CZ20001040A3 - Processes and intermediates for preparing antifolates - Google Patents

Abstract

Compounds of formula IV wherein M is a metal cation; n is 1 or 2; R 2 is NHCH (CO 2 R 3) CH 2 CH 2 CO 2 R 3 or OR 3; R3is independently of each occurrence, a protecting group carboxy; and X is a bond or C 1 -C 4 alk-diyl which are useful as intermediates in the production of antifolate-5 substituted pyrrolo [2,3-d] pyrimidines. Method of preparation the compounds of formula III wherein r 2 is NHCH (CO> R 3) CH 2 CH 2 C 0 R 3 or OR 3; and R 3 is independently from at each occurrence a carboxy-protecting group; aX is a bond or C 1 -C 4 alk-diyl. by reacting the compound of formula IV and a trialkylsilyl halide in a solvent.

Description

Methods and intermediates suitable for the production of antiphialates

Technical field

The present invention relates to synthetic organic chemistry. In particular, the invention relates to a process for the preparation of intermediates useful for the synthesis of valuable antifolate compounds.

BACKGROUND OF THE INVENTION

Compounds known to have antifolate activity are well known as chemotherapeutic agents for the treatment of cancer. Currently, a series of S-substituted pyrrolo [2,3-d] pyrimidine compounds of formula XVI have been described:

AND

COR wherein R is NHC * H (C02R ¹⁾ CH2CH2CO2R ¹ or OR ^1, the configuration at the carbon atom designated * is L, each R ¹ is hydrogen or represents the same or different carboxy protecting, m is 2 or 3, and A is aryl groups and pharmaceutically acceptable salts thereof as antifolates or intermediates for antifolates.

U.S. Pat. Patent No. No. 5,416,211 (U.S.'211).

The key intermediate for compounds of formula XVI is α-haloaldehyde of formula XV:

• • • 1 • 0 0 0 0 0 0 0 0 0 0

(CH3) —A — COR

Among the possible synthesis routes that lead to the compounds of formula XV described in U.S. Pat. '211, is the shortest alpha haiogenation of aldehydes of formula XIV:

^H Y ~ xf ^OR

If (CH ₂ ) —ao

XIV:

The synthesis, published by Taylor and Harrington, leads to compounds of formula XIV pathway, as shown in the following scheme:

OH

Pd (0) + Br-A-OH

COR

H

COR

AND

-AND

H-,

XI

COR

XII

H

(CH ₂₎ -N

OH [O]

COR

XIII

XIV, ·· ♦ ·

- 3 • ···

Taylor, E. C., Harrington, P. M., J. Org. Chem., 55, 3222, (1990).

Other syntheses published by Larock, et.al. may utilize the preparation of the auxiliary aldehydes of formula XIV by a simple palladium catalyzed coupling reaction, which is further illustrated in the scheme:

VIII

Br or I-A-COR Pd

IX

+ by-products

Larock, R.C., Leung, W., Stolz-Dunn, S., Tet. Let., 30, 6629, (1989).

If followed by the Larock synthesis, a mixture of the desired products with the undesired products is obtained, the components of which are difficult to separate from one another, making it difficult to purify the compound of formula XIV. Furthermore, irrespective of the way in which they were prepared, the aldehydes of formula XIV usually cannot be isolated because they are inherently unstable and therefore alpha is halogenated in situ to yield the haloaldehydes of formula XIX as described in U.S. Pat. '211.

An improvement over the prior art may be an elegant method for the selective preparation of a compound of formula XIV and capable of isolation, performance, and storage by converting to an aldehyde form.

- 4 · · ^{w w} 4 4 ^w I I ^{w w} I I I I! · · · · · · · · · · · · · ·

SUMMARY OF THE INVENTION

The invention relates to compounds of formula IV:

M is a metal cation; n is 1 or 2;

R ² is NHCH (CO 2 R ³⁾ CH 2 CH ₂ CO ₂ R ³ or OR ^3;

R ³ is independently a carboxy-protecting group; and

X is a bond or C 1 -C 4 alk-diyl which are useful as intermediates in the manufacture of said antifolate-5-substituted pyrrolo [2,3-d] pyrimidines disclosed in U.S. Pat. 211 which correspond to the parameters of the compounds of formula IV.

The invention further relates to formula III: a process for preparing compounds Y ^x H Y o \ COR III where: R ² is NHCH (CO 2 R ³⁾ CH 2 CH ₂ CO ₂ R ³ or OR ³ ; and

R ³ is independently a carboxy-protecting group;

which comprises reacting a compound of formula IV with a trialkylsilyl halide in a solvent.

The invention also relates to a process for the preparation of compounds of formula IV which comprises reacting a compound of formula III with a compound of formula M (HSC 3 ') n in a solvent.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula IV wherein R ² is OR ³ are enantiomeric and compounds of formula IV wherein R ² is NHCH (CO ² R ³ ) CH ₂ CH ₂ CO ₂ R ³ are diastereomeric. The individual enantiomers, individual diastereomers, and mixtures thereof are included within the scope of this invention. It is preferred that the chiral center of the glutamic acid residue (R ² = NHC * H (CO 2 R ³⁾ CH2CH2CO2R ³ where C * is the chiral center), when present, has the L configuration.

Throughout this document, all expressions of concentrations, percentages, ratios, and the like are expressed in weight units unless otherwise stated, except for solvent mixtures which are expressed in volume units.

All temperatures, unless otherwise indicated, are expressed in degrees Celsius. Compounds or mixtures of compounds in brackets, except for brackets that are used to characterize compounds in salt forms, refer to intermediates that are preferably not isolated prior to use in the next reaction step.

In the general formulas of the compounds herein, conventional chemical terms have the usual meaning. For example, the term • · • ♦

Alkyl means a fully saturated, linear or branched, monovalent hydrocarbon group having the specified number of carbon atoms, examples of the meanings of which are, inter alia, selected from from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl and t-butyl, and the term also includes the higher homologues and isomers that are suitable.

The term C 1 -C 4 alk-diyl means a fully saturated linear divalent hydrocarbon group having from 1 to 4 carbon atoms, wherein each carbon atom in the chain can be independently once substituted with a C 1 -C 4 alkyl group.

