DE1090670B - Process for the preparation of 3,5-dioxo-pyrazolidine derivatives - Google Patents

Description

GERMAN

The subject of patent 1,063,170 is the preparation of 3,5-dioxo-pyrazohdin derivatives of the general Formula I.

Method of manufacture
of 3,5-dioxo-pyrazolidine derivatives

Addition to patent 1,063,170

R ₄ -C CO

OC N-H

10

in which R _{2 is} an alkyl radical and R ₃ and R _{4 are} alkyl, ao aryl, aralkyl, alkaryl or cycloalkyl radicals, by condensation of [N-alkyl-piperidyl- (4)] hydrazines with reactive α, α disubstituted malonic acid derivatives, such as dihalides, diesters, diamides, esteramides or diazides, preferably in the presence of a tertiary base.

It has now been found that these 3,5-dioxopyrazolidine derivatives can be obtained of the general formula I can also be achieved by referring to a compound of the general formula II

R ₃

CH

OC NH ₂ \ / »'

II

wherein R ₂ , R ₃ and R _{4 have} the above meaning, phosgene can act.

The method can e.g. B. be carried out so that a solution of co- [N-methyl-piperidyl- (4)] - ct) -diäthylacetylhydrazine in a suitable solvent, for. B. benzene or toluene, with a solution of triphenylmethyl sodium in abs. Ether added, and the benzene-ethereal solution of the resulting sodium applicant:
Sandoz AG, Basel (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland from July 24, 1957

Dr. Ernst Jucker, Binningen,

and Dr. Arnold Vogel, Basel (Switzerland),

have been named as inventors

compound of w- [N-methyl-piperidyl- (4)] - w-diethylacetylhydrazine with phosgene dissolved in a suitable solvent such as benzene or toluene, reacted.

The 3,5-dioxo-pyrazolidines which can be prepared according to the process are valuable medicines.

The derivatives of 3,5-dioxo-pyrazolidine prepared by the present process are at room temperature solid, crystallized bases, the salts stable with organic and inorganic acids form. They have pharmacodynamic properties that make them valuable drugs. So draw they are mainly characterized by an excellent anti-inflammatory effect, which they come in handy lack of toxicity makes valuable anti-rheumatic drugs. They are intended to be used therapeutically, but serve also as intermediate products for the manufacture of medicines.

In the compounds used as starting substances, the radicals R ₂ to R _{4 can,} for. B. have the following meanings: R ₂ alkyl groups, in particular lower alkyl groups, such as a methyl, ethyl, butyl or hexyl group; R ₃ and R _{4 are} alkyl groups such as methyl, ethyl, butyl or hexyl groups, substituted alkyl groups such as chloroethyl groups; Aryl groups such as phenyl or chlorophenyl groups; Aralkyl groups such as

009 627/410

Benzyl groups; Cycloalkyl groups such as cyclohexyl cooling dropwise with the solution of 8.26 g of digroups; Alkaryl groups such as tolyl groups. The residues of n-butylacetyl chloride are mixed in 10 ecm of methylene chloride, can be the same or different. Proceed as described in Example 1. Of the

The following examples serve to illustrate the oily residue is then in a high vacuum the execution of the procedure. 5 distilled, the co- [N-methyl-piperidyl- (4)] - ft) - (di-

n-butylacetyl) -a / isopropylidene hydrazine at 125 to Example 1 passes 130 ° C / 0.02mmHg. The splitting off of the iso-

100 g of [N-methyl-piperidyl- (4)] - hydrazine are dissolved in the propylidene group according to the procedure described in Example 1 using 300 ecm acetone with cooling and the process described. The starting substance is heated to boiling under reflux for ^{1 and} _{2 hours.} Evaporation of the w- [N-methyl-piperidyl- (4)] - (w-di-n-butylacetylder solution in vacuo yields the "- [N-methyl-piperhydrazine] melts at 66 to 67 ° C. after recrystallization idyl- (4)] - co'-isopropylidenehydrazine in quantitative extract from petroleum ether. 0.05 mol of this compound are recovered. It crystallizes on cooling in needles Purified, but rather sizing from benzene-petroleum ether melts the 1- [N-methyl acetylated. 15 piperidyl- (4 ')] - 4,4-dibutyl-3,5-dioxo-pyrazolidine at 116

The solution of 52.06 g of ra- [N-methyl-piperidyl- (4)] - to 119 ° C. Yield 7 to 8%.
<y'-isopropylidene hydrazine in 250 ecm chloroform is _.

while stirring and cooling dropwise with 42.0 g of example ό

Diethylacetyl chloride added, then the solution without The solution of 8.1 g of co- [N-methyl-piperidyl- (4)] -

