DE1926024A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

Dr 'W. S. Sc'k. Γ »· -'- Ing. P. Wirth I 3 4 O U * H

Dipl .-! - · G. O-.r.onberg

Dr. V. ι "Kowarzik

Dr. P. Wv; , .- κ. ,,. Dr. D. Gua'el "

6 Fronk (url; M " Gr. Ti..i. .N.ieimer Str. 39.

SANDOZ AG. Case 10-2915 Basel. -

Process for the preparation of new heterocyclic compounds

The present invention relates to a process for the preparation of new N ¹ -substituted N-acylpyrazolidine compounds, which is characterized in that an aldehyde or one of its reactive functional derivatives, an N ¹ -monosubstituted N-acylhydrazine and an olefin whose C / C double bond is built into a strained ring system and / or is conjugated to at least one further multiple bond, are reacted with one another with the escape of water. ^{The new N 1} -substituted N-acyl-pyrazolidine compounds produced by the process according to the invention are likewise encompassed by the present invention.

As an aldehyde component, for example, formaldehyde, benzaldehyde or 4-nitrobenzaldehyde can be used ( the formaldehyde can also be used in the polymeric form known as paraformaldehyde), and as a reactive functional derivative of an aldehyde, for example, ethyl glyoxylate-ethyl half-acetal. Suitable hydrazine components include N-methyl-N ¹ -phenylacetylhydrazine, N-acetyl-N ¹ -methylhydrazine, N-acetyl-N'-isopropylhydrazine, N-acetyl-N ¹ -benzylhydrazine, N-acetyl-N'-phenylhydrazine, N-dimethylaminoacetyl-N'-methylhydrazine, N- ( ² l-methyl-l-piperazinyl) acetyl ~ N ^! -methylhydrazine, N-acetyl-N ¹ - (1-methyl-lJ-pIperidyl) -hydrazine etc. The C / C double bond of the olefin component is built into a strained ring system ( ^like ^ Ä ^ 8 ^ gB- in norbornene, Benzonor -

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bornadiene or 1,4-dihydro-1,4-epoxynaphthalene is the case) and / or conjugated with at least one further multiple bond, e.g. with an aromatic system such as the benzene ring, a C / N triple bond or a C / O double bond, such as are present, for example, in a cyano or ethoxycarbonyl group; Examples of suitable olefin components with conjugated C / C double bonds are styrene, acrylic acid ethyl ester, Ethyl cinnamon ester, 1,1-diphenylethylene, 1,2-dihydronaphthalene, Acrylonitrile or indene.

The procedure can be carried out as follows, for example:

The three components are mixed with one another, the aldehyde component (or the reactive functional aldehyde derivative) or the olefin component being used in excess and thus serving as a solvent; according to another embodiment, the three components are added in equimolar amounts in an inert organic solvent under the reaction conditions, which permits removal of the water formed in the reaction by azeotropic distillation, i as in benzene, toluene, dioxane, dimethylformamide, etc. The ζ The mixture is then refluxed for approx. 1-10 hours, the condensate flowing back from the cooler through a water separator or (e.g. in a Soxleth apparatus) through a solid drying agent, such as in particular so-called molecular sieves or magnesium sulfate, calcium sulfate etc., is directed. But it is also possible to introduce the drying agent into the reaction mixture. According to a variant of the process, the aldehyde component (or the reactive functional aldehyde derivative) is first reacted with the hydrazine component, e.g. by briefly heating to approx. 50 ° in a suitable organic solution which is inert under the reaction conditions

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medium, such as 1,2-DiTnethoxyäthaTii the resulting intermediate is then - possibly after previous isolation and purification - for 1 - ID hours under the otien described water-separating conditions with the olefin component "at elevated temperature reacted, wherein the olefin component is presented in a suitable inert solvent or used in excess.

According to a further variant of the method, the Aldehyde component (or the reactive, functional aldehyde derivative) under the above-described water-separating conditions with the hydrazine component, the reaction temperature being expediently should not exceed approx. 115 ° ;; the intermediate product obtained is then - without previous isolation and purification - reacted with the olefin component at elevated temperature, wherein the olefin component is either initially introduced into a suitable inert solvent or used in excess.

After the reaction has ended, the N ¹ -substituted N-acylpyrazole oil produced according to the invention can be isolated in the usual way, for example by evaporation of the reaction mixture, and purified by known methods, for example by chromatography, crystallization, distillation, etc. N-ethylpyrazole lines have so far been used Accessible only to a limited extent _, in particular through acylation of the corresponding pyrazolidines, which in turn have to be prepared by relatively complicated and expensive processes. The process according to the invention now allows the synthesis of a broad class of N ¹ -substituted M-acylpyrazolidine compounds in a one-step reaction, with mostly excellent yields and also using simple, easily accessible starting materials. So were

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e.g. numerous ring systems produced with a previously unknown degree of hydrogenation.

