FI95242C - Process for the preparation of pyrrole derivative diesters and intermediates useful in the process - Google Patents

Description

x 95242

Process for the preparation of diesters of pyrrole derivatives and intermediates useful in the process

This invention relates to a new process for the preparation of diesters of pyrrole derivatives of the formula

(XVI) k C00R

^ jl ^^ COOR (XVI)

X

Wherein each R is independently lower alkyl and X is halogen, and compounds of formula (XHIa) useful as intermediates in this process

C00R

20 μl CO 2

(XHIa). Wherein each R is independently lower alkyl and X 'is halogen or -O-S (O) 2 CH3 (-O-mesyl).

The process according to the invention is characterized in that a) di (lower alkyl) -1,3-acetone dicarboxylate of the formula

C00R

^ L ^ COOR

Wherein R is as defined above, is treated in an aprotic 2 95242 solvent with HOCH 2 CH 2 NH 2 to form the hydroxyamine of formula (XIV)

COOR

5 Jl ^ COOR

HN (XIV)

OH

B) treating the hydroxynamine of formula (XIV) in an aprotic solvent with mesyl chloride and a base to form the mesylenamine of formula (XV)

COOR

15 \ COOR

OMs 20 wherein Ms is mesyl and R is as defined above; c) treating the mesylenamine of formula (XV) in an aprotic solvent with an alkali metal halide to give a compound of formula (XIII)

COOR

^^ yCOOR

HN (XIII) ^ -λ

X

Wherein R and X are as defined above, d) treating a compound of formula (XIII) in aqueous solution with 2-haloacetaldehyde XCH 2 CHO, wherein X is halogen.

95242 3

The diesters of pyrrole derivatives of formula (XVI) and intermediates of formula (XHIa) prepared according to the invention can be prepared from 1,2-dihydro-3H-pyrrolo (1,2-a] pyrrole-1,7-dicarboxylic acid 5 and its di (lower alkyl) esters of formula (XII)

COOR

<XII)

10 lJ

wherein each R is independently lower alkyl or hydrogen, as described in parent application 880133 of this application (corresponding FI patent 90344) and in division-separated application 912709 (corresponding FI patent 92488). As also disclosed in these applications, 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid of formula (XII) and its di (lower alkyl) esters are in turn useful as intermediates in the preparation of 5-Aroyl-1,2,4-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids, also known as 5-aroyl-1,2-dihydro-3H-pyrrolizinicarboxylic acids, having formula (I) c 7 - 25 ΑΓ-οΧ3 ^ εοοΗ (i>

S f_I

3 2 These acids and their pharmacologically acceptable salts and esters are useful as analgesic, anti-infective and antipyretic agents in mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds under clinical investigation are ketorolac, 5-35 benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrolyl-carboxylic acid, -95242 silicic acid (I, Ar = C6H5) and anirolak, p-anisoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid (I, Ar = p-CH 3 O-C 6 H 4), both of which are disclosed in U.S. Patent 4,089 969 (Muchowski et al.) · Other compounds in which the 5-aroyl substituents are substituted or unsubstituted benzoyl, furoyl, thienoyl or pyrroloyl groups and the 6-arms of the pyrrolopyrrole nucleus are optionally lower alkyl or halogen substituted and have their use substituted disclosed in a number of patents published 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, 4,505,927, 4,456,759, 4,353,829, 4,397,862, 4,457,941 and 15,454,151. U.S. Patent Nos. 4,511 724 and 4,536,512 to Merck & Co., Inc. disclose 5- (substituted pyrrol-2-yl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole. 1-carboxylic acid derivatives and 5- (1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-2-yl) -1,2-dihydro-3H-20-pyrrolo [1,2-a] pyrrole-1 carboxylic acid derivatives, respectively, while U.S. Patent 4,533,671, also assigned to Merck & Co., Inc., discloses 5- (1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-2-yl) -2-pyrrolalkanoic acids and their analogs.

v Examples of various methods for the preparation of these pyrrolopyrroles 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-30 [1,2-a] pyrrole-1,7-dicarboxylic acid. (II, R = H) or a dialkyl ester thereof

e 7 C00R

, γΥ 35 J) -C00R (II) 1 2 5 95242 The preparation of an intermediate 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.

