NO123051B - - Google Patents

Description

Process for the production of 3,5-diketo-pyrazolidine derivatives.

It has been shown that it is possible to come

up to 3,5-diketo-pyrazolidine derivs

with the general formula I

where R, and R2 is an aliphatic, aromatic, aryl-aliphatic or alkyl-aromatic residue, R;j is H or alkyl (1-4 C) and R4 is alkyl (1-4 C) in that piperidyl-4'- hydrazines of the general formula II

where R., and R+ have the same meaning as

above, are traded with reactive

malonic acid derivatives with the common one

formula III

where R, and R2 have the same meaning as

above and X means Br, Cl, N3, O-alkyl or NH2.

The procedure can, for example,

is conducted so that a solution of diphenyl-malonyl chloride in an inert solvent, e.g. tetrahydrofuran or chloroform, is mixed at room temperature with a solution of N-methyl-piperidyl-4'-hydrazine in the same solvent and then with a tertiary base, e.g. triethylamine. The reaction product can be isolated from the reaction mixture in a known manner, e.g. by evaporation of the solvent, absorption of the residue in a chlorinated coal hydrogen, removal of all acidic by-products from this solution by washing with soda solution, evaporation of the organic layer and purification of the residue by recrystallization.,

The reaction can also be carried out without the presence of a tertiary base, but with poorer yields.

The 3,5-diketoprazolidine derivatives produced by the method according to the invention are at room temperature solid, crystallized bases which form permanent salts with organic and inorganic acids. They have pharmacodynamic properties that make them valuable drugs. They have antipyretic and analgesic effects and in particular have a specific antirheumatic effect and also a strong anti-arousal (antiphlogistic) effect. They can be used therapeutically, intramuscularly, orally or as suppositories. Because their salts are so well soluble in water, they can be used for the production of highly concentrated ampoule solutions. However, they can also serve as an intermediate in the manufacture of drugs.

The diketo-pyrazolidines are thus suitable for the treatment of chronic rheumatism, chronic rheumatic polyarthritis and various arthritic processes.

When the method according to the invention is to be used for the production of 1-(N-methyl-piperidyl-4')-3,5-diketo-4,4-diethyl-pyrazolidine with the formula I where R, = R2 = C2H5, R3 = H and R4 = CH3, N-methyl-piperidyl-4'-hydrazine is reacted with diethyl malonyl dichloride.

Furthermore, 3,5-diketo-pyrazolidine derivatives with the R1 = R2 = n-butyl or -phenyl, general formula I, where /R3 = R4 = CH3 can be prepared by a-(N-methyl-piperidyl-4) - α'-methyl-hydrazine is reacted with an α,α-disubstituted derivative of malonyl dichloride with the formula III where R1 = R2 has the above meaning and X = Cl.

Furthermore, 3,5-diketo-pyrazolidine derivatives can be prepared with the formula I stated above, where Rt = R2 = CH3, C2H5, n-C4H9, C6H5, R3 = CH3, C3H7 and R4 = CH3, by w - (N-methyl-piperidyl-4)-w'-alkyl hydrazines of the general formula II are reacted with α,α-disubstituted malonyl dichlorides of the general formula III where X = C1.

3,5-diketo-pyrazolidine derivatives of formula IV

where R, = R2 = n-C4H9 or C6H5 can be prepared by o>-(N-isopropyl-piperidyl-4)-m'-methyl-hydrazine of formula V

NH-NHCHg

is reacted with α, α-disubstituted malonyl dichlorides of formula III where X = Cl. 1-(N-methyl-piperidyl-4')-3,5-diketo-4,4-diethyl-pyrazolidine with • formula I where R1 = R2 = C2H5, R3 = H and R4 = CH3 can be prepared by (N -methyl-piperidyl-4)-hydrazine is reacted with diethylmalonic acid dimethyl ester. 1-(N-methyl-piperidyl-4')-3,5-diketo-4,4-dimethyl-pyrazolidine of formula I where R, = R2R4 = CH3 and R3 = H can be prepared by (N-methyl-piperidyl -4)-hydrazine is reacted with dimethylmalonic acid diethyl ester.

3,5-diketo-pyrazolidine derivatives of formula I where R3 = R2 = methyl or ethyl, R3 = H and R4 = CH3 can be prepared by reacting n-methyl-piperidyl-4-hydrazine with reactive derivatives of malonic acid of formula III where X = NH2, OC2H5

or N3.

According to a further development of the invention, 3,5-diketo-pyrazolidine derivatives can be produced which are acylated in the 2-position and which have the general formula I where Rj and R2, in addition to the meanings indicated on page 1, can also have meaning H, where R4 = CuH2ntl (n-1,2,3,4) and where R3 is an acyl residue, in that u>-(piperidyl-4)-m'-acylhydrazines of the general formula II where, however, now R4 in addition to the above meaning can also be a benzyl group, is reacted with reactive malonic acid derivatives of formula III where Rj and R2 have the same meaning as above and X means a chlorine or bromine atom, an alkoxy group containing 1-4 C atoms or N3 and that the benzyl group is optionally removed reductively in a known manner.

The 3,5-diketo-pyrazolidine derivatives just mentioned which are acylated in the 2-position and of formula I, but where R, = CH3, C9H5, n-C4H9, CfiH5 or C(iHRCH.„ R„ = CH3, C2Hfl , n-C4H9 or C(iH5CH2, R3 = COCH3 and R4 = CH3 or n-C4H9 can be prepared by co-(N-alkyl-piperidyl-14)-æ'-aceyl-hydrazines of formula II where R3 and R4 have same meaning as in formula I, is reacted with malonic acid dichlorides of formula III where X = Cl.

The 3,5-diketo-pyrazolidine derivatives which are acylated in the 2-position and which have been prepared as just indicated can be used for the preparation of 3,5-diketo-pyrazolidine derivatives of formula I where R, R2 and R4 have the same meanings as just indicated, but where R 3 = H, by reacting with reagents that cleave acyl groups.

If in the embodiment just mentioned derivatives of formula I are used where Rx methyl, ethyl, n-butyl, phenyl or benzyl, R2 = methyl, ethyl, n-butyl or benzyl, R3 = COCH3 and R4 = methyl or n- butyl, by reacting these with reagents that cleave acetyl groups, derivatives of formula I are obtained where R1, R2 and R4 are the same as in the starting derivatives but R3 = H.

Some examples will now be given of the various applications of the method according to the invention.

