartar. To a solution of 3-methyl-5 , 6,7,8-roquinoline-8-thiocarboxamide tetrahydride (13 g) in hot isopropyl alcohol (130 ml) to Add a solution of 9.5 g of tartaric acid in hot isopropyl alcohol (5 ml). The solution is filtered and allowed to cool. The precipitated crystals of terrate can be filtered off, washed with a small amount of cold isopropyl alcohol and dried. 158-.16О ° С. Found,%: C 50.56; H 5.67; N 7.90. C, H, LOB. Calculated,%: C 50.55; H 5.65; H 7 , 66. Example 32. Methyl-3-methyliyl-gloptane (b) -pyridn-9-carboxylate. 3-Methyl-cylesloheptan (t) pyridine is obtained from cyclopentanone and 3-amine-3-methylacropein by the method described for the synthesis of 5,6,7,8-tetrahydroquinoline (Example 10), and is isolated as a colorless mask with Kip, mm Hg. Art. A 15% solution of butyl lithium in hexane (16 ml, about 0.04 mol) is added in portions to a solution of 3-methylcycloheptane (b) pyridine (5 g, 0, 03 m) in ether (50 ml) under a nitrogen atmosphere and the mixture is allowed to stand for 30 minutes at room temperature. The mixture is treated with carbon dioxide until the red color disappears and the solvent is removed in vacuo. The residue was dissolved in water (25 ml) and extracted with ether (3 × 5 ml). The aqueous solution is evaporated in vacuo and the residue is treated with methanol, saturated with hydrogen chloride (10 ml), and left with iOT at room temperature for 12 hours. The solvent is removed and the residual may be dissolved in water (5O ml) and extracted with ether ( Zx5O ml). The aqueous pacTV boron is adjusted to pH 9.0 with the addition of sodium carbonate and extracted with ether (3 × 50 ml). The combined extracts are dried, evaporated in vacuo to give the title compound as a bpedio-yellow oil (0.8 g, 11%). Example GC Methyl-3-meticycclopentene (b) pyridine-7-carboxylate. 3-Methylcyclopentene (b) pyridine is obtained as a colorless oil with m.p. 100-105 ° C / 15 mmHg Art. A solution of 3-methylcyclopentene (fe) pyridine (Yu g, 0.07 8 mol) in ether (l5O ml) is treated with a 15% solution of Nbutyl lithium in hexane (ZO mp, about 0.08 mol / s and the mixture is treated with carbon dioxide. Lithium 3-Methyl-sol-cyclopentene (t)) pyridine-8-carboxylic acid salt Isolate and is authenticated with methanol, a-. Oxygenated hydrochloride, as described for methyl 3-m-type 1 penthene (t)) liridine-9-carboxypate (Example 32), The title compound is isolated in the form of a brilliant yellow oil (1, 1 g, 10%). Example 34 Methl-3,7,7-trimethyl-5 J 6,7,8-tetrahydroquinopin-8-arboxylate, 3,7,7-Trimethyl-5,6,7,8-tetrahydroquinoline- (17.5 g 0.1 mol) is dissolved in dry ether (2OO ml) and treated with a solution of H-utilize in hexane (15% solution, 56 mp) under nitrogen atmosphere. The reaction mixture is allowed to stand at KOf at a natal temperature for 30 minutes, then it is treated with carbon dioxide until the intense red color disappears. The solvent is removed, the solid oily residue pacTBOpsnoT in water (20 ml) and then extracted with ether (3 x 50 ml). The ether extracts are left to regenerate unreacted starting material. The aqueous solution is evaporated to dryness, the residue is treated with methanol, saturated with dry hydrogen chloride (1OO mp), and the solution is allowed to stand at room temperature for 8 hours. The solvent is removed and the residual oil is dissolved in water (.50 ml) , extracted with ether (3 × 50 ml) and the extracts discarded. The aqueous solution is adjusted to pH 9.0 with sodium carbonate and extracted with ether (3x50). The combined extracts are dried, evaporated in vacuo to give the title compound as a pale yellow maspa (1.8 g, 10%). The picrate of the title compound is obtained by dissolving the free base (C02) in ethanol (1 ml) and adding a saturated solution of picric acid in ethanol (5 ml) and allowing the mixture to crystallize. The picrate is filtered off, dissolved in a minimum volume of ethanol. And precipitated with ether. Get yellow needle-shaped crystals with m. PL. 95-97 ° C Found,%: C 5O, 2; H 4.7; N12.1. C H, N O Privet 3,4. Calculated,%: C 50.5; H 5.0; N 11.8. Example 35. 