Reaction scheme shown in that patent publication: CCOQCH, C00CH, γι hn 10 CH, * 0 \ L · <»> Λ, (III) j (v) C00CH, / 1 COOCH,» 0 ^ COOCH3 nCz-OCH, \ 4 - ^ N '^ (VII) V ^ (VI) OMs X.

x. OH

COOCH3 N * _COOCH3 [Tj ^ / C00CH3 --► ^ jj ^ COOCH,

N \ _ I_J

(VIII) '(II, R, CH 3) 25 contains a reaction (in equivalent molar amounts) between ethanolamine (III) and dimethyl-1,3-acetonodicarboxylate (IV) to form a solution of hydroxynamine (V), which compound is then treated , preferably in 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- 95242

O

diethyl) pyrrole (VIII) by reaction with sodium iodide. Either compounds (VII) and (VIII) can be converted to dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate (II, R ® CH 3) 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 to the pa 5 position, an aroyl group can be attached, for example, by the methods described above in said patents and U.S. Pat. No. 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) -15 alkyl ketone bypasses hydroxysamine (V) and directly yields the 4-alkyl analog of compound (VI). This compound can be converted to pyrrolopyrrole in the same manner as the previously substituted 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 preparing 5-aroyl-NR-pyrrole-2-acetic acid wherein R is 25 H, lower alkyl or benzyl, and analogs thereof. . 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, 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 ice-cold hydrochloric acid to give compounds of formula (IX) 7-95242 R 'COOR "I and COOR" (IX)

5 I

R

wherein the click on R, R 'and R "is lower alkyl. A similar process using chloroacetaldehyde for the preparation of 4-unsubstituted compounds (IX, R' * H) is disclosed in U.S. Patent 4,048,191 (Carson).

GB Patent 2,034,304 A, filed by Mallinckrodt, Inc., discloses a process for the preparation of compounds of formula (IX) wherein R 'is hydrogen or alkyl by either (a) forming an alkylamine 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 an excess of the dicarboxylate and a ketone used simultaneously to the aqueous alkylamine. Preferably, the dicarboxylate and the excess ketone used are added to the alkylamine dispersion.

Other variations of Carson's syntheses have been disclosed in a number of patent publications owned by Ethyl Corporation, including 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 4,565,878,30 discloses that a water-immiscible cosolvent [a halogenated hydrocarbon which dissolves well and di- (lower alkyl) -1] is added to a mixture of chloromethyl (lower alkyl) ketone, dicarboxylate and lower alkylamine containing water. , 3-acetonodicarboxylate that I produce]. U.S. Patent 4,565,879 discloses aro-. S5242 use of a terrestrial hydrocarbon as a co-solvent. U.S. Patent No. 4,374,255 discloses the addition of an "anti-solids amount of a lower alkanol" to a mixture of a ketone, a dicarboxylate and an aqueous alkylamine. The reaction is usually carried out in the presence of a co-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 in a solvent (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 then heated to 70-100 ° C. U.S. Patent No. 4,383,117 discloses the use of an anhydrous lower alkylamine instead of an aqueous solution and the use of a single phase 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 No. 4,333,878 discloses the synthesis of compounds of formula (IX) by reacting enamine 25 (X) with 2-carboxy-1-nitroalkane (XI, R '= lower alkyl, tolyl or benzyl).

C00R "R * C00 ί ^ .CHCH NO, jl C00R" / * z 30 «'R (X) (XI)

The enamine can be prepared by reacting the di (lower alkyl) -35 1,3-acetonecarboxylate with the lower alkylamine 95242 "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.

