DE1420086C - 1 Alkyl pipendyl (4) hydrazine and process for their preparation - Google Patents

Description

in which R, a low molecular weight alkyl group, R ₂ denotes hydrogen or a low molecular weight alkyl group and R ₃ denotes hydrogen, a low molecular weight aliphatic acyl group or the benzoyl radical, and their salts with inorganic or organic acids.

2. [l'-Isopropyl-piperidyl- (4 ')] hydrazine.

3. 1-Benzoyl-2- [r-methyl-piperidyl- (4 ')] hydrazine.

4. Process for the preparation of the compounds according to claim 1, characterized in that one by methods known per se either

a) a hydrazine derivative of the general formula II

R,

H, N —N:

(II) and Hai means a chlorine, bromine or iodine atom, condensed and from the thus obtained Hydrazine optionally splitting off the acyl group or

e) chloramine with a 1-alkyl-4-aminopiperidine of the general formula VII

R ₁ -N

NH ₂ (VII)

in which R _{1 has} the meaning given, reacts and the reaction product is optionally acylated and / or alkylated
and if appropriate, the compounds of general formula I thus obtained are converted into their acid addition salts.

The invention relates to [1-alkyl-piperidyl- (4)] hydrazines of the general formula I

R ₁ -N

> - NH - N:

in which R _{2 has the} above meaning and R ₃ 'denotes a low molecular weight aliphatic acyl group or the benzoyl radical, with an 1-alkyl-piperidone- (4) of the general formula III

R ₁ -N

(ΠΙ)

in which R _{1 has the} above meaning, condenses, the hydrazone thus obtained is reduced and then, if appropriate, the acyl group is split off or

b) a hydrazine derivative of the general formula IV

H ₂ N-NH-R ₂ '(IV)

HoN-N:

(V)

R ₁ -N

Shark

(VI)

in which R _{1 has} the meaning given in which R _{1 is} a low molecular weight alkyl group, R _{2 is} hydrogen or a low molecular weight alkyl group and R _{3 is} hydrogen, a low molecular weight aliphatic acyl group or the benzoyl radical, their salts with inorganic or organic acids and processes for their preparation.

According to the invention, the [1-alkyl-

piperidyl- (4)] - hydrazines of the general formula 1 and their salts, by following known per se Methods

a) a hydrazine derivative of the general formula Ii

40

in which R ₂ 'denotes a low molecular weight alkyl group, condensed with a l-alkyl-piperidone- (4) of the general formula III and the hydrazone thus obtained is reduced and the hydrazine optionally acylated or

c) a hydrazine derivative of the general formula IV with an 1-alkyl-piperidone- (4) der general formula III condensed, acylated the hydrazone thus obtained and then reduced and eventually splitting off the acyl group or, if appropriate

d) a hydrazine derivative of the general formula V.

in which R ₂ and R _{3 have} the meaning given, with an 1-alkyl-4-halopiperidine of the general formula VI

H ₂ N - N:

(II)

R,

in which R _{2 has the} above meaning and R ₃ 'denotes a low molecular weight aliphatic acyl group or the benzoyl radical, with a 1-alkylpiperidone- (4) of the general formula III

R ₁ -N

(III)

in which R _{1 has the} above meaning, condenses, the hydrazone thus obtained is reduced and then, if appropriate, the acyl group is split off or

b) a hydrazine derivative of the general formula IV

H ₂ N-NH-R ₂ '(IV)

in which R ₂ 'denotes a low molecular weight alkyl group, condensed with an l-alkyI-piperidone- (4) of the general formula III, the hydrazine thus obtained is reduced and the hydrazine optionally acylated or

c) a hydrazine derivative of the general formula IV with an l-alkyI-piperidone- (4) of the general Formula III condensed, the hydrazone thus obtained acylated and then reduced and eventually splitting off the acyl group or

d) a hydrazine derivative of the general formula V.

R ₂

η, ν - ν:

in which R ₂ and R _{3 have} the meaning given, with an 1-alkyl-4-halopiperidine of the general formula VI

R ₁ -N

Shark

(Vl)

in which R _{1 has} the meaning given and Hal denotes a chlorine, bromine or iodine atom, condenses and optionally splits off the acyl group from the hydrazine obtained in this way or
e) chloramine with a 1-alkyl-4-aminopiperidine of the general formula VIl

R ₁ -N

V- NH,

(VII)

in which R _{1 has} the meaning given, reacts and the reaction product is optionally acylated and / or alkylated

and optionally converting the compounds of general formula I thus obtained into their acid addition salts convicted.

