FI92488B - Process for the preparation of 1,2-dihydro-3H-pyrrolo[1,2- a]pyrrole-1,7-dicarboxylic acid and di(lower alkyl) ester thereof. - Google Patents

Abstract

The invention relates to a process for the preparation of (+-)-dihydro-3H-pyrrolo[1,2-A]pyrrole-1,7-dicarboxylates of the formula XII <IMAGE> wherein R is lower alkyl, by cyclizing a compound of the formula XVI <IMAGE> wherein X is halogen, with a steric hindered amine in an aprotic polar solvent. The invention further relates to a process where from compounds with the structural formula XII a compound is produced of the formula <IMAGE> wherein Ar is optionally substituted phenyl, furyl, thienyl or pyrrolyl and R is hydrogen or alkyl.

Description

92488

The present invention relates to a new process for the preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and its di (lower alkyl) esters. For the preparation of -3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and its di (lower alkyl) esters of formula (XII)

C00R

j— / IL il ^ -COOR (XII)

15 i_I

wherein each R is independently lower alkyl or hydrogen.

The process according to the invention is characterized in that the compound of formula (XVI)

C00R

a *. <XVI>

S

wherein R is lower alkyl and X is Br or Cl, cyclized with a protected lithium amine in an aprotic solvent, preferably tetrahydrofuran, and optionally hydrolyzing the resulting diester of formula (XII) to the corresponding dicarboxylic acid.

The pyrrolo [1,2-a] pyrrole derivatives of formula (XII) prepared according to the invention are useful as intermediates in the preparation of 5-aroyl-1,2-dihydro-92488 2-ro-3H-pyrrolo [1,2-a] pyrrole. -1-carboxylic acids, also known as 5-aroyl-1,2-dihydro-3H-pyrrolecinecarboxylic acids, of formula (I) 5 * -7 ° C -

It »i t

o I_I

3 2 10 These acids and their pharmacologically acceptable salts and esters are useful as analgesic, anti-inflammatory and antipyretic agents in mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds in clinical trials 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-CH30-C6H4), both of which are disclosed in U.S. Patent No. 2,089,969. (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 is also disclosed in a number of patents (USA), Inc. and include U.S. Patents 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, 30,450,957, 4,456,759, 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., discloses 5- (substituted pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives and 5- (1,2-35 dihydro- 3H-pyrrolo [1,2-a] pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives, in particular

II

3,92488, while U.S. Patent 4,533,671, also assigned to Merck & Co., Inc., discloses 5- (1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole). 2-Oyl) -2-pyrrolealkanoic acids and their analogous compounds.

Examples of various methods for preparing these pyroploprolols 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-10 [1,2-a] pyrrole-1,7-dicarboxylic acid ( II, R = H) or a dialkyl ester thereof

6 7 C00R

_ / 15 5 li Ji __C00R (II)

Cr 3 2, 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.

The reaction scheme shown in that patent publication: 25 ·· coocH- • ^ COOCH j f | H2 C00CH3> hN ^ C00CH3

T: ', »> S

OH 0H

(III) j (v) is C00CH, * _ / 3 COOCH, 0sc °° ch> (VII) \>. \ -, (VI)

QMS

I \ 35 p00CH3 N * _COOCHj [TjLy “0CH! -►

(VIII) '-V

(II, R * ch3) 92488 4 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 (for example 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 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 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 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 substituted 4-substituted-30 ton 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 preparing 5-aroyl-NR-pyrrole-2-acetic acid wherein R is H, lower alkyl or benzyl, and analogs thereof. 92488 for the preparation of these 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 alkylamine, a di (lower alkyl) -1,3-acetonedicarboxylate and a chloromethyl (lower alkyl) ketone, which is carried out "preferably in an aqueous medium". and followed by pouring the reaction mixture into ice-cold hydrochloric acid to give compounds corresponding to (IX) 10 R 'COOR "\ _ / I | COOR" (IX)

R

Wherein each of R, R 'and R "is lower alkyl. A similar process using chloroacetaldehyde to prepare 4-unsubstituted compounds (IX, R' = H) is disclosed in U.S. Patent 4,048,191,20 (Carson).

