WO2019219758A1

WO2019219758A1 - Processes in the preparation of polyunsaturated ketone compounds

Info

Publication number: WO2019219758A1
Application number: PCT/EP2019/062506
Authority: WO
Inventors: Marcel Sandberg; Inger Reidun Aukrust
Original assignee: Avexxin As
Priority date: 2018-05-15
Filing date: 2019-05-15
Publication date: 2019-11-21
Also published as: GB201807892D0

Abstract

A process comprising the following steps: a-i) treating a polyunsaturated ester with a base in a solvent of lower alcohol and water to form the corresponding polyunsaturated acid; a-ii) treating the product from step a-i), especially the crude product, with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone; and a-iii) treating the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol and water to convert the polyunsaturated halolactone to the corresponding polyunsaturated epoxide lower alkyl ester.

Description

Processes in the preparation of polyunsaturated ketone compounds Field of the Invention

This invention relates to a method of making a polyunsaturated epoxide compound and optional subsequent conversion of that epoxide compound into a polyunsaturated ketone. In particular, the invention relates to the conversion of a polyunsaturated ester to a polyunsaturated epoxide compound in a single vessel or “pot”. The polyunsaturated epoxide is an intermediate that can then be converted to a polyunsaturated ketone thus enabling the formation of that ketone in fewer steps. The invention significantly reduces or in preferred cases avoids separate work up procedures and thus simplifies the process without a significant reduction in overall yield or purity.

In a second embodiment, the invention relates to the conversion of a polyunsaturated alcohol to a polyunsaturated thioester and optional subsequent conversion of that thioester into a polyunsaturated ketone. In particular, the invention relates to the conversion of a polyunsaturated alcohol to a polyunsaturated thioester compound in a single vessel or pot. That polyunsaturated thioester can then be converted to a polyunsaturated ketone thus enabling the formation of that ketone in fewer steps. The invention significantly reduces or in preferred cases avoids separate work up procedures and thus simplifies the process without a significant reduction in overall yield or purity. Background

There have been reports that certain polyunsaturated trifluoromethyl ketone compounds have useful biological activities. See, for example, U.S Pat. No.

7,687,543; Huwiler, A et al. (2012) Br. J. Pharm. 167: 1691.

Methods for preparing particular polyunsaturated ketones have been disclosed. In one method disclosing the synthesis of particular polyunsaturated trifluoromethyl ketones, a Mitsunobu-type reaction was used to transform an alcohol to the corresponding thioester. Further chemical reactions were said to produce the polyunsaturatcd trifluoromethyl ketone (compound 18 therein) in 71% yield. See Holmeide, A and L. Skattebol (2000) J. Chem. Soc. Perkin Trans. 1 : 2271. In WO2016/116334 the manufacture of a polyunsaturated thiol and eventually a corresponding polyunsaturated ketone is described.

While such synthetic methods have been useful for some applications, there is a need for more efficient and cost-effective methods for making such compounds. In particular, the process for making the target compounds would be more attractive if fewer synthetic steps were involved.

Accordingly, the present inventors sought a process for the manufacture of a polyunsaturated ketone compound that requires fewer steps without a significant reduction in overall yield or purity.

The present invention relates to the manufacture of certain intermediates useful in the manufacture of the target compounds as well as an overall process for the preparation of the compounds of the invention.

After extensive synthetic work, the inventors have determined that particular processes as claimed herein offer an ideal route to the compounds of the invention as the processes use a single pot without separate work up procedures to reduce the number of steps in the process. The process described herein not only achieves very high purity but achieves very high yield. It can also be readily scaled up to industrial operation. As the process uses fewer steps, the overall process is cheaper and faster.

Moreover, the fact that the reactions detailed herein can be carried out in a single pot is remarkable. The inventors anticipated that combining the reactions into a single step would result in the formation of numerous side products. Surprisingly, this has not occurred. It is also surprising that the reactions defined in the first embodiment can be effected in the same solvent.

Summary of invention

The present inventors have found that a polyunsaturated ester can be converted to a polyunsaturated epoxide in a single reaction vessel or pot. The chemistry described herein avoids or at least reduces the formation of side products and enables the formation of a polyunsaturated epoxide and eventually a

polyunsaturated thiol which can be used in further synthetic steps to form desired target polyunsaturated ketone molecules.

It is therefore an object of the invention to prepare polyunsaturated epoxide compounds in a single pot. Such polyunsaturated epoxide compounds can ultimately be converted to the advantageous compounds such as the polyunsaturated ketone compounds discussed herein.

The method of the invention involves a single step process comprising hydrolysis and then halolactonisation of a polyunsaturated ester and conversion to the corresponding polyunsaturated epoxide. That epoxide can be reduced to a polyunsaturated aldehyde and then polyunsaturated alcohol. The alcohol can be converted to a thioester (of formula -SCOR₄ wherein R₄ is a Ci-₂₀ hydrocarbyl group) in one pot, with subsequent conversion of the thioester to desired target compounds.

Thus, viewed from one aspect the invention provides a process comprising the steps of:

(a) combining, in a vessel, a polyunsaturated ester and a halolactonization agent in a solvent of lower alcohol and water to form a mixture,

(ab) treating, e.g. heating, the mixture in the presence of a reagent and under conditions sufficient to form a polyunsaturated epoxide lower alkyl ester in the vessel.

Viewed from another aspect the invention provides a process comprising the following steps:

a-i) treating a polyunsaturated ester with a base in a solvent of lower alcohol and water to form the corresponding polyunsaturated acid;

a-ii) treating the product from step a-i), especially the crude product, with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone; and

a-iii) treating the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol and water to convert the polyunsaturated halolactone to the corresponding polyunsaturated epoxide lower alkyl ester It is particularly preferred if steps a-i) to a-iii) are carried out in the same reaction vessel.

a-i) treating in a vessel a polyunsaturated ester with a base in a solvent of lower alcohol and water to form the corresponding polyunsaturated acid;

a-ii) treating in the vessel the product from step a-i), especially the crude product, with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone; and

a-iii) treating in the vessel the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol and water to convert the polyunsaturated halolactone to the corresponding polyunsaturated epoxide lower alkyl ester.

(a-i) treating a polyunsaturated alkyl ester of formula (F) RI-CH=CH-CH₂CH₂COOR₆ (F) such as the compound

wherein R¹ is an optionally substituted CY22 unsaturated hydrocarbon group, said hydrocarbon group comprising at least 2, preferably at least 4 double bonds; and R₆ is a C1-C4 alkyl group;

with a base in a solvent of lower alcohol/water to form the corresponding polyunsaturated acid of formula (IF):

R_I-CH=CH-CH₂CH₂COOH (IF) such as the compound

wherein Ri is as hereinbefore defined;

a-ii) treating the product from step a-i), especially the crude product, with a iodolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone compound

wherein Ri is as hereinbefore defined; and

a-iii) treating the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol/water to convert the iodolactone to the corresponding polyunsaturated epoxide lower alkyl ester of formula (IV):

wherein Ri is as hereinbefore defined and Rs is Ci-₄alkyL It is particularly preferred if steps (a-i) to (a-iii) are carried out in the same reaction vessel.

a-i) treating a polyunsaturated alkyl ester of formula (VI):

wherein R₆ is a C1-C4 alkyl group;

with a base in a solvent of lower alcohol and water to form the corresponding polyunsaturated acid;

a-ii) treating the product from step a-i), especially the crude product, with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding halolactone; and

a-iii) treating the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol and water to convert the halolactone to the corresponding epoxide of formula (IX):

wherein R₅ is Ci-₄alkyL

It is particularly preferred if steps (a-i) to (a-iii) are carried out in the same reaction vessel.

