3-(2-haloethylamino)pentenedioic acid esters and their use as intermediates for preparing 3-carboxy-1-(2-haloethyl)-1h-2-pyrrole-acetic acid diesters

This PDF First Page has been artificially created from the Israelian Abstracts

אסטריס של חומצות 3־(2-הלואתילאמינו) פנטנדיואיות והשימוש בהם כתרכבות ביניים להכנת דיאסטריס של חומצות 3-קרבוקס<-1(2-הלואת<ל)-}2-11-פירולאצטי ות

3-(2-Haloethylamino) pentenedioic acid esters and their use as intermediates for preparing 3-carboxy-l-(2-haloethyl) -ΙΗ-2-pyrroleacetic acid diesters

SYNTEX (U.S.A.) INC.,

C: 82063 a BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to 3-(2-substituted ethylamino)-2-pentenedioic acid esters, to their preparation and to their use as intermediates for preparing 3-carboxy-1(2-haloethyl)-lH-2-pyrroleacetic acid diesters which, in turn are intermediates in the synthesis of l,2-dihydro-3Hpyrrolo[l,2-a]pyrrole-l,7-dicarboxylic acid and its dialkyl esters.

The present application was divided out of Israel Patent Application No. 85094.

Sackground to the Invention

5-Aroyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-lcarboxylic acids, also known as 5-aroyl-l,2-dihydro-3H96389/2 pyrrolizine-l-carboxylic acids, of formula I, and the

7

<img file="IL96389A_D0001.tif" />

(I) pnarmacologically acceptable salts and esters thereof, are useful as analgesic, anti-inflammatory, and anti-pyretic agents for mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds under clinical study in man are ketorolac, 5-benzoyl-

1.2- d!hydro-3H-pyrrolo[1,2-a ]pyrrole-l-carboxy lie acid , (I, Ar - C.HL), and anirolac, 5-jo-anisoyl-

כ ס

1.2- dihydro-3H-p.y rrolo[ 1,2-a ]pyrrole-l-car boxy lie acid , (I, Ar = 2_-CH₃Q-C₆H₅), both disclosed in. U.S.

Patent No. 4,089,969 to Muchowski et a 1 (corresponding to Israel

Patent 52493). Other compounds, where the 5-aroyl substituents are substiy/ tuted or unsubstituted benzoyl, furoyl, thenoyl, and pyrrol, and where the 6-position on the pyrrolo-pyrrole nucleus is optionally substituted by lower alkyl or halogen, and uses thereof, are also disclosed in a series of patents assigned to Syntex (U.S.A.) Inc., beginning with U.S.

Patent No. 4,089,969 (corresponding to Israel Patent 52493), and including U.S. Patents Nos. 4,087,539 (corresponding to Israel Patent 52492); 4,097,579; 4,140,698 (corresponding to Israel Patent 55181); 4,232,038; 4,344,943 (corresponding to Israel Patent 63047); 4,347,186; 4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759; 4,353,829 (corresponding to Israel Patent 64329); 4,397,862;

4,457,941; and 4,454,151. U.S. Patents Nos. 4,511,724 and

4,536,512, assigned to Merck &amp; Co., Inc., disclose 5-(substituted pyrrol-2-oy1)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid derivatives and 5-(1,2-dihydro-3H_-py rrolo[ 1,2-a ]pyrrol-2-oyl )-1,2-dihydro3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid derivatives, respectively; while U.S. Patent No. 4,533,671, also assigned to Merck &amp; Co., Inc., discloses

5-(1,2-di hy dr 0-3IH-py rrolo[ 1,2-a]pyrrol-2-oyl )-2-pyrrolealkanoic acids and analogs.

Various methods for the preparation of these pyrrolo-pyrroles are exemplified in the patent and chemical literature, and many proceed through a common intermediate, 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7dicarbaxylic acid, (II, R = H), or its dialkyl ester;

₆ 7 COOR .COOR (II)

J the preparation of which from dimethyl 1,3-acetonedicarboxylate, ethanolamine, and a haloacetaldehyde is disclosed in, for example, U.S. Patent No. 4,089,969, 20 which is incorporated herein by reference.