The practical implementation of the individual process variants is, for example, as follows:

a) The solution of a hydrazide of the general formula II, e.g. B. acetic acid or benzoic acid hydrazide and a 1-alkyl-piperidone of the general formula III in a suitable one organic solvents, e.g. B. anhydrous ethanol, is used until the reaction has ended slightly warmed, e.g. B. 40 minutes to 50 to 75 ° C. The water formed can after this Addition of benzene distilled off azeotropically and that which remains after concentration in vacuo Acylhydrazone can be purified by recrystallization. The reduction of this acylhydrazone is expediently done catalytically, at room temperature and normal pressure, in one Glacial acetic acid solution, metals of group VIII of the periodic as catalysts Systems, e.g. B. nickel or platinum can be used. From the hydrazide thus obtained the acyl group can easily be split off hydrolytically, e.g. B. by heating in a aqueous mineral acid.

b) The condensation of an alkylhydrazine of the general formula IV with a 1-alkyl-piperidone of the general formula III can be carried out analogously as described under a), as well the reduction of the hydrazone thus obtained. For the acylation of the l-alkyl-2- [l'-alkyl-piperidyl- (4 ')] hydrazines in particular the acid halides of low molecular weight aliphatic carboxylic acids are used or benzoic acid halides in question, so z. B. acetyl chloride or benzoyl chloride. This Acylation can advantageously be carried out in an inert organic solvent, e.g. B. Chloroform, at room temperature or below.

c) The condensation of an alkylhydrazine of the general formula IV with a 1-alkyl-piperidone of the general formula III, the acylation of the hydrazone, the reduction of the acylhydrazone and finally the cleavage of the acyl group can be carried out as described under a) and b) will. This procedure as well as the procedure described under a) has opposite the process b) has the advantage that the acylhydrazones are much easier and better Reduce the yield as the non-acylated hydrazones to the corresponding hydrazines.

d) The reaction of a hydrazine derivative of the general formula V with an 1-alkyl-4-halopiperidine of the general formula VI can, for example, by heating the components in a suitable organic solvent, z. B. absolute ethanol. The remaining after evaporation of the solvent The residue is made alkaline and the base released by distillation lation in a high vacuum and / or via a salt with an organic or inorganic acid cleaned.

e) This process is expediently carried out so that the reactants in an aqueous gelatin solution initially reacting with one another while cooling with ice, the mixture acidified after prolonged standing at room temperature or elevated temperature, evaporated in vacuo and the hydrazine derivative isolated from the residue as described under d). Subsequent acylation (such as under b) or alkylation (ζ. B. with alkyl halides) the corresponding acyl or alkyl derivatives are obtained.

The [1-alkyl-piperidyl- (4)] hydrazine prepared according to the process are crystalline or liquid at room temperature and cannot be decomposed in a vacuum distill. As bases they form with organic or inorganic acids at room temperature stable, crystallized salts. The hydrazine derivatives prepared according to the invention have therapeutic properties utilizable pharmacodynamic properties that make them valuable active ingredients. So draw they are mainly characterized by a strong monoamine oxidase inhibition and should therefore be used in medicine find use as monoamine oxidase inhibitors.

In the pharmacological test, the following were compared:

= l-isopropyl-2- [l'-methyl-piperidyl- (4 ')] - hy-

drazin

II = 1-isopropyl-2- [1'-isopropyl-piperidyl- (4 ')] hydrazine

III = [1'-isopropyl-piperidyl- (4 ')] hydrazine

IV = l-methyl-l-acetyl-2- [l'-isopropyl-piperi-

dyl- (4 ')] hydrazine

V = 1-benzoyl-2- [1'-methyl-piperidyl- (4 ')] hydrazine

VI = 1-isonicotinoyl-2-isopropylhydrazine (known reference substance)

The experiments were carried out on cats under urethane-chloral anesthesia and on mice. The trials on cats are based on the fact that monoamine oxidase (MAO) inhibitors reduce the action of biogenic amines

on the nictitating membrane and on blood pressure. The test substances were / 9-phenylethylamine, adrenaline and norepinephrine chosen. The smallest dose of the compound in question was determined at i. v. Administration of the effect of the mentioned amines on the nictitating membrane or on blood pressure can strengthen.

The experiments on mice are based on the fact that MAO inhibitors have the cardiazole convulsive effect of reserpine are able to inhibit. The smallest dose of the compound in question was determined, the at s. c. Administration and a 20-hour exposure time the potentiating effect of 2.5 mg per kg / animal of reserpine s.c. able to neutralize the cardiazole spasm.

In addition, the compounds according to the invention with the known compound VI were also compared for their in vitro effect on the liver monoamine oxidase of the guinea pig. When Substrate was used tyramine and determined the molarity of the solution, which is necessary to be 50% Hcmmwohliing to unfold.

The toxicity was measured in the usual way; H. it became that amount of the compound in question determined that was fatal for half of the animals. For the toxicity tests, per compound used between 12 and 24 animals.

The values found are compiled in the following table, which clearly shows that the compounds prepared according to the invention are significantly superior to the known compound VI:

Connect HD ,,,
Effective doses mouse 50% inhibition DL ₅₀
Acute manure in mg / kg 10 in vitro toxicity cat 25th M / I in mg / kg i.v. I. 12th 5 2 to 3 x 10 ^e 780 II 25th 18th ίο- ⁶ 1200 III 7th 12th 6 ■ ΙΟ- ⁷ 640 IV 15th 38 3 x 10 ^β 1020 V 10 ίο- ⁶ 980 VI 30th 8-10 ⁶ 690

Compounds with potent MAO inhibition are increasingly being used as remedies for control used by depression and are therefore 'for both clinical and outpatient treatment endogenous psychoses of increasing importance.

