FI92488C - Process for the preparation of 1,2-dihydro-3H-pyrrolo / 1,2-a / pyrrole-1,7-dicarboxylic acid and di (lower alkyl) esters thereof - Google Patents

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 dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and its di (alemplate alkyl) ester of formula (XII)

C00R

r- / IL il ^ -COOR (XII)

15 i_I

wherein each R is independently lower alkyl or hydrogen. The processes according to the invention are characterized in that the compound of formula (XVI)

C00R

325 · OO ”0" (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 iron-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-292488 ro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids known as tnytts 5-aroyl-1,2-dihydro-3H-pyrrolecinecarboxylic acids of formula (I) 5 * -7 (X)

S ΐί T

o I_I

3 2 10 NSraS acids, as well as their pharmacologically acceptable salts and esters, are useful as analgesic, anti-inflammatory and antipyretic agents, including in the human neck. They are myOs 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 among patent publications owned by Syntex (USA), Inc. and including 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 4,536,511. 2, in which the patent holder 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- (1,2-35 dihydro-3H-pyrrolo [1,2-a] pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives, equ. -

II

3,92488, while U.S. Patent 4,533,671 to Halti and Mybs Merck & Co., Inc. discloses 5- (1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole). - 2-oyl) -2-pyrrolalkanoic acids and compounds analogous thereto.

Examples of various methods for preparing these pyroplopyrroles have been reported in the patent literature and in the chemical literature, and many of them proceed from the common product, 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 product 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.

Reaction scheme shown in that patent publication: 25 ·· cooch, • ^ COOCH j r | H2 <; X ^ C00CH3 ”hA-C °° CH3

L "2 * S

OH 0H

(III) j (v) is cooch, * _ / 3 COOCH, \ 4- ^ (VII) \>. \ -, (VI)

OMS

i \ 35 pOOCHj COOCHj

(VIII) '-V

(II, R * ch3) 92488 4 contains a silent reaction (in equivalent molar mass) of ethanolamine (III) and dimethyl-1,3-acetonediocarboxylate (IV) to form a solution of hydroxynamine (V), which compound is then treated, preferably in 5 in situ, in a suitable organic solvent (for example aprotic solvents such as acetonitrile, dichloromethane, etc.), under drawn conditions and in an elevated lamp compartment, 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 (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 the aroyl group 20 can be attached to the 5-position, for example, by methods described in 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-acetonodicarboxylate and (halomethyl) alkyl ketone bypasses hydroxysamine (V) and directly results in 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 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. 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 processes involve the silent reaction of a lower alkylamine, di (lower alkyl) -1,3-acetonedicarboxylate and chloromethyl (lower alkyl) ketone, which is carried out "preferably in aqueous medium". and followed by pouring the reaction mixture into part-cold hydrochloric acid to give compounds corresponding to (IX) 10 R 'COOR "/ II COOR" (IX)

R

Wherein each of R, R 'and R "is lower alkyl. A similar process for the use of 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 an additional dicarboxylate and a ketone (or aldehyde) substantially simultaneously therewith, or (b) an additional dicarboxylate and a ketone used simultaneously with an excess of water. 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. 6,92488 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 alempl alkyl ketone, dicarboxylate, and water-containing lower alkyl amine-5 nl is added a water-immiscible cosolvent [a halogenated hydrocarbon that dissolves well both di- (alempl alkyl) -1,3-acetonodicarboxylate and the product] in U.S. Pat. U.S. Pat. No. 4,374,255 discloses the addition of an "anti-solids to a lower alkanol" to a mixture of a ketone, a dicarboxylate and a water-containing alkylamine. The reaction is usually carried out in the presence of a co-solvent. as in 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, to a cooled solution containing an alkylamine and a dicarboxylate in a suitable solvent (e.g. in an aromatic hydrocarbon, halo-20 generated hydrocarbon, water or a mixture thereof) and having a temperature below 60 ° C, a ketone is added and (b) the reaction mixture is then heated to 70-100 ° 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 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).