Cooling 2 ¹ I ₂ hours, then cooled to 0 ° C 2 ° co'-isopropyHden-hydrazine (preparation see Example 1) in, washed with 20%, ice-cold sodium hydroxide solution, 25 ecm of methylene chloride is stirred and cooled with sodium sulfate dried and evaporated in a vacuum dropwise with the solution of 12.4 g of dibenzylacetyl. The residue is mixed with frac chloride in 10 ecm of methylene chloride in a high vacuum. One vertions. After a short advance, it continues below 0.4mmHg, as described in example 1. The back at 130 to 132 ° C ω- [N-methyl-ρiperidyl- (4)] - ω-diethyl 25 was fractionated in a high vacuum, with acetyl-co'-isopropylidene hydrazine over. 0.02 mm Hg and a bath temperature of 180 to 200 ° C

20.72 g of the isopropylidene compound are dissolved in 100 ecm of the co- [N-methyl-piperidyl- (4)] - cü-dibenzylacetyl-cü'-iso-90% ethanol and converted into the solution under ice propylidene hydrazine . The elimination of the isocooling hydrogen chloride initiated up to the strongly acidic propylidene group takes place according to the reaction on Congo paper in Example 1. After standing for 1 hour, follow the 3 ° procedure. The obtained cü- [N-methyl-piperidyl- (4)] - (w-diene), which is used as starting point at room temperature, is evaporated to the solution in vacuo (water bath temperature 40 ° C), a cylacetyl-hydrazine being converted from an ether-methylene-thick oil remains. this is dissolved in chloroform Open chloride petroleum ether mixture recrystallized. Prisgenommen thickness and with 20 ° / ₀ hydrochloric, ice-cold, men with sodium, F. 128-129 ° C. 0.05 mole of this compound chloride saturated sodium hydroxide solution, the Base is released. The 35 are reacted further analogously to Example 1. After the chloroform layer has been dried with sodium sulfate, it is crystallized from methylene chloride-acetone which melts in vacuo. The residue is made from 1- [N-methylpiperidyl- (4 ')] -4, 4-dibenzyl-3,5-dioxo-pyrazole-ether — petroleum ether recrystallized. Pure "- [N-methylidyne at 210 to 212 ° C. Yield about 5%.
piperidyl- (4)] - a> -diethyIacetylhydrazine, which is used as the starting point. .

used, melts at 121 to 124 ⁰ C. 4 ° Example 4

To a solution of 0.04MoI triphenylmethyl- The preparation of the starting substance

Sodium in abs. A co- [N-methyl-piperidyl- (4)] - co-dimethylacetylhydrazine solution of 0.04 mol ft) - [N-methyl-piperidyl- (4)] - a> -di is left in ether with stirring - takes place analogously to the Arbeitsäthylacetylhydrazine described in Example 1 in abs. Add benzene dropwise, being wise by introducing [N-methyl-piperidyl- (4)] - hydrazine with nitrogen at the same time. After the acetone has reacted, the resulting isopropylidene added dropwise is stirred for a further 20 minutes and acylated dung with dimethylacetyl chloride and then a benzene phosgene solution (containing 0.04 mol of the isopropylidene group by ethanolic chlorophosgene) is slowly added, whereupon the mixture is slowly added VJ splits off hydrogen for _{2 hours.} After releasing the base it is heated to boiling. After cooling, chloroform with sodium chloride saturated sodium hydroxide solution is added to ice water, the aqueous layer is separated in a 5 °, the chloroform separating funnel, dried over sodium sulfate, is shaken off thoroughly and the layers are evaporated. The resulting <w- [N-methylpiper-extracts the benzene-ethereal layer twice more idyl- (4)] ^ - dimethylacetylhydrazine is directly further with water. The combined aqueous solutions are processed by evaporating 4 g of the residue (0.02 mol) to dryness in vacuo, the residue in abs. Benzene dissolves and a solution of 0.02 mol with a solution of 0.04 mol of sodium in methanol 55 triphenylmethyl sodium in abs. Ether is added with stirring, and the mixture is allowed to drip in well over the course of 5 minutes, with nitrogen being introduced at the same time and shaking. After removing the excreted is. After the end of the dropwise addition, stirring of sodium chloride is carried out, the filtrate is stirred in vacuo to dryness for 25 minutes and then a benzene solution is evaporated in drops, the residue is slowly dissolved in a benzene-chloroform-phosgene solution (containing 0.02 mol of phosgene) and a mixture (4: 1) the solution of aluminum oxide 60 to whereupon the mixture I ¹ Z _{heated to boiling for 2} hours (Brockmann) chromatographed, the 1- [N-methyl- is. Then proceed as in Example 1. After umpiperidyl- (4 ')] - 4,4-diethyl-3,5-dioxo-pyrazolidine crystallize with ChIo from methanol-ether melts the 1- [N-meroform and chloroform-ethanol eluted will. After thyl-piperidyl- (4 ')] - 4,4-dimethyl-3,5-dioxo-pyrazolidine with two recrystallizations from methanol-ether 262 to 265 ° C (decomposition). The yield is about 8 ° / _0th

the compound melts at 188 to 189 ° C. Yield 9%. 65 ". ""