It should also be emphasized that the process using isomer-free 1,2-disubstituted olefin components gives pyrazolidines in which the two ring carbon atoms resulting from the olefin component used have a relative configuration which corresponds to that of the olefin component (cis or trans) . For example, formaldehyde and N-methyl-M ¹ -phenylacetylhydrazine give cis-1-methyl-2-phenylacetyl-1,2,3, J5a in the reaction with indene (which can be regarded as 1,2-cis-disubstituted olefin) ₃ 4,8b-hexahydroindeno [1,2-cJpyrazole, in the reaction with ethyl cinnamate, however, trans-3-ethoxycarbonyl-1-methyl-phenylacetyl- ^ -phenyl-pyrazolidine or trans-Ί-ethoxycarbonyl-1-methyl-2- phenylacetyl-3-phenylpyrazolidine. A stereospecific reaction is also obtained from ethyl glyoxylate-ethyl hemiacetal, N-methyl-N'-phenylacetylhydrazine and indene (3SR, 3aSR, 8bSR) -l-methyl-2-phenylacetyl-1,2, 3 , 3a , 4, 8b-hexahydroindeno [1,2-c J pyrazole-3-carbonic acid ethyl ester, in which the two 5-south rings show cis linkages, etc.

The N ¹ -substituted N-acylpyrazolidine compounds prepared according to the invention can be used as versatile intermediates in the synthesis of organic compounds, in particular in the production of valuable medicinal products.

The following examples illustrate the invention in more detail explain, but should not limit their scope in any way, all temperatures are given in degrees Celsius, without corrections.

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Example 1: 1-methyl-2-phenylacetyl -> - phenylpyrazolide

A mixture of 1.64 g of N-methyl-N ¹ -phenylacetylhydrazine, 6 ml of toluene, 6 ml of styrene and 1.5 g of paraformaldehyde is refluxed under a nitrogen atmosphere for 21/2 hours, the condensate being removed for the purpose of removal of the water split off during the reaction passes through 4 g of molecular sieve. The reaction mixture is evaporated, the residue is applied to 14 g of silica gel and eluted with 50 ml of benzene / ethyl acetate (1: 1). The eluate is evaporated, the compound named in the title remaining as a residue; M.p. 99 100 °, after crystallization from ether.

Example 2: 1-methyl-2-phenylacetyl-3-phenylpyrazolidine .

A solution of 1.64 g of N-methyl- N'-phenylacetyl hydrazine in 20 ml of 1,2-dimethoxyethane is mixed with 0.9 ml of a 58% aqueous formaldehyde solution, the mixture is heated to 50 ° for 5 minutes and the reaction mixture is evaporated at 25 ° ° / l5 now Hg. The residue is dried for 30 minutes at 25 ^O / Q> 1 mm Hg and then taken up in 15 ml of methylene chloride / ether (1: 1); After standing for 20 hours, the precipitated crystals are filtered off, washed with methylene chloride / ether and dried. Further crystals separate out from the mother liquor after 16 hours and are isolated as above. After crystallization from methylene chloride, the N '-' hydroxymethyl ^ N'-methyl-phenylacetic acid hydrazide melts at 92-93 °.

A mixture of 0 * 78 g of N'-hydroxymethyl ^ N'-methyl-phenylacetic acid hydrazide, 8 nil of toluene and 4 ml of styrene is used for 2 1/2 Hours under reflux under a nitrogen atmosphere heated, whereby manι the, Koncfens ^ t, for the purpose of removing the at

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the reaction split off water over 4 g molecular sieve directs. Working up is carried out as described in Example 1; the compound mentioned in the title is obtained from the smp. 99 - 100 ° (from ether).

example J: J5-Aethoxycarbony 1-1-methyl-2-pheny / acetylpyrazolldln

A mixture of 1.64 g of N-methyl-N'-phenylacetylhydrazine, 6 ml of toluene, 8 ml of ethyl acrylate and 1.5 g of paraformaldehyde is refluxed under a nitrogen atmosphere for 2 1/2 hours, the condensate being passed through 4 g Molecular sieve conducts. The evaporated reaction mixture is chromatographed on 130 g of silica gel with benzene / ethyl acetate (3: 1), 100 ml fractions being collected. When fractions 5-9 are evaporated, the compound mentioned in the title is obtained as an oily residue which is crystallized from ether / pentane at -20 ° and then melts at 33.

Example 4; 3-ethoxycarbonyl-1-methyl-2-phenylacetylpyrazolldin

A mixture of 1.64 g of N-methyl-N'-phenylacetylhydrazine, 1.5 S paraformaldehyde and 12 ml of toluene is refluxed for 16 hours under a nitrogen atmosphere, the condensate being passed over 4 g of molecular sieve. The reaction mixture is then cooled to 0 ° and filtered; After adding 6 ml of ethyl acrylate, the piltrate is refluxed for 2 1/2 hours. After processing (as in

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Example 3 described) one obtains pure 3-ethoxycarbonyl 1-methyl-2-phenylacetylpyrazolidine of m.p. 33-3 °.

Example 5:

hyd roindeno [1,2-c] pyrazole

A mixture of 1.64 g of N-methyl-N ¹ -phenylacetylhydrazine, 6 ml of toluene, 12 ml of indene and 1.5 g of paraformaldehyde is refluxed under a nitrogen atmosphere for 2 1/2 hours, the condensate being passed over 4 g molecular sieve conducts. The reaction mixture is evaporated and the residue is chromatographed on 100 g of silica gel with benzene / ethyl acetate (9: 1), while fractions of 100 ml are collected. When fractions 4-6 are evaporated, the compound named in the title remains as a crystalline residue; it is recrystallized from ether and then melts at 92.5 ° -93.5 °.

