Preparation of(-+)-1,2-dihydro-3h-pyrrolo(1,2-a)pyrrole 1,7-dicarboxylates and preparation of 5-aroyl-1,2-dihydro-3h-pyrrolo(1,2-a)pyrrole-1-carboxylic acid derivatives thereof

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to pyrrolo[l,2-a]pyrroles, and especially to the synthesis of l,2-dihydro-3H-pyrrolo[l,2-

a]pyrrole-l,7-dicarboxylic acid and its dialkyl esters.

An alternative process for preparing 1,2-dihydro-3Hpyrrolo[l,2-a]pyrrole-l,7-dicarboxylic acid and its dialkyl esters is described and claimed in Israel Patent Specification No. 85094 from which the present application was divided out.

Background to the Invention

5-Aroyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1carboxylic acids, also known as 5-aroyl-l,2-dihydro-3H_96388/2 pyrrolizine-l-carboxylic acids, of formula I, and the

7

<img file="IL96388A_D0001.tif" />

COOH (I) pnarmacologically acceptable salts and esters thereof, are useful as analgesic, anti-inflammatory, and anti-pyretic agents for mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds under clinical study in man are ketorolac, 5-benzoyl-

1.2- dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxy lie acid , (I, Ar = CgH^), and anirolac, 5-p-anisoyl-

1.2- dihydro-3]H-pyrrolo[ 1,2-a ]pyrrole-1-carboxylic acid, (I, Ar = _&amp;-CH₃0-C₆H₅), both disclosed in.U.S.

Patent No. 4,089,969 to Muchowski et a 1 (corresponding to Israel

Patent 52493). Other compounds, where the 5-aroyl substituents are substiy/ tuted or unsubstituted benzoyl, furoyl, thenoyl, and pyrrol, and where the 6-position on the pyrrolo-pyrrole nucleus is optionally substituted by lower alkyl or halogen, and uses thereof, are also disclosed in a series of patents assigned to Syntex (U.S.A.) Inc., beginning with U.S.

Patent No. 4,089,969 (corresponding to Israel Patent 52493), and including U.S. Patents Nos. 4,087,539 (corresponding to Israel Patent 52492); 4,097,579,4,140,698 ־ (corresponding to Israel Patent 55181); 4,232,038; 4,344,943 (corresponding to Israel Patent 63047); 4,347,186; 4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759; 4,353,829 (corresponding to Israel Patent 64329); 4,397,862;

4,457,941; and 4,454,151. U.S. Patents Nos. 4,511,724 and a 4,536,512, assigned to Merck &amp; Co., ־Inc., disclose

5-( substituted pyrr.ol-2-oyl) -1,2-dihydro-3H-pyrrolo[1,2-a ]pyrrole-l-carboxylic acid derivatives and

5-(1,2-dihydro-3H_-py rrolo [ 1,2-a]pyrrol-2-oyl)-1,2-dihydro 3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid derivatives, respectively; while U.S. Patent No. 4,533,671, also

Various methods assigned to Merck 4 Co., Inc., discloses

5-(1,2-dihydro-3H-pyrrolo[1,2-a]pyrrol-2-oyl)-2-pyrrol alkanoic acids and analogs, for the preparation of these exemplified in the patent and and many proceed through a common pyrrolo-pyrroles are chemical literature, intermediate, 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7dicarboxylic acid, (II, R = H), or its dialkyl ester;

סו

7 COOR

<img file="IL96388A_D0002.tif" />

COOR

2 (ID the preparation of which from dimethyl 1,3-acetonedicarboxylate, ethanolamine, and a haloacetaldehyde is disclosed in, for example, U.S. Patent No. 4,089,969, which is incorporated herein by reference.

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The reaction scheme set forth in that patent:

<img file="IL96388A_D0003.tif" />

CH_OI ²CH₂(Jh

<img file="IL96388A_D0004.tif" />

<img file="IL96388A_D0005.tif" />

<img file="IL96388A_D0006.tif" />

<img file="IL96388A_D0007.tif" />

<img file="IL96388A_D0008.tif" />

<img file="IL96388A_D0009.tif" />

(II, R = CH₃) includes the reaction of equimolar amounts of ethanolamine (III) and dimethyl 1,3-acetonedicarboxylate (IV) to form a solution of the hydroxyenamine (V), which is then treated, preferably in situ, in a suitable organic solvent (aprotic solvents such as acetonitrile, dichloromethane, etc. are exemplified), under anhydrous conditions, with a 2-haloacetaldehyde at elevated temperatures to produce the N-(2-hydroxyethyl)pyrrole (VI). Compound (VI) is esterified with methanesulfonyl chloride to produce the mesylate (VII), which is optionally converted to the N-(2-iodoethyl)pyrrole (VIII)

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Dy reaction with sodium iodide. Either of compounds (VII) and (VIII) may be converted to dimethyl

1.2- dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (II, R = CHj) by treatment with sodium hydride in dimethylformamide. The thus-formed dimethyl

1.2- dihydro-3H-pyrrolo[1,2-a]-pyrrole-1,7-d!carboxylate may then be selectively 7-decarboxylated and 5-aroylated, by methods such as those described in the previously-cited patents and in U.S. Patent No. 4,496,741 to Doherty, to yield a 5-aroyl-l, 2-dihydro-3H_-pyrrolo [l,2-a]pyrrole-l-carboxylic acid (I). A similar process, involving the reaction of ethanolamine, dimethyl

1.3- acetonedicarboxylate, and a halomethyl alkyl ketone, bypasses the hydroxyenamine (V) and produces the 4-alkyl analog of (VI) directly. That compound may be converted to the pyrrolo-pyrrole in the same manner as for the

4-unsubstituted compound previously described.

Various methods for the preparation of pyrroles are exemplified in the patent and chemical literature. Processes for the preparation of 5-aroyl-N-R-pyrrole-

2-acetic acid, where R is H, lower alkyl, or benzyl, and analogous compounds are disclosed in U.S. Patents Nos. 3,752,826; 3,865,840; and 3,952,012 to Carson. They include, for the 4-alkyl substituted but not for the

4-unsubstituted compounds, the reaction between a lower alkylamine, a didower alkyl) 1,3-acetonedicarboxylate, and a chloromethyl lower alkyl ketone, ^,’preferably in an aqueous medium”, followed by pouring into ice-cold hydrochloric acid, to produce compounds of

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25880/25890-FF formula (IX), where each of R, R’, and R״ is lower alkyl.

R' COOR

<img file="IL96388A_D0010.tif" />

A similar process for the 4-unsubstituted compounds (IX, R' = H) using chloroacetaldehyde is disclosed in U.S. Patent No. 4,048,191 to Carson.

U.K. Published Application No. 2 034 304 A, assigned to Mallinckrodt, Inc., discloses a process for the preparation of compounds of formula (IX), wherein R' may be hydrogen or alkyl, by either (a) forming a two-phase reaction medium of an aqueous solution of the alkylamine and an inert, water-immiscible organic solvent, and adding the dicarboxylate and ketone (or aldehyde) substantially simultaneously, or (b) adding the dicarboxylate and ketone substantially simultaneously, with the ketone in excess, to an aqueous alkylamine. Preferably, dicarboxylate and excess ketone are added to an alkylamine dispersion.

