New process for the preparation of specialized pro-resolving mediators (SPMS)

Abstract

The subject of invention is new process for the preparation of esters, carboxylic acids and their pharmaceutically acceptable salts of formula (I): (I) via a compound of formula (IV): (IV) and the preparation of new intermediates applied in the new synthetic route.

Description

[0001] New Process for the Preparation of Specialized Pro-resolving Mediators (SPMs)

[0002] The subject of the invention

[0003] The subject of the invention is a new process for the preparation of esters, carboxylic acids and their salts of formula (I) and the new intermediates applied in the synthetic route of the present invention as well as their preparation.

[0004] Background of the invention

[0005] Numerous potential medical treatments have been identified for the molecules that can economically be produced with our invention, especially Maresinl (Marl) and Protectin DI (PD1):

[0006] Such treatments include vulvar pain (US2020121617A 1 Treatment of Vulvar Pain), vitiligo (WO2022193029 Specialized pro-resolving mediators as melanocyte growth promoter and pro-survival factors and uses thereof), vascular injury (US2020113861A1 Compounds and Methods for Modulating Vascular Injury), ischemic stroke (WO2013044176A2 Methods and Compositions for the Treatment of Ischemic Stroke), skin inflammation and oxidative stress caused by UVB (Cezar, T. L. C, Martinez, R. M., Rocha, C. da, Melo, C. P. B., Vale, D. L., Borghi, S. M., Casagrande, R. (2019). Treatment with maresin 1, a docosahexaenoic acid- derived pro-resolution lipid, protects skin from inflammation and oxidative stress caused by UVB irradiation. Scientific Reports). Clinical trials are run for various indications, such as macula degradation and newborns retina injuries. Due to high biological activities of these SPMs, developments of new high efficacy drug products with extremely low daily doses are expected in the near future.

[0007] Process for the preparation of a compounds according to formula (I) has been described in several articles.

[0008] Spur et. al. (Tetrahedron Letters 53 (2012) 4169-4172) synthetize the molecule by Sonogashira coupling. One of the coupling agents (2) is prepared according to Scheme 1 in the cited article as follows:

[0009] A new approach was applied for achieving the required stereochemistry of the hydroxyl group. The main disadvantage of the process of viny-iodide (2) is the use of special reagents (e.g. m-chloro-peroxy-benzoic acid), catalysts (e.g. (S,S)-(salen)Co(III)(OAc), Lindlar catalyst) and solvents (e.g. benzene) that makes industrial scale-up impossible. Takai olefin synthesis, used for synthesis of vinyl iodide group, is also difficult to apply in industrial environment. According to the article hydroxyl group of vinyl-iodide (2) is protected by triethyl-silyl protecting group.

[0010] The coupling agent (3) is prepared according to a well-known reaction scheme below: However, according to our experiments, the process of terminal acetylene formation by LDA is not economical at scale-up, as the yield is decreasing significantly.

[0011] Spur et. al. perform the Sonogashira coupling and final steps of the synthesis as shown below:

[0012] The synthesis is widely used in the literature and the hydroxyl group of acetylene derivatives (3) is unprotected in the process. Due to the unprotected hydroxyl group, the yield of selective reduction of triple bond by Zn(Cu / Ag) catalyst is low. Not only low yield but significant increase of decomposition products is also expected. It is also worth to mention the limitation of using the special catalyst Zn(Cu / Ag) for industrial scale.

[0013] Petasis et. al. (Tetrahedron Letters, 53(14), 1695-1698) perform Sonogashira coupling by vinyl-iodide (5) and acetylene structure (22). Following steps of synthesis contain well-known reactions and reagents:

[0014] Main advantages of the process are the use of well-known robust reactions and the use of non-special reagents. Hydroxyl groups of both coupling agents are protected and this provides good yield and proper impurity profile of the product of Sonogashira coupling. The process cannot be applied for industrial scale due to the requirement of using special reagents (e.g. CBr4, Lindlar catalyst for the preparation of (22)) and special reactions (e.g. Takai olefin synthesis, Lindlar reduction for (5)). Having Sonogashira coupling completed, both hydroxyl groups undergo deprotection, and a robust and scalable reduction is performed by Zn powder. However, a significant decrease of yield is expected in reduction with Zn powder with unprotected hydroxyl groups.

[0015] The protection strategy of Petasis et. al. results in yield of merely 36%. Aursnes et al. (Org. Biomol. Chem., 12(3), 432-437) perform Sonogashira coupling by using vinyl-bromide (21) and acetylene derivative (5). Further steps of the synthesis are well- known from literature:

[0016] Protectin D1 The process has significant advantages due to the application of robust reactions with non-special reagents. The protection of hydroxyl groups of both coupling agents (21, 5) provides good yields and proper impurity profile of product of Sonogashira coupling (22).

[0017] Disadvantages of the process include the bromination step for preparation of vinyl-iodide (21) which is difficult to scale-up and involves the use of dangerous bromine. Further disadvantage is the use of sensitive Lindlar catalyst for hydrogenation reaction (reduction). The robust reduction process with Zn powder has not been selected for the protected structure (22) most likely because the hydroxyl protection groups can only be removed with significant loss and impurity formation from the reduced molecule (contains only double bonds).

[0018] Ogawa et. al. (Tetrahedron Leters, 52(23), 3001 -3004) apply a coupling reaction where they could avoid the cumbersome selective reduction of triple bond and the side reactions. They react terminal acetylene (29) with bis(l,2-dimethylpropyl)boran (Sia2BH) in a hydroboration process and the resulting structure is reacted with vinyl-iodide (4b).

[0019] Advantages of the process are the selectivity of hydroboration and the simple reactions in the end of the synthesis. Significant disadvantages are the use of special / dangerous (for health and environment) reagents (e.g. t-Bu00H / D-DIPT / Ti(0Pr4), DMPU (N,N'- Dimethylpropylene urea), bromine) for the production of starting materials (4b) and (3). Moreover, there are sensitive and hardly scalable reactions (e.g. epoxidation, hydroboration by freshly prepared Sia2BH) in the process of starting materials. Above cited articles from the literature describe processes for mg-scale, with very limited information for purity of the products. Processes of Rodriguez’s, Ogawa’s and Aursnes’ are not scalable for industrial use and Petasis is also using special, not scalable reaction steps with poor yields.

[0020] Products of the above evaluated processes are more likely below 90% HPLC purity or hardly reach this limit.

[0021] According to scientific expectations and internationally accepted directives, drug substances must meet min. 95% purity level while other related impurity must not be over 3%.

[0022] We can conclude that prior art processes have poor yields and purity, and special reagents / reactions make industrial use unlikely. The goal of the present invention was to develop a scalable process with good yields which provides high purity products for drug substance application.

