AT364844B - METHOD FOR PRODUCING NEW 5-AROYL-1,2-DIHYDRO-3H-PYRROLO- (1,2-A) -PYRROL-1-CARBONIC ACIDS AND THEIR SALTS - Google Patents

Description

  

    <Desc / Clms Page number 1>
 



   The invention relates to a process for the preparation of new 5-aroyl-1, 2-dihydro- - 3H-pyrrolo [1, 2-a] pyrrole-1-carboxylic acids of the general formula
 EMI1.1
 wherein
R is hydrogen or a lower alkyl radical having 1 to 4 carbon atoms and
R is hydrogen, a lower alkyl radical having 1 to 4 carbon atoms, a lower
Alkoxy radical having 1 to 4 carbon atoms or chlorine, fluorine or bromine, where the substituent R 1 is in the 0-, m- or p-position of the aryl radical, and their optical isomers and pharmaceutically acceptable salts.



   With the exception of the (d) acid isomers and their salts, the compounds which can be prepared according to the invention have anti-inflammatory, analgesic and antipyretic effects and are therefore valuable for the treatment of inflammation, pain and / or pyrexia in mammals and humans, as is described in detail below . They are also excellent muscle relaxants.



   The process according to the invention is characterized in that an ester of the general formula
 EMI1.2
 wherein R 1 are as defined above and
Rx denotes an unbranched or branched alkyl radical having 1 to 12 carbon atoms, converted into the corresponding acid of the formula (A) or a salt thereof, if desired the acid obtained is separated into its optical isomers and / or converted into its pharmaceutically acceptable salt.



   The starting esters of formula (I) are also new compounds.



   Typical alkyl ester groups are, for example, the methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl esters.



   Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, mangano, aluminum, ferric and manganese salts, etc. are particularly preferred the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable, organic, non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cycloamines and basic ion exchange resins such as e.g. B.

   Isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, glucosaminobromine, ethylenediamine diamine, ethylenediamine diamine, ethylenediamine diamine Piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.

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 EMI2.1
 
 EMI2.2
 

  <Desc / Clms Page number 3>

 
 EMI3.1
 wherein R 1 has the above meanings and R 2 is a lower alkyl radical having 1 to 4 carbon atoms, e.g. B. the methyl, ethyl, isopropyl or n-butyl radical means.



   When carrying out the present process in practice, equimolecular amounts of ethanolamine of the formula (I) and 1,3-acetone dicarboxylic acid dimethyl ester of the formula (II) are used at a temperature for the preparation of the compound of the formula (IV) in which R is the hydrogen atom from about 0 ° C to about room temperature to readily obtain a solution of the vinylamine of formula (III) which is then preferably in situ in a suitable inert organic solvent under anhydrous conditions
 EMI3.2
 solvents for this reaction are aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane, etc.

   In the preferred embodiments, the reaction in acetonitrile solution takes place at the reflux temperature for about 1 hour. The compounds used as reactants, i.e. H. 2-bromoacetaldehyde and 2-chloroacetaldehyde are known compounds. They can be obtained by pyrolysis of the corresponding diethylacetals in the presence of oxalic acid dihydrate.

  <Desc / Clms Page number 4>

 



   To the compounds of the formula (IV), wherein R is a lower alkyl radical having 1 to 4 carbon atoms, which is preferably a straight-chain radical, an aqueous mixture of ethanolamine of the formula (I) and 1, 3-acetone dicarboxylic acid dimethyl ester of the formula (II ) with a compound of the following formula:
 EMI4.1
 wherein
X is bromine or chlorine and
R3 represents a lower alkyl group of 1 to 4 carbon atoms, which is preferably a straight chain group, treated at about 40 to about 100 C for about 30 minutes to about 16 hours. Before-
 EMI4.2
 from about -100C to about room temperature for about 1 hour to about 6 hours. The compounds of the formula:
 EMI4.3
 are known.



   The esterification of a compound of formula (IV) with methanesulfonyl chloride in the presence of a tertiary amine, e.g. B. triethylamine, pyridine or the like., Is preferably carried out in the presence of a
Cosolvents such as B. dichloromethane at a temperature in the range of about -100C to about room temperature for about 10 minutes to about 2 hours, resulting in a corresponding mesylate of formula (V) which is then reacted with sodium iodide in acetonitrile solution at reflux temperature for a period of time from about 1 hour to about
Is converted into a corresponding N- (2-iodoethyl) pyrrole for 10 h.



   After the reaction of the iodomethyl compounds of formula (VI) with sodium hydride in a suitable, inert, organic solvent, such as. B. dimethylformamide, a 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 is obtained. 7-dicarboxylic acid dimethyl ester and 6-position alkyl-substituted derivatives thereof of the formula (VII). This cyclization takes place in an inert atmosphere, i.e. H. in an argon or nitrogen atmosphere, at temperatures in the range of about 15 C to about 40 C for a period of about 15 minutes to about 4 hours. The best results are obtained if the reaction is carried out at room temperature for about 30 minutes, provided that the radical R represents the hydrogen atom.



   On the other hand, the compounds of formula (VII) can also be obtained by direct cyclization of a mesylate of formula (V) using sodium hydride in dimethylformamide solution at a temperature from about -100C to about room temperature for about 30 minutes to about 2 hours.



   The basic hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate, e.g. As sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous, low aliphatic alcohol, e.g. As methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 hours to about 24 hours leads to a free diacid of formula (XIII), i.e. 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole - 1, 7-dicarboxylic acid and 6-alkyl derivatives thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for about 10 hours.



   The carboxylic acid group at the C-1 position in a compound of formula (VIII) is then treated by treatment with a lower aliphatic alcohol, e.g. B. methanol, ethanol, isopropanol, n-butanol or the like. In the presence of hydrogen chloride selectively esterified, one

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 EMI5.1
 
 EMI5.2
 wherein
Rl has the above meaning leads to corresponding 5-aroyl-1, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-1-carboxylic acid alkyl esters of the formula (XI). This reaction is carried out in an inert, organic, aprotic solvent and in the presence of phosphorus oxychloride at the reflux temperature for about 1 hour to about 175 hours in an inert atmosphere, followed by refluxing in the presence of sodium acetate for about 2 to about 10 hours.

   Instead of phosphorus oxychloride, other acid chlorides, e.g. B. phosgene or oxalyl chloride.



   According to preferred embodiments, this condensation is carried out by adding a solution of a compound of the formula (X) in a suitable solvent to a mixture of 1.1 to 5 molar equivalents of both the desired amide and the phosphorus oxychloride, which has previously been refluxed, in the same solvent the resulting reaction mixture is refluxed for about 6 to about 72 hours in an argon atmosphere and then about 3 to about 10 molar equivalents of sodium acetate are added. The mixture is then heated to boiling under reflux for about 4 to about 6 hours.
 EMI5.3
 and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.



   Examples of suitable N, N-dimethylarylamides are:
N, N-dimethyl-benzamide, N. N-dimethyl-o-toluamide, N. N-dimethyl-m-toluamide, N. N-dimethyl-p-
 EMI5.4
    N-dimethyl-p-ethyl-benzamide, N, N-dimethyl-o-propyl-benzamide, N, N-dimethyl-m-butyl-- m-chloro-benzamide, N, N-dimethyl-p-chloro-benzamide , N, N-dimethyl-o-fluoro-benzamide, N, N-dimethyl- - p-fluoro-benzamide, N, N-dimethyl-m-bromo-benzamide and N, N-dimethyl-p-bromo-benzamide.



   These amides are known, commercially available compounds. You can in the usual way from the corresponding acids, i.e. H. by conversion into the acid chlorides and subsequent treatment with dimethylamine.



   After alkaline hydrolysis of the alkyl ester group in a compound of the formula (XI), the corresponding free acid of the formula (A) is obtained. This hydrolysis takes place in a manner known per se with an alkali metal hydroxide or alkali metal carbonate, e.g. B. sodium hydroxide,

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 Potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous, lower aliphatic alcohol, e.g. B. methanol, ethanol or the like., At a temperature in the range from about room temperature to reflux temperature for about 15 minutes to about 2 hours, and this in an inert atmosphere. According to the preferred embodiments, this hydrolysis is carried out by means of aqueous, methanolic potassium carbonate at the reflux temperature for about 30 minutes.