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The reaction scheme set forth in that patent:

₂ק ch₂

CH₂Jh

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<img file="IL96389A_D0003.tif" />

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<img file="IL96389A_D0005.tif" />

includes the reaction of equimolar amounts of ethanolamine (III) and dimethyl 1,3-acetonedicarboxylate (IV) to form a solution of the hydroxyenamine (V), which is then treated, preferably in situ, in a suitable organic solvent (aprotic solvents such as acetonitrile, dichloromethane, etc. are exemplified), under anhydrous conditions, with a 2-haloacetaldehyde at elevated temperatures to produce the N-(2-l1־ydroxyethyl)pyrrole (VI). Compound (VI) is esterified with methanesulfonyl chloride to produce the mesylate .(VII), which is optionally converted to the N-(2-iodoethyl)pyrrole (VIII)

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25880/25890-FF by reaction with sodium iodide. Either of compounds (VII) and (VIII) may be converted to dimethyl

1.2- dihydro-3H-pyrr010[1,2-a]pyrrole-1,7-dicarboxylate (II, R = CH ) by treatment with sodium hydride in

^כ 5 dimethylformamide. The thus-formed dimethyl

1.2- dihydro-3H-pyrrolo[1, 2-a ]-pyrrole-1,7-dicarboxylate may then be selectively 7-decarboxylated and 5-aroylated, by methods such as those described in the previously-cited patents and in U.S. Patent No. 4,496,741 θ to Doherty, to yield a 5-aroyl-l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-l-carboxylic acid (I). A similar process, involving the reaction of ethanolamine, dimethyl

1.3- acetonedicarboxylate, and a halomethyl alkyl ketone, bypasses the hydroxyenamine (V) and produces the 4-alkyl

IE analog of (VI) directly. That compound may be converted to the pyrrolo-pyrrole in the same manner as for the

4-unsubstituted compound previously described.

Various methods for the preparation of pyrroles are exemplified in the patent and chemical literature.

Processes for the preparation of 5-aroyl-N-R-pyrrole-

2-acetic acid, where R is H, lower alkyl, or benzyl, and analogous compounds are disclosed in U.S. Patents Nos. 3,752,826; 3,865,840; and 3,952,012 to Carson. They include, for the 4-alkyl substituted but not for the

4-unsubstituted compounds, the reaction between a lower alkylamine, a diQower alkyl) 1,3-acetonedicarboxylate, and a chloromethyl lower alkyl ketone, preferably in an aqueous medium, followed by pouring into ice-cold hydrochloric acid, to produce compounds of

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25880/25890-FF —6 formula (IX), where each of R, R' , and R is lower alkyl.

R' COOR \_____/ ן COOR (IX)

R

A similar process for the 4-unsubstituted compounds (IX, R' = H) using chloroacetaldehyde is disclosed in U.S. Patent No. 4,048,191 to Carson.

U.K. Published Application No. 2 034 304 A, assigned to Mallinckrodt, Inc., discloses a process for the preparation of compounds of formula (IX), wherein R’ may be hydrogen or alkyl, by either (a) forming a two-phase reaction medium of an aqueous solution of the alkylamine and an inert, water-immiscible organic solvent, and adding the dicarboxylate and ketone (or aldehyde) substantially simultaneously, or (b) adding the dicarboxylate and ketone substantially simultaneously, with the ketone in excess, to an aqueous alkylamine. Preferably, dicarboxylate and excess ketone are added to an alkylamine dispersion.