[0023] Short description of the invention

[0024] To achieve the objectives described above, the inventors of the present invention have developed a process that produces high quality products from appropriate intermediates containing all carbon atoms and hydroxyl groups of the final structures. To do so, it was necessary to find the proper intermediates with the final structure / stereochemistry that can be transformed into final product without significant decomposition and / or isomerization. Another goal was to remove potential isomers at early stages of the process (i.e., at early intermediates) to decrease purification steps (and therefore avoiding potential decompositions) in the final part of the process.

[0025] Our finding is even more surprising, by choosing a strategy based on the proper choice and location of the protecting group, the Sonogashira coupling can be performed with good yield. Using this strategy, the obtained compound of formula (IV) can be reduced and deprotected without significant decompositions.

[0026] In a first aspect, the present invention relates to a process for the preparation of a compound of formula (I): wherein,

[0027] R represents H atom or Ci-4 alkyl, preferably methyl or ethyl; n equals 1 and z equals 2, or n equals 2 and z equals 1; or a pharmaceutically acceptable salt thereof, wherein the process comprises:

[0028] Step 1) Sonogashira coupling of a compound comprising a terminal acetylene group and a protected hydroxyl group with a corresponding compound comprising a vinyl iodide structure and an unprotected hydroxyl group; followed by

[0029] Step 2) selective reduction of the triple bond formed in Step 1) to double bond with Z stereochemistry; followed by

[0030] Step 3) hydroxyl deprotection; and if desired followed by,

[0031] Step 4) ester hydrolysis to carboxylic acid and if desired salt formation. In a second aspect, the present invention relates to a compound of formula (IV):

[0032] R’ represents Ci-4 alkyl;

[0033] R” represents a silyl protecting group; and n equals 1 and z equals 2, or n equals 2 and z equals 1.

[0034] In a third aspect, the present invention relates to a compound of formula (Va):

[0035] In a fourth aspect, the present invention relates to a compound of formula (Illa): wherein R’ means Ci-4 alkyl.

[0036] In a fifth aspect, the present invention relates to a compound of formula (Illb):

[0037] Detailed description of the invention

[0038] In a first aspect, the present invention relates to a process for the preparation of a compound of formula (I): wherein,

[0039] R represents H atom or Ci-4 alkyl, preferably methyl or ethyl; n equals 1 and z equals 2, or n equals 2 and z equals 1; or a pharmaceutically acceptable salt thereof, wherein the process comprises:

[0040] Step 1) Sonogashira coupling of a compound comprising a terminal acetylene group and a protected hydroxyl group with a corresponding compound comprising a vinyl iodide structure and an unprotected hydroxyl group; followed by

[0041] Step 2) selective reduction of the triple bond formed in Step 1) to double bond with Z stereochemistry; followed by

[0042] Step 3) hydroxyl deprotection; and if desired followed by,

[0043] Step 4) ester hydrolysis to carboxylic acid and if desired salt formation.

[0044] A particular embodiment of the invention is a process for the preparation of a compound of formula (I’):

[0045] In one particular embodiment, the compound comprising a terminal acetylene group and a protected hydroxyl group in Step 1) is of formula (II): or in a more particular embodiment it is a compound of formula (II’) wherein R" represents a silyl protecting group, and the value of n is as defined above; and the vinyl iodide structure comprising an unprotected hydroxyl group in Step 1) is a compound of formula (III): or in a more particular embodiment it is a compound of formula (IIP) wherein R’ represents Ci-4 alkyl, preferably methyl or ethyl, and the value of z is as defined above.

[0046] In other particular embodiment, the resulted product of the Sonogashira coupling in Step 1) is a compound of formula (IV): or in a more particular embodiment it is a compound of formula (IV’) wherein the meanings of R’ and R” and the values of n and z are as defined above.

[0047] In other particular embodiment, the compound with a new double bond with Z stereochemistry obtained in Step 2) of the process is a compound of formula (V): or in a more particular embodiment it is a compound of formula (V’) wherein the meanings of R’ and R” and the values of n and z are as defined above.

[0048] In other particular embodiment, the compound with the hydroxyl group deprotected in Step 3) is a compound of formula (lb) or in a more particular embodiment it is a compound of formula (lb’) wherein the meanings of R’, and the values of n and z are as defined above.

[0049] In a particular embodiment, the compound with the hydrolyzed ester group obtained in Step 4) is a compound of formula (la), or in a more particular embodiment it is a compound of formula (la’) wherein the values of n and z are as defined above; or its corresponding pharmaceutically acceptable salt.

[0050] In a preferred embodiment, the process of the present invention comprises the following steps:

[0051] Step 1) The Sonogashira coupling. A compound of formula (II): wherein

[0052] R” is a silyl protecting group selected from: dimethyl-isopropyl silyl (DMIPS), diethylisopropyl silyl (DEIPS), 2-norbornyl-dimethyl silyl (NDMS), di-terc-butyl-isobutyl silyl (BIBS), terc-butyl-diphenyl silyl (TBDPS), terc-butyl-dimethyl-silyl (TBDMS), tribenzyl silyl, triphenyl silyl, diphenyl-methyl silyl (DPMS), di-t-butyl-methyl silyl (DTBMS), terc-butyl- methoxyphenyl silyl (TBMPS), terc-butoxy-diphenyl silyl (DPTBOS), dimethyl-thexyl silyl (DMTS), particularly R” is terc-butyl-dimethyl-silyl (TBDMS); and n is 1 or 2; is reacted with a compound of formula (III) where hydroxyl group is unprotected: wherein

[0053] R’ is Ci-4 alkyl, and n equals 1 and z equals 2, or n equals 2 and z equals 1.

[0054] According to a specific embodiment of the invention in the Sonogashira coupling a compound of formula (II’) is reacted with a compound of formula (III’) wherein R”, R’, n and z are as defined above.

[0055] An important invention was the unnecessary protection of vinyl iodide compound’s hydroxyl group adjacent to highly unstable conjugated double bonds. Missing protection does not generate decompositions in this region of the structure.

[0056] According to an embodiment of the present invention, unprotected (containing free hydroxyl group) vinyl iodide compound of formula (III) is reacted with hydroxyl-protected terminal acetylene compound of formula (II) in an alkylamine as solvent, in the presence of a palladium catalyst at 20 - 80°C. In a particular embodiment, the palladium catalyst is selected from [Pd(PPh3)2C12], [Pd(dppe)C12], [Pd(dppp)C12], and [Pd(dppf)C12],

[0057] In a more particular embodiment, the palladium catalyst is tetrakis-triphenylphosphine.

[0058] In a particular embodiment, the solvent is a primer, secondary or tertiary amine or mixtures thereof.