Example 6: trans-3-ethoxycarbonyl-1-methyl-2-phenylacetyl- -4-phenyl-pyrazolidine or trans-4-ethoxycarbonyl-1-methyl-2-p'n ouy incetyl-3-phenyl-pyrazolidine

A mixture of 1.64 g of N-methyl-N ¹ -phenylacetylhydrazine, 8 ml of toluene, 3 ml of ethyl trans-cinnamate and 1 * 5 g of paraformaldehyde is refluxed under a nitrogen atmosphere for 3 1/2 hours, the condensate being poured over 4 g molecular sieve conducts. The reaction mixture is then left to stand at 25 ° for 16 hours, filtered and evaporated. The residue that remains is chromatographed on 28 g of silica gel with benzene / ethyl acetate (9: 1), fractions of 28 ml being collected. When fractions 2-4 are evaporated, a uniform, oily product remains, which after crystallization

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from ether / pentane melts at 65 ° -65 °; it is a matter of
one of the two compounds mentioned in the title.

. Example 7; 2-acetyl-3,5-diphenyl-1-methyl-pyrazolidine

A mixture of 4.4 g of N-acetyl-N ¹ -methylhydrazine, 5.3 S benzaldehyde and 60 ml of toluene is refluxed for 9 hours, the condensate being gelled over 4 g of molecular sieve. The reaction mixture is then cooled to 20 ° and filtered; the filtrate is evaporated. A solution of 1 g of the oily residue in 2 ml of styrene is stirred for 20 hours at 110 ° under nitrogen. The excess styrene is then evaporated off at 30.degree. / 0.1 mm Hg, a mixture of the cis and trans forms of the compound mentioned in the title remaining. The residue is on 50 g of silica gel with benzene / ethyl acetate
(9: 1) chromatograph, collecting fractions of 50 ml. On evaporation, fractions 8 and 9 give one of the two stereoisomers as a pure oily product. NMR spectrum: (CDCl3): 3H (s) / = 2.20, 2H (signal cluster) o ° = 2.3-3.0,
3H (sK = 2.8l, lH (t, J = 5) cf = 4.2, lH (t, J = SK ^, 33,
ppm.

When fractions 11 and 12 are evaporated, the other stereoisomer remains as a residue.

Example 8;

hydrobenz [g] indazole

Into a refluxing mixture of 160 g 1,2-dihydronaphthalene and 120 ml of toluene is a mixture of 68 g of N-methyl-N'-phenylacetylhydrazine and within 9 hours

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16.5 R paraformaldehyde was added in 10 portions of 8.5 g each, the condensate flowing back from the cooler being passed through a water separator. The reaction mixture is then evaporated, the residue is applied to 500 g of silica gel and eluted first with 1.5 It benzene and then with 7 It benzene / ethyl acetate (9: 1) *, collecting fractions of 0.5 IU. When fractions 4-18 are evaporated, the compound mentioned in the title remains as a residue; M.p. 70.5-71 * 5 ° after crystallization from ether / pentane.

Example 9; l-methyl-2-phe nylacety lp yrazolidine-3-carbonltril and
1-methyl-2-phenylacetylpyrazolidine-4-carbonitrile

A solution is added of 1.64 g of N-methyl-N'-phenylacetylhydrazine in 20 ml lj, 2-dimethoxyethane with 0.9 ml of an aqueous formaldehyde solution 38ioigen., Heated 5 minutes at 50 ° and evaporation, the reaction mixture at 25 ^O / 15 mm Hg a. The residue will be 30 minutes at 25VOj! mm Hg dried and then taken up in 15 ml of methylene chloride / ether (1: 1)? After standing for 20 hours, the precipitated crystals are filtered off, washed with methylene chloride / ether and dried. After 16 hours, further crystals separate from the mother liquor and are isolated as above. After crystallization from methylene chloride, the M'-hydroxymethyl-N'-methyl-phenylacetic acid hydraside melts at 92 - 93 ° »

A solution of 1.94 g of N ¹ -hydroxymethyl-U'-methyl-phenylacetic acid hydrazide in 15 ml of hot benzene is refluxed for 1 hour, the condensate being passed through a water separator 8 ml of acrylonitrile in a pressure vessel during

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Heated to 120 ° for 5 hours. The reaction mixture is evaporated and the residue is chromatographed on 120 g of silica gel with benzene / ethyl acetate (1: 1), fractions of 120 ml catches. Evaporation of fractions 4-6 gives 1-methyl-2-phenylacetylpyrazolidine-; 3-carbonitrile of melting point 68 - 69 ° (after crystallization from ether / pentane) j fractions 7-8 give 1-methyl-2-phenylacetylpyrazolidine-4-carbonitrile on evaporation of m.p. 84-86 ° (after crystallization from ether / pentane).