Viewed from another aspect the invention provides a process for the preparation of a polyunsaturated thioester comprising:

(e) reacting a polyunsaturated alcohol in the presence of a compound of formula R₂-S0₂Hal wherein R₂ is a Ci_₂o hydrocarbyl group, such an Ci_io alkyl group, to form a polyunsaturated sulphonyl ester;

(f) converting the polyunsaturated sulphonyl ester to a polyunsaturated thioester by reacting with an anion of formula SC(=0)R₄ wherein R₄ is a Ci_₂o hydrocarbyl group;

wherein steps (e) and (f) are carried out sequentially or preferably consecutively in one vessel. It is preferred if the same solvent is used in steps (e) and (f). It is preferred if there are no work up procedures between step (e) and (f). Ideally, the anion of formula SC(=0)R₄ is added to the crude product of step (e). Viewed from another aspect the invention provides a process including at least the following steps:

(e) reacting a polyunsaturated alcohol of formula (XV) R1CH2OH (XV) wherein R¹ is an optionally substituted CY22 unsaturated hydrocarbon group, said hydrocarbon group comprising at least 2, preferably at least 4 double bonds; in the presence of a compound of formula R₂-S0₂Hal wherein R₂ is a Ci_-20 hydrocarbyl group, such an Ci-io alkyl group, to form a polyunsaturated sulphonyl ester of formula (XVI)

RICH₂0S0₂R₂ (XVI); (f) converting the polyunsaturated sulphonyl ester of formula (XVI) to a polyunsaturated thioester (XVII)

RICH₂SC(=0)R₄ (XVII) by reacting with an anion of formula SC(=0)R₄ wherein R₄ is a Ci_-20 hydrocarbyl group;

wherein steps (e) and (f) are carried out consecutively in one vessel.

Viewed from another aspect the invention provides a process including at least the following steps:

(e) reacting (3Z,6Z,9Z,l2Z,l5Z)-octadeca-3,6,9,l2,l5-pentaen-l-ol

or (2E,6Z,9Z, 12Z, 15Z,)-octadeca-2,6,9, 12, 15-pentaen- 1 -ol;

with methanesulphonyl chloride in the presence of a base so as to form a

(f) reacting the reaction product of step (e) with a thioacetate ion to form a thioester of formula:

wherein steps (e) and (f) are carried out consecutively in one vessel.

In one embodiment (step g), the product of step (f) is reacted with a metal carbonate in the presence of an antioxidant to form a thiol of formula:

In one embodiment, the thiol produced in step (g) is reacted with 3- bromo-l,l,l-trifluoroacetone under conditions that produce compounds A or B:

where X is CF₃.

Definitions

The term polyunsaturated in the term polyunsaturated thiol or

polyunsaturated ester and so on refers to compounds which contains a hydrocarbon chain containing multiple double bonds, i.e. 2 or more. That chain is preferably free of any rings. It is preferred if double bonds present are not conjugated. The chain is preferably aliphatic. In any polyunsaturated ester group, it is preferred if there is a double bond gamma to the carbonyl in order to enable the formation of the halolactone.

Any polyunsaturated ester is preferably a lower alkyl ester.

The term acid typically refers to a carboxylic acid unless context permits. The term Hal means halide, i.e. F, Cl, Br or I.

The term Ci-20 hydrocarbyl group refers to a group containing 1 to 20 carbon atoms and H atoms only. The group may be a Ci-io hydrocarbyl group, such as a Ci-10 alkyl group, C2-10 alkenyl, C_6-io aryl group, C₇_io alkylaryl, C₇_ioarylalkyl group, C3-io-cycloalkyl group, C_4-ioalkylcycloalkyl or C_4-iocycloalkylalkyl group and so on. As long as there are only C and H atoms present and up to 20 carbon atoms, any arrangement of those atoms is possible. Any hydrocarbyl group is preferably a Ci_ _loalkyl group. Any hydrocarbyl group is preferably a linear Ci-ioalkyl group.

Generally, any polyunsaturated compound of the invention will have an Mw of less than 500 g/mol, preferably 450 g/mol or less, more preferably 400 g/mol or less.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term lower alcohol means a Cl -4 alcohol such as methanol or ethanol. The term lower alkyl means a Cl -4 alkyl.

Detailed Description of Invention

This invention generally relates to processes useful in the preparation of certain polyunsaturated ketone compounds, e.g. of formula R₁CH₂-SCH₂COCF₃, in particular compounds A and B below.

Compound B

Compound A where X is CF_3.

In a first embodiment, this invention particularly relates to a process for the manufacture of a polyunsaturated epoxide that is a useful intermediate in the synthesis of these compounds. The process offers high yields and high purity but uses fewer separate steps than are used in prior art processes. Remarkably, despite fewer steps, there is no significant loss of purity or yield. The process can also be readily scaled up for industrial operation.

In a first embodiment therefore, the invention provides a way of making a polyunsaturated epoxide intermediate. In other embodiments, the invention relates to the subsequent conversion of that polyunsaturated epoxide to a polyunsaturated thioester, then to a polyunsaturated thiol and then to a polyunsaturated ketone.

In a second embodiment, the invention relates to the preparation of a polyunsaturated thioester intermediate useful in the formation of compounds like compounds A and B above. The polyunsaturated thioester is obtained from a polyunsaturated alcohol in high yield and purity and preferably without any inter step purification. The combination of embodiments one and two forms a still yet further aspect of the invention.

WO2015/011206 (PCT/EP2014/065853) and WO2016/116634 (PCT/EP2016/051456) describe a process in which a polyunsaturated ester is converted, via an epoxide to a polyunsaturated ketone (Scheme 1).

Scheme 1 In order to prepare the epoxide, the necessary steps are a-i), a-ii) and a-iii).

These represent a sequence of hydrolysis (a-i), halolactonization (a-ii) and epoxide formation (a-iii).

In W02015/011206 (PCT/EP2014/065853), the hydrolysis step is performed using LiOH in EtOH/H₂0, while iodolactonization is performed in THF/water and the epoxide formation takes place in MeOH (leading therefore to the formation of a methyl ester). There is a work-up step after each one of steps a-i), a-ii) and a-iii).