A number of patents assigned to Ethyl Corporation, including U.S. Patents Nos. 4,565,878; 4,565,879; 4,374,255; 4,388,468; 4,383,117; 4,455,433; and 4,333,878, disclose other modifications of the Carson syntheses. U.S. Patent No. 4,565,878 discloses the addition of a water-immiscible co-solvent [a halogenated hydrocarbon of good solubility for both the didower alkyl) 1,3-acetonedicarboxylate and the product] to the mixture of chloromethyl lower alkyl ketone, dicarboxylate, and aqueous lower alkylamine. U.S. Patent No. 4,565,789 discloses the use of an aromatic

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-רhydrocarbon as the co-solvent. U.S. Patent No. 4,37a,255 discloses the addition of a solids formation inhibiting amount of a lower alkanol to the ketone/dicarboxylate/aqueous alkylamine mixture. The reaction is normally carried out in the presence of a co-solvent as in U.S. Patents Nos. 4,565,878 or 4,565,879. U.S. Patent No. 4,388,468 discloses a two-stage process in which (a) the ketone is added to a pre-mixed cooled solution of the alkylamine and the dicarboxylate in a suitable solvent (e.g. aromatic hydrocarbons, chlorinated hydrocarbons, water, or mixtures thereof) at a temperature less than 60°C, followed by (b) heating the reaction mixture to 70 - 100°C. U.S. Patent No. 4,383,117 discloses the use of an anhydrous lower alkylamine instead of an aqueous solution, and the use of a single-phase non-aqueous reaction medium. U.S. Patent No. 4,455,433 discloses the addition of a yield-enhancing amount of an acid having a dissociation constant of at least 1.3 x 10^ at 25°C to a ketone/dicarboxylate/(preferably anhydrous) lower alkylamine mixture, preferably in an organic solvent. U.S. Patent No. 4,333,878 discloses the synthesis of compounds of formula (IX) by the reaction of an enamine (X)

COUR

R*COO chch₂no₂ (X) (XI) with a 2-carboxy-l-nitroalkane (XI, R* = lower alkyl, tolyl, or benzyl). The enamine may be prepared by the reaction of a didower alkyl) 1,3-acetonedicarboxylate with a lower alkylamine in a suitable solvent, such as ethanol or methanol, followed by

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25880/25890-FF evaporation of the solvent and heating to dehydrate the thus-formed carbinolamine to the corresponding enamine.

Albert et al., in U.S. Patent No. 4,363,918, disclose the synthesis of compounds of formula IX where R is lower alkyl, R' is hydrogen or lower alkyl, and R is H by the reaction of 1,3-acetonedicarboxylic acid with C1CH₂COR and a lower alkylamine, preferably by the slow addition of an aqueous solution of the lower alkylamine to an aqueous solution of the acid, followed by slow addition of the l-chloro-2-alkanone, with both additions preferably occurring below 20°C or lower.

European Published Applications Nos. 92 487 and 105 664, assigned to Montedison S.p.A., disclose the preparation of compounds of formula IX wherein R is CH^ and R is H, and R' is 0Η_? (EP92487) or Η (EP105664) by the reaction of 1,3-acetonedicarboxylic acid or an alkali metal salt tnereof with methylamine and a halo(ketone or aldehyde) in aqueous solution, preferably by adding the haloketone to an aqueous mixture of the methylamine and the dicarboxylic acid.

The known processes for the preparation of pyrrolo pyrroles require high volumes of organic solvents, tend to produce tars, and are difficult to scale up to production quantities. We have now discovered a process for the preparation of pyrrolo pyrroles which uses aqueous solvents to a much greater extent than the previous known reactions and can be readily used for production scale quantities.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to the preparation of L,2-dihydro-3H-pyrrolo[l,2-a]pyrrole5976Y

25880/25890-FF ,7-dicarboxylates of formula XII,

COOR

<img file="IL96388A_D0011.tif" />

C00R1 (XII) io which each R is independently H, lower alkyl or cycloalkyl, from didower alkyl) 1,3-acetonedicarboxylates .

The preparation may be represented schematically:

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Step 1

Alternate II

Step 1 Alternate I (XIII)

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.COOR

COOR

HN^Z \ (XIV)

OH

׳1

COOR \\ _/ COOR

HN^Z \ (XV) '------------\

OMs

Step 2 Alternate I

<img file="IL96388A_D0014.tif" />

(XII) in which

R is 3s previously defined, Ms is mesyl; and

X is halogen.

in another aspect, this invention relates to a process for preparing compounds of formula (I) from compounds of formula (XII), which comprises the further steps of (a) saponifying a diester of the formula (XII) to the corresponding diacid (XII, R⁼H);

(b) esterifying a compound of formula (XII) in which both R groups are hydrogen to form a compound of formula (XVIII) in which the R group at position 1 is alkyl;

(c) decarboxylating a compound of formula (XVIII) to form a compound of formula (XIX); and (c) aroylation of a compound of formula (IX) with an aryl amide or aryl morpholide to form a compound of formula (I) or (IA).

Ar ⁵ I! I COUR

Cl) or (IA) 0 I1 wherein Ar is substituted or unsubstituted phenyl,2- or

3-furyl,2 ׳- or 3-thienyl, or 2- or 3-p.yrryl and which,if substituted, can have one or more lower alkyl, lower alkoxy, or halo groups in any available position on the ring, and R is hydrogen (formula I) or alkyl of 1 to 12 carbon atoms (formula IA).

In another aspect, this invention relates to a process for preparing certain deriva/es of compounds of formula (I) from compounds of formula (XII), which further comprises one or more of the steps:

(a) converting a compound of formula (I) to a pharmaceutically acceptable salt of a compound of formula (I); or (b) converting a salt of a compound of formula (I) to the corresponding free compound of formula (I); or (c) esterifying a compound of formula (I) to give a compound of formula (IA); or (d) converting an ester of formula (IA) to the corresponding free compound of formula (I).

These steps can' Pe illustrated dy the following r eaction scheme :

COOR (XII)

R = alkyl

COOH

COOH (XIX) (XVIII) (XII)

R = H

R = alkyl (IA) (I) in which R is as previously defined and R^ is substituted or unsubstituted phenyl, 2- or 3-furyl, 2-. or 3-thienyl, or 2- or 3-pyrryland which, if substituted, can have one or more lower alkyl, lower alkoxy, or halo groups in any available position on the ring.

DETAILED DESCRIPTION OF THE INVENTION

Definitions '

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below :

lower alkyl, denoted generally by R refers to straight or branched saturated hydrocarbon radicals having from one to six carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, pentyl, hexyl and the like. Preferred lower alkyls are methyl, ethyl, and n_-propyl, and a particularly preferred lower alkyl is methyl. If more than one alkyl radical is present in a given molecule, each may be independently selected from lower alkyl unless .otherwise stated.

lower alkoxide, lower alkanol, lower alkylamine, lower alkyl ester, and similar terms refer to alkoxides, alkanols, alkylamines, alkyl esters, etc. in which the (or each) alkyl radical is a lower alkyl as defined above.

halogen, denoted generally by X, refers to chlorine, bromine, or iodine. Preferred halogens are chlorine and bromine.

aprotic polar solvent includes organic solvents which may be either water-immiscible, such as halcgenated hydrocarbons, e.g. methylene chloride, chloroform, etc., or water-miscible, such as tetrahydrofuran, dimethoxyethane, bis(2-methoxyethyl) ether (also known as diglyme), dimethylformamide, N-methylpyrrolidone,

A dimethylsulfoxide , etc. The solvent may^also contain minor proportions of aprotic non-polar solvents such as hydrocarbons, e.g. cyclohexane, toluene, and tne like, provided that the solvent properties are largely determined by the polar solvent.

weak base refers to the alkali metal or alkaline earth salt of a weak acid, e.g. sodium acetate, potassium bicarbonate, etc., or to a buffer mixture (such as NaH₉P0./Na₉HP0d giving a similar pH.

