FI91148C - Alkyl 3-alkoxycarbonyl-2-pyrrolidinylidene carboxylates and process for their preparation - Google Patents

Description

i 91148

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

Divided by application 880 133 5

The present invention relates to alkyl 3-alkoxycarbonyl-2-pyrrolidinylidenecarboxylates which can be used as intermediates in pyrrolo [1,2-a] pyrroles and in particular 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1, 7-Dicarboxylic acid-10 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

M ^^ 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

jc / COOR

Hf <XVI

'I

OMs 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 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate and the corresponding dicarboxylic acid of formula (XII)

COOR

20 JL COOR

I (XII> wherein each R is independently alempl alkyl or hydrogen. This process is characterized in that a compound of formula (XVII) of the present invention is reacted with a 2-haloacetaldehyde of formula XCH 2 CHO wherein X is halogen. , optionally hydrolyzing the resulting compound of formula (XII) wherein R is lower alkyl, in a known manner to give a compound of formula (XII) wherein R is hydrogen.

The 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.

II

91148 3 ol-1-carboxylic acids, also known as 5-aroyl-1,2-dihydro-3H-pyrrolizine-1-carboxylic acids of the formula (I) a] -i 10 These acids and their pharmacologically acceptable salts and esters are Useful as analgesic, anti-in-flammator and antipyretic agents in mammals, including man. They are myOs 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 (I, Ar -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 possibly lower alkyl or halogen substituted, and there are a number of patented owned by Syntex (USA), Inc. and includes 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, in which p the holder of the atom is Merck & Co., Inc., discloses 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-3-ol [1,2-a] pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives , in this order, while U.S. Patent 4,533,671, which is owned by myOs Merck & Co., Inc., discloses 5- (1,2-dihydro-3H-pyrrolo [1,2-a] ] pyrrol-2-yl) -2-pyrroloalkanoic acids and their analogs.

Examples of various methods for preparing 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) 3 2 15, the preparation of which from dimethyl 1,3-acetonedicarboxylate, ethanolamine and haloacetaldehyde is disclosed, for example, in U.S. Patent 4,089,969, which is incorporated herein by reference.

20 Reaction scheme shown in that patent publication: CC00CH,

C00CH

I c Luuun3 HN

25 ch2 + 0 \

Jh (IV)

0H OH

(III): · (V) C00CH, * _ / 3 C00CH, 30 FjLv000 '^ Γ ~ £ yC00CH, \ 4- (VII) \ v \ -. (VI) OMs

OH

i \ 35 j; ooch3 '> 4 cooch3 ζΧ / ° 0CH' -

(vin) ^ —V

\ (II, R CH3)

II

91148 5 contains a silent reaction (in equivalent molar amounts) of ethanolamine (III) and dimethyl-1,3-acetonecarboxylate (IV) to form a solution of hydroxynamine (V) which is then treated, preferably in 5 situ, in a suitable organic solvent ( exemplified by aprotic solvents such as acetonitrile, dichloromethane, etc.), under anhydrous conditions and under elevated temperature to give 2-haloacetaldehyde 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 of 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 methods described in is 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-acetone dicarboxylate and (halomethyl) alkyl ketone bypasses hydroxynamine (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 are given 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 "followed by pouring the reaction mixture into cold hydrochloric acid to give compounds of formula 10 (IX) R 'C00R" \ - (\\ C00R "I · II / (ix) 15 l wherein each of R, R' and R "is lower alkyl. A similar process for the use of chloroacetaldehyde S 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 an additive substantially simultaneously with a dicarboxylate and a ketone (or an aldehyde), or . 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, 4,455,433 and 4,333,878. U.S. Patent 4,565,878 discloses that chloromethyl (lower alkyl) ) to a mixture of ketone, di-5 carboxylate and reduced alkylamine containing water is added a water-immiscible co-solvent [halogenated hydrocarbon which dissolves well both di (lower alkyl) -1,3-acetone dicarboxylate 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 a "lower alkanol" to a mixture of ketone, dicarboxylate and water-containing alkylamine. 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 20 (e.g., an aromatic hydrocarbon, a halogenated hydrocarbon, water, or a mixture thereof) and having a temperature below 60 ° C, a ketone is added, and (b) the reaction mixture is heated to 70 to 100 ° C. U.S. Patent No. 4,383,117 discloses the use of an aqueous lower alkylamine instead of an aqueous solution and the use of a single phase aqueous reaction medium. U.S. Patent No. 4,455,433 discloses that a "yield-enhancing amount of 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 ketone, dicarboxylate and alenuna (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