Example 1:

A solution of 27.2 g of benzoylhydrazine in 400 cc of ethanol was mixed with 22.6 g of N-methyl-4-piperidone and the mixture heated for 2 hours with stirring to reflux. The remainder of the reaction mixture, after it has been evaporated in vacuo to dryness, gave by recrystallization from benzene/ether N-methyl-4-piperidone-benzenehydrazone, m.p. 146-147 °. A solution of 34.6 g of the benzoyl hydrazone in 275 ems glacial acetic acid was hydrated in the presence of 400 mg of platinum oxide catalyst at room temperature and atmospheric pressure. After 4y2 hours, the theoretical amount of hydrogen was taken up, after which the solution, filtered off from the catalyst, was evaporated in vacuo to dryness. The rest was heated with 250 cm>! 23% aqueous hydrochloric acid for 4 hours to reflux, the solution was after cooling extracted with ether and the aqueous layer was evaporated in vacuo to dryness. The residue was mixed with a solution of 27 g of potassium hydroxide in 200 ems of methanol and the mixture was heated in a water bath until all the oily substance had dissolved. The separated potassium chloride was then filtered off and the filtrate evaporated in a vacuum to dryness. The residue was dissolved in boiling tetrahydrofuran, the filtered solution was evaporated in vacuo to dryness and the residue fractionated in high vacuum. N-methyl-piperidyl-4'-hydrazine boils at 0.25-0.32 mm Hg at 66-70°. Colorless substance that hardens crystalline in the publisher.

A solution of 29.2 g of diphenyl-malonyl chloride in 100 ems of tetrahydrofuran was first mixed dropwise at room temperature with a solution of 12.9 g of N-methyl-piperidyl-4'-hydrazine in 40 cm.3 of tetrahydrofuran and then with 20 .2 g of triethylamine, and the mixture, after being diluted with 80 cm 3 of chloroform, was heated for three hours with stirring to reflux, and the filtered solution evaporated in vacuo. The solution of the residue in methylene chloride was washed twice with 2-n soda solution, dried over sodium sulfate and evaporated in vacuo. The crystalline residue gave, after fractional crystallization from ethanol, pure 1-(N-methyl-piperidyl-4')-4,4-diphenyl-3,5-diketo-pyrazolidine with m.p. 173-174°.

Example 2:

A solution of 7.96 g of diethylmalonyl dichloride in 150 ems of tetrahydrofuran was mixed at room temperature dropwise with a solution of 5.22 g of N-methyl-piperidyl-4'-hydrazine and 11.2 cm<3> triethylamine in 50 cm< 3 >tetrahydrofuran. Then a further 11.2 cm<3> of triethylamine was added and the mixture was further stirred for 4 Va hours at room temperature. Filtration was carried out from the separated salts and the filtrate was evaporated to dryness in vacuo. A solution of the residue in 150 cm<3> methylene chloride was washed twice with 2-n. soda solution, dried over sodium sulfate and evaporated in vacuo. The solution of the oily residue in 50 ems benzon was fed to a column of 235 g of aluminum oxide and with mixtures of ether and alcohol, first in the ratio 9 : 1, then 4 : 1 and finally 1 : 1 eluted a crystallized substance, 1- (N-methyl-piperidyl-4')-3,5-diketo-4,4-diethyl-pyrazolidine, which after three recrystallizations from acetone melts at 188-189°.

Example 3:

A solution of 19.2 g of N-methyl-4-piperidone in 10 cm<3> abs ethanol was mixed dropwise with 8.0 g methyl-hydrazine, dissolved in 10 cm<3> abs ethanol during which the temperature was kept between 20 and 30° when cooling, possibly with an ice-table salt mixture. The mixture was then heated for 40 min. to 60-65°. After adding 25 ems of benzene, the water that had formed was distilled off azeotropically with the alcohol, and the solution evaporated at 80° under reduced pressure. The residue was distilled in vacuo. Below 11 mm Hg, (N-methyl-4-piperidone)-methyl hydrazone decomposed at 98-99°.

A solution of 10.0 g of (N-methyl-4-piperidone)-methylhydrazone in 30 cm<3> of chloroform was mixed dropwise with 10 g of benzoyl chloride, dissolved in 25 cm<3> of chloroform, during which the temperature was maintained at no more than 10° by cooling with an ice-table salt mixture. The solution was evaporated after standing for 12 hours at room temperature. A solution of the resinous residue in 20 cm3 of water was mixed with 20 cm3 of 10% caustic soda and extracted with chloroform. The chloroform solution gave, after drying over sodium sulphate and evaporation, a viscous yellow oil which crystallized through trituration. The product, (N-methyl-4-piperidone)-methyl-benzoyl-hydrazone, crystallized from acetone in vacuo with m.p. 96—102°, bp. 145—150° at 0.1 mm Hg.

A slurry of 80 mg of prehydrated platinum oxide in 10 cm<:i> of glacial acetic acid was mixed with a solution of 4.0 g of (N-methyl-4-piperidone)-methyl-benzoyl-hydrazone in 70 cm<:i> of glacial acetic acid and the mixture hydrated under atmospheric pressure at room temperature, during which the amount of hydrogen that was necessary for the creation of the C — N double bond was taken up within 3 hours. After filtration from the catalyst, the solution was evaporated under reduced pressure at 60° and the residue mixed with 10 cm3 of ice water. After adding 15 cm3 of 20% caustic soda and saturating with common salt, extraction was carried out with chloroform and the chloroform extract was evaporated after drying over sodium sulphate. The residue gave by distillation in high vacuum co-(N-methyl-piperidyl-4)-to'-methyl-benzoyl-hydrazine, bp 145-150° at 0.3 mm Hg, which was obtained from ether/petroleum ether in small plates and needles with mp 70-76°. However, for the production of the hydrazine derivative itself by splitting off the benzoyl group from the benzoyl derivative, it is not necessary to produce this in its pure state, but the crude hydration product obtained after evaporation of the glacial acetic acid can be further processed directly.

The crude oi-(N-methyl-piperidyl-4)methyl-benzoyl-hydrazine, which was obtained by hydrogenating 55.5 g of the benzoyl derivative after evaporation of the glacial acetic acid, was mixed with 800 cm<3> of 23% hydrochloric acid and the mixture heated to reflux for five hours. The solution became, after cooling to

•:- 5°, filtered off from the separated benzoic acid and evaporated to dryness at 12 mm Hg and 80°. The residue gave on recrystallization from methanol/ether w-(N-methyl-piperidyl-4)-<>)'-methyl-hydrazine dihydro-chloride in colorless fine needles which, after drying at 50° in high vacuum over phosphorus pentoxide, melt at 187—210° with evolution of hydrogen chloride. The dihydrochloride gave, on treatment with methanolic potassium chloride, free m-(N-methyl-piperidyl-4)-U)'-methyl-hydrazine as a clear, colorless liquid with bp 60°

22

at 0.3 mm Hg, n D = 1.4835.

A solution of 2.93 g of diphenyl-malonyl dichloride in 40 cm 3 of tetrahydrofuran, cooled to 0°, was mixed with further ice-cooling and stirring dropwise first with a solution of 1.43 g of w-(N-methyl-piperidyl-4 ) - u>'-methyl-hydrazine in 15 cc of tetrahydrofuran and then with 2.8 ems of triethylamine dissolved in 10 cc of tetrahydrofuran and the mixture heated to reflux for 2 hours. The cooled reaction mixture was diluted with ether and extracted three times with 2-n. hydrochloric acid. The hydrochloric acid aqueous layer was made alkaline with concentrated sodium hydroxide solution and extracted three times with methylene chloride.