For example, 1,2-dimethylprop-1,3-diyl falls within the definition of "C 1 -C 4 alk-diyl", but 1,1-dimethylprop-1,3-diyl does not belong there. The term is further elucidated by examples which fall within its scope, inter alia. They are the following groups: -CH 2 -, -CH ₂ CH ₂ -, -CH ₂ (CH ₂ ) CH ₂ -, methyleth-1,2-diyl, -CH ₂ (CH ₂ ) ₂ CH ₂ - and but-1,3-diyl. Preferred C 1 -C 4 alk-diyl groups are those which are unsubstituted and most preferred are -CH 2 - and -CH 2 CH 2 -.

The term C 2 -C 6 alkenyl means mono-unsaturated, monovalent hydrocarbon groups containing from 2 to 6 carbon atoms, which may have a chain in branched or linear configuration. This term expresses, for example, groups such as, ethyl enyl, propylenyl, allyl, butyl enyl, and pentylenyl.

The term C1-C4 alkoxy means a methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy and t-butoxy group.

The terms halogen and halide mean chloride, bromide or iodide.

»0 •

• · ·

0 • »

- 7 • 0

0 * · ····

The terms substituted benzyl, substituted benzhydryl and substituted trityl mean a benzyl, benzhydryl or trityl group, substituted 1 to 5 times independently by nitro, C 1 -C 4 alkoxy, C 1 -C 0 alkyl, or a hydroxy (C 1 -C 6 alkyl) group. These substitutions are steric, so that the group is chemically stable.

The terms substituted C 1 -C ₆ alkyl and substituted C 2 -C 6 alkenyl mean C 1 -C 6 alkyl and C 2 -C 6 alkenyl substituted 1 to 3 times independently by halogen, phenyl, tri (C 1 -C 4 alkyl) silyl, or substituted phenylsulfonyl.

The terms substituted phenyl and substituted phenylsulfonyl means phenyl and phenylsulfonyl, wherein the phenyl group in the para position is substituted with a C 1 -C 6 alkyl, a lower group or a halogen group.

The term leaving group means a monovalent substituent molecule capable of nucleophile substitution. Typical leaving groups are, inter alia, sulfonates such as phenylsulfonate, substituted phenylsulfonates, C1-C6 alkylsulfonates and C1-C6 perfluoroalkylsulfonates; halides and diazonium salts such as diazonium halides.

The term carboxy-protecting group as used herein refers to groups that are generally not present in the final, therapeutically active compounds, but are specifically introduced into the intermediate molecule during the part of the synthesis process to protect a group that would otherwise could be undesirable in chemical reactions of other groups

- 8 to respond and which will later be removed. Examples of such carboxylic acid protecting groups are C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, benzyl, substituted benzyl, benzhydryl, substituted benzhydryl, trityl, substituted trityl, trialkylsilyl, aroyl groups such as phenylacyl and the like. The type of carboxy protecting group to be used is not critical as long as the carboxylic acid in the form of the appropriate protecting group derivative is stable to the conditions of the subsequent reaction (s) carried out elsewhere in the molecule and can be removed at the appropriate time breaking the rest of the molecule. The carboxy protecting groups used herein are similar to those used to protect the carboxyl substituent in the chemistry of cephalosporins, penicillin. Further examples of these groups can be found in E.Haslam, Protective Groups in Organic Chemistry, JGW McOmie, Ed., Plenum Press, New York, NY, 1981, Chapter S and TW Greene, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, NY, 1991, Chapter 5. When R ¹ or R ³ is a carboxy protecting group, the protecting group is preferably C 1 -C 4 alkyl. Most preferred protecting groups are methyl and ethyl.

The term trialkylsilyl means a monovalent silyl group substituted 3 times independently with a C 1 -C 6 alkyl group.

The term trialkylsilyl halide means a compound of formula (C 1 -C 6 alkyl) 3 -Si-halogen, wherein C 1 -C 6 alkyls may be the same or different. Trialkylsilyl halides are, among others, trimethylsilyl, triethylsilyl, tripropylsilyl chloride, bromide and iodide.

The term metal cation means an alkali metal or alkaline earth metal cation. Alkali metals form ions • 9

- 9 · 9 9 9 9 9 _e 9 · 9 9 9 9

99 9 9 9 9 9; 9 with one positive charge, eg, Li * ¹ , Na ⁺¹ , and K ⁺¹ , while the alkaline earth metals form ions charged with two elementary charges, eg, Mg ⁺² and Ca ^{+ 2} . The resulting charge on compounds of formula IV, on compounds of formula M (HSO3) n, or on chlorides with these metal ions as a whole is, of course, zero. Thus, if M is a Group I metal, the molar ratio between cation and anion is 1: 1, and if M is Group II metal, the molar ion ratio is 1: 2.

The term pharmaceutical salt, as used herein, means salts prepared by reacting the compounds of the invention with a mineral or organic acid (e.g., hydrochloric, hydrobromic, hydrogenated or p-toluene sulfonic acid) or an inorganic base (e.g., hydroxide, carbonate or sodium, potassium, lithium or magnesium bicarbonate). Such salts are known as "addition salts" and "base addition salts". As another example of methods for preparing a pharmaceutical salt, see, e.g., Berge, S.M, Bighley, L.D., and Monkhouse, D.C., J. Pharm. Sci., 66, 1, 1977.

The term phase transfer catalyst refers to a salt in which the cation has a large non-polar substituent group that confers good solubility of the salt in organic solvents. The best known examples are tetraalkylammonium and tetraalkylphosphonium ions, i.e. as compounds, for example tetraalkylammonium chloride or tetraalkylammonium bromide.

The term palladium catalyst means an agent that is a source of zero valency palladium (Pd). Suitable sources of Pd include, but are not limited to, palladium bis (dibenzylidinacetone) and palladium acetate.

. · * ···· · · · · · ·

The term halogenating agent means a reagent that can act on the target molecule as an electrophilic halogen source. Typical halogenating agents include, but are not limited to, benzeneseleninyl chloride, bromide or iodide, thionyl bromide or chloride, dibrombarbituric acid, Ν-bromo-, N-iodo- and N-chloro succinimide, elemental chlorine, elemental bromine (including bromine complexes such as bromodioxane complex ), elemental iodine and the like.

