DE1795172A1 - Cyclic pyrrole ketones and process for their preparation - Google Patents

Description

Cyclic Pyrrole Ketones and Process for Their Production The invention relates to cyclic pyrrole ketones having the structural formula A. and methods of making them.

These new products have valuable pharmacodynamic effectiveness In relation to the Z central nervous system and anti-inflammatory factors, are particularly as Sedatives and mild TranquiliZers are suitable and can also be used as intermediates for the manufacture of other therapeutic products, such as those in the older registration P 16 70 634.6 are described.

In the structural formula above, R1, R2 and R3 each denote hydrogen, Alkyl with a maximum of 6 carbon atoms, phenyl, phenylalkyl with a maximum of 3 carbon atoms in the alkyl radical or substituted phenyl or phenylalkyl, the one on the phenyl ring pendant substituent from halogen, alkyl or alkoxy with a maximum of 4 carbon atoms each or haloalkyl of at most 4 carbon atoms, e.g.

(£ rifluoromethyl, R4 is hydrogen, alkyl or alkylidene with each not more than 4 carbon atoms, benzylidene or benzene and n is the number 1, 2 or 3. This symbol meaning applies to the entire description, unless otherwise is specified.

The formula A products are obtained by cyclizing a pyrrole of structural formula B. in which R1, R2, R3 and R4 have the meaning given earlier, for n and m the formula 1 <n + m <5 applies and X stands for hydroxyl, halogen or a secondary amine, with dehydration or condensation.

If X is hydroxyl, it is used as a dehydrating agent preferably polyphosphoric acid, although you can also use other dehydrating agents such as sulfuric acid, can work. But you can use such Formula B bindings X = OH the dehydration also thermally, i.e. simply by heating in the absence of solvents or by refluxing their solution in e.g. 1,1,2,2-tetrachloroethane and effect azeotropic water removal, in the latter case using a cation exchange resin, .B. the commercial product Amberlite IR 120, can be added as a catalyst. is falls the pyrrole compound is an acid halide (with X equal to Halegen), one can cyclization by a suitable Friedel-Crafts catalyst, e.g. boron trifluoride, tin (IV) chloride or aluminum chloride. For compounds where X is a secondary amine, e.g. N, N-dimethylamine, N, N-diethylamine, morpholine, piperidine or n-methylaniline, sometimes uses a condensation agent in the sense of the Vilsmeier implementation for cyclization, thus phosphorus oxychloride, phosgene or their equivalents Dic formula B compounds themselves represent novel substances. Ian obtains them in the following ways: a) by means of Friedel-Crafts synthesis. According to the invention, pyrroles can be prepared with the aid of Boron trifluoride as a catalyst through cyclic acid anhydrides, such as amber or Glutaric anhydride, acylate to # - (3-: Pyrrolca.rbonyl) alkanoic acids, which in turn according to known processes, e.g. by means of Wolff-Kishner reduction, to Pormel B products with n equal to 1 or 2 can be reduced.

This synthesis can take place in the following way, for example: Instead of cyclic acid anhydrides, it is also possible to work with lactones, such as ß-propiolactones, # -butyrolactones or # -valerolactones. b) by means of Grignard synthesis: the first synthesis step can also be carried out by means of Grignard instead of the Friedel-Crafts reaction and then proceeds, for example, as follows: @ by means of malonic ester synthesis; the method of IIerz and Settine (Jeurn. Org. Chem., 24, 201 (1959)) is suitable for the production of pyrrol-3-ylmalonic esters, which give formula B products with n equal to 1 through hydrolysis and decarbonization. For example, the reaction scheme is as follows: d) by means of lactone synthesis: instead of malonic esters, reductive pyrrole alkanoic acids can also be obtained with lactones by either working under acidic conditions as in c) or under alkaline conditions according to the following schematic example: e) by means of Michael addition to acrylic esters instead of malonic esters or lactones one can also work with acrylic esters, which are already in 1-. and 5-position substituted pyrroles add according to Michaelart to form 3-pyrrole propionic acids.

These synthesis methods are also suitable for the production of Pormel A compounds in which R2 means something other than hydrogen.

Instead, you can also use many Formula A compounds in which R2 is a carbon-containing substituents means to produce by the fact that the corresponding Connection where R2 is hydrogen under basic conditions alkylated.

