EP4188917A1

EP4188917A1 - Preparation of erdosteine or a derivative thereof using a continuous flow process

Info

Publication number: EP4188917A1
Application number: EP21752189.7A
Authority: EP
Inventors: Matteo ZACCHÈ; Fabio Rondina; Pier Andrea Gatti; Davide SBARBADA; Antonio COTUGNO
Original assignee: Edmond Pharma SRL
Current assignee: Edmond Pharma SRL
Priority date: 2020-07-28
Filing date: 2021-07-26
Publication date: 2023-06-07
Also published as: IT202000018286A1; WO2022023929A1

Abstract

Disclosed is a process for the production of erdosteine or the analogues and derivatives thereof which comprises reacting a solution of an activated derivative of thiodiglycolic acid with a solution of homocysteine thiol actone or a salt thereof, characterised in that the reaction is conducted under continuous flow in a microreactor.

Description

PREPARATION OF ERDOSTEINE OR A DERIVATIVE THEREOF USING A

CONTINUOUS FLOW PROCESS

The present invention relates to a process for the production of erdosteine or the analogues and derivatives thereof which comprises reacting a solution of an activated derivative of thiodiglycolic acid with a solution of homocysteine thiolactone or a salt thereof, characterised in that the reaction is conducted under continuous flow in a microreactor.

The compounds of general formula I:

I wherein Ri can be hydrogen (or a counterion), an alkyl group or a (CH2)_n-Ar group, wherein Ar is a substituted aryl group, and wherein * denotes a stereogenic carbon atom, are a class of substances with mucolytic pharmacological activity of great importance in therapeutic terms. When Ri = H the compound is erdosteine, a well-known mucolytic medicament; otherwise, it is one of the salts or esters thereof. The continuous flow process according to the invention has the advantage of not requiring isolation of intermediates or intermediate purifications during the process, and of using compatible reagents and reaction conditions.

BACKGROUND TO THE INVENTION

Organic process chemistry is a continually developing science that studies the synthesis of complex molecules using processes designed to optimise all the parameters specific to an industrial process, such as yield, purity, number of operations to be conducted, use of increasingly environment-friendly and sustainable materials, productivity in the unit of time, and energy consumption. In the chemical/pharmaceutical industry, said processes are usually conducted in discontinuous mode, in “batch” or “semi-batch” reactors wherein the entire process is repeated iteratively to produce various batches of substance which, when combined, give a total amount consistent with industrial production. Although said methods are well-established and have excellent potential, they usually produce a large amounts of waste and, because of the discontinuity of production and the presence of successive isolation and purification steps at the end of each reaction, their productivity per unit of time is usually suboptimal.

Erdosteine (2-[N-3-(2-oxotetrahydrothienyl)]acetamido)-thioglycolic acid) of formula II is a highly efficient mucolytic disclosed in FR 2,502,153 and US 4,411,909:

Erdosteine possesses a stereogenic carbon atom (indicated by * in formula II), and can therefore exist in two enantiomerically distinct forms, namely R-erdosteine and S- erdosteine, having formulas III and IV respectively:

Other erdosteine derivatives can include carboxyl salts with alkali metals or alkaline earth metals, or with organic bases, or carboxyl esters with alkyl or aryl groups. Said derivatives are expressed by general formula I, wherein * denotes a stereogenic carbon atom, and wherein Ri is hydrogen, an alkyl group or a group wherein n is 0 or 1, and X defines one or more groups selected from hydrogen and alkyl, alkoxyl or nitro groups. The term “alkyl” defines an alkyl group with 1 to 3 carbon atoms, i.e. methyl, ethyl, propyl or isopropyl. The term “alkoxyl” defines a hydroxyl group wherein the hydrogen is substituted by an alkyl group.

The currently known industrial processes for the production of erdosteine, described, for example, in WO 20157028957, CN 101 941 963 and II Farmaco, vol 40(11), 1994, 703-708, involve condensation of the two main synthons V and VI:

The usual synthesis reaction currently used on an industrial scale involves the formation of an amide bond by activation of the carboxyl with a condensing agent, in an anhydrous organic solvent. The salts deriving from the condensation reaction have to be removed from the resulting intermediate by means of successive treatments of trituration in water, filtration and drying.