The organic layer gave, after drying over

sodium sulphate, on evaporation an oil if

solution in benzene was chromatographed on 90 g of alumina. In the development of

the chromatogram with benzene, benzene ether mixtures in the ratio 4 : 1, then 1 : 1 and finally with only ether was 1-(N-methyl-piperidyl-4')-2-methyl-4,4-diphenyl-3,5- diketo-pyrazolidine eluted, which after recrystallization from ether/petroleum ether showed mp 112-113°.

Example h: 1-(N-methyl-piperidyl-4')-2-methyl-4,4-di-n-butyl-3,5-diketo-pyrazolidine.

In the same way as in Example 3, from 2.53 g of di-n-butyl-malonyl-dichloride and 1.43 g of w-(N-methyl-piperidyl-4)-o)'-methyl-hydrazine in the presence of 2.8 cm3 triethylamine prepared 1 - (N-methyl-piperidyl-4')-2 - methyl-4,4-di-n-butyl-3,5-diketo-pyrazolidine which could not be crystallized after chromatography, but which was obtained as an oily substance whose solution in abs ethanol by introduction of dry hydrogen chloride gave the monohydrochloride of the base in crystals which after recrystallization from acetone/ether showed m.p. 200-202°.

Example

A solution of 1.97 g of diethylmalonyl dichloride in 50 cm<3> of tetrahydrofuran was mixed dropwise under ice-cooling first with a solution of 1.43 g of o>-(N-methyl-piperidyl-4 )-w'- methylhydrazine in 15 cm3 of tetrahydrofuran and then with 2.02 g of triethylamine and the mixture heated to reflux for four hours. After cooling with ether, the mixture was diluted and extracted three times with 2-n. hydrochloric acid. The hydrochloric acid aqueous layer was made alkaline with concentrated caustic soda and extracted three times with chloroform. The chloroform solution, after drying over sodium sulfate, after evaporation in vacuo left an oily crude product. A solution of this in 50 cm<3 >benzene was added to a column of the 30-fold amount of alumina. Benzol, as well as benzene-ether mixtures 4:1 and 1:1 eluted 1 - (N-methyl-piperidyl-4')-2-methyl-4,4-diethyl-3,5-diketo-pyrazolidine.

To prepare the hydrochloride, dry hydrogen chloride was passed into the ethanolic solution of the free base and the reduced solution was mixed with ether, after which 1-(N-methyl-piperidyl-4')-2-methyl-4,4-diethyl The -3,5-diketo-pyrazolidine hydrochloride crystallized out. Temp. 220-221° (sp) after recrystallization from ethanol/ether.

Example 6:

A solution of 1.69 g of dimethylmalonyl dichloride in 50 cm3 of tetrahydrofuran was first mixed dropwise with a solution of 1.43 g of w-(N-methyl-piperidyl-4)-«'-methyl-hydrazine in 15 cm<3 >tetrahydrofuran and then with 2.02 g of triethylamine and the mixture heated with stirring for four hours to boiling with reflux. After cooling with ether, the mixture was diluted and extracted 3 times with 2-n. hydrochloric acid. The hydrochloric acid aqueous layer was made alkaline with cone. caustic soda and extracted three times with chloroform. The chloroform solution left, after drying over sodium sulfate, after evaporation in vacuo an oily crude product. A solution of this in 50 cm3 of benzol was added to a column of the 30-fold amount of aluminum oxide. Benzol, as well as benzene-ether mixtures 4:1 and 1:1 eluted 1-(N-methyl-piperidyl-4')-2-methyl-4,4-dimethyl-3,5-diketo-pyrazolidine.

The free base is crystalline, but cannot be recrystallized.

To prepare the hydrochloride, dry hydrogen chloride was passed into the ethanolic solution of the free base and the reduced solution was mixed with ether, after which 1-(N-methyl-piperidyl-4')-2-methyl-4,4-dimethyl The -3,5-diketo-pyrazolidine hydrochloride crystallized out, mp 261-262° (sp) after recrystallization from ethanol/ether.

Example 7 :

131.7 g of N-methyl-4-piperidone and 86.5 g of isopropyl-hydrazine in ethanol solution were brought together under cooling, the mixture heated for 30 min. to 60-80° evaporated in vacuum after adding 200 cm<3> of benzene and (N-methyl-4-piperidone)-isopropyl-hydrazone which was obtained as a residue was distilled in vacuum. Kp 95—103°/8 mm Hg. 44.5 g of hydrazone in chloroform solution was benzoylated with 37.0 g of benzoyl chloride. (N-methyl-4-piperidone)-isopropyl-benzoyl-hydrazone

boils below 0.003 mm Hg at 128—130°. Hydrogenation of 10.65 g of benzoyl-hydrazone in 75 cm-' of glacial acetic acid in the presence of 200 mg of prehydrated platinum oxide at room temperature and atmospheric pressure gave co-(N-methyl-piperidyl-4)-co'-isopropyl-benzoyl-hydrazine, whose hydrolysis on heating with 23% hydrochloric acid for five hours to boiling with reflux gave α>-(N-methyl-piperidyl-4-co'-isopropyl-hydrazine (bp 49-54°/0.3 mm Hg.

24 5°

n q = 1.4708).

c

A solution of 2.93 g of diphenyl-malonyl dichloride in 50 cm 3 of tetrahydrofuran was first mixed dropwise with a solution of 1.71 g of w-(N-methyl-piperidyl-4)-«'-isopropyl-hydrazine in 15 cm3 of tetrahydrofuran and then with 2.02 g of triethylamine and the mixture heated with stirring for 4 hours to reflux. After cooling with ether, the mixture was diluted and extracted three times with 2-n. hydrochloric acid. The hydrochloric acid aqueous layer was made alkaline with cone. caustic soda and extracted three times with chloroform. The chloroform solution left, after drying over sodium sulfate and after evaporation in vacuo, an oily crude product. A solution of this in 50 cnV<J>> benzol was added to a column of the 30-fold amount of alumina. Benzol, as well as benzole ether mixtures 4 : 1 and 1 : 1 eluted 1-(N-methyl-piperidyl-4')-2-isopropyl-4,4-diphenyl-3,5-diketo-pyrazolidine, which after recrystallization from ether /petroleum showed a m.p. at 124-125°.

To prepare the hydrochloride, dry hydrogen chloride was introduced into the ethanol solution of the free base and the reduced solution was mixed with ether, after which 1-(N-methyl-piperidyl-4')-2-isopropyl-4,4-diphenyl -3,5-diketo-pyrazolidine hydrochloride crystallized out. mp 247-252°

(sp) after recrystallization from ethanol/ether.

