FI91148B - Alkyl-3-alkoxycarbonyl-2-pyrrolidinylidene carboxylates and process for their preparation - Google Patents

Description

91148

Alkyl 3-alkoxycarbonyl-2-pyrrolidinylidenecarboxylates and process for their preparation

This invention relates to alkyl 3-alkoxycarbonyl-2-pyrrolidinylidenecarboxylates which can be used as intermediates for pyrrolo [1,2-a] pyrroles and in particular 1,2-dihydro-3H-pyrrolo [1,2-a] in the preparation of pyrrole-1,7-dicarboxylic acid-10-acid and its dialkyl esters. The invention also relates to a process for the preparation of these alkyl 3-alkoxycarbonyl-2-pyrrolidinylidene carboxylates.

More specifically, the present invention relates to compounds of formula (XVII) 15

C00R

II ___ C00R

(XVII) 20 - 'wherein each R is independently lower alkyl.

In the process (a) of the present invention, a compound of formula (XIII) 25

C00R

H ^^ coor

HN

\ (XIII) 30 U ^

X

wherein R is as defined above and X is halogen, is reacted with a strong base in an aprotic, polar solvent or 2 (b) a compound of formula (XV)

COOR

JO0 ** HN <XV> '\ OM s 10 where Ms is nylyl is reacted with a phase transfer catalyst and a strong base in an aprotic solvent.

FI patent application 880 133 discloses a new process for the preparation of 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate and the corresponding dicarboxylic acid of formula (XII)

COOR

20 y 11 COOR

] f (XII) wherein each R is independently lower alkyl or hydrogen. This process is characterized in that a compound of formula (XVII) of the present invention is reacted with a 2-haloacetalaldehyde of formula XCH 2 CHO, wherein X is halogen, followed by optionally hydrolyzing the resulting compound of formula (XII). a distation in which R is lower alkyl, in a manner known per se to give a compound of formula (XII) in which R is hydrogen.

Pyrrolo [1,2-a] pyrrole derivatives of formula (XII) are in turn useful as intermediates in the preparation of 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-91148 3 ol-1 -carboxylic acids, also known as 5-aroyl-1,2-dihydro-3H-pyrrolizine-1-carboxylic acids, of formula (I) 5 * '

AR-C ^ JL ^ C00H

»M

These acids and their pharmacologically acceptable salts and esters are useful as analgesic, anti-in-inflammatory and antipyretic agents in mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds under clinical investigation are ketorolac, 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (I, Ar - C6H5) and anirolak, 5-p-anisoyl-1 , 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (1,1'-p-CH3O-C6H4), both of which are disclosed in U.S. Patent 4,089,969 to Muchowski et al. ). Other compounds in which the 5-aroyl substituents are substituted or unsubstituted benzoyl, furoyl, thienoyl or pyrroloyl groups and the 6-position of the pyrrolopyrrole nucleus is optionally lower alkyl or halogen substituted, and their use has also been disclosed in a number of patent publications. USA), Inc. and including 4,089,969, 4,087,539, 4,097,579, 4,140,698, 4,232,038, 4,344,943, 4,347,186, 4,458,081, 4,347,187, 4,454,326, 4,347. 185, 4,505,927, 4,456 30,759, 4,353,829, 4,397,862, 4,457,941 and 4,454,151. U.S. Patent Nos. 4,511,724 and 4,536,512 to Merck & Co., Inc. ., 5- (substituted pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives and 5- (1,2-dihydro-3H- pyrro-35 [[1,2-a] pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives, in this order when again in U.S. Patent 4,533,671, if 5 patents are also held by Merck & Co., Inc., disclosing 5- (1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-2-yl) -2-pyrroloalkanoic acids and analogous compounds.

Examples of various processes for the preparation of pyrrolopyrroles of formula (XII) 5 have been reported in the patent literature and in the chemical literature, and many of them proceed from the common intermediate, 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid. (II, RH) or a dialkyl ester thereof, via 10

e 7 C00R

.rf \ C00R (II)

No. 3 2 15, the preparation of which intermediate from dimethyl 1,3-acetone dicarboxylate, ethanolamine and haloacetaldehyde is disclosed, for example, in U.S. Patent 4,089,969, which is incorporated herein by reference.