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

Other variations of Carson's syntheses have been reported in 35 patent publications in which the patentee has

Ethyl Corporation and U.S. Patent Nos. 92488 6 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 ( to a mixture of a lower alkyl) ketone, a dicarboxylate and a lower alkylamine containing water is added a water-immiscible co-solvent [a halogenated hydrocarbon which dissolves well both the 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. Pat. No. 4,374,255 discloses that a “anti-solid amount of a lower alkanol” is added to a mixture of a ketone, a dicarboxylate and an aqueous alkylamine, and the reaction is usually carried out in the presence of a co-solvent, such as U.S. Pat. No. 4,565. 878 and 4,565,879. U.S. Patent 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 the like). below 60 ° C, a ketone is added and (b) the reaction mixture is then heated to 70-100 ° C. U.S. Patent 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 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 a ketone, a dicarboxylate and a lower (preferably anhydrous) alkylamine. U.S. Patent 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).

11 92488 7

COOR "R * COO

f "^ chch-no., JL ^ COOR" / 2 2

Htf R * 5 R / y \ (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. 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 the synthesis is 1,3-acetonecarboxylate. the carboxylic acid is reacted with ClCH 2 CO 2 and the lower alkylamine, preferably by slowly adding an aqueous solution of the lower alkyl-20 amine 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 assigned to 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 a mixture of methylamine and dicarboxylic acid containing water.

Known processes 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 process of this invention allows for the use of much larger amounts of aqueous solvents 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).

The process of the invention includes, 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 represented by the seu-10 fat in Reaction Scheme A.

COOR .COOR

\ COOR _Step — 1 ► Ϊ COOR

Option II

0 HN

\ (XIV) is ^ - \

Step 1 OH

Option I

v 'r

COOR COOR

(XIII) .COOR \\ .COOR

20 A ".

HN 4- HN

\ (xv) X ÖMs

Step 1 Option I 25

COOR

30 li if

1! J. COOR

(XVI) | _.

V COOR

Step 3 ITjf COOR (XI1) 35 -> \ ^ \

II

9 92488 wherein R and X are as defined above and Ms is mesyl.

From the compounds of formula (XII) prepared according to the invention, 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids of formula (I) can be prepared by the method described in the following reaction scheme:

COOR

10 * - 000 * I (XII) '-' R = alkyl

_ ^ COOH ^ COOH

LnJC, _— COOR - ΧΧγ ^ -COOH

l — l L_T

r = alkyl 20 _ * ^ Xn-'coob_ „" "(XIX) 6 i-f <„, 1 25

Jl JL COOH

(I)

il I

o I-1 wherein R is as defined above and R 1 is substituted or unsubstituted phenyl, 2- or 3-furyl, 2- or 3-thienyl or 2- or 3-pyrrolyl, which, when substituted, may contain any available one or more lower alkyl, lower alkoxy or halogen substituents at position 35. In this process, 10,92488 (a) a compound of formula (XII) wherein each R is hydrogen is esterified to a compound of formula (XVIII) wherein the group R at the 1-position is alkyl; (b) decarboxylating a compound of formula (XVIII) to give a compound of formula (XIX); and (c) aroylating a compound of formula (XIX) with an amide or morpholide to give a compound of formula (I). These methods are known; they are described, for example, in U.S. Patent Nos. 4,089,969 and 4,353,829.

10 The following terms used in the specification and claims have the meanings given below, unless otherwise stated: "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 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropylmethyl, pentyl, hexyl, cyclohexyl, cyclohexyl . 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 alkyls", unless otherwise specified.

"Halogen" generally means chlorine, bromine or iodine, unless specifically defined to mean chlorine or bromine, in which case it is denoted by X.

"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 tetrahydrofuran, dimethoxyethane, bis (2-methoxyethyl) ether. (also known as diglyme), dimethylformamide, 35 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 has a wide range of properties. partly according to the polar solvent.