   The compounds of the formula (A) can be broken down by methods known per se for the preparation of the corresponding individual isomers thereof.



   The (D-acid isomers and (d) acid isomers of the compounds of the formula (A) can be obtained by using the known technique of high pressure liquid chromatography (HPLC) on the diastereoisomeric a-phenylethyl esters of the compounds of the formula ( A) and then uses an acid to break it down, for example the compounds
 EMI6.1
 
 EMI6.2
 
 EMI6.3
 game 4.



   The starting alkyl esters of formula (I) can also be prepared from free acids of formula (A), e.g. B. by treatment with a) the alcohol corresponding to the desired ester in the presence of a strong mineral acid, b) with an ethereal diazoalkane or c) the desired alkyl iodide in the presence of lithium carbonate.

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   The salts of the compounds of formula (A) and the (D-acid isomers thereof are obtained by combining these free acids with an appropriate amount of a pharmaceutically acceptable one
Base treated. Suitable pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide,
Lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide, ferric hydroxide, manganese hydroxide,
Isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylgline Piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.

   The reaction is carried out in water alone or in combination with an inert, water-miscible, organic solvent at a temperature of about 0 to about 1000C and preferably at room temperature. Typical, inert, water-miscible, organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydiofuran. The molar ratio of the compounds of formula (A) or of the (D-acid isomers thereof, based on the base used) is selected so that the correct ratio is present depending on the salt used.

   For example, in order to prepare the calcium salts or magnesium salts of the compounds of formula (A) or the (D-acid isomers thereof), the free acid used as a starting material can be treated with at least 1/2 molar equivalent of a base which is permissible under the driving license to obtain a neutral salt. If the aluminum salts of the compounds of the formula (A) or the (D-acid isomers thereof) are to be prepared, then at least 1/3 mol equivalent of the pharmaceutically acceptable base is used, if one wishes to obtain a neutral salt.



   According to the preferred embodiment, the calcium salts and magnesium salts of the compounds of formula (A) and the (D-acid isomers thereof can be prepared by treating the corresponding sodium or potassium salts thereof with at least 1/2 molar equivalent of calcium chloride or magnesium chloride in an aqueous solution Solution alone or in combination with an inert, water-miscible organic solvent at a temperature of about 20 to about 100 oe. Preferably, the aluminum salts of such compounds can be prepared by reacting the corresponding free acids with at least 1/3 mole equivalent of an aluminum alkoxide , e.g. aluminum triethoxide, aluminum tripropoxide or the like, in a hydrocarbon solvent such as

   Benzene, xylene, cyclohexane or the like, treated at a temperature between about 20 and about 115 ° C. Similar measures can be taken to produce salts of inorganic bases which are not sufficiently soluble for easy implementation.



   Of course, the isolation of the compounds described in the invention can, if desired, be carried out using any suitable separation and purification methods such as e.g. B. extraction, filtration, evaporation, distillation, allowing to crystallize, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or by combination
 EMI7.1
 apply methods.



   The compounds of formula (A) and the (1) acid isomers thereof and the pharmaceutically acceptable non-toxic salts thereof are valuable anti-inflammatory agents, analgesic agents, agglutination inhibitors, fibrinolytics and muscle relaxants. These compounds can be used both prophylactically and therapeutically.



   The preparations containing these compounds as active ingredients are valuable for the treatment and healing of inflammation, such as. B. inflammation of the skeletal muscles, joints and other tissues, for example in the treatment of inflammation of the type such as. B.



  Rheumatism, concussio, laceratio, arthritis, bone fractures, post-traumatic conditions and gout. In those cases where. If the above states cause pain and fever, coupled with inflammation, the compounds which can be produced according to the invention are extremely valuable for eliminating these conditions and the inflammation.



   The administration of the active compounds of the formula (A) or the (D-acid isomers thereof and the pharmaceutically permissible, non-toxic salts thereof in suitable pharmaceutical preparations can in itself be used for the treatment of inflammation, pain or pyrexia or

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 for prophylaxis there are suitable forms of administration means. For example, administration can be administered orally, parenterally or topically in the form of solid, semi-solid or liquid dosage forms, e.g. B. as tablets, suppositories, pills, capsules, powders, solutions,
Carry out suspensions, emulsions, creams, lotions, ointments or the like, preferably in unit dosage forms which are suitable for simple administration of precise dosage amounts.



   The preparations contain customary pharmaceutical carriers or fillers and an active substance according to formula (A) or a (D-acid isomer thereof and / or pharmaceutically permissible, non-toxic salts thereof. You can additionally other drugs, pharmaceutical agents, carriers , Auxiliaries, etc. contain.



   The preferred mode of administration for the conditions detailed below is oral administration using an appropriate daily dosage amount, depending on the degree of the disease. Generally one is given daily
Dosage of between 25 and 500 mg of active substance. In most cases, the treatment is carried out with a dosage of 0.5 to 6 mg per kg of body weight per day. For such oral ones
Administrations will form pharmaceutically acceptable, non-toxic preparations by adding any of the normally used excipients, such as, for example, to the active substance or substances. B. pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and. Like., admits.



   Such preparations can be in the form of solutions, suspensions, tablets, pills, capsules, powders,
Prolonged-release medications, etc. are sold.



   The active substances can be processed into a suppository using, for example, polyalkylene glycols, such as polypropylene glycol, as carriers.



   Liquid, pharmaceutically administrable preparations can be, for example, by dissolving, dispersing, etc., an active substance of the type described above and optionally pharmaceutical excipients in a carrier, such as. As water, saline, aqueous dextrose, glycerin, ethanol and the like. Like., Are prepared, whereby a solution or suspension is obtained.



  If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, e.g. B. wetting or emulsifying agents, pH-buffering agents, etc., z. As sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. included.



   Methods for the preparation of such dosage forms are well known or readily available to the person skilled in the art. In this connection, reference is made, for example, to Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. In all cases, the preparation to be administered will contain a certain amount of active substance or active substances in a pharmaceutically effective amount.



   The compounds of formula (A), the (D-acid isomers and their non-toxic, pharmaceutically acceptable salts, as described above, are also relaxants for the uterine muscles and are therefore valuable as agents which benefit both the mother and the child / or the fetus until the final stage of pregnancy, and it should be noted that in certain cases, for example, those in which the contractions have already started, ie in those cases in which the mother already feels uterine contractions, what is immediate before birth, in particular, the administration of the compounds described here cannot prolong the state of pregnancy for an indefinite period.

   In such cases, the pregnancy is most likely only slightly "prolonged", a factor that can be beneficial for the mother and / or the fetus.



   In particular, the new active ingredients are used as a means of delaying the onset or postponing the contractions. The term "delaying the onset of contractions" is intended to encompass the delay in contractions which is caused by the administration of the active substance at any point in time before the onset of the lower muscle contractions. This designation is thus intended to prevent abortus at the beginning of pregnancy, i.e. H. before the fetus is viable, as well as delaying premature labor, a term that is sometimes used to refer to premature labor, which experience has shown to occur later in pregnancy, when the fetus is already considered viable.

   In any case, the agents are used as prophylactic agents.

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 sets because such administration prevents the onset of labor. Administration is in the treatment of women with a history, spontaneous abortion, miscarriage or preterm delivery, i.e. H. Delivery before the end of the entire gestation period, particularly valuable. Such administration is also valuable in those cases where there are clinical indications that the pregnancy should end prematurely, so that such administration could be particularly advantageous for the mother and / or the fetus.



   As for animals, this treatment can also be used to synchronize the birth of a group of pregnant animals or to control such births at the desired time and / or location where such births can be performed with greater ease.



   In the invention, the term "labor shift" is intended to include the labor delay caused by the administration of compounds of formula (A), (D-acid isomers thereof, and pharmaceutically acceptable non-toxic salts thereof after the onset of uterine muscle contractions The patient's condition, including the length of time in the gestational period in which the contractions started, the extent of the contractions, and the duration of the contractions will affect the results obtained by the administration of the compounds, for example, the effect may be that
 EMI9.1
 prolonging the gestation period causes, although depending on the patient's conditions, the effect can either be very weak or, under certain circumstances, somewhat larger.