ί ^ CHCH NO

JL COOR "/ z z HNX R '

5 I

R (X) (XI)

The enamine can be prepared by reacting the 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. 15,363,918 a synthesis for 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 20 to the aqueous acid solution and then slowly adding 1-chloro-2-alkanone with both additions, preferably at a temperature below 20 ° C.

EP-A-92 487 and 105 664, in which Montedison SpA is the applicant, 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 its alkali metal salt with methylamine or a haloketone (or aldehyde) in aqueous solution, preferably by adding a haloketone to a mixture of methylamine and dicarboxylic acid in water.

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 disclosed in FI patent application 880 113 enables the use of a much larger amount of aqueous solvents and can be easily applied on a production scale. Silia is also obtained in 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 involves, as a final step, 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 \ _ ^ <KIV)

Step 1 OH

Option I

; I

^ COOR COOR

2Q (XIII) COOR ^ __ ^ COOR

HN ^ 4- HN ^ V (xv)

X v 0MS

1 \ Step 2 | y .. 2

Step 2 X.Option II 1

«C Option I N. Option III

I X

V

COOR

30 li il ^ COOR

KJ ^ C00R

(xvi) I_v H | I C00R (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.

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

The following terms, as used in the specification and claims, have the meanings given below, unless otherwise stated: "Lower alkyl", which is generally denoted by R (which may mean myOs hydrogen, even if it is "). lower alkyl ") means a straight, branched or cyclic saturated hydrocarbon group containing from 1 to 6 carbon atoms, for example methyl, ethyl, n-propyldis, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropylmethyl, pentyl , hexyl, cyclohexyl or the like. 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 stated.

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

"Halogen", 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) ethyl acetate. 91148 11 ri (known as myOs diglyme), dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc. The solvent may contain small amounts of aprotic non-polar solvents such as hydrocarbons, for example cyclohexane, toluene and the like. properties are largely determined by the polar solvent.

"Weak em & s" means an alkali metal salt of a weak acid alkali metal salt, for example, sodium acetate, potassium hydrogen carbonate or the like, or a buffer mixture providing a similar pH (such as NaH 2 PO 4 -Na 2 HPO 4).

By "strong emaxyl" is meant emas such as alkali metal hydroxides, reduced 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 Msrlia, 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.

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 the dimethyl ester and, preferably, the carboxylic acid esterification process, which are well known in the art. There is no specific hybrid of any substitution of alkyl groups, so dimethyl ester (R CH 3) is preferred.

The starting materials and silicon products of formulas 10 (XIII), (XIV) and (XVI) may, if desired, be isolated 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 (XIII)

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-acetonedicarboxylate 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 used in the reaction as an solvent in an aqueous solution of a weak base such as sodium acetate, but other methods of 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 relied upon in either the simultaneous order of water and the addition of solid weak base to give 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 di (lower alkyl) -3- (2-haloethylamino) -2-pentenedioate ("haloamine") obtained as an intermediate is usually crystallized and can be isolated by filtration as a mixture of the E and Z isomers. Each R is preferably methyl-11, X is preferably Br tal Cl and sodium acetate is preferably used to adjust the pH to Kay-15.

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 hydroxynamine (XIV), which compound is then converted via mesylenamine (XV) to halogenenamine. XIII). The conversion is based on the mesylenamine step and the mesylenamine can 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), the following reaction requires an aqueous solution of hydroxysamine and it is therefore convenient to carry out the formation of hydroxynamine in an aprotic carrier. 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 1, Alternative I, the preferred R group is methyl. The preferred solvent for Eras is dichloromethane.

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 at about 0 ° C and 10 ° C. n, in the lamp mode. It is convenient to add the tertiary amine to the solution 10-1 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 the E and Z isomers of mesylenamine (XV) which can be used in the next reaction without further purification, although purification is preferred. is intended to be cyclized directly without first being converted to a haloeneamine.