"Weak base" means an alkali metal or alkaline earth metal salt of a weak acid, 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).

"Strong bases" means 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 methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, sodium hydride, lithium di (isopropylamine, lithium bis- (trimethylsilyl) amine, etc.

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

"Water-miscible cosolvent" means a lower alkanol, di (lower alkyl ketone, tetrahydrofuran, dioxane, sulfolane, dimethylformamide, etc. Preferred cosolvents include methanol, acetone, and similar C 1-4 alkyl alcohols and ketones.

30 Starting materials and cleaning

Dimethyl 1,3-acetonedicarboxylate is a commercial 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 methods 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 corresponding to formulas (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 10 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-haloethylamine hydrohalide. or 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 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 the 2-haloethylamine hydrohalide to the basic solution unless the solution already contains acetone dicarboxylate to form aziridines. to avoid duplication. Usually, the 2-haloethylamine hydrohalide and the acetonide dicarboxylate are dissolved either simultaneously or in that order in water, and a solid weak base is added to the solution to obtain the reaction mixture. The reaction is preferably carried out at a temperature of 0 to 35 ° C, more preferably approximately. 92488 at about 20 to 30 ° C, with a reaction time of preferably about 15 minutes to 24 hours, more preferably about 4 to 18 hours. The intermediate di (lower alkyl) -3- (2-haloethylamino) -2-pentene-5-dioate (XIII, "haloamine") usually crystallizes and can be isolated by filtration as a mixture of the E and Z isomers. Each R is preferably methyl and sodium acetate is preferably used to control the pH.

In Step 1, Option II, the di (lower alkyl) -10 1,3-acetonodicarboxylate is treated with 2-hydroxyethylamine (2-aminoethanol) in an aprotic polar solvent to provide hydroxyamine (XIV), which is then converted via mesylenamine (XV) to haloenamine (XIII). . Usually, the dicarboxy-15 bar 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 hydroxynamine can be formed under less restrictive conditions (see, for example, U.S. Patent 4,089,969), an anhydrous hydroxysamine solution is required for the next reaction, and it is therefore convenient to effect hydroxynamine formation 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 between about -10 ° C and room temperature, preferably between about 0 ° C and 10 ° C. at the current temperature. It is convenient to add the tertiary amine to the solution from the previous reaction cooled to the appropriate temperature, and the mesyl chloride is slowly added to the resulting solution 92488 14 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.

The mesylamine (XV) is converted to the corresponding halogenamine (XIII) by reacting it with an anhydrous alkali metal chloride, preferably bromide, for example 10 lithium bromide or the like, in an aprotic polar solvent at a temperature between about room temperature and the boiling point of the solvent, for example about 30 to 100 ° C. -30 hours, for example 5-20 hours, depending on the reaction time 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 haloamine, which may be appropriate to purify by recrystallization.

Preparation of compounds of formula (XVI)

In Step 2, the haloenamine (XIII) from Step 1 is cyclized with a strong base in an aprotic polar solvent.

In this case, halogenamine (XIII) is treated with 2-25; with 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, preferably at pH 5 to 8.5. The reaction is preferably carried out at 0 to 65 ° C, more preferably at about room temperature, for a reaction time of about 30 to 48 hours, preferably 6 to 24 hours. X is preferably

The control of Br and pH is preferably carried out by adding a weak base, for example sodium acetate or sodium hydrogen carbonate, 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 acetone.

I! 92488 15

Halogenamine (XIII) is added to an aqueous solution containing a weak base and 2-haloacetaldehyde. Preferably, a water-miscible co-solvent is also added. The mixture is stirred for a suitable time and N- (2-haloethyl) -5-pyrrole is added. (XVI) is isolated by filtration. 2-Haloacetaldehyde 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-10-alkyl) (1,2-dibromoethyl) ether, 1,2-dibromoethyl acetate, etc. with an acid, each of which is hydrolysed results in an aqueous solution of 2-bromoacetaldehyde to which a weak base can be added.