20 The reaction scheme shown in that patent publication:

CcnocH,

C00CH

| c l'UUL'n3 HN

25 CH2 + 0 \

Jh (IV)

0H OH

(III) i · (V) C00CH, * _ / 3 C00CH, 30 FjLv000 "^ Γ-fyCOOCH, \ 4- (VII) \ v \ -. (VI) OMs

OH

1 \ 35 j; ooch3 'N * cooch3

(vin) ^ —V

\ (II, R CH3)

II

91148 5 contains a reaction (in equivalent molar amounts) between ethanolamine (III) and dimethyl 1,3-acetonediocarboxylate (IV) to form a solution of hydroxynamine (V), which compound is then treated, preferably in 5 situ, in a suitable organic solvent ( as examples, aprotic solvents such as acetonitrile, dichloromethane, etc.) under anhydrous conditions and at elevated temperature with 2-haloacetaldehyde to give N- (2-hydroxyethyl) pyrrole (VI). Compound (VI) is esterified with methanesulfonyl chloride to give the mesylate (VII), which is optionally converted to N- (2-io-diethyl) pyrrole (VIII) by reaction with sodium iodide. Either compounds (VII) and (VIII) can be converted to dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate (II, R-CH3) by treatment with sodium hydride in dimethylformamide. The 7-position of the dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid thus formed can then be selectively decarboxylated and an aroyl group 20 can be attached to the 5-position, for example, by the methods described in the aforementioned patents and U.S. Patent 4,496,741 (Doherty) to give 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (I). A similar process involving the reaction of ethanolamine, dimethyl-1,3-acetonedicarboxylate and (halomethyl) alkyl ketone bypasses hydroxysamine (V) and directly yields the 4-alkyl analog of compound (VI). This compound can be converted to pyrrolopyrrole in the same manner as the previously described 4-unsubstituted compound.

Examples of various methods for preparing pyrroles have been reported in the patent literature and in the chemical literature. U.S. Patent Nos. 3,752,826, 3,865,840 and 3,952,012 (Carson) disclose methods for the preparation of 5-aroyl-NR-pyrrole-2-acetic acid wherein R is H, lower alkyl or benzyl, and analogs thereof. to prepare compounds. In the case of 4-alkyl-substituted compounds, but not in the case of 4-unsubstituted compounds, the methods include the reaction between a lower alkyl-5-amine, a di (lower alkyl) -1,3-acetonedicarboxylate and a chloromethyl (lower alkyl) ketone, which is carried out "preferably in aqueous medium". and followed by pouring the reaction mixture into ice-cold hydrochloric acid to form compounds of formula 10 (IX) R 'C00R "\ - (\\ C00R" li 11 / dx) 15 l wherein each of R, R' and R "is lower alkyl A similar process using chloroacetaldehyde for the preparation of 4-unsubstituted compounds (IX, R '= H) is disclosed in U.S. Patent 4,048,191 (Carson).

GB Patent 2,034,304Ά, issued to Mallinckrodt, Inc., discloses a process for preparing compounds of formula (IX) wherein R 'is hydrogen or alkyl-25 by either (a) forming an alkylamine from aqueous solution and water. a biphasic reaction medium consisting of an immiscible inert organic solvent and adding substantially simultaneously the dicarboxylate and the ketone (or aldehyde), or (b) adding the dicarboxylate and the ketone, which are used in excess, substantially simultaneously to the aqueous alkyl. Preferably, the dicarboxylate and the excess ketone used are added to the alkylamine dispersion.

Other variations of Carson's syntheses have been disclosed in 35 patent publications in which the patent holder is 91148 7

Ethyl Corporation and U.S. Patent Nos. 4,565,878, 4,565,879, 4,374,255, 4,388,468, 4,388,117, 4,545,433 and 4,333,878. U.S. Patent 4,565,878 discloses that chloromethyl (lower alkyl) ) to a mixture of a ketone, a di-5 carboxylate and a lower alkylamine containing water is added a water-immiscible cosolvent [a halogenated hydrocarbon which dissolves well both the di (lower alkyl) -1,3-acetonodicarboxylate and the product]. U.S. Patent 4,565,879 discloses the use of an aromatic hydrocarbon as a co-solvent. U.S. Patent No. 4,374,255 discloses the addition of an “anti-solid amount of a lower alkanol” to a mixture of a ketone, a dicarboxylate, and an aqueous alkylamine, and the reaction is usually carried out in the presence of an auxiliary solvent, such as U.S. Patent Nos. 4,565,878 and 4,565,879. U.S. Patent No. 4,388,468 discloses a two-step process in which (a) a premixed, cooled solution containing an alkylamine and a dicarboxylate in a suitable solvent (e.g., an aromatic hydrocarbon, a halogenated hydrocarbon, water, or a mixture thereof) and at a temperature below 60 ° C, a ketone is added and (b) the reaction mixture is then heated to 70 to 100 ° C. U.S. Patent No. 4,383,117 discloses the use of anhydrous lower alkylamine instead of an aqueous solution and the use of a single phase anhydrous reaction medium. U.S. Patent 4,455,433 is issued to it is shown that a "yield-enhancing amount of an acid having a dissociation constant of at least 1.3 x 10 * 5 at 25 ° C, preferably in an organic solvent, is added to a mixture of a ketone, a dicarboxylate and a lower (preferably anhydrous) alkylamine. U.S. Patent No. 4,333,878 discloses the synthesis of compounds of formula (IX) by reacting enamine (X) with 2-carboxy-1-nitroalkane (XI, R * - lower alkyl, tolyl or benzyl).