11 92488 7

COOR "R * COO

f Ns'chch0no ^ JL ^ COOR "/ 2 2 R * 5 R / y \ (XI)

The enamine can be prepared by reacting the di (lower alkyl) -1,3-acetonecarboxylate with the lower alkylamine 10 "in a suitable solvent such as ethanol and 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 for the synthesis of compounds of formula (IX) wherein R is alempl alkyl, R 'is hydrogen or lower alkyl and R "is hydrogen wherein the synthesis of 1,3-acetone dicarb the carboxylic acid is reacted with ClCH 2 CO 2 and lower alkyl, preferably an aqueous solution of the lower alkyl-20 amine in an aqueous solution of the acid and then addition of 1-chloro-2-alkanone at a temperature of less than 20 ° C, preferably at less than 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 water-containing methylamine and dicarboxylic acid.

Known processes for the preparation of pyrrolopyrroles require large amounts of organic solvents and tend to form a tar and are difficult to apply on an industrial scale. The process of the present invention allows the use of a much larger amount of aqueous solvents and can be easily applied on a production scale. S111M achieves better yields of myOS 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 shown in Reaction Scheme A below.

C00R C00R

\ C00R _Step — 1 ► Ϊ C00R

Option II

0 HN

\ (XIV) 15

Step 1 OH

Option I

v v

^ COOR C00R

(XIII) i C00R \\ COOH

20 A ".

HN 4- HN

\ (xv) X 0Ms

Step 1 Option I 25

C00R

30 (i J

1! J. C00R

(XVI) I_.

V C00R

Step 3 11 I COOR (XI1)

35 -> ^ LJ

II

9 92488 wherein R and X are as previously defined 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 methods described the following reaction scheme:

COOR

ίο i I (XII) 1- 'R = alkyl

_ ^ COOH ^ COOH

COOR "- ΧΧ · Γ - 'Μ0Η r = alkyl 20 _ *

„R -cXXr-c °° R

rø) & '- ‘(IS)’ 25 »(j il

Jl JL COOH

(I) ο I-1 30 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 and may contain at one of the available 35 positions one or more lower alkyl, lower alkoxy or halogen substituents. In this method, 92488 (a) a compound of formula (XII) wherein each R is hydrogen is esterified to a compound of formula (XVIII) wherein the group R in 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). NSmS methods are known; niitS is described, for example, in U.S. Patent Nos. 4,089,969 and 4,353,829.

The following terms used in the specification and claims have the meanings given below, unless otherwise stated: "Lower alkyl", which generally means R (which may mean mytts hydrogen, although it is not "lower"). alkyl ") means 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 , 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 alkyls", unless otherwise stated.

"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. ri (known as myOs diglyme), dimethylformamide, 35 N-methylpyrrolidone, dimethyl sulfoxide, etc. The solvent may contain small amounts of aprotic non-polar solvents such as hydrocarbons, for example cyclohexane, 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).

By "strong emaxyl" is meant emas 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 to which include lithium, sodium, potassium, rubidium, and cesium, for example, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, sodium hydride, lithium di (isopropyl) amine, lithium bis- (trimethylsilyl) amine, and the like.

"Mesyl" or "mesylate", denoted by Ms, means in particular methanesulfonyl, but 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 1-4 alkyl alcohols and ketones.

30 Refrigerants and cleaning

Dimethyl 1,3-acetonedicarboxylate is a commercial compound (Aldrich) as well as 1,3-acetonedicarboxylic acid known as myOs 3-oxopentanedicarboxylic acid. Other di (lower alkyl) -1,3-acetonedicarboxylates can be readily prepared from either the dimethyl ester or, preferably, the dicarboxylic acid by ester ester methods well known in the art. There is no explicit hydrogenation of the alkyl group, so dimethyl ester (R * CH3) is preferred.

Substances and silicon products corresponding to 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. Such substances may 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 with 2-hydroxyethylamine (2-aminoethanol), the hydroxyl group of which is replaced by halogen.

In Step 1, Option I (which is preferred) is a di (lower alkyl) -1,3-acetonedicarboxylate with a 2-haloethylamine hydrohalide in aqueous solution. The pH of the solution is preferably 5 to 12, more preferably 5 to 8. The pH of the solution is usually used in the reaction as an aqueous solution of a weak base such as sodium acetate, but other methods for adjusting the pH are 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 challenge the decision. Usually, the 2-haloethylamine hydrohalide and the acetonide dicarboxylate are dissolved either simultaneously or in said 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 0 to 35 ° C, more preferably with approximately care. 92488 at about 20 to 30 ° C, the reaction time being preferably about 15 minutes to 24 hours, more preferably about 4 to 18 hours. The di (lower alkyl) -3- (2-haloethylamino) -2-pentene-5-dioate (XIII, "haloamine") obtained as a product is usually crystallized and can be isolated by filtration as a mixture of the E and Z isomers. Kurapik R is preferably methyl and preferably sodium acetate is used to adjust the pH.