   Such administration can prevent spontaneous abortion, make the birth easier and / or less painful for the mother, or can lead to the fact that the birth can be carried out at a more suitable time and / or in a more suitable place.



   In all cases, the administration of the active ingredients should be reconciled with the best and / or acceptable medical or veterinary practices for the purposes mentioned above, in order to maximize the benefits for the mother and the fetus. For example, administration should not continue long after the scheduled date for the fetus in the uterus to die.



   In practice, a therapeutically effective amount of a compound of formula (A), a (l) acid isomer thereof or a pharmaceutically acceptable non-toxic salt thereof or a pharmaceutical preparation containing such an active ingredient will be given to the pregnant woman or the pregnant animal according to the previously known, customary and permissible methods administered. The compound can be administered either as such or in conjunction with another compound or with other compounds of the type defined above or with other pharmaceutical agents, carriers, excipients, etc. Such a compound or compounds or preparations can be administered orally, parenterally either in the form of solid, semi-solid and liquid dosage forms.

   In particular, administration is carried out with the aid of a pharmaceutical preparation which contains the pharmaceutically active compound and one or more pharmaceutical carriers or auxiliaries.



   The administrable pharmaceutical preparation can be in the form of oral tablets, vaginal tablets or uterine tablets or suppositories, pills, capsules, liquid solutions, suspensions and the like. The like, preferably in unit dosage forms suitable for easy administration of precise dosages. Usual, non-toxic, solid carriers include, for example, pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate etc. The active substance defined above can be in the form of suppositories using, for example, polyalkylene glycols, such as polypropylene glycol , are present as carriers.

   Liquid, pharmaceutically administrable preparations can be prepared, for example, in such a way that an active substance of the type defined above and suitable pharmaceutical additives in a carrier, such as. As water, saline, aqueous dextrose, glycerin, ethanol, etc., dissolves, disperses, etc., so as to obtain a solution or suspension. If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, e.g. B. network

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 or emulsifiers, pH buffering agents, etc., e.g. B. sodium acetate, sorbitan monolaurate,
Triethanolamine, oleate, etc.

   Methods for producing such dosage forms are well known or are readily available to the person skilled in the art, reference being made in particular to Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. The preparation to be administered will be such an amount in all cases
Contain active substance or substances which is sufficient to delay the onset of contractions or to prolong the contractions if the uterine contractions have already started. In general, a daily dosage of 0.5 to about 25 mg of active substance per kg
Administer body weight, such administration being carried out once a day or in smaller doses regularly three or four times a day.

   The amount of active substance to be administered naturally depends on the respective action of this active substance.



   The following examples illustrate the invention without restricting it. The abbreviation t. I. l. c., if it occurs here, refers to thin layer chromatography, while all mixing ratios with respect to liquids represent volume ratios. If necessary, the examples are repeated to provide additional material for the examples below.



   Unless otherwise stated, the reactions are carried out at room temperature, i.e. H. at temperatures in the range of 20 to 300C.



   Example 1 :
A solution of 336 mg isopropyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrol-l-carboxylate in 10 ml methanol is mixed with a solution of 690 mg potassium carbonate in 5 ml of water treated.



   The reaction mixture is then heated to reflux in a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. The residue is taken up in 10 ml of a 10% aqueous hydrochloric acid solution and 50 ml of water and the resulting mixture is extracted twice with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. By allowing the residue to recrystallize from a mixture of ethyl acetate and hexane, 238 mg (89%) of 5-p-toloyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid [(A ), R = H, R = p-CHa], mp.



  182 to 183 C.



   Example 2:
A solution of 250 mg of isopropyl-5-p-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylate in 8 ml of methanol is dissolved in a nitrogen atmosphere with a solution of 200 mg of sodium hydroxide treated in 1 ml of water, the reaction mixture being kept at room temperature for 1 1/2 hours. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with 5 ml of water and extracted with ether to remove any unsaponified product which may be present. The aqueous solution is then acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure.

   The residue is crystallized from a mixture of ethyl acetate and hexane to give 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, which is obtained with the product according to Example 1 is identical.



   Example 3:
Assuming the following isopropyl esters:
Isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,3-a] pyrrole-1-carboxylate, pale yellow oil with the following physical constants:
 EMI10.1
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 215 <SEP> nm <SEP> (# <SEP> = <SEP> 6020);
 <tb> max
 <tb> I.R .: <SEP> vCHCl3 <SEP> 1725 <SEP> cm-1 <SEP>;
 <tb> max
 <tb> N.M.R .: <SEP> # CDCl3 <SEP> 1.22 <SEP> (d, <SEP> J <SEP> = <SEP> 7 <SEP> Hz, <SEP> 6H), <SEP> 2.40 <SEP> - <SEP> 2.90 <SEP> (m, <SEP> 2H), <SEP> 3.60 <SEP> - <SEP> 4.20 <SEP> (m, 2H),
 <tb> TMS <SEP> 4.65 <SEP> - <SEP> 5.2 <SEP> (m, <SEP> 1H), <SEP> 5.73 <SEP> - <SEP> 5.92 <SEP> (m, <SEP> 1H), <SEP> 6.10 <SEP> (t, <SEP> J <SEP> = <SEP> 3 <SEP> Hz. <SEP> 1H),
 <tb> 6.43 <SEP> - <SEP> 6.53 <SEP> TpM <SEP> (m, <SEP> 1H).
 <tb>
 



   Isopropyl-5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, light yellow oil with the following physical constants:

  <Desc / Clms Page number 11>

 
 EMI11.1
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 245, <SEP> 311 <SEP> nm <SEP> (# <SEP> 7230, <SEP> 17800);
 <tb> max
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1735, <SEP> 1620 <SEP> cm-1;
 <tb> max
 <tb> N.M.R. <SEP>: <SEP> # CDCl3 <SEP> 1.24 <SEP> [d, <SEP> 6H, <SEP> (CH3) 2CH], <SEP> 2.50 <SEP> - <SEP> 3.13 <SEP> (m, <SEP> 2H; <SEP> H-2), <SEP> 3.97 <SEP> (dd, 1H,
 <tb> TMS <SEP> H-1), <SEP> 4.18 <SEP> - <SEP> 4.70 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 5.00 <SEP> [sept., <SEP> 1H, <SEP> (CH3) 2CH], <SEP> 6.00
 <tb> (d, <SEP> 1H, <SEP> H-7), <SEP> 6.86 <SEP> (d, <SEP> 1H, <SEP> H-6), <SEP> 7.10 <SEP> - <SEP> 7.90 <SEP> TpM <SEP> (m, <SEP> 5H, <SEP> phenyl protons);
 <tb> M.S .: <SEP> m / e <SEP> 297 <SEP> (M +).
 <tb>
 



   Isopropyl-5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil with the following physical constants:
 EMI11.2
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 252. <SEP> 303 <SEP> nm <SEP> (# <SEP> 4460, <SEP> 19100);
 <tb> max
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1735, <SEP> 1620 <SEP> cm-1;
 <tb> max
 <tb> N.M.R. <SEP>: <SEP> # CDCl3 <SEP> 1.18 <SEP> [d, <SEP> 6H, <SEP> (CH3) 2CH], <SEP> 2.28 <SEP> (s, <SEP> 3H, <SEP> o-CH3), <SEP> 2.50 <SEP> - <SEP> 3.13 <SEP> (m, <SEP> 2H,
 <tb> TMS <SEP> H-2). <SEP> 3.92 <SEP> (dd, <SEP> 1H, <SEP> H-1), <SEP> 4.17 <SEP> - <SEP> 4.70 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 4.98 <SEP> [sept. <SEP> 1H,
 <tb> (CH3) 3CH], <SEP> 5.92 <SEP> (d, <SEP> 1H, <SEP> H-7), <SEP> 6.43 <SEP> (d, <SEP> 1H, <SEP> H-6), <SEP> 6.97 <SEP> - <SEP> 7.45 <SEP> TpM
 <tb> (m, <SEP> 4H. <SEP> phenyl protons).
 <tb>
 