W. Example IQ: 2-Acetyl-3,3-diphenyl-1-methylpyrazolidine

A mixture of 0.88 g of N-acetyl-N'-methylhydrazine, 8 ml of toluene, 6.4 g of 1,1-diphenylethylene and 1.0 g of paraformaldehyde is refluxed under a nitrogen atmosphere for 4 hours, the Condensate passes through 4 g of molecular sieve, the reaction mixture is evaporated and the residue is chromatographed on 100 g of silica gel first with 400 ml of benzene / ethyl acetate oil) and then with 600 ml of ethyl acetate, collecting fractions of 100 ml. Evaporation of fractions 5-10 gives the compound named in the title; Mp. 12j 124 °, after crystallization from ether.

Example 11: 2-Acetyl- 1-isopropyl-3-phenylpyrazolidine

A mixture of 17 * 4 g of N-acetyl-N'-isopropylhydrazine, 90 ml Toluene, 90 tnl styrene and 6 g paraformaldehyde is heated to the boil under a nitrogen atmosphere at reflux, whereby the Condensate passes through a water separator. The residue remaining on evaporation of the reaction mixture becomes on

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100 g of silica gel first chromatographed with 300 ml of benzene and then with 1000 ml of benzene / ethyl acetate (3: 1), fractions of 300 ml being collected. When fractions 2-4 are evaporated, the compound mentioned in the title is obtained as an oily product. Nuclear Magnetic Resonance Spectrum (CDCI,): 6H (signal clusters) 6 : 0.8-1.4, 7H (signal clusters) «f: 2.0-3.15, IH (m) S : 3.4, IH (t ) J = 8.5 cpsf: 5.38, 5H (s) ο: 7.3 ppm.

Example 12: 2-Acetyl-1-benzyl-3-phenylpyrazolidine

A mixture of 1.64 g of N-acetyl-N ¹ -benzylhydrazine, 12 ml of toluene, 8 ml of styrene and 0.4 g of paraformaldehyde is refluxed for 8 hours under a nitrogen atmosphere, the condensate being passed through 4 g of molecular sieve. The residue remaining on evaporation of the reaction mixture is chromatographed on 150 g of silica gel first with 300 ml of benzene and then with 1050 ml of benzene / ethyl acetate (9: 1), 150 ml fractions being collected. Evaporation of fractions 5-9 gives the compound named in the title; Melting point 94 96 ⁰ after crystallization from ether / pentane.

Example 13:

indeno [1,2-c] pyrazole

A mixture of 1.64 g of N-acetyl-N'-benzylhydrazine, 12 ml of toluene, Γ "ml of indene and 0.4 g of paraformaldehyde is added under nitrogen atmosphere heated to boiling under reflux for 6 hours, the condensate being passed through 4 g of molecular sieve. Man the reaction mixture is evaporated and the residue is chromatographed on 12 g of silica gel with 30 ml of benzene, followed by

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6O ml benzene / ethyl acetate (3: 1), fractions of 30 ml catches. Evaporation of fractions 2-3 gives the compound named in the title; M.p. 99-100 °, after crystallization from ether / pentane.

Example 14: cis-l-y \ cetyl-2-benzyl-1,3,3a, 4,5,9b-hexahydrobenz [gjindazole

In a refluxing mixture of 4 ml of 1,2-dihydronaphthalene and 12 ml of toluene, a mixture of 1.64 g of N-acetyl-N ¹ -benzylhydrazine and 0.4 g of paraformaldehyde in 10 portions of 0 , 2 g entered, the reflux condensate being passed over 4 g molecular sieve. The reaction mixture is then refluxed for a further 5 hours and then evaporated. The residue is chromatographed on 12 g of silica gel with 30 ml of benzene, followed by 60 ml of benzene / ethyl acetate (3: 1), and fractions of 30 mm are collected. When fractions 2-3 are evaporated, the compound named in the title remains as a residue! M.p. 110-111 °, after crystallization from ether / pentane,

Example 15: ei s-1-Acetyl-2-phenyl-1,2,3,3a, 4,8b-hexahydroindeno [1,2-c jpyrazole

To a refluxing mixture of 300 ml indene and 300 ml of toluene are added over the course of 9 hours to a mixture of 45 g of N-acetyl-N'-phenylhydraain and 12 g of paraformaldehyde in 10 portions of 5 * 7 g each, with the reflux condensate passes through a water separator. Then the reaction

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tion mixture heated to boiling under reflux for a further 5 hours and then evaporated. The residue is applied to 1600 g of silica gel and washed successively with 6 It benzene, 2 It benzene / ethyl acetate (9: 1) and then with 6 It benzene / ethyl acetate (3: 1) eluted, collecting fractions of 2 It. When fractions 3-5 are evaporated, the compound named in the title remains as a residue; M.p. 115 - H7 °> after crystallization from ether / pentane.

Example 16: 4,7-Methano-2-methyl-1-phenylacetyl-2,3 _> 3a, 4.5 »6.7» 7a.-octahydro-1H-indazole

A mixture of 1.64 g of N-methyl-N ¹ -phenylacetylhydrazine, 12 ml of toluene, 14 g of norbornene and 1.5 g of paraformaldehyde is refluxed for 9 hours under a nitrogen atmosphere, the condensate being passed through 4 g of molecular sieves. The reaction mixture is evaporated and the residue is chromatographed on 60 g of silica gel with benzene / ethyl acetate (1: 1), fractions of 60 ml being collected. When fractions 3-5 are evaporated, the compound named in the title is obtained as a residue which slowly crystallizes through. The greasy crystals are pressed onto clay and recrystallized twice from ether / pentane at -20 °; M.p. 55 »5 - 56.6 °.