Formula A compounds in which R4 is a carbon-containing substituent means, arise from suitably substituted succinic or glutaric anhydrides, Malonic esters, ß-propiolactones, γ-butyrolactones or # -valerolactones or Acrylic esters.

But you can also synthesize many compounds with R4 substituents from simpler products in the following sequence of steps: The invention is of particular importance for the production of formula A compounds which are suitable as intermediates in the preparation of Mannich bases according to structural formula C below, because the latter, together with their pharmaceutically acceptable acid addition salts, are excellent drugs for the treatment of anxiety states and mental illness.

Here, X and Y each denote substituents in pendant to nitrogen Porm of hydrogen and aliphatic or aromatic radicals. Palls X and Y are related, the unit consisting of N, X and Y also forms a saturated heterocyclic Ring system.

The pharmacological evaluation of the formula A compounds showed that They also have different damping effects on the central and autonomic nervous system as well as exercise on the skeletal muscle system. Many of these compounds also work also anti-inflammatory. For example, 4,5,6,7-tetrahydoro-1,3-methyl-4-oxoisoindole, which only becomes toxic at oral doses of more than 500 mg / kg in rats and mice when administered orally at doses of 2 to 4 mg / kg, a 50% decrease in spontaneous locomotor activity. Even in doses of less than 1 mg / kg, it potentiated that of Hexabarbital sodium evoked Sleep time and showed in the carrageenin test according to Winter (J.P.E.T. 141 (1963) 369, at a dose of 50 mg / kg a noticeable, anti-inflammatory effect.

Such results demonstrate the usefulness of these compounds as sedatives, tranquilizers, skeletal muscle relaxants and antiarthritics.

These compounds can be used in the same known manner as known ones Compounds of equal effectiveness, e.g. diazepam, meprobamate and phenylbutazone, formulated, brought into dosage form, i.e. tablets, capsules and all the usual Porms of pharmaceutical agents are processed and administered.

The invention is illustrated below with the aid of some exemplary embodiments explained in more detail.

Example 1: 2,5-dimethylpyrrole-3-butyric acid Method A. A solution of 736 g (7.36 mol) of succinic anhydride in 6000 ml of benzene was initially in hot state with 2.09 kg (14.7 mol) boron trifluoride etherate, then after cooling down 666 g (7.00 mol) of 2,5-dimethylpyrrole are added to 3400 with vigorous stirring, where the Temperature increased to 420C, stirring continued for 2 hours and finally poured onto an ice-water mixture.

The crude acid which separated out was collected and poured into dilute aqueous Sodium hydroxide solution dissolved, the basic solution clarified with charcoal using kieselguhr (Commercial product Celite) filtered and acidified to pH 2.

The precipitated product was collected and dried.

This gave 508 g of 2,5-dimethyl-γ-oxopyrrole-3-butyric acid, 158-159.5 ° C.

195.2 g (1.0 mol) of this substance were together with 139 g (2.36 Mol) 85% hydrazine in a solution of 224 g (3.38 mol) 85% potassium hydroxide placed in 700 ml of ethanol, the total solution heated to 1950C for 17 hours, then cooled and freed from excess alcohol. The salt residue was treated with water and ether, the ether layer discarded and the aqueous layer brought to pH 6, whereupon an acidic oil separated. This became in ether taken up and dried over magnesium sulfate. 168 g of crude 2,5-dimethylpyrrole-3-butyric acid were obtained in this way.

In a similar way, 2,5-diethylpyrrole can be obtained via 2,5-diethyl-γ-oxopyrrole-3-butyric acid into the 2, 5-diethylpyrrole-3-butyric acid and 2,5-di-tert-butylpyrrole via the 2,5-Di-tert-butyl - # - oxopyrrole-3-butyric acid convert into 2,5-di-tert-butylpyrrole-3-butyric acid.

Method B. In one of 13.5 g magnesium, 60.5 g ethyl bromide and 150 ml of ether-prepared Grignard solution was initially a solution of 47.6 g of 2,5-dimethylpyrrole in 140 ml of ether and 15 minutes later a solution of 55.5 g of succinic anhydride introduced into 560 ml of tetrahydrofuran.