strong base refers to bases such as alkali metal hydroxides, lower alkoxides, hindered amines such as didower alkyDamines and bis(tri lower alkylsilyl) amines, hydrides, and the like, which contain alkali metals including lithium, sodium, potassium, rubidium, ³ and cesium, e.g. sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, sodium hydride, lithium didsopropyDamide, lithium bis (trimethylsilyl )amide, etc.

mesyl or mesylate, denoted by Ms, refers particularly to methanesulfonyl, but includes other equivalent alkyl- or arylsulfonyls, such as ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, and the like.

aryl or Ar refers to a substituted or ²⁵ unsubstituted monovalent unsaturated radical, for example, phenyl, 2- or 3- furyl, 2- or 3-thienyl, or 2or 3-pyrryl, which, if substituted, can have one or more lower alkyl, lower alkoxy, or halo groups in any available position on the ring. Phenyl and ³⁰ p-methoxyphenyl are preferred.

water-miscible co-solvent includes lower alkanols, didower alkyl) ketones, tetrahydrofuran, dioxane, sulfolane, dimethylformamide, and the like. Preferred co-solvents are methanol, acetone, and similar or ³⁵ C₂ alkyl alcohols and ketones.

l pharmaceutically acceptable salt refers to salts derived from inorganic bases which include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic salts and the like. Particluarly preferred are 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, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine,

2-dimethylaminoethanol, 2-di־ethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline, and caffeine.

pharmaceutically acceptable esters refers to alkyl esters derived from hydrocarbons of branched cr straight chain having from one to twelve carbon atoms. Typical alkyl ester groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isuamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl, and dodecyl.

Starting Materials and Purification

Dimethyl 1,3-acetonedicarboxylate is commercially available (Aldrich), as is 1,3-acetonedicarboxylie acid, also known as 3-oxopentanedioic acid. Other didower alkyl) 1,3-acetonedicarboxylates may readily be prepared from either tne dimethyl ester or, preferably, the diacid, by esterification techniques well-known to the art. However, there is no particular advantage in varying the alkyl groups, so that the dimethyl ester (R = CH-j) is preferred.

The starting materials and the intermediates of formulae (XIII), (XIV), (XV), and (XVI) may be isolated, if desired, using conventional techniques, including Out 1n not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means,including physical constants and spectral data.

Preparation of Compounds of Formula XIII

In Step 1, a didower alkyl) 3-(2-haloethylamino) -

2-pentenedioate (haloenamine) is prepared from a didower alkyl) 1,3-acetonedicarboxylate, either by ²⁰ direct reaction with a 2-haloethylamine hydrohalide salt, or Py reaction with 2-hydroxyethylamine (2-aminoethanol) followed by replacement of the hydroxy group by a halide.

In Step 1, Alternate I (which is preferred), the didower alkyl) 1,3-acetonedicarboxylate is treated with ²⁵³ a 2-haloethylamine hydrohalide salt in aqueous solution.

The solution preferably has a pH between 5 and 12, more preferably between 5 and 8. Typically, the pH is controlled by employing an aqueous solution of a weak base, such as sodium acetate, as the reaction solvent, but other pH control methods may be employed, if desired. The reactants may be added simultaneously or consecutively, as desired, but it is desirable that the

2-haloethylamine hydrohalide not be placed in basic solution unless that solution already contains the acetonedicarboxylate, to avoid the formation of

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25880/25890-FF aziridines. Typically, the 2-haloethylamine nydrohalide and acetonedicarboxylate are dissolved, either simultaneously or in the order stated, in water, and a solid weak base added to produce the reaction mixture. ’ The reaction is preferably conducted at a temperature between 0 and 35°C, more preferably at about room temperature, i.e. between about 20 and 30°C; over a time preferably between about 15 minutes and 24 hours, more preferably oetween abbut 4 and 18 hours. The θ intermediate didower alkyl) 3-(2-haloethylamino)-2pentenedioate (haloenamine) typically crystallizes and may be isolated by filtratibn, as a mixture bf the E_ and Z_ isomers. Each R is preferably methyl, X is preferably Br or Cl, and sodium acetate is preferably used to 5 .

control pH.

In Step 1, Alternate II, the didower alkyl)

1,3-acetone-dicarboxylate is treated with

2-hydroxyethylamine (2-aminoethanol) in an aprotic polar solvent to produce the hydroxyenamine (XIV), which is 'θ then converted to the haloenamine (XIII) via the mesylenamine (XV). The conversion may stop at the mesylenamine stage, and the mesylenamine be cyclized directly (Step 2, Alternate II) if desired. Typically, the dicarboxylate is dissolved in the solvent, the 25 2-hydroxyethylamine is added slowly to the resulting solution, and the water formed during the reaction is removed by azeotropic distillation. While the hydroxyenamine may be formed under less stringent conditions (see, e.g., U.S. Patent No. 4,089,969), an ³θ anhydrous solution of the hydroxyenamine is required for the next reaction, and it is therefore convenient to carry out the formation of the hydroxyenamine in an aprotic medium. The resulting solution contains a mixture of the E and 2. isomers of the hydroxyenamine, and ³⁵ may be used without purification in the next step. As in

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Step 1, Alternate I, a preferred R is methyl. A preferred solvent is dichloromethane.

Esterification of the hydroxyenamine' (XIV) with mesyl chloride in the presence of an organic Pase such as a tertiary amine, optionally in the presence of an aprotic polar solvent, takes place at a temperature between about -10°C and room temperature, preferably oetween about 0 and 10°C. Conveniently, the tertiary amine is added to the solution from the previous reaction, which nas been cooled to the appropriate temperature, and the mesyl chloride is added slowly to the resulting solution over a period between about 30 minutes and 10 hours, typically about 2 to 5 hours. The solution of the resulting mesylenamine (XV) is quenched with water, and solvent removed from the organic phase to afford a mixture of the and Z_ isomers of the mesylenamine (XV), which may be used without further purification in the next reaction.

The mesylenamine (XV) is converted into the corresponding haloenamine (XIII) by reaction with an anhydrous alkali halide, preferably a bromide or iodide, e.g. sodium iodide, lithium oromide, etc., in an aprotic polar solvent at a temperature between about room temperature and the reflux temperature of the solvent, e.g. between about 30 and 100°C, for 1 to 30 hours, e.g. between 5 and 20 hours, the period depending on the reagents and reaction temperature. The haloenamine (XIII) may be readily isolated by adding water to the reaction mixture, washing the organic phase, and removing the solvent to afford a mixture of the E and Z. isomers of the haloenamine, which may conveniently be purified by recrystallization.

Preparation of Compounds of Formula XII

In Step 2, the haloenamine (XIII) is cyclised with a strong base in an aprotio polar solvent.

In Step 2 (Alternate I), the haloenamine (XIII) is treated with a 2-haloacetaldehyde, XCH^CHO, wherein X is as defined above. The process is preferably conducted in aqueous solution at a pH between 4.5 and 10, preferaoly between 5 and 8.5. The reaction is preferably carried out between 0 and 65°C, more preferably at about room temperature, for from about 1 to 48 hours, preferably between 6 and 24 hours. X is preferably Br, and pH control is preferably achieved by the presence of a weak base, e.g. sodium acetate or sodium bicarbonate, in tne solution. The process is preferably conducted in the presence of 10 to 50 volume percent of a water-miscible co-solvent, such as acetone.

To an aqueous solution of a weak base and the

2-haloacetaldehyde is added the haloenamine (XIII). A water-miscible co-solvent is preferably also added. The mixture is stirred for the appropriate time, and the N_--(2-haloethyl)-pyrrole (XVI) is isolated by filtration. The 2-haloacetaldehyde may be obtained commercially or prepared by any desired route. Xn the case of the preferred 2-bromoacetaldehyde, exemplary preparative methods include the acid hydrolysis of a

2-bromoacetaldehyde didower alkyl) acetal, a lower alkyl

1,2-dibromoethyl ether, 1,2-dibromoethyl acetate, etc., each of which results in an aqueous solution of

2-bromoacetaldehyde, to which may be added the weak base.