A number of patents assigned to Ethyl Corporation, including U.S. Patents Nos. 4,565,878; 4,565,879; 4,374,255; 4,388,468; 4,383,117; 4,455,433; and 4,333,878, disclose other modifications of the Carson syntheses. U.S. Patent No. 4,565,878 discloses the addition of a water-immiscible co-solvent [a halogenated hydrocarbon of good solubility for both the didower alkyl) 1,3-acetonedicarboxylate and the product] to the mixture of chloromethyl lower alkyl ketone, dicarboxylate, and aqueous lower alkylamine. U.S. Patent No. 4,565,789 discloses the use of an aromatic

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25880/25890-FF hydrocarbon as the co-solvent. U.S. Patent No. 4,374,255 discloses tne addition of a solids formation inhibiting amount of a lower alkanol to the ketone/dicarOoxylate/aqueous alkylamine mixture. The reaction is normally carried out in the presence of a co-solvent as in U.S. Patents Nos. 4,565,878 or 4,565,879. U.S. Patent No. 4,388,468 discloses a two-stage process in which (a) the ketone is added to a pre-mixed cooled solution of tne alkylamine and the dicarboxylate in a suitable solvent (e.g. aromatic hydrocarbons, chlorinated hydrocarbons, water, or mixtures thereof) at a temperature less than 60°C, followed by (b) heating the reaction mixture 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-pnase non-aqueous reaction medium. U.S. Patent No. 4,455,433 discloses the addition of a yield-enhancing amount of an acid having a dissociation constant of at least 1.3 x 10”^ _at 25°C to a ketone/dicarboxylate/(preferably anhydrous) lower alkylamine mixture, preferably in an organic solvent. U.S. Patent No. 4,333,878 discloses the synthesis of compounds of formula (IX) by the reaction of an enamine (X)

<img file="IL96389A_D0006.tif" />

R*COO_x^X.CHCH N0₂

R’ (XI) with a 2-carboxy-l-nitroalkane (XI, R* = lower alkyl, tolyl, or benzyl). The enamine may be prepared by the reaction of a didower alkyl) 1,3-acetonedicarboxylate with a lower alkylamine in a suitable solvent, such as ethanol or methanol, followed by

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25880/25890-FF evaporation or the solvent and heating to dehydrate the thus-formed carbinolamine to tne corresponding enamine.

Albert et al., in U.S. Patent No. 4,363,918, disclose the synthesis of compounds of formula IX where R is lower alkyl, R’ is hydrogen or lower alkyl, and R is H 0y the reaction of 1., 3-acetonedicarboxylic acid with C1CH₂COR and a lower alkylamine, preferably by the slow addition of an aqueous solution of the lower alkylamine to an aqueous solution of the acid, followed by slow addition of the l-chloro-2-alkanone, with both additions preferably occurring below 20°C or lower.

European Published Applications Nos. 92 487 and 105 664, assigned to Montedison S.p.A., disclose the preparation of compounds of formula IX wherein R is CH^ and R is H, and R' is CH^ (EP92487) or Η (EP105664) Py the reaction of 1,3-acetonedicarboxylic acid or an alkali metal salt thereof with methylamine and a halo(ketone or aldehyde) in aqueous solution, preferably by adding the haloketone to an aqueous mixture of the methylamine and the dicarboxylic acid.

The known processes for the preparation of pyrrolo pyrroles require high volumes of organic solvents, tend to produce tars, and are difficult to scale up to production quantities. We have now discovered a process for the preparation of pyrrolo pyrroles which uses aqueous solvents to a much greater extent than the previous known reactions and can be readily used for production scale quantities.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to the preparation of 3-carboxy-1 - (2-haloethyl)-־I H-2-pyrroleacetic acid diesters of formula (XVI).

<img file="IL96389A_D0007.tif" />

(XVI) in which each R is independently H, lower alkyl, _or cyclo:hlkyl; and X is halogen; from di(lower alkyl) 1,3-acetone dicarboxylates .

The preparation may de represented schematically:

<img file="IL96389A_D0008.tif" />

Step 1

Alternate II

Step 1 Alternate I

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Step 2 Alternate I

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Step 3 Alternate I in which

R is as previously defined;

Ms is mesyl; and

X is halogen.

In a second aspect, this invention relates to novel compounds of formulae (XIII) and (XV) which are useful as intermediates in the process herein.