[0059] In a more particular embodiment, the solvent is selected from triethylamine, diethylamine, N-isopropylamine, and N,N-diisopropylamine,

[0060] In a much more particular embodiment the solvent is N,N-diisopropylamine.

[0061] In a particular embodiment, Step 1) is performed by applying 20-80°C temperature range.

[0062] In a more particular embodiment, Step 1) is performed by applying 20-30 °C temperature range.

[0063] In a particular embodiment, the reaction is protected from light.

[0064] In a more preferred embodiment, the silyl protecting group is TBDMS.

[0065] Significant invention of the process is that Sonogashira coupling (the leading reaction to the final structure) can be performed with good efficacy (good yield, negligible side-reactions) by applying unprotected vinyl iodide (III) derivative in the reaction. The outstanding advantage of the approach is avoiding the deprotection of this hydroxyl group in the later phase of the process, where the deprotection reaction initiates significant decomposition processes in this position of the final structure.

[0066] In a particular embodiment, the z value of the compound of formula (III) is 1 :

[0067] (Illa’) wherein R’ represents Ci-4 alkyl, preferably methyl or ethyl.

[0068] In a particular embodiment, the z value of the compound of formula (III) is 2 and R’ is ethyl:

[0069] (nib’) .

[0070] Having reaction completed, the mixture quenched by aqueous solution and solvent, such as N,N-diisopropylamine, is removed by addition of sodium hydrogen sulphate solution forming sulphate salt of the amine. The organic phase containing the product, is dried over sodium sulphate, concentrated by evaporation, and dissolved in toluene as a preparation for the chromatographic purification.

[0071] In this reaction, it is obtained the crude product of formula (IV): wherein R’ is Ci-4 alkyl, preferably ethyl or methyl; R” is a silyl protecting group; and n equals 1 and z equals 2, or n equals 2 and z equals 1.,

[0072] According to a specific embodiment in the Sonogashira coupling of compound of formula (II’) and compound of formula (III’) the compound of formula (IV’) is formed wherein R’, R”, n and z are as defined above.

[0073] The crude product is purified by chromatography. In a particular embodiment, the obtained crude product (IV) or (IV’) is purified by normal phase chromatography.

[0074] Step 2) The selective reduction of the triple bond. The present invention revealed the surprising fact that the selective reduction reaction of triple bond induces degradation processes when there is an unprotected hydroxyl group adjacent to triple bond’s carbon atom. More surprisingly, the other hydroxyl of the molecule is merely involved in these degradation processes even without protecting group. By avoiding the mentioned decomposition processes / products a compound of formula (V) is obtained through the process of the present invention, with high purity and thus no further purification step is needed before introduction in next process step.

[0075] Selective reduction of the triple bond of compound of formula (IV) is performed without experiencing significant degradation due to silyl group protection of hydroxyl group at the adjacent carbon atom of triple bond. To perform selective reduction of triple bond, zinc powder is suspended in a mixture of protic polar solvent and water, and a trimethyl-silyl auxiliary material is added to the suspension. In one of the embodiments, Step 2) is performed by using protic polar solvents or mixtures thereof.

[0076] In the preferred embodiment, the solvent is a mixture of methanol and water.

[0077] In a particular embodiment, the protic polar solvent is an alkyl alcohol.

[0078] In a more particular embodiment, the alkyl alcohol solvent is selected from propanol, ethanol, methanol, or mixtures thereof.

[0079] In a much more particular embodiment, the alkyl alcohol solvent is methanol.

[0080] In the preferred embodiment of the process, the reduction of compound (IV) is performed in the presence of zinc.

[0081] In one of the embodiments, the trimethyl-silyl auxiliary material is trimethyl silyl chloride.

[0082] Methanol solution of compound (IV) is added to the reaction mixture while stirring. Having the reaction completed, zinc powder is filtered, and compound product (V) is extracted by an aprotic polar solvent from the reaction mixture. The solution of the product is concentrated by evaporation and used for following steps in the synthesis without further purification. Optionally, the product can be purified.

[0083] In a particular embodiment, the aprotic polar solvent is dichloromethane.

[0084] In a more particular embodiment, the aprotic polar solvent is selected from tert-butyl- dimethyl ether and diisopropyl ether.

[0085] Step 2) yields a compound of formula (V): wherein R’ is Ci-4 alkyl, preferably ethyl or methyl; R” is a silyl protecting group; and n equals 1 and z equals 2, or n equals 2 and z equals 1.

[0086] In a specific embodiment by the selective reduction of a compound of formula (IV’) a compound of formula (V’) is obtained

[0087] (V’), wherein R’, R”, n and z are as defined above. Optionally, the crude compound of formula (V) or (V’) can be purified by chromatography.

[0088] The molecule below is an example of a compound of formula (V), and is also one of the aspects of our invention:

[0089] (Va) .

[0090] Another example of a compound from formula (V):

[0091] (Vb) .

[0092] Step 3) The hydroxyl deprotection. The single protecting group of a compound of formula (V) or can be removed by unexpectedly low reagent excess, and it minimize further degradations to provide product of formula (lb) with good quality: wherein the meaning of R’, and the values of n and z are as defined above.

[0093] In a specific embodiment of the invention the deprotection of the hydroxyl group of a compound of formula (V’) results a compound of formula (lb’) wherein the meaning of R’, and the values of n and z are as defined above.

[0094] According to our experience, removing two protecting groups is not advantageous for the stability of the product compound as resulting an impurity profile not adequate for pharmaceutical purposes. Having deprotected the final structure, the polarity of compound (lb) made enable the development and use of high efficiency chromatographic purifications. Properly selected multi-component solvent systems and thoroughly investigated stationary phases provide us with an unexpectedly high purity of (lb) compound that meets pharmaceutical requirements even in ester form.

[0095] A compound of formula (V), resulting from the reduction of compound (IV) in Step 2), undergoes deprotection by removing the only silyl protecting group present in the molecule with no remarkable degradation, resulting an ester compound of formula (lb).

[0096] The deprotection of a compound of formula (V) is performed in an aprotic polar solvent with tetrabutyl ammonium fluoride reagent.

[0097] In a particular embodiment, the aprotic polar solvent is tetrahydrofuran.

[0098] Once the reaction is complete, saturated ammonium chloride solution and deionized water are added. Organic phases were washed with sodium chloride solution, dried with anhydrous sodium sulfate, filtered and the solvent removed under reduce pressure yielding a compound of formula (lb).

[0099] (Ib) .

[0100] The crude product of a compound for formula (Ib) of (Ib’) is purified by chromatography.

[0101] In a particular embodiment, the crude product of (Ib) or (Ib’) is purified by normal phase chromatography.

[0102] In a particular embodiment, the crude product of (Ib) or (Ib’) is purified by reverse phase chromatography.