Finally, in Step 3, Alternate I, ths

N_-(2-haloethyl) pyrrole (XVI) is cyclized with from 1 to 2 equivalents, preferably about 1.1 to 1.5 equivalents, of a strong base in an aprotic polar solvent. The process may further include the saponification of the diester to the dicarboxylic acid (XII, R = H), which may conveniently be performed on the solution of the diester from the cyclization process.

A preferred X is Br or Cl. The strong base is preferably a lithium hindered amine, such as lithium di(isopropyl)amide or lithium bis(trimethylsilyl)amide; and the solvent is preferably tetrahydrofuran.

The compound of formula (XVIT is dissolved in the aprotic polar solvent, and a solution of the strong base is added slowly (i.e. over a period of from about 1 to 24 hours, e.g. about 2 to 8 hours) at a temperature of about -10 to 35°C, e.g. at room temperature, and the resulting solution is stirred to afford a solution of the pyrrolo-pyrrole diester (XII). The reaction temperature is preferably 0 to 10°C for X = Br, and 15 to 30°C for X = Cl, when the strong base is lithium di(isopropyl)amine. Compound (XII) may be recovered from the solution by removal of the solvent and purification by conventional organic chemical means, or, more usually, may be converted directly to the dicarboxylic acid (XII, R = H).

If the dicarboxylic acid, (XII, R = H), is desired, the diester may be saponified by conventional chemical means, i.e. reaction with a strong base to remove the ester groups and treatment with acid to generate the dicarboxylic acid. The diester is dissolved in an aqueous alkali metal hydroxide or carbonate solution, e.g., sodium hydroxide solution, which may also contain a water-miscible co-solvent, e.g., methanol, at a temperature between about room temperature and the solvent reflux temperature for from about 30 minutes to 24 hours, e.g. 1 to 4 hours. The cooled solution is then acidified with an aqueous strong acid, e.g. 35% hydrochloric acid, and the dicarboxylic acid precipitates and may be removed by filtration. The dicarboxylic acid may be purified by conventional means, especially conveniently by recrystallization from aqueous solution.

Ths saponification may be performed on isolated material; Out may conveniently Ce performed on the solution produced in the cyclization reaction described above. For example, water may be added to the solution, the > aprotic polar solvent at least partially removed by distillation, and a strong base, e.g. sodium hydroxide, may be added directly to the resulting solution of the gyrrolo-pyrrole diester, the solvent further partially removed (if desired or necessary), and an aqueous strong 0 acid, e.g. 35% hydrochloric acid, added. The dicarboxylic acid precipitates from the solution, and may be removed by filtration. The dicarboxylic acid may be purified by conventicnal chemical means, especially conveniently by recrystallizatibn from aqueous solution. 5

The C-l acid group of the resulting dicarboxylic acid (XII, R = H) may then be selectively esterified by treatment with a lower alkanol, e.g. methanol, ethanol, isopropanol, π-butanol, and the like in the 20 presence of hydrogen chloride, to;produce the corresponding alkyl l,2-dihydro-3H-pyrrolo(l,2-a]pyrrols-l-carboxylate-7-carboxylie acid of Formula (XVIII). The reaction is conducted at a temperature of from about 0°C to about 50°C, for about 1 to about 4 25 hours .

Decarboxylation of the monoesterified compounds (XVIII) to the. corresponding compounds of Formula (XIX) is achieved by heating (XVIII) at an elevated temperature, of the order of from about 230°C to about 280°C, for a 30 period of time sufficient to complete the reaction. The course of the reaction can be followed by the rate of carbon dioxide evolution and thin-layer chromatography, decarboxylation being generally completed within from about 45 to about 90 minutes. The reaction product, ³⁵ namely, alkyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-241-carboxylate and the derivatives thereof (XIX) can be purified by chromatographic techniques. Alternatively, and particularly for the decarboxylation of small batches of compound (xv1II),the reaction product (XIX) can be ⁵ distilled directly from the reaction vessel.

Condensation of a compound of formula (XIX)can be accomplished in one of two ways , with an amide or with a morpholide.

Condensation of a compound of formula (XIX)with an ¹⁰ amide of the formula p׳_ c. M (C H ₅ } ¹⁵ wherein R¹ is one of the substituents defined above, affords the corresponding alkyl 5-aroyl-l,2-dihydro3H-pyrrolo[l,2-a]pyrrole-l-carboxylate (IA). This reaction is conducted in an inert organic aprotic solvent and in the presence of phosphorj/us oxychloride, at reflux temperature for from about 1 to about 175 hours, under an inert atmosphere, followed by further reflux in the presence of sodium acetate, for from about 2 to about 10 hours. Alternatively, instead of phosphorous oxychloride, other acid chlorides such as phosgene or .25 oxalyl chloride may be used. In the preferred embodiment, this condensation is carried out by adding a solution of compound (XIX) in a suitable solvent to a previously refluxed mixture of 1.1 to 5 molar equivalents of both the desired amide and phosphorous oxychloride in 30 the same solvent, refluxing the reaction mixture thus obtained for from about 6 to about 72 hours under an argon atmosphere and thereafter adding thereto from about 3 to about 10 molar equivalents of sodium acetate, followed by an additional reflux period of from about 4 35 to about 6 hours. Adequate solvents for this reaction

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25880/25890-FF are the halogenated hydrocarbons such as dichloromethane,

1,2-dicnlaroethane, chloroform, carbon tetrachloride and the like, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane .

Representative of the Ν,Ν-dimethyl arylamides which can de used are: N,N-dimethyl-benzamide ,

N,N-dimethy 1-0-toluamide , N,N-dimethy1-m-toluamide , N,N-dimethy1-p-toluamide , N,N-dimethy1-p-ethyl-benzamide, N,N-dimethy1-0-propy1-benzamide, N,N—dimethy1-m-butylbenzamide, N,N-dimethy 1-0-methoxy-benzamide, N,N-dimethy1-m-methoxy-benzamide ,

N,N-dimethyl-p-ethoxy-benzamide , N,N-dimethy1-pisopropoxy-benzamide, N,N-dimethy 1-0-chloro-benzamide , N,N-dimethyl-m-chloro-oerizamide, N,N-dimethyl-p-chlorobenzamide, N,N-dimethy1-0-fluoro-benzamide, Ν,Ν-dimethylp-fluro-benzamide, N,N-dimethy1-m-bromo-benzamide, and N,N-dimethy1-p-bromo-benzamide. These amides are known, commercially available compounds or can be prepared in a conventional manner from the corresponding acids, i.e., by conversion into the acid chlorides followed by treatment with dimethylamine.

If an aroyl morpholide is used, the compound of formula (XIX) is treated with an aroyl morpholide of the formula

<img file="IL96388A_D0015.tif" />

in which Ar is as defined above, in the presence of an inorganic acid halide, such as POC1₃, P0Br₃, SOC1₂ and the like, preferably POCl-j. The relative amounts are not critical. Optionally an inert organic solvent such as ethane dichloride, chloroform, or carbon tetrachloride, but preferably methylene chloride, may be included in this

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25880/25890-FF mixture. The presence of the solvent, however, is not particularly advantageous in all cases. The mixture is agitated, preferably stirred, for about 0.5 to 36 hours, preferably 1 to 5 hours at about 30 to 50°C, preferably to 45°C.