In another aspect, this invention relates to a process for preparing compounds of formulae (XIII) and (XVI).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

lower alkyl, denoted generally by R refers to straight or branched: saturated hydrocarbon radicals having from one to six carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl,. pentyl,_ hexyl and the like. Preferred lower alkyls are methyl, ethyl, and [[-propyl, and a particularly preferred lower alkyl is methyl. If more than one alkyl radical is present in a given molecule, each may be independently selected from lower alkyl unless .otherwise stated.

lower alkoxide, lower alkanol, lower alkylamine, lower alkyl ester, and similar terms refer to alkoxides, alkanols, alkylamines, alkyl esters, etc. in which the (or each) alkyl radical is a lower alkyl as defined above.

halogen, denoted generally by X, refers to chlorine, bromine, or iodine. ־ Preferred halogens are chlorine and bromine.

aprotic polar solvent includes organic solvents which may be either water-immiscible, such as halogenated hydrocarbons, e.g. methylene chloride, chloroform, etc., or water-miscible, such as tetrahydrofuran, dimethoxyethane, bis(2-methoxyethyl) ether (also known as diglyme), dimethylformamide, N_-methy!pyrrolidone , □ imethy!sulfoxide, etc. The solvent may also contain minor proportions of aprotic non-polar solvents such as hydrocarbons, e.g. cyclohexane, toluene, and tne like, provided that the solvent properties are largely determined by the polar solvent.

weak base refers to the alkali metal or alkaline earth salt of a weak acid, e.g. sodium acetate, potassium bicarbonate, etc., or to a buffer mixture (such as NaH₂P0_a/Na₂HP0_a) giving a similar pH.

¹ '^,strong base refers to bases such as alkali metal hydroxides, lower alkoxides, hindered amines such as didower alkyDamines and bis(tri lower alkylsilyl) amines, hydrides, and the like, which contain alkali metals including lithium, sodium, potassium, rubidium, ³ and cesium, e.g. sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, sodium hydride, lithium di(isopropyl)amide, lithium bis(trimethylsilyl)amide, etc.

mesyl or mesylate, denoted by Ms, refers θ particularly to methanesulfonyl, but includes other equivalent alkyl- or arylsulfonyls, such as ethanesulfonyl, benzenesulfonyl, £-toluenesulfonyl, and the like. ' ־ aryl or Ar refers to a substituted or ⁵־ unsubstituted monovalent unsaturated radical, for example, phenyl, 2- or 3- furyl, 2- or 3-thienyl, or 2or 3-pyrryl, which, if substituted, can have one or more lower alkyl, lower alkoxy, or halo groups in any available position on the ring. Phenyl and ³⁰ p-methoxyphenyl are preferred.

water-miscible co-solvent includes lower alkanols, didower alkyl) ketones, tetrahydrofuran, dioxane, sulfolane, dimethylformamide, and the like. Preferred co-solvents are methanol, acetone, and similar or ³5 C₂ alkyl alcohols and ketones.

Starting Materials and Purification

Dimetnyl 1,3-acetonedicarboxylace is commercially availaole (Aldricn), as is 1,3-acetonedicardoxyiic acid, also known as 3-oxopentanedioic acid. Other di(10wer &lt;־ alkyl) 1,3-acetonedicarboxylates may readily be prepared from either tne dimethyl ester or, preferably, the diacid, Py esterification techniques well-known to the art. However, there is no particular advantage in varying the alkyl groups, so that the dimethyl ester (R = CH_?) is preferred.

The starting materials and the intermediates of formulae (XIII), (XIV), (XV), and (XVI) may be isolated, if desired, using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means,including physical constants and spectral data.

Preparation of Compounds of Formula XIII_

In Step 1, a didower alkyl) 3-(2-haloethylamino) -

2-pentenedioate (haloenamine) is prepared from a didower alkyl) 1,3-acetonedicarboxylate, either by direct reaction with a 2-haloethylaroine hydrohalide salt, or by reaction with 2-hydroxyethylamine (2-aminoethanol) followed by replacement of the hydroxy group by a halide.