The term thermodynamic base means a base that causes reversible deprotonation of an acidic substrate or acts as a proton trap for those protons that are formed as byproducts of a given reaction, and is sufficiently reactive to cause the desired reaction without significantly promoting undesired reactions. Examples of thermodynamic bases are, but are not limited to, acetates, acetate dihydrates, carbonates, bicarbonates and hydroxides (eg, acetate, acetate dihydrate, carbonate, bicarbonate or hydroxide of lithium, sodium or potassium), tri (C 1 -C 4 alkyl) amines or aromatic aromatic nitrogen containing heterocycles (eg, imidazole and pyridine).

The term suitable solvent means any solvent or mixture of solvents inert to the reaction being carried out, which sufficiently dissolves the reactants in which the desired reaction is carried out.

Compounds of formula IV may be prepared in a novel manner as shown below in Scheme 1 wherein Lg is a leaving group, R ⁴ is hydrogen or C 1 -C 4 alkyl, and X 1 is C 1 -C 4 alk-diyl;

with the proviso that if X 'is not a chemical bond alone, then the alpha carbon of the alcohol must be in the -CH ₂ - group; and ⁿ , R ² and X are as defined above for formula IV.

Scheme 1

Lg

COR ²

Undesirable by-products

II III

A composition comprising a compound of Formula III can be prepared by dissolving or suspending a compound of Formula II in a suitable solvent, in the presence of a suitable thermodynamic base and a phase transfer catalyst, optionally in the presence of a metal ion chloride, and adding a compound of Formula I and a palladium catalyst. The reactants are mixed at one time, and the reaction can be carried out at temperatures ranging from at least 0 ° C to about 100 ° C. Within this wide range, when Lg is bromine in the compound of formula II, the reaction mixture should be heated to at least 50 ° C, more preferably to at least about 60 ° C, most preferably to at least one to one.

About 65 ° C for about 8 to about 24 hours. If Lg is iodine, the reaction proceeds more violently, and therefore a temperature range of 0 ° C to about 25 ° C is typical, with room temperature being preferred. temperature. The reaction is preferably allowed to proceed for about 8 to about 10 hours.

Suitable solvents for this reaction include, but are not limited to, dimethylsulfoxide, tetrahydrofuran, Ν, Ν'-dimethylimidazole, diethyl ether, dimethoxyethane, dioxane, acetonitrile, mixtures thereof, and the like. Typically, the preferred thermodynamic base is an alkali metal acetate and in certain cases lithium acetate. However, when Lg is bromine, the preferred base is lithium acetate dihydrate. Generally, preferred solvents are dimethylformamide or dimethylacetamide. The preferred phase transfer catalyst is generally tetrabutylammonium bromide. Palladium (II) acetate is a typical preferred palladium catalyst. Although not necessary, it is preferred to use an alkali metal chloride to maximize the yield of the desired product of formula III. Lithium chloride is the preferred metal ion chloride. Preferred compounds of formula I are those wherein R ⁴ is hydrogen and X 1 is a bond, -CH 2 -, or -CH 2 CH 2 -. In the compounds of formula II, Lg is preferably bromine, iodine or trifluoromethylsulfonyloxy. The most preferred Lg is iodine. The most preferred compound of formula I is 3-butenol.

In relation to the individual compounds of formula II, the following amounts of the commonly used reactants are preferred:

a thermodynamic base - 1.0 to about 3.0, preferably about 1.05 to about 1.3 equivalents;

metal cation chloride - 0 to about 4, preferably about 2.8 to about 3.2 equivalents;

a phase transfer catalyst of - 0 to about 3.0, preferably 0.4 to about 0.6 equivalents; and • ·

13 palladium catalyst - 0.015 to about 0.1, preferably about 0.02 to about 0.03 equivalents.

compound of formula I - 1.0 to about 2.0, preferably about 1.1 to about

1.3 equivalents.

The above reaction results in a product mixture comprising a compound of formula III which can be isolated or preferably further reacted according to Scheme 1. Excessive purification of the compound of formula III or separation from unwanted by-products is not necessary prior to the next, new step of the process. . Preferably, prior to further processing, a simple extraction is performed using a water-immiscible solvent followed by filtration of the palladium catalyst. Suitable solvents for the extraction are, but are not limited to, methylene chloride, chloroform, methyl acetate, carbon tetrachloride, mixtures thereof, and the like. Ethyl acetate is usually the preferred solvent.

A reagent of formula M (HSO ₃ ') _n can be added to the organic extract obtained as the filtrate from above (a mixture comprising a compound of formula III and by-products). Usually, a lower alcohol, preferably ethanol denatured with 5% methanol (3A ethanol) or ethanol denatured with 0.5% toluene (2B-3 alcohol) and water, is also added as another solvent (cosolvent). The volume of ethanol added is preferably approximately equal to the volume of ethyl acetate initially present at the start of the reaction and the volume of water in the mixture is proportional to the volume of denatured ethanol, preferably in a ratio of about 1: 5. Suitable bisulfite reagents include, but are not limited to, sodium bisulfite (NaHSO ₃ ), potassium (ΚΗδΟβ), lithium (LiHSO ₃ ), and magnesium (Mg (HSO ₃ ) 2). A preferred metal bisulfite reagent is sodium bisulfite. The amount of metal bisulfite-based reagent to be used typically ranges from about 0.5 to about 0.5%.

- 14 ·············································· In the range of about 0.85 equivalents to about 1.2 equivalents, depending on the compound of formula III. The preferred amount of the metal bisulfite reagent is usually about 0.90 to 1.1, and most preferably about 0.95 to 1.0 equivalents. The reaction may be carried out for 2 to about 15 hours at a temperature ranging from about room temperature to about 55 ° C. It is preferred to carry out the reaction for about 2 to 5 hours at a temperature of about 35 ° C to about 50 ° C.

When the reaction is complete, the resulting mixture containing the compound of formula III contains, as prepared, varying amounts of different metal-cationic sulfonic acid salts as by-products. The main component is the metal sulfonic acid salt of formula IV. Most often, the main component, which is a compound of formula IV, falls out of the mixture spontaneously, but if spontaneous crystallization does not occur, it can be caused by careful adjustment of the solvent volumes. Usually, the amount of ethyl acetate needs to be increased in relation to both ethanol and water, whereby the precipitation of the main component, the sulfonic acid salt with a metal cation, can be positively influenced. This technique of adjusting solvent volume ratios is well known to those skilled in the art. The precipitated desired major component, which is the metal cation sulfonic acid salt of formula IV, can then be separated by filtration.