8

COOR "R * COO

{NhCH NO

JL COOR "/ z z HNX R '

5 I

R (X) (XI)

The enamine can be prepared by reacting a di (lower alkyl) -1,3-acetonecarboxylate with a lower alkylamine 10 "in a suitable solvent such as ethanol or methanol", followed by evaporation of the solvent and heating to dehydrate the carbinolamine thus formed to the corresponding enamine.

Albert et al. have disclosed in U.S. Patent No. 4,363,918 a synthesis of compounds of formula (IX) wherein R is lower alkyl, R 'is hydrogen or lower alkyl and R "is hydrogen, wherein 1,3-acetonedicarboxylic acid is administered react with ClCH 2 CO 2 and the lower alkylamine, preferably by slowly adding an aqueous solution of the lower alkylamine to the aqueous acid solution and then slowly adding 1-chloro-2-alkanone with both additions preferably below 20 ° C.

EP-A-92 487 and 105 664, which are claimed by Montedison SpA, disclose compounds of formula (IX) wherein R is CH 3, R "is H and R 'is CH 3 (EP-A-92 487 ) or H (EP-A-105 664), by reacting 1,3-acetonedicarboxylic acid or an alkali metal salt thereof with methylamine or a haloketone (or aldehyde) in aqueous solution, preferably by adding a haloketone to an aqueous mixture of methylamine and dicarboxylic acid.

The processes described above for the preparation of pyrrolopyrroles require large amounts of organic solvents and tend to form tar, and are difficult to apply on an industrial scale.

The method presented in FI patent application 880 113 enables the use of aqueous solvents to a much greater extent, and can be easily applied on a production scale. It also achieves better yields than previous methods in the overall synthesis of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate-5 of formula (XII), as shown below.

This process is included as a final step in the preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylates from di (lower alkyl) -1,3-acetonedicarboxylates. This preparation can be illustrated by the following Reaction Scheme A.

COOR COOR

\ COOR --Va, ihe ... l-► or COOR

Z '*' Option II f ** '

o HN

15 \ _ (XIV)

Step 1 OH

Option I

^ J

^ COOR COOR

2Q (XIII) f ^ ^ COOR ^ __ ^ COOR

HN ^ 4- HN ^ V (xv) X v ÖMs 1 \ Step 2 | y .. 2

Step 2 N. 1Option II 1

«C Option I N. Option III

I \

V

COOR

30 li il ^ COOR

kj ^ coor r (XVI) | _v «H ^ y000 * (XVII) V / Step 3 oc Step 3 N. '

Option I \ Option II

* COOR

COOR (XII) 10 wherein R is as defined above, Ms is mesyl and X is halogen.

This method is described in more detail in F1 patent application 880 133. The intermediate compounds of formulas 5 (XVI) and (XIII) shown in Reaction Scheme A are also novel and are the subject of FI patent applications 912,709 and 912,710, respectively.

The following terms used in the specification and claims have the meanings given below, unless otherwise indicated: "Lower alkyl", which is generally denoted by R (which may also mean hydrogen, although it is not "lower alkyl") , denotes a straight, branched or cyclic saturated hydrocarbon group containing from 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropylmethyl, pentyl, hexyl, cyclo . Preferred lower alkyls are methyl, ethyl and n-propyl and particularly preferred lower alkyl is methyl. When a particular molecule contains more than one alkyl group, each of them may be independently selected from "lower alkyl", unless otherwise indicated.

"Lower alkanol", "lower alkyl ester" and the like refer to an alkanol, alkyl ester, etc., wherein (each) alkyl group is as defined below for "lower alkyl".