Example 8:

In the same way as in Example 7, from 2.53 g of di-n-butyl-malonyl-dichloride and 1.71 g of 2-(N-methyl-piperidyl-4)-a)'-isopropyl-hydrazine in the presence of 2.02 g of triethylamine prepared 1-(N-methyl-piperidyl-4')-2-isopropyl-4,4-di-n-butyl)-3,5-diketo-pyrazolidine, which after chromatography could not be crystallized, but which was obtained as an oily substance whose solution in absolute ethanol by the introduction of dry hydrogen chloride gave the monochloride of the base in crystals which, after recrystallization from acetone, show a m.p. of 234—236° (sp).

Example 9:

In the same manner as described in Example 7, from 1.69 g of dimethylmalonyl dichloride and 1.71 g of o)-(N-methyl-piperidyl-4)-α>'-isopropylhydrazine in the presence of 2.02 g triethylamine prepared 1-(N-methyl-piperidyl-4')-2-isopropyl-4,4-dimethyl-;3,5-diketo-pyrazolidine. The free base formed without solvent crystals which were very well soluble in organic solvents. Their solution in abs ethanol gave, on introduction of dry hydrogen chloride, the monochloride of the base in crystals which, after recrystallization from acetone/ether, showed a m.p. of 261-262° (sp).

Example 10:

37.7 g of a 39.5% aqueous methylhydrazine solution was dropped into a solution of 45.0 g of N-isopropyl-4-piperidone in 75 cm 3 of ethanol while cooling, and the mixture was kept for one hour at 65°. After evaporation of the ethanol and part of the water, the solution of the residue in the triple amount of chloroform was dried over sodium sulfate. After filtering and evaporating the solvent in vacuo, the residue was distilled in high vacuum. It was obtained (N-isopropyl-4-piperidone-methyl-hydrazone

as light yellowish oil. Bp 78° at 1 mm Hg 11.86 g of hydrazone in chloroform solution was benzoylated with 9.85 g of benzoyl chloride under cooling. (N-isopropyl-4-piperidone)-methyl-benzoyl-hydrazone boiled at 155-158° at 0.002 mm Hg. By hydration of 4.79 g of this benzoyl-hydrazone in 50 cm3 of glacial acetic acid in the presence of 100 mg of pre-hydrated piatina oxide at room temperature and atmospheric pressure, «-(N-isopropyl-piperidyl-4)-«'-methyl-benzoyl-hydrazine was obtained which on hydrolysis by heating with 75 cm<3 >23% hydrochloric acid for 5 hours to reflux gave m-(N-isopropyl-piperidyl-4)-o)'-methyl-hydrazine dihydrochloride, which after four times recrystallization from methanol/ether melted at 247-253° with cleavage. The dihydrochloride on treatment with methanolic potassium hydroxide gave the free base bp 76° at 0.3 mm Hg.

A solution of 2.93 g of diphenyl-malonyl dichloride in 50 cm 3 of tetrahydrofuran was mixed dropwise under ice-cooling first with a solution of 1.71 g of c>-(N-isopropyl-piperidyl-4)-«'-methyl-hydrazine in 15 cm3 of tetrahydrofuran and then with 2.02 g of triethylamine and the mixture heated with stirring for 4 hours to reflux. After cooling with ether, the mixture was diluted and extracted three times with 2-n. hydrochloric acid. The hydrochloric acid aqueous layer was made alkaline with cone. caustic soda, and extracted three times with chloroform. The chloroform solution gave, after drying over sodium sulfate and evaporation in vacuo, an oily crude product, a solution of which in 50 cm3 of benzene was added to a column of 100 g of aluminum oxide. Benzene and benzene-ether mixture 4:1 and 1:1 eluted 1-(N-isopropyl-piperidyl-4')-2-methyl-4,4-diphenyl-3,5-diketo-pyrazolidine, which after recrystallization from ether/petroleum ether had mp 119-120°. To prepare the hydrochloride, dried hydrogen chloride was introduced into the ethanolic solution of the free base and the concentrated solution mixed with ether, after which 1-(N-isopropyl-piperidyl-4')-2-methyl-4,4- diphenyl-3,5-diketo-pyrazolidine hydrochloride was crystallized, mp 235-239°

(sp) after recrystallization from ethanol/ether.

Example 11:

A solution of 2.53 g of di-n-butyl-malonyl-dichloride in 50 cm<3> of tetrahydrofuran was mixed with ice-cooling dropwise first with a solution of 1.71 f<.>-(N-isopropyl-piperidyl-4) -«'-methyl-hydrazine in 15 cm<3 >tetrahydrofuran and then with 2.02 g of triethylamine and the mixture heated with stirring for four hours to reflux. After cooling, the mixture was diluted with ether and extracted three times with 2-n. hydrochloric acid. The hydrochloric acid aqueous layer was made alkaline with cone. caustic soda and extracted three times with chloroform. The chloroform solution, after drying over sodium sulfate and evaporation in vacuo, left an oily crude product whose solution in 50 cm" of benzol was added to a column of 90 g of alumina. Benzol, as well as benzene-ether mixture 4:1, eluted 1-(N-isopropyl-piperidyl-4*)-2-methyl-4,4-di-n-tyutyl-3,5-diketo-pyrazolidine as an oily substance. To prepare the hydrochloride, dry hydrogen chloride was introduced into the ethanol solution of the free base, and the reduced solution was mixed with ether, whereupon 1-(N-isopropyl-piperidyl-4')-2-methyl-4,4-di-n The -butyl-3,5-diketo-pyrazolidine hydrochloride crystallized out. Temp. 237 -240° (sp) after recrystallization from ethanol/ether.

Example 12:

6.45 g of (N-methyl-piperidyl-4)-hydrazine and 9.4 g of diethylmalonic acid dimethyl ester were introduced into a solution of 2.3 g of sodium in 50 ems methanol. The methanol was then distilled off at atmospheric pressure and the remaining residue heated for 2 hours on a sinking cooler to 180°. The solid reaction mixture was taken up in 500 cm<3> of ethanol and the solution filtered off from a little undissolved. The clear filtrate was mixed with solid carbon dioxide in excess, filtered off from the salts that separated and the filtrate evaporated to dryness under reduced pressure. A semi-crystallized residue remained, from which pure 1-(N-methyl-piperidyl-4')-4,4-diethyl-3,5-diketo-pyrazolidine was isolated by fractional crystallization from ethanol and acetone, m.p. 186.5—190°. Example 13: In a solution of 23 g of sodium in 400 cm 3 of ethanol, 64.5 g of (N-methyl-piperidyl-4)-hydrazine and 94 g of dimethyl malonic acid diethyl ester were introduced. The ethanol was then distilled off under atmospheric pressure and the residue that was left was heated for two hours on a descending cooler to 180°. The solid reaction mixture was taken up in 3000 cm 3 of ethanol and the solution filtered off from a little undissolved. The clear filtrate was mixed with an excess of solid carbon dioxide, filtered off from precipitated salts and the filtrate evaporated to dryness under reduced pressure. A semi-crystalline residue remained, from which pure 1-(N-methyl-piperidyl-4')-4,4-dimethyl-3,5-diketo-pyrazolidine was isolated by fractional crystallization from methanol and ether. mp 262-266° (sp).