5 Albert et al. have disclosed in U.S. Patent No. 4,363,918 for the synthesis of compounds of formula (IX) wherein R is lower alkyl, R 'is hydrogen or lower alkyl and R "is hydrogen, wherein 1,3-acetonedicarboxylic acid is administered react with ClCH 2 COR and the lower alkyl-10-amine, preferably by slowly adding an aqueous solution of the lower alkylamine to the aqueous acid solution and then slowly adding 1-chloro-2-alkanone, with both additions preferably taking place 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) in which R is CH 3, R "is H and R 'is ch 3 (EP-A-92 487) or H (EP Application Publication 105,664), prepared by reacting 1,3-acetonide-20 carboxylic acid or an alkali metal salt thereof with methylamine or a haloketone (or aldehyde) in aqueous solution, preferably by adding a haloketone to an aqueous mixture of methylamine and dicarboxylic acid.

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 and intermediates of this invention allow the use of aqueous solvents to a much greater extent and the process can be easily applied on a production scale. With it . better yields than previous methods are also obtained in the overall synthesis of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylates of formula (XII).

The process of the invention is included in the preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylates from di (lower alkyl) -1,3-acetonedicarboxylates. This preparation can be illustrated by the following Reaction Scheme A, in which the process of the invention comprises the reaction steps di (lower alkyl) -1,3-acetonodicarboxylate - * 5 (XIV) - * (XV) - (XIII) - (XVI).

Reaction Scheme A

X00R COOR

10 ί .COOR - ^ * ihe 1-► f. C00R

Option II

0 HN

\ _ (XIV)

Step 1 OH

Option I

1 1 15 *

^ COOR COOR

(XIII) Jl ^ COOR I ^ COOR

HN 4- h / Y_ ^ \ _ ^ (xv)

20, X ÖMS

Step 2 25

'*' COOR

/ COOR

fj / COOR fY rn \ wA ^^ C00R (xii)

ίχνη I_ 1_J

30 \ 11 95242 wherein R and X are as defined above and Ms is mesyl. Compounds of formula (XHIa) useful as intermediates in the invention include those represented by formulas (XV) and (XIII) in Reaction Scheme A.

5 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, even if 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, cyclo, 15 equivalent. 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 indicated in Erik-20.

"Lower alkoxide", "lower alkanol", "lower alkylamine", "lower alkyl ester" and the like refer to alkoxides, alkanols, alkylamines, alkyl esters, etc., wherein (each) alkyl group 25 is as defined above. " lower alkyl ".

"Halogen" 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- * · hydrofuran, dimethoxyethane, bis (2-methoxyethyl) ether. (also known as diglyme), dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. Solvent 35 may also contain small amounts of aprotic non-polar solvents such as hydrocarbons, for example cyclohexane, toluene and the like, provided that the properties of the solvent are largely determined. according to the polar solvent.

"Weak base" means an early metal or alkaline earth metal salt of a weak acid, for example, sodium acetate, potassium hydrogen carbonate, and 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 (isopropyl) amine, 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.

"Aryl" or "Ar" means a substituted or unsubstituted monovalent unsaturated group, for example 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 alkoxyl or halogen substituents at position 30. Preferred groups are phenyl and p-methoxyphenyl.

"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.

Starting materials and cleaning

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

The starting materials and intermediates corresponding to formulas (XIII) and (XIV) may be isolated, if desired, by conventional procedures including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These substances can be characterized by conventional means, including physical 20 Constants and spectral data.

Preparation of compounds of formula (XIII)

In Step 1, a di (lower alkyl) -3- (2-haloethylamino) -2-pentenedioate ["haloamine" of formula (XIII)] is prepared from a di (lower alkyl) -1,3-acetone dicarboxylate according to the invention by administering it react with 2-hydroxyethylamine (2-aminoethanol), after which the hydroxyl group is replaced by halogen. It can also be prepared by reacting di (lower alkyl) -1,3-acetonecarboxylate directly with 2-haloethyl-30-amine hydrohalide.