In Step 1, Alternate I (which is preferred), the didower alkyl) 1,3-acetonedicarboxylate is treated with a 2-haloethylamine hydrohalide salt in aqueous solution. The solution preferably has a pH between 5 and 12, more preferably between 5 and 8. Typically, the pH is controlled by employing an aqueous solution of a weak base, such as sodium acetate, as the reaction solvent, but other pH control methods may be employed, if desired. The reactants may be added simultaneously or consecutively, as desired, but it is desirable that the

2-haloethylamine hydrohalide not be placed in basic solution unless that solution already contains the acetonedicarboxylate, to avoid the formation of

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25880/25890-FF aziridines. Typically, ths 2-haloethylamins hydrohalide ana acetonedicarboxylate are dissolved, either simultaneously or in the order stated, in water, and a solid weak base added to produce the reaction mixture. The reaction is preferably conducted at a temperature between 0 and 35°C, more preferably at about room temperature, i.e. between about 20 and 30°0; over a time preferaoly between about 15 minutes and 24 hours, more preferably oetween about 4 and 18 hours. Tne intermediate diQower alkyl) 3-(2-haloethylaiT1ino)-2pentenedioate (haloenamine) typically crystallizes and may be isolated by filtration, as a mixture of the E and Z_ isomers. Each R is preferably methyl, X is preferably Br ar 01, and sodium acetate is preferably used to control pH.

In Step 1, Alternate II, the didower alkyl)

1,3-acetone-dicarooxylate is treated with

2-hydroxyethy!amine (2-aminoethanol) in an aprotic polar solvent to produce the hydroxyenamine (XIV), which is then converted to the haloenamine (XIII) via the mesylenamine (XV). Typically the dicarboxylate is dissolved in the solvent, the 2-hydroxyethylamine is added slowly to the resulting solution, and the water formed during the reaction is removed by azeotropic distillation. While the hydroxyenamine may be formed.under less stringent conditions (see, e.g., U.S. Patent No. 4,089,969), an anhydrous solution of the hydroxyenamine is required for the next reaction, and it is therefore convenient to carry out the formation of the hydroxyenamine in an aprotic medium. The resulting solution contains a mixture of the E and Z_ isomers of the hyaroxyenamine, and may de used without purification in the next step. As in

Step 1, Alternate I, a preferred R is methyl. A preferred solvent is dichloromethane.

Esterification of the hydroxyenamine (XIV) with mesyl chloride in the presence of an organic Oase such as a tertiary amine, optionally in the presence of an aprotic polar solvent, takes place at a temperature between about -10°C and room temperature, preferably oetween about 0 and 10°C. Conveniently, the tertiary amine is added to the solution from the previous reaction, which has been cooled to the appropriate temperature, and the mesyl chloride is added slowly to the resulting solution over a period between about 30 minutes and 10 hours, typically about 2 to 5 hours. The solution of the resulting mesylenamine (XV) is quenched with water, and solvent removed from the organic phase to afford a mixture of the E and Z isomers of the mesylenamine (XV), which may be used without further purification in the next reaction.

The mesylenamine (XV) is converted into the corresponding haloenamine (XIII) by reaction with an anhydrous alkali halide, preferably a bromide or iodide, e.g. sodium iodide, lithium bromide, etc., in an aprotic polar solvent at a temperature between about room temperature and the reflux temperature of the solvent, e.g. between about 30 and 100°C, for 1 to 30 hours, e.g. between 5 and 20 hours, the period depending on the reagents and reaction temperature. The haloenamine (XIII) may be readily isolated by adding water to the reaction mixture, washing the organic phase, and removing the solvent to afford a mixture of the E and Z isomers of the haloenamine, which may conveniently be purified by recrystallization.

Preparation of Compounds of Formula XVI

In Step 2 (Alternate I), the haloenamine (XIII) is treated with a 2-haloacetaldehyde, XCH^CHO, wherein X is as defined above. The process is preferably conducted in aqueous solution at a pH between 4.5 and 10, preferaoly between 5 and 8.5. The reaction is preferably carried out between 0 and 65°C, more preferably at about room temperature, for from about 1 to 48 hours, preferably between 6 and 24 hours. X is preferably Br, and pH control is preferably achieved by the presence of a weak base, e.g. sodium acetate or sodium bicarbonate, in tne solution. The process is preferably conducted in the presence of 10 to 50 volume percent of a water-miscible co-solvent, such as acetone.