A solution of the pyrrolo pyrrole substrate of formula (XIX) in an inert solvent, most preferably CH₂C1₂, is then added to the above mixture. Again tne ratio of reactants is not critical, but it is preferable that the molar amount of the substrate be slightly less than the molar amount of the minority reactant in the prepared morpholide/halide mixture. Tne resulting reaction mixture is kept at about 30 to 70°C, preferably 40׳ to 45°C until the desired reaction has taken place, usually about 1 to 8 hours, most usually 1.5 to 3 hours .

The entire procedure to this point is carried out in an inert atmosphere in order to exclude Water. Any anhydrous gas could be used, but nitrogen is the most convenient choice. As the reaction is scaled up, the problem of water in the ambient air becomes smaller because of less proportional available surface area. However, it has been found prudent to use nitrogen as a matter of routine.

The reaction product formed at this point cannot conveniently be isolated, but must be hydrolyzed either to the ester of formula (IA), or to the free acid of formula (I). '

If it is desired to prepare a compound of formula (I), a single step procedure is preferred. In this embodiment, the reaction mixture is poured into a solution in polar solvent, preferably aqueous, of a strong base, such as a mineral hydroxide or carbonate, preferably sodium hydroxide. A large excess of the base is used. The mixture is then kept at about 30 to 100°C, «

preferably 40 to (50°C until reaction is complete.

Alternatively, if the two-step procedure is to be used, dr a compound of formula (IA) is to be prepared, an amount of from about 3 to about 10 molar equivalents of sodium acetate or other weak base may be added directly to the reaction mixture, followed by an additional reaction time of about 4 to 6 hours during which the mixture is refluxed to produce the compound of formula (IA).'

If subsequent conversion of the ester of formula (I) to the corresponding free acid compound of formula (I) is desired, further hydrolysis is required. This hydrolysis is effected in a conventional manner, with an alkali metal hydroxide or alkali metal carbonate, e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like, in an aqueous lower alkanol, e.g., methanol, ethanol, and the like, at a temperature of from about room temperature to reflux, for from about 15 minutes to about 3 hours, under an inert atmosphere. In the preferred embodiment, this hydrolysis is effected with aqueous methanolic potassium carbonate, at reflux temperature for about 30 minutes.

Upon alkaline hydrolysis of the alkyl ester group in a compound of formula (IA) there is obtained the corresponding free acid of formula (I).

The free acids of formula (I) can be converted into other alkyl esters having from 1 to 12 carbon atoms by conventional methods, e.g., by treatment with (a) the k

alcohol corresponding to the aesired ester in the presence of a strong mineral acid, (b) an etheral diazoalkane or (c) the desired alkyl iodide in the presence of lithium carbonate.

The salt derivatives of the compounds of formula (I) are prepared by treating the free acids with an appropriate amount of a pharmaceutically acceptable oase. The reaction is conducted_i.n__w.ater, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0°C to about 100°C, preferably at room temperature. Typical inert, water-miscible־organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. The molar ratio of compounds of formula (I) to base used are chosen to provide the ratio desired for any particular salt.

It should de noted that all of these’methods to afford compounds of formula I are set forth in, e.g. U.S. Patent Nos. 4,089,969 and 4,353,829.

EXAMPLES

The following Examples illustrate this invention, but are not intended to limit its scope.

Example 1: Preparation of dimethyl 3-(2-bromoethylamino) -

2-pentenedioate. (Step 1 - Alternate I)

A. 2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved in water (30 mL) at room temperature (20°C) with stirring, and dimethyl

1,3-acetonedicarboxylate (10.0 g, 57 mmol) was added. After 5 to 10 minutes, solid anhydrous sodium acetate (14.35 g, 175 mmol) was added, and stirring continued. After approximately 80 minutes, precipitation of dimethyl

3-(2-bromoethylamino)-2-pentenedioate began, and the solution was stirred for 17 hours at room temperature. The thick slurry was diluted with cola water (20 mL), and aged at 0 to 5°C for 30 minutes and filtered, and the precipitate washed with cold (0 to 5°C) water (50 mL) and dried to constant weight, to afford 13.9 g (86% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as a white solid, m.p. 71 - 72°C, NMR (CDC1 ): δ: 8.80 (IH, oroad singlet); 4.60 (IH, singlet); 3.85 (3H, singlet); 3.77 (3H, singlet); 3.35 3.72 (4H, broad multiplet); 3.25 (2H, singlet).

B. Substituting 2-chloroethylamine hydrochloride (7.0 g, 60 mmol) for the 2-bromoethylamine hydrobromide in the procedure of part A of this Example, there was obtained 10.8 g (80% yield) of dimethyl

3-(2-chloroethylamino)-2-pentenedioate as a white solid, m.p. 75 - 76°C,

NMR (CDCl-j): 5: 8.80 (IH, broad singlet); 4.60 (IH, singlet); 3.75 (3H, singlet); 3.65 (3H, singlet); 3.60 (4H, multiplet); 3.27 (2H, singlet).

C. Substituting for dimethyl 1,3-acetonedicarboxylate in the procedure of parts A or B of this Example, diethyl 1,3-acetonedicarboxylate, dipropyl 1,3-acetonedicarboxylate, di (_i-propyl) 1,3-acetonedicarboxylate, di(t.-butyl) 1,3-acetonedicarboxylate, or dihexyl 1,3-acetonedicarboxylate, one obtains, respectively, diethyl 3-(2-bromoethylamino)-2-pentenedioate, dipropyl 3-(2-bromoethylamino)-2-pentenedioate, di(i-propyl) 3-(2-bromoethylamino)2-pentenedioate, di(t_-butyl) 3-(2-bromoethylamino)-2-pentenedioate ,

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25880/25890-FF dihexyl 3-(2-םromoethylamino)-2-pentenedioate, diethyl 3-(2-chloroethylamino)-2-pentenedioate, dipropyl 3-(2-chloroethylamino)-2-pentenedioate, di (!.-propyl) 3-( 2-chloroethylamino) 2-pentenedioate , di(t_-butyl) 3-(2-chloroethylamino)2-pentenedioate, or dihexyl 3-(2-chloroethylamino)-2-pentenedioate.

Example 2: Preparation of dimethyl 3-(2-bromoethylamino) -

2-pentenedioate. (Step 1 - Alternate II)

A. Dimethyl 1,3-acetonedicarboxylate (196.1 g,

1.13 mol) was placed in a 3 L three-neck flask containing a stirrer bar and fitted with a thermometer, a water extractor on a reflux condenser, and an addition funnel; and the flask then purged with nitrogen. The extractor was filled with dichloromethane, and dichloromethane (800 mL) added to the flask. Ethanolamine (68.8 g,

1.13 mol) was added via the addition funnel over 10 minutes, and the mixture warmed to 30°C. The mixture was then heated under reflux for 24 hours, by which time tnin-layer chromatography indicated that very little residual dicarboxylate remained and 20 mL water had collected in the extractor.

The solution of dimethyl 3-(2-hydroxyethylamino)2-pentenedioate was cooled to 0°C, and triethylamine (235 mL, 170.6 g, 1.69 mol) was added in one portion. Methanesulfonyl chloride (168.8 g, 1.47 mol) was added dropwise via an addition funnel over 3.75 hours, with the temperature rising to 5 to 7°C. The medium-yellow slurry darkened to yellow-orange as the last 10 mL methanesulfonyl chloride was added. The mixture was stirred at 0°C for an additional 2 hours, and water (250 mL) added. The organic phase was washed with water (4 x 500 mL) and brine (250 mL), and dried overnight over anhydrous magnesium sulfate. After filtration, the

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25880/25890-FF solvents were evaporated on a rotary evaporator under reduced pressure at 50°C to afford 310.0 g (93% yield) of dimethyl 3-(2-methane sulfonylethylamino)-2-pentenedioate _c as a red oil. The mesylenamine may be purified at this

ס point, if necessary or desired, and may be converted to the haloenamine by the following method or used directly in Step 2, Alternate II.