The use of a different solvent system in each step requires solvent removal and new solvent addition between steps. The intermediate acid and lactone are therefore purified during the prior art procedure. This has the downside that the method is made more complex by the need to remove and add solvent, and is made more expensive by the need for fresh solvent in each step.

WO2016/116634 also describes step a-i) being carried out in EtOH/H₂0. A solvent change is needed in step a-ii) where THF/H₂0 is used. Step a-iii) is then carried out in MeOH.

The inventors have now surprisingly established that it is possible to carry out the hydrolysis, halolactonization and epoxidation steps without a change of solvent between each step. The inventors have surprisingly established that it is possible to carry out steps a-i) to a-iii) using a mixture of lower alcohol/H₂0 in each of the steps. This is surprising because until now it was thought that different solvents were needed for each of steps a-i) to a-iii). Furthermore, it is possible to carry out this sequence of reactions without detriment to epoxide purity or yield.

This is highly surprising given the complex chemistry involved and the potential for the formation of side-reactions in steps a-i) to a-iii).

Moreover, it is preferred if steps a-i) to a-iii) are carried out without any organic and/or aqueous washing steps between steps a-i) and a-ii) and a-ii) to a-iii).

Moreover, it is also preferred if there is no requirement to remove any reactant from an earlier step before carrying out a subsequent step although it may be necessary to quench the reaction mixture.

In a most preferred embedment therefore, steps a-i) to a-iii) are carried out in one pot using the same solvent and ideally without any work up procedures between the steps.

Embodiment 1

Step a-i) - Ester hydrolysis

The starting material in the process of the invention is a polyunsaturated ester. Preferably that polyunsaturated alcohol is of formula (G):

RI-CH=CH-CH₂CH₂COOR₆ ( ) wherein Ri is an optionally substituted CY22 unsaturated hydrocarbon group, said hydrocarbon group comprising at least 2, preferably at least 4 double bonds; and R₆ is a C1-C4 alkyl group. The double bond in formula (G) is preferably in cis thus making the compound formula (I):

In any embodiment of the invention, it is preferred if in any group Ri, double bonds are not conjugated. The group Ri preferably comprises 5 to 9 double bonds, preferably 5 or 8 double bonds, e.g. 5 to 7 double bonds such as 5 or 6 double bonds.

It is also preferred if the double bonds do not conjugate with the double bond depicted in formula (G).

The double bonds present in the group Ri may be in the cis or trans configuration however, it is preferred if the majority of the double bonds present (i.e. at least 50%) are in the cis configuration. In further advantageous embodiments all the double bonds in the group Ri are in the cis configuration or all double bonds are in the cis configuration except the double bond nearest the -CH=CH- CH2CH2COOR6 group which may be in the trans configuration.

The group Ri may have between 8 and 22 carbon atoms, preferably 10 to 19 carbon atoms, especially 16 to 18 carbon atoms. Carbon atoms are preferably linear in the Ri group (i.e. there are no side chain groups). Ri group is preferably aliphatic and does not contain rings.

The Ri group may by optionally substituted, e.g. carry up to three

substituents, e.g. selected from halo, Ci_₆ alkyl e.g. methyl, Ci_₆ alkoxy. If present the substituents are preferably non-polar, and small, e.g. a methyl group. It is preferred however, if the Ri group remains unsubstituted.

The Ri group is preferably linear, i.e. there are no branches in the Ri chain.

It preferably derives from a natural source such as a long chain fatty acid or ester. In particular, the Ri group may derive from arachidonic acid, docosahexaenoic acid or eicosapentaenoic acid.

It is thus preferred if the polyunsaturated ester is a compound of formula (I”) Rr-CH=CH-CH₂CH₂COOR6 (I”) wherein Rr is a linear, unsubstituted Ci_4-22 unsaturated aliphatic hydrocarbon group, said hydrocarbon group comprising at least 4 double bonds.

In a preferred embodiment, the polyunsaturated ester is of formula (VI):

wherein R₆ is a C1-C4 alkyl group.

In any embodiment, R₆ may be methyl, ethyl, n-propyl, i-propyl, n-buyl, 2- methyl propyl, 3-methyl propyl or tert-butyl. Preferably R₆ is ethyl.

The polyunsaturated ester is hydrolysed in the presence of an aqueous base in a mixture of lower alcohol and water, wherein the term lower alcohol means a C1-C4 alcohol group. The alkyl portion may be methyl, ethyl, n-propyl, i-propyl, n- butyl, 2-methyl propyl, 3-methyl propyl or tert-butyl. Preferably the alcohol is methanol or ethanol.

Preferably together solvents lower alcohol and H₂0 form 90-100 vol% of the solvent in step a-i), preferably 95-100 vol%, preferably 98-100 vol%.

The ratio of lower alcohol to water (vol/vol) in step a-i) is preferably 50:50 to 90:10, preferably 55:45 to 85:15, more preferably 60:40 to 80:20. Ratios of 65:35 to 75:25 are particularly suitable.

Any suitable base may be used, such as a metal carbonate, a metal hydrogen carbonate or a metal hydroxide, especially alkali metal carbonates or alkali metal hydrogen carbonates, or alkali metal hydroxides. Suitable bases include the carbonates, hydrogen carbonates or hydroxides of Li, Na, K, Rb or Cs. A

particularly preferred base is LiOH.

The skilled person will readily be able to determine suitable conditions (concentration, temperature and time) for step a-i). It is preferred if step a-i) is heated, e.g. to 20 to lOO’C, such as 50 to 90°C, e.g. under reflux. By way of example only, suitable conditions include LiOH as base in a mixture of EtOH/H₂0. As a further example, suitable conditions include LiOH as base in a mixture of MeOH/H₂0.

Step a-i) involves hydrolysis of the ester unit, e.g. the -CO2R6 unit within the polyunsaturated ester, such as a compound of formula (G) or (VI). Once the hydrolysis is completed (which may be determined by routine methods known in the art) the reaction mixture will typically be acidified, e.g. to a pH of ~5 to neutralize the base, e.g. by addition of aqueous acid. Alternatively, an acidified alcohol could be used. For instance, methanolic HC1 could be used if step a-i) has been carried out in MeOH/H₂0. The alcohol used in any acidified alcohol is ideally the same as the alcohol used as the solvent.

In some embodiments the solvent mixture may be adjusted before carrying out step a-ii), e.g. by removing a portion (but not all) of the lower alcohol/H₂0 solvent, or addition of more lower alcohol and/or more H₂0. Preferably however, there is no removal of solvent. It will be appreciated that the alcohol to water solvent ratio may change as the addition of alcoholic acid changes the ratio.