Example 1h:

10 g of diethylmalonyl dichloride were added

stirring and ice-cooling within 30 min. dropped into 30 cm<3> of hydrazine hydrate where a colorless precipitate was immediately precipitated. After 10 min of stirring, suction was carried out, washing with a little hydrazine hydrate and good squeezing. Diethylmalonic acid dihydrazide was obtained after recrystallization from abs ethanol in small plates which, on rapid heating, melted at about 140° while giving off hydrazine. Smp vec slow heating 255-265°.

To a solution of 4.7 g of diethylmalonic acid dihydrazide in 50 cm» of 1 n. hydrochloric acid, within 10 min. while stirring and ice-cooling, a solution of 3.45 µ sodium nitrite in 10 cm<3> of water was dripped in. After addition of 50 cm<3> of ether, the stirring was continued for another 20 min. and then filtration was carried out from a slightly precipitated precipitate. The ether layers separated from the filtrate were washed with sodium bicarbonate and sodium chloride solution and dried over sodium sulfate.

A solution of 3.2 g of N-methyl-piperidyl-4-hydrazine in 25 cm<3> of ether was added dropwise to the dried ether solution while stirring and cooling with ice. After 6 hours of stirring at room temperature, the mixtures were allowed to stand for three days and finally heated for four hours to reflux. After decanting off the above solution, the colorless, oily precipitate was distilled under high vacuum. Below 0.07 mm Hg, it passed at a bath temperature that rose from 14 to 180° over a large part of a colorless oil in The oil that passed below 0.07 mm H at a bath temperature that rose from 190-210° crystallized partial. From methanol, 1-(N-methyl-piperidyl-4')-4,4- diethyl-3,5-diketo-pyrazolidine which, after a single recrystallization from methanol/ether, melted at 190-195°.

Example 15:

12.90 g of N-methyl-piperidyl-4-hydrazine and 13.0 g of dimethyl-malonic acid diamide were introduced into a solution of 4.6 g of sodium in 100 cm" abs ethanol. The ethanol was then distilled off at atmospheric pressure, and the residue that remained was heated for five hours on a descending cooler to 170°. The reaction mixture was then dissolved

in ethanol, filtered, and the filtrate mixed with an excess of solid carbon dioxide. Filtration was carried out from the precipitated salts, and the filtrate was evaporated to dryness under reduced pressure. From the remaining residue, pure 1-(N-methyl-piperidyl-4')-4,4-dimethyl-3,5-diketo-pyrazolidine with mp 262-266° (sp) was obtained by fractional crystallization from methanol/ether .

Example 16:

12.9 g of N-methyl-piperidyl-4-hydrazine and 17.5 g of diethylmalonic acid ethyl esteramide were introduced into a solution of 4.6 g of sodium in 100 cm<3> abs of ethanol. The ethanol was then distilled off at atmospheric pressure and , the remaining residue heated for five

. hours with descending cooler to 180°.

I The reaction mixture was then taken up in

ethanol, filtered and the clear filtrate mixed

- with an excess of solid carbon dioxide. Filtration was carried out from the precipitated salts and - the filtrate was evaporated under reduced pressure to a dry state. From the remaining residue - by fractional crystallization from - ethanol/acetone pure 1-(N-methyl-t-piperidyl-4')-4,4-diethyl-3,5-diketo-pyra-t zolidine was obtained with m.p. 186 .5—190°. t For the production of 3,5-diketo-pyrazolidine derivatives are acylated in the 2-position for example, the following production method can be used: a A mixture of an a, «-disubstituted - malonyl dichloride, e.g. diethyl-malonyl-- dichloride with the calculated amount of a n o)-(N-alkyl-piperidyl-4)-co'-acyl-hydrazine, • t e.g. w-(N-methyl-piperidyl-4)-4-acetyl-:r hydrazine was mixed with an anhydrous organic solvent, e.g. tetra-.-hydrofuran with an acid binding agent, k preferably a tertiary organic base, e.g. :0 triethylamine and then heated for a certain time in. to boiling. The condensation can also be carried out without an acid-binding agent, but then with a - poorer yield. After the solution is cooled and diluted with ether, the 3,5-diketo-pyrazolidine derivative was formed which is

acylated in the 2-position, extracted with aqueous acid, released from the aqueous layer with alkali and extracted with chloroform. On evaporation, the dried chloroform solution gave the base in an almost solid crystallized state and can be recrystallized and/or transferred to a salt for purification.

Example 17:

a) Acetylhydrazone of N-methyl-4-piperidone.

A solution of 50 g of acetic acid hydrazide in 60 cm<3> of ethanol was mixed dropwise with 76.2 g of N-methyl-4-piperidone, during which the temperature of the mixture was maintained at no more than 40°. It was then heated to reflux for two hours and then evaporated to dryness in vacuo. Recrystallization from methylene chloride/petroleum ether gave the acetylhydrazone of N-methyl-4-piperidone in crystals with mp 108-109°. b) n-acetyl-o)'-(N-methyl-piperidyl-4)-hydrazine. 120 g of N-methyl-4-piperidone-acetylhydrazone was dissolved in a suspension of 1.0 g of platinum oxide in 500 cm<3> of glacial acetic acid and hydrated at atmospheric pressure and room temperature. When the calculated amount of hydrogen was taken up, filtration was carried out from the catalyst and the filtrate was evaporated in vacuum. The solution of the viscous residue was shaken out in 600 cm<3 >chloroform with 600 cm<3> 20% caustic soda cooled to 0°C and saturated with sodium chloride, the aqueous layer extracted twice each time with 500 cm<3 > chloroform and the combined llmmmmmmingy-ldi 00od0 -position chloroform extracts were, after drying over sodium sulfate, evaporated in vacuo. The crystalline residue gave on recrystallization from methylene chloride/ether "-(N-methyl-piperidyl-4)-co',-acetyl-hydrazine in crystals with mp 101-103°. c) 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolidine.

A solution of 19.7 g of diethylmalonyl dichloride in 40 cm<3> of tetrahydrofuran was mixed with stirring at room temperature with a solution of 17.1 g of w-(N-methyl-piperidyl-4)-«'-acetyl- hydrazine in 45 cm<3>tetrahydrofuran and then, with further stirring, 28 cm<3> triethylamine was added dropwise. The mixture was heated to reflux for four hours. After cooling, the solution, which had been diluted with 85 cm3 of ether, was extracted with 300 cm3 of 2-n. hydrochloric acid which had been cooled to 0°, the hydrochloric acid layer was made alkaline with concentrated caustic soda and extracted with 800 cm<3>rchloroform. The chloroform solution left, after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolidine as a crystalline residue. As the free base is very easily soluble in all common solvents, it was transferred to the hydrochloride to be purified. Gaseous hydrogen chloride was introduced into its solution in a little ethanol, until a litmus acid reaction and dilution was made with the same volume of acetone, after which the hydrochloride crystallized out. 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolidine hydrochloride. shows after recrystallization from ethanol/ether mp 195-199°

Example 18:

a) Benzoyl hydrazone of N-methyl-4-piperidone.