Example 17: 4,9-Methano-2-methyl-1-phenylacetyl-2,3,3a, 4,9 _> 9a-hexahydro-1H-benz [flindazole

A mixture of 1.64 g of N-methyl-N ¹ -phenylacetylhydrazine »10 ml of toluene, 4.3 g of benzonorbornadiene and 0.4 g of paraformaldehyde is refluxed under a nitrogen atmosphere for 9 hours, the condensate being passed through 4 g of molecular sieves IeI-

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tet. The reaction mixture is evaporated in a high vacuum and the residue crystallizes from ether / pentane, giving the compound mentioned in the title with a melting point of .105 ° -118 °.

Example 18: 4,9-Epoxy-2-methyl-1-phcnyllactyl -2,3,3a, 4 , 9 , 9ahexahydro-1H-benz {fjindazole

A mixture of 1.3 g of N-methyl-N ^r -phenylacetylhydrazine, 10 ml of toluene, 3.4 S l, 4-dihydro-l, 4-epoxynaphthalene and 0.3 g of paraformaldehyde is refluxed for 3 hours under a nitrogen atmosphere heated, the condensate being passed through 4 g of molecular sieve. The reaction mixture is evaporated in a high vacuum and the residue is crystallized from ether / pentane, giving the compound mentioned in the title with a melting point of 123 ° -125 °.

Example 19: (3RS _> 3aRS, 8bRS) -2-methyl-1-phenylacetyl-1,2,3 _> 3a, 4,8b-hexahydroindeno [1,2-c} pyrazole-3-carboxylic acid ethyl ester

A mixture of 1.64 g of N-methyl-N ¹ -phenylacetylhydrazine, 1.62 g of ethyl glyoxylate, ethyl hemi-acetal, 12 ml of indene and 12 ml of toluene is refluxed for 20 hours, the condensate being passed through 4 g of molecular sieves. The reaction mixture is evaporated and the residue is chromatographed on 40 g of silica gel with 200 ml of benzene, followed by 350 ml of benzene / ethyl acetate (9: 1), 50 ml fractions being collected. Evaporation of fractions 6-11 gives an oily residue which, after crystallization from ether / pentane, gives a first portion of the compound mentioned in the title with a melting point of 93 ° -95 °. The mother liquor gives after fractional distillation

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lation an oily distillate - bp 150-160 ° / 0.01 mm Hg, which, after crystallization from ether / pentane, gives a further portion of the compound mentioned in the title with a melting point of 93 ° -95 °.

For game 20: 3-Acetyi-2-methyl-3- (4-nitrophenyl) -5-phenyl-

pyrazolidine

A mixture of 0.9 g of N-acetyl-N ¹ -methylhydrazine, 10 ml of toluene, 8 ml of styrene and 1.51 g of 4-nitrobenzaldehyde is refluxed under a nitrogen atmosphere for 3.5 hours, the condensate being passed through 4 g molecular sieve conducts. The reaction mixture is then cooled to 20 ° and filtered. The filtrate is evaporated in a high vacuum and the residue is chromatographed on 75 g of silica gel first with 450 ml of benzene / ethyl acetate (9: 1) and then with 750 ml of benzene / ethyl acetate (3si), 50 ml fractions being collected. On evaporation, fractions 11 give one of the two possible stereoisomers of the compound mentioned in the title; Mp. 189-190 °, after crystallization from methylene chloride / ether. When fractions 13-15 are evaporated, the other stereoisomer of the compound mentioned in the title remains as a residue; Mp. 163-164 °, after crystallization from methylene chloride / pentane.

Example 21:

benz [ g] in dazol

The compound mentioned in the title is prepared analogously to the preceding examples from N-acetyl-N ¹ -methylhydrazine, 1,2-dihydronaphthalene and paraformaldehyde and

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tography cleaned on silica gel; M.p. 97-98 °, after crystallization from ether / pentane.

Example 22: cis-l-Dimethylaminoacetyl-2-methyl-1,3,3a, 4,5., 9b-hexahydrobenz [g] indazole

The compound mentioned in the title is prepared analogously to the preceding examples from N-dimethylaminoacetyl-N ¹ -methylhydrazine, 1,2-dihydronaphthalene and paraformaldehyde and converted with ^ maleic acid into the crystalline hydrogen maleate, which after crystallization from ethanol / ether at

melts. The N-dimethylaminoacetyl-N ¹ -methylhydrazine required as the starting product is prepared by heating a mixture of ethyl dimethylaminoacetate and N-methylhydrazine.

Example 2j5; cis-1- (4-methyl-1-piperazinyl) acetyl-2-methyl- 1 $ Ί> ι3 & 3 ^ tb> 9b-hexahydrobenz [g] indazole

The compound named in the title is prepared analogously to the preceding examples from N- (4-methyl-1-piperazinyl) acetyl-N ¹ -methylhydrazine, 1,2-dihydronaphthalene and paraformaldehyde and purified by chromatography; M.p. 100-101 °,
after crystallization from ether / pentane. The N- (4-methyl-1-piperazinyl) acetyl-N'-methylhydrazine required as the starting material is prepared by heating a mixture of ethyl (4-methyl-1-piperazinyl) -acetate and N-methylhydrazine.