The final purification involves dissolution of the molecule as salt in aqueous solution by adjusting pH, and repeated procedures of extraction with chlorinated solvents, pH correction, and subsequent filtration and drying.

Methods like the one described above, or other similar methods reported in the literature, suffer from various drawbacks, such as the use of large amounts of solvents, longer times due to the pH corrections, the large number of operations required for trituration and extraction with solvents, the use of toxic chlorinated solvents to eliminate impurities which are difficult to remove, and basically, low productivity in the unit of time.

There is therefore a need for an efficient process for the preparation of erdosteine which does not use toxic solvents, can be applied on an industrial scale, does not involve the formation of impurities that are difficult to remove, and involves a small number of operations with an intensified production capacity.

DISCLOSURE OF THE INVENTION

The present invention provides an innovative, efficient process for the synthesis of erdosteine, which does not require isolation of reaction intermediates or intermediate purification steps, using a continuous flow microreactor. In a general aspect of the invention, the process involves the following steps: a) thiodiglycolic acid (of formula VI) is reacted with a condensing agent, optionally in the presence of a base, to obtain an activated species of the carboxy group for nucleophilic substitution, or alternatively is pre-converted to an activated species for nucleophilic substitution (internal anhydride); b) the activated species is reacted with homocysteine thiolactone (of formula V), to obtain erdosteine by formation of the amide bond; c) the resulting erdosteine is precipitated from the reaction medium or extracted with solvents; optionally, d) erdosteine is further purified by crystallisation or known methods.

Said steps are conducted without isolation of intermediates or further purifications. Moreover, all reactions take place in solution, optionally with pre-filtration of any precipitated salts, in a flow microreactor. The steps take place sequentially in a microreactor equipped with multiple inlets and outlets or in a plurality of microreactors connected sequentially, wherein the first step takes place in the first microreactor or its module, and the second step takes place in the second microreactor or its downstream module. The end-of-reaction mixture is then collected from the last microreactor outlet, and the erdosteine is precipitated directly from said mixture, or alternatively extracted with solvents.

Optionally, the resulting erdosteine can be further purified by crystallisation, trituration in solvent or a mixture of said methods, or other known methods, to obtain an active ingredient of pharmaceutical grade.

The advantages and characteristics of the invention will be described in relation to erdosteine, including with reference to specific aspects of the invention. However, it should be noted that said aspects can also be applied to the derivatives of formula I, i.e. a salified form, an ester, or one of the two single enantiomers III and IV, which, in turn, can be “as is” or in the form of salts or esters, without modifying the scope of the invention, as will be easily understood by the skilled person.

DETAILED DISCLOSURE OF THE INVENTION

Unless otherwise stated, all the technical and scientific terms used herein have their commonly known meaning. All the numerical values indicated should be taken as approximate and not precise values, as they may vary slightly upwards or downwards. Although the numerical values indicated are approximate, in the description and examples they are indicated with the greatest possible precision according to the instruments used.

The term “microreactor” refers to a device able to conduct a chemical or physical process by pumping a fluid into tubes or channels of different shapes and sizes, ranging from a few microns to several millimetres; said tubes or channels are housed in modular or preassembled elements. The characteristics of a microreactor are its physical size, which is smaller than that of conventional chemical reactors, and the high area-to-volume ratio to which the reaction fluid is subjected, which allows a considerable increase in the mass transport characteristics and heat transmission effect. By using systems of this type, and optimising the shape and size of the channels, the flow of the reaction ingredients (on which the residence time, i.e. the reaction time in the channels, directly depends), the reaction temperature and concentration of the reagents, chemical selectivity, process speed and productivity, intrinsic safety of the chemical reaction and control of the critical process parameters can be increased.

In a flow microreactor, each module can be connected to a subsequent downstream module, so as to receive the reaction mixture from the first module and optionally conduct a second chemical reaction by adding further reagents. The modules can be connected either in parallel, to increase productivity, or in series, so that successive reactions can be conducted. Each module comprises a continuous channel, of various shapes and sizes, which can include different curves and changes of direction so as to create a tortuous path to facilitate mixing of the reaction ingredients.