[0103] In a more particular embodiment, the crude product of (Ib) or (Ib’) is purified by normal phase chromatography followed by reverse phase chromatography to remove polar and nonpolar structure-related impurities.

[0104] By removing only one protecting group from the final structure is also a major point of our invention. By this approach (i.e., C7 / C10 hydroxy is not protected in compounds Vb / Va) we can avoid decompositions generated by deprotection reaction by tetra-butyl ammonium fluoride on carbon (C7 / C10) adjacent to conjugated double bonds. The properly selected protecting group strategy at Sonogashira coupling provide us with this advantage both at the reduction step and deprotection step.

[0105] Major invention of our process is the two-stage chromatographic purification of ester of formula (Ib) or (Ib’), to achieve the purity and stability required for pharmaceutical use of the product. The sequence of chromatographies will determine the purity and stability of product aimed to be used as drug substance. Accordingly, to achieve purity and stability requirements of a drug substance, normal phase chromatographic method should be followed by reverse phase chromatography.

[0106] Significant advantages of the invention are avoiding the deprotection process (requires harsh conditions and reagents) of two protecting groups in step c) from both hydroxyls of sensitive compound (V). Additionally, our invention’s protecting group strategy provides high stability for compound (V) formed in the triple bond reduction of compound (IV).

[0107] Step 4) Ester hydrolysis to carboxylic acid. If desired the hydrolysis of the ester function of formula (lb) is performed by aqueous solution of lithium hydroxide as reagent. Having achieved the required conversion to the corresponding free acid, the reaction is quenched by ammonium chloride aqueous solution and extracted by methyl-tert-butyl-ether. Organic solution comprising the product (la) is washed with brine, dried over anhydrous sodium sulphate and concentrated by evaporation. The crude product of formula (la) wherein z and n are as defined above, is purified.

[0108] In a specific embodiment by the hydrolysis of the ester of formula (lb’) the compound of formula (la’) is obtained wherein z and n are as defined above.

[0109] In a particular embodiment, the crude product of formula (la) or (la’) is purified by chromatography.

[0110] In a more particular embodiment, the crude product of formula (la) or (la’) is purified by normal phase chromatography.

[0111] In a particular embodiment, the crude product of formula (la) is purified by reverse phase chromatography.

[0112] In a more particular embodiment, the crude product of formula (la) or (la’) is purified by normal phase chromatography followed by a reverse phase chromatography. The highly efficient chromatographic purification processes provides compounds of formula (la) or (la’) with high quality without remarkable decompositions. Moreover, the properly selected sequence of chromatographies unexpectedly increased the stability of the product.

[0113] In a much more particular embodiment, the crude product of formula (la) or (la’) is purified by normal phase chromatography followed by reverse phase chromatography to remove polar and nonpolar structure-related impurities.

[0114] If desired the preparation of a pharmaceutically acceptable salt from a carboxylic acid compound of formula (la) or (la’) is performed in a protic solvent with an appropriate source of a cation. Having completed the salt formation, the reaction mixture is filtered to obtain the corresponding salt of a compound of formula (la) or of (la’).

[0115] Major invention of the present invention of process is performing salt formation by using anhydrous solvent, powder of monohydrate (e.g., ISfeCCh’^O) salt. By using aqueous solution of salts (e.g., NaOH, ISfeCCh solutions) decomposition processes could be observed.

[0116] In a particular embodiment, the formation of a pharmaceutically acceptable salt is carried out by treating the corresponding carboxylic acid of formula (la) or (la’) with alkali salts.

[0117] In a more particular embodiment, the formed salt is a sodium or potassium salt of a compound of formula (la’).

[0118] In a particular embodiment, the protic solvent is anhydrous.

[0119] In one of the embodiments of this invention, the synthesis a salt of a compound of formula (la) or (la’) is performed by anhydrous salt of alkali metal or with monohydrate.

[0120] In a more particular embodiment, the protic solvent is ethanol, methanol, or mixtures thereof.

[0121] In a much more particular embodiment, the protic solvent is ethanol.

[0122] In a particular embodiment, the appropriate source of cation is a base.

[0123] In a more particular embodiment, the appropriate source of cation is a monohydrate base.

[0124] In a much more particular embodiment, the appropriate source of cation is sodium carbonate monohydrate.

[0125] In a particular embodiment, the reaction mixture comprising the sodium salt of compound (la’) is filtered and concentrated by evaporation.

[0126] The mild conditions applied in our invention unexpectedly do not deteriorate the impurity profile of the product during salt formation. Therefore, the salt of a compound of formula (la) or (la’) does not require further purifications, it instantly meets pharmaceutical requirements of drug substances.

[0127] Additional subject of our invention is the brand-new intermediates of the process applied for the new synthetic strategy.

[0128] Further subject of our invention is the synthesis of new chemical entities and new purification methods resulting high quality intermediates serving as building block in the Sonogashira coupling. Quality of starting materials of Sonogashira reaction will define the impurity profile of product, the drug substance. Starting material with inferior quality will result in uneconomical synthesis and poor impurity profile of Special Pro-resolving Mediators intended for pharmaceutical use.

[0129] Compounds of formula (II) have been synthetized and processes published in several articles (Aursnes et al. Org. Biomol. Chem., 12(3), 432-437; Tungen et al. Chemistry - A European Journal, 20(2014), 14575-14758), however, these methods are significantly different from our invention’s synthetic route. Methods in the above-mentioned articles are aiming the preparation of product in few gram-scale and do not give information for quality / purity of the product. None of those processes are scalable as they involve sensitive reactions, expensive reagents and in certain methods dangerous, explosive intermediates are prepared.

[0130] All in all, prior art published methods are not capable to provide processes for industrial use.

[0131] In the present invention, the production of compounds with general structures (II) have been synthetized via new intermediates (new chemical entities) and by selection of optimized protecting groups.

[0132] In a particular embodiment, the protecting group used in compounds of formula (II) are silyl protecting groups.

[0133] In a more particular embodiment, the silyl protecting group is selected from dimethylisopropyl silyl (DMIPS), diethyl-isopropyl silyl (DEIPS), 2-norbornyl-dimethyl silyl (NDMS), di-terc-butyl-isobutyl silyl (BIBS), terc-butyl -di phenyl silyl (TBDPS), terc-butyl-dimethyl- silyl (TBDMS), tribenzyl silyl, triphenyl silyl, diphenyl-methyl silyl (DPMS), di-t-butyl- methyl silyl (DTBMS), terc-butyl-methoxyphenyl silyl (TBMPS), terc-butoxy-diphenyl silyl (DPTBOS), or dimethyl-thexyl silyl (DMTS).