A solution of 27.2 g of benzoic acid hydrazide in 400 cm 3 of ethanol was mixed with 22.6 g of N-methyl-4-piperidone and the mixture heated to reflux for two hours. The residue of the reaction mixture after evaporation in vacuo gave, by recrystallization from benzene/ether, the benzoyl hydrazone of N-methyl-4-piperidone. mp 146-147°. b) co-(N-methyl-piperidyl-4)-o)'-benzoyl-hydrazine.

A solution of 34.6 g of N-methyl-4-piperidone-benzoyl-hydrazone was hydrated in 275 ems of glacial acetic acid in the presence of 400 mg of platinum oxide at room temperature and atmospheric pressure. After 4y2 hours, the theoretical amount of hydrogen was taken up, after which the solution, after filtration from the catalyst, was evaporated in a vacuum to a dry state. The solution of the viscous residue in 150 cm3 of chloroform was shaken out with 150 cm<3> of 20% caustic soda saturated with sodium chloride and cooled to 0°. The aqueous layer was extracted twice, each time with 120 cm» of chloroform, and the combined chloroform extracts were evaporated in vacuo after drying over sodium sulphate. The residue gave on recrystallization from benzol w-(N-methyl-piperidyl-4)-«/-otensoyl-hydrazine in crystals with m.p. 150°. c) 1-(N-methyl-piperidyl-4')-2-benzoyl-4,4-diethyl-3,5-diketo-pyrazolidine.

A solution of 19.7 g of diethylmalonyl dichloride in 50 cm3 of tetrahydrofuran was mixed with stirring at room temperature with a solution of 23.3 g of u>-(N-methyl-piperidyl-4)-w'-benzoyl-hydrazine in 50 cm3 of tetrahydrofuran, and then, with further stirring, 28 cm3 of triethylamine was added dropwise. The mixture was heated to reflux for four hours. After cooling and diluting with 100 cm3 of ether, the solution was extracted with 300 cm<3 >2-n. hydrochloric acid which was cooled to 0°, the hydrochloric acid aqueous layer was made alkaline with cone. caustic soda and extracted with 900 cm<3 >chloroform. The chloroform solution left, after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-benzoyl-4,4-diethyl-3,5-diketo-pyrazolidine as a crystalline residue. The free base melted at 104-105° after recrystallization from ether/petroleum ether.

In the solution of the base in a little ethanol, gaseous hydrogen chloride was introduced until litmus acid reaction, and dilution was carried out with an equal volume of acetone, after which the hydrochloride crystallized out. After recrystallization from ethanol/ether, the hydrochloride had a m.p. of 227-229 °.

Example 19:

A solution of 16.9 g of dimethylmalonyl dichloride in tetrahydrofuran was mixed with stirring with a solution of 17.1 g of w-(N-methyl-piperidyl-4)-w'-acetyl-hydrazine in tetrahydrofuran, after which 28 cm3 triethylamine was added dropwise with further stirring. The mixture was heated to reflux for three hours. Then the volume was doubled with chloroform, the solution washed twice with 2-n. soda solution, dried over sodium sulfate and evaporated in vacuo. In the solution of the oily residue in a little ethanol, hydrogen chloride gas was introduced until litmus acid reaction. After addition of ether, the hydrochloride of 1-(N-methyl-piperidyl-4')-2-aceyl-4,4-dimethyl-3,5-diketo-pyrazolidine crystallized out. After recrystallization from acetone/ether, the compound melted at 187-190°. (sp).

Example 20:

A solution of 25.32 g of di-n-butyl-malonyl-dichloride in tetrahydrofuran was mixed with 17.12 g of w-(N-methyl-piperidyl-4)-N'-acetyl-hydrazine while stirring

in tetrahydrofuran and with further stirring, 28 cm3 of triethylamine was added dropwise. The mixture was heated to reflux for four hours. After cooling and diluting with ether, the solution was extracted with 2-n. hydrochloric acid, the aqueous-acidic extract mixed with cone. caustic soda and shaken out with chloroform. The chloroform solution was dried and evaporated in vacuo. In the solution of the oily residue in a little ethanol, hydrogen chloride gas was introduced until litmus acid reaction,

the solution evaporated to dryness and the residue crystallized from acetone/ether. 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-di-n-butyl-3,5-diketo-pyrazolidine hydrochloride melted at 177-180° (sp).

Example 21:

A solution of 19.7 g of diethylmalonyl dichloride in tetrahydrofuran was mixed with stirring with 21.3 g of "-(N-n-butyl-piperidyl-4)-<o'-acetyl-hydrazine in tetrahydrofuran and, with further stirring, 28 cm3 of triethylamine was dripped in. The mixture was heated to reflux for three hours. After cooling and diluting with ether, the solution was extracted with 2-n. hydrochloric acid, the aqueous-acidic extract mixed with cone. caustic soda and shaken out with chloroform. The chloroform solution was dried and evaporated in vacuo. In the solution of the oily residue in a little ethanol, hydrogen chloride gas was introduced until litmus acid reaction, the solution was evaporated to dryness and the residue crystallized from acetone. 1-(N-n-butyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolidine hydrochloride melted at 213-216° (sp).

Example 22:

A solution of 32.1 g of dibenzyl-malonyl-dichloride in tetrahydrofuran was mixed with stirring with 17.12 g of "-(N-methyl-piperidyl-4)-w'-acetyl-hydrazine in tetrahydrofuran, and with further stirring 28 cm3 of triethylamine was then dripped in. The preparation took place as indicated in example 21. 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-dibenzyl-3,5-diketo pyrazolidine, which was obtained as an oil, was dissolved in a little ethanol , the solution mixed with methyl iodide and diluted with a little ether. After some time, 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-dibenzyl-3,5-diketo-pyrazolidine-iodomethylate crystallized out. After recrystallization from ethanol/ether, the compound melted at 230-232°.

Example 23:

A solution of 24.5 g of phenyl-ethyl-malonyl-dichloride in tetrahydrofuran was mixed under stirring with 17.12 g of <u-(N-methyl-piperidyl-4)-u>'-acetyl-hydrazine in tetrahydrofuran, and under with further stirring, 28 cm<3> of triethylamine were then added dropwise. The preparation took place as indicated in example 21. 1-(N-methyl-piperidyl-4')-2-acetyl-4-phenyl-4-ethyl-3,5-diketo-pyrazolidine boils at a bath temperature of 200-225 ° /0.2—0.5 mm Hg.