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example 2h: 3- (3,4-Dlacetoxyphenyl) -l-methyl-2-'phenacetylpyrazolldin

.A mixture of 29 g of 3,4-diacetoxystyrene, 100 ml of toluene, 16.5 S N-methyl-N * -phenacetylhydrazln and 8.2 g of paraformaldehyde is refluxed for 5 hours under a nitrogen atmosphere, whereby the Condensate passes through a water separator. The residue remaining on evaporation of the reaction mixture is chromatographed on 1 kg of silica gel with benzene / ethyl acetate (3 * 1), fractions of 1.5 l being collected. Evaporation of fractions 5-7 gives the compound mentioned in the title with a melting point of 91 ° -92 ° (after crystallization from ether / pentane).

Example 25: 2-Acetyl-3- (3,4-dlacetoxyphenyl) -1-isopropylpyrazole thin

A mixture of 46 g of 3,4-diacetoxystyrene, 200 ml of toluene, 12 g of N-acetyl-N'-isopropylhydrazine and 4 g of paraformaldehyde is refluxed for 30 minutes under a nitrogen atmosphere, the condensate being passed through a water separator. After adding a further 6 g of N-acetyl-N'-isopropylhydrazine and 2 g of paraformaldehyde, the mixture is again heated to boiling for 30 minutes, then 3 g of N-acetyl-N'-isopropylhydrazine and 1 g of paraformaldehyde are added and an additional 3 hours on Boiled under reflux. The residue remaining on evaporation of the reaction mixture is chromatographed on 1 »5 kg of silica gel with benzene / Esslgester (3sl), fractions of 2 l being collected. When fractions 8-10 are evaporated, the compound mentioned in the title is obtained as an oily residue. IR spectrum (CHgCIg) X max: 1770, 1653cm " ¹ .

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Bei Piel 26: cis-l-Aeetyl -2- (l ~ methyl-l-4-p; i peridyl) -l, 2,3> 3a h, 8b-hexahydr o-indeno [1,2-c] pyrazole

A mixture of 3.2 g of N-acetyl-N ¹ ~ (l-methyl-4-piperidyl) hydrazine, 20 ml of toluene, 10 ml of indene and 0.8 g of paraformaldehyde is refluxed for 4 hours under a nitrogen atmosphere heated, the condensate being passed through a water separator. The evaporated reaction mixture is dissolved in methanol and 30 ml of 5N methanolic hydrochloric acid are added to the solution. When the solution is evaporated, the hydrochloride of the compound mentioned in the title remains as a residue; Mp. 130-132 ° (after crystallization from ethanol / ether).

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Claims (1)