[0134] In a much more particular embodiment, the silyl protecting group selected is TBDMS. Our goal was, to develop a method for production of compound (II) optimal for industrial scale-up and provides good quality coupling intermediate (starting material) from what pharmaceutical grade of product can be synthetized.

[0135] The compounds of the invention may contain one or more chiral centers and therefore, may exist as stereoisomers, such as enantiomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers of the illustrated compounds including the stereoisomerically pure form (e.g. enantiomerically pure or diastereomerically pure) and enantiomeric mixtures. Enantiomeric mixtures can be resolved into their component enantiomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

[0136] “Pharmaceutically acceptable” means approved by a regulatory agency of a state government or listed in a generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0137] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include salts formed when an acidic proton is present in the parent compound and either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, triethylamine, propylamino, diazabicycloundecane and the like.

[0138] We were able to synthetize compound of formula (II) by our method subject of invention, with scalable reactions, applying new purification methods by taking also into account economical production.

[0139] The use of new chemical entity of formula (IX) wherein,

[0140] TIPS represents triisopropyl silyl hydroxyl protecting group,

[0141] R2 represents the silicon atom containing protecting group, for example trimethyl-silyl, triethyl-silyl, triisopropyl-silyl, tertbutyl-dimethyl-silyl, tertbutyl-diphenyl-silyl, n equals 1 or 2; makes possible a significant scale-up while efficiently removes structure-related trans impurity.

[0142] Further subject of our invention is compound of formula (II) wherein R” is a silyl protecting group, and n equals 1 or 2, synthetized by the following steps: a compound of formula (X2), wherein,

[0143] R2 represents the silicon atom containing protecting group, for example trimethyl-silyl, triethyl-silyl, triisopropyl-silyl, tertbutyl-dimethyl-silyl, tertbutyl-diphenyl-silyl, preferably trimethyl-silyl; and

[0144] THP represents tetrahydropyranyl; is reacted with a compound that able to introduce protecting group for the hydroxyl, preferably triisopropyl-silyl chloride, and the obtained compound (X3) wherein, the meanings of R2 and THP are as defined above; andTIPS represents triisopropyl- silyl; is reacted with acidic reagent aiming deprotection of hydroxyl and the obtained alcohol (X4) wherein the meanings of R2 and TIPS are as defined above; undergoes Swern oxidation reaction to form aldehyde (X5), wherein the meanings of R2 and TIPS are as defined above; which is reacted with properly selected phosphonium salt,

[0145] X6 wherein w equals 0 or 1; and

[0146] X represents iodine- or bromine atom; and by Wittig reaction compound (IX) will be formed, wherein the meanings of R2 and TIPS are as defined above, and n equals 1 or 2; and by removing R2 and TIPS protections from compound (IX), the obtained (X7) alcohol’s hydroxyl wherein n equals 1 or 2; is protected and the terminal acetylene containing compound of formula (II) is obtained.

[0147] Major advantage of our invention is the preparation and application of intermediate (X3) in the syntheses, as selecting triisopropyl silyl (TIPS) protecting group makes possible the selective removal of THP group from primer hydroxyl. TIPS protecting group shows also good stability in the later stages of the process (e.g., in Swern oxidation) while it can be removed in one step along with TMS protecting group in mild conditions, to avoid decomposition of the target molecule (X7).

[0148] According to our invention terminal acetylene compound of formula (II) is produced by applying general structure (X2) as starting material. In the synthesis an alcohol of formula (X2) is protected by properly selected protecting group to obtain compound of formula (X3).

[0149] Selecting the most suitable protecting group is highly important to produce adequate quality product. By realizing the importance of protecting groups and disadvantages of published protection strategies, new protection strategy should have been developed. Unexpectedly, not an expensive and rarely available protecting reagent answered for our need, but a simple protecting group was selected that has not yet been published.

[0150] The protecting group should be stable enough to provide us with the selective deprotection of THP group with no major decompositions and should also be stable in the Swern oxidation reaction. Moreover, the protecting group should be stable in the following steps of compound (II) but needed to be removed in mild conditions from the structure of (II) avoiding further degradations.

[0151] To protect the hydroxyl group a compound of formula (X2) is reacted with triisopropylsilyl chloride (TIPS-C1) in acetonitrile and in the presence of dimethylamino pyridine and imidazole.

[0152] The THP protecting group is selectively removed from the resulting compound (X3) by acidic reagent. The reaction is performed in methanol with catalytic amount of p-toluene- sulfonic acid monohydrate.

[0153] The preferably and properly selected triisopropyl silyl (TIPS) protecting group enables a highly selective deprotection with good yields by avoiding decompositions and side reactions. The obtained alcohol compound (X4) is purified by column chromatography.

[0154] Having compound (X4) purified by chromatography, purified compound of formula (X4) is converted to aldehyde by Swern oxidation according to method described by Omura and Swern (Tetrahedron, 34(1978), 1651-1660).

[0155] The obtained aldehyde of formula (X5) is reacted with phosphonium salt of formula (X6) in a Wittig reaction. Diethyl ether and tetrahydrofuran are used as solvent mixture in the Wittig reaction and sodium bis(trimethyl-silyl) amide as base. The product of formula (IX) of the Wittig reaction is used in the following steps without further purification.

[0156] The crude product of Wittig reaction (IX) is deprotected in tetrahydrofuran with tetra- butyl-ammonium-fluoride trihydrate to obtain the acetylene derivative (X7). The properly selected protecting groups provide us with the advantage of removing both protecting groups (TIPS and TMS) in single reaction step without degradation and with good yield.

[0157] The acetylene derivative (X7) is purified by column chromatography.

[0158] Compound of formula (II) is prepared by reacting a compound of formula (X7) with a reagent that is able to introduce a silyl protecting group, preferably tert-butyl-dimethyl-silyl (TBDMS) protecting group on the hydroxyl, in a specific embodiment the compound of formula (X7) is reacted with tert-butyl-dimethyl-silyl chloride (TBDMS-C1).

[0159] In a more specific embodiment the hydroxyl group of the compound of formula (X7) is reacted with TBDMS-C1 in acetonitrile and in the presence of dimethyl amino pyridine and imidazole.

[0160] The obtained crude product of formula (II) is purified by column chromatography.

[0161] By introducing a new intermediate of formula (X)

[0162] X wherein

[0163] Ri represents the aldehyde (C=O) structure or the following thiazolidine group, and R3 represents H or tert-butyl-diphenyl-silyl hydroxyl protecting group; in the synthesis, the process for the preparation of a compound of formula (III) became scalable for industrial production and the epimer impurity can be removed with high efficacy.

[0164] A compound of formula (III) can be prepared according to analogue processes (Org. Biomol. Chem., 2014, 12, 432-437, J. Chem. Soc., Perkin Trans. 1, 1997, 1639-1645) via intermediates M3, M4 and M5 (all described by structure X).