   Isopropyl-5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil with the following physical constants:
 EMI11.3
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 250 <SEP> - <SEP> 251, <SEP> 310 <SEP> - <SEP> 312 <SEP> nm <SEP> (# <SEP> 6460, <SEP> 17400);
 <tb> max
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1735, <SEP> 1620 <SEP> cm-1:
 <tb> max
 <tb> N.M.R. <SEP>: <SEP> # CDCl3 <SEP> 1.25 <SEP> [d, <SEP> 6H, <SEP> (CH3) 2CH], <SEP> 2.27 <SEP> (s, <SEP> 3H, <SEP> CH3), <SEP> 2.52 <SEP> - <SEP> 3.13 <SEP> (m, <SEP> 2H,
 <tb> TMSH-2), <SEP> 3.92 <SEP> (dd, <SEP> 1H, <SEP> H-1), <SEP> 4.13 <SEP> - <SEP> 4.70 <SEP> (m, <SEP> 2H, <SEP> H-3). <SEP> 4.95 <SEP> [sept. <SEP> 1H,
 <tb> (CH3) 2CH], <SEP> 5.95 <SEP> (d, <SEP> 1H, <SEP> H-7), <SEP> 6.67 <SEP> (d, <SEP> 1H, <SEP> H-6), <SEP> 7.03 <SEP> - <SEP> 7.57 <SEP> TpM
 <tb> (m, <SEP> 4H, <SEP> phenyl protons).
 <tb>
 



   Isopropyl-5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate with the following physical constants:
 EMI11.4
 
 <tb>
 <tb> U.V .: <SEP> #MeOH <SEP> 218. <SEP> 270 <SEP> - <SEP> 284 <SEP> (shoulder), <SEP> 314 <SEP> nm <SEP> (# <SEP> 3780, <SEP> 9320, <SEP> 22400);
 <tb> max
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1730, <SEP> 1605 <SEP> cm-1;
 <tb> max
 <tb> N.M.R. <SEP>:

    <SEP> # CDCl3 <SEP> 1.24 <SEP> [d, <SEP> 6H, <SEP> J <SEP> = <SEP> 6 <SEP> Hz, <SEP> [CH3) 2CH-1, <SEP> 2.50 <SEP> - <SEP> 3.10 <SEP> (M, <SEP> 2H, <SEP> H-2), <SEP> 3.78
 <tb> TMS <SEP> (s, <SEP> 3H, <SEP> CH3O), <SEP> 3.93 <SEP> (dd, <SEP> 1H, <SEP> JAX <SEP> = <SEP> 6 <SEP> Hz, <SEP> JBX <SEP> = <SEP> 7 <SEP> Hz, <SEP> H-1), <SEP> 4.13
 <tb> to <SEP> 4.60 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 4.95 <SEP> [sept., <SEP> 1H, <SEP> J = 6 <SEP> Hz, <SEP> (CH3) 2CH], <SEP> 5.95
 <tb> (s. <SEP> 1H, <SEP> J <SEP> = <SEP> 4 <SEP> Hz, <SEP> H-7). <SEP> 6.68 <SEP> (d, <SEP> 1H, <SEP> J <SEP> = <SEP> 4 <SEP> Hz, <SEP> H-6), <SEP> 6.70 <SEP> - <SEP> 7.90
 <tb> TpM <SEP> (m, <SEP> 4H, <SEP> phenyl protons);
 <tb> M.S .: <SEP> m / e <SEP> 327 <SEP> (M +).
 <tb>
 



   Isopropyl-5-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, mp. 50 to 5lOC,
Isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3H-dihydro-3H-pyrrolo [1,2] pyrrole-1-carboxylate, mp. 94 to 95 C,
Isopropyl-5-o-chlorobenzoyl1-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil with the following physical constants:
 EMI11.5
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 251, <SEP> 306 <SEP> nm <SEP> (# <SEP> 5750, <SEP> 16600);
 <tb> max
 <tb> I.R. <SEP>: <SEP> # CHCl3 <SEP> 1735, <SEP> 1625 <SEP> cm-1;
 <tb> max
 <tb> N.M.R. <SEP>:

    <SEP> # CDCl3 <SEP> 1.22 <SEP> [d, <SEP> 6H, <SEP> (CH3) 2CH], <SEP> 2.55 <SEP> - <SEP> 3.05 <SEP> (m, <SEP> 2H, <SEP> H-2], <SEP> 3.97 <SEP> [dd, <SEP> 1H,
 <tb> TMS <SEP> H-1), <SEP> 4.17 <SEP> - <SEP> 4.70 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 4.97 <SEP> [sept., <SEP> 1H, <SEP> (CH3) 2CH], <SEP> [5.93]
 <tb> (d, <SEP> 2 / 3H), <SEP> 6.00 <SEP> (d, <SEP> 1 / 3H) <SEP> H-7 <SEP>], <SEP> [6.42 <SEP> (d, <SEP> 2 / 3H), <SEP> 6.67 <SEP> (d, <SEP> 1 / 3H)
 <tb> H-6], <SEP> 7.07 <SEP> - <SEP> 7.80 <SEP> TpM <SEP> (m, <SEP> 4H, <SEP> phenyl protons).
 <tb>
 

  <Desc / Clms Page number 12>

 



   Isopropyl-5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil with the following physical constants:
 EMI12.1
 
 <tb>
 <tb> U.V .: <SEP>
 <tb> #MeOHmax
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1735, <SEP> 1620, <SEP> 1570 <SEP> cm-1;
 <tb> max
 <tb> N.M.R .: <SEP> # CDCl3 <SEP> 1.27 <SEP> [d, <SEP> 6H, <SEP> (CH3) 2CH], <SEP> 2.50 <SEP> - <SEP> 3.18 <SEP> (m, <SEP> 2H, <SEP> H-2), <SEP> 3.93 <SEP> (dd, <SEP> 1H,
 <tb> TMS <SEP> H-1), <SEP> 4.10 <SEP> - <SEP> 4.63 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 4.98 <SEP> [sept., <SEP> 1H, <SEP> (CH3) 2CH], <SEP> 5.98
 <tb> (d, <SEP> 1H, <SEP> H-7), <SEP> 6.67 <SEP> (d, <SEP> 1H, <SEP> H-6), <SEP> 7.07 <SEP> - <SEP> 7.78 <SEP> TpM <SEP> (m, <SEP> 4H, <SEP> phenyl protons);
 <tb> M.S .: <SEP> m / e <SEP> 331 <SEP> - <SEP> 333 <SEP> (M +).
 <tb>
 



   Isopropyl-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 80, 5 to 81-C,
 EMI12.2
 
 EMI12.3
 
 <tb>
 <tb> 2-dihU.V .: <SEP> #max <SEP> 250, <SEP> 315 <SEP> nm <SEP> (# <SEP> 6170, <SEP> 14100);
 <tb> I.R .: <SEP> vCHCl3 <SEP> 1734, <SEP> 1605, <SEP> 1593 <SEP> cm-1 <SEP>;
 <tb> max
 <tb> N.M.R. <SEP>:

    <SEP> # CDCl3 <SEP> 1.25 <SEP> (d, <SEP> 6H, <SEP> J <SEP> = <SEP> 6 <SEP> Hz, <SEP> ester <SEP> CH3), <SEP> 1.83 <SEP> (s, <SEP> 3H, <SEP> ring <SEP> CH3), <SEP> 2.49
 <tb> TMS <SEP> to <SEP> 3.00 <SEP> (m, <SEP> 2H. <SEP> CH2), <SEP> 3.90 <SEP> (t. <SEP> 1H, <SEP> X <SEP> J <SEP> = <SEP> 7.4 <SEP> Hz, <SEP> CHCO), <SEP> 4.10 <SEP> to
 <tb> 4.23 <SEP> (m, <SEP> 2H, <SEP> N-CH2). <SEP> 4.98 <SEP> (sept., <SEP> 1H, <SEP> J <SEP> = <SEP> 6 <SEP> Hz, <SEP> ester <SEP> CH), <SEP> 5.84
 <tb> (s, <SEP> 1H, <SEP> H-3), <SEP> 7.00 <SEP> (t, <SEP> 2H, <SEP> Jortho <SEP> = <SEP> 8.4 <SEP> Hz, <SEP> JHF <SEP> = <SEP> 8 <SEP> Hz, <SEP> H-3 ', 5'),
 <tb> 7.55 <SEP> (1. <SEP> 2H, <SEP> Jortho <SEP> = <SEP> 8.4 <SEP> Hz, <SEP> JHF <SEP> = <SEP> 5.5 <SEP> Hz, <SEP> H-2,6 ');
 <tb> M.S .:

    <SEP> m / e <SEP> 1% <SEP> 329 <SEP> 25 <SEP> M +
 <tb> 242 <SEP> 100 <SEP> M + -CO2CH <SEP> (CH3) 2
 <tb> 123 <SEP> 36 <SEP> F-C6H4CO.
 <tb>
 



   Isopropyl-5-p-fluorobenzoyl-6-ethyl-3H-pyrrolo 1, 2-a] pyrrole-l-carboxylate, oil is obtained by hydrolysis of the isopropyl ester group in accordance with the procedures described in Example 1 or 2, the corresponding free acids, namely:
5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp. 160 to 161 C,
5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, an oil with the following physical constants:
 EMI12.4
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 253, <SEP> 307 <SEP> nm <SEP> (# <SEP> 3310, <SEP> 16980);
 <tb> max
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1720, <SEP> 1620 <SEP> cm-1;
 <tb> max
 <tb> N.M.R. <SEP>:

    <SEP> # CDCl3 <SEP> 2.32 <SEP> (s, <SEP> 3H, <SEP> CH3), <SEP> 2.53 <SEP> - <SEP> 3.03 <SEP> (m, <SEP> 2H, <SEP> H-2), <SEP> 3.97 <SEP> (dd, <SEP> 1H, <SEP> H-1),
 <tb> TMS <SEP> 4.17 <SEP> - <SEP> 4.67 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 6.92 <SEP> (d, <SEP> 1H, <SEP> H-7), <SEP> 6.40 <SEP> (d, <SEP> 1H, <SEP> H-6),
 <tb> 6.83 <SEP> - <SEP> 7.37 <SEP> (m, <SEP> 4H, <SEP> phenyl protons), <SEP> 8.60 <SEP> TpM <SEP> (b.s., <SEP> 1H, <SEP> COOH).
 <tb>
 
 EMI12.5
 
2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid, 5-m-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

   M.p. 155 to 156 C, 5-p-ethoxybenzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, m.p. 169.5 to 170 C, 5-p-isopropoxybenzoyl- 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp. 157 to 158 C,

  <Desc / Clms Page number 13>

 
5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, with the following physical constants:
 EMI13.1
 
 <tb>
 <tb> U.V. <SEP>: <SEP> #MeOH <SEP> 250, <SEP> 307.5 <SEP> nm <SEP> (# <SEP> 4360, <SEP> 17400);
 <tb> max
 <tb> I.R. <SEP>: <SEP> vCHCl3 <SEP> 1715, <SEP> 1620 <SEP> cm-1;
 <tb> max
 <tb> N.M.R .:

    <SEP> # CDCl3 <SEP> 2.60 <SEP> - <SEP> 3.15 <SEP> (m, <SEP> 2H, <SEP> H-2), <SEP> 4.02 <SEP> (dd, <SEP> 1H, <SEP> JAX <SEP> = <SEP> 6 <SEP> Hz, <SEP> JBX <SEP> = <SEP> 7 <SEP> Hz,
 <tb> TMS <SEP> H-1), <SEP> 4.20 <SEP> - <SEP> 4.70 <SEP> (m, <SEP> 2H, <SEP> H-3), <SEP> 5.98 <SEP> (d, <SEP> 1H, <SEP> J <SEP> = <SEP> 4 <SEP> Hz, <SEP> H-7), <SEP> 6.42
 <tb> (d, <SEP> 1H, <SEP> J <SEP> = <SEP> 4 <SEP> Hz, <SEP> H-6), <SEP> 7.00 <SEP> - <SEP> 7.77 <SEP> (m, 4H, <SEP> phenyl protons),
 <tb> 8.67 <SEP> TpM <SEP> [s, <SEP> (br), <SEP> 1H, <SEP> COOH].
 <tb>
 



   5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp. 180 to 181 C,
5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 201, 5 to 202.5 C.



   5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 179, 5 to 180, 5 C,
5-p-Toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [(A). R = CHa. R = p-CHa], m.p. 187 C,
 EMI13.2
 
Example 4:
0.58 g of trifluoroacetic anhydride are added to a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 25 ml of dry benzene. Then the mixture is stirred for 10 min at room temperature and the resulting solution is cooled to 0 to 5 C and then 1.4 g of dry triethylamine and then immediately mixed with 0.5 g of (1) -α-phenylethyl alcohol.

   The reaction solution thus obtained is stirred at room temperature for 15 minutes and then poured into 20 ml of water containing 1 ml of triethylamine and then extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and the solvent and the excess (t) -c -phenylethyl alcohol removed in vacuo. In this way, 0.42 g of a mixture of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole is obtained.
 EMI13.3
 Stirred for 70 min at room temperature. The reaction solution thus obtained is poured into 60 ml of dry benzene and the solvents are removed in vacuo and at room temperature.

   Purification is carried out by high pressure liquid chromatography (using a column as described above with the difference that 35% EtOAc / Hexane in 1 / 2Yó acetic acid is used instead of 4% EtOAc / Hexane), whereby 63 mg (1) -5-Benzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid [αCHCl3 -153.7], mp. 153 to 155 ° C.



   Similarly, the less polar ester is split according to the method of how
 EMI13.4
 racemize and recycle.



   Similarly, other (dl) compounds can be converted to the corresponding (D isomers and (d) isomers.

  <Desc / Clms Page number 14>

 



   Example 5:
To a solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide in the form of an oil in solution .



  The solvent is then evaporated under reduced pressure and the residue is taken up in 2 ml of methanol and then precipitated with ether. In this way, sodium - 5-p-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylate is obtained, which can be crystallized from a mixture of ethyl acetate and hexane.



   In a similar manner, the ammonium and potassium salts of 5-p-toluoyl-1,2-dihydro- 3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid and the other starting acids (A) can be prepared if ammonium hydroxide or potassium hydroxide is used instead of sodium hydroxide.



   Example 6:
To a solution of 175 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1. 2-a] pyrrole-l-carboxylic acid in 5 ml of methanol are added 1 mol equivalent of potassium hydroxide in the form of an oil in solution,
 EMI14.1
 
Contains 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate. A solution of 40 mg of calcium carbonate, which has been dissolved in the smallest possible amount in hydrochloric acid in order to be able to dissolve the calcium carbonate, is buffered with 100 mg of solid ammonium chloride, after which 5 ml of water are added.

   The buffered calcium solution thus obtained is then added in a solution of potassium 5-p-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] - pyrrole-1-carboxylate and the precipitate formed is collected by filtration , washed with water and air-dried to give calcium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylate.



   Magnesium-5-p-tol uoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylate is obtained in a similar manner if magnesium carbonate is used instead of calcium carbonate.



   Example 7:
To a solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid in 5 ml of methanol is added 1 mol equivalent of potassium hydroxide in the form of an oil in solution . The solvent is removed and the residue is dissolved in 5 ml of water. The aqueous solution of potassium 5-p-toluoyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1-carboxylate thus obtained is added to a solution of 150 mg of cuprinitrate trihydrate in 5 ml of water. The precipitate so formed is
 EMI14.2
 



   Example 8:
A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is then allowed to cool to room temperature and the product is filtered off, washed with ether and dried, giving the isopropylamine salt of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1- receives carboxylic acid.



   Similarly, other amine salts, e.g. B. the diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole - 1-carboxylic acid and Other starting acids (A) are obtained if the corresponding amines are used instead of isopropylamine.



   Example 9:
A solution of 770 mg of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexylamine. The reaction mixture is then stirred for 10 min and the solid product formed is separated off by filtration and washed with anhydrous ether, 965 mg of the dicyclohexylamine salt of 5-o-toluoyl-1,2-dihydro-3H-pyrrolo [1,2- a] pyrrole-1-carboxylic acid. Mp 161-163 ° C.



   Similarly, the other free acid compounds (A) can be converted into the corresponding dicyclohexylamine salts, e.g. B. the dicyclohexylamine salt of 5-0-chlorobenzoyl-1, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid, mp. 173 to 175 C, transfer.