In the continuous flow process for the production of erdosteine (or a derivative thereof of formula I), thiodiglycolic acid of formula VI is converted to an activated species of the carboxy group for nucleophilic substitution, which is reacted with homocysteine thiolactone of formula V in a microreactor, using solvents or mixtures thereof that enable the reaction to be conducted in solution.

Erdosteine is thus obtained, dissolved in solution, from the outlet of the last module or microreactor. The methods for its isolation comprise all those known, such as evaporation, trituration with solvents, crystallisation, extraction with solvents, chromatography, and the like. In a preferred embodiment, the solution is evaporated and diluted again with a solvent or mixture of solvents that allows direct crystallisation of erdosteine from the final reaction medium, thus facilitating industrial production and minimising the operations required.

The bases used for this purpose can be tertiary amines with a pK sufficient to salify thiodiglycolic acid. Examples include triethylamine, diisopropylethylamine and diazabicycloundecene. The solvents used should allow complete dissolution of the ingredients at the concentration selected for the reaction, and can be, for example, tetrahydrofuran (THF), acetone, isopropanol, dimethyl sulphoxide, dichloromethane, water or mixtures thereof.

In a first aspect of the invention, thiodiglycolic acid is pre-converted to an internal anhydride, activated towards nucleophilic substitution, by known methods.

As reported, for example, in Justus Liebigs Annalen der Chemie, 1893, vol. 273, p. 66, and in Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 4, pp. 558-562, thiodiglycolic acid can be treated with a dehydrating agent such as acetyl chloride or acetic anhydride to obtain its internal anhydride, l,4-oxathiane-2,6-dione, as a stable molecule, according to the scheme below:

The resulting internal anhydride of thiodiglycolic acid can then be dissolved in a suitable compatible solvent or mixture of said solvents, at concentrations such that a solution is also obtained in the subsequent condensation reaction step with homocysteine thiolactone in the flow microreactor. Homocysteine thiolactone can in turn be dissolved in a solvent or mixtures thereof, optionally using a base to neutralise it if it is used as the hydrochloride, the common commercial form, or other mineral acid salt or organic acid salt. In a preferred embodiment, l,4-oxathiane-2,6-dione is dissolved in acetone or THF, while homocysteine thiolactone hydrochloride is dissolved in a mixture of water, acetone and triethylamine. The two solutions are pumped into the microreactor at a flow rate such as to obtain a residence time of about 2.5 minutes at a temperature of 60°C. The resulting solution at the outlet of the microreactor is evaporated and diluted with a mixture of water and isopropanol, then cooled to precipitate erdosteine.

In a further aspect of the invention, thiodiglycolic acid is converted to its internal anhydride as first reaction step in the microreactor. Said first step involves preparation of a solution of thiodiglycolic acid and optionally of a base in a suitable solvent, and of a second solution containing the dehydrating agent, optionally with the addition of a base. Said two solutions are pumped into the channels of the first module of the flow microreactor, to obtain the internal anhydride as a transient species in solution.

The two solutions can be prepared with the same solvents or mixtures and the same bases or mixtures, provided that they are chemically compatible with the ingredients. The dehydrating agent can be selected from those commonly known, such as acetic anhydride, propionic anhydride, butyric anhydride, acetyl chloride, propionyl chloride, phosphoryl chloride, etc..

The solutions of thiodiglycolic acid and dehydrating agent are then pumped into the microreactor at a temperature ranging between -20 and 250°C, using flow rates that give a residence time such as to give rise to acceptable conversion of thiodiglycolic acid to its internal anhydride.

The resulting internal anhydride reacts with a solution of homocysteine thiolactone, and optionally a base, to form erdosteine in the second module of the microreactor or in a second microreactor. The same solvent and the same base as used for the internal anhydride formation reaction can also be used to prepare a solution of homocysteine thiolactone and for the optional neutralisation of a salt thereof; alternatively, a solvent that is different but chemically compatible with the solution of said internal anhydride can be used.

The resulting homocysteine thiolactone solution is pumped into the module or microreactor so that it mixes with the internal anhydride solution originating from the first module or microreactor, at a temperature and flow rate that give rise to acceptable conversion for the condensation reaction to give erdosteine. Different permutations of parameters can give comparable results, depending on the ingredients used.