[0165] wherein,

[0166] R’ represents the straight, or branched carbon chain groups, x equals 0 or 1, and z equals 1 or 2.

[0167] According to our invention, we used the industrially feasible iodine for the synthesis instead of bromine preferred by literature. Important finding was the selection of t-butyl- diphenyl-silyl (TBDPS) protecting group, that provides high efficacy and low rate of degradation in the Wittig reaction by using aldehyde (M5). TBDPS protecting group makes feasible the scale-up to industrial production.

[0168] New, not yet published intermediates (M3, M4 and M5) were synthetized in our process providing us with stable intermediates. Those new intermediates can be purified with high efficiency decreasing epimer impurities to the level that ensure pharma grade drug substance product by the end of the process. Further details of the invention are demonstrated by the following examples without limiting the invention to the examples. Examples:

[0169] Production of TBDMS-cis-octadienyl-propargyl alcohol (II’; n=2)

[0170] 1. 3S-TIPSO-5-THPO-l-TMS-pentynol (X3’, R2 = TMS):

[0171] Charge reactor with 200 g 3S-5-THPO-l-TMS-pentynol (X2’) in 2.1 L of acetonitrile and cool the reaction mixture to 0-5 °C. Add solution of 19.1 g of dimethylaminopyridine and 95.6 g of imidazole in 1 L of acetonitrile to the reaction mixture. Add 271 g triisopropylsilyl chloride (TIPS-C1). Stir the reaction mixture at ambient temperature overnight. Check the conversion by TLC. Prepare a quenching mixture of 1.0 L of saturated ammonium chloride solution, 0.6 L of water and 1.0 L of methyl-tert-butylether. Once the reaction is complete add the quenching mixture to the reaction mixture. Separate phases and extract aqueous phase with 0.9 L of methyl-tert-butylether. Unify organic phases and wash it with 1.0 L of IM sodium-hydrogen sulfate solution, 1.0 L of water, 1.0 L of IM sodium bicarbonate solution and 0.5 L saturated sodium chloride solution. Dry the organic phase on 0.24 kg of anhydrous sodium sulphate and evaporate it. The product is not purified further, and the yield is regarded as theoretical 100%.

[0172] 2. 3S-TIPSO-5-TMS-pentynol (X4’):

[0173] 100 g of intermediate 3S-TIPSO-5-THPO-l-TMS-pentynol (X3’) is dissolved in 1.9 L methanol and 1.8 g p-toluene-sulphonic acid is added while stirring at ambient temperature. Check the conversion by TLC. Once the reaction is completed, it is quenched by 2.2 ml of triethyl-amine. Reaction mixture is evaporated and a mixture of 0.8 L water and 0.5 L methyl- tert-butylether is added. Phases are separated and the aqueous phase is extracted twice with 0.4 L methyl-tert-butylether. Organic phases are unified, washed with 0.4 L saturated sodium chloride solution and evaporated. Silica gel column is prepared from 1.95 kg silica and 20 : 1 mixture of ethyl acetate and hexane. The column is eluted with ethyl acetate-hexane mixture. The column purification is monitored by TLC. Fractions containing pure product are unified in main fraction. Unified yield of Step 1 and 2 is 70%. According to TLC, pure, single product is obtained.

[0174] 3. 3S-TIPSO-5-TMS-pentynal (X5’):

[0175] Charge reactor with 1,7 L of di chloromethane and 66 ml of dimethyl sulfoxide. Cool the mixture to -70±5 °C. Dissolve 49 ml of oxalyl chloride in 66 ml of dichloromethane and slowly charge the solution while keep -70±5 °C. Stir the reaction mixture for 15-20 minutes while keep -70±5 °C. Slowly charge the solution of 100 g of 3S-TIPSO-5-TMS-pentynol (X4’) in dichloromethane while keep -70±5 °C. Stir the reaction mixture for 20-25 minutes while keep -70±5 °C. Remove the cooling bath and add 195 ml of triethylamine to the reaction mixture. Check the conversion by TLC. Quench the reaction with mixture of 0.55 L of 1 M sodium hydrogen sulfate and 0.55 L of 15% sodium chloride solution. Separate phases and extract the aqueous phase with 0.55 L of toluene. Unify the organic phases and wash with 0.8 L of 1 M sodium hydrogen carbonate solution and with 1.6 L of 15% sodium chloride solution. Dry the organic phase over 0.17 kg of anhydrous sodium sulphate for and evaporate it. The product is not purified further, and the yield is 93%.

[0176] 4. 3S-TIPSO-cis octadienyl-TMS-propargyl alcohol (IX’, n=2)

[0177] 0,24 kg of cis-hexenyl-phosphonium-iodide (X6, w=l) is added to 7.2 L of diethyl ether and the suspension is stirred. Charge the solution of 0.23 L of 2 M sodium bis(trimethylsilyl)amide in tetrahydrofuran to the suspension. Stir the reaction mixture and cool the reaction mixture to -70±3 °C. Dissolve 83 g of 3S-TIPSO-5-TMS-pentynal (X5’) in toluene and slowly charge the solution in the reaction mixture while keep -70±3 °C. Stir the reaction mixture while keep -70±3 °C. Check the conversion by TLC. Quench the reaction with 0.83 L of IM sodium hydrogen sulfate solution. Filter the precipitate and wash it with 0.75 L of diethyl ether. Separate phases and extract the aqueous phase with 0.42 L of diethyl ether. Unify the organic phases and wash it with 0.83 L of 1 M sodium hydrogen carbonate solution and with 0.83 L of 15% sodium chloride solution. Separate phases and dry the organic phase on 0.25 kg of anhydrous sodium sulphate and evaporate it. The product is not purified further, and the yield is regarded as theoretical 100%.

[0178] 3S-TIPSO-cis-pentenyl-TMS-propargyl alcohol (IX’, n=l) is produced by the same process by using propyl-phosphonium bromide (X6, w=0).

[0179] 5. 3S-Cis-octadienyl-propargyl alcohol (X7’, n=2)

[0180] To the solution of 100 g of 3S-TIPSO-cis-octadienyl-TMS-propargyl alcohol (IX’, n=2) in 1.45 L of tetrahydrofuran 201 g of tetrabutylammonium fluoride in 0.45 L of tetrahydrofuran is added. Stir the solution at room temperature and check the conversion by TLC. Once the reaction is completed add 1.0 L of saturated ammonium chloride solution to quench the reaction and stir the mixture. Separate phases and wash the aqueous phase with 0.15 L of methyl-tert-butylether. Unify the organic phases and wash it with 0.5 L of 15% sodium chloride solution and after with 0.5 L of saturated sodium chloride solution. Dry the organic phase on 0.2 kg of anhydrous sodium sulfate and evaporate it. Prepare chromatographic column with 1.68 kg silica gel in the hexane-ethyl acetate mixture of 20: 1. Load the crude product on the column and eluate with hexane-ethyl acetate mixture of 10: 1. The column chromatography is monitored by TLC. Fractions containing pure product are unified in the main fraction. Unified yield of Step 4 and 5 is 85%. According to TLC, pure, single product is obtained.