"Halogen", which is generally denoted by X, means chlorine, bromine or iodine. Preferred halogens are chlorine and bromine.

"Aprotic polar solvent" means an organic solvent which may be either water-immiscible, such as halogenated hydrocarbons, for example methylene chloride, chloroform, etc., or water-miscible, such as tetra-35 hydrofuran, dimethoxyethane, bis (2-methoxyethyl) ether. 91148 11 (also known as diglyme), dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. The solvent may also contain small amounts of aprotic non-polar solvents such as hydrocarbons, for example cyclohexane, toluene and the like, provided that the solvent properties are largely polar. according to the solvent.

"Weak base" means an alkali metal or alkaline earth metal salt of a weak acid, for example, sodium acetate, potassium bicarbonate, or the like, or a buffer mixture having a similar pH (such as NaH 2 PO 4 -Na 2 HPO 4).

By "strong bases" is meant bases such as alkali metal hydroxides, lower alkoxides, sterically hindered amines such as di (lower alkyl) amines, and bis [tri (lower alkyl) silyl] amines, hydrides, and the like, which contain alkali metals including lithium, sodium , potassium, rubidium and cesium, for example, sodium hydroxide, potassium hydroxide, potassium methoxy-20 di, sodium methoxide, potassium ethoxide, sodium ethoxide, sodium hydride, lithium di (isopropyl) amine, lithium bis- (trimethylsilyl) amine, etc.

"Mesyl" or "mesylate", denoted by Msr, means in particular methanesulfonyl, but also includes other corresponding alkyl and arylsulfonyls, such as ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, and the like.

"Water-miscible co-solvent" means a lower alkanol, di (lower alkyl) ketone, tetrahydrofuran, dioxane, sulfolane, dimethylformamide or the like. Preferred co-solvents are methanol, acetone and similar C 1-2 alkyl alcohols and ketones.

Starting materials and cleaning

Dimethyl 1,3-acetonedicarboxylate is a commercially available compound (Aldrich) as well as 1,3-acetonedicarboxylic acid, also known as 3-oxopentanedicarboxylic acid. Other di (lower alkyl) -1,3-acetonedicarboxylates can be readily prepared from either dimethyl ester or, preferably, dicarboxylic acid by esterification procedures well known in the art. However, there is no particular benefit from exchanging alkyl groups, so dimethyl ester (R-CH3) is preferred.

The starting materials and intermediates of formulas (XIII), (XIV) and (XVI) may be isolated, if desired, by conventional procedures including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These substances can be characterized by conventional means, including physical 15 Constants and spectral data.

Preparation of compounds of formula fXIII)

In Step 1, di (lower alkyl) -3- (2-haloethylamino) -2-pentenedioate ("haloamine") is prepared from di (lower alkyl) -1,3-acetonedicarboxylate by reacting it either directly with 2-haloethyl with an amine hydrohalide or with 2-hydroxyethylamine (2-aminoethanol), after which the hydroxyl group is replaced by halogen.

In Step 1, Alternative I (which is preferred), the di (lower alkyl) -1,3-acetone dicarboxylate is treated with 2-haloethylamine hydrohalide in aqueous solution. The pH of the solution is preferably 5 to 12, more preferably 5 to 8. The pH is usually adjusted by using an aqueous solution of a weak base such as sodium acetate as the solvent in the reaction, but other methods for adjusting the pH may be used if desired. The reactants may be added simultaneously or sequentially as desired, but it is not desirable to add 2-haloethylamine hydrohalide to the basic solution unless the solution already contains acetopidecarboxylate.

II

91148 13 to avoid the formation of aziridines. Usually, 2-haloethylamine hydrohalide and acetonide dicarboxylate are dissolved either simultaneously or in that order in water, and a solid weak base is added to the solution to obtain a reaction mixture. The reaction is preferably carried out at a temperature of 0 to 35 ° C, more preferably at about room temperature, i.e. about 20 to 30 ° C, with a reaction time of preferably about 15 minutes to 24 hours, even more preferably about 4 to 18 hours.

The intermediate di (lower alkyl) -3- (2-haloethylamino) -2-pentenedioate ("haloamine") usually crystallizes and can be isolated by filtration as a mixture of the E and Z isomers. Each R is preferably methyl, X is preferably Br or Cl, and sodium acetate is preferably used to control the pH.