The effect of MAOIs on the depressed Symptoms consist of an improvement in mood and an increase in drive; the mental and physical Patient activity increases significantly. They are different from other stimulants MAO inhibitors in that, with the correct dosage, the mood swings without any significant psychomotoric Stimulation comes about and that habituation is practically never observed.

The following examples are intended to explain the preparation of the compounds according to the invention in more detail. The melting and boiling points are not corrected.

example 1

The solution of 27.2 g of benzoylhydrazine in 400 ecm of ethanol is mixed with 22.6 g of 1-methyl-4-piperidone and the mixture is refluxed with stirring for 2 hours. The residue of the evaporated to dryness in vacuo the reaction mixture provides the benzoylhydrazone of l-methyl-4-pipcridons, mp Recrystallization from benzene / ether. 146-147 ⁰ C. Stir the solution of 34.6 g of hydrogenated Benzoylhydrazons in 275 cc of glacial acetic acid in the presence of 400 mg of platinum oxide catalyst at room temperature and atmospheric pressure. After 4.5 hours the theoretical amount of hydrogen has been absorbed,

ίο whereupon the solution filtered off from the catalyst is evaporated to dryness in vacuo. The l-benzoyl-2- [l'-methyl-piperidyl- (4 ')] hydrazine which remains as residue is heated _{to boiling under reflux for 4 hours with 250 ecm 23 ° / 0} ' ger aqueous hydrochloric acid, and the solution is re-extracted cooling with ether and evaporating the aqueous layer to dryness in vacuo. The residue is mixed with a solution of 27 g of potassium hydroxide in 200 ecm of methanol and the mixture is heated on the water bath until all of the oily substance has dissolved. The precipitated potassium chloride is then filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in boiling tetrahydrofuran, the filtered solution is evaporated to dryness in vacuo and the residue is fractionated in a high vacuum. [l'-methylpiperidyl (4 ')] - hydrazine boiling below 0.25 to 0.32 mm Hg at 66 to 70 ⁰ C. Colorless substance which solidifies in crystalline form in the template.

In game 2

19.2 g of 1-methyl-4-piperidone are added to the solution in 10 ecm of absolute ethanol drop by drop with 8.0 g of methylhydrazine, dissolved in 10 ecm

solutem ethanol, being maintained by cooling, if necessary with an ice-salt mixture, the temperature of 20-30 ⁰ C. The mixture is then heated to 60 to 65 ° C. for 40 minutes. After adding 25 ecm of benzene, the water formed is distilled off azeotropically with the alcohol and the solution is evaporated at 80 ° C. under reduced pressure. The residue is distilled in vacuo. (1-Methyl-4-piperidone) -methylhydrazone passes below 11 mm Hg at 98 to 99 ° C.

10.0 g of (1-methyl-4-piperidone) methylhydrazone are added to the solution in 30 ecm of chloroform with 10 g of benzoyl chloride dissolved in 25 ecm Chloroform, the temperature being kept at a maximum of 10 ° C by cooling with ice-table salt.

The solution is evaporated after standing for twelve hours at room temperature. You move them Solution of the resinous residue in 20 ecm of water with 20 ecm of 10 '/ o' sodium hydroxide solution and extracted with chloroform. The chloroform solution, dried over sodium sulfate, leaves behind after evaporation a viscous yellow oil that crystallizes when rubbed. The product, (l-methyl-4-piperidone) -methyl-benzoyl-hydrazone, crystallized from acetone in cuboids with a melting point of 96 to 102 ° C .; Bp. 145 to 150 ° C / 0.1 mm Hg.

The suspension of 80 mg of prehydrogenated platinum oxide in 10 ecm of glacial acetic acid is added Solution of 4.0 g of (1-methyl-4-piperidone) -methyl-benzoyl-hydrazone in 70 ecm of glacial acetic acid and hydrogenated the Mixture under atmospheric pressure at room temperature, where the hydrogenation of the C = N double bond required amount of hydrogen is absorbed within 3 hours. The catalyzer

sator filtered solution is evaporated under reduced pressure at 60 ⁰ C and the residue treated with 10 cc of ice water. After the addition of 15 cc of 20 ° / ₀ sodium hydroxide solution and saturation with sodium chloride it was extracted with chloroform and evaporate the chloroform extract dried over sodium sulfate. The residue gives 1 - methyl -1 - benzoyl - 2 - [I '- methyl - piperidyl (4')] - hydrazine, bp. 145 to 150 ° C / 0.3 mm Hg, on distillation under high vacuum,

temperature, the amount of hydrogen required for the hydrogenation of the C = N- 'double bond being absorbed within 3/2 hours. The filtered from the catalyst solution is evaporated under reduced pressure at 6O ⁰ C, and the remaining residue as 1-isopropyl-l-benzoyl-2- [l-methyl-piperidyl (4 ')] - hydrazine, a thick, slightly brown-colored oil, in 100 cc of 23 ° / _o hydrochloric acid for 5 hours under reflux to boiling.

that of ether / petroleum ether in platelets and needles 10 The solution, cooled to -5 ° C., is removed from the

divorced benzoic filtered and evaporated under 12 mm Hg at 8O ⁰ C to dryness, the residue l-isopropyl-2- [r-metnyl-piperidyl (4 ')] - hydrazine dihydrochloride crystallized in fine needles.