It is a preferred feature of the present invention that no purification steps (besides adjustment of pH or adjustment of solvent content) are carried out between steps a-i) and a-ii). In one embodiment therefore, the process steps (a-i) to (a-iii) proceed without purification by chromatography and/or distillation between steps. Ideally, the reaction mixture is taken directly from substrate ester to product epoxide. Importantly, no aqueous or organic washes need to be carried out. There is ideally no work up therefore. Preferably therefore, no purification of the polyunsaturated acid is carried out before the next step. The mixture from step a-i) is preferably a “crude mixture”. The product of step (a-i) is therefore a polyunsaturated acid, such as R_I-CH=CH-CH₂CH₂COOH, especially the acid of formula VII

Step a-ii) - Halolactonization In a second step a-ii) of a process according to the present invention the mixture of polyunsaturated acid formed in step a-i) is treated with a reagent to effect halolactonization of the acid (halolactonization agent). This is preferably carried out in the same vessel as step a-i).

The skilled person will be aware of suitable reagents to effect

halolactonization. An exemplary reagent is I₂, which is typically added as a mixture of I₂, KI and NaHCCb. Other suitable reagents include N-halo compounds, such as N-bromosuccinimide and N-bromo-phthalimide.

Typically the halolactonization agent should be in molar excess relative to the amount of polyunsaturated ester inputted to step a-i) (to ensure conversion to the halolactone). The molar equivalents of halolactonization agent relative to the amount of polyunsaturated acid (assumed to be the same as the amount of polyunsaturated ester) may be between 1.05 to 1.5 mol, particularly where I₂ is used.

Preferably lower alcohol and H2O together form 90-100 vol% of the solvent in step a-ii), preferably 95-100 vol%, preferably 98-100 vol%.

The ratio of lower alcohokfhO (vokvol) in step a-ii) is preferably 50:50 to 90:10, preferably 55:45 to 85:15, more preferably 60:40 to 80:20. Ratios of 65:35 to 75:25 are particularly suitable.

The conditions (concentration, temperature and time) used for the

halolactonization step a-ii) will depend in part on the solvent mixture present in step a-ii). The lower alcohol solvent used in a-ii) is the same as the lower alcohol used is step a-i).

One option is EtOH/fbO iodolactonization using I2, KI and NaHC0₃. In another option, MeOH/fbO is used as solvent, using I2, KI and NaHC0₃. The use of methanol typically leads to a faster reaction.

The use of lower alcohol/water as solvent in the halolactonization step significantly accelerated the iodolactonization procedure relative to the use of THF/water, which has previously been described as requiring 3 days for completion when carried out using I2, KI and NaHC0₃ in a mixture of THF/H2O (see W02015/011206). The skilled person will readily be able to determine suitable conditions (concentration, temperature and time) for step a-ii). It is preferred if step a-ii) is heated, e.g. to 20 to lOO’C, such as 50 to 90°C, e.g. under reflux.

It is a preferred feature of the present invention that no work-up (besides optional adjustment of solvent content or quenching of any residual iodolactonization agent) is carried out between steps a-ii) and a-iii). Importantly, it is preferred if there are no aqueous or organic washes are carried out. Preferably, no other purification of the halolactone is carried out.

The iodolactone is not isolated but is believed to have the structure:

The inventors have appreciated that iodolactones are useful intermediates in a variety of chemical products such as prostaglandins. The techniques discussed herein could therefore be useful in the synthesis of other products. In particular, the one vessel preparation of an iodolactone from the corresponding alkyl ester is an interesting reaction in chemical synthesis.

Thus, viewed from another aspect the invention provides a process comprising the steps of:

(a) hydrolysing, in a vessel, an ester of formula (XX)

wherein R20 is lower alkyl;

R21 is H or substituted or unsubstituted hydrocarbyl;

R22 is H or substituted or unsubstituted hydrocarbyl;

R23 is H or substituted or unsubstituted hydrocarbyl;

to the corresponding acid in a solvent of lower alcohol and water and adding an iodolactonization agent to form a mixture;

(b) treating, e.g. heating, the mixture under conditions sufficient to form the iodolactone in the vessel.

Step a-iii) - Epoxidation

In a third step a-iii) of a process according to the present invention the halolactone product formed in step a-ii) is treated with a reagent/reagents to effect opening of the halolactone with formation of an epoxide. It is preferred that the reagent/reagents are added straight to the crude mixture from step a-ii). This step is preferably carried out therefore in the same vessel as step a-i) and a-ii).

The skilled person will be aware of suitable reagents for converting halolactones into the corresponding epoxides with concomitant ring opening of the halolactone. A particularly suitable reagent is a carbonate, e.g. metal carbonate such as potassium carbonate. Na₂S₂0₃, and NaHCCh can be used to work up the process.

It is possible to adjust the solvent content before carrying out step a-iii). This may be achieved by removing a portion of the lower alcohol/water solvent or, preferably, by addition of more lower alcohol and/or H₂0. The lower alcohol used in step a-iii) is the same as that used in steps a-i) and a-ii). It is required therefore that the solvent in all three steps a-i) to a-iii) comprises the same lower alcohol. The inventors have established that if a mixture of MeOH/H₂0 is used in steps a-i) and a-ii), then it may be preferable to increase the increase the proportion of MeOH in the solvent mixture in step a-iii). This can be achieved by adding additional MeOH to the mixture formed at the end of step a-ii) before adding the reagents for step a-iii).

Preferably together solvents lower alcohol and H₂0 form 90-100 vol% of the solvent in step a-iii), preferably 95-100 vol%, preferably 98-100 vol%.

The ratio of lower alcohol:H₂0 (vohvol) in step a-iii) is preferably 50:50 to 90:10, preferably 55:45 to 85:15, more preferably 60:40 to 80:20. Ratios of 65:35 to 75:25 are particularly suitable.

The epoxide that forms is preferably of formula

wherein Ri is as hereinbefore defined and Rs is Ci-₄alkyl; especially of formula (IX):

Each of steps a-i) to a-iii) may independently be effected at a temperature of 20 to 1 l0°C, such as 25 to l00°C. A particularly preferred range is 50 to 90°C such as 55 to 80°C, e.g. about 60°C. In one embodiment, the temperature of all three steps a-i) to a-iii) is about the same and the temperature of the reaction can be kept constant over the three reactions.

The inventors therefore demonstrate that the ester can be converted to the epoxide in a one pot reaction. The inventors have surprisingly established that the purity of epoxide product formed after step a-iii) (crude material as measured by ¹ H NMR) is comparable to that formed when work-up steps are included after steps a-i) and a-ii). It was an unexpected advantage that a one-pot approach is feasible given the complex chemistries involved and propensities to make unwanted side products.

In some embodiments it may be appropriate to purify the crude epoxide product after work-up of step a-iii), typically by chromatographic purification. The purity of the epoxide may be 70 to 100%, such as 80 to 100%, especially 90 to 100% as judged by chromatography.

In another aspect of the invention the crude product from step a-iii) can be used crude in subsequent steps, e.g. to prepare the polyunsaturated ketone using chemistry described in W02015/011206 and WO2016/116634.

It will typically be appropriate to carry out a work-up procedure after step a- iii) before conducting subsequent steps. Such a work-up procedure may include removing solvent from the crude mixture formed in step a-iii) and may also include aqueous/organic extraction.