3-Methyl- 5,6,7,8. Rahydroquinoline-8-carboxylic acid. Methyl 5,6,7,8-tetrahydroquinoline 8-carboxylate (5 g) is treated with 10% sodium hydroxide (4 O ml) and heated under reflux for 1.5 h. The cooled reaction mixture is extracted with ether and the aqueous layer. to pH 7 with acetic acid, filtered and evaporated to dryness under reduced pressure. The residue is triturated with benzene. The benzene solution is filtered and evaporated under reduced pressure, and the residue is triturated with ether to yield the desired compound sodium salt as a white powder, 1.8 g. Found,%: C b.O; H 5.6; N 6.4. 1 / 2H, 0. Calculated,%: C 59.6; H 5.8; N 6.4. Another 1.4 g of sodium salt is obtained by further extraction of the insoluble in benzene product. Example Pi 36. 3-Methyl-5,6,7,8 tetrahydroch (Scholin-8- (N-n-butyl) -thiocar "boxamide. Following the general procedure of Example 27, methyl-3-methyl-5 6 , 7,8-tetrahydroquinoline-8-carboxylate is treated with n-butyl-amine to obtain 3-methyl-5,6,7,8-tetrahydroquinoline-8- (m-n-butyl) to boxamide, which is treated with a five-grained phosphorus in pyridine n gives the desired compound as a yellow oil. The oil is dissolved in an excess of ether, watches cervical with hydrogen chloride. The resulting solid is crystallized from isopropanol to obtain the hydrochloride of the target compound as colorless needle-like crystals with mp (decomposes). Example 37, 4 Methyl-5,, 8-tetragon idrohi 1l l-8-thio carboxides, According to the procedure of examples 19.2O and 22 4-methyl-5, 6,7,8-tetrahydroquinoline is converted into the hydrochloride of the target compound, in the form of colorless needle-like crystals with a melting point Example 38. 3,7,7-Trimethyl-5 6, 7,8-tetrahydroquinolin-thiocarboxamide. 3,7,7-trnmethyl-5, 6,7,8-tetrahydroquinoline-8-carboxylate, prepared as described in example 34, is converted to 8-carboxamide. The product is treated with phosphorous phosphorus and hydrogen sulfide in pyridine according to Example 22 and the desired compound is obtained, which is converted to the hydrochloride salt. Hydrochloride is crystallized from isopropinol and get 1,1,4-hydrate with so pl. . Example 39: 1,2,3,5,6,7-Guxaxhydro-dicyclopenta (t), e) pyridine-3-thiocarboxamide hydrochloride. A mixture of 2-GCA-dimethylaminomethyl) cyclopentanone (87 g) and cyclopentanone (210 g) is heated under reflux for 12 hours. The excess cyclopenanone is removed by distillation, the residue is dissolved in ethanol (30 ml), treated with hydroxylamine hydrochloride (SO d) and the mixture is heated under reflux for 1.5 hours, the reaction mixture is dissolved in water (1 l), washed with ether (3 × 2 ml), the aqueous phase is adjusted to pH 1O, O with sodium carbonate and extracted with ether (3). X 2OO ml). The combined extract is dried and the solvent is removed. An oil is obtained which is distilled at O, 2 mmHg. Art. with BtoioaoM 1,2,3,5,6,7-hexahydrodidiclopent (b, e,) pyridine in the form of a single masse (5Og) with t, kip. , Pyridine is converted to methyl 3-carboxypate by the method of example 18, the carboxylate is converted to 1,2,3,5,6,7-hexahydrodicyclopenta (t) e,) pyridine-3-carboxamide by the method of example 17, carboxamide is isolated into as colorless needle-like crystals of methanop. T. pl. 188 ° C. Found,%: C 71.1; H 7.2; N 14.3. C “H ,, N., 0. Calculated,%: C 71.3; H 7.0; N13.9 Caoboxamide is converted (1.9 g) to thio amide according to Example 22 and isolated into a pale yellow solid, which is converted to hydrochloride by treatment of a solution of a base (BOO mg) in methanol (b ml) with excess ether hydrogen chloride. . The resulting solid is crystallized from methanol; ether and get the target compound in the form of colorless needle-shaped crystals with so pl. 2990s, Found,%: С 56,4; H 6.1; N 10.8. 