Preferred compounds of formula IV are:

• • •

By applying the above chemistry, compounds of formula IV can be synthesized, including but not limited to:

-hydroxy-3- (4-methoxycarbonylphenyl) propane sulfonic acid, sodium salt;

-hydroxy-3- (4-ethoxycarbonylphenyl) propane sulfonic acid, potassium salt;

hydroxy-2,3-dimethyl-4- (4-methoxycarbonylphenyl) butanesulfonic acid lithium salt;

N- (4 - [(3-hydroxy-3-sulfonic acid, sodium) propyl] benzoyl) -L-glutamic acid, dimethyl ester;

N- (4 - [(3-hydroxy-3-sulfonic acid potassium salt) propyl] benzoyl) -L-glutamic acid, diethyl ester;

N- (4 - [(1,2-dimethyl-4-hydroxy-4-sulfonic acid lithium salt) butyl] benzoyl) -L-glutamic acid, dipropyl ester;

Compounds of formula III can be prepared from compounds of formula IV by the novel process shown in Scheme 2 below, wherein M, n, R ₂ , and X are as defined above for formula IV.

- 16 Scheme 2

Compounds of formula IV can be converted to aldehydes of formula III by dissolving or suspending a compound of formula IV in a suitable solvent and adding a trialkylsilyl halide. Suitable solvents include, but are not limited to, acetone, tetrahydrofuran, diethyl ether, methylene chloride, methyl acetate, ethyl acetate, chloroform, mixtures thereof, and the like. The preferred solvent is usually acetonitrile. It has been found that the yields of this reaction can be increased if the solution containing the compound of formula IV is degassed by the injection of an inert gas before the addition of the trialkylsilyl chloride. Nitrogen is usually used as an inert gas for this purpose. The preferred trialkylsilyl halide is usually trimethylsilyl chloride. The tri-alkanes are usually used in a stoichiometric excess. For example, a 2 to 4 fold stoichiometric excess, often calculated based on the compound of Formula IV, is often used. A stoichiometric excess of about 2.7 to about 2.9 times is usually preferred. Typically, the mixture is allowed to react for about fifteen minutes to about one hour. The reaction is usually carried out at elevated temperature, that is, at a temperature of at least about 30 ° C, preferably at least about 40 ° C, more preferably at about 50 ° C, and most preferably the mixture is reacted at a temperature between about 60 ° C and 70 ° C.

Although the isolation and purification of the compounds of formula III prepared by the novel process of the present invention is possible, these compounds are more often converted, not completely purified, to 5- 17.

The substituted pyrrolo [2,3-d] pyrimidine compound of formula VII (a) in the manner depicted in in Scheme 3 below, wherein R ² and X are as defined above for Formula IV.

Scheme 3

Compounds of formula V can be prepared by adding a halogenating agent to a solution containing a compound of formula III, prepared as described in Scheme 2. The addition can be accomplished by heating the reaction mixture to 60 ° C to 70 ° C, which is preferred but rather before adding the halogenating agent. the reagents of the component are to be cooled. The addition of the halogenating agent may be carried out at a temperature of from 0 ° C to 60 ° C, but it has been found that addition at a temperature of about 35 ° C to about 45 ° C is preferred. When the halogenating agent is added, the resulting mixture is stirred for from about 5 minutes to about 2 hours. Generally speaking, the time for the halogenation reaction is from about 5 minutes to about 1 hour, but is preferably carried out from 24 minutes or less. The preferred halogen substituent in the compounds of formula V is bromine and the preferred halogenating agent is usually elemental bromine.

···· · · ······ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- I Ο “· ··· · · · · ·

When the reaction is complete, it can be quenched by the addition of an aqueous solution of known halogen scavengers of unwanted by-products such as sodium bisulfite. The compound of formula V can then be extracted into a suitable water-immiscible organic solvent. This solution, which contains a compound of formula V, is of high purity and can be used directly to prepare compounds of formula VII (a) or compounds of formula VII:

VII and their pharmaceutical salts and solvates; by the following procedures described in U.S. Patent No. 5,416,211, the contents of which are hereby incorporated by reference.

When any compound of formula II, IV, IV, VII, or VII (a) contains carboxy-protecting groups, it can be removed by methods known in the art, all reactions for introducing and removing carboxy-protecting groups that are See, for example, The Peptides, vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965) and reference to Green, cited above. Methods for removing the preferred carboxy protecting group, especially methyl and ethyl groups, are essentially described in Examples 5 and 7, which follow.

······················· · 1 · 1 · 1 9 1

1111

1,111 · 1,111

When R is NHCH (CO ² R ¹ ) CH 2 CH 2 CO ² R ¹ in compounds of formula VII or when R ² is NHCH (CO ² R ³ ) CH 2 CH 2 CO ² R ³ in compounds of formula II, IV, IV, or VII (a), R or R ² groups may be introduced in any point of synthesis. For example, the glutamic acid residue can be introduced after the reactions of Schemes 1-3, essentially as described in Examples 5 and 6, below. Alternatively, a commercially available glutamic acid dialkyl ester of formula NH 2 CH (CO 2 R ³ ) CH 2 CH 2 CO 2 R ^{3 may} be coupled with commercially available p-halobenzoic acid first, followed by the reaction of Scheme 1.

The optimal time for carrying out the reactions of Schemes 1-3 can be determined by monitoring the degree of conversion of the reaction by conventional chromatographic techniques. The choice of the reaction solvent is generally not critical since the solvent used is inert to the reaction being carried out and sufficiently dissolves the reactants to create the environment in which the desired reaction takes place. Unless otherwise indicated, all reactions described herein are preferably carried out under an inert atmosphere. The preferred inert atmosphere is nitrogen.

The process illustrated in Scheme 1 for the preparation of the novel compounds of formula IV greatly simplifies the purification of the compounds of formula III formed by the coupling of an alkenol and an aryl halide. This process, illustrated in Scheme 2, represents the hitherto unknown formation of aldehydes from metal cation sulfonic acid salts. This conversion can be expected to be generally applicable and to have a great potential for synthesis in general. Specifically in this case, this conversion allows to selectively obtain pure compounds of formula III. Further, compounds of formula IV which can be considered as aldehyde analogs within the meaning of the present invention are

- 20 stable, usually crystalline materials, capable of mass production, cleaning and storage. Thus, in general, commercial processes which require aldehydes of formula III, or similar aldehydes, are now simpler when carried out using the process of the invention.