Preparation of compounds of formula (XII) 15 (process according to the invention)

In Step 3, N- (2-haloethyl) pyrrole (XVI) is cyclized with 1-2 equivalents, preferably about 1.1 to 1.5 equivalents, of a strong base in an aprotic polar solvent.

The strong base is a protected lithium amine such as lithium di (isopropyl) amine or lithium bis (trimethylsilyl) amine and the solvent is preferably tetrahydrofuran.

Use of sodium hydride in dimethylformamide 25; The cyclization of N- (2-iodoethyl) pyrrole is known, for example, from U.S. Patent 4,089,969.

In the process of the invention, the compound of formula (XVI) is dissolved in an aprotic polar solvent and added slowly to this solution (i.e. over about 1 to 30 hours, for example about 2 to 8 hours) at a temperature of about -10 to -35 ° C. , for example at about room temperature, the strong base solution and the resulting solution are mixed to give a solution containing pyrrolopyrrole diester (XII). The reaction temperature is preferably 0 to 10 ° C with X being Br and 15 to 30 ° C being X when the strong base is lithium di (isopropyl) amine-92488 16 nl. Compound (XII) can be isolated from solution by removing the solvent and purifying the residue by conventional means in organic chemistry or, as usual, hydrolyzed directly with dicarboxylic acid (XII, R = 5 H), which can be conveniently carried out using a diester solution from the cyclization process.

The dicarboxylic acid (XII, R = H) can be obtained by hydrolyzing the corresponding diester (XII, R = lower alkyl-11) by conventional chemical means, i.e. by reacting it with a strong base to remove ester groups and treating the product with 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 reacted 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 expedient to carry it out 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, e.g. sodium hydroxide, may be added directly to the resulting pyrrolopyrrolid diester solution, and an additional portion of the solvent 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 the preparation of a compound of formula (XVI) used as a starting material in the process of the invention (Examples 1 to 3) and the process of the invention (Examples 4 and 5). Examples of the preparation of compounds of formula (I) from a compound of formula (XII) are disclosed in Finnish patent application 880133 (corresponding Finnish patent 10 90344).

Example 1

Preparation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate (XIII) (Step 1 - Option I) 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. 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 0-5 ° 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 g. .9 g (yield 86%) of dimethyl 3- (2-bromoethylamino) -2-pentenedioate as a white solid, m.p. 71-72 ° C.

NMR (CDCl 3): δ 8.80 (1H, broad singlet); 4.60 (1H, 30 singlets); 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 of 35 (yield 80%) dimethyl-3- (2-chloroethylamino) -2- pentee 92488 18 nidioate as a white solid, m.p. 75 - 76 eC. NMR (CDCl 3) δ: 8.80 (1H, broad singlet); 4.60 (1H, singlet); 3.75 (3H, singlet); 3.65 (3H, singlet); 3.60 (4H, multiplet); 3.27 (2H, singlet).

5 Example 2

Preparation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate (XIII) (Step 1 - Option II) A. In a 3-necked 3-liter flask containing a stir bar equipped with a thermometer, a water separator at reflux and a dropping funnel. funnel, dimethyl 1,3-acetonodicarboxylate (196.1 g, 1.13 mol) was charged and the flask was then purged with nitrogen. The separator was charged 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 remaining and 20 ml of hydrogen had accumulated in the separator.

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 addition funnel over 3.75 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 at 50 ° C to give 310.0 g (yield 93%) of dimethyl 3- (2-methane-92488 19 sulphonylethylamino) -2-pentenedioate as a red oil. . If necessary or desired, the mesyleneamine can be purified in this process and converted to the haloenamine by the following method or used directly in process 2, 5 in option II.

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 3- (2-bromoethylamino) -2-pentenedioate as a yellow oil which rapidly solidified 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 (61.2% yield) of dimethyl-3- (2- bromoethylamino) -2-pentenedioate as white needles. The NMR spectrum in CDCl 3 showed a ratio of Z to E isomer of 19: 1 and re-measurement of the CDCl 3-30 solution three days later showed a ratio of Z to E isomer of 4: 1. The two isomers were not separated.