233 ° C.

Example 4

of m.p. 70 to 76 ° C is obtained. For the production of the hydrazine derivative itself by splitting off the benzoyl group from the benzoyl derivative
However, it is not necessary to produce this in a pure state, but can be processed directly after the 15 The salt is slightly hygroscopic and has the crude hydrogenation recrystallization from ethanol obtained after evaporation of the glacial acetic acid, the melting point 229 to product.

The crude l-methyl-l-benzoyl-2- [l'-methylpiperidyl- (4 ')] hydrazine obtained by hydrogenation of 55.5 g of benzoyl hydrazone after evaporation of the glacial acetic acid is added at 800 ecm 23 ° / _o iger hydrochloric acid and the mixture is heated to boiling under reflux for 5 hours. The solution, cooled to -5 ° C., is released from the benzoic acid

filtered off and under 12 mm Hg at 80 ⁰ C to dryness 25 of 15.0 g of l-isopropyl-4-piperidone in 20 ecm of methane evaporated. The residue gives dropwise recrystalline nol and keeps the reaction mixture from methanol / ether 1-methyl-2- [1'-methylpiperidyI- (4 ')] - hydrazine dihydrochloride in colorless
fine needles that after drying at 50 ° C

in a high vacuum over phosphorus pentoxide at 187 30 stood in 30 ecm of ether and filtered. After Abbis 210 ° C with evolution of hydrogen chloride-melting, evaporation of the solvent in vacuo at 40 ⁰ C

25.0 g of methylhydrazine dihydrochloride are added to the mixture and 20 ecm of methanol with vigorous stirring dropwise with 1.55 n-methanolic Potassium hydroxide until the pH is about 10 is added to the mixture, which has been cooled to 0 ° C

then to 50 ° C. for 3 hours. It is then cooled and removed from the precipitated potassium chloride filtered off. The filtrate is concentrated, the back

Zen. When treated with methanolic potassium hydroxide solution, the dihydrochloride gives the free l-methyl-2- [l'-methyl-piperidyI- (4 ')] hydrazine as a water-clear, colorless liquid with a temperature of 60 ° C / O, 3 mm Hg.nf ° = 1.4835.

Example 3

the residue is distilled in a high vacuum. The fraction passing over at 63 to 65 ° C / 0.1 mm Hg is (l-isopropyl-4-piperidone) methyl hydrazone.

The solution of 11.86 g of (1-isopropyl-4-piperidone) methyl hydrazone in 11 ecm of chloroform is added dropwise with 9.85 g of benzoyl chloride, dissolved in 11 ecm of chloroform, the temperature being between 0 and 10 ⁰ C is held.

131.7 g of 1-methyl-4-piperidone are added to the solution in 75 ecm ethanol with drop by drop

86.5 g of isopropylhydrazine, dissolved in 75 ecm of ethanol, are allowed to stand for two and a half hours at room temperature, the temperature being kept at -15 ° C. by cooling, the reaction mixture being kept with a further 30 ecm-5 ° C. Then heated to the chloroform and added with good cooling 50 ecm mixture for 30 minutes at 60 to 8O ⁰ C. After a 12% sodium hydroxide solution, shake addition of 200 cc of benzene is distilled under comparable well and the layers separated. The watery diminished! Pressure the water formed together 45 portion is extracted twice with chloroform, with the ethanol and the benzene and fractionated whereupon the chloroform extracts once with the residue in vacuo. The sodium chloride solution, saturated under 12 mm Hg, is shaken out 15 ecm, the fraction passing over at 86 to 115 ° C. is dried again. The combined chloroform solutions are then distilled. (l-methyl-4-piperidone) -isopropylhydrazone filtered and the chloroform evaporated at 40 ⁰ C under boiling below 8 mm Hg at 95 to 103 ⁰ C; «F ° = 1.4925. 50 reduced pressure. The residue is added to the solution of 44.5 g (1-methyl high vacuum distilled at 155 to 158 ° C / 0.002 mm

4-piperidone) -isopropyl-hydrazone dropwise in 65 cc of chloroform at 10 ⁰ C with 37.0 g of benzoyl chloride dissolved in 65 cc of chloroform, the solution is heated _^3/4 hours to boiling under reflux and added to the cooled to 0 ⁰ C solution / oig with ice-cold 6 ° ^he sodium hydroxide solution. It is extracted twice with chloroform, the chloroform extract is washed with saturated sodium chloride solution and, after drying, it is evaporated

Hg goes the benzoylmethylhydrazone of 1-isopropyl-4-piperidone as a viscous yellow oil that does not crystallize even after standing for a long time.