In the process of the invention (Reaction Scheme A, Step 1, Option II), the di (lower alkyl) 1,3-acetonodicarboxylate is first treated with 2-hydroxyethylamine (2-aminoethanol) in an aprotic polar solvent to provide hydroxynamine (XIV). , which compound is then converted to the haloenamine (XIII) via mesylenamine (XV). 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 hydroxynamine can be formed under less restrictive conditions (see, e.g., U.S. Patent 4,089,969), an anhydrous hydroxysamine solution is required for the next reaction, and it is therefore appropriate to 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. The preferred R group is methyl. One preferred solvent 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, at a temperature between sa. It is convenient to add the tertiary amine to the solution from the previous reaction cooled to the appropriate temperature, and mesyl chloride is added slowly to the resulting solution 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 the E and Z isomers of mesylenamine (XV), which can be used in the next reaction for further purification.

The mesylenamine (XV) is converted to the corresponding halogenamine (XIII) by reacting it with an anhydrous alkali metal chloride, preferably bromide, for example lithium bromide or the like, in an aprotic polar solvent at about room temperature and a boiling point of the solvent between 95242 mp, for example about 30-100 ° C. at a temperature of 1 to 30 hours, for example 5 to 20 hours, depending on the reaction time and the reaction temperature. The haloenamine (XIII) can be easily isolated by adding water to the reaction mixture, washing the organic phase and removing the solvent to give a mixture of the E and z isomers of the haloamine, which may be appropriate to purify by recrystallization.

Alternatively, the halo-enamine of formula (XIII) can be prepared according to Step 1, Option I of Scheme A, wherein the di (lower alkyl) -1,3-acetonedicarboxylate is treated with 2-haloethylamine hydrohalide in aqueous solution. The pH of the solution is preferably 5-12, more preferably 5-8. The pH is usually adjusted by using an aqueous solution of a weak base such as sodium acetate as the solvent in the reaction, but other methods for adjusting the pH may be used if desired. The reactants may be added simultaneously or sequentially as desired, but it is not desirable to add the 2-haloethylamine hydrohalide to the basic solution unless the solution already contains acetone dicarboxylate to avoid the formation of aziridines. 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 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 resulting di (lower alkyl) -3- (2-haloethylamino) -2-pentenedioate (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.

95242 BC

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, the haloeneamine (XIII) is treated with 2-haloacetaldehyde, XCH 2 CHO, where X is as defined above. The process is preferably carried out in aqueous solution at pH 4.5 to 10, 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 1 to 48 hours, preferably 6 to 24 hours. X is preferably Br and the pH adjustment 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.

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) pyrrole (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) (1,2-dibromoethyl) ether, 1,2-dibromoethyl acetate, etc. with an acid, of which each hydrolysis results in an aqueous solution of 2-bromoacetaldehyde to which a weak base can be added.

Examples of the use of compounds of formula (XVI) and compounds of formula (XHIa) obtained by the process of the invention in the preparation of compounds of formula (XII) and formula (I) are disclosed in parent application 880133 (corresponding FI-35 patent 90344) and in a separate application 912709 (corresponding FI patent 92488).

17 95242

The invention is further illustrated by the following examples, in which Example 1 shows the above-mentioned alternative process for the preparation of intermediates of formula (XIII) and Examples 2 and 3 illustrate the process according to the invention for the preparation of compounds of formula (XVI).

Example 1

Preparation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate (XIII) (Step 1 - Option I) 10 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-acetonedicarboxylate (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 0-20 ° C for 30 minutes, filtered and the precipitate was washed with cold (0-5 eC) water (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 (1H, broad singlet); 4.60 (1H, singlet); 3.85 (3H, singlet); 3.77 (3H, singlet); 3.35 - 3.72 (4H, broad multiplet); 3.25 (2H, singlet).