It is thus preferred if the polyunsaturated ester is a compound of formula (G) RI-CH=CH-CH₂CH₂COOR₆ (G) wherein Ri is a linear, unsubstituted CV22 unsaturated aliphatic hydrocarbon group, said hydrocarbon group comprising at least 2, preferably at least 4 double bonds; is converted to an epoxide of formula (IV)

wherein Ri and Rs are as hereinbefore defined in a one pot process especially without inter step purification.

In a more preferred embodiment, the polyunsaturated ester is of formula

(VI): /=\/⁼\/⁼\/^NCo_2Re

\=/\=/\=/\

(VI)

wherein R₆ is a C1-C4 alkyl group is converted to an epoxide of formula

(ix);

wherein Rs is Ci_₄alkyl;

in a one pot process especially without inter step purification. Aldehyde Formation (step b)

The polyunsaturated epoxide of the invention can be converted to its corresponding polyunsaturated aldehyde and then to a polyunsaturated alcohol following published protocols. Preferably the polyunsaturated aldehyde that is formed is of formula RiCHO where Ri is as hereinbefore defined.

It is preferred if a polyunsaturated epoxide of formula IX:

wherein Rs is Ci-₄alkyl;

is treated with a reagent to produce an aldehyde of formula X:

The polyunsaturated epoxide may be formed by the methods described for steps a-i) to a-iii) and may have been purified following step a-iii), or may be used crude following step a-iii).

Suitable chemistry for step b) has been previously described in W02015/011206 and WO2016/116634 (NaI04/Me0H/H20), and in Flock et al.

Acta Chemica Scandinavia 54, 1999, 436-445.

In a preferred embodiment, step b) is carried out by treatment of the epoxide with an excess of H5IO6. Sodium periodate or hydrogen peroxide could also be used. A typical excess is 1.5 to 3 molar equivalents of H₅IO₆, especially 2 ± 0.5 equivalents. Alternatively, an aldehyde can be prepared via the dialkylacetal in an alcohol solvent with formic acid work up.

In a preferred embodiment step b) is carried out in a mixed solvent of THF/Et20. Suitable volume ratios range from 1 :3 to 3:1. It will be appreciated that the aldehyde and reagent (e.g. H5IO6) may initially be dissolved in separate solvents, with the mixed THF/Et20 solvent system only being formed upon mixture of the two. Any solvent is preferably anhydrous.

In one embodiment, step (b) follows step (a-iii) without purification of the (a-iii) product, i.e. steps a-i to (b) can be carried out in one pot. Optional Step c) Aldehyde isomerization

The aldehyde RiCHO or more preferably the compound (X) may be used in step (d) below. However, before reduction, an isomerisation reaction can be effected. In a preferred embodiment, an aldehyde of formula X can be isomerized to an aldehyde of formula XI:

Suitable reagents and conditions for achieving this are described in W02015/011206 (DBU/Et20). Typically step c) will involve treating the aldehyde with an amine base in slightly polar solvents. Typical amine bases include 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) and l,5-Diazabicyclo[4.3.0]non-5-ene (DBN). Typical solvents are THF or ether.

Typically, a work-up procedure will be carried out between steps b) and c), which may include aqueous/organic extraction. The solvent may also be changed between steps b) and c). However, typically no purification (e.g. chromatography) occurs between steps b) and c).

Step d) - alcohol formation The invention further comprises therefore conversion of a compound of the polyunsaturated aldehyde, e.g. RiCHO to R1CH2-OH;

wherein R¹ is as hereinbefore defined.

The use of diisobutylaluminium hydride (DIBAH) is particularly preferred in this regard. The present inventors have surprisingly found that some other well known reducing agents such as sodium borohydride cannot be used successfully in this reduction as they increase the number of impurities formed. It is surprising that the use of DIBAH seems to reduce isomerism and hence minimises impurity formation.

In a preferred step d), an aldehyde of formula (X) or (XI) is treated with a reducing agent to form an alcohol of formula (XII) or (XIII)

Second Embodiment - Thioester Formation

Step (e)

In a second aspect, the invention relates to the conversion of a

polyunsaturated alcohol to a polyunsaturated thioester in a single pot. This process is effected by reaction of the polyunsaturated alcohol with a sulphonyl halide, i.e. a compound of formula R₂S0₂Hal where R₂ is a Ci_-20 hydrocarbyl group, preferably Ci-io hydrocarbyl group, especially Ci-io alkyl group, such as Ci_-4 alkyl group, especially methyl. R₂ is preferably a linear Ci_-20 hydrocarbyl group such as linear Ci-io alkyl group.

The halide (hal) can be F, Cl, Br or I, especially Br or Cl, most especially Cl.

The reaction of the polyunsaturated alcohol with the sulphonyl halide is preferably effected in the presence of a base, ideally to neutralise any halide acids (e.g. HC1) that form during the reaction. The base should not itself react with the polyunsaturated compounds. Suitable bases are well known in the art, such as trialkylamines, in particular triethylamine. Well known non nucleophilic bases are therefore appropriate.

The starting material is preferably R_ICH₂OH (XV), especially compounds (XII) or (XIV).

This reaction preferably forms therefore a compound of formula (XVI):

RICH₂-0S0₂R₂ (xvi) wherein Ri and R₂ are as hereinbefore defined.

Step (f) of the process of the invention requires the conversion of the sulphonyl ester (XVI) into a polyunsaturated thioester. The -0S0₂R₂ group is thus converted into -SC(=0)R₄ group.

This can be achieved by reaction using a compound comprising a salt with a SCOR4 ion where R₄ is a Ci_-20 hydrocarbyl group. The counterion can be a metal such as an alkali metal, e.g. Li, Na or K. R4 is preferably a Ci-io hydrocarbyl group, especially a Ci-io alkyl group, such as Ci_-6 alkyl group especially Ci_-4 alkyl group such as methyl. Any R4 group is preferably linear. The use of a thioacetate ion is preferred.

The reaction forms a compound (XVII)

R1CH2-SCOR4 (XVII) wherein Ri and R₄ are as hereinbefore defined.

This process should be effected in a single vessel. Steps e) and f) are carried out consecutively and preferably without a purification procedure between steps. It is preferred if step e) forms a precipitate. Once that precipitate is formed then a salt of-SC(=0)R₄ such as a thioacetate salt can be added. There is no need to wash the precipitate or isolate the precipitate between its formation and the addition of the salt of-SC(=0)R₄. In particular, aqueous or organic washing can be avoided between steps (e) and (f).

In a preferred embodiment, steps e) and f) involve the conversion of an alcohol of formula XIII or (XIV):

to a thioester of formula:

wherein R₄ is as hereinbefore defined.

It is an preferred feature of the present invention that no purification occurs between steps e) and f).

The skilled person will be able to determine suitable to solvents to carry out step e) and f). THF is a preferred solvent or DMF. Steps e) and f) are preferably carried out in the same solvent.