In Step 1, Option II, the di (lower alkyl) -1,3-acetonedicarboxylate is treated with 2-hydroxyethylamine (2-aminoethanol) in an aprotic polar solvent to provide hydroxyamine (XIV), which compound is then converted via mesylenamine (XV) to haloenamine (XIII). . The conversion may terminate in the mesylenamine step and the mesylenamine may be cyclized directly if desired (Step 2, Option II). Usually, the dicarboxylate is dissolved in a solvent, and 2-hydroxyethylamine is slowly added to the resulting solution, and the water formed during the reaction is removed by azeotropic distillation. Although hydroxyenamine can be formed under less restrictive conditions (see, e.g., U.S. Patent 4,089,969), an anhydrous hydroxysamine solution is required for the next reaction, and it is therefore appropriate to carry out the formation of hydroxynamine in an aprotic medium. The resulting solution contains a mixture of the E and Z isomers of hydroxysamine and can be used crude in the next step. As in Step I, Alternative I, the preferred R group is methyl. One preferred solvent is dichloromethane.

The esterification of hydroxynamine (XIV) with mesyl chloride in the presence of an organic base such as a tertiary amine and optionally an aprotic polar solvent is carried out at about -10 ° C and room temperature, preferably about 0 ° C and 10 ° C, at a temperature between. It is convenient to add the tertiary amine to the li-10 solution from the previous reaction, cooled to the appropriate temperature, and the mesyl chloride is added slowly to the resulting solution over about 0.5 to 10 hours, usually about 2 to 5 hours. Water is added to the resulting solution of mesylenamine (XV) and the solvent is removed from the organic phase to give a mixture of E and Z isomers of mesylenamine (XV) which can be used in the next reaction without further purification, although purification is preferred if mesylenamine is intended. cyclized directly without first converting it to haloenamine.

The mesyleneamine (XV) is converted to the corresponding haloeneamine (XIII) by reacting it with an anhydrous alkali metal halide, preferably bromide or iodide, for example sodium iodide, lithium bromide or the like in an aprotic polar solvent at about room temperature for about 30 minutes. - at a temperature between 100 ° C for 1 to 30 hours, for example 5 to 20 hours, the reaction time depending on the reagents and the reaction temperature. The haloamine (XIII) can be easily isolated by adding water to the reaction mixture, washing the organic phase and removing the solvent to give a mixture of the E and Z isomers of the haloamine, which may be appropriate to purify by recrystallization.

In Step 3, Option I, a pyrrole ring of pyrrolo-35 is formed by reacting cyclic enamine (XVII) 91148 with 2-haloacetaldehyde, XCH 2 CHO, where X is as defined above. The process is preferably carried out in aqueous solution at pH 4.5 to 10, more preferably at pH 5 to 8.5. The reaction is preferably carried out at 15 to 35 ° C, more preferably at about room temperature, for a reaction time of about 1 to 10 hours, preferably 2 to 5 hours. X is preferably Br and the pH adjustment is preferably carried out by adding a weak base, for example sodium acetate or sodium bicarbonate, to the solution. The process is preferably carried out in the presence of 10 to 50% by volume of a water-miscible co-solvent such as methanol.

Usually the cyclic enamine (XVII) is added to an aqueous solution of 2-haloacetaldehyde and a weak base. Preferably, a water-miscible co-solvent is also added. The mixture is stirred for a suitable time and the resulting compound of formula (XII) can be isolated from the reaction mixture, for example, by evaporating the solvent and, if desired, purifying. 2-Haloacetaldehyde 20 can be obtained commercially or prepared by any desired route. In the case of the preferred 2-bromoacetaldehyde, examples of the preparation methods include hydrolysis of 2-bromoacetaldehyde (lower alkyl) acetal, (lower alkyl) (1,2-dibromoethyl ether), 1,2-dibromoethylacetate, etc. with an acid, each hydrolysis lead to an aqueous solution of 2-bromoacetaldehyde.

If desired, the dicarboxylic acid (XII, R «H) diester can be hydrolyzed by conventional chemical means, i.e., by reacting it with a strong base to remove ester groups and treating the product with an acid to form the dicarboxylic acid. The diester is dissolved in an aqueous solution of an alkali metal hydroxide or carbonate, for example sodium hydroxide solution, which may also contain a water-miscible co-solvent, for example methanol, at a temperature between about room temperature and the boiling point of the solvent and allowed to react for about 0.5 to 24 hours, for example 1-4 hours. The cooled solution is then acidified with an aqueous solution of a strong acid, for example 25% hydrochloric acid, and the dicarboxylic acid precipitates and can be removed by filtration. The carboxylic acid can be purified by conventional means, particularly conveniently by recrystallization from aqueous solution. The hydrolysis can be carried out using an isolated substance, but it is convenient to carry out it using the solution formed in the cyclization reaction described above. For example, water may be added to the solution and at least a portion of the aprotic, polar solvent may be removed by distillation, and a strong base may be added directly to the resulting pyrrolopyrrolid diester solution, e.g. sodium hydroxide, and the remainder may be removed (if desired or necessary) and an aqueous strong acid solution added, e.g. 35% hydrochloric acid. The dicarboxylic acid precipitates from solution and can be removed by filtration. The dicarboxylic acid can be purified by conventional chemical means, particularly conveniently by recrystallization from aqueous solution.