  <Desc / Clms Page number 15>

 



  Examples of use:
 EMI15.1
 
 <tb>
 <tb> 1. <SEP> components <SEP> amount <SEP> pro <SEP> tablet, <SEP> mg
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> - <SEP> 3H-pyrrolo <SEP> [1, <SEP> 2-a <SEP>] <SEP> - <SEP>
 <tb> pyrrole-1-carboxylic acid <SEP> 25
 <tb> cornstarch <SEP> 20
 <tb> lactose <SEP> (spray dried) <SEP> 153
 Magnesium stearate <SEP> 2
 <tb>
 
The above ingredients are thoroughly mixed together and pressed into individual grooved tablets.
 EMI15.2
 
 <tb>
 <tb>



  2nd <SEP> components <SEP> amount <SEP> pro <SEP> tablet, <SEP> mg
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> - <SEP> 3H-pyrrolo <SEP> [1, <SEP> 2-a <SEP>] - <SEP>
 <tb> pyrrole-1-carboxylic acid <SEP> 200
 <tb> cornstarch <SEP> 50
 <tb> lactose <SEP> 145
 Magnesium stearate <SEP> 5
 <tb>
 
The above ingredients are thoroughly mixed together and pressed into individual grooved tablets.



   100 mg of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are used in place of 200 mg of the (dl) compound of the above composition.
 EMI 15.3
 
 <tb>
 <tb>



  3rd <SEP> components <SEP> amount <SEP> pro <SEP> capsule, <SEP> mg
 <tb> sodium 5-benzoyl-1, <SEP> 2-di- <SEP>
 <tb> hydro-3H-pyrr010 <SEP> [1, <SEP> 2-a] <SEP> - <SEP>
 <tb> pyrrole-1-carboxylate <SEP> 108
 <tb> lactose <SEP> 15
 <tb> cornstarch <SEP> 25
 Magnesium stearate <SEP> 2
 <tb>
 
The above ingredients are mixed together and placed in hard shell gelatin capsules.
 EMI 15.4
 
 <tb>
 <tb>



  4th <SEP> components <SEP> amount <SEP> pro <SEP> capsule, <SEP> mg
 <tb> calcium-5-benzoyl-1, <SEP> 2-di- <SEP>
 <tb> hydro-3H-pyrrolo <SEP> [1, <SEP> 2-a] pyrrole-1-carboxylate <SEP> 115
 <tb> lactose <SEP> 93
 <tb> cornstarch <SEP> 40
 Magnesium stearate <SEP> 2
 <tb>
 

  <Desc / Clms Page number 16>

 
The above ingredients are mixed together and introduced into hard walled gelatin capsules.
 EMI16.1
 
 <tb>
 <tb>



  5. <SEP> components <SEP> amount <SEP> pro <SEP> tablet, <SEP> mg
 <tb> isopropyl <SEP> ammonium-5-ben- <SEP>
 <tb> zoyl-1, <SEP> 2-dihydro-3H- <SEP>
 <tb> - <SEP> pyrrolo <SEP> [1, <SEP> 2-a] <SEP> pyrrole-
 <tb> - <SEP> 1-carboxylate <SEP> 245
 <tb> cornstarch <SEP> 75
 <tb> lactose <SEP> 175
 <tb> Magnesium stearate <SEP> 5
 <tb>
 
The above ingredients are intimately mixed together and pressed into individual, scored tablets.
 EMI16.2
 
 <tb>
 <tb>



  6. <SEP> components <SEP> amount <SEP> pro <SEP> tablet, <SEP> mg
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> -3H-pyrrolo <SEP> [l, <SEP> 2-a] <SEP> - <SEP>
 <tb> pyrrole-l-carboxylic acid <SEP> 300
 <tb> sucrose <SEP> 300
 <tb>
 
The above ingredients are thoroughly mixed together and processed into individual grooved tablets, one tablet being administered every 3 to 4 hours.
 EMI 16.3
 
 <tb>
 <tb>



  7. <SEP> components <SEP> amount <SEP> pro <SEP> capsule, <SEP> mg
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> - <SEP> 3H-pyrrolo <SEP> [1, <SEP> 2-a] <SEP> - <SEP>
 <tb> pyrrole-1-carboxylic acid <SEP> 100
 <tb> lactose <SEP> 148
 <tb> dextrose <SEP> 2
 <tb>
 
The above ingredients are thoroughly mixed together and introduced into hard-shell gelatin capsules.



   50 mg (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are added in place of 100 mg of the (dl) compound of the above preparation.
 EMI 16.4
 
 <tb>
 <tb>



  8th. <SEP> components <SEP> amount <SEP> pro <SEP> tablet, <SEP> mg
 <tb> Calcium-5-benzoyl-
 <tb> - <SEP> l, <SEP> 2-dihydro-3H-pyrrolo- <SEP>
 <tb> [1, <SEP> 2-a] <SEP> pyrrole-l-carb- <SEP>
 <tb> oxylate <SEP> 230
 <tb> cornstarch <SEP> (paste) <SEP> 40
 <tb> cornstarch <SEP> 50
 Magnesium stearate <SEP> 2
 <tb> lactose <SEP> 178
 <tb>
 

  <Desc / Clms Page number 17>

 
The above ingredients are thoroughly mixed together and pressed into individual grooved tablets.
 EMI17.1
 
 <tb>
 <tb>



  9. <SEP> components <SEP> amount <SEP> pro <SEP> tablet, <SEP> mg
 <tb> sodium 5-benzoyl-1, <SEP> 2-di- <SEP>
 <tb> hydro-3H-pyrrolo [l, <SEP> 2-a] - <SEP>
 <tb> pyrrole-1-carboxylate <SEP> 217
 <tb> cornstarch <SEP> 50
 Magnesium stearate <SEP> 2
 <tb> gelatin <SEP> 226
 <tb> lactose <SEP> 5
 <tb>
 
The above ingredients are thoroughly mixed together and pressed into individual grooved tablets.
 EMI17.2
 
 <tb>
 <tb>



  10th <SEP> components <SEP> amount <SEP> pro <SEP> capsule, <SEP> mg
 <tb> isopropylammonium-5-benzoyl-1, <SEP> 2-dihydro-3H- <SEP>
 <tb> - <SEP> pyrrolo <SEP> [1, <SEP> 2-a] <SEP> pyrrole-
 <tb> - <SEP> 1-carboxylate <SEP> 122
 <tb> cornstarch <SEP> 30
 <tb> lactose <SEP> 98
 <tb>
 
The above ingredients are mixed together and introduced into hard shell gelatin capsules.



   11. An injectable preparation of the following composition, buffered to a pH of 7, is produced:
 EMI17.3
 
 <tb>
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> -3H-pyrrolo <SEP> [1,2-a] pyrrole
 <tb> -1-carboxylic acid
 <tb> K <SEP> 2HPO4 buffer <SEP> (0.4 molar
 <tb> solution) <SEP> 2 <SEP> ml <SEP>
 <tb> In <SEP> KOH <SEP> q. <SEP> s. <SEP> to <SEP> PH <SEP> 7
 <tb> water <SEP> (dest. <SEP> sterile) <SEP> q. <SEP> s. <SEP> to <SEP> 20 <SEP> ml
 <tb>
 
0.1 g (l) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acid are used instead of 0.2 g of the (dl) compound of the above composition used.



  12. A total suppository weighing 2.8 g of the following composition is produced:

  <Desc / Clms Page number 18>

 
 EMI18.1
 
 <tb>
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> - <SEP> 3H-pyrrolo <SEP> [1, <SEP> 2-a <SEP>] <SEP> pyrrole-
 <tb> - <SEP> 1-carboxylic acid <SEP> 25 <SEP> mg
 <tb> "Witepsol <SEP> H-15 "
 <tb> (triglycerides <SEP> from <SEP> saturated,
 <tb> vegetable <SEP> fatty acids <SEP>; <SEP> on
 <tb> product <SEP> the <SEP> company <SEP> RichesNelson, <SEP> Inc., <SEP> New <SEP> York, <SEP> N. <SEP> Y.) <SEP> rest
 <tb>
 
12.5 mg of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are used instead of the 25 mg of the (dU compound of the above composition.