4.79 g of the benzoylated (l-isopropyl-4-piperidone) methyl hydrazone are hydrogenated in 50 ecm of glacial acetic acid in the presence of 100 mg of prehydrogenated platinum oxide as a catalyst at room temperature and 730 mm Hg. After 3 ¹ 1/2 hours, the theoretically required

over sodium sulfate. The residue is taken up in a high amount of hydrogen. The mixture is filtered from the vacuum-fractionated, wherein from less than 0.003 mm Hg, the catalyst, the acetic acid evaporated in vacuo (l-methyl-4-piperidone) -isopropyl-benzoyl-hydrazone at 60 ° C and the saponified as an oily residue verbei 128 to 130 ⁰ C passes. permanent l-methyl-l-benzoyl-2- [l'-isopropyl-piperi-

Is added to the slurry of 200 mg dyl- (4 ')] - hydrazine by heating in 75 cc 5stündiges prehydrogenated platinum oxide in 10 cc of glacial acetic acid with 65 23 ° / _o hydrochloric acid to reflux. Solution of 10.65 g of (l-methyl-4-piperidone) isopropyl. One cools to 0 ⁰ C, the precipitated benzoyl hydrazone is filtered off in 65 ecm of glacial acetic acid and benzoic acid is hydrogenated and the filtrate is evaporated at 80 ° C Mixture to dryness under atmospheric pressure at room in vacuum. The greasy one, in part

309 620/109

9 10

The crystallized residue is extracted from methanol-ether and the lye extract is extracted twice with 300 ecm each time

recrystallized, whereby l-methyl-2- [l'-isopropyl-piperi-chloroform, washes the chloroform extracts with

dyl- (4 ')] - hydrazine dihydrochloride in colorless prisms of saturated sodium chloride solution, combine them and

is obtained, which after four recrystallization it evaporates after drying over sodium sulfate.

from this solvent at 247 to 253 ^C C below 5 The remaining residue distilled as a viscous,

Melt decomposition. yellow colored oil at 145 to 155 ° C / O, OO2 mm Hg.

By acylation of (l-isopropyl-4-piperidone) - the suspension of 2700 mg is added

methyl-hydrazone with acetyl chloride in chloroform and hydrogenated platinum oxide in 100 ecm glacial acetic acid with the

subsequent hydrogenation of the resulting acetyl solution of 205.03 g (l-isopropyl-4-piperidone) iso-

derivative in the presence of prehydrated platinum oxide io propyl-benzoyl-hydrazone in 1000 ecm glacial acetic acid and

in glacial acetic acid, l-methyl-l-acetyl-2- [l'-iso-hydrogenated the mixture under atmospheric pressure

propyl-piperidyl- (4 ')] - hydrazine, which at the room temperature, the hydrogenation of the

Soap also l-methyl-2- [l'-isopropyl-piperidyl- C = N double bond required amount of hydrogen

(4 ')] - gives hydrazine. is recorded within 9 hours. One steams

. 15 the solution filtered off from the catalyst under

13 c ι s ρ ι e I 5 less pressure at 6O ⁰ C and heated the solution

The solution of 19.2 g of 1-methyl-des is added as a viscous, yellow-colored residue-

4-piperidone in 10 ecm of absolute ethanol dripping 1 - isopropyl - 1 - benzoyl -2- [Y- isopropyl-

as dissolved with 8.0 g of methylhydrazine in 10 cc piperidyl (4 ')] - hydrazine into 1200 cc 23%' ^er g wäß-

absolute ethanol, whereby by cooling, necessary hydrochloric acid 8 hours for boiling under reflux,

if with a mixture of ice and salt, the temperature.After cooling down, the

between 20 and 30 ⁰ C is kept. Then the solution filtered off benzoic acid crystallized in

the mixture is heated for 40 minutes to 60 ° ^{C vacuum at 8O 0} C, whereupon the residue, 1-Iso-

up to 65 "C. After adding 25 ecm of benzene, the propyi-2- [l'-isopropyl-piperidyl- (4 ')] -hydrazine-dihy-

The water formed is distilled off azeotropically with the alcohol, and it solidifies in crystalline form. Colorless needles from

and the solution under reduced pressure at melting point 258 to 262 ⁰ C (decomposition) after recrystallization

8O ⁰ C evaporated. The residue is sieren in vacuo from ethanol.

distilled. Below 11 mm Hg goes (1-methyl-4-piperi- The dihydrochloride supplies with the treatment

don) methyl hydrazone at 98 to 99 ⁰ C over. Man methanolic potassium hydroxide solution the free 1-isopropyl-

hydrogenates the solution of 65.0 g (l-methyl-4-piperidone) - 30 2- [l'-isopropyI-piperidyl- (4 ')] - hydrazine as clear water

melhylhydrazone in 595 ecm 0.87 η-aqueous salt-colorless liquid with the bp. 80 ° C / 0.25 mm Hg.