42 H N S-HCe Calculated,%: C 56.6; H 5.9; N 11.0 EXAMPLE 4O. 1,2,3,4,5,7,8,9,10, 1-decahydrodicyclichepta (1h, e) pyridine-5, thiocarbox midhydrochloride. A mixture of shkloheptan (190 g) and 2- (ot-dimethylaminomethyl) -cycloheptane (72 g) HarpeBiMOT at 17 for 12 hours. The excess cycloheptanone is removed, the residue is dissolved in ethanol (ZOO ml), treated with hydroxylamine hydrochloride (JO g) and the mixture is heated under reflux for 2 h. Cool, dilute with water (1 L) and extract with ether (3 x ZOO ml). The aqueous phase is adjusted to pH 1 with sodium carbonate and extracted with ether (3 × 250 ml); the combined extracts are dried, the solvent is removed and an oil is obtained which is distilled at 0.2 mm Hg. Art. Get 1,2,3,4,5,7,8,9,10,11-decahydrodicyclichepta- (1), e) -pyridine (ZO g) with so Kip, which is converted into methyl 5-carboxylate for example i, the carne boxyl is treated with methanol, saturated with ammonia, for 1.2, 3,4.5,7,8,9, lp, l 1-decahydrodicy cloghepta- (b, e) -pyridine-5-carboxamide as colorless needle-like crystals (l, 5r with m. pl. 179C. Found,%: C 74.5; H 8.7; NlO, 7. I “22 20Calculated,%: C 74.4; H 8.6; N10.9 Amide (1.3 g) is converted to thioamide according to example 22, the product cristaplut from isopropanol and get the target compound in the form of a hemihydrate with T. pl. 8 (jt, Found,%: 60.2; H 7.5; N8, 3. C- iuH jN-jS-Hce-i / a. Calculated,%: C, 60.1; H, 7.6; 148.7. Example 41. 3-Methyl-cyclopenteno (b) pyridine-7-thiocarboxamide. The methylcarboxylate of Example 33 is treated with methanol, saturated with ammonia gas, as described in Example 16, to obtain 3-methylcyclopentane (b) liridine-7-carboxamide with a melting point of 159 ° C. The latter is converted into the desired compound by total N-ieTOAy described in example 22, Claim 1, Method for producing pyridine derivatives of the general formula R. Wherein RR s are the same or different and represent hydrogen, trifluoromethyl, alk "l, aralkyl or ari l, of which carbon dioxide can be substituted by alkyl, alkoxet {uppa, halogen, nitrgroup or trifluoromethyl, or R. i. together they are unbranched alkylene, with the restraint of 3-5 carbon atoms; R is one or more substituents which are hydrogen, alkyl, aralkyl or eryl, and when R and Rg together are unbranched alkylene, the resulting ring can also be substituted by one or more radicals Rj and R are the same or different and are hydrogen, alkyl, aralkip or aryl, any of which can be replaced by an alkyl, alkoxy, halogen, nitro or trifluormethyl; W 1,2 or 3; . . or their salts, characterized in that the amide of the general formula P H RCONR R K H YT1 have R., R. where ix, yyyy, pd, rm,, mutually indicated values are exposed to five-grained phosphorus when heated and organic solvent medium, for example 1-yridine, the compound produced by it, or excreted in free form, either as a soya, or, if RE 4 is hydrogen, is subjected to alkylation with an amine of the general formula where is hydrogen, alkyl, Rg-alkyl, when heated in an organic solvent e.g. alcohol, in the presence of hydrogen sulfide. 6 526 2, the method according to claim 1, wherein the interaction with sulfurous phosphorus is carried out in the presence of hydrogen sulfide, in the case of RJ, hydrogen or alkyl, and Cd is hydrogen. 3. The method according to claim 1, about tl and h and y and the fact that the interaction with n-grained phosphorus has a lot at the boiling point of the reaction mass, 4. The method according to a.1, I distinguish y and with the fact that Alkylation is carried out at a temperature of 120 ° C in a hermetic vessel. Sources of information taken into account for exporters: 1. Vengakd-Hilgetag, Methods of experiment in organic chemistry, Moscow, 1969, p. 598.