The following examples illustrate this invention. Examples 1-3 illustrate the preparation of compound 25 of formula (XVII) and Examples 4 and 5 illustrate a process in which an intermediate compound of the invention is used.

Example 1

Preparation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate (XIII) (Step 1 - Option I) 30 A. 2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved at room temperature (20 ° C) with stirring. to water (30 mL) and to the solution was added dimethyl 1,3-acetonodicarboxylate (10.0 g, 57 mmol). After 5-10 minutes, solid anhydrous sodium acetate (14.35 g, 175 mmol) was added and stirring was continued.

91148 17

After about 80 minutes, precipitation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate began and the solution was stirred at room temperature for 17 hours. The slurry was diluted with cold water (20 mL), allowed to stand at 50-5 ° C for 30 minutes, filtered and the precipitate was washed with cold (0-5 ° C) water (50 mL) and dried to constant weight to give 13.9 g. g (86% yield) of dimethyl 3- (2-bromoethylamino) -2-pentenedioate as a white solid, m.p. 71-72 ° C. NMR (CDCl 3): δ 8.80 δ (1H, broad singlet); 4.60 (1H, singlet); 3.85 (3H, singlet); 3.77 (3H, singlet); 3.35 - 3.72 (4H, broad multiplet); 3.25 (2H, singlet).

B. Substitution of 2-bromoethylamine hydrobromide with 2-chloroethylamine hydrochloride (7.0 g, 60 mmol) in the process of Part A of this Example afforded 10.8 g (80% yield) of dimethyl-3- (2-chloroethylamino) -2- pentene dioate as a white solid, m.p. 75-76 ° C.

NMR (CDCl 3) δ: 8.80 (1H, broad singlet); 4.60 (1H, singlet); 3.75 (3H, singlet); 3.65 (3H, singlet); 3.60 δ (4H, multiplet); 3.27 (2H, singlet).

Example 2

Preparation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate (XIII) (Step 1 - Option II) A. Return to a 3-necked 3-liter flask containing 25 stirring rods equipped with a thermometer, a water separator in a condenser and a dropping funnel , dimethyl 1,3-acetonedicarboxylate (196.1 g, 1.13 mol) was added and the flask was then purged with nitrogen. The separator was filled with dichloromethane and dichloromethane (800 ml) was added to the flask. Ethanolamine (68.8 g, 1.13 mol) was added via addition funnel over 10 minutes and the mixture was warmed to 30 ° C. The mixture was then refluxed for 24 hours, after which time thin layer chromatography showed very little dicarboxylate and 20 ml of water had accumulated in the separator.

18

The dimethyl 3- (2-hydroxyethylamino) -2-pentenedioate solution 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 dropping funnel 3.75 over 5 hours as the temperature rose to 5-7 ° C. Upon addition of the last 10 mL of methanesulfonyl chloride, the medium yellow slurry darkened to a yellow-orange color. The mixture was stirred at 0 ° C for an additional two hours and water (250 mL) was added. The organic phase was washed with water (4 x 500 ml) and saturated sodium chloride solution (250 ml) and dried overnight over anhydrous magnesium sulfate. After filtration, the solvents were evaporated on a rotary evaporator under reduced pressure and at 50 ° C to give 310.0 g (yield 93%) of dimethyl 3- (2-methanesulfonyl ethylamino) -2-pentenedioate as a red oil. If necessary or desired, the mesylenamine can be purified at this stage and converted to the haloenamine by the following method or used directly in step 2, 20 in option 11.