Example 5

^ei P ^ie The production of the starting substance

The solution of 7.34 g of co- [N-methyl-piperidyl- (4)] - «- [N-methyl-piperidyl- (4)] - cu-diphenylacetylhydrazine

co'-isopropylidene hydrazine (prepared according to Example 1) is carried out analogously to the procedure described in Example 1 30 ecm of methylene chloride is added with stirring and ice-7 ° by using [N-methyl-piperidyl- (4)] - hydrazine

Reacts acetone, the isopropylidene compound formed is acylated with diphenylacetyl chloride and then the isopropylidene group is split off by ethanolic hydrogen chloride. After liberating the base in chloroform with sodium chloride saturated sodium hydroxide solution, the dried over sodium sulfate chloroform layer is t-evaporated. The co- [N-methyl-piperidyl- (4)] - ß) -diphenylacetylhydrazine obtained is further processed directly by adding 16 g of the residue (0.05 mol) in abs. Benzene dissolves and a solution of 0.05 mol of triphenylmethyl sodium in abs. Ether can be added dropwise with stirring, nitrogen being introduced at the same time. When the dropwise addition is complete, the mixture is stirred for a further 25 minutes and a benzene phosgene solution (containing 0.05 mol of phosgene) is slowly added dropwise, whereupon the mixture is heated to the boil for ^{1 x} / _{2 hours.} Then work up analogously to Example 1. After recrystallizing twice from methanol-ether, the 1- [N-methyl-piperidyl- (4 ')] - 4,4-diphenyl-3,5-dioxo-pyrazolidine melts at 258 to 263 ° C. Yield 10 to 11%.

Example 6

The βj- [N-butyl-piperidyl- (4)] - o) -diethylacetylhydrazine is produced as the starting substance analogous to the procedure described in Example 1, by [N-butyl-piperidyl- (4)] - hydrazine with acetone reacts, the isopropylidene compound formed is acylated with diethylacetyl chloride and then the isopropylidene group split off by ethanolic hydrogen chloride. After releasing the base in chloroform with sodium chloride saturated sodium hydroxide solution, the chloroform layer, dried over sodium sulfate, is evaporated. The obtained a> - [N-butyl-piperidyl- (4)] - co-diethylacetylhydrazine is processed further directly by adding 11 g of the residue (0.04MoI) in abs. Benzene dissolves and to a solution of 0.04 mol of triphenylmethyl sodium in abs. Lets ether drip in while stirring, at the same time nitrogen is introduced. The procedure is then as in Example 1. After recrystallization from Methylene chloride — acetone melts the 1- [N-butyl-piperidyl- (4 ')] - 4,4-diethyl-3,5-dioxo-pyrazolidine at 176-178 ° C. Yield about 7%.

Example 7

The ß) - [N-methyl-piperidyl- (4)] - o) -ethylphenylacetylhydrazine, which is used as the starting substance, is prepared analogously to the procedure described in Example 1 by [N-methyl-piperidyl- (4)] - hydrazine is reacted with acetone, the isopropylidene compound formed is acylated with ethylphenylacetyl chloride and the isopropylidene grape is then split off by means of ethanolic hydrogen chloride. After liberating the base in chloroform with sodium hydroxide solution saturated with sodium chloride, the chloroform layer, dried over sodium sulfate, is evaporated. The ω-pSi-methyl-piperidyl- (4)] - o) -äthylphenylacetylhydrazine obtained is further processed directly by adding 11 g of the residue (0.04 mol) in abs. Benzene dissolves and a solution of 0.04MoI triphenylnethyl sodium in abs. Ether can be added dropwise with stirring, nitrogen being introduced at the same time. After the end of the dropwise addition, stirring is continued for a further 25 minutes and a benzene phosgene solution (containing 0.04 mol of phosgene) is slowly added dropwise, whereupon the mixture I ¹ Z is heated to the boil for _{2 hours.} Then work up as in Example 1. After two recrystallizations from methanol-water, the l- [N-methyl-piperidyl (4 ')] melts - 4-ethyl-4-phenyl-3,5-dioxo-pyrazolidin at 237-240 ⁰ C. Yield 6 ⁰ Z ₀ . The production of the starting substances is not claimed.

Claims (1)

Claim: Modification of the procedure according to patent 1063170 for the preparation of 3,5-dioxo-pyrazolidine derivatives of the general formula I. R ₄ -C -CO OC Ν —Η in which R _{2 is} an alkyl radical and R ₃ and R _{4 are} an alkyl, aryl, aralkyl, alkaryl or cycloalkyl radical, characterized in that a compound of the general formula II R ₃ R ₄ -CH OC NH ₂ wherein R ₂ , R ₃ and R _{4 have} the above meaning, phosgene can act. © 009 627/411) 10.60