The total mixture was stirred and refluxed for 2G minutes boiled and then to interrupt the reaction with 25% aqueous ammonium chloride solution offset. The ether-tetrahydrofuran layer was evaporated to dryness and the Shaken out residue with aqueous sodium hydroxide solution and washed with ether. At the Acidification of the @@@ alic layer precipitated the product, which after recrystallization from methyl ethyl ketone than with the 2,5-dimethyl-γ-oxopyrrole-3-butyric acid prepared according to method A proved identical. It was converted into the 2,5-dimethylpyrrole-3-butyric acid converted.

Similarly, using glutaric anhydride instead obtained from succinic anhydride 2, 5-dimethyl-oxopyrrole-3-valeric acid, which after recrystallization melted from ethyl acetate at 149-150 ° C. It became 2,5-dimethylpyrrole-3-valeric acid in the manner described above reduced.

Method C. A stainless steel bomb was weighed 76 grams (0.8 moles) 2,5-dimethylpyrrole, 78 g γ-butryolactone and 75 g (1.1 mol) potassium hydroxide (85% KOH) and shaken at 260 ° to 26500 for 21 hours. To after cooling, the contents were washed with 500 ml of water and the supernatant oil layer severed. The aqueous layer was initially used to remove the unreacted 2, 5-Dimethylpyrrole extracted with ether and then by means of cooling and stirring concentrated hydrochloric acid brought to pH 3.5-4.0. The resulting oil was extracted with methylene chloride, and the extract was obtained after drying and evaporating off the solvent, the 2,5-dimethylpyrrole-3-butyric acid.

Example 2: 2,5-dimethylpyrrole-3-propionic acid A mixture of 30.8 g of diethyl 2,5-dimethyl-3-pyrrole methyl malonate, 19 g of 85% potassium hydroxide and 17 ml of water was heated on a steam bath for 1 hour under a nitrogen blanket and the resulting solution acidified with 6N hydrochloric acid against Kongorotopaper. The thereby acid released was extracted with ether and the extract after Distilled drying with magnesium sulfate for the purpose of decarbonization. One received so 2,5-dimethylpyrrole-3-propionic acid with a boiling point of 153-1540 / 0.7-0.8 mm, example 3: 4,5,6,7-Tetrahdyro-1,3-dimethyl-4-oxoisoindole crude, according to one of the in Example 1 2, 5-dimethylpyrrole-3-butyric acid produced in the process described was in Mix in with five times the weight of polyphosphoric acid for 2 1/2 hours Umrtihren heated to 139-142 ° C. When the resulting melt is poured onto ice the product crystallized and was collected. More small amounts of darker ones Materials were obtained by adjusting the phosphoric acid solution to pH 5. The product passed by dissolving it in benzene and sending its solution through A short column of alumina conveniently clears dark impurities. After removal of the benzene, 85 g of product were obtained in the form of prisms, B. 151-1520.

In the same way were 2,5-diethylpyrrole-3-butyric acid in 1,3-diethyl-4,5,6,7-tetrahydor-4-oxoisoindole, 2,5-di-tert-butylpyrrole-3-butyric acid in 1,3-di-tert-butyl-4,5,6,7-tetrahydoro-4-oxoisoindole and 2,5-dimethylpyrrole-3-valeric acid in 2,4,5,6,7,8-hexahydro-1,3-dimethyl-4-oxocycloheptatecj converted to pyrrole.

Example 4: 4,5,6,7-Tetrahydro-1,3-dimethyl-4-oxoisoindole A solution of 8.4 g (0.046 col) of 2,5-dimethylpyrrole-3-butyric acid in 200 ml of 1,1,2,2-tetrachloroethane was refluxed for 10 hours for azeotropic dehydration cooked. Subsequent removal of solvent under reduced pressure resulted in a dark oil, au was stirred with acetone and filtered. The filtrate gave on evaporation semi-solid mass, from which the crude product is obtained by stirring with 15 ml of benzene and filtering was obtained.

Example 5: 4,5,6,7-Tetrahydro-1,3-dimethyl-4-oxoinoindole 2,5-dimethylpyrrole-3-butyric acid was heated for four hours while slowly increasing the temperature from 130 ° to 174 ° C.

After cooling, the contents of the flask were taken up in Aoeton and the solution is filtered and freed from the solvent using reduced pressure. The residue was stirred with water made basic by adding sufficient ammonia and delivered the crude product as a festival, which was filtered off.