To a 3-necked 2-liter flask equipped with a mechanical stirrer, thermometer, and reflux condenser was added dimethyl 3- (2-methanesulfonyl-ethylamino) -2-pentenedioate (156.3 g, 529 mmol). Dichloromethane (750 mL) was added and the mixture was stirred until the mesylate was completely dissolved, anhydrous lithium bromide (69.0 g, 794 mmol) was added and the mixture was stirred at 35 ° C for 19 hours. The mixture was cooled to 0 ° C, water (250 ml) was added and then stirred for five minutes and the phases were separated. The organic phase was washed with water (3 x 250 ml) and saturated sodium chloride solution (150 ml) and dried over anhydrous potassium carbonate for 15 minutes. Evaporation of the solvent on a rotary evaporator under reduced pressure (50 ° C) gave 128.4 g of crude dimethyl 91148 19 3- (2-bromoethylamino) -2-pentenedioate as a yellow oil which solidified rapidly to a yellow solid. The crude material was purified by extraction into boiling hexane (5 x 750 mL) and recrystallization from hexane, and the residue was extracted from the vessel and recrystallized to give a total of 90.8 g (yield 61.2%) of dimethyl-3- (2- bromoethylamino) -2-pentenedioate as white needles. The NMR spectrum run in CDCl 3 showed a ratio of Z to E isomer of 19: 1 and re-measurement of CDCl 3 solution 10 days later showed a ratio of Z to E isomer of 4: 1. The two isomers were not separated.

B. In the same manner as in Part A of this example, using sodium iodide instead of lithium bromide and acetone or acetonitrile instead of dichloromethane in all cases, crude dimethyl 3- (2-iodoethylamino) -2-pentenedioate was obtained as a light brown oil which could be purified. by conventional methods.

C. Replacing lithium bromide with lithium chloride and using a procedure similar to that in Part A of this example gives dimethyl 3- (2-chloroethylamino) -2-pentenedioate.

Example 3

Preparation of methyl 3-methoxycarbonyl-2-pyrrolidinylidene-carboxylate (XVII) (Step 2 - Option II) A. (Option II) To a 100 mL flask containing a stir bar was added dimethyl-3- (2-bromoethylamine). no) -2-pentenedioate (5.00 g, 17.8 mmol). Dichloromethane (50 ml) was then added and the mixture was stirred until complete dissolution. Sodium methoxide (1.92 g, 35.5 mmol) was gradually added to the solution over 18 minutes, generating some heat. The reaction mixture was stirred at room temperature for 23 hours, after which it was extracted with water (4 x 50 ml) and saturated sodium chloride solution (50 ml), and dried over anhydrous magnesium sulfate. Evaporation of the solvents on a rotary evaporator gave 2.27 g of a pale yellow solid which was divided into three components by preparative thin layer chromatography. The major product was recrystallized from hexane to give crystalline methyl (Z) -3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate, m.p. 84 - 85 eC. NMR (CDCl 3) δ: 7.8 - 8.0 (1H, broad singlet); 4.70 (1H, doublet, J = 0.67 Hz); 3.75 (3H, singlet); 3.64 (3H, singlet); 3.5 - 3.8 (3H, multiplet); 2.1 - 2.5 (2H, multiplet).

One minor product, methyl (E) -3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate, was isolated as an oil. NMR (CDCl 3) δ: 7.8 - 8.0 (1H, broad singlet); 4.64 (1H, singlet); 4.08 (1H, doublet, J = 11 Hz); 3.77 (3H, singlet); 3.65 (3H, singlet); 3.55 (1H, doublet, J = 11 Hz); 3.5 - 3.9 (1H, multiplet); 2.0 - 2.4 (2H, multiplet).

Another very minor product, dimethyl 3- (1-azi-20-ridinyl) -2-pentenedioate, was isolated as an oil.

B. (Option II) To a solution of dimethyl 3- (2-chloroethylamino) -2-pentenedioate (4.71 g, 20 mmol) in dichloromethane (50 mL) was added at room temperature in four equal portions over 45 minutes. Sodium methoxide (1.62 g, 30 mmol). The reaction mixture, which had turned somewhat yellow and had formed a slight precipitate, was stirred for 27 hours, after which it was treated to isolate the product as described in Part A of this example to give 2.8 g of a yellow oil as determined by preparative thin layer chromatography and NMR spectra containing methyl (Z) and - (E) -3-methoxycarbonyl-2-pyrrolidinyl dienecarboxylate.