Dimethyl 3-(2-methanesulfonylethylamino) -

0ן-pentenedioate (156.3 g, 529 mmol) was added to a 2 L three-neck flask, which was fitted with a mechanical stirrer, thermometer, and reflux condenser. Dichloromethane (750 mL) was added and stirred until the mesylate had completely dissolved, anhydrous lithium 1c bromide (69.0 g, 794 mmol) was added, and the mixture stirred at 35°C for 19 hours. The mixture was cooled to 0°C and water (250 mL) added, then stirred for 5 minutes and the phases separated. The organic phase was washed with water (3 x 250 mL) and brine (150 mL), and dried 2θ over anhydrous potassium carbonate for 15 minutes.

Rotary evaporation of the solvent under reduced pressure (50°C) gave 128.4 g of crude dimethyl

3-(2-bromoethylamino)-2-pentenedioate as a yellow oil, which quickly solidified to a yellow solid. The crude 2g material was purified by extraction into coiling hexane (5 x 750 mL) and recrystallization from hexane, and the pot residues extracted and recrystallized, to give a total of 90.8 g (61.2% yield) of dimethyl

3-(2-bromoethylamino)-2-pentenedioate as white needles. An NMR spectrum in CDC1, indicated an Z/E isomer ratio

^כ 30 of 19:1, and remeasurement of the CDCl^ solution after three days indicated an Z/E ratio of 4:1. The two isomers were not separated.

B. In a similar manner to that of part A of this 35 . .

Example, using sodium iodide in place of lithium bromide,

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25880/25890-FF and .acetone or acetonitrile in place of aichloromethane, tnere was obtained in eacn instance crude dimethyl

3-(2-iodoethylamino)-2-pentenediQate as a light drown oil, wnich could Pe purified by conventional methods.

C. Substituting lithium chloride for lithium bromide, and using a similar procedure to that in part A of this Example, one obtains dimethyl 3-(2-cnloroethylamino)-2-pentenedioate .

D. Similarly, using other didower alkyl)

1,3-acetonedicarboxylates in the procedures of parts A through C of this Example, one obtains other didower alkyl) 3-(2-haloethylamina)-2-pentenedioates.

Example 3; Preparation of methyl N-(2-oromoethyl)-3methaxycarbonyl-2-pyrroleacetate. (Step 2 - Alternate I)

A. (Alternate I) 2-Bromoacetaldehyde diethyl acetal (42.2 g, 214 mmol) was added to a 100 mL three-neck flask fitted with a mechanical stirrer, reflux condenser, and a thermometer. Hydrobromic acid (9 M, 4.0 mL, 36 mmol) in water (16 mL) was added, and the mixture heated under reflux for 1 hour and then cooled to room temperature to provide a solution of 2-bromoacetaldehyde.

Sodium acetate (41.0 g, 500 mmol) was added to the

2- bromoacet4aldehyde solution, and stirred for 5 minutes, at which point the solution had a pH of 6. The flask was placed in a cool tap water bath and dimethyl

3- (2-bromoethylamino)-2-pentenedioate (20.0 g, 71 mmol) was added, followed by isopropanol (40 mL), and the solution was stirred at room temperature (25°C). Within aoout 35 minutes, all the solids had dissolved, and a precipitate started forming within 90 minutes. Stirring

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25880/25890-FF was continued at room temperature for 20 hours, and the solution then cooled to 0°C and stirred at that temperature for 1 hour, then filtered through a coarse fritted glass filter. The precipitate was washed with ice-cold water (400 mL) and ice-cold isopropanol (150 mL) and dried, to give 15.7 g (72% yield) of crude methyl N-(2-bromoethy1)-

3-methoxycaroony1-2-pyrroleacetate as a light tan solid, m.p. 129 - 130.5°C, NMR (CDC1 ): δ: 6.58 (2H, quartet); 4.20 (2H, triplet); 4.10 (2H, singlet); 3.75 (3H, singlet); 3.65 (3H, singlet); 3.50 (2H, triplet).

B. (Alternate 1) 2-Bromoacetaldehyde diethyl acetal (20.9 g, 106 mmol) was added to a 100 mL three-neck flask fitted with a stirrer bar, reflux condenser, and a thermometer. Hydrobromic acid (48.5%, 17.7 g, 106 mmol) in water (54 mL) was added, and the mixture heated to 40°C for 3 hours and then cooled to room temperature and extracted with hexane (100 mL) to provide a solution of 2-bromoacetaldehyde.

The hydrolysis solution was added to a mechanicallystirred slurry of sodium acetate (17.8 g, 212 mmol) in water (15 mL) at 0°C over 1 hour, then stirred for a further 10 minutes. Dimethyl 3-(2-chloroethylamina) -

2- pentenedioate (20.0 g, 85 mmol) was added, followed oy acetone (50 mL), and the solution allowed to warm to room temperature and stirred for 20 hours. The resulting slurry was cooled to 0°C and kept at that temperature for hours, then filtered through a coarse fritted glass filter. The precipitate was washed with water (300 mL) and dried, to give 19.9 g (90% yield) of methyl N-(2-chloroethyl)-

3- methoxycarbonyl-2-pyrroleacetate as white crystals, m.p. 110 - 111°C,

NMR (CDC1 ): δ: 6.65 (2H, quartet); 4.25 (2H, triplet); 4.18 (2H, singlet); 3.82 (3H, singlet); 3.75 (2H, triplet); 3.73 (3H, singlet).

C. (Alternate I) Substituting 2-chloroacetaldehyde diethyl acetal for 2-bromoacetaldehyde diethyl acetal, and using a similar procedure to that in parts A or B of this Example, one obtains methyl N-(2-bromoethyl)-3-methoxycarbonyl2-pyrroleacetate, or methyl N-(2-chloroethyl)-3-methoxycarbonyl-

2- pyrroleacetate.

D. (Alternate I) Similarly, substituting other diClower alkyl) 3-(2-haloethylamino)-2-pentenedioates , such as dimethyl 3-(2-iodoethylamino)-2-pentenedioate, diethyl 3-(2-bromoetnylamino)-2-pentenedioate, etc., for the equivalent materials in parts A through C of this Example, one obtains other alkyl N_-(2-haloethyl) -

3- alkoxycarbonyl-2-pyrroleacetates, such as methyl

N-(2-iodoethyl)-3-methoxycarbony1-2-pyrroleacetate, ethyl N-(2-Promoethyl)-3-ethoxycarbonyi-2-pyrroleacetate, etc.

Example 4 : Preparation of dimethyl 1,2-dihydro3H-pyrrolo[l,2-a]pyrrole-1,7-dicarboxylate and

1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-

1,7-dicarboxylic acid. (Step 3)

A. (Alternate I) Under nitrogen, n-butyllithium (1.3 M in hexane, 75 mL, 98 mmol) was added slowly at -5 to 0°C, with stirring, to a solution of di(isopropyl)amine (13.8 mL, 10.0 g, 98 mmol) in tetrahydrofuran (dry^ 50 mL). The resulting solution was transferred to an addition funnel and added, under nitrogen at 0 to 5°C, to a stirred slurry of methyl N-(2-bromoethyl)-3-methoxycarbonyl-2-pyrroleacetate (20.0 g, 66 mmol) in tetrahydrofuran (dry, 100 mL). There was a slight temperature rise, and complete dissolution occurred after addition of about two-tnirds of the lithium di(isopropyl)amine solution. The resulting solution was stirred for 2 hours while warming to 1O°C, then diluted with water (100 mL) with slight heat evolution. The solvents were stripped by atmospheric distillation: 240 mL collected, with a pot temperature of 80°C, to afford a solution of dimethyl

1,2-dinydro-3H-pyrrolo-[l,2-a]pyrrole-1,7-dicarooxylate. The diester may be isolated at this point by quenching ^0ו with water, extraction into an organic solvent such as ethyl acetate, and evaporation of the solvent; and purified by conventional methods. However, it is also convenient to saponify the diester to the dicarboxylic acid without isolation from the solution.