acid, in which 1.2 g of platinum oxide are suspended, n "° = 1.4711.

under atmospheric pressure at room temperature, where- Example 7
at those for the hydrogenation of the C = N double bond

Required amount of hydrogen within 6V2 hours 35 The solution is added with 107.0 g of ethyl-hyauftaken. The filtered from the catalyst ■ Drazin dihydrochloride in 800 cc of ethanol at 20 ⁰ C solution is evaporated in vacuo at 85 ° C. dropwise with 800 ecm of ethanol, in which 35.5 g of the residue have been treated in the cold with sodium, and the 259 ecm of 1.78 N-methanolic potassium hydroxide solution is heated and the mixture is filtered for half an hour under reflux. In from the excreted potassium chloride. The filtrate 4 ° the cooled to 10 ⁰ C mixture is allowed to which is under reduced pressure at 4O ⁰ C evaporated solution of 91.5 g of l-methyl-4-piperidone in 90 cc and the residue under 11 mm Hg fractionated. Drip in the ethanol while stirring. The mixture is heated anunter this pressure at 98 to 110 ° C for continuous closing ¹ J ₂ hours to reflux, fraction, a colorless, basic oil, 1-methyl-cooled to 0 ⁰ C, filtered from the precipitated sodium chloride 2- [l '-methyl-piperidyl (4')] - hydrazine, b.p. 6O ⁰ C / 45, and the filtrate evaporated at 6O ⁰ C under vermin-0.3 mm Hg, nT -. 1.4835. the pressure. The residue is in vacuo _R. . distilled. Below 0.1 mm Hg (l-methyl-4-piperi ^example don ^b) ethyl hydrazone proceeds at 58 to 6I ⁰ C. The solution of 110.28 g of 1-isopropyl is added, the solution of 39.57 g of (l-methyl-4-piperidone) -4-piperidone in 200 ecm of absolute ethanol is added dropwise 50 ethyl hydrazone in 300 ecm of chloroform dropwise with 79.2 g of isopropyl hydrazine hydrate, dissolved in 35.85 g of benzoyl chloride, dissolved in 35 ecm chloro-40 ecm absolute ethanol ⁰ C. The temperature is kept at 10 to 20 ° C. The mixture is then heated for 40 minutes. The yellow-colored reaction solution is heated Va hour to 60 to 65 ° C and the solution is evaporated under 55 to boiling under reflux and after the reduced pressure at 8O ⁰ C. The residue is cooled twice with 100 ecm of 10% sodium hydroxide each time and is distilled in vacuo. Under 1 mm Hg, lye is shaken out. The mixture is extracted twice with about 100 cc of chloroform to 88 ⁰ C, the combined (l-isopropyl-4-piperidone) -isopropyl-hydrazone in 86 liquor extracts. and the dried over sodium sulfate is evaporated. The solution of 150.3 g (1-isopropyl-60 combined chloroform extracts. The remaining 4-piperidone) -isopropylhydrazone in 450 ecm of chloro residue is distilled dropwise as a viscous oil in a mold with 108 g of benzoyl chloride, dissolved bath temperature of 135 to 163 ° C / 0.2 mm Hg. One in 220 ecm chloroform, whereby by cooling with added the slurry of 800 mg of prehydrated ice-common salt mixture the temperature to 15 ° C platinum oxide in 100 ecm glacial acetic acid is kept with the solution of. The solution is heated to boiling for ₂ hours ¹ I 65 72.3 g (l-methyl-4-piperidone) in -äthylbenzoylhydrazon under reflux, then with 300 cc of chloroform 500 cc glacial acetic acid and the mixture hydrogenated under diluted and, after cooling with ice with 400 cc of atmospheric pressure at room temperature, the ice-cold 10 ° / ₀ sodium hydroxide solution by shaking. For the hydrogenation of the C = N double bond,

11 12

required amount of hydrogen builds up within 6 hours. The precipitated potassium chloride is filtered off

is taken·. The catalyst is evaporated off and the methanol is evaporated off under reduced pressure

filtered solution under reduced pressure, under pressure. The residue is distilled in vacuo,

60 ° C and heated the solution of the more viscous being [l'-n-butyl-piperidyl- (4 ')] - hydrazine, identical

Residue remaining l-ethyl-l-benzoyl-2- [l'-me-5 with the substance described in Example 8 obtained

thyl-piperidyl- (4 ')] - hydrazines in 600 ecm 23%' 8 ^he will.

aqueous hydrochloric acid reflux for 8 hours to Be is Diel 10
Boil. After cooling down, the from

the solution filtered off from the crystallized benzoic acid. The solution is mixed with 24.05 g of benzoyl

in a vacuum at 80 ° C, whereupon the residue, io hydrazine in 150 ecm of ethanol with 24.94 g of 1-isopropyl

l-Ethyl-2- [l'-methyl-piperidyl- (4 ')] - hydrazine-dihydro-4-piperidone and heated the mixture for 4 hours

chloride solidified in crystalline form. Colorless needles from reflux to simmer. When the solution evaporates