The mesyleneamine (XV) is converted to the corresponding halogeneneamine (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, for example a room temperature of about 30 - in a lamp room at 100 ° C for 1 to 30 hours, for example 5 to 20 hours, depending on the reaction time and the reaction conditions. 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 recrystallize the soil.

In Step 3, Option I, a pyrrole ring of pyrrolo-35 pyrrole is formed by reacting cyclic enamine (XVII) 91148 with 2-haloacetaldehyde, XCH 2 CHO, wherein X is as described above. The process is preferably carried out in aqueous solution at a pH of 4.5 to 10, more preferably at a pH of 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 is preferably carried out in a solution of a weak base, for example sodium acetate or sodium bicarbonate. The process is preferably carried out in the presence of 10 to 50% by volume of a water-miscible cosolvent 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 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 of which hydrolysis lead to an aqueous solution of 2-bromoacetaldehyde.

If desired, the diicarboxylic 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 about room temperature and 16 times the boiling point of the solvent, and is allowed to react for 0.5 hours. -klksl 1-4 hours. The cooled solution is made with an aqueous solution of a strong acid, for example with 25% hydrochloric acid, and the dicarboxylic acid precipitates and can be removed by filtration. The carboxylic acid can be purified by conventional means, in particular by recrystallization from an aqueous solution. The hydrolysis can be carried out using an isolated substance, but it is convenient to carry out the above 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 mother may be added directly to the resulting pyrrolopyrrolid diester solution, e.g., sodium hydroxide, and a portion of the solvent may be removed (if desired or necessary). , for example 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, with particular care to recrystallize it from aqueous solution.

The following examples illustrate this invention. Examples 1-3 illustrate the preparation of a compound of formula (XVII) and Examples 4 and 5 illustrate a process in which a selected product 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 in a room lamp (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 aqueous sodium acetate (14.35 g, 175 mmol) was added and stirring was continued.

91148 17

After 80 minutes, precipitation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate began and the solution was stirred at room temperature for 17 hours. The thick slurry was diluted with cold liquid (20 mL), allowed to stand at 50 ° C for 30 mL, filtered, and the precipitate was washed with cold (0-5 ° C) liquid (50 mL) and dried to constant weight to give 13.9 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 the 2-bromoethylamine hydrobromide 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. In a 3-necked 3-liter flask containing 25 stirring rods equipped with a 1SMPO meter, a water separator in a reflux condenser, and with a dropping funnel, dimethyl 1,3-acetonedicarboxylate (196.1 g, 1.13 mol) was charged and the flask was 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 that the dicarboxylate was very waxy and 20 ml of water had accumulated in the separator.

18

A solution of dimethyl 3- (2-hydroxyethylamino) -2-pentenedioate was cooled to 0 ° C and trethylamine (235 mL, 170.6 g, 1.69 mol) was added in one portion. Methanesulfonyl chloride (168.8 g, 1.47 mol) was added dropwise over a period of 5 hours via a dropping funnel 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. The mixture was stirred at 0 ° C for two hours and then water (250 ml) was added. The organic phase was washed with water (4 x 500 ml) and brine (250 ml) and dried over anhydrous magnesium sulphate. The filtrate was evaporated on a rotary evaporator under reduced pressure and at 50 ° C to give 310.0 g (93% yield) of dimethyl 3- (2-methanesulphonylethylamino) -2-pentenedioate as a red solid. -as. If necessary or desired, the mesylenamine can be purified at this stage and converted to the haloenamine by the following methods or used directly in Step 2, 20 in Option II.

To a 3-necked 2-liter flask equipped with a mechanical stirrer, lamp gauge, 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, aqueous 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 the mixture was stirred for five minutes and the phases were separated. The organic phase was washed with liquid (3 x 250 ml) and brine with brine (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 epd-pure dimethyl 91148 19 3- (2-bromoethylamino) -2-pentenedioate as a yellow ¢ 51 grain which was rapidly ground to a yellow solid. The crude Alne was purified by extraction into boiling hexane (5 x 750 mL) and the crystals were recrystallized from hexane and the portions extracted from the vessel and recrystallized to give a total of 90.8 g (61.2% yield) of dimethyl. -3- (2-bromoethylamino) -2-pentenedioate as white needles. The NMR spectrum in CDCl3 showed a 19: 1 ratio of Z to E isomer and re-measurement of the CDCl3 solution three days later showed a 4: 1 ratio of Z to E isomer. These two isomers were not separated.