In Step 1, Option II, di (lower alkyl) -10 1,3-acetonodicarboxylate 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). Usually, the dicarboxy-15 bar is dissolved in the 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), the next reaction requires a solution of hydroxynamine in water 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 I, 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. , in the l & mpd mode. The tertiary amine is suitably added to the solution from the previous reaction cooled to the appropriate temperature, and the mesyl chloride is added slowly to the resulting solution 92488 14 over a period of 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 mesylenamine (XV) is converted to the corresponding halogenenamine (XIII) by reacting it with anhydrous alkali metal chloride, preferably bromide, for example 10 lithium bromide or the like, in an aprotic polar solvent at a temperature of about room temperature and the boiling point of the solvent, for example about 30 to 100 ° C. at a temperature of 1 to 30 hours, for example 5 to 20 hours, depending on the reaction time of 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 recrystallize the soil.

Preparation of compounds of formula (XVI)

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

TailOin haloeneamine (XIII) in case of 2-25; haloacetaldehydeM, XCH 2 CHO, wherein 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

Br and pH are preferably included in a solution of a weak base, for example sodium acetate or sodium hydrogen carbonate. 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. A water-miscible co-solvent is also preferably 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 using any desired route. In the case of the preferred 2-bromoacetal dehyde, examples of the preparation methods include hydrolysis of 2-bromoacetaldehyde (lower alkyl) acetal, (lower 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) (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, a compound of formula (XVI) is dissolved in an aprotic polar solvent and added to any solution slowly (i.e., 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 Br and 15 to 30 ° C with X being Cl, the strong base being lithium di (isopropyl) amine- ----- - · τ ~ 92488 16 ni . Compound (XII) can be isolated from solution by incineration of the solvent and purification of the residue in an organic chemically conventional solvent, such as the more conventional hydrolyzate directly with dicarboxylic acid (XII, R = 5 H), which can be carried out comprehensively from the cyclization process.

The dicarboxylic acid (XII, R = H) can be obtained by hydrolyzing the corresponding diester (XII, R = lower alkyl-11) with conventional chemical chelating agents, i.e. by reacting it with a strong base to polystersse the ester groups and treat the product with acid to form the dicarboxylic acid. The diester is relied upon in an aqueous solution of an alkali metal hydroxide tal carbonate, for example sodium hydroxide solution, which also contains a water-miscible co-solvent, for example methanol, at a temperature of about 0.5 ° C and the boiling point of the solvent at room temperature. 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 from conventional cologne, especially by recrystallization from an 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 can be added to the solution and at least a portion of the aprotic polar solvent can be removed by distillation, and a strong base can be added directly to the resulting pyrrolopyrrolid diester solution, e.g., sodium hydroxide, and a portion of the solvent can be removed (if desired) and an aqueous strong acid solution added. , 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 being taken of the aqueous solution again.

The following examples illustrate the preparation of a compound of formula (XVI) according to the invention (Examples 1 to 3) and the process according to the invention (Examples 4 and 5) for use as a starting material in the process according to the invention. Examples of the preparation of a compound of formula (I) from a compound of formula (XII) are disclosed in Finnish patent application 880133 (corresponding Finnish patent 10 90344).

Article 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 in a room lamp (20 ° C) with stirring. to water (30 mL) and to the solution was added dimethyl 1,3-acetone dicarboxylate (10.0 g, 57 mmol). After 5-10 minutes, solid aqueous 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 (86% yield) 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 - · ---- - T- 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 pond meter, a water separator in a reflux condenser and a dropping funnel. funnel, dimethyl 1,3-acetonedicarboxylate (196.1 g, 1.13 mol) was charged and the flask was purged with nitrogen. The separator was quenched with dichloromethane and dichloromethane (800 mL) was added to the flask. Ethanolamine (68.8 g, 1.13 mol) was added via addition funnel-15 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.