[0181] 3S-Cis-pentenyl-propargyl alcohol (X7’, n=l) is prepared by the same process described above.

[0182] 6. 3S-TBDMS-cis-octadienyl-propargyl alcohol (II’, n=2):

[0183] Charge reactor with 350 ml of acetonitrile and add the solution of 39 g of 3S-cis-octadienyl- propargyl alcohol (X7’, n=2) in dichloromethane. Cool the reaction mixture to 0-5 °C and add 72 g of tert-butyldimethylchlorosilane (TBDMS-C1). Charge solution of 5.8 g of dimethylaminopyridine and 29.1 g of imidazole in 0.22 L of acetonitrile while keep 0-10 °C. Stir the reaction mixture at ambient temperature and monitor the reaction by TLC. Once the reaction is completed quench with the mixture of 0.2 L of saturated ammonium chloride solution and 0.2 L of water. Stir the mixture and separate phases. Extract aqueous phase with 0.24 L ml of di chloromethane. Unify organic phases and wash it with 0.2 L of 15% sodium chloride solution. Separate phases and dry the organic phase on 47 g of anhydrous sodium sulphate. Evaporate the solution of product. Prepare chromatographic column with 1.3 kg silica gel in the hexane-toluene mixture of 20: 1. Load the crude product on the column and eluate with hexane-toluene mixture of 20: 1. The column purification is monitored by TLC. Fractions containing pure product are unified in the main fraction. Yield is 93%. According to HPLC, product’s purity is 95%.

[0184] 3S-TBDMS-cis-pentenyl-propargyl alcohol (II’, n=l) is prepared by the same process described above.

[0185] Production of compounds of formula (I’):

[0186] Maresin methyl ester (n=2, z=l, R=Me) and Protectin DI ethyl ester (n=l, z=2, R=Et)

[0187] 7. Dehydro-TBDMS-Maresinl methyl ester (IV’, n=2, z=l, R=Me)

[0188] Charge reactor with 2.8 g of copper(I) iodide and 8.6 g of palladium(O) tetrakis (triphenylphosphine). Add 1.0 L of diisopropylamine in the reactor and charge the toluene solution of 50 g 7R-OH-iodoundeka-trienacid-methyl ester (Illa’, R’=Me). Charge the toluene solution of 45.6 g of intermediate 3S-TBDMS-cis-octadienyl-propargyl alcohol (IF, n=2, R’ ’=TBDMS). Stir the reaction mixture at room temperature. Check the conversion by TLC. Once the reaction is completed add 0.8 L of saturated ammonium chloride solution and stir the mixture. Separate phases and extract the aqueous phase with 1.8 L of methyl- tert-butylether. Charge 1.5 L 5M sodium hydrogen sulfate solution to the unified organic phases. Wash the organic phases with 1.2 L of 15% sodium chloride solution. Dry the organic phase on 0.18 kg of anhydrous sodium sulfate and evaporate it. Prepare chromatographic column with 2.2 kg silica gel in the hexane- methyl-tert-butylether mixture of 5: 1. Load the crude product on the column and eluate with the hexane- methyl-tert- butylether mixture of 3: 1. The column chromatography is monitored by TLC. Fractions containing pure product are unified in main fraction. Yield is 68%. According to TLC, pure, single product is obtained.

[0189] Dehydro-TBDMS-ProtectinDl ethyl ester (IV’, n=l, z=2, R=Et) is prepared by the same process described above. lOR-OH-iodotetradeka-tetraenacid-ethyl ester (Illb’) and 3S- TBDMS-cis-pentadienyl-propargyl alcohol (IF, n=l) are used as starting materials. Yield is 75%. According to TLC, pure, single product is obtained.

[0190] 8. TBDMS-Maresinl methyl ester (V’, n=2, z=l, R’= Me, R”=TBDMS)

[0191] Charge reactor with 600 g zinc powder and add 1.25 L methanol and 1.25 L water in the reactor. Cool the suspension to 0-5 °C and add 78 ml of trimethyl silyl chloride. Stir the suspension for 3 hours and warm up to 20 - 25°C. Charge reactor with methanol solution of 50 g of dehydro-TBDMS-Maresinl methyl ester (IV’, n=2, z=l, R’=Me, R”=TBDMS). Monitor the reaction by TLC. Once the reaction is completed filter the zinc powder from reaction mixture. Transfer the solution in the extractor and separate phases. Extract aqueous phases with 2.0 L of dichloromethane and wash the organic phase with 2.0 L of 15% sodium chloride solution. Dry the organic phase on 0.25 kg of anhydrous sodium sulfate and evaporate the solution of the product. The product is used without further purification and yield is regarded as theoretical 100%.

[0192] TBDMS-ProtectinDl ethyl ester (V’, n=l, z=2, R’=Et, R”=TBDMS) is produced by the same process described above, from starting material dehydro-TBDMS-Protectin DI ethyl ester (IV’, n=2, z=l, R’=Et, R”=TBDMS). 9. Maresinl methyl ester (lb’, n=2, z=l, R’=Me)

[0193] Charge reactor with 1.0 L of tetrahydrofuran and add the solution of 50 g of TBDMS- Maresinl methyl ester (V’, n=2, z=l, R’= Me, R”=TBDMS) intermediate in the reactor. Add 58 g of tetrabutylammonium fluoride to the reaction mixture and stir the solution at ambient temperature. Check the conversion by TLC. Once the reaction is completed add 0.5 L of saturated ammonium chloride solution and 0.2 L of water to quench the reaction. Transfer reaction mixture to extractor. Separate phases and wash the aqueous phase with 0.6 L of methyl-tert-butylether. Unify the organic phases and wash it with 1.0 L of 15% sodium chloride solution. Dry the organic phase on 0.15 kg of anhydrous sodium sulfate and evaporate the solution of the product. Prepare silica gel column with 3.0 kg spherical silica gel and diisopropylether-hexane-ethylacetate (3: 1.5: 1) mixture. The crude product is purified by eluting the column with diisopropylether-hexane-ethylacetate (3: 1 : 1) mixture. The chromatography is monitored by TLC. Fractions containing pure product are unified in main fraction and evaporated. Yield is 60%. Prepare column with reverse phase silica gel and acetonitril. Product is purified by eluting acetonitril-water mixture (60:40). The chromatography is monitored by UV detection. Fractions containing pure product are unified in the main fraction and evaporated. Product is extracted with methyl-tert-butylether from the aqueous phase and evaporated. Yield of reverse phase chromatography is 70%. According to HPLC test the purity of product is 95%. Combined yield of the two chromatographies is 42%.