- 19-10-2913 Claims; 1. A process for the preparation of new N ¹ -substituted N-acylpyrazolidine compounds, characterized in that an aldehyde or one of its reactive functional derivatives, an N'-monosubstituted N-acylhydrazine and an olefin whose C / C double bond is in one tensioned ring system is incorporated and / or conjugated to at least one further multiple bond, are reacted with one another with the escape of water. 2. Process for the preparation of new N ¹ -substituted N-acylpyrazolidine compounds according to claim 1, characterized in that formaldehyde, an N'-monosubstituted N-acylhydrazine and an olefin whose C / C double bond is incorporated in a strained ring system and / or is conjugated to at least one further multiple bond, are reacted with one another with the escape of water. 3. The method according to claim 2, characterized in that the formaldehyde in the polymer known as paraformaldehyde Form sets in. 4. The method according to one or more of claims 1-3, characterized in that the resulting in the reaction Water is removed and / or bound by a drying agent. 5. The method according to claim 4, characterized in that the water formed in the reaction is removed from the reaction mixture by azeotropic distillation. 909848/1304 - 20 - 10-2913 6. The method according to claim 4, characterized in that the condensate is fed back into the reaction mixture through a water separator or via a solid drying agent will. 7. The method according to claim 4, characterized in that a solid drying agent is added to the reaction mixture
will. 8. The method according to claim 6 or 7, characterized in that so-called molecular sieve is used as the drying agent 9. The method according to one or more of claims 1-8, characterized in that l-methyl-2-phenylacetyi- ^ -phenylpyi ^ azolidine is produced ^{from formaldehyde, N-methyl-N 1 -phenylacetylhydrazine and styrene.} 10. The method according to one or more of claims 1-8, characterized in that formaldehyde, N-methyl-N'-phenylacetylhydrazine and ethyl acrylate 3-ethoxycarbonyl-1-methyl-2-phenylacetylpyrazolidine manufactures. 11. The method according to one or more of claims 1-8, characterized in that from formaldehyde, N-methyl-N'-phenylacetylhydrazine and indene cis-2-methyl-1-phenylacetyl-1, 2, J>, J5a, 4,8b-hexahydroindeno [1,2-cJpyrazole produces, 909848/1304 - 21 - 10-2915 12. Method according to an or several of claims 1 - Q, characterized in that from formaldehyde, N-methyl-N ¹ -phenylacetylhydrazine and trans -cinnamon acid eäthy lest it trans ~ J5- ethoxy carbonyl -1-methyl 2-phenylacetyl-4-phenylpyrazolidine or trans-4-ethoxycarbonyl-1-methyl-2-phenylacetyl-3-phenyipyrazolidine produces, l'S>. Method according to an or several of claims 1-8, characterized in that 2-acetyl-3,5-diphenyl-1-methylpyrazolidine is produced ^{from benzaldehyde, N-acetyl-N l -methylhydrazine and styrene.} Ik. Method according to an or several of claims 1-8, characterized in that from formaldehyde, N-methyl-N ¹ -phenylacetylhydrazine and 1,2-dihydronaphthalene cis ^ -Methyl-1-phenylacetyl-lOOa, ^^, ^ - hexahydrobenzfgJindazole is made. 15. The method according to one or more of claims 1-8, characterized in that from formaldehyde, N-methyl-N'-phenylacetylhydrazine and acrylonitrile 1-methyl-2-phenylacetylpyrazolidine-3-carbonitrile and produces 1-methyl-2-phenylacetylpyrazolidine-4-carbonitrile. 16. The method according to one or more of claims 1-8, characterized in that from formaldehyde, N-acetyl-N'-methylhydrazine and 1,1-diphenylethylene 2-Acetyl-3>! 5-diphenyl-1-methylpyrazolidirL produces. 17. The method according to one or more of claims 1-8, characterized in that formaldehyde, M-acetyl-N'-isopropylhydrazine and styrene 2-acetyl "l" isopropyl "3" phenylpyrazolidine, 18. The method according to one or more of claims 1 - S _7, characterized in that formaldehyde »N-acetyl-N '» benssylhyclra'-vin and Si-yruL 2-Aae- 0 0 9 8 4 8/1 Π 0 4 ^BATH - 22 - 10-2913 tyl-1-benzyl-3-phenylpyrazolidine. 19. Ancestors according to one or more of claims 1 - 8, characterized in that from formaldehyde, N-acetyl-N'-benzylhydrazine and indene cls-1-acetyl-2-benzyl-1,2,3,3a, 4,8b-hexahydroindeno [1,2-c] -pyrazole manufactures. 20. The method according to one or more of claims 1-8, characterized in that from formaldehyde, N-acetyl-N ¹ -benzylhydrazine and 1,2-dihydronaphthalene cis-1-acetyl-2-benzyl-1, ^, 3a , 4,5,9b-hexa- U produces hydrobenz [g) indazole. 21. The method according to one or more of claims 1 - ö, characterized in that from formaldehyde, N-acetyl-N ¹ -phenylhydrazine and indene cis-l-acetyl-2-phenyl-l, 2,3,3a, 4,8b-hexahydroindeno [1,2-c] pyrazole. 22. The method according to one or more of the Ansprücne 1-8, characterized in that one of formaldehyde, N-methyl-N'-phenylacetylhydrazine and standards native 4,7- ^ lethano-2-methyl-l-phenylacetyl-2 3,3a, 4,5,6,7 _J 7a- oetahydro-1H-indazole . 