B. Substitution of lithium bromide with lithium chloride and using a procedure similar to that in Part A of this Example 35 gives dimethyl 3- (2-chloroethylamino) -2-pentenedioate.

92488 20

Example 3

Preparation of methyl N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrrole acetate and methyl N- (2-chloroethyl) -3-methoxycarbonyl-2-pyrrole acetate (XVI) (Step 2) A. To a three-necked 100 To a 1 mL flask equipped with a mechanical stirrer, reflux condenser, and thermometer was added 2-bromoacetaldehyde ethyl acetal (42.2 g, 214 mmol). Hydrobromic acid (9M, 4.0 mL, 36 mmol) in water (16 mL) was added and the mixture was refluxed for one hour and then cooled to room temperature to give a 2-bromoacetaldehyde solution.

To the 2-bromoacetaldehyde solution was added sodium acetate (41.0 g, 500 mmol) and stirred for 5 minutes at which point the pH of the solution was 6. The flask was placed in a cold tap water bath and dimethyl 3- (2-bromoethylamino) -2-pentenedioate was added. (20.0 g, 71 mmol) followed by isopropanol (40 mL) and 20 solutions were stirred at room temperature (25 ° C). All solids dissolved in about 35 minutes and a precipitate began to form within 90 minutes. Stirring was continued at room temperature for 20 hours, then the solution was cooled to 0 ° C and stirred at that temperature for one hour and then filtered through coarse sinter. The precipitate was washed with ice-cold water (400 ml) and ice-cold isopropanol (150 ml) and dried to give 15.7 g (yield 72%) of crude methyl N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrroleacetate. lean as a tan solid, m.p. 129 -130.5 eC.

NMR (CDCl 3) 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. To a 3-necked 100 mL flask equipped with a stir bar, reflux condenser, and thermometer was added 2-bromoacetaldehyde diethyl acetal 92488 21 11a (20.9 g, 106 mmol). Hydrobromic acid (48.5%, 17.7 g, 106 mmol) in water (54 mL) was added and the mixture was warmed to 40 ° C for 3 h, then cooled to room temperature and extracted with hexane (100 mL) to give 2-bromiasetaldehydiliuos.

The hydrolysis solution was added at 0 ° C over one hour to a slurry containing sodium acetate (17.8 g, 212 mmol) in water (15 mL) which was stirred mechanically and then stirred for an additional 10 minutes.

Dimethyl 3- (2-chloroethylamino) -2-pentenedioate (20.0 g, 85 mmol) was added followed by acetone (50 mL) and the solution was allowed to warm to room temperature and stirred for 20 minutes. The resulting slurry was cooled to 0 ° C and held at that temperature for four hours, after which it was filtered through coarse sinter. 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-pyrrole acetate as white crystals, m.p. 110-111 ° C.

NMR (CDCl 3) 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).

Example 4

Dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-25. Preparation of dicarboxylate and 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (XII) (Step 3) A. To a solution containing diisopropylamine (13.8 mL, 10 .0 g, 98 mmol) in tetrahydrofuran (dry, 50 mL) was added slowly under nitrogen at -5-0 ° C while stirring n-butyllithium (1.3M hexane, 75 mL, 98 mmol). The resulting solution was transferred to a dropping funnel and added under nitrogen at 0-5 ° C to a slurry containing methyl N- (2-bromoethyl) -3-methoxycarbon-35-carbonyl-2-pyrrole acetate (20.0 g, 66 mmol). ) in tetrahydrofuran (dry, 100 mL) and stirred. The temperature 92488 22 rose slightly and after about two thirds of the lithium di (isopropyl) amine solution was added, complete dissolution occurred. The resulting solution was stirred for about two hours while warming to 5 ° C and then the solution was diluted with water (100 mL) to generate some heat. The solvents were removed by distillation at atmospheric pressure (solvents were collected in a 240 ml vessel at 80 ° C) to give a dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] -10 pyrrole-1,7-dicarboxylate solution. At this point, the diester can be isolated by adding water to the solution and extracting the diester into an organic solvent such as ethyl acetate and evaporating the solvent and purifying by conventional methods. However, it is convenient to hydrolyze the diester to the dicarboxylic acid without isolating it from solution.