[0194] Protectin DI ethyl ester (lb’, n=l, z=2, R’=Et) is prepared analogue purification methods from TBDMS-Protectin DI ethyl ester (V’, n=l, z=2) starting material. The combined yield of purifications is 70%. According to HPLC test the purity of product is 93%.

[0195] Production of ProtectinDl and ProtectinDl Na salt

[0196] 10. Protectin DI (la’, n=l, z=2)

[0197] To the solution of 13.3 g of Protectin DI ethyl ester (lb’, n=l, z=2, R’=Et) in 0.44 L tetrahydrofuran, 0.18 L of IM lithium hydroxide is added and the reaction mixture is stirred at ambient temperature. The reaction is monitored by TLC. Once the reaction is completed, 0.33 L of water and 0.53 L of methyl-tert-butylether are added to the reaction mixture. Phases are separated and the organic phase is extracted by 1.0 L water. 0.2 L 1 M sodium hydrogen sulphate solution is added to the aqueous phase and the product is extracted with 1.2 L methyl-tert-butylether. The organic phase is washed with 0.2 L of water and 0.2 L sodium chloride solution. The organic phase is dried over 60 g of anhydrous sodium sulphate and evaporated. The crude product is purified by column chromatography. Prepare silica gel column with 1.3 kg spherical silica gel and dichloromethane-methanol (30: 1) mixture. The crude product is purified by eluting the column with dichloromethane-methanol (20: 1) mixture. The chromatography is monitored by TLC. Fractions containing pure product are unified in the main fraction and evaporated. Yield is 80%. Prepare column with reverse phase silica gel and acetonitril. Product is purified by eluting acetonitril-water mixture. The chromatography is monitored by UV detection. Fractions containing pure product are unified in main fraction and evaporated. Product is extracted with methyl-tert-butylether from the aqueous phase and evaporated. Yield of reverse phase chromatography is 52%. Combined yield of the two chromatographies is 42%. According to HPLC test the purity of product is 96%.

[0198] 11. Protectin DI Na salt (la’, n=l, z=2) To the ethanol solution of 6.6 g of Protectin DI (la’, n=l, z=2) 1.27 g of sodium carbonate monohydrate is added. The mixture is stirred at ambient temperature and the remaining sodium carbonate is filtered. The product is dissolved in ethanol. The yield is regarded as theoretical 100%.

Claims

CLAIMS1. A process for the preparation of a compound of formula (I):wherein,R represents H atom or Ci-4 alkyl; and n equals 1 and z equals 2, or n equals 2 and z equals 1; or a pharmaceutically accepted salt thereof, wherein the process comprises:Step 1) Sonogashira coupling of a compound comprising a terminal acetylene group and a protected hydroxyl group with a corresponding compound comprising a vinyl iodide structure and an unprotected hydroxyl group; followed byStep 2) selective reduction of the triple bond formed in Step 1) to a double bond with Z stereochemistry; followed byStep 3) hydroxyl deprotection; and if desired followed byStep 4) ester hydrolysis to carboxylic acid, and if desired salt formation.

2. A process according to claim 1, wherein in Step 1) the compound comprising a terminal acetylene group and a protected hydroxyl group is a compound of formula (II):wherein R" represents a silyl protecting group, and n is as defined above; and the compound comprising a vinyl iodide structure and an unprotected hydroxyl group of Step 1) is a compound of formula (III):wherein R’ represents Ci-4 alkyl, and z is as defined above.

3. A process according to claim 1 or 2, wherein in Step 1) is obtained a compound of formula (IV):wherein R’, R”, n and z are as defined above.

4. A process according to any of claims 1 to 3, wherein in Step 2) is obtained a compound of formula (V):wherein R’, R’, n and z are as defined above.

5. A process according to any one of claims 1 to 4, wherein in Step 3) is obtained a compound of formula (lb):wherein R’, n and z are as defined above.

6. A process according to any of claims 2 to 5, wherein R” is selected from dimethylisopropyl silyl (DMIPS), diethyl-isopropyl silyl (DEIPS), 2-norbornyl-dimethyl silyl (NDMS), di-terc-butyl-isobutyl silyl (BIBS), terc-butyl -di phenyl silyl (TBDPS), terc-butyl-dimethyl- silyl (TBDMS), tribenzyl silyl, triphenyl silyl, diphenyl-methyl silyl (DPMS), di-t-butyl-methyl silyl (DTBMS), terc-butyl-methoxyphenyl silyl (TBMPS), terc-butoxy-diphenyl silyl (DPTBOS), and dimethyl-thexyl silyl (DMTS).

7. A process according to claim 6, wherein R” is terc-butyl-dimethyl-silyl (TBDMS).

8. A process according to any of claims 1 to 7, wherein in Step 4) is obtained a compound of formula (la):wherein n and z are as defined above; or a pharmaceutically acceptable salt thereof.

9. A process according to any of claims 1 to 8, for the preparation of a compound of formula (I’)wherein R n and z are as defined above, wherein the process comprises in Step 1) a compound comprising a terminal acetylene group and a protected hydroxyl group, of formula (Ila)wherein TBDMS represents tert-buthyl-dimethyl-silyl; and n is as defined above; is reacted with the corresponding compound comprising a vinyl iodide structure and an unprotected hydroxyl group, of formula (III’)wherein R’ represents Ci-4 alkyl, preferably methyl and ethyl; and z is as defined above; and in Step 2) the triple bond of the compound of formula (IVa’) thus obtainedwherein TBDMS, R’, an and z are as defined above, is reduced by selective reduction to a double bond with Z stereochemistry; and in Step 3) the tert-buthyl-dimethyl-silyl protecting group of the compound of formula (Va’) thus obtainedwherein TBDMS, R’, n and z are as defined above; is removed to obtain a compound of formula (lb’)wherein R’, n and z are as defined above; and if desired in Step 4) the ester group of compound of formula (lb’) is hydrolysed, to obtain a compound of formula (la’)wherein n and z are as defined above; and if desired the carboxylic acid of formula (la’) is transforemed into its salt, preferably into its alkly metal salt, more preferably into its sodium or its potassium salt.

10. A compound of formula (IV):wherein,R’ represents Ci-4 alkyl;R” represents a silyl protecting group; and n equals 1 and z equals 2, or n equals 2 and z equals 1.

11. A compound of formula (Va):

12. A compound of formula (Illa):wherein R’ means Ci-4 alkyl.

13. A compound of formula (Illb):

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