   13. An oral suspension for pediatric use of the following composition is prepared:
 EMI18.2
 
 <tb>
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> - <SEP> 3H-pyrrolo <SEP> [1, <SEP> 2-a] <SEP> pyrrole- <SEP>
 <tb> - <SEP> I-carboxylic acid <SEP> 0, <SEP> 1 <SEP> g <SEP>
 <tb> fumaric acid <SEP> 0, <SEP> 5 <SEP> g <SEP>
 <tb> sodium chloride <SEP> 2, <SEP> 0 <SEP> g <SEP>
 <tb> methyl paraben <SEP> 0, <SEP> 1 <SEP> g <SEP>
 <tb> granular <SEP> sugar <SEP> 25, <SEP> 5 <SEP> g <SEP>
 <tb> sorbitol <SEP> (70% <SEP> solution) <SEP> 12, <SEP> 85 <SEP> g
 <tb> Veegum <SEP> K <SEP> (Vanderbilt <SEP> Co. <SEP>) <SEP> 1, <SEP> 0 <SEP> g <SEP>
 <tb> flavor correcting <SEP> medium <SEP> 0, <SEP> 035 <SEP> ml
 <tb> colorant <SEP> 0, <SEP> 5 <SEP> mg
 <tb> dest. <SEP> water <SEP> q. <SEP> s.

    <SEP> to <SEP> 100 <SEP> ml
 <tb>
 
0.05 g of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid is used instead of 0.1 g of the (dl) compound of the above composition used.



    14. - 15. For veterinary purposes, the following powder is put together:
 EMI18.3
 
 <tb>
 <tb> 14 <SEP> 15
 <tb> 5-benzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> -3H-pyrrolo <SEP> [1,2-a] pyrrole-1-carboxylic acid <SEP> 0, <SEP> 1 <SEP> g <SEP> 1, <SEP> 2 <SEP> g
 <tb> sucrose <SEP> 5, <SEP> 7 <SEP> g <SEP> 3, <SEP> 7 <SEP> g
 <tb> polyvinyl pyrrolidone <SEP> 0, <SEP> 3 <SEP> g <SEP> 0, <SEP> 3 <SEP> g
 <tb>
 
0.05 g of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid is used instead of 0.1 g of the (dl) compound of composition 14 used.



     0.6 g of (1) -5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are used instead of the 1.2 g of the (dl) compound of composition 15 used.



  Biodata A) Analgesic mouse test (action against torso twisting) Carrying out the test: The test material is orally in an aqueous carrier using a gastric tube 18 to 20 g

  <Desc / Clms Page number 19>

 
 EMI19.1
 
 EMI19.2
 
 <tb>
 <tb> 255-p-ethoxybenzoyl-1, <SEP> 2-dihydro-3H-pyrrolo- <SEP>
 <tb> [1, <SEP> 2-a] pyrrole-1-carboxylic acid <SEP> 35
 <tb> 5-p-isopropoxybenzoyl-1, <SEP> 2-dihydro-3H-pyrrolo- <SEP>
 <tb> [1, <SEP> 2-a <SEP>] pyrrole-1-carboxylic acid <SEP> 1 <SEP>
 <tb> 5 m ethoxybenzoyl-1, <SEP> 2-dihydro-3H-pyrrolo-
 <tb> [l, <SEP> 2-a] pyrrole-1-carboxylic acid
 <tb> 5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo-
 <tb> [1,2-a] pyrrole-1-carboxylic acid <SEP> 250
 <tb> 5-p-methylbenzoyl-6-methyl-1,2-dihydro-3H-
 <tb> - <SEP> pyrrolo <SEP> [l, <SEP> 2-a <SEP>] pyrrole-1-carboxylic acid <SEP> 250
 <tb> 5-p-methoxybenzoyl-6-methyl-1, <SEP> 2-dihydro-3H- <SEP>
 <tb> pyrrolo [1,

  2-a] pyrrole-1-carboxylic acid <SEP> 130
 <tb> 5-p-chlorobenzoyl-6-methyl-1, <SEP> 2-dihydro-3H- <SEP>
 <tb> - <SEP> pyrrolo [l, <SEP> 2-a] pyrrole-1-carboxylic acid <SEP> 190
 <tb> 5-benzoyl-6-dthyl-1, <SEP> 2-dihydro-3H-pyrrolo- <SEP>
 <tb> [l. <SEP> 2-a] pyrrole-1-carboxylic acid <SEP> 80
 <tb> 5- <SEP> (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-
 <tb> - <SEP> pyrrolo <SEP> [1, <SEP> 2-a <SEP>] pyrrole-1-carboxylic acid <SEP> 130
 <tb>
 
 EMI 19.3
 
 EMI 19.4
 
 <tb>
 <tb>;,) 5-p-ethoxybenzoyl-1, <SEP> 2-dihydro-3H-pyrrolo- <SEP>
 <tb> [ <SEP> 1, <SEP> 2-a <SEP>] pyrrole-1-carboxylic acid <SEP> 606 <SEP> mg / kg
 <tb> 5 m chlorobenzoyl-1,2-dihydro-3H-pyrrolo-
 <tb> [1, <SEP> 2-a <SEP>] pyrrole-1-carboxylic acid <SEP> 606 <SEP> mg / kg
 <tb>
 

  <Desc / Clms Page number 20>

 
C) Test for anti-inflammatory effects in the rat using a
Carrageenin-induced inflammation of the paw
Protocol :

  
Female Simonsen rats weighing 80 to 90 g were used. The test materials were administered orally at 0 o'clock using a gastric tube in 1 ml of an aqueous vehicle.
 EMI20.1
 Hind paw injected. This injection causes inflammation of the paw. The rats were sacrificed at hour 4, at which time both hind paws were removed and weighed separately.



   End point:
 EMI20.2
 
 EMI20.3
 The following effects were determined according to the above protocol (phenylbutazone = 1):
 EMI20.4
 
 <tb>
 <tb> 5-p-ethoxyhenzoyl-1,2-dihydro-3H-pyrrolo-
 <tb> [1,2-a] pyrrole-1-carboxylic acid <SEP> 30
 <tb> 5-p-isopropoxybenzoyl-1, <SEP> 2-dihydro- <SEP>
 <tb> -3H-pyrrolo <SEP> [1,2-a] pyrrole-1-carboxylic acid
 <tb> 5 m ethoxybenzoyl-1, <SEP> 2-dihydro-3H-pyrrolo-
 <tb> [l, <SEP> 2-a] <SEP>] pyrrole-1-carboxylic acid <SEP> 1
 <tb> 5-benzoyl-6-methyl-1, <SEP> 2-dihydro-3H-pyrrolo- <SEP>
 <tb> [l, <SEP> 2-a] <SEP> pyrrole-l-carboxylic acid <SEP> about <SEP> 25
 <tb> 5-p-methylbenzoyl-6-methyl-l, <SEP> 2-dihydro- <SEP>
 <tb> -3H-pyrrolo <SEP> [1, <SEP> 2-a] <SEP> pyrrole-1-carboxylic acid <SEP> about <SEP> 35
 <tb> 5-p-methoxybenzoyl-6-methyl-1, <SEP> 2-dihydro- <SEP>
 <tb> -3H-pyrrolo [1,

  2-a] pyrrole-1-carboxylic acid <SEP> about <SEP> 45
 <tb> 5-p-chlorobenzoyl-6-methyl-1, <SEP> 2-dih <SEP> ydro- <SEP>
 <tb> - <SEP> 3H-pyrrolo <SEP> [l, <SEP> 2-a] <SEP> pyrrole-l-carboxylic acid <SEP> about <SEP> 60
 <tb> 5-benzoyl-6-ethyl-1, <SEP> 2-dihydro-3H-pyrrolo-
 <tb> [l, <SEP> 2-a] pyrrole-1-carboxylic acid <SEP> 25
 <tb> 5- <SEP> (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-
 <tb> -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid <SEP> 38
 <tb>
 Preparation of an initial connection Regulation A) A 250 ml three-necked round bottom flask, which has a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is directly (via one of the outer openings) with a feed line and a short (3 ") water condenser with the Acetal pyrolysis device connected.