The solution left in the vessel obtained in the previous paragraph was cooled to 50 ° C and sodium hydroxide (6.0 g, 150 mmol) was added thereto, and then methanol 20 was removed by distillation at atmospheric pressure, whereby the temperature of the vessel rose to 97 ° C. The solution remaining in the vessel was cooled to 5 ° C and acidified with hydrochloric acid (12M, 18 mL, 216 mmol), resulting in a rise in temperature to 15 ° C. The resulting mixture was cooled to 5 ° C and filtered and the precipitate was washed with cold water and dried to give 11.4 g of crude 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7- a dicarboxylic acid. Analysis of the crude material showed it to contain 91.4% of 1,2-dihydro-3H-pyrrolo-30 [1,2-a] pyrrole-1,7-dicarboxylic acid (and 7.0% of N-vinyl-3-carboxylic acid). -2-pyrroleacetic acid).

B. To a solution of diisopropylamine (109.3 mL, 78.9 g, 0.78 mol) in tetrahydrofuran (freshly distilled, 200 mL) was added dropwise at 0-3 ° C with stirring. n-butyllithium (2.6M hexane solution, 295.5 mL, 0.77 mol). The resulting solution was transferred to 11,92488 23 dropping funnels and added dropwise at room temperature to a solution of methyl N- (2-chloroethyl) -3-methoxycarbonyl-2-pyrrole acetate (150.0 g, 0.58 mol) in tetrahydrofuran (dry , 750 ml) and stirred. The addition lasted four hours and the temperature was maintained between 23 and 27 eC. The resulting solution was stirred for 16 hours and then diluted with water (500 mL) over 10 minutes to generate some heat. The solvents were removed by distillation at atmospheric pressure, in which the temperature of the vessel rose to 75 ° C. The solution remaining in the vessel was cooled to 50 ° C and sodium hydroxide (53.0 g, 1.33 mol) was added and the methanol was then removed by distillation at atmospheric pressure, raising the vessel temperature to 95 ° C to collect a total of 1 370 ml of solvents. The solution remaining in the vessel was cooled to -3-0 ° C and acidified with hydrochloric acid (12M, 180 mL, 216 mmol), followed by a rise in temperature to 18 ° C. The resulting mixture was cooled to -3-0 ° C, allowed to stand at that temperature for 30 minutes, filtered and the precipitate washed with ice-cold water (300 ml) and dried to give 107.8 g of crude 1,2-dihydro-3H- pyrrolo [l, 2-a] pyrrole-l, 7-dicarboxylic acid. Analysis of the crude material showed it to be 96.6% 25. 1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid.

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

Claims (2)

A process for the preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and its di (lower alkyl) esters of formula (XII) COOR Π -COOR (XII) L_1 in which each R is independently lower alkyl or hydrogen, characterized in that the compound of formula (XVI) wherein R is lower alkyl and X is Br or Cl is cyclized with a protected alkyl group. with lithium amine in an aprotic polar solvent, preferably tetrahydrofuran, and optionally: hydrolyzing the resulting diester of formula (XII) to the corresponding dicarboxylic acid. 9 '92488 25 For the preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and di (5-alpha) esters of the active compound (XII) COOR ί jl COOR (XII) io 1_ color vardera R självständigt är lägre alkyl eller väte, kännetecknat därav, att en förening med for-15 mein (XVI) COOR ί 11 COOR (XVI) ^ H 20 \ color R är lägre alkyl och X is Br or Cl, cyclized with a solution of lithium amine and an aprotic polyside, converted to tetrahydrofuran, and optionally hydrolysed as a diester with formula (XII) to a dicarboxylic acid.