A particularly preferred choice of thiocarboxylate is potassium thioacetate (KSC(=0)Me). Typically the crude product will be purified following completion of step f).

In some embodiments it may be appropriate to purify the crude thioester product after work-up of step f), typically by chromatographic purification. The purity of the thioester may be 70 to 100%, such as 80 to 100%, especially 90 to 100% as judged by chromatography.

Thioester to Thiol

The first and second embodiments discussed above produce intermediate compounds that are useful in the formation of certain target compounds such as compounds A and B identified above. The remaining steps required to convert the product of step (f) to the target compounds of the invention are known.

Target compounds of the invention are those of formula R₁CH₂-S- CH₂COCF₃ where Ri is as hereinbefore defined.

In a preferred embodiment, the invention provides a method of producing a pharmaceutically acceptable 1,1,1 -trifluoro-3-(((2E,6Z,9Z, 12Z, 15Z,)-octadeca- 2 , 6 , 9 , 12 , 15 -p entaein- 1 -y l)thio)prop an-2 -one :

where X is CF₃; or related compound

where X is CF3.

One route from the alcohol is summarised below:

Scheme 2

To prepare these compounds, in step (g) of the process

Step g) - Deprotection

In step g) a thiocarboxylate is deprotected to provide a thiol. Deprotection may be by any means suitable, which include reaction with a base in an alcoholic solvent, such as potassium carbonate in methanol.

Preferably step g) is carried out in the presence of an antioxidant to prevent formation of the thiol. A preferred antioxidant is a-tocopherol.

The crude product from step g) is preferably used in step h) without purification.

Preferred thiols that are formed are simply of formula

R1CH2-SH wherein Ri is as hereinbefore defined.

The last step of the process of the invention therefore involves reaction of the thiol with a suitable ketone to form the desired compounds. The reaction preferably involves a compound is of formula (LG)CH₂CO-X i.e.

RSR3COX

LG represents a leaving group which is nucleophilicly substituted by the thiol group. Preferably, the reagent is LG-CH₂-COX, where LG is a leaving group such as a halide, tosyl, mesyl and so on. Ideally LG is a halide such as Br. X is preferably CF3. Most preferably (LG)R³-COX is BrCH₂-COCF3.

This final reaction step may take place in the presence of anti-oxidant as hereinbefore defined. The use of tocopherol is especially preferred, particularly (+/- )-alpha-tocopherol.

In a preferred embodiment, the invention comprises a process comprising steps a-i) to a-iii) as herein defined and the subsequent conversion of the epoxide lower alkyl ester to the target compounds such R₁CH₂-S-CH₂COCF₃ where Ri is as hereinbefore defined;

e-g.

where X is CF₃; or related compound

where X is CF₃

In a second embodiment, the invention covers a process in which steps (e) and (f) as hereinbefore defined are carried out and the product thioester is converted to the target compounds such R₁CH₂-S-CH₂COCF₃ where Ri is as hereinbefore defined;

e-g- where X is CF₃; or related compound

where X is CF3

In a most preferred embodiment, the invention provides a process comprising steps (a-i) to (a-iii) as hereinbefore defined, conversion of the epoxide to the corresponding alcohol (steps b-d), followed by steps (e) and (f) as hereinbefore defined and conversion of the thioester to the target compounds such RiCFb-S- CH2COCF3 where Ri is as hereinbefore defined;

e-g.

where X is CF₃; or related compound

where X is CF₃

It will be appreciated that the compounds made in the process of the invention have a variety of applications, e.g. in the treatment of chronic

inflammatory disorders. They can be formulated as pharmaceutical compositions using well known techniques. They may be converted into salts where appropriate. A further discussion of such techniques is not required here. In one embodiment therefore the invention provides:

Steps a-i to a-iii and (e)-(f) are carried out in one pot as herein defined. The invention will now be described with reference to the following non limiting examples and figures.

Description of the Figures

Figure 1. HPLC of starting material DHA ethyl ester.

Figure 2. HPLC of crude material after step a-i) on 200 g scale.

Figure 3. HPLC of crude iodolactone after step a-ii) on 200 g scale.

Figure 4a. HPLC of crude epoxide after step a-iii) on 200 g scale.

Figure 4b. 1H NMR of crude epoxide after step a-iii) on 200 g scale.

Figure 4c. 1H NMR of crude epoxide where work-up procedures were performed at the end of steps a-i) and a-ii).

Figure 5. 1H NMR of crude thioacetate made from the one-pot synthesis.

Example 1: One-pot Synthesis of Methyl 3-(3-((2Z,5Z,8Z,l lZ,14Z)-heptadeca- 2,5,8,ll,14-pentaen-l-yl)oxiran-2-yl)propanoate

A mixture of DHA ethyl ester (5.00 g, 14.0 mmol) and LiOH H₂0 (95.3 mmol) in MeOH/water (50 ml / 20 ml) was stirred at 60 °C under N₂-atmosphere for 50 minutes. The reaction mixture was cooled to room temperature and added 3 M HC1 in MeOH to pH ~5. Potassium iodide (2.805 g, 16.9 mmol) and KHCO3 (8.42 g, 84.1 mmol) was added and the reaction mixture was stirred for 10 minutes at room temperature before addition of iodine (4.277, 16.9 mmol) was added. The reaction mixture was stirred for 19 hrs. NaHCCh (1.958 g, 23.3 mmol) and Na₂S03 (1.552 g, 12.3 mmol) was added and the reaction mixture was stirred for 40 minutes. Potassium carbonate (5.879 g, 42.5 mmol) was added and the reaction mixture was stirred for 24 hrs. HPLC and TLC of the reaction mixture confirmed formation of the title compound.

This crude ¹ H NMR (Figure 4a) corresponds well with the ¹ H NMR obtained from the reactions where DHA is worked-up.

Example 2: Preparation of (3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaenal

A solution of methyl 3-(3-((2Z,5Z,8Z,l lZ,l4Z)4ieptadeca-2, 5,8,1 l,l4-pentaen-l- yl)oxiran-2-yl)propanoate (100.7 mg, 0.279 mmol) in dry diethyl ether (3 ml) was flushed with N₂, capped and added a solution of H5IO6 (130.5 mg, 0.57 mmol) in dry THF (2 ml) drop wise over 5 minutes. The reaction mixture was stirred at room temperature for 1 hr, diluted with heptane (25 ml) and washed with NaHCCh (sat) (aq) (15 ml) the water phase was extracted with heptane (25 ml) and the combined organic phase was dried (Na₂S0₄), filtered and concentrated under reduced pressure to afford the crude title compound as a dark yellow oil. Isomerisation of (3Z,6Z,9Z,l2Z,l5Z)-octadeca-3,6,9,l2,l5-pentaenal to the trans-Cl8 alcohol is then carried out following procedures described in W02015/011206.

trans C-18 aldehyde ^ ^ trans C-18 alcohol

Chemical Formula: C-igl^O Chemical Formula: C-igFksO Molecular Weight: 258,40 Molecular Weight: 260,41 0 A solution of trans C-18 aldehyde (96.31 g, 372.7 mmol) in dry toluene (1 L) was cooled to - 78 °C under N₂-atmosphere. DIBAL-H 1 M in toluene (in hexanes also works) (456.8 mL, 456.8 mmol) was added drop wise through a dropping funnel over 20 minutes. The reaction mixture was stirred at - 78 °C for 1 hr. 6 M HC1 (aq) (100 mL) was added drop wise / portion wise through the dropping funnel. The 5 cooling bath was removed and the reaction mixture was stirred for 30 minutes. Brine (1 L) was added and the reaction mixture was extracted with diethyl ether (4 x 500 mL). The combined organic phase was dried (Na₂S0₄), filtered and concentrated under reduced pressure to afford crude trans C-18 alcohol. (Store crude alcohol at - l8°C under argon.) Careful purification by chromatography is subsequently carried0 out.