Mp. 231 to 233 ⁰ C (decomposition) after Umkristalli- means in vacuo at 60 ⁰ C remains (1-isopropyl

size from ethanol / methanol. 4-piperidone) benzoyl hydrazone as crystalline back

The dihydrochloride gives stand on treatment with 15, the fine on recrystallization from benzene

methanolic potassium hydroxide, the free l-ethyl-2- [l-me- matted needles, mp. 107 provides to 108 ⁰ C.

thyl-piperidyl- (4 ')] - hydrazine as a water-clear, colorless one, the solution of 47.5 g (1-isopropyl-

Liquid. 4-piperidon) benzoyl hydrazone in 280 ecm glacial acetic acid

B ice T he I 8 ^m the presence of 750 mg of platinum oxide at room

ao temperature and atmospheric pressure, the for

The solution of 14.8 g of acetylhydrazine required for hydrogenation of the C = N double bond in 200 ecm of ethanol is added with 31.04 g of in-butyl-4-piperidone amount of hydrogen within 110 minutes and the mixture is refluxed for 4 hours is taken. The catalyst is evaporated to the boil. Evaporation of the solvent filtered solution in vacuo at 70 ⁰ C and under vacuum, a granular, crystalline rear 25 76 remains the solution heated understood as the viscous residue, mp. To 78 ° C. The solution of l-benzoyl-2- [l'-isopropyl-piperidyl- (4 ')] - of 39.2 g of (in-butyl-4-piperidone) acetyl hydrazone in hydrazine is hydrogenated at 500 ecm 23 ° / _o iger aqueous hydrochloric acid 300 ecm glacial acetic acid in the presence of 400 mg platinum - 11 hours under reflux to boiling. After the oxide at room temperature and atmospheric pressure, cooling, evaporation of the crystallized said for the hydrogenation of the C = N double 30 benzoic filtered solution in vacuo at bond required amount of hydrogen within 8O ⁰ C and treated the brown colored back-4 Hours is recorded. The solution filtered off from the stand with the calculated amount of 1.76 n-methano catalyst is evaporated under reduced potassium hydroxide solution. The mixture is filtered from the precipitated pressure at 6O ⁰ C and the solution is heated as the potassium chloride, and the methanol evaporated under viscous residue remaining l-acetyl-2- [l-n-bu- 35 reduced pressure. The residue is distilled in vatyl-piperidyl- (4 ')] hydrazine in 100 ecm of 23% aqueous vacuum. Under 0.7 mm Hg, [l'-isopropyl hydrochloric acid boils under reflux for 8 hours. pyl-piperidyl- (4 ')] hydrazine at 75 to 77 ° C. The solution is evaporated under vacuum at 8O ⁰ C. Distillate is a colorless, viscous oil that solidifies when the residue is cooled down with the calculated amount. The melting point is only slightly mixed with methanolic potassium hydroxide solution. Filter from 40 above room temperature,
deposited potassium chloride and evaporates the

Methanol under reduced pressure. The residue example 11
is distilled in vacuo. Boils below 0.3 mm Hg

[l'-n-butyl-piperidyl (4 ')] - hydrazine at 8I ⁰ C. The solution is added 50 g of acetylhydrazine

Distillate crystallizes in the template, melting point 30 to 45 in 60 ecm ethanol with 76.2 g of 1-methyl-

35 ° C. 4-piperidone, the temperature of the mixture

Until the 1 9 ^au ^ ^max ' ^ma l 40 ⁰ C is kept. It is then refluxed for 2 hours and then heated in

The solution of 13.6 g of benzoyl vacuum is then evaporated to dryness. Recrystallize

hydrazine in 100 ecm of ethanol with 15.5 g of 1-n-butyl 50 from methylene chloride / petroleum ether provides the acetyl

4-piperidone and heated the mixture for 4 hours to the hydrazone of the l-methyl-4-piperidone in crystals

Reflux. Upon evaporation of the solvent of mp. 108-109 ⁰ C. Dissolve 7.5 g (1-methyl-

by means of a vacuum, a viscous yellow-colored 4-piperidone) acetylhydrazone remains in 100 ecm ethanol and

Residue which crystallizes on trituration. The solution is hydrogenated in the presence of 1.5 g of Raney

hydrogenated the solution of 17.0 g (in-butyl-4-piperidone) -55 nickel under atmospheric pressure at 20 ⁰ C, the

benzoyl hydrazone in 170 ecm glacial acetic acid in the presence calculated amount of hydrogen within 1772 hours

of 200 mg of platinum oxide at room temperature and is absorbed. The catalytic converter

Atmospheric pressure, the one used for the hydrogenation of the filtered solution is evaporated in vacuo and

C = N double bond required amount of water - the residue is distilled in a high vacuum. Under

substance is absorbed within 3 hours. 60 0.01 mm Hg is used at a bath temperature of 120

if the solution filtered off by the catalyst evaporates below 130 ° C, the l-acetyl-2- [l'-methyl-piperidyl- (4 ')] -

reduced pressure at 6O ⁰ C and heats the hydrazine over as a colorless viscous oil, which when

Solution of the cool remaining as a viscous residue solidified in crystalline form. Mp. 101 to 103 ⁰ C.

l-Benzoyl-2- [l'-n-butyl-piperidyl- (4 ')] - hydrazines in The hydrogenation in the presence of Raney nickel

200 ecm 23 ° / ο 8 ^εΓ aqueous hydrochloric acid 12 hours for the 65 can even with increased pressure and room temperature

Reflux. The solution is evaporated at rature or at elevated temperature.