Example 6: 4,5,6,7-Tetrahdyro-1,2,3-trimethyl-4-oxoisoindole One Mixture of 100 g of succinic anhydride and 800 ml of benzene was made for 15 minutes cooked, still hot with 284 g of boron fluoride ether and then after cooling to 45 ° 109 g of 1,2,5-trimethylpyrrole were added while stirring, while the temperature was restored rose to 580C. The mixture was stirred for an additional 11/2 hours and then in water poured.

The resulting crystalline product was collected with water washed, dried and recrystallized from acetone. This gave 1,2,5-trimethyl-γ-oxopyrrole-3-butyric acid, P. 163-1640.

61.5 g of this compound along with 34.7 g of 85% Hydra entered into a solution of 27e1 g of sodium in 500 ml of ethanol. The emerging Solution was heated to 190 ° C for 18 hours and then vol excess ethanol freed.

The residue was dissolved in water and this solution was washed with ether and acidified. The ether extract was dried and evaporated to the luicketend together with 400 g of polyphosphoric acid heated to 14,000 for 2.5 hours and that The mixture was then poured onto ice, the product separating out in solid form. It was dissolved in benzene and its solution was used to remove colored impurities sent through a short column of alumina. After evaporation of benzene and recrystallization of the solid residue from cyclohexane gave the pure Connection, F.82 - 83 °.

Similarly, there was obtained from benzylamine and hexane-2,5-dione 1-benzyl-2,5-dimethylpyrrole, F. 48 - 490 via 1-benzyl-2,5-dimethyl-γ-2-benzyl-4,5,6,7-tetraphydro-1,3-dimethyl-4- oxoisoindole converted.

Example 7: 4,5,6,7-Tetrahydro-1-methyl-4-oxo-3-phenylisoindole One hot solution of 38.3 g of succinic anhydride in 400 ml of benzene was initially used 72.4 g of boron trifluoride etherate and, after cooling to 350C, in rapid rotation 40 g of 2-methyl-5-phenylpyrrole were added to the feed, and the mixture was stirred for a further 2 1/2 hours and then mixed with ice and water.-The crude acid which separated out was collected and dissolved in dilute ammonia, treated with charcoal in the solution reprecipitated with acetic acid and finally recrystallized from acetone.

This gave the pure 2-methyl-γ-oxo-5-phenylpyrrole-3-buttersäuyre, 212-213 °.

19.3 g of this product was added along with 8.8 g of 85% hydrazine in a solution of 6.9 g of sodium in 250 ml of ethanol entered. The resulting solution was heated to 20,000 for 20 hours, then cooled and freed from excess ethanol under reduced pressure. The residue was washed with water mixed and extracted with ether. The ether extract was discarded. When acidifying the reduced acid crystallized out of the aqueous solution, which after recrystallization from benzene melted at 120 - 12200.

A mixture of 9.8 g of this 2-methyl-5-phenylpyrrole-3-butyric acid and 75 g of polyphosphoric acid was heated to 1480C for 1 hour and the resulting, dark mixture then poured onto ice and water. That which crystallizes out Crude product (9 g) was dissolved in benzene and its solution colored to remove Sent impurities through a short column of alumina. The eluate delivered at Concentrate the product, P. 190-191.3%.

Example 8: 4,5,6,7-Tetrahydro-1-oxo-2,3-diphenylisoindole A mixture from 13.7 g of succinic anhydride and 150 ml of dichloroethane was initially mixed with gaseous Saturated boron trifluoride and then with a solution of 23.3 g of 2-methyl-1,5-diphenylpyrrole, F. 83-80, mixed in 50 ml of dichloroethane. The reaction mixture was 2 hours stirred for a long time and then poured onto ice. The dichloroethane layer was with watery Ammonia extracted. When this ammonia extract was acidified, 2-methyl-γ-oxo-1 crystallized, 5-diphanylpyrrole-3-butyric acid, which after recrystallization was added to benzene 160 - 181 0C melted. This material was obtained by means of hydrazine from 2-methyl-1,5-diphenylpyrrole-3-butyric acid reduced and this in turn in the usual way to 4,5,6,7-tetrahydor-1-methyl-4-oxo-2,3-diphenylsiondol cyclized.