Example 3 - One pot conversion of polyunsaturated alcohol to thioester

S-((2L,6Z,9Z, 12 Z, 15Z)-octadeca-2,6,9, 12, 15-pentaen- 1 -yl) ethanethioate

A solution of (2L,6Z,9Z,l2Z,l5Z)- octadeca-2,6,9,l2,l5-pentaen-l-ol (30.11 g, 115.6 mmol) in dry THF (300 ml) was flushed with N₂ before addition of mesyl chloride (11.6 ml, 149.9 mmol) and triethyl amine (32 ml, 229.9 mmol) and capped. The reaction was exothermic and a precipitate was formed. The reaction mixture was stirred for 1 hr before potassium thioacetate (26.3 g, 230.3 mmol) and DMF (60 ml) was added. The reaction mixture was stirred for 18.5 hrs and diluted with water (500 ml) and extracted with heptane (300 ml x 3). The combined organic phase was washed with brine (150 ml), dried (Na₂S0₄), filtered and concentrated under reduced pressure. Dry-flash chromatography on silica gel (1 kg) eluting with heptane - heptane:EtOAc (100:1) afforded 29.12 g (79 %) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCb) d 5.75 - 5.56 (m, 1H), 5.51 - 5.18 (m, 9H), 3.48 (d, J= 7.1, 2H), 2.97 - 2.71 (m, 6H), 2.30 (s, 3H), 2.20 - 1.87 (m, 6H), 0.96 (t, J= 7.5, 3H). Example 4: Synthesis of Compound A

3 4 The compound of example 3 (5.27 g, 16.5 mmol) was dissolved in methanol (50 mL) containing 10 mg alpha-tocopherol. Potassium carbonate (2.53 g, 18. mmol) was added in one portion at room temperature and the mixture was stirred for 45 minutes under inert atmosphere. The reaction mixture was quenched by way of drop-wise addition of 50 mL 1 M HC1, while cooled on an ice-bath. Subsequently, the mixture was extracted with heptane (3 x 50 mL), and the combined organic phases washed with brine (50 mL). Drying over Na₂S0₄ and subsequent filtration and removal of solvent under reduced pressure provided 4.45 g of 4 (97.5% yield) as an orange oil. The crude product was used in the next step without further purification.

4 Compound A

Sodium hydrogen carbonate (2.87 g, 34.2 mmol) was added to thiol 4 (4.45 g, 16.1 mmol), followed by water (50 mL) and ethanol (75 mL). The resulting inhomogeneous mixture was stirred vigorously at room temperature for 20 min under inert atmosphere. 3-Bromo-l,l,l-trifluoroacetone (2.1 ml, 20 mmol) was then added in one portion, and stirring was continued for 45 minutes. The reaction mixture was extracted with «-heptane (2 x 100 ml). The combined organic phase was washed with brine (50 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. This afforded 6.26 g crude product.

From the crude product, two 2.00 g aliquots were withdrawn and purified further using two different methods.

(Y) One aliquot was applied to a 90 g silica column and eluted by way of dry column vacuum chromatography (DCVC, 100 mL fractions, gradient elution

«-heptane - 100:2 «-heptane: ethyl acetate). Pure fractions were combined and evaporation of solvent under reduced pressure gave 1.64 g of 5 as a pale yellow oil. This corresponds to 82.5% yield for the last step. (Z) second aliquot was applied to a column with 90 g ODS-AQ stationary phase. Elution was performed by way of DCVC (100 mL fractions, gradient elution 20:80 acetonitrile: water - 70:30 acetonitrile: water), and after evaporation of acetonitrile from the fractions containing pure product, the product was extracted back to an organic solvent with 3 x 100 mL «-heptane. The combined organic extracts were washed with brine (50 mL), dried over

Na₂S0₄, filtered and concentrated under reduced pressure to give 1.28 g of 5 as a pale orange oil. This corresponds to 64.4% yield for the last step. Mass and NMR spectral data are similar, except for ratio hydrated/unhydrated in NMR. The given data are for purification method Z).

¹ H NMR (mixture of hydrated/unhydrated), CDCb, 400 MHz):□ 0.98 (3H, t, J = 5 7.5 Hz), 2.08 (2H, dq, Ji = Ji = 7.4 Hz), 2.12-2-21 (4H, m), 2.76-2.89 (6H, m), 3.10

(0.5H, t, J= 7.5 Hz), 3.26 (1.5H, t, J= 7.5 Hz ), 3.45 (0.5H, s), 3.93 (1.5H, s), 5.28- 5.46 (9H, m), 5.56-5.66 (1H, m). MS (ES): m/z 385 (M-H⁺) .

The products from purification method Y) and Z) were analysed by HPLC and the 0 impurities were compared with impurities in a batch prepared with a sequential thioester production step with work up between steps. The results are shown in Table 1 below

Table 1 Results for impurities in Compound A

**; RRT(Relative Retention Time), these are approximate values and will vary slightly between runs.

***; Exact RRT is 1.39. The identity has been confirmed by HPLC analysis of reference of impurity 7.

ND; Not detected

N/A Method run; 22 minutes

LOQ; Limit of quantification = 0.05%

****It should be noted that the peaks at RRT > 3 might be HPLC an artifact

COMPARATIVE EXAMPLE 1

A polyunsaturated alcohol was made according to a method described in PCT/EP2014/065853. The synthetic scheme used (Scheme 1) is shown below:

Comparative Scheme 1

To obtain the key trans C-18 alcohol in the required purity time -intensive chromatography is required.

Claims

1. A process comprising the steps of:

(a) combining, in a vessel, a polyunsaturated ester and a halolactonization 5 agent in a solvent of lower alcohol and water to form a mixture,

(ab) treating, e.g. heating the mixture in the presence of a reagent and under conditions sufficient to form a polyunsaturated epoxide lower alkyl ester in the vessel.