The pot solution from the previous paragraph was cooled to 50°C and sodium hydroxide (6.0 g, 150 mmol) added; then methanol was removed by atmospheric distillation to a pot temperature of 97°C. The pot solution was cooled to 5°C and acidified with ²θ hydrochloric acid (12 M, 18 mL, 216 mmol), resulting in a temperature rise to 15°C. The resulting mixture was cooled to 5°C and filtered, and the precipitate washed with cold water (50 mL) and dried, to give 11.4 g of crude 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole35 1,7-dicarboxylic acid. Assay of the crude material indicated that it contained 91.4½ 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l,7-dicarboxylic acid (and 7.0% N-vinyl-

3-carboxy-2-pyrroleacetic acid).

3θ B. (Alternate I) n-Butyllithium (2.6 M in hexane, 295.5 mL, 0.77 mol) was added dropwise at 0 to 3°C, with stirring, to a solution of di(isopropyl)amine (109.3 mL, 78.9 g, 0.78 mol) in tetrahydrofuran (freshly distilled, 200 mL). The resulting solution was transferred to an addition funnel and added dropwise at room temperature to

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25880/25890-FF

-1/a stirred solution of methyl N-(2-chloroethyl)3-methoxycarbonyl-2-pyrroleacetate (150.0 g, 0.58 mol) in tetrahydrofuran (dry, 750 mL)-. The addition took 4 hours, and the temperature was maintained in the range of 23 to 27°C. The resulting solution was stirred for 16 hours, then diluted with water (500 mL) over 10 minutes with slight heat evolution. The solvents were stripped Py atmospheric distillation to a pot temperature of 75^QC. The pot solution was cooled to 50°C and sodium hydroxide (53.0 g, 1.33 mol) added; then methanol was removed by atmospheric distillation to a pot temperature of 95°C; with a total of 1370 mL of solvents collected. The pot solution was cooled to -3 to 0°C and acidified . with hydrochloric acid (12 M, 180 mL, 216 mmol), resulting in a temperature rise to 18°C. The resulting mixture was cooled to -3 to 0°C, aged for 30 minutes at that temperature, and filtered, and the precipitate washed with ice-cold water (300 mL) and dried, to give

107.8 g of crude l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-

1,7-dicarboxylic acid. Assay of the crude material indicated that it contained 96.6% 1,2-dihydro-3H-pyrrplo [1,2-a]pyrrole-1,7-dicarboxylic acid.

C. (Alternate I) Similarly, substituting for the methyl N-(2-bromoethy1)-3-methoxycarbonyl-2pyrroleacetate or methyl N-(2-chloroethyl)-3-methoxycarbonyl-2-pyrroleacetate of parts A and B of this Example, methyl N_-(2-iodoe thy 1)-3-methoxy carbonyl2-pyrroleacetate, ethyl h[-(2-chloroethyl)-3-ethoxycarbony 12-pyrroleacetate, and similar (lower alkyl) _N-(2-haloethyl)-3-(lower alkoxy)carbony1-2-pyrroleacetates , one obtains dimethyl 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole5976Y

25880/25890-FF

1.7- dicarboxylate or l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-

1.7- dicarooxylic acid, diethyl 1,2-dihydro-3H-pyrro10[1,2-a]pyrrole-

1.7- dicarboxylate or 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-

1.7- dicarboxylic acid, and similar di dower alkyl) 1,2-dihydro-3H-pyrrolo[1,2-a ]pyrrole-1,7-dicarboxylates or 1,2-dihydro-3H-pyrrolo[1,2-a ]pyrrole-1,7-dicarboxylic acids.

Example 5: Preparation of 1,2-dihydro-3H-pyrrolo[1,2-a ]pyrrole-1,7-dicarboxylic acid.

A. Dimethyl 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-

1,7-dicarboxylate (1.26 g, 5 mmol) and sodium hydroxide (1.00 g, 25 mmol) were heated in water (10 ml_) at reflux for 1 hour. The resulting solution was cooled to 0°C and acidified with hydrochloric acid (12 M) to pH 1.

1.2- Dihydr0-3H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylic acid (0.70 g, 71.4% yield) was collected by filtration and dried.

B. Similarly, substituting for the dimethyl

1.2- dihydr0-3H-pyrro10[1,2-a]pyrrole-1,7-dicarboxylate of part A of this Example, diethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-

1,7-dicarboxylate , and similar didower alkyl) 1,2-dihydro-32ipyrrolo[l,2-a]pyrrole-l,7-dicarboxylates, one obtains

1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-1,7-dicarboxylic acid.

' - 38 Example β : Preparation of 5-aroyl-l,2-dihydro-3Hpyrro10[l,2-a]pyrrole-1-carboxylie acids

A. A solution of 1.34 g of 1,2-dihydro-3Hpyrrolo[l,2-a]pyrrole-l,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath is saturated with gaseous hydrogen chloride, maintaining the temperature of the reaction mixture below 50°C. The ice bath is then removed and the reaction mixture is stirred for 1.5 hours at room temperature, and evaporated to dryness under reduced pressure; 10 ml of benzene is added to the residue and the solution is evaporated under vacuum once again, repeating this׳ process a total of three times to completely remove the excess hydrogen chloride, thus obtaining 1.58 g (96%) of isopropyl 1,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-l-carboxylate-7-carboxylie acid , which upon crystallization from methanol-ethy1 acetate has a melting point of 144-145°0.

B. 1.054 g of isopropyl 1,2-dihydro-3Hpyrrolo[!,2-a]pyrrole-l-carbaxylate-7-carboxylic acid is heated to 240-250°C in a dry 10 ml round bottomed flask, distilling directly the reaction product from the reaction vessel. In this manner there is obtained 745 mg (87%) of isopropyl l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-

1-carboxylate, a pale yellow oil, having the following physical constants: U.V. λ 715 nm (e 6020),

I.R. _v^CHC13 1725 cm¹־; N.M.R. 1-22 max ח. ו j (d. 0= 7 Hz, 6H), 2.40-2.90 (m, 2H) , 3.60-4.20 (m, 2H) , 4.65-5.2 (m, IH), 5.73-5.92 (m, IH), 6.10 (t, 0= 3 Hz,

IH), 6.43-6.53 ppm (m, IH).

C. A 100 ml 3-necked round bottomed flask equipped with a condenser, nitrogen inlet tube and a gas bubbler is charged with 5.0 g of isopropyl 1,2-dihydro3H-pyrrolo[l,2-a]pyrrole-l-carboxylate-7-carboxy 11c acid. The apparatus is thoroughly flushed with nitrogen .־&lt;597

-A5and then tne nitrogen flow is stopped. The apparatus is immersed in an oil Path heated at 270°C and the reaction is followed by the rate □f carbon dioxide evolution (gas bubbler) and by t.l.c. on silica gel, using benzene :dioxar^acetic acid (90:10:1) as developing solvent. After 45 minutes the reaction is almost complete. After one hour, the vessel is removed from the oil bath and the contents of tne reaction flask are transferred to a round bottomed flask with 500 ml of acetone. The solvent is removed under reduced pressure, and the residue is purified by column chromatography on 100 g of silica gel. The fractions eluted with hexane: benzene (70:30) and hexane : benzene (50:50) afford 2.77 g (68%) of isopropyl 1,2-dihydro-3H-pyrrolo(1,2-a]pyrrole-l-carboxylate, an oil.