The following examples are illustrative only and are not intended to limit the scope of the invention in any way.

The terms and abbreviations used in the following examples have the usual meaning unless otherwise indicated. For example, ° C, N, mmol, g, d, ml, M HPLC, ¹ H NMR, ¹³ C NMR, and v. Means Celsius, normality or valence, millimoles or millimoles, gram or grams, density, milliliter or milliliters, molarity or molar concentration, high performance liquid chromatography, proton nuclear magnetic resonance, C-13 nuclear magnetic resonance, and volume used in ml / gram. In addition, absorption maxima, which are reported as characterizing IR spectra, are only those that are of interest and not all of the observed maxima are reported.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4- (4-Methoxycarbonyl ifenyl) butanal

The Deloxan® THP type 2 resin used below was pretreated with isopropyl alcohol (2.0 vol. 20 mL) and washed with ethyl acetate (4.0 vol., 40 mL). The slurry containing the organic coating on the resin was then filtered and subsequently used as described.

·· fefe ··········································. · · · · · · · ·

4-Bromobenzoic acid, methyl ester (60.0 g, 279.00 mol), lithium acetate dihydrate (31.31 g, 306.90 mol), lithium chloride (35.48 g, 837 mol) and tetrabutylammonium chloride (41 , 22 grams, 131.49 mol) was added to dimethylformamide (698 mL). The resulting solution was degassed using subsurface nitrogen. 3-Buten-1-ol (24.19 grams, 28.81 mL, 334.81 mol) and palladium acetate (1.57 grams, 6.98 mol) were then added and the reaction mixture was heated to 65 ° C while The reaction was determined by the consumption of the starting materials (less than 0.4% 4-bromobenzoic acid methyl ester remaining) as shown by HPLC (reverse phase, 60% acetonitrile 1: 2.5). % acetic acid buffer). The reaction mixture was cooled to 25 ° C - 30 ° C and water (700 mL) and ethyl acetate (700 mL) were added. The reaction mixture was stirred for 10 minutes and then the layers were allowed to separate. The organic layer was separated and the remaining aqueous layer was extracted twice more with ethyl acetate (720 mL). The ethyl acetate washes were combined with the original organic layer and the combined organic layers were washed with brine (350 mL). The organic layer was filtered to remove elemental palladium and slurried with Deloxan® THP Type II resin (3.0 grams dry weight) for 45 minutes. The title compound was obtained as a solution in ethyl acetate in about 87% yield. A small amount of the ethyl acetate solution was concentrated to analyze the product.

Results analysis:

¹ H NMR: (d ₆ -DMSO) δ 9.65 (t, J = 1.5 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.63 (t, J = 7.7 Hz, 2H), 2.43 (td, J = 7.4, 1.5 Hz) 2H, 1.82 (m, 2H).

¹³ C NMR: (ds-DMSO) δ 203.1, 166.2, 147.4, 129.3, 128.7, 127.4,

51.9, 42.4, 34.3, 23.0.

Example 2

-Hydroxy-4- (4-methoxycarbonylphenyl) butanesulfonic acid, sodium salt

The ethyl acetate extracts of Example 1 were concentrated to

3.6 vol (8.7 mL) under vacuum at about 37 ° C, 3A alcohol (3 vol, 7.2 mL) and water (0.63 vol, 1.51 mL) were added followed by bisulfite sodium (1.04 g, 10.03 mol). The reaction mixture was stirred for about 8 hours. After 10 minutes, the sulfonic acid began to crystallize. The completion of the reaction was determined by ¹ H NMR analysis of the filtrate of the reaction mixture. The resulting white slurry was filtered to give the title compound (2.78 grams, 8.98 mol) as a white crystalline solid in about 80% yield. The filter cake was washed with ethanol (1.8 vol) and dried under vacuum at 40 ° C. Isomeric impurities were not detectable by NMR. Analysis results:

¹ H NMR: (d ₆ -DMSO) δ 7.86 (d, J v = 8.27 Hz, 2H), 7.32 (d, J = 8.27 Hz, 2H), 5.33 (d, J = 2.3 Hz, 1H), 3.84 (m, 1H), 3.81 (s, 3H), 2.63 (m, 2H), 1.75 (m, 1H), 1.73 ( m, 1H), 1.61 (m, 1H), 1.48 (m, 1H). ¹³ C NMR: (d 6 -DMSO) δ 166.2, 148.3, 129.2, 128.7, 127.1, 82.7,

51.9, 35.1, 31.2, 27.2.

IR: (as KBr pellets) 3237, 2962, 2930, 2889, 1726 cm ^-1 .

Example 3

Hydroxy-2-bromo-4- (4-methoxycarbonylphenyl) butanal

To a 50 mL round bottom flask with a magnetic stirrer was added 4- (4-oxobutyl) benzoic acid methyl ester / sodium bisulfite adduct (3.10 grams, 10 mol), followed by acetonitrile (14 mL) and chlorotrimethylsilane (3.6 mL, 28 mL). mol). The mixture was bubbled through gaseous »0000 for five minutes

0 «0« • ·

- 23 00 ·· • 0 0 ·

0 0 *

0 0 *

And heated in a 60 ° C bath for one hour under nitrogen. The mixture was slightly yellow at this stage. Then the reaction mixture was cooled to 5 ° C and bromine (0.5 mL, 9.7 mol) was added and the brownish bromine was removed over 1 minute. The solution was slightly yellow and the visible solids appeared colorless. The cooling bath was removed and the mixture was stirred for an additional 2 hours. The mixture was diluted and quenched by the addition of water (14 ml) and sodium bisulfite (0.14 grams), the residual bromine was removed and the resulting mixture was stirred for 1 hour. . The mixture was then partitioned between methylene chloride (14 mL) and an additional 7 mL of water. The organic phase was then separated and stripped on a rotary evaporator until the volume was reduced to 26 ml. In this 26 mL is the title compound which may not be further purified or isolated prior to the next reaction as shown in Example 4 below. A small amount of the methylene chloride solution was concentrated and used for accurate analytical characterization of the product.