Vacuum at 8O ⁰ C a. The residue is mixed with the The solution of 10 g of l-methyl-4-piperidone-acetyl-

calculated amount of methanolic potassium hydroxide solution hydrazone in 50 ecm ethanol is in the presence of

2 g Raney-Nickcl hydrogenated at 12 to 13 ° C under 50 atmospheres or at 65 ° C under 90 atmospheres. In both cases the desired hydrazine derivative is isolated as above. 10 g of l-acetyl-2- [l'-methyl-piperidyl- (4 ')] -hydrazine are ^{heated to boiling under reflux for 8 hours with 100 ecm 23 ° / o'g cr} aqueous hydrochloric acid and the aqueous solution is evaporated in vacuo Dry up. The residue is treated with the calculated amount of 2N methanolic potassium hydroxide solution. The precipitated potassium chloride is then filtered off and the filtrate is freed from methanol in vacuo. The residue is distilled in a high vacuum. [l'-methyl-piperidyl (4 ')] - hydrazine boiling below 0.25 to 0.32 mm Hg at 66 to 70 ⁰ C. Colorless substance which solidifies in crystalline form in the template.

Example 12

The solution of 25 g of 1-methyl-4-bromopiperidine in 30 ecm of absolute ethanol is added at room temperature to the solution of 13.5 g of anhydrous hydrazine in 50 ecm of ethanol and the mixture is refluxed for 4 hours; then the solvent and excess hydrazine are distilled off under reduced pressure at 75.degree. The viscous residue is extracted four times with 75 ecm of ether each time and the colorless reaction product that has become solid is suspended in 25 ecm of methanol. This suspension is treated with the calculated amount of methanolic potassium hydroxide solution, the precipitated potassium bromide is filtered off and the filtrate is evaporated to dryness under reduced pressure at 75.degree. The residue is extracted with 100 ecm boiling tetrahydrofuran and the extract is evaporated to dryness. The Rücksta.nd delivered to the distillation under 0.3 mm Hg be ¹ a bath temperature of 75 to 8O ⁰ C [l'-methylpiperidyl (4 ')] - hydrazine as a colorless viscous oil which solidifies in crystalline form in the cold.

Example 13

47 ecm of a 0.25 molar aqueous chloramine solution are mixed with the solution of 8.0 g of 1-methyl-4-aminopiperidine and 60 mg of gelatin mixed in 20 ecm of water. The temperature of the reaction mixture is left within one hour Rise to room temperature and heat to complete the reaction for 30 minutes the steam bath. Concentrated hydrochloric acid is added to the solution until a Congo acidic reaction occurs then evaporated to dryness under reduced pressure. Dissolve the remaining salts in 30 ecm Water, saturates the solution with solid potassium carbonate

and extracted it six times with 50 ecm of ethylene chloride each time. The [l'-methylpiperidyl- (4 ')] hydrazine can be obtained from the residue remaining after the solvent has been evaporated off be isolated by fractional distillation in a high vacuum. The substance boils at 66 to 70 ° C / 0.3 mm Hg.

Example 14

The solution of 25 g of 1-methyl-4-bromopiperidine is added in 30 ecm of absolute ethanol at room temperature with a solution of 7 g of methylhydrazine in 50 ecm of ethanol and the mixture is refluxed for 4 hours. Then distilled the solvent and unreacted methylhydrazine are removed under reduced pressure. The remaining The residue is extracted several times with ether. After removing the extractant the substance is slurried in a little methanol and mixed with the calculated amount of methanolic Potassium hydroxide. The precipitated potassium bromide is filtered off and the filtrate is evaporated under reduced pressure Pressure to dryness. The residue is extracted with boiling tetrahydrofuran and evaporate the extract to dryness. The 1-methyl-2- [l'-methyI-piperidyl- (4 ')] hydrazine is finally obtained by distilling the residue with a bp 60 ° C / 0.3 mm Hg.

If the above process is carried out using 11 g of acetylhydrazine, l-acetyl-2- [r-methyl-piperidyI- (4 ')] hydrazine is finally obtained, which at a pressure of 0.01 mm Hg at a bath temperature of 120 to 130 ⁰ C passes. By splitting off the acetyl group according to Example 11, [l'-methyl-piperidyl- (4 ')] hydrazine is obtained.

Claims (1)

Patent claims: 1. [1-Alkyl-piperidyl- (4)] - hydrazines of the general Formula I. R ₁ -N > —NH-N R ₂
R. (D