In a preferred embodiment, by way of example, triethylamine is used as base and acetone as solvent for thiodiglycolic acid, while the condensing agent is selected from acetic anhydride and butyric anhydride, and again dissolved in acetone. When the internal anhydride is obtained as described above, homocysteine thiolactone hydrochloride is dissolved in water to conduct the condensation reaction. In said embodiment, the base required for neutralisation is premixed in the thiodiglycolic acid solution. With said combinations of ingredients, for example, the residence time required to obtain sufficient conversion is about 3.5 minutes for the formation of the internal anhydride, and 3.5 minutes for the condensation reaction, at a temperature of 60°C for both reaction steps.

In a further preferred embodiment, thiodiglycolic acid is dissolved in acetone and reacted with a solution of acetic anhydride in acetone in the first module, while homocysteine thiolactone hydrochloride is dissolved in a mixture of acetone and water; the triethylamine required for its neutralisation is pumped through a further inlet in the microreactor simultaneously with the solution of homocysteine thiolactone, and said mixture is pumped into the second module of the microreactor. With said combinations of ingredients, for example, the total residence time required to obtain sufficient conversion is about 2.5 minutes at a temperature of 180°C to complete both reaction steps.

The solutions obtained with the preferred embodiments described above are then evaporated and diluted with a mixture of water and isopropanol, then cooled to precipitate erdosteine, which is isolated by filtration. Alternatively, after evaporation, the residue is diluted with water, and erdosteine is extracted with solvents. After re-evaporation and dilution with a mixture of water and isopropanol, erdosteine is obtained as a filterable solid.

In a further aspect of the invention, thiodiglycolic acid is pre-converted to an activated species of the carboxy group according to the scheme below: wherein X represents a leaving group. Said derivatives can be acyl chlorides (wherein X is represented by a halogen), carbodiimides (wherein X is an acyl-isourea), phosphoric anhydrides (wherein X is a phosphonate or alkylphosphonate group) or mixed anhydrides (wherein X is a carboxylic acid or alkyl formate derivative). The condensation reagents usable for said purpose are commonly known. For example, thionyl chloride, oxalyl chloride, phosphorus trichloride or similar reagents can be used to form an acyl chloride. Examples of carbodiimide comprise dicyclohexylcarbodiimide, ethyl- dimethylaminopropyl carbodiimide and the like. When a phosphoric anhydride is to be formed, polyphosphoric anhydride or alkyl derivatives thereof, such as propylphosphonic anhydride, are used. A mixed anhydride is commonly formed using an alkyl halogen formate such as ethyl chloroformate or isobutyl chloroformate and similar reagents, or the acyl chloride of a carboxylic acid such as acetyl chloride or isobutyryl chloride. There are also numerous coupling reagents commonly known for the formation of an amide bond, such as hydroxybenzotriazole and derivatives, carbonyldiimidazole and derivatives, and many others.

The carboxyl -activated derivative of thiodiglycolic acid can be pre-prepared by reacting thiodiglycolic acid with one of said coupling reagents in a suitable compatible solvent, optionally in the presence of a base. Any precipitated salts from the activation reaction can then be filtered. Said solution can be pumped into the flow microreactor together with a solution of homocysteine thiolactone or a salt thereof, at a temperature ranging between -20 and 250°C and at flow rates that give a residence time useful for completion of the reaction.

In a preferred embodiment, the carboxyl is activated by formation of a phosphoric anhydride, by mixing thiodiglycolic acid and triethylamine in acetone and adding a solution of tripropanephosphonic anhydride. The precipitated salts are filtered, and the resulting solution is pumped into the microreactor together with a solution of homocysteine thiolactone base in acetone. Under said conditions, the residence time required for complete conversion is about 2 minutes at a temperature of 50-60°C. The solution thus collected is evaporated and diluted with isopropanol to obtain erdosteine as a filterable solid.