Analysis results:

¹ H NMR: (CDCl 3) δ 9.40 (d, 1H), 7.95 (d, 2H), 7.26 (d, 2H), 4.15 (ddd, 1H), 3.88 (s, 3H), 2.89 (m, 1H), 2.79 (m, 1H), 2.35 (m, 1H), 2.21 (m, 1H).

¹³ C NMR: (CDCl ₃ ) δ 191.4, 166.8, 145.1, 129.9, 128.5, 128.5, 54.4, 52.0, 32.7, 32.6.

Example 4

4- [2- (2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid methyl ester ml of the organic layer of Example 3 which contains 1-hydroxy-2-bromo-3- (4-methoxycarbonylphenyl) butanal, was added to 2,4-diamino-6-hydroxypyrimidine (1.26 grams, 10 mol), acetate. ···················

_{Α Α} · ··· ♦ * · · · · · ·

Sodium (1.68 grams, 20 mol) and water (23 mL) were added. Nitrogen was bubbled through the mixture for 5 minutes and then heated to 40 ° C under N ₂ for 2 hours. The mixture was cooled to ambient conditions and the solids were filtered off. They were then washed with 23 ml of a 1: 1 mixture of acetonitrile and water. The filter cake was dried, yielding 1.47 grams of light yellow needles. The analysis is shown, the combined yield for Examples 3 and 4 was 45%, and the purity of the title compound was also shown to be 94.8% by HPLC (reverse phase, gradient 50% to 30% methanol: 20 mM potassium dihydrogen phosphate or ammonium dihydrogen phosphate buffer). Analysis results:

¹ H NMR (d 6 -DMSO) δ 10.66 (s, 1H), 10.23 (s, 1H), 7.84 (d, 2H),

7.32 (d, 2H), 6.31 (s, 1H), 6.08 (s, 2H), 3.80 (s, 3H), 2.98 (dd, 2H), 2.86 (dd) , 2H).

¹³ C NMR (dg-DMSO) δ 166.3, 159.4, 152.3, 151.3, 148.4, 129.2, 128.7, 127.1, 117.6, 113.6, 98 , 8, 52.0, 36.3, 27.9.

Example 5

4- [2- (2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid

The flask was charged with 13.0 grams of 4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid methyl ester and 150 mL 2N aqueous sodium hydroxide. Stirring was applied and the slurry was heated to 40 ° C. The reaction was monitored by HPLC (reverse phase, gradient of 50% to 30% methanol: 20 mM potassium dihydrogen phosphate or ammonium dihydrogen phosphate buffer). To the solution was added 3A alcohol (230 mL), whereupon the solution was seeded using true 4- [2 (2 amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidine-5-). yl) ethyl] benzoic acid (obtained according to the procedure of US Patent 5,416,211). The pH of the solution was adjusted to 4.4 with 6N acid. · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0

- 25 hydrochloric acid (48.5 ml). The solids were filtered and washed with 30 mL water: 3A alcohol, 1: 1. The solids were dried under vacuum at 50 ° C. 10.84 g of the title compound was obtained.

Analysis results:

¹ H NMR (d 6 -DMSO) δ 10.66 (br s, 1H), 10.33 (br s, 1H), 7.83 (d, 2H), 7.30 (d, 2H), 6.31 (s, 1H), 6.17 (br s, 2H), 2.97 (m, 2H), 2.85 (m, 2H).

¹³ C NMR (d 6 -DMSO) δ 167.6, 159.5, 152.4, 151.4, 147.9, 129.4, 128.6, 128.4, 117.7, 113.6, 98 , 8, 36.4, 28.0.

Example 6

N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl) -L-glutamic acid, diethyl ester, addition salt with p-toluenesulfonic acid ml flask with mechanical stirrer, thermometer and equipped with N2 inlet was charged with 1.93 g (adjusted during tests) 4- [2- (2-amino-4,7-dihydro-4- oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid (2.5 g, 77% purity) and 13.5 mL of dimethylformamide. The slurry was stirred for 15 minutes and 1.94 grams of N-methylmorpholine (2.9 eq) was added. The mixture was cooled to 5 ° C using an ice / water bath and all chlorodimethoxytriazine (1.46 grams, 1.28 eq.) Was added in one portion. The mixture was stirred for 40 minutes and then L-glutamic acid diethyl ester (1.99 g, 1.28 eq) was added in one portion. The reaction mixture was allowed to warm to ambient temperature. The reaction was monitored by HPLC (reverse phase, gradient 20% to 46% acetonitrile: 0.5% acetic acid buffer) and terminated in 1 hour at 23 ° C. The reaction mixture was then transferred to a 250 mL Erlenmeyer flask containing 36 mL deionized water and 18 mL methylene chloride. The reaction vessel was washed with 18 mL of methylene chloride and this rinse was added to the reaction vessel.

0 ··

- 26,000 · · · · · · ·

0 0 ·

0 · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

0 0 0

0 00

Erlenmeyer flasks. The mixture was stirred for 15 minutes and the layers allowed to separate. The methylene chloride layer was concentrated from 46 grams to 13 grams on a rotary evaporator under reduced pressure at a bath temperature of 45 ° C. The concentrate was dissolved in 55 mL of 3A alcohol and again concentrated to 10 grams by removing methylene chloride. The concentrate was then dissolved to a total volume of 60 mL of 3A alcohol and the resulting solution was heated to 70-75 ° C. Ptoluenesulfonic acid (3.16 g, 2.57 eq) dissolved in 55 mL of 3A alcohol was added over 30-90 minutes. The resulting slurry was refluxed for an hour. The slurry was cooled to ambient temperature and filtered on a 7 cm Buchner funnel. The wet cake was washed with 25 mL ethanol and dried under vacuum at 50 ° C overnight to give 3.66 grams of the title compound (95%).

Analysis results:

¹ H NMR (d ₆ DMSO) δ 11.59 (br s, 1H), 11.40 (s, 1H), 8.66 (d, 1H), 7.88 (br s, 1H), 7.79 (d, 2H), 7.58 (d, 2H), 7.29 (d, 2H), 7.16 (d, 2H), 6.52 (s, 1H), 4.42 (m, 1H) 4.09 (q, 2H), 4.03 (q, 2H), 2.94 (m, 2H), 2.89 (m, 2H), 2.43 (m, 2H), 2.28 (s, 3H), 2.08 (m, 1H), 2.02 (m, 1H), 1.17 (t, 3H), 1.14 (t, 3H).