To an aqueous solution of a weak base and the 2-haloacetaldehyde is added the haloenamine (XIII). A water-miscible co-solvent is preferably also added. The mixture is stirred for the appropriate time, and the N-(2-haloethyl)-pyrrole (XVI) is isolated by filtration. The 2-haloacetaldehyde may be obtained commercially or prepared by any desired route. In the case of the preferred 2-bromoacetaldehyde, exemplary preparative methods include the acid hydrolysis of a 2-bromoacetaldehyde didower alkyl) acetal, a lower alkyl

1,2-dibromoethyl ether, 1,2-dibromoethyl acetate, etc., each of which results in an aqueous solution of 2-bromoacetaldehyde, to which may be added the weak base.

EXAMPLES

The following Examples illustrate this invention, but are not intended to limit its scope.

Example 1: Preparation of dimethyl 3-(2-bromoethylamino)2-pentenedioate. (Step 1 - Alternate I)

A. 2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved in water (30 mL) at room temperature (20°C) with stirring, and dimethyl

1,3-acetonedicarboxylate (10.0 g, 57 mmol) was added. After 5 to 10־ minutes , solid anhydrous sodium acetate (14.35 g, 175 mmol) was added, and stirring continued. After approximately 80 minutes, precipitation of dimethyl

9

־/^־

3-(2-bromoethylamino)-2-pentenedioate began, and the solution was stirred for 17 hours at room temperature.

The thick slurry was diluted with cola water (20 mL), and aged at 0 to 5°C for 30 minutes and filtered, and the precipitate washed with cold (0 to 5°0) water (50 mL) and dried to constant weight, to afford 13.9 g (86% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as a white solid, m.p. 71 - 72°C, NMR (CDC1 ): &lt;$: 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. Substituting 2-chloroethylamine hydrochloride (7.0 g, 60 mmol) for the 2-bromoethylamine hydrobromide in the procedure of part A of this Example, there was obtained 10.8 g (80% yield) of dimethyl 3-(2-chloroethylamino)-2-pentenedioate as a white solid, m.p. 75 - 76°C,

NMR (CDC1 ): 6: 8.80 (1H, broad singlet); 4.60 (1H, 20 ?

singlet); 3.75 (3H, singlet); 3.65 (3H, singlet); 3.60 (4H, multiplet); 3.27 (2H, singlet).

C. Substituting for dimethyl 1,3-acetonedicarboxylate in the procedure of parts A or B of this

Example, diethyl 1,3-acetonedicarboxylate, dipropyl 1,3-acetonedicarboxylate, di (.1-propyl) 1,3-acetonedicarboxylate, di(t_-butyl) 1,3-acetonedicarboxylate, or ³⁰ dihexyl 1,3-acetonedicarboxylate, one obtains, respectively, diethyl 3-(2-bromoethylamina)-2-pentenedioate, dipropyl 3-(2-bromoethylamino)-2-pentenedioate, di(.i-propyl) 3-(2-bromoethylamino)2-pentenedioate, ³⁵ diU-butyl) 3-(2-bromoethylamino)2־-pentenedioate ,

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-Λϋdihexyl 3-(2-0romoethylamino)-2-pentenedioate , diethyl 3-(2-chloroethylamino)-2-pentenedioate, dipropyl 3-(2-ch10roethylamino)-2-pentenedioate, di (!.-propyl) 3-(2-c h 10 roetny lamino )2-pentenedioate, di(t_-butyl) 3-(2-chloroethylamino)2-pentenedioate, or dihexyl 3-(2-chloroethylamino)-2-pentenedioate.