When the 3,5-diketo-pyrazolidine derivatives which are acylated in the 2-position are to be used for the production of 3,5-diketo-pyrazolidine derivatives with formula I, as stated above, the 3,5-diketo-pyrazolidine- derivatives that are acylated in the 2-position, e.g. The 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolide is dissolved in e.g. ether and heated to reflux together with a secondary amine, e.g. diethylamine. Here, the de-acetylated compound crystallizes directly.

Example 2A:

By condensation of 50 g of acetic acid hydrazide and 76.2 g of N-methyl-4-piperidone in 60 cm<3> of ethanol, the acetylhydrazone of N-methyl-4-piperidone was produced, m.p. 108—109 0 after recrystallization from methylene chloride/petroleum ether. A solution of 120 g of N-methyl-4-piperidone-acetyl-hydrazone in 500 cm<3> of glacial acetic acid was hydrated in the presence of 1.0 g of platinum oxide at room temperature and atmospheric pressure to <.>-(N-methyl-piperidyl-4 )-w-acetyl-hydrazine m.p. 101-103 0 after recrystallization from methylene chloride/ether.

A solution of 19.7 g of diethyl-malonyl-dichloride bg 17.1 g of w-(N-methyl-piperidyl-4)-w'-acetyl-hydrazine in tetrahydrofuran was mixed dropwise with 28 cm<3> of triethylamine and the mixture heated for four hours to reflux. After dilution with ether, the reaction solution was extracted with hydrochloric acid, the base liberated from the acid extract with cone. and extracted with chloroform. The chloroform solution left caustic soda, after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolidine as a crystalline residue.

A solution of 10.0 g of 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolide in 175 ems of hot ether was mixed with 9.0 g of diethylamine and heated to reflux for two hours. Below this, a de-acetylated compound crystallized out. A further amount was obtained by evaporating the mother liquor to a dry state and recrystallization of crystalline residue therein. After recrystallization from methanol/ether, 1-(N-methyl-piperidyl-4')-4,4-diethyl-3,5-diketo-pyrazolidine melted at 189-190°.

Example 25:

By condensing 27.2 g of benzoic acid hydrazide and 22.6 g of N-methyl-4-piperidone in 400 cm3 of ethanol, benzoylhydrazone was produced from N-methyl-4-piperidone, m.p. 146—147 0 after recrystallization from benzol/ether. A solution of 34.6 g of N-methyl-4-piperidone-benzoyl-hydrazone in 275 cm<3> of glacial acetic acid was hydrated in the presence of 400 mg of platinum oxide at room temperature and atmospheric pressure to w-(N-methyl-piperidyl-4)- w'-benzoyl hydrazone, m.p. 150 ° after recrystallization from benzol.

A solution of 19.7 g of diethylmalonyl dichloride and 23.3 g of a>'-(N-methyl-piperidyl-4)-co' benzenehydrazine in tetrahydrofuran was mixed dropwise with 28 cm 3 of triethylamine and the mixture heated for four hours to boiling with return flow. The reaction solution was, after dilution with ether, extracted with hydrochloric acid, from the acid extract the base was liberated with cone. caustic soda and extracted with chloroform. The chloroform solution left after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-benzoyl-4,4-diethyl-3,5-diketo-pyrazolidine as a crystalline residue.

An ether solution of 10.0 g of 1-(N-methyl-piperidyl-4')-2-benzoyl-4,4-diethyl-3,5-diketo-pyrazolidine was heated with 9.0 cm<3> diethylamine to boiling with reflux, as described in example 24. After similar work-up, 1-(N-methyl-piperidyl-4')-4,4-diethyl-3,5-diketo-pyrazolidine was obtained m.p. 189-190 °, identical to the substance obtained in example 24.

Example 26:

A solution of 16.9 g of dimethylmalonyl dichloride and 17.1 g of u-(N-methyl-piperidyl-4)-<u'-acetyl-hydrazine in tetrahydrofuran was mixed dropwise with 28 cm<3> triethylamine and the mixture heated for four hours to reflux. The reaction resolution. was, after dilution with ether, extracted with hydrochloric acid and from the acid extract the base was liberated with cone. caustic soda and extracted with chloroform. The chloroform solution left, after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-plperidyl-4')-2-acetyl-4,4-dimethyl-3,5-diketo-pyrazolidine as an oily residue.

A solution of 2.55 g of 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-dimethyl-3,5-diketo-pyrazolidine in 75 cm<3> of hot ether was mixed with 5 cm <3> diethylamine and heated 2l/ 2 hours to reflux. During this, the de-acetylated compound crystallized out. After recrystallization from methanol/ether 1-(N-methyl-piperidyl-4')-4,4-dimethyl-3,5-diketo-pyrazolidine at 264-266°.

Example 27:

A solution of 25.32 g of di-n-butyl-malonyl dichloride and 17.12 g of u>-(N-methyl-piperidyl-4)-u>'-acetyl-hydrazine in tetrahydrofuran was mixed dropwise with 28 cm<3 >triethylamine and the mixture heated to reflux for four hours. The reaction solution was, after dilution with ether, extracted with hydrochloric acid, the base liberated from the acid extract with cone. caustic soda and extracted with chloroform. The chloroform solution left after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-di-n-butyl-3,5-diketo-pyrazolidine as an oily residue.

A solution of 20.0 g of 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-di-n-butyl-3,5-diketo-pyrazolidine in 250 cm<3> of hot ether was mixed with 15 cm3 of diethylamine and heated for four hours to reflux. During this, the de-acetylated compound crystallized out. After recrystallization from benzoyl/petroleum ether, 1-(N-methyl-piperidyl-4')-4,4-di-n-butyl-3,5-diketo-pyrazolidine melted at 116-118°.

Example 2$ :

By condensation of 14.8 g of acetic acid hydrazide and 31.04 g of N-n-butyl-4-piperidone in 200 cm3 of ethanol, the acetylhydrazone of N-n-butyl-4-piperidone was produced, m.p. 76-78°. A solution of 39.2 g of (N-n-butyl-4-piperidone)-acetyl-hydrazone in 300 cm<3> of glacial acetic acid was hydrated in the presence of 400 mg of platinum oxide at room temperature and atmospheric pressure to w-(N-n-butyl -piperidyl-4)-io-acetyl-hydrazine, bp 81 °/0.3 mm Hg. m.p. 92-93° after recrystallization from methylene chloride-ether-petroleum ether.

A solution of 19.7 g of diethylmalonyl dichloride and 21.3 g of «-(N-n-butyl-piperidyl-4)-o>'-acetyl-hydrazine in chloroform was mixed dropwise with 28 cm3 of triethylamine and the mixture heated in 2Va hour to boil with reflux. The solution left after washing with 2-n. soda solution and drying over sodium sulfate and evaporation in vacuo 1-(N-n-butyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diketo-pyrazolidine as an oily residue.