¹³ C NMR (d ₆ DMSO) _δ 172.3, 171.9, 166.7, 157.2, 150.6, 145.8, 144.4, 138.6, 138.3, 131.3, 128 , 4, 128.3, 127.5, 125.6, 119.2, 11.4, 99.1, 60.6, 60.0, 52.0, 35.8, 30.2, 27, 2, 25.8, 20.8, 14.1,

14.1.

Example 7

N- [4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid

To 1.00 g of N- [4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid of the acid, the ester salt was added in a 50 mL Erlenmeyer funnel to the solution. Toluenesulfonic acid and 1N aqueous sodium hydroxide (6.7 ml) were added. ) and the resulting mixture was stirred until all solids had dissolved (approximately 20 minutes). The solution was light green. Then an additional 6-7 ml of deionized water was added and the pH was adjusted to 2.8-3.1 with hydrochloric acid solution. The resulting slurry was heated to about 70 ° C to obtain larger solid product particles. The solids were filtered to give the title compound.

Example 8

N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3d] pyrimidin-5-yl) ethyl] benzoyl) -L-glutamic acid, disodium salt

N- [4- [2- (2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid of Example 7 was dissolved in 3.8 mL of water and 2.2 mL of 1N sodium hydroxide. The pH of the mixture was adjusted to 7.5-8.5 with hydrochloric acid and 1N sodium hydroxide. The solution was heated to 70 ° C and 40 mL of 3A alcohol was added. The solution was allowed to cool to room temperature and gradually turned into a thick slurry. The solids were filtered and washed with ethanol: water 4: 1. The solids were dried at 50 ° C in a vacuum oven. 640 mg of the title compound were obtained as a solid.

Analysis results:

¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ 7.67 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 6 30 (s, 1H); 4.09 (m, 1H); 2.88 (m, 2H); 2.83 (m, 2H); 2.05-1.71 (m, 4H).

¹³ C NMR (75 MHz, DMSO-d ₆ / D ₂ O) δ 179.9, 176.9, 167.1, 160.8

152.9, 151.7, 146.7, 132.6, 129.4, 127.9, 11.7, 115.2, 99.5,

56.1, 36.8, 35.3, 30.1, 28.4.

• fc

QQ fc ··· fcfc fc fcfcfc fc · fc

- O · ··· ··· »· ··· ·· ·

Example 9

-Hydroxy-4- (L-N- [1,3-diethoxycarbonylpropyl] benz-4-amide) butanesulfonic acid, sodium salt

LN-1,3- (Diethoxycarbonylpropyl) -4-iodobenzamide (10.00 g, 23.1 mol), lithium chloride (2.937 g, 69.3 mol), lithium acetate (2.592 g, 25.4 mol) were mixed. , tetrabutylammonium chloride (3.412 g, 11.55 mol) and dimethylformamide (57.7 mL). The mixture was thoroughly purged with nitrogen. 3-Buten-1-ol (1.998 g,

27.7 mol) and palladium acetate (0.130 g, 0.577 mol). The mixture was heated to 60 ° C under nitrogen for 24 h. At this point, the completion of the reaction was determined by HPLC (reverse phase, 60% acetonitrile: 2.5% acetic acid buffer). The reaction mixture was partitioned between ethyl acetate (58 mL) and water (58 mL). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (58 mL per extraction). The organic layers were combined and washed with brine (30 mL). The resulting organic solution was concentrated to 25 mL and ethyl acetate (15 mL), water (3.25 mL) and sodium bisulfite (0.636 g, 6.11 mol) were added. The mixture was stirred at 25 ° C for 16 h and acetone (75 mL) was added. The product precipitate was collected by filtration and dried in a vacuum oven to give 1.59 g of the title compound. Yield: 48.60.

Example 10

N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3d] pyrimidin-5-yl) ethyl] benzoyl) -L-glutamic acid diethyl ester

1-Hydroxy-4- (LN- [1,3-diethoxycarbonylpropyl] benz-4-amide) butanesulfonic acid, sodium salt (0.922 g, 2.0 mol), acetonitrile was mixed in a 25 mL round bottom flask with a magnetic stirrer. (5 mL) and trimethylsilyl chloride (0.72 mL). Mixture

- 29 to · to to to to to to to to 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 Was purged with nitrogen for 5 minutes, and then heated to 60 ° C for 1 hour. The temperature was set at 40 ° C and bromine was added (98 ° C). μΙ, 1.9 mol). ¹ H NMR indicated pure conversion to the α-bromide intermediate. The reaction mixture was then cooled to ambient temperature and washed with 1% aqueous sodium bisulfite solution (2.5 mL). The organic phase was stripped to an oil and 2,4-diamino-6-hydroxypyrimidine (300 mg,

2.4 mol), sodium acetate (500 mg), water (5 ml) and acetonitrile (5 ml). The mixture was heated at 40 ° C for 6 hours. The upper organic phase of the thus obtained mixture was collected and concentrated to an oil (450 mg). ¹ H NMR and HPLC (reverse phase gradient 20% to 46% in acetonitrile 1: 0.5% acetic acid buffer) confirmed that the oil was primarily the title compound.

The invention has been described in detail, including preferred embodiments thereof. However, it will be clear to those skilled in the art that many modifications and / or improvements may be made to the scope and spirit of the invention as defined in the following claims based on the information provided herein.