Example 2: Preparation of dimethyl 3-(2-bromoethylamino) 2-pentenedioate. (Step 1 - Alternate II)

A. Dimethyl 1,3-acetonedicarboxylate (196.1 g,

1.13 mol) was placed in a 3 L three-neck flask containing a stirrer bar and fitted with a thermometer, a water extractor on a reflux condenser, and an addition funnel; and the flask then purged with nitrogen. The extractor was filled with dichloromethane, and dichloromethane (800 mL) added to the flask. Ethanolamine (68.8 g,

1.13 mol) was added via the addition funnel over 10 minutes, and the mixture warmed to 30°C. The mixture was then heated under reflux for 24 hours, by which time thin-layer chromatography indicated that very little residual dicarboxylate remained and 20 mL water had collected in the extractor.

The solution of dimethyl 3-(2-hydroxyethylamino)2-pentenedioate 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 an addition funnel over 3.75 hours, with the temperature rising to 5 to 7°C. The medium-yellow slurry darkened to yellow-orange as the last 10 mL methanesulfonyl chloride was added. The mixture was stirred at 0°C for an additional 2 hours, and water (250 mL) added. The organic phase was washed with water (4 x 500 mL) and brine (250 mL), and dried overnight over anhydrous magnesium sulfate. After filtration, the

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־ ^ו2. ־ solvents were evaporated on a rotary evaporator under reduced pressure at 50°C to afford 310.0 g (93% yield) of dimethyl 3-(2-me thane sulfanylethylamino)-2-pentenedioate as a red oil. The mesylenamine may be purified at this point, if necessary or desired, and may be converted to the haloenamine by the following method.

Dimethyl 3-(2-me thane sulfonylethylamino)-

2- oentenedioate (156.3 g, 529 mmol) was added to a 2 L three-neck flask, which was fitted with a mechanical stirrer, thermometer, and reflux condenser. Dichloromethane (750 mL) was added and stirred until the. mesylate had completely dissolved, anhydrous lithium bromide (69.0 g, 794 mmol) was added, and the mixture stirred at 35°C for 19 hours. The mixture was cooled to 0°C and water (250 mL) added, then stirred for 5 minutes and the phases separated. The organic phase was washed with water (3 x 250 mL) and brine (150 mL), and dried over anhydrous potassium carbonate for 15 minutes. Rotary evaporation of the solvent under reduced pressure (50°C) gave 128.4 g of crude dimethyl

3- (2-bromoethylamino)-2-pentenedioate as a yellow oil, which quickly 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 pot residues extracted and recrystallized, to give a total of 90.8 g (61.2% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as white needles. An NMR spectrum in CDCl-j indicated an Z/E isomer ratio of 19:1, and remeasurement of the CDCl^ solution after three days indicated an Z/E ratio of 4:1. The two isomers were not separated.

B. In a. similar manner to that of part A of this Example, using sodium iodide in place of lithium bromide, and acetone or acetonitrile in place of dichloromethane, there was obtained in eacn instance crude dimethyl 3-(2-iodoethylamino)-2-pentenedioate as a light brown oil, which could be purified by conventional methods.

C. Substituting lithium chloride for lithium bromide, and using a similar procedure to that in part A of this Example, one obtains dimethyl 3-(2-cnloroethylamino)-2-pentenedioate. 10

0. Similarly, using other didower alkyl)

1,3-acetonedicarboxylates in the procedures of parts A through C of this Example, one obtains other didower alkyl) 3-(2-haloethylamino)-2-pentenedioates.

Example 3: Preparation of methyl N-(2-bromoethyl)-3methoxycarbonyl-2-pyrroleacetate. (Step 2 - Alternate I) ²⁰ A. (Alternate I) 2-Bromoacetaldehyde diethyl acetal (42.2 g, 214 mmol) was added to a 10Q mL three-neck flask fitted with a mechanical stirrer, reflux condenser, and a thermometer. Hydrobromic acid (9 M, 4.0 mL, 36 mmol) in water (16 mL) was added, and the mixture heated under reflux for 1 hour and then cooled to room temperature to provide a solution of 2-bromoacetaldehyde.