   The latter consists of one
100 ml round bottom flask, which was previously prepared with 15.6 g oxalic acid dihydrate and 11.82 g bromoacetal aldehyde diethyl acetal, made from vinyl acetate as described by P.Z. Bedoukian, J. Am. Chem. Soc. 66,651 (1944)
Device a 6 "Vigreux column, which has a thermometer, is attached, which is connected to the aforementioned condenser.



   The three-necked flask is cooled to 0 to 100 ° C. with 3.36 g of ethanolamine in an ice bath, charged and treated dropwise with 8.7 g of dimethyl-1,3-acetone-dicarboxylate while stirring. This spontaneously forms methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) - - aminoacrylate (III). When the addition is complete, the ice bath is removed and 100 ml dry

  <Desc / Clms Page number 21>

 added acetonitrile. The pyrolysis part of the device is placed in an oil bath and the temperature of the latter is allowed to rise to 150 to 160 ° C. The bromoacetaldehyde solution formed is distilled directly into the magnetically stirred solution of the vinylamine (III) (boiling point 80 to 830C / 580 mm).

   As soon as the distillation temperature has dropped below BOOG, the pyrolysis device is interrupted and replaced by a reflux condenser equipped with a drying tube containing calcium chloride. The solution is then heated at the reflux temperature for 1 h, the solvent is removed under reduced pressure and the residue is then added
200 ml of methanol and 20 g of silica gel are added. The mixture is evaporated to dryness in vacuo and fed to a column which contains 200 g of silica gel and contains hexane. The column is then eluted with a mixture of hexane and ethyl acetate (mixing ratio 80:20; 500 ml) and a mixture of hexane and ethyl acetate (mixing ratio 1: 1; 9 x 500 ml).

   Fractions 2 and 3 contain less polar impurities and dimethyl-1, 3-acetone dicarboxylate; fractions 4 to 8 yield 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H), which after recrystallization from a mixture of ether and hexane gives a melt - Point of 52 to 54 C.



  B) In a solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate in
35 ml of dry dichloromethane, cooled to -100C, 2.65 ml of triethylamine are stirred in, whereupon 1.46 ml of methanesulfonyl chloride are added dropwise while maintaining a temperature of the reaction mixture of -10 to -50C. The course of the
The reaction is observed by thin-layer chromatography analysis using a mixture of chloroform and acetone (mixing ratio 90:10). As soon as the reaction can be regarded as complete (30 min after the addition of
Methanesulfonyl chloride), slowly add 10 ml of water. The organic phase is separated off, washed three times with 30 ml of water each time, dried over sodium sulfate and evaporated to dryness under reduced pressure.

   The residue is crystallized from a mixture of dichloromethane and hexane
4.75 g (77.7%) methyl-N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H),
Mp 99-1010C.



  C) A solution of 785 mg methyl-N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and
1.83 g of sodium iodide in 10 ml of acetonitrile is heated to boiling under reflux for 1 h. Then the reaction mixture is cooled and then under reduced pressure
The pressure was evaporated to dryness and the residue was triturated with water. The insoluble
Material is separated off by filtration and air-dried, whereby
840 mg (97%) methyl-N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp.



   137 to 138 ° C.



  D) A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred in an argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is then kept at room temperature for 30 minutes and then treated with 100 ml of water. The product is extracted three times with 50 ml of ethyl acetate each time and the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. By chromatography of the residue over 20 g of silica gel using a mixture of
Hexane and ethyl acetate (mixing ratio 4: 1) as eluent give 500 mg (80%) dimethyl-1, 2-dihydro-3H-pyrrolo [1, 2-a] pyrrole-1, 7-dicarboxylate (VII, R = H ), Mp.



   70 to 71 C.



   A solution of 1.80 g of dimethyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate in 20 ml of methanol is mixed with a solution of 4,48 g of potassium hydroxide in 20 ml of water treated and the reaction mixture then heated to reflux for 6 h. The cooled solution is evaporated to dryness and the residue with
Treated 50 ml of saturated sodium chloride solution. The resulting solution is with 6n
Acidified hydrochloric acid and extracted three times with 50 ml of ethyl acetate each. The Ver-

  <Desc / Clms Page number 22>

 The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, 1.55 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII R = H), mp 220 C (decomposition).



  E) A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid in 50 ml
Isopropanol, cooled in an ice bath, is saturated with gaseous hydrogen chloride while maintaining a reaction mixture temperature of less than 500C. The
An ice bath is then removed and the reaction mixture is stirred for 1 1/2 hours at room temperature and evaporated to dryness under reduced pressure. Then the residue is mixed with 10 ml of benzene. The solution is then evaporated once more in vacuo, this process being repeated three times in total in order to remove the excess hydrogen chloride.

   In this way, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R2 = iC 3 H,), which has a melting point of 144 to 1450C after crystallization from a mixture of methanol and ethyl acetate.



   Similarly, when using methanol, ethanol, propanol and n-butanol instead of isopropanol, the following compounds are obtained:
 EMI22.1
 F) 1,054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid are heated to 240 to 250 ° C. in a dry round-necked flask with a capacity of 10 ml , wherein the reaction product is distilled off directly from the reaction vessel.

   In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate (X, R = H, R '= iC H,) are obtained, pale yellow oil with the following physical
 EMI22.2
    : 4.65 - 5.2 (m, 1H), 5.73 - 5.02 (m, 1H), 6.10 (t, J = 3 Hz, 1H), 6, 43-6, 53 TpM ( m, 1H). or
 EMI22.3
 and is equipped with a gas inlet pipe, it is charged with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid. The device is flushed out thoroughly with nitrogen and the nitrogen supply is then stopped.

   The device is then immersed in an oil bath heated to 270 ° C. and the reaction is observed on the basis of the evolution of carbon dioxide (gas inlet connector) and by thin-layer chromatography on silica gel using a mixture of benzene, dioxane and acetic acid (mixture ratio 90: 10: 1) as developer solvent . The reaction is practically complete after 45 minutes. After 1 h, the container is removed from the oil bath and the contents of the reaction flask are introduced into a round-bottom flask, which is also used
500 ml of acetone is provided. The solvent is removed under reduced pressure and the residue is purified by column chromatography over 100 g of silica gel.

   Provide the fractions eluted using a mixture of hexane and benzene (mixing ratio 70:30) and a mixture of hexane and benzene (mixing ratio 50:50)
2.77 g (68%) isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylate (X, R = H, R "= iC H,), an oil whose physical constants are identical to those in Section F).



  G) A solution of 179 mg N, N-dimethyl-p-toluamide and 0.11 phosphorus oxychloride in
2 ml of 1,2-dichloroethane is heated to boiling under reflux for 30 min. Then

  <Desc / Clms Page number 23>

 a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole - 1-carboxylate in 2 ml of 1,2-dichloroethane is added to this solution. The reaction mixture is then refluxed for 8 h in an argon atmosphere, then treated with 405 mg of sodium acetate and then refluxed for a further 5 h. The mixture obtained is then evaporated to dryness and the residue is chromatographed over 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (mixing ratio 3: 1).

   In this way, 208 mg (66%) of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate (XI, R = H, R1 = p -CH3.R2 = iC3H7), an oil with the following physical constants:
 EMI23.1
 
J = 8 Hz, 2H).

 

Claims (1)

 PATENT CLAIM: Process for the preparation of new 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids of the general formula  EMI23.2  wherein R is hydrogen or a lower alkyl radical having 1 to 4 carbon atoms and R 1 is hydrogen, a lower alkyl radical having 1 to 4 carbon atoms, a lower one Alkoxy radical having 1 to 4 carbon atoms or chlorine, fluorine or bromine, where the substituent R 1 is in the 0-, m- or p-position of the aroyl radicals, and their optical isomers and pharmaceutically acceptable salts, characterized in that one Esters of the general formula  EMI23.3  wherein Rund R 1 are as defined above and Rx is an unbranched or branched alkyl radical having 1 to 12 carbon atoms,    <Desc / Clms Page number 24>  converted into the corresponding acid of formula (A) or a salt thereof, if desired the acid obtained is separated into its optical isomers and / or converted into its pharmaceutically acceptable salt.