Claims (29)

1. A compound of formula IV: IV where: M is a metal cation; n is 1 or 2; R ² is NHCH (CO ² R ³ ) CH ₂ CH ₂ CO ² R ³ or OR ³ ; R ³ is independently a carboxy-protecting group; and X is a bond or C 1 -C 4 alk-diyl. A compound according to claim 1 wherein X is a bond of -CH 2 -, or -CH 2 CH 2 - and R ² is NHC * H (CO ² R ³ ) CH ₂ CH ₂ CO ² R ³ or OR ³ wherein the configuration on the carbon atom indicated by * is L. A compound according to claim 2 wherein X is -CH ₂ 4. A compound according to claim 1 wherein M is an alkali metal cation and n is 1 and ^R2 is NHC * H (CO 2 R ³⁾ CH 2 CH ₂ CO ₂ R ³ or OR ³ where the configuration at the carbon atom designated * is L. The compound of claim 4, wherein the alkali metal is sodium. - 31 • 9 99,999 «• 9 9 9 9 9 9 9 9999 9 99 · 99999 10 999 99 10 9 99 9 9999 99 99 99 99 99 6. A compound according to claim 1 wherein M is sodium, n is 1, X is -CH2-, and ^R2 is NHC * H (CO 2 R ³⁾ CH2CH2CO ₂ R ³ or OR ³ wherein kcnfigurace the carbon atom designated * is L. 7. A process for preparing compounds of formula III: COR III wherein: R ² is NHCH (CO ² R ³ ) CH ² CH ² CO ² R ³ or OR ³ ; R ³ is independently a carboxy-protecting group; and X is a bond or C 1 -C 4 alk-diyl; including: reaction of a compound of formula IV: COR " Where: X and R ² are as defined above for formula III; IV '' s - - fefefe · fefefe fefe fefefe · fefefefe fefefefefe fefe fefefe fefe M is a metal cation; and n is 1 or 2; with a trialkylsilyl halide in a solvent. The method of claim 7 wherein the compound of formula IV is a compound wherein X is a bond, -CH 2 -, or -CH 2 CH 2 - and R ² is NHC * H (CO ² R ³ ) CH 2 CH 2 CO 2 R ³ or OR ³ wherein the configuration on the carbon atom indicated is L. The method of claim 8 wherein X is -CH 2 -. The process of claim 7 wherein the compound of formula IV is a compound wherein M is an alkali metal cation, n is 1 and R ² is NHC * H (CO ² R ³ ) CH ₂ CH ₂ CO ² R ³ or OR ³ wherein the r configuration and the carbon atom labeled * is L. The process of claim 10 wherein the alkali metal is sodium. The process of claim 7, wherein the solvent is acetonitrile, the trialkylsilyl halide is a trimethylsilyl chloride and the reaction is carried out at a temperature between 50 ° C and 70 ° C. The method of claim 12 wherein the compound of formula IV is a compound wherein M is sodium, n is 1, X is -CH ₂ -, and R ² is NHC * H (CO ² R ³ ) CH ₂ CH ₂ CO ₂ R ³ or OR ³ , the carbon configuration the atom marked with * is L. 14. A process for the preparation of compounds of formula IV: • to · IV wherein: M is a metal cation; n is 1 or 2; R ² is NHCH (CO ² R ³ ) CH ² CH ² CO ² R ³ or OR ³ ; R ³ is independently a carboxy-protecting group; X is a bond or C 1 -C ₄ alk-diyl; including: reaction of a compound of formula III: where: R ² and X are as defined above for formula IV; with a compound of formula M (HSO 3 ') n'. where: M is as defined above for Formula IV; and n is 1 or 2; in a solvent - 34 • 9 · ·· 9999 99 99 9 9 9 9 9999 9 99 9 • 99999 9,999 · 9 9 • 9 99 9 9999 999 99 99 The method of claim 14 wherein the compound of formula III is a compound wherein X is a bond, -CH ₂ -, or -CH ₂ CH ₂ - and R ² is NHC * H (CO ² R ³ ) CH ₂ CH ₂ CO ₂ R ³ or OR ³ wherein the configuration on the carbon atom designated * is L. The method of claim 15 wherein X is -CH 2 -. The process of claim 16 wherein the compound of formula M (HSO ₃ ') _n is a compound wherein M is an alkali metal cation and _n is 1 and the reaction is carried out at a temperature between 35 ° C and 50 ° C. The process of claim 17 wherein the alkali metal is sodium. The process of claim 14 wherein the solvent is a mixture of ethyl acetate, 3A-ethanol and water. The method of claim 14, further comprising: reaction of a compound of formula Z: H wherein: R ⁴ is hydrogen or C 1 -C 4 alkyl; and X 'is a bond or C 1 -C 4 alk-diyl; • this ······························ · · · - oo - with the proviso that if X 'is not a bond, then the alpha carbon in the alcohol must be part of the -CH2- group; with a compound of formula II: where: R ² is as defined above for formula IV; and Lg is a leaving group; in a solvent, in the presence of a palladium catalyst, and a phase transfer catalyst, and in the presence of a metal cation chloride, to prepare a compound of formula III. The method of claim 7, further comprising: a) halogenates a compound of formula III for the preparation of a compound of formula V: IN - 36 00 00 00 00 00 00 0000 000 0000 00 0 0 0000 0 00 0 • 00000 · 000 00 0 0 0 00 0 0000 000 00 00 000 00 00 wherein: R ² and X are as defined above for formula III; and the halogen is chloride, bromide or iodide; in a solvent; and b) a base and a compound of formula VI are added to the product of step a): nh ₂ a O h ₂ n N VI; c) optionally removing the carboxy protecting groups in the product of step b); and d) optionally converting the product of step b) or step c) into a salt, to prepare a compound of formula VII: VII where: R is NHCH (CO 2 R ¹⁾ CH 2 CH ₂ CO ₂ R ¹ or OR ^1; and R ¹ is independently at each occurrence hydrogen or a carboxy-protecting group; or a pharmaceutical salt or solvate thereof. • 44 •·· 4444 44 44 • 44 »4 4 · 44 * 4 44 4 4444 4 44 4 4,444 44 4,444 44 4 4 44 44 4444 44 44 44 44 44 * 4 22. The method of claim 21 wherein the compound of formula V is a compound wherein X is a bond, _-CH2 -, or _{-CH2 CH2} - and ^R2 is NHC * H (CO 2 R ³⁾ CH 2 CH ₂ CO ₂ R ³ or OR ³ wherein the configuration on the carbon atom marked with * is L. The process of claim 22, wherein step a) of claim 21 is carried out at a temperature of 35 ° C to 45 ° C. The method of claim 22, wherein the compound of formula VII is a compound wherein R is NHCH (CO ₂ R ¹ ) CH ₂ CH ₂ CO ₂ R ¹ The method of claim 24, wherein the compound of formula V is a compound wherein X is -CH ₂ -. The process of claim 25, wherein step c) of claim 21 is carried out and the compound of formula VII is a sodium hydroxide addition salt as a base. A compound of formula IV as substantially described above with reference to any example. A process for preparing compounds of formula IV as essentially described above with reference to any example. A process for preparing compounds of formula III as essentially described above with reference to any example.