Example 9: 4,5,6,7-Tetrahydro-1,3,5,5-tetramethyl-4-oxoisoindole One Mixture of 15 g of α, α-dimethylsuccinic anhydride and 75 ml of benzene was first with 35 g of boron trifluoride etherate, then 11 g of 2, while stirring. 5-Dimethylpyrrole was added and, after 4 hours, poured into water. The separating, crystalline acid collected and additional product from the benzene layer by extraction brought out with alkali. After recrystallization from methyl ethyl ketone, this melted α, α, 2,5-Tetramethyl-γ-oxopyrrole-3-butyric acid at 203.5 - 204 ° C and after reduction and cyclization gave 4,5,6,7-tetrahydro-1,3,5,5-tetramethyl-4-oxoisoindole.

In the same way, α, ß-dimethylsuccinic anhydride was formed α, ß, 2,5-tetramethyl-γ-oxopyrrole-3-butyric acid, which was converted to 4,5,6,7-tetrahydro-1,3,5,6-tetramethyl-4-oxoisoindole.

Example 10: 4,5,6,7-Tetrahydro-1,3-dimethyl-5-methylene-4-oxoisoindole A mixture of 76 g of 4,5,6,7-tetrahydoro-1,3-dimethyl-4-oxoisoindole, 51.5 g of dimethylamine hydrochloride and 12 g of paraformaldehyde was refluxed under nitrogen blanket for 24 hours cooked. The resulting 1,3-dimethyl-5-dimethylaminomethyl-4-oxoisoindole hydrochloride, M.p. 188-189.5 ° was obtained in aqueous solution by treatment with aqueous sodium hydroxide solution converted into the free Be F. 169 - 1700, which in turn was dissolved in acetone and treated with gaseous methyl bromide. That which crystallizes out of the solution methobromide salt, mp 236-238 °, was collected, dissolved in water and washed with aqueous Sodium hydroxide treated. The yellow methylene compound which separated out in the process melted after recrystallization from ethanol at 150-151 ° C.

Example 11: 4,5,6,7-Tetrahydro-1,3,5-trimethyl-4-oxoisoindo di / an Solution of 8.0 g of 4,5,6,7-tetrahydro-1,3-methyl-5-methylene-4-oxoisoindole in 150 ml Ethanol was together with hydrogen of 3.16 atmospheres in the presence of 0.5 g of a 10% palaldium-on-charcoal catalyst shaken until after 20 minutes the Hydrogen uptake ceased. The solution was after filtering off the catalyst evaporated to dryness. The residue melted after recrystallization from benzene 156-15700.

Example 12: 5-enzylidene-4,5,6,7-tetrahydro-1,3-dimethyl-4-oxoisoindole A mixture of 14 g benzaldehyde, 11 g 4,5,6,7-tetrahydro-1,3-dimethyl-4-oxoisoindole and 27 ml of 10% aqueous sodium hydroxide solution was added under a nitrogen blanket for 24 hours boiled under reflux conditions. The organic layer was taken up in ether, for the purpose of removing unreacted benzaldehyde with aqueous bisulfite solution washed and freed from the ether. The residue was chromatographed on clay. An orange band of the product was eluted with benzene and gave out from benzene and cyclohexane deep yellow crystals, mp 186-188 °.

Example 13: 5-Benzyl-4,5,6,7-tetrahydro-1,3-dimethyl-4-oxoisoindole 5-Benzylidene-4,5,6,7-tatrahydro-1,3-dimethyl-4-oxoisoindole was prepared according to the procedure of Example 11 in ethanolic solution in the presence of 10% palladium-on-charcoal catalyst shaken with hydrogen and thus provided the reduced 5-benzyl product.

Example 14: A tablet preparation was produced from the following approach: Ingredients mg per tablet 4,5,6,7-tetrahydro-1,3-20 dimethyl-4-oxoisoindole spray-dried Lactose 170 USP Starch USP 10 Magnesium Stearate USP 1 Stcaxic Acid USP Flavor q.s.

All components were passed through a sieve with a mesh size of 0.25 mm (60 mesh USS), mixed for 30 minutes and in a tablet machine using 8.7 mm large biconcave grooving punch pressed directly into tablets weighing 206 mg each.

It goes without saying that the preceding examples are intended to be those in the claims Only explain the identified invention and in no way limit its scope of protection.