In a further preferred embodiment, the carboxyl is activated by formation of an acyl-isourea, by mixing thiodiglycolic acid and ethyl-dimethylaminopropyl carbodiimide in a mixture of isopropanol and ethyl acetate. The resulting solution is pumped into the microreactor together with a solution of homocysteine thiolactone hydrochloride in isopropanol, ethyl acetate and diazabicycloundecene. Under said conditions, the residence time required for complete conversion is about 2 minutes at a temperature of 25°C. The solution thus collected is evaporated and diluted with water to obtain erdosteine as a filterable solid. In a further preferred embodiment, the carboxyl is activated by formation of a mixed anhydride with the use of a carboxylic acid acyl halide. For example, thiodiglycolic acid and triethylamine can be mixed in acetone, and the mixed anhydride obtained by adding isobutyryl chloride. The precipitated salts are filtered, and the resulting solution is pumped into the microreactor together with a solution of homocysteine thiolactone hydrochloride in a mixture of acetone, water and triethylamine. Under said conditions, the residence time required for complete conversion is about 1.3 minutes at a temperature of about 100°C. The solution thus collected is evaporated and diluted with water and isopropanol to obtain erdosteine as a filterable solid.

In a further preferred embodiment, the carboxyl is activated by formation of a mixed anhydride with the use of an alkyl formate. For example, thiodiglycolic acid and triethylamine can be mixed in acetone, and the mixed anhydride obtained by adding ethyl chloroformate or isobutyl chloroformate. The precipitated salts are filtered, and the resulting solution is pumped into the microreactor together with a solution of homocysteine thiolactone hydrochloride in a mixture of acetone, dimethylsulphoxide and triethylamine, with filtration of the salts. Under said conditions, the residence time required for complete conversion is about 5 minutes at a temperature of 25°C. The solution thus collected is evaporated and diluted with water to obtain erdosteine as a filterable solid.

In a further aspect of the invention, the activated species of the carboxy group is generated as first reaction step in the microreactor. Said first step involves preparation of a solution of thiodiglycolic acid and optionally of a base in a suitable solvent, and of a second solution containing the coupling agent. Said two solutions are pumped into the channels of the first module of the flow microreactor, to obtain the activated species as a transient species in solution, at a temperature ranging between -20 and 250°C and at flow rates that give a residence time useful for completion of the reaction. The solvent or mixture of solvents used in said first reaction step should be selected in such a way as to prevent precipitation of the salts in the microreactor. Solvents useful for said purpose are, for example, alcohols such as ethanol, propanol, isopropanol and butanol, or water- soluble solvents mixed with water, such as acetone/water or THF/water or alcohol/water mixtures. Said solvents or mixtures are also reactive towards the activated species by solvolysis, i.e. hydrolysis in the case of water and esterification in the case of an alcohol. However, the solvolysis kinetics can be moderated by using optimised parameters to maximise the formation of the amide bond with homocysteine thiolactone, because the primary nitrogen of said molecule is kinetically favoured over the solvolysis reaction.

The resulting activated species reacts with a solution of homocysteine thiolactone, and optionally a base, to form erdosteine in the second module of the microreactor or in a second microreactor. The same solvent and the same base as used for the activated species formation reaction can also be used to prepare a solution of homocysteine thiolactone and for the optional neutralisation of a salt thereof; alternatively, a solvent that is different but chemically compatible with the solution of said activated species can be used. The resulting homocysteine thiolactone solution is pumped into the second module or the microreactor so that it mixes with the solution of the activated species of thiodiglycolic acid originating from the first module or microreactor at a temperature and flow rate that give rise to acceptable conversion for the condensation reaction to give erdosteine, and reduces the solvolysis of the activated species. In a preferred embodiment, the carboxyl is activated by formation of a mixed anhydride with the use of an alkyl formate. For example, thiodiglycolic acid and triethylamine are dissolved in isopropanol to form a first solution, while ethyl chloroformate is dissolved in isopropanol to form a second solution. Said solutions are pumped into the first module of the microreactor to obtain the formation of the mixed anhydride derived from condensation between thiodiglycolic acid and ethyl chloroformate, which reacts in the second module of the microreactor with a solution of homocysteine thiolactone hydrochloride dissolved in a mixture of acetone, water and triethylamine. Under said conditions, the residence time required to complete all the chemical reactions involved is about 5 minutes at 50°C. The solution thus collected is evaporated and diluted with water and isopropanol to obtain erdosteine as a filterable solid.

If isobutyl chloroformate is used instead of ethyl chloroformate, the residence time required to complete the process is about 1.5 minutes at 70°C.