A solution of 11.0 g of 1-(N-n-butyl-piperidyl-4')-2-acetyl-4,4-diethyl-3,5-diket pyrazolidine in 150 cc of hot ether was mixed with 10 cc of diethylamine and heated for four hours to reflux. After evaporation to dryness, the de-acetylated compound crystallized out. After recrystallization from methylene chloride-acetone, 1-(N-n-butyl-piperidyl-4'j-4,4-diethyl-3,5-diketo-pyrazolidine melted at 176-178°.

Example 29:

A solution of 32.1 g of dibenzyl-malonyl dichloride and 17.12 g of co-(N-methyl-piperidyl-4)-w'-acetyl-hydrazine in tetrahydrofuran was mixed dropwise with 28 cm 3 of triethylamine and the mixture heated for four hours for boiling with reflux. The reaction solution was, after dilution with ether, extracted with hydrochloric acid, the base liberated from the acid extract with cone. caustic soda and extracted with chloroform. The chloroform solution left after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-dibenzyl-3,5-diketo-pyrazolidine as a viscous residue which eventually crystallises.

A solution of 7.4 g of 1-(N-methyl-piperidyl-4')-2-acetyl-4,4-dibenzyl-3,5-diketo-pyrazolidine in 100 cm<3> of hot ether was mixed with 6, 0 cm3 of diethylamine and heated for two hours to reflux. During this, the de-acetylated compound crystallized out. After recrystallization from methylene chloride/ether, 1-(N-methyl-piperidyl-4')-4,4-dibenzyl-3,5-diketo-pyrazolidine melted at 210-212°.

Example 30:

A solution of 24.5 g of phenyl ether malonyl dichloride and 17.12 g of w-(N-methyl-piperidyl-4)-w'-acetyl hydrazine in tetrahydrofuran was mixed dropwise with 28 cm3 of triethylamine and the mixture heated in four hours to boil with reflux. The reaction solution was, after dilution with ether, extracted with hydrochloric acid, the base liberated from the acid extract with cone. caustic soda and extracted with chloroform. The chloroform solution left after drying over sodium sulfate and evaporation in vacuo 1-(N-methyl-piperidyl-4')-2-acetyl-4-phenyl-4-ethyl-3,5-diketo-pyrazolidine as an oily residue. A solution of 4.0 g of 1-(N-methyl-piperidyl-4')-2-acetyl-4-phenyl-4-ethyl-3,5-diketo-pyrazolidine in 75 cm» of hot ether 4 4-diphenyl -3,5-diketo-pyrazolidine was mixed with 4.0 cc of diethylamine and heated to reflux for 2½ hours. The reaction solution was then evaporated in vacuo to dryness and the oily residue heated with ether, during which the de-acetylated compound crystallized out. After recrystallization from methanol/water, 1-(N-methyl-piperidyl-4')-4-phenyl-4-ethyl-3,5-diketo-pyrazolidine melted at 238-240°.

Claims (7)

1. Process for the preparation of 3,5-diketo-pyrazolidine derivatives of the general formula I: where R, and R2 is an aliphatic, aromatic, aryl-aliphatic or alkyl-aromatic residue, R3 is H or alkyl (1 - 4 C), and R4 is alkyl (i - 4 C), characterized in that piperidyl-4'-hydrazines of the general formula II: where R3 has the above meaning or means an acyl group, is reacted with reactive derivatives of malonic acid with the general formula III: where X = Br, Cl, N3, O-alkyl or NH2, after which the possibly obtained 2-acyl-pyrazolidine compounds are treated with reagents which cleave the acyl group. 2. Procedure as stated in the condition 1 for the preparation of 3,5-diketo-pyrazolidine derivatives of formula I where R, = R2 = alkyl or aryl, R3 = H and R4 = alkyl, characterized in that (N-alkyl-piperidyl-4)-hydrazines with formula II, where R 3 and R 4 have the above meaning, are reacted with <*,ff-disubstituted malonic acid dihalides of formula III where R, and R 2 have the above meaning and X = chlorine or bromine. 3. Process as stated in claim 1 for the preparation of 3,5-diketo-pyrazolidine derivatives of formula I where R, = R2 = alkyl, R3 = H and R4 = alkyl, characterized in that (N-alkyl-piperidyl -4)-hydrazines of formula II, where R3 and R4 have the above meanings, are reacted with reactive malonic acid derivatives of formula III where X = OCH3, OC2H5, NH2 or N3. 4. Process as stated in claim 1, for the preparation of 3,5-diketo-pyrazolidine derivatives of formula I, where R and R2 can be different and mean aryl, alkyl or aralkyl, R3 = H and R4 = alkyl , characterized in that «-(N-alkyl-piperidyl-4)o)'-acyl-hydrazines of formula II, where R3 = acyl, are reacted with reactive malonic acid derivatives of formula III where X = Cl, Br, O-alkyl or N3 , and the 2-acyl-3,5-diketo-pyrazolidine derivatives that are thereby formed are treated with reagents that cleave off acyl groups. 5. Process as stated in claim 1 for the preparation of 3,5-diketo-pyrazolidine derivatives of formula I, where R and R2 can be different and mean alkyl, aryl or aralkyl, R3 = H and R4 = alkyl, characterized in that «-(N-alkyl-piperidyl-4)-u>'-acyl-hydrazines of formula II, where R3 = acyl, are reacted with reactive malonic acid derivatives of formula III, where X = Cl, Br, O- alkyl, NH2 or N3, and the 2-acyl-3,5-diketo-pyrazolidine derivatives which are formed are treated with primary or secondary amines or with ammonia to cleave off the acyl group. 6. Process as stated in claim 1 for the production of 1-(N-methyl-piperidyl-4')-4,4-diethyl-3,5-diketo-pyrazolidine, characterized in that diethylmalonic acid dichloride or a diester or an ester-amide of diethylmalonic acid is reacted with (N-methyl-piperidyl-4)-hydrazine or with a <u-(N-methyl-piperidyl-4)-«> '-acyl-hydrazine, and the 1-(N- methyl-piperidyl-4')-2-acyl-4,4-diethyl-3,5-diketo-pyrazolidine which is formed in the latter case is treated with diethylamine to cleave off the acyl group. 7. Process as stated in claim 1, for the production of 1-(N-methyl-piperidyl-4')-4,4-diphenyl-3,5-diketopyrazolidine, characterized in that diphenylmalonic acid dichloride or a diester or a diamide of diphenylmalonic acid is reacted with (N-methyl-piperidyl-4)-hydrazine or with an o)-(N-methyl-piperidyl-4)-w'-acyl-hydrazine, and the 1-(N-methyl- piperidyl-4')-2-acyl-4,4-diphenyl-3,5-diketo-pyrazolidine formed in the latter case is treated with diethylamine to cleave off the acyl group.