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 a period of 3.75 hours as the lamp 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 an additional two hours and water (250 mL) was added. The organic phase was washed with liquid (4 x 500 ml) and brine with brine (250 ml) and dried over anhydrous magnesium sulphate. The solvents of the filtrate were evaporated on a rotary evaporator under reduced pressure at 50 ° C to give 310.0 g (93% yield) of dimethyl 3- (2-methane-92488 19 sulphonylethylamino) -2-pentenedioate. as red oil. If necessary, if desired, the mesyllenamyl can be purified in this lie and converted to the haloeneamine by the following methods used directly in false 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, 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 brine (3 x 250 mL) and brine with brine (150 mL) and dried over aqueous potassium carbonate for 15 minutes. Evaporation of the solvent on a rotary evaporator under reduced pressure (50 ° C) gave 128.4 g of pure crude dimethyl 3- (2-bromoethylamino) -2-pentenedioate as a yellow O-grain which was rapidly ground to a yellow solid. The crude material was purified by extraction into boiling hexane (5 x 750 mL) and recrystallized from hexane, and the portions were extracted from the vessel and recrystallized to give 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 for three days myOhemml showed a ratio of Z to E isomer of 4: 1. N3it & the two isomers were not separated.

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

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 pond gauge 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.

Sodium acetate (41.0 g, 500 mmol) was added to the 2-bromoacetaldehyde solution 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) was added. 2-Pentenedioate (20.0 g, 71 mmol) and a portion of 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 in a room lamp room for 20 hours, the solution of its fraction was cooled to 0 ° C and stirred in that lamp tube for one hour and then filtered through a coarse sinter. The precipitate was washed with cold water (400 ml) and cold cold isopropanol (150 ml) and dried to give 15.7 g (72% yield) of pure methyl N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrrole acetate. -30 lean as a golden brown 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 ammeter was added 2-bromoacetaldehyde diethyl acetate (11.92488 21 11a) (20.9 g, 106 mmol). Hydrogen bromic 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, cooled to room temperature and extracted with hexane (100 mL). solution of 2-bromoacetaldehyde.

The hydrolysis solution was added at 0 ° C over one hour to a slurry of 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 stand at room temperature for 1 hour and stirred for 20 minutes. The resulting slurry was cooled to 0 ° C and held at that temperature for 15 hours, after which it was filtered through a 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. LåmpOtila 92488 22

rose slightly and its fraction when 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 the solution of its fraction was diluted with water.

(100 ml), developing a slight temperature. The solvents were removed by distillation at atmospheric pressure (solvents were collected in a 240 ml vessel at 80 ° C) to give dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] -10 pyrrole-1.7 -dikarboksylaattiliuos. In this step, the diester can be isolated by adding the solution to a solution of water 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 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 its methanol was removed by distillation at atmospheric pressure, whereupon the temperature of the vessel rose to 97 ° C. . The solution partitioned into the vessel was cooled to 5 ° C and acidified with hydrochloric acid (12M, 18 mL, 216 mmol), resulting in an increase 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 that it contained 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. (well, 750 ml) and stirred. The addition lasted for four hours and the temperature was maintained at 23 to 27 eC. The resulting solution was stirred for 16 hours and then diluted with water (500 mL) over 10 minutes to give a stirred lamp. The solvents were incinerated in the burnt atmosphere of the atmosphere by distillation, during which the temperature was raised to 75 ° C. The solution in the flask was cooled to 50 ° C and sodium hydroxide (53.0 g, 1.33 mol) and methanol were added thereto, followed by distillation in atmospheric distillation, in which case the flask was raised to 95 ° C, whereupon a mixture was added. 370 ml lluottlmla. The solution was cooled to -3-0 ° C and acidified with hydrochloric acid (12M, 180 mL, 216 mmol), followed by an increase 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 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 contain 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-3H-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (0.70 g, 71.4% yield) was collected by filtration and dried.

Claims (2)

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 II and COOR (XII) Wherein L is each 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 lithium amine in an aprotic polar solvent, preferably tetrahydrofuran, and optionally hydrolyzing the resulting diester of formula (XII) to the corresponding dicarboxylic acid. II „92488 25 For the preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and di (algre al-5 kyl) estrar tarav, vilka har formuleln (XII) COOR ί jl COOR (XII) io 1_ vari vardera R sjålvstSndigt & r lagre alkyl eller vate, kannetecknat darav, att en forening med for-15 Black (XVI) COOR I 1 * C00R (XV1) 20 \ vari R ar lagre alkyl och X with Cl or Cl, cyclized with a solution of lithium amine and aprotic polystyrene-25, converted to tetrahydrofuran, and optionally hydrolysed with an ester of the formula (XII) to a dicarboxylic acid.