23 · Procedure according to an or several of claims 1-8, characterized in that from formaldehyde, N-methyl-N ¹ -phenylacetylhydrazine and benzonorbornadiene 4,9-methano-2-methyl-1-phenylacetyl-2,3> 3a-, 4, 9j9a- hexahydro ~ 1H-benz [fJindazole produces. 24. Procedure according to an or several of claims 1 - B, characterized in that from formaldehyde, N-methyl-N'-pherr / lacety-hydrazine and 1,4-D: lhydro-1,4-epoxynaphtha "LJn 4,9-Epu ^ y-2-methyl-1-phenyLacet, yl-P, 5 »3a, 4,9,9a ~ hex £ ihy-lro» LH-bftnzifJindazole manufactures, 25 · Method according to tinem or several of claims 1 - B _} thereby g = '. .mn ? ^ inhnet , (\ άγ> β ' auü Ql / -;: -: y - !. säia'eäHiyl5 itrT -Hch ^ / liiaj-L : ^> ϊη L, Π-Ί; Lhv L - ν Ϊ '--phvii / L ^ J fj 3 8 : ■ ti /] 3 0 L - 23-10-2913 aoetylhydrazine and Inder »(3RS, JaRS, BbRS) -2-methyl-1-phenylacetyl-1,2,3,3a, h, 8b-hexahydroindeno [1,2-c] pyrazole-3-carboxylic acid ethyl ester. 26. The method according to one or more of claims 1-8, characterized in that from ^ -nitrobenzaldehyde, N-acetyl-N ¹ -methylhydrazine and styrene 1-acetylr2-methyl-3- (4-nitrophenyl) -5-phenylpyrazolidine manufactures. 27. The method according to one or more of claims l-δ, characterized in that from formaldehyde, K-acetyl-N'-methylhydrazine and 1,2-dihydronaphthalene cis -1-acetyl-2-methyl-1,3j3a, 4,5,9b-hexahydrobenz [g] indazole manufactures. 28. The method according to one or more of claims 1-8, characterized in that from formaldehyde, N-dimethylaminoacetyl-N ¹ -methylhydrazine and 1,2-dihydronaphthalene cis-l-dimethylaminoacetyl-2-methyl-I, 3j3a-, ^, 5 * 9b-hexahydrobenz [gjinda.zol manufactures. 29. The method according to one or more of claims 1-8, characterized in that from formaldehyde, N - (^ - methyl-l-piperazinyl-acetyl-N'-methylhydrazine and 1,2-dihydronaphthalene cis-l- (4-methyl -l-piperazinyl) acetyl-2-methyl- ^{1,3> 3 a} i ^ ϊ5j9b-hexahydrobenz [g} indazole. 30. The method according to one or more of claims 1-8, characterized in that one of formaldehyde, N-methyl-N ¹ -phenylaeetylhydrazine. and. 3,4-diacetoxystyrene 3- (3i ^ -diacetoxyphenyl) -l-methyl-2-phenylacetylpyrazolidine. 31. Procedure according to an or several of claims 1 - 8, characterized in that from formaldehyde, N-acetyl-N'-isopropylhydrazine and 3,4-diacetoxystyrene 2-acetyl ~ 3- (3i4-diacetoxyphenyl) -1-isopropylpyrazolidine manufactures. 909 8-A 8/1304 - "24-10-2913 32. The method according to one or more of claims 1-8, characterized in that formaldehyde, N-acetyl-N '- (l-methyl-4-piperidyl) hydrazine and indene cis-l-acetyl-2- (l- razol manufactures. 33. N'-substituted N-acyl-pyrazolidine compounds, thereby characterized in that they are produced by reaction of an aldehyde or one of its reactive functional derivatives with an N'-monosubstituted N-acylhydrazine and an olefin, its C / C double bond built into a tensioned ring system and / or to at least one further multiple bond is conjugated, can be obtained with the escape of water. 1-methyl ^ -phenylacetyl ^ -phenylpyrazolidine 909848/1304 - 25 - 10-2915 55. J-ethoxycarbonyl-1-methyl ^ -phenylacetylpyrazolidine. 56. cis-2-methyl-1-phenylacetyl ~ 1,2,5 »5a» 4 * 8b-hexahydroindeno [1,2-c] pyrazole. 57 · trans-5-ethoxycarbonyl-1-methyl-2-phenylacetyl-4-phenyl-pyrazolidine or trans-4-ethoxycarbonyl-1-methyl-2-phenylacetyl-5-phenyl-pyrazolidine. 58. g-Acetyl ^^ - diphenyl-l-methyl-pyrazolidine. 59. cis -2-methyl-1-phenylacetyl-1 _J 5J5a, 4,5J9b-hexahydrobenz- [gjindazole. 40. 1-methyl-2-phenylacetylpyrazolidine-5-carbonitrile. 41. l-Methyl-S-phenylacetylpyrazolidine - ^ - carbonltrile. 42. 2-Acetyl-5,5-diphenyl-1-methylpyrazolidine. 43. 2-Acetyl-1-isopropyl-5-phenylpyrazolldine. 44. 2-Acetyl-1-benzyl-3-P 1-lenylpyrazolidine. 45. cis -1-acetyl-2-benzyl-1,2,5,3a, 4,8b-hexahydroindeno [1,2-c] pyrazole. 46. cis-1-Acetyl-2-benzyl-1,3,5a, ⁱ f »5i9b-hexahydrobenz [gIindazole. 47. cis -1-acetyl-2-phenyl-1,2,3,3a, 4,8b-hexahydroindeno [1,2-c] pyrazole. . ' 909848/1304 - 26 - 10-2913. 48. 4 _> 7-Methano-2-methyl-1-phenylaeetyl-2,2, ^, 4,5,6,7,7 aoctahydro-1 H -indazole. 49. 4,9-Methano-2-methyl-1-phenylacetyl-2,; 5,; 3a, 4,9,9a-hexahydro-1H-benz [p-indazole. 50. 4,9-epoxy-2-methyl-1-phenylacetyl-2,>, j5a, 4,9,9a-hexahydro-1H-benz [fjindazole. 51. (3RS _J 3aRS, 8bRS) -2-methyl-1-phenylacetyl-1 _J 2,3,>, 4 _J 8bhexahydroindeno [1,2-c] pyrazole-3-carboxylic acid ethyl ester. 52. 1-Acetyl-2-methyl-3- (4-nitrophenyl) -5-phenylpyrazolidine. 53 • cis -1-acetyl-2-methyl- _{1,3i! 5a J} 4,5i9b-hexahydrobenz [g jindazole. hydrobenz [g] indazole. 55. cis -1- (4-methyl-1-piperazinyl) acetyl-2-methyl-1,3 _J 3a, 4,5, 9b -hexahydrobenz [gI indazole. 56. 3- (3i ^ -Diacetoxyphenyl) -l-methyl-2-phenylacetylpyrasoll din. 57 · 2-Acetyl-j5- (3,4-diacetoxyphenyl) -1-isopropylpyraaoidine . 58. cis -1-Acetyl-2- (1-methyl-4-piperidyl) -1, 2,3 _i ^ a, 4,8b-hexahydro-indeno [1,2-cJpyrazole . 909848/1304