The erdosteine obtained by the process according to the invention is substantially devoid of impurities and foreign material, and is therefore suitable for use as an active pharmaceutical ingredient (API) for the preparation of a pharmaceutical form, including an injectable form, which clearly requires a higher degree of purity. The advantages over a standard industrial process are obvious. Primarily, the times required for conversion are a few minutes, compared with the hours required for a batch process. This gives rise to high productivity, far greater than that of a classic process. Moreover, in the embodiments described, all the solvents used are environment-friendly and non-toxic. The operations are few and simple, involving simple preparations of some solutions, and not all the process is managed by the production operatives, thereby increasing the intrinsic safety of the facility and reducing the possibility of errors. Moreover, in view of the greater control over the reaction parameters and the speed of the process, impurities likely to require long and inconvenient successive purification steps are not formed, thereby even further improving productivity and further reducing the number of operations.

The process according to the invention is therefore innovative, simple, economical, efficient, environment-friendly and suitable for industrial-scale production of erdosteine and the derivatives of formula I with high yields and high purity.

The following examples illustrate the invention in more detail. EXAMPLE 1

Preparation of erdosteine using l,4-oxathiane-2,6-dione

A solution of l,4-oxathiane-2,6-dione (47.2 g) in THF (421 mL), and a second solution of homocysteine thiolactone hydrochloride (50 g) in a mixture of THF (166 mL), water (166 mL), acetone (166 mL) and triethylamine (32.9 g), are prepared. The two solutions are pumped into a microreactor with an internal volume of 5.4 mL at flow rates of 1 mL/min for both (corresponding to a residence time of 2.7 minutes) at 60°C. 640 mL of solution is collected, evaporated until the residue only contains water, and diluted with isopropanol (160 mL). After cooling, filtration and drying, 16.7 g of pure erdosteine is obtained.

EXAMPLE 2

Preparation of erdosteine with formation in situ of internal anhydride

A solution of thiodiglycolic acid (45 g) and triethylamine (60.7 g) in acetone (400 mL), and a solution of butyric anhydride (47.4 g) and triethylamine (60.7 g) in acetone (400 mL), are prepared. A third solution is prepared with homocysteine thiolactone hydrochloride (46 g) in water (450 mL). The first two solutions are pumped into the first module of a microreactor with an internal volume of 2.7 mL at flow rates of 0.27 mL/min at 60°C. The output of the first module is pumped simultaneously with the third solution into the second module of the microreactor with an internal volume of 2.7 mL at flow rates of 0.27 mL/min (total residence time 6.7 minutes) at 60°C. When 300 mL of solution has been collected, the pH is corrected to 5.5, and the mixture is evaporated until the residue only contains water. The mixture is extracted with ethyl acetate, the combined organic phases are evaporated, and the residue is crushed with acetone. After filtration and drying, 9.5 g of pure erdosteine is obtained.

EXAMPLE 3

Preparation of erdosteine with formation in situ of internal anhydride

A solution of thiodiglycolic acid (45 g) and triethylamine (60.7 g) in acetone (400 mL), and a solution of acetic anhydride (30.6 g) and triethylamine (60.7 g) in acetone (400 mL), are prepared. A third solution is prepared with homocysteine thiolactone hydrochloride (46 g) in water (450 mL). The first two solutions are pumped into the first module of a microreactor with an internal volume of 2.7 mL at flow rates of 0.27 mL/min at 60°C. The output of the first module is pumped simultaneously with the third solution into the second module of the microreactor with an internal volume of 2.7 mL at flow rates of 0.25 mL/min (total residence time 6.8 minutes) at 60°C. 800 mL of solution is collected, the pH is corrected to 5.7, and the mixture is evaporated until the residue only contains water. The mixture is extracted with ethyl acetate, the combined organic phases are evaporated, and the residue is crushed with acetone. After filtration and drying, 8.4 g of pure erdosteine is obtained.