Sodium acetate (41.0 g, 500 mmol) was added to the

2- bromoacetialdehyde solution, and stirred for 5 minutes, at which point the solution had a pH of 6. The flask was ²⁰ placed in a cool tap water bath and dimethyl

3- (2-bromoethylamino)-2-pentenedioate (20.0 g, 71 mmol) was added, followed by isapropanol (40 mL), and the solution was stirred at room temperature (25°C). Within aoout 35 minutes, all the solids had dissolved, and a precipitate started forming within 90 minutes. Stirring

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25880/25890-FF גw a s cantinusd at room t 3 m 0 9 r a t u r e ״or 0 0 n a u r s , a ה a - m c solution then cooled to 0° C and s tirrea at tnat temperature for 1 hour, then riltered through a course fritted glass filter. The precipitate was washed with ice-cold water (400 mL) and ice-cold isopropanol (150 mL) and dried, to give 15.7 g (72% yield) of crude methyl N-(2-oromoethyl) 3-metncxycarqonyl-2-oyrraleacetate as a iignt tan sauid, m.p. 129 - 130.5°C, NMR (CDCL_): δ: 6.58 (2H, quartet); 4.20 (2H, ¹ triplet); 4.10 (2H, singlet); 3.75 (.3H, singlet); 3.=5 (3H, singlet); 3.50 (2H, triplet).

3. (Alternate I) 2-3romoacetaldenyde aietnyl acetal (20.9 g, 106 mmol) was added to a 100 mL three-neck tlask

י׳ כ fittea with a stirrer oar, reflux condenser, ana a thermometer. Hydrooromic acid (48.5%, 1/.7 g, 10□ h׳u>1/ in water (54 mL) was adaea, and tne mixture neatea to 40°C for 3 hours and then cooled to room temperature ana extracted with hexane (100 mL) to provide a solution 0־ ;0 ״ . ד

2- 0romoacetalaehyde .

The hydrolysis solution was addea to a mechanicallystirred slurry of sodium acetate (17.8 g, 212 mmol) 10. water (15 mL) at 0°C over 1 hour, then stirred rar a further 10 minutes. Dimethyl 3-(2-chloroethylamina; 25 2-pentenedicate (20.0 g, 85 mmol) was added, followed dy acetone (50 mL), and the solution allowed to warm to roam temperature and stirred for 20 hours. The resulting slurry was cooled to 0°C ana kept at that temperature for 4 hours, then filtered througn a coarse fritted glass filter. The ³θ precipitate was washed with water (300 mL) and dried, !.0 give 19.9 g (90% yield) of methyl N-(2-chloroethyl.)-

3- methoxycaroony1-2-oyrralsacetate as white crystals, m.p. 110 - 111°C,

NMR (CDC1J: <5: 6.65 (2H, quartet); 4.25 (2H, ⁰⁵ triplet); 4.18 (2H, singlet); 3.82 (3H, singlet); >.75 (2H, triplet); 3.73 (3H, singlet).

C. (Alternate I) Substituting 2-chloroacetaldehyde diethyl acetal for 2-bromoacetaldehyde diethyl acetal, and using a similar procedure to that in parts A or B of this Example, one obtains methyl N-(2-bromoethyl)-3-methoxycarbonyl2-pyrroleacetate , or metnyl N-(2-chloroethyl)-3-methoxycarbonyl-

2- pyrroleacetate.

D. (Alternate I) Similarly, substituting other didower alkyl) 3-(2-haloethylamino)-2-pentenedioates , such as dimethyl 3-(2-iodoethylamino)-2-pentenedioate, diethyl 3-(2-0romoetnylamino)-2-pentenedioate, etc., for the equivalent materials in parts A through C of this Example, one obtains other alkyl N.-(2-haloethyl) -

3- alkoxycarbonyl-2-pyrroleacetates, such as methyl

N-(2-iodoethyl)-3-methoxycarbony1-2-pyrroleacetate, ethyl N-(2-promoethyl)-3-ethoxycarbonyl-2-pyrroleacetate, etc.

A process for producing a compound of formula