C. (Option II) To a solution of dimethyl 3- (2-iodoethylamino) -2-pentenedioate (3.3 g, 10 91148 21 mmol) in tetrahydrofuran (distilled, 20 mL) was added tetrabutylammonium bromide (0, 32 g, 1 mmol) and sodium hydroxide granules (0.41 g, 10.3 mmol) and the resulting mixture was stirred at room temperature for 5.5 hours during which time it turned lime colored. Dichloromethane (30 ml) and water (20 ml) were added and the mixture was stirred for five minutes to form a light brown aqueous layer and a pale yellow organic lower layer. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 20 mL). The washings were combined with the organic layer and the combined organic phase was washed with water (2 x 20 mL) and brine (20 mL). Removal of the solvents on a rotary evaporator gave 1.8 g (90% yield) of a light brown oil which solidified on standing. Thin layer chromatography and NMR spectra showed it to contain mostly methyl (Z) -3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate and a smaller amount of methyl (E) -methoxycarbonyl-2-pyrrolidinylidene carboxylate, as well as a very small amount of thioacorate. dimethyl 3- (vinylamino) -2-pentenedioate.

D. (Option III) To a 3-necked 1 L flask purged with nitrogen and equipped with a stir bar and reflux condenser was added sodium hydroxide (32.00 g, 800 mmol) and water (32.0 mL) and stirred until the sodium hydroxide was completely dissolved. Dichloromethane (640 mL) was then added followed by dimethyl 3- (2-methanesulfonyl-ethylamino) -2-pentenedioate (40.12 g, 136 mmol) and tetrabutyl-ammonium bromide (6.57 g, 20 mmol). The reaction mixture was refluxed for seven hours, during which time thin layer chromatography revealed that a small amount of mesyleneamine starting material remained. Therefore, the reaction mixture was stirred for an additional 14 hours at room temperature, after which time thin layer chromatography indicated that no mesylamine was remaining and the mixture was washed with water (3 x 200 mL) and saturated sodium chloride solution (200 mL) and dried over anhydrous magnesium sulfate to give a yellow solution. . Evaporation of the solvent on a rotary evaporator under reduced pressure gave a red light liquid which was distilled (Kugelrohr, 0.3 mmHg, 50-55 eC) to give 19.74 g (72.9% yield, distilled) of methyl (Z) and - (E) -3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate as a clear colorless oil.

Example 4

Preparation of dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate (XII) (Step 3) A. 2-Bromoacetaldehyde dimethyl acetal (1.70 g, 15 mmol), hydrobromic acid (48.5%, 0.25 mL, 2 mmol) and water (2.5 mL) were refluxed for 75 minutes to give a 2-bromoacetaldehyde solution. The solution was cooled to room temperature and sodium acetate (0.50 g) was added. The resulting solution was added over 3 hours to a mixture of methyl 3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate (1.00 g, 5 mmol), sodium acetate (3.10 g) and water (2 mL) in methanol (10 mL) and which was stirred. The mixture was stirred for a further hour and then most of the solvents were removed by evaporation under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and the solution was washed with aqueous sodium hydrogen carbonate solution (2 x 25 ml) and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation gave 1.26 g of crude dimethyl 1,2-dihydro-3H-pyrro-30 [1,2-a] pyrrole-1,7-dicarboxylate, which was purified by chromatography to give 0.825 g (74%). said compound.

B. (Option II) Substitution of 2-bromoacetaldehyde-diethylacetal with 2-chloroacetaldehyde-diethylacetal 35 and using a procedure similar to that in Part D of this exemplary 231148 23 gives dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a]. ] pyrrole-l, 7-dicarboxylate.

Example 5 Preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (XII) A. Dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] a] Pyrrole-1,7-dicarboxylate (1.26 g, 5 mmol) and sodium hydroxide (1.00 g, 25 mmol) were refluxed in water (10 mL) for one hour. The resulting solution was cooled to 0 ° C and the pH was adjusted to 1 with hydrochloric acid (12M). 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (0.70 g, 71.4% yield) was collected by filtration and dried.

Claims (4)

A compound of formula (XVII) COOR I C00R (XVII) HNR r or L__ '1 each of which R is independently a lower alkyl. A compound according to claim 1, characterized in that each R is CH 3. A process for preparing a compound of formula (XVII) COOR 20 II II COOR (XVII) 25. each of which R is independently a lower alkyl, characterized in that (a) a compound of formula (XIII) 30 .COOR ^ 1L ^ x: over HN L_ | (Xiii> Wherein R is as defined above and X Sr halogen is reacted with a strong base in an aprotic polar solvent or (b) a compound of formula (XV) COOR COOR η / In OMs in which Ms is mesyl, it is reacted with a phase-shift catalyst and a strong base in an aprotic solvent. 4. A process according to claim 3, characterized in that each R is CH 3 and X is Br or Cl.