EXAMPLE 4

Preparation of erdosteine with formation in situ of internal anhydride

A solution of thiodi glycolic acid (100 g) in acetone (400 mL), a solution of acetic anhydride (68.3 g) in acetone (370 mL), and a solution of homocysteine thiolactone hydrochloride (96 g) in water (160 mL), acetone (540 mL) and triethylamine (63.2 g), are prepared. The first two solutions are pumped into the first module of a microreactor with an internal volume of 2.7 mL at flow rates of 0.65 mL/min at 175°C. The output of the first module is pumped simultaneously with the third solution into the second module of the microreactor with an internal volume of 2.7 mL at flow rates of 1.2 mL/min (total residence time 2.5 minutes) at 175°C. 450 mL is collected, the acetone is evaporated, and the residue is diluted with isopropanol. After filtration and drying, 24.4 g of pure erdosteine is obtained.

EXAMPLE 5

Preparation of erdosteine with activation by phosphoric anhydride

A suspension of homocysteine thiolactone hydrochloride (21.3 g) in acetone (250 mL) and triethylamine (14 g) is prepared. After 2 hours under stirring, the suspension is filtered from the salts to obtain a solution of homocysteine thiolactone base in acetone at the same molar concentration. A second solution is prepared with thiodiglycolic acid (27 g), acetone (125 mL) and triethylamine (18.2 g), to which tripropanephosphonic anhydride (114.4 g of 50% w/w solution) is added. After one hour under stirring, the suspension is filtered from the salts to obtain a solution of phosphoric anhydride and thiodiglycolic acid. The two solutions are pumped into a microreactor with an internal volume of 5.4 mL at flow rates of 1.0 mL/min (total residence time 2.7 minutes), at temperatures ranging between 50 and 60°C. 500 mL of solution is collected, the solvent is evaporated, and the residue is crushed with isopropanol (125 mL). After cooling, filtration and drying, 17.2 g of pure erdosteine is obtained.

EXAMPLE 6

Preparation of erdosteine with activation by mixed anhydride

A solution of thiodiglycolic acid (5 g) in acetone (60 mL) and triethylamine (3.88 g) is prepared. Ethyl chloroformate (4.23 g) is added, and after 1 hour the salts are filtered to obtain a mixed anhydride solution between thiodiglycolic acid and ethyl chloroformate. A second solution is prepared by mixing homocysteine thiolactone hydrochloride (3.58 g), acetone (48 mL), triethylamine (2.36 g) and dimethylsulphoxide (12 mL); after 30 minutes, the salts are filtered to obtain a solution of homocysteine thiolactone base. The two solutions are pumped into a microreactor with an internal volume of 5.4 mL at flow rates of 0.5 mL/min (total residence time 5.4 minutes), at a temperature of 25°C. 75 mL of solution is collected, the solvent is evaporated, and water (180 mL) is added. After cooling, filtration and drying, 2.4 g of pure erdosteine is obtained.

EXAMPLE 7

Preparation of erdosteine with activation by mixed anhydride in situ

A first solution of thiodiglycolic acid (100 g) in isopropanol (300 mL) and triethylamine (66.8 g) is prepared. A second solution is prepared by mixing ethyl chloroformate (73 g) in isopropanol (360 mL). A third solution is prepared with homocysteine thiolactone hydrochloride (100 g) in acetone (600 mL), water (120 mL) and triethylamine (66.8 g). The first two solutions are pumped into the first module of a microreactor with an internal volume of 2.7 mL at flow rates of 0.25 mL/min at 50°C. The output of the first module is pumped simultaneously with the third solution into the second module of the microreactor with an internal volume of 2.7 mL at flow rates of 0.5 mL/min (total residence time 5.4 minutes) at 50°C. 500 mL of solution is collected, the solvent is evaporated and the residue is crushed with isopropanol (125 mL). After cooling, filtration and drying, 17.2 g of pure erdosteine is obtained.

EXAMPLE 8

Preparation of erdosteine with activation by mixed anhydride in situ

A first solution of thiodiglycolic acid (100 g) in isopropanol (300 mL) and triethylamine (66.8 g) is prepared. A second solution is prepared by mixing isobutyl chloroformate (73 g) in isopropanol (360 mL). A third solution is prepared with homocysteine thiolactone hydrochloride (100 g) in acetone (600 mL), water (120 mL) and triethylamine (66.8 g). The first two solutions are pumped into the first module of a microreactor with an internal volume of 2.7 mL at flow rates of 0.25 mL/min at 70°C. The output of the first module is pumped simultaneously with the third solution into the second module of the microreactor with an internal volume of 2.7 mL at flow rates of 0.5 mL/min (total residence time 1.5 minutes) at 50°C. 500 mL of solution is collected, the solvent is evaporated and the residue is crushed with isopropanol (125 mL). After cooling, filtration and drying, 21.2 g of pure erdosteine is obtained.