B. Substitution of 2-bromoethylamine hydrobromide with 2-chloroethylamine hydrochloride (7.0 g, 60 mmol) in the process of Part A of this Example afforded 10.8 g (80% yield) of dimethyl-3- (2-chloroethylamino) -2- pentene dioate as a white solid, m.p. 75-76 ° C. NMR (CDCl 3) δ: 8.80 (1H, broad singlet); 4.60 (1H, singlet); 3.75 (3H, singlet); 3.65 (3H, singlet); 3.60 (4H, multiplet); 3.27 (2H, singlet).

18 95242

Example 2

Preparation of dimethyl 3- (2-bromoethylamino) -2-pentenedioate (XIII) (Step 1 - Option II) A. Return to a 3-necked 3-liter flask containing 5 stirring rods equipped with a thermometer, a water separator in a condenser and a dropping funnel , dimethyl 1,3-acetonedicarboxylate (196.1 g, 1.13 mol) was added and the flask was then purged with nitrogen. The separator was filled with dichloromethane and dichloromethane (800 ml) was added to the flask. Ethanolamine (68.8 g, 1.13 mol) was added via addition funnel over 10 minutes and the mixture was heated 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 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 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-methanesulfonylethylamino) -2-pentenedioate as a red oil. The methylenamine thus obtained can be purified and converted to a halogenamine by the following method.

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) ** · 20 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 solution three days later showed a ratio of Z to E isomer of 4: 1. The two isomers were not separated.

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

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

20 95242

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.

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) -2-pentenedioate was added. (20.0 g, 71 mmol) followed by isopropanol (40 mL) and a solution 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. 25 sa one hour and then it was filtered through a 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 ° C. 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 (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 5 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 15 was cooled to 0 ° C and maintained 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-pyrroleacetate as white crystals, mp 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).

Claims (9)

22 9E242 A process for the preparation of a compound of formula (XVI) COOR gCco ° R <xvi> 10 x wherein each R is independently lower alkyl and X is halogen, characterized in that a) di (lower alkyl) -1,3-acetone dicarboxylate , wherein R is as defined above, is treated with HOCH 2 CH 2 NH 2 in an aprotic solvent to form a hydroxyamine of formula (XIV) CO 2 R 2 COOR. B) treating a hydroxynamine of formula (XIV) in an aprotic solvent with mesyl chloride and a base to form mesylenamine of formula (XV) <imin min i, it st ΟκΟ / o 23> v> L · COOR \ COOR Hhl "'(XV) S OMs wherein Ms is mesyl and R is as defined above; c) mesylienamine of formula (XV) is treated in an aprotic solvent with an alkali metal halide to form a compound of formula (XIII) COOR V (yC00R 15 (XIII) x .. where R and X are as defined above, d) The compound of formula (XIII) is treated in aqueous solution with 2-haloacetaldehyde XCH2CHO, where X is halogen. Process according to Claim 1, characterized in that each R is CH 3 and X is Br 25 or Cl. Process according to Claim 2, characterized in that X is Br and 2-bromoacetaldehyde is prepared by hydrolysis of its di (lower alkyl) acetal with acid. 4. A compound of formula (XHIa); · COOR ^ i ^^ COOR HN (XHIa) 35 V — Λ X '24 S5242 wherein each R is independently lower alkyl and X' is halogen or -O-S (O) 2 CH3 (-O-mesyl). A compound according to claim 4, characterized in that each R is CH 3. Compound according to Claim 5, characterized in that X 'is Cl or Br. A compound according to claim 4, characterized in that each R is CH 3 and X 'is Cl. A compound according to claim 4, characterized in that each R is CH 3 and X 'is -O-mesyl. 1 I IU 1 Ulf) I 1 i SEt - 4 »· · 25 95242