Claims (1)

P a. tent claims 1. Cyclic pyrrole ketones with the structural formula A in which R1, R2 and R3 are each hydrogen, alkyl with a maximum of 6 carbon atoms, phenyl, phenylalkyl with a maximum of 3 carbon atoms in the alkyl radical or substituted phenyl or phenylalkyl, the substituent attached to the phenyl ring consisting of halogen, alkyl or alkoxy with a maximum of 4 carbon atoms each or haloalkyl with at most 4 carbon atoms, e.g. Trifluoromethyl, R4 is hydrogen, alkyl or alkylidene with each not more than 4 carbon atoms, benzylidene or benzene and n is the number 1, 2 or 3 mean. 2. A compound with the structural formula A, in which R4 is hydrogen or methyl and n is the number 1. 3. A compound with the structural formula A in which R4 is hydrogen or methyl and n is the number 2. 4. 2,4,5,6-Tetrahydro-1,3-dimethyl-4-oxocyclopenta [c] pyrrole. 5. 4,5,6,7-tetrahydro-1,3-dimethyl-4-oxoisoindole. 6. 4,5,6,7-tetrahydro-1,2,3-trimethyl-4-oxoisoindole. 7. 4,5,6,7-Tetrahydro-1,3,5-trimethyl-4-oxisoindole. 8. 4,5,6,7-Tetrahydro-1-methyl-4-oxo-3-phenylisoindole. 9. Process for the preparation of cyclic pyrrole ketones with the structural formula A in which R1, R2 and R3 each hydrogen, alkyl with a maximum of 6 carbon atoms, phenyl, PhZnylalkyl with a maximum of 3 carbon atoms in the alkyl radical or substituted phenyl or phenylalkyl, the substituent attached to the phenyl ring consisting of halogen, alkyl or alkoxy each with a maximum of 4 carbon atoms or haloalkyl with at most 4 carbon atoms, e.g. Trifluoromethyl, R4 is hydrogen, alkyl or alkylidene each having a maximum of 4 carbon atoms, benzylidene or benzene and n is the number 1, 2 or 3, characterized in that a pyrrole with the structural formula B in which Ra, R2, R3 and R4 have the meaning given earlier, for n and m the formula 1zane + mc5 applies and X stands for hydroxyl, halogen or a secondary amine, cyclized, namely if X is hydrocyl, either with the aid of a dehydrating agent, such as polyphosphoric acid or sulfuric acid, or by thermal dehydration in the presence or absence of a solvent and / or a cation exchange resin, if X is a halogen, either with the aid of a Friedel-Crafts catalyst or with the aid of a condensation agent such as phosphorus oxychloride , Phosgene or their equivalents, and if x is a secondary amine, with the help of the vilsmeier reaction, and if desired, produces the pharmaceutically acceptable salts. 1P. The method according to claim 9, characterized in that one Pyrrole with X being hydroxyl by means of polyphosphoric acid or sulfuric acid under Wuserentzug cyclialert. 11. The method according to claim 9, characterized in that one is a Pyrrole cyclized with 1 equal to hydroxyl by heating without a solvent. 12. The method according to claim 9, characterized in that one Pyrrole where x is hydroxyl by refluxing its solution in a solvent such as 1,1,2,2-tetrachloroethane and azeotropic water removal dehydrating cyclized. 13. The method according to claim 12, characterized in that the azeotropic water removal by adding a. Cation exchange resin, s, B. Amberlite IR-12O, catalyzed. 14. The method according to claim 9, characterized in that one is a Pyrrole where X is halogen, e.g. chlorine, with the help of a Friedel-Crafts catalyst, such as boron trifluoride, tin (IV) chloride or aluminum chloride, cyclized. 15. The method according to claim 9, characterized in that one Pyrrole where X is secondary amine, such as dialkylamine, alkylarylamine, heterocyclic Amin or Diar @ lamin with the help of a condensing agent such as phosphorus oxychloride, Phosgene or its equivalents are cyclized. 16. A process for the preparation of a formula A compound according to claim 9, characterized in that a pyrrole is cyclized in which x is hydrogen or methyl and n + m = 2. 17. A process for the preparation of a formula A compound according to claim 9, characterized in that a pyrrole is cyclized in which X is hydrogen or Xethyl and n + m = 3.