B. In the same manner as in Part A of this example, using lithium bromide instead of lithium bromide and dichloromethane instead of acetone or acetonitrile, in all cases crude dimethyl 3- (2-iodoethylamino) -2-pentenedioate was obtained as a light brown purifier, 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 added gradually over 18 minutes to give some lampda. The reaction mixture was stirred at room temperature for 23 hours, after which it was extracted with brine (4 x 50 mL) and brine (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 main 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 waxy product, methyl (E) -3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate, was isolated as 61-grain. 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 waxy product, dimethyl 3- (1-azi-20-ridinyl) -2-pentenedioate, was isolated as 61.

B. (Option II) To a solution of dimethyl 3- (2-chloroethylamino) -2-pentenedioate (4.71 g, 20 mmol) in dichloromethane (50 mL) was added in room iamp6 in four equal portions. sodium methoxide (1.62 g, 30 mmol) over 1 minute. The reaction mixture, which had turned yellow somewhere and had formed a slight precipitate, was stirred for 27 hours, and the residue was treated to isolate the product as described in Part A of this example to give 2.8 g of a yellow oil which was found to be preparative thin. based on chromatographic chromatography and NMR spectra to contain 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, at which point it became calcareous at 5. Dichloromethane (30 ml) and water (20 ml) were added and the mixture was stirred for 1 minute to give a light brown, water-containing upper 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 brine (2 x 20 mL) and brine (20 mL). Trituration of the solvents with a pyr6r6 evaporator gave 1.8 g (90% yield) of a light brown 15 oily oil which crushed on standing. Thin layer chromatography and NMR spectra showed that it was largely found in methyl (Z) -3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate and in the lower form of methyl (E) -methoxycarbonyl-2-pyrrolidinylideneacarboxylate-2-pyrrolidinylideneacarboxylate. dimethyl 3- (vinylamino) -2-pentenedioate.

D. (Option III) To a 3-necked 1 L flask, which was 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) and a portion of dimethyl 3- (2-methanesulfonyl-ethylamino) -2-pentenedioate (40.12 g, 136 mmol) and tetrabutyl-ammonium bromide (6.57 g, 20 mmol) were then added. The reaction mixture was refluxed for seven hours, during which time thin layer chromatography revealed that a small amount of mesyleneamine was still present. For this reason, the reaction mixture was stirred for an additional 14 hours at room temperature, which showed that 35 mesh thin layer chromatography showed no more mesylamine and was washed with water (3 x 200 mL) and brine (200 mL) and dried over anhydrous magnesium sulfate. . Evaporation of the solvent on a pyroO-5 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 10 mana.

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 three 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 one hour and then most of the solvents were removed by evaporation under reduced pressure. The solution 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-diethyl acetal with 2-chloroacetaldehyde diethyl acetal 35 and using a procedure similar to that in Part D of this exemplary 91148 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] pyrrole-1,7-dicarboxylate (1.26 g, 5 mmol) and sodium hydroxide (1.00 g, 25 mmol) in refluxing water (10 mL) for one hour. The resulting solution was cooled to 0 ° C and adjusted to pH 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)

24 A compound of formula (XVII) 5 COOR J1 COOR - (XVII) 10 wherein each R is independently lower alkyl. A compound according to claim 1, characterized in that each R is CH 3. A process for the preparation of a compound of formula (XVII) COOR 20 1 - COOR (XVII) 25 wherein each R is independently lower alkyl, characterized in that (a) a compound of formula (XIII) COOR HN 35 x II \ (XIII) 91148 25 wherein R is as defined above and X is halogen is reacted with a strong base in an aprotic polar solvent or (b) a compound of formula (XV) 5 COOR CCOOR (XV ) HN 10 '-i OMs where Ms is mesyl is reacted with a phase transfer catalyst and a strong base in an aprotic solvent. Process according to Claim 3, characterized in that each of R is CH 3 and X is Br or Cl. 26