EXAMPLE 9

Preparation of erdosteine with activation by acyl-urea

A first solution of thiodiglycolic acid (11.3 g) in isopropanol (200 mL) is prepared, and ethyl-dimethylaminopropyl carbodiimide (14.4 g) is added, followed by ethyl acetate (50 mL). A second solution is prepared by mixing homocysteine thiolactone hydrochloride (10.4 g) in isopropanol (240 mL), ethyl acetate (50 mL) and diazabicycloundecene (10.4 g). The two solutions are pumped into the microreactor with an internal volume of 5.4 mL at a total flow rate of 2.7 mL/min (total residence time 2 minutes) at 25°C. 380 mL of solution is collected, the solvent is evaporated, and the residue is diluted with water (100 mL). After cooling, filtration and drying, 9.8 g of pure erdosteine is obtained.

EXAMPLE 10

Preparation of erdosteine with activation by mixed anhydride in situ

A solution of thiodiglycolic acid (25.5 g) in acetone (158 mL) and triethylamine (17.2 g) is prepared. Isobutyryl chloride (18.1 g) is added, and after 30 minutes the salts are filtered to obtain a mixed anhydride solution between thiodiglycolic acid and isobutyric acid. A second solution is prepared by mixing homocysteine thiolactone hydrochloride (50 g) in acetone (300 mL), water (60 mL) and triethylamine (33.4 g). The two solutions are pumped into a microreactor with an internal volume of 5.4 mL at flow rates of 2 mL/min (total residence time 1.35 minutes), at a temperature of 100°C. 100 mL of solution is collected, the solvent is evaporated, and water (5 mL) and isopropanol (40 mL) are added. After cooling, filtration and drying, 5.7 g of pure erdosteine is obtained.

Claims

1. Process for the preparation of a compound of formula I

I wherein Ri can be hydrogen (or a counterion), an alkyl group or a (CH2)_n-Ar group, wherein Ar is a substituted aryl group, and wherein * denotes a stereogenic carbon atom, which comprises the reaction between a solution of an activated derivative of thiodiglycolic acid of formula VI

VI with a solution of homocysteine thiolactone of formula V or a salt thereof,

V characterised in that the reaction is carried out in continuous flow in a microreactor.

2. Process according to claim 1 wherein the compound of formula I is erdosteine.

3. Process according to claim 1 or 2 wherein the microreactor is equipped with multiple inlets and outlets or the microreactor comprises several microreactors or modules connected sequentially.

4. Process according to claim 3 wherein the first step takes place in a first microreactor or a module thereof and the second step takes place in a second microreactor or a module thereof positioned downstream.

5. Process according to claim 1, 2, 3 or 4 wherein the activated derivative of thiodi glycolic acid VI is the internal l,4-oxathian-2,6-dione anhydride obtained by treating thiodiglycolic acid with a dehydrating agent.

6. Process according to claim 5 wherein the dehydrating agent is acetyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, acetyl chloride, propionyl chloride or phosphoryl chloride.

7. Process according to claim 5 or 6 wherein l,4-oxathian-2,6-dione is dissolved in acetone or THF, preferably acetone, and the dehydrating agent is a solution in acetone of acetic anhydride or butyric anhydride.

8. Process according to claim 1 or 2 wherein the activated derivative is a halide, preferably an acyl chloride, a carbodiimide, a phosphoric anhydride or a mixed anhydride.

9. Process according to any one of claims 5 to 8 wherein homocysteine thiolactone hydrochloride is dissolved in the presence of triethylamine in water or in a mixture of water and acetone.

10. Process according to one or more of claims 1 to 9, wherein the solution of the activated derivative of thioglycolic acid is pumped into the flow microreactor together with the solution of homocysteine thiolactone or a salt thereof, at a temperature ranging between -20 and 250°C.