0. A solution of 179 mg of

N,N-dimethyl-p-toluamide and 0.11 ml of phosphorous oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 193 mg of isopropyl 1,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-

1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 405 mg of sodium acetate and refluxed for a further 5 hours. The resultant mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel, eluting with hexane:ethyl acetate (3:1), thus obtaining 208 mg (66%) of isopropyl 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylate, an oil, having the following physical constants: U.V. 256, 312 nm (ε 8700, 19500); I.R. v^^lm 1735, 1620, 1605 cm¹־; N.M.R. 1-23 (d, 0 = 7 Hz,

6H), 2.38 (s, 3H), 2.5-3.0 (m, 2H), 3.75-4.10 (m, IH),

4.2-4.60 (m, 2H), 4.85-5.20 (m, IH), 5.95 (d, 0 = 4 Hz, IH), 6.70 (d, 0 = 4 Hz, IH), 7.10 (d, 0 = 8 Hz, 2H), 7.60

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VL ־Μ־ ppm (d , J = 8 Hz, 2H).

E. A solution of 336 mg of isopropyl 5-p-toluoyl- l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate in 10 ml of methanol is treated with a solution of 690 mg of potassium carbonate in 5 ml of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water and the resultant mixture extracted with ⁰ ethyl acetate (2 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane affords 238 mg (89%) of

5-p-toluoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole'5 1-carboxylic acid, m.p. 182-183°C.

F. A solution of 250 .mg of isopropyl 5-p-toluoyl- l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate in 8 ml of metnanol is treated under an atmosphere of nitrogen, with a solution of 200 mg of sodium hydroxide in 1 ml of water, maintaining the reaction mixture at room temperature for 1.5 hours. ־The methanol is then removed under reduced pressure and the basic solution which remains is diluted with 5 ml of water and extracted with ether to remove any unsaponifiable product. The 25 aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 5-p-toluoyl-l,2-dihydro-3H³⁰ pyrrolo[1,2-aJpyrrole-l-carboxylic acid.

G. By following the above methods using 1.1 to 5 molar equivalents of N,N-dimethy!־.benzamide in place of N,N-dimethy1-p-toluamide, and monitoring the course of the reaction by t.l.c., there is ootained:

isopropy1-5-benzoy1-1,2-dihydro-3H-pyrrolo[1,2-a]5976Y

25880/25890-FF pyrrole-l-carboyxlate, a light yellow oil, having the following physical constants: U.V. λ 245,

311 nm (ε 7230, 17800); I.R. _{י1735 3} 01^ ע

1620 cm¹־; N.M.R. 1.24 [d, 6H, (CH )₂CKJ, 2.50-3.13 (m, 2H; H-2), 3.97 (dd, 1H, H-l), 4.18-4.70 (m, 2H, H-3), 5.00 [sept., 1H, (CH₃)₂CH], 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons); M.S.: m/e 297 (M+). Upon hydrolysis of the isopropyl ester group, in accordance with the above methods, there is obtained:

5-benzoy1-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-.

1-carboxylic acid, m.p. 160-161°C.

H'. Benzmorpholide (1.45 g, 7.90 mmole), was placed in a 25 ml round bottom flask. POCl-j (1.25 ml,

13.4 mmole) was added. This was stirred and heated in a 40° oil batn for 2.5 hours. A solution of methyl

1,2-dihydro-3H-pyrro10(1,2-a]pyrrole-l-carboxylate (1.00 g, 6.10 mmole) in 3.4 ml CH₂C1₂ was added and heating was continued for 2 hours, at this time, thin layer chromatography (TLC) of the reaction mixture showed reaction to be complete. The reaction mixture was added carefully to a solution of NaOH (3.09 g, 77.3 mmole) in 10 ml ¾0, and the mixture was heated to 50’C, allowing the CH₂C1₂ to boil off. More NaOH (1.30 g, 32.5 mmole) was added. TLC 15 minutes later showed complete hydrolysis. The mixture was cooled and extracted with 2 x 10 ml CH₂C1₂. The aqueous layer was acidified by the addition of 3.30 ml (39.6 mmole) cone. HC1. A milk formed. This was extracted with 5 x 10 ml CH₂C1₂. Extract numbers 1-4 were dried (Na^O^) and charcoaled (Oarco 660), then evaporated to a tan solid, which was a mixture of all benzoyl isomers. This solid was dissolved in 10 ml 2-propanol and hexane (10 ml) was added. A crystalline solid formed slowly. The first crop had a weight of 0.90 g (58.5%) and was pure (by TLC)

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47 yW5-benzoyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole1-carboxylic acid, m.p. 160-161°C.

I. A solution of 200 mg of 5-benzoyl-l,2dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl θ acetate-methanol, to yield methyl 5-benzoyl-l,2-dihydro3H-pyrrolo[l,2-a]pyrrole-l-carboxylate.

J. A solution of 300 mg of 5-p-toluoyl-l,2dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen ¹⁵ chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue purified by chromatography on alumina, to yield isoamyl 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-

1-carboxylate.

־° K. To a solution of 300 mg of 5-p-toluoyl-

1.2- dihydro-3H-pyrrolo[l,2-a]pyrrole־l-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide, in tne form of a 0.1N solution. The solvent is then evaporated under reduced pressure and the residue ²⁵ taken up in 2 ml of methanol, followed by precipitatibn with ether, to yield crude sodium 5-p-toluoyl-

1.2- dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate which can be crystallized from ethyl acetate-hexane.

L. To a solution of 175 mg of 5-p-toluoyl³⁰ 1,2-dihydro-3H-pyrrolo[l,2־a]pyrrole-l-carboxylie acid in ml of methanol is added 1 molar equivalent of potassium hydroxide, in the form of a 0.1N solution, thus yielding a solution containing potassium 5-p-toluoyl-

1.2- dihydro-3H-pyrroloil,2-a jpyrrole-l-carboxylate. A ³⁵ solution of 40 mg of calcium carbonate dissolved in tne

5976Y

25880/25890-FF . 43 W minimum amount of IN hydrochloric acid necessary to effect solution of the calcium carbonate, is buffered with 100 mg of solid ammonium chloride, followed by the further addition of 5 ml of water. The thus obtained 5 buffered calcium solution is then added to the solution of potassium 5-p-toluoyl-l,2-dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylate and the precipitate which forms is collected by filtration, washed with water and air dried, to yield calcium 5-p-toluoy1-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate .

M. A solution of 200 mg of 5-p-toluoyl-l,2dihydro-3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is allowed to cool to room temperature and the product filtered off, washed with ether and dried to yield the isopropylamine salt of 5-p-toluoyl-l,2-dihydro-3H-pyrro10[1,2-a]pyrrole-1carboxylic acid.

N. 100 mg of sodium 5-benzoyl-l,2-dihydro20

3H-pyrrolo[l,2-a]pyrrole-l-carboxylate is dissolved in 50 ml of water. 10 ml of concentrated hydrochloric acid are added with stirring at room temperature. The aqueous solution is then extracted with 2 x 50 ml portions of ethyl acetate, the organic extracts combined, and dried and evaporated. The product, 5-benzoyl-l,2-dihydro3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid, is then recrystallized from ethanol/ether, m.p. 160-161°C.