10 2. A process comprising the following steps:

a-ii) treating the product from step a-i), especially the crude product, with a halolactonization agent in the solvent of lower alcohol and water, to form the 15 corresponding polyunsaturated halolactone; and

a-iii) treating the product from step a-ii), especially the crude product, with a reagent in the solvent of lower alcohol and water to convert the polyunsaturated halolactone to the corresponding polyunsaturated epoxide lower alkyl ester.

20 3. A process as claimed in claim 2 wherein steps a-i) to a-iii) are carried out in the same reaction vessel.

4. A process as claimed in claim 2 to 3 wherein the process proceeds without purification by chromatography and/or distillation between steps a-i)/a-ii) and/or between ¾Seps a-ii)/a-iii).

5. A process comprising the following steps:

(a-i) treating a polyunsaturated alkyl ester of formula (G)

30 RI-CH=CH-CH₂CH₂COOR₆ (G) such as the compound

R_I-CH=CH-CH₂CH₂COOH (IF) such as the compound

wherein Ri is as hereinbefore defined;

a-ii) treating the product from step a-i) with a iodolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone compound:

wherein Ri is as hereinbefore defined; and

a-iii) treating the product from step a-ii) with a reagent in the solvent of lower alcohol/water to convert the iodolactone to the corresponding polyunsaturated epoxide lower alkyl ester of formula (IV):

wherein Ri is as hereinbefore defined and Rs is Ci-₄alkyL

6. A process comprising the following steps:

a-i) treating a polyunsaturated alkyl ester of formula (VI):

wherein R₆ is a C1-C4 alkyl group;

a-ii) treating the product from step a-i) with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding halolactone; and a-iii) treating the product from step a-ii) with a reagent in the solvent of lower alcohol and water to convert the halolactone to the corresponding epoxide of formula (IX):

wherein Rs is Ci-4alkyl.

7. A process as claimed in claim 2 to 6 wherein lower alcohol is methanol or ethanol.

8. A process as claimed in claim 2 to 7 wherein the base in step a-i) is LiOH.

9. A process as claimed in claim 2 to 8 wherein the volume of lower alcohol: water in step a-i) is 50:50 to 90:10 (vol/vol), e.g. 55:45 to 85:15 (vol/vol).

10. A process as claimed in claim 2 to 9 wherein the molar ratio of

halolactonization agent added in step a-ii) : ester added in step a-i) is 1.05:1 to 1.5:1.

11. A process as claimed in any preceding claim wherein said halolactonization agent is I₂.

12. A process as claimed in claim 2 to 11 wherein lower alcohol is methanol and the volume of MeOH : water in step a-iii) is 70:30 to 95:5 (vol/vol).

13. A process as claimed in claim 2 to 12 wherein step a-iii) involves the addition of a metal carbonate such as K₂CO₃.

14. A process as claimed in any preceding claim wherein the purity of the epoxide is 70 to 100% when measured by HPLC on the crude product, e.g. of step a- iii) in accordance with the HPLC method in the Experimental Section, preferably 80-100%.

15. A process as claimed in claim 2 to 14 wherein steps (a-i) to (a-iii) are carried out at a temperature of 25 to l00°C, such as 50 to 80°C.

16. A process as claimed in claim 2 to 15 wherein step a-iii) is followed by a step b) of converting the epoxide to an aldehyde, e.g. one of formula (X):

preferably wherein no purification is carried out between steps a-iii) and b).

17. A process as claimed in claim 16 wherein step b) is carried out using H₅IO₆.

18. A process as claimed in any of claims 16 or 17 wherein step b) is followed by a step c) of isomerizing the aldehyde of formula (X) to an aldehyde of formula

(XI):

using an amine base.

19. A process as claimed in claim 18 wherein step c) is carried out using DBU in diethyl ether.

20. A process as claimed in any of claims 16 to 19 wherein step b) or c) is followed by a step d) of converting the aldehyde into an alcohol.

21. A process for the preparation of a polyunsaturated thioester comprising:

(e) reacting a polyunsaturated alcohol in the presence of a compound of formula R₂-S0₂Hal wherein R₂ is a Ci_-20 hydrocarbyl group, such an Ci-io alkyl group, to form a polyunsaturated sulphonyl ester;

(f) converting the polyunsaturated sulphonyl ester to a polyunsaturated thioester by reacting with an anion of formula SC(=0)R₄ wherein R₄ is a Ci_-20 hydrocarbyl group;

wherein steps (e) and (f) are carried out sequentially or preferably consecutively in one vessel.

22. A process including at least the following steps:

(e) reacting a polyunsaturated alcohol of formula (XV)

R1CH2OH (XV) wherein R¹ is an optionally substituted CY22 unsaturated hydrocarbon group, said hydrocarbon group comprising at least 2, preferably at least 4 double bonds; in the presence of a compound of formula R₂-S0₂Hal wherein R₂ is a Ci_-20 hydrocarbyl group, such an Ci-io alkyl group, to form a polyunsaturated sulphonyl ester of formula (XVI)

wherein steps (e) and (f) are carried out consecutively in one pot.

23. A process including at least the following steps:

(e) reacting (3Z,6Z,9Z,l2Z,l5Z)-octadeca-3,6,9,l2,l5-pentaen-l-ol

with methanesulphonyl chloride in the presence of a base so as to form a

wherein steps (e) and (f) are carried out consecutively in one pot.

24. A process as claimed in claims 21 to 23 wherein there are no purification steps between steps (e) and (f).

25. A process as claimed in claim 21-24 wherein said sulfonyl ester is ClSC Me, tosyl chloride, brosyl chloride, nosyl chloride, triflyl chloride, tresyl chloride and dansyl chloride.

26. A process as claimed in claim 21-25 wherein step e) is carried out in the presence of an amine base.

27. A process as claimed in claim 21-26 wherein step e) is carried out in the presence of triethylamine.

28. A process as claimed in any of claims 21-28 wherein step e) is preceded by steps a) to d) as defined in claims 1 to 20.

29. A process as claimed in claim 21-28 wherein step f) is carried out by reacting with potassium thioacetate in DMF.

30. A process as claimed in any preceding claim wherein the purity of the thioester is 70 to 100% when measured by HPLC on the crude product of step f) in accordance with the HPLC method in the Experimental Section, preferably 80- 100%.

31. A process as claimed in any of claims 21-30 wherein step f) is followed by converting the thioester to compound A or B:

Compound B

Compound A wherein X is CF₃.

32. A process as claimed in any of claims 1-4 wherein step a-iii) is followed by converting the epoxide to compound A or B:

Compound B

Compound A wherein X is CF3.

33. A process comprising the following steps:

a-ii) treating the product from step a-i) with a halolactonization agent in the solvent of lower alcohol and water, to form the corresponding polyunsaturated halolactone;

a-iii) treating the product from step a-ii) with a reagent in the solvent of lower alcohol and water to convert the polyunsaturated halolactone to the corresponding polyunsaturated epoxide lower alkyl ester;

b-d) converting said polyunsaturated epoxide lower alkyl ester into the corresponding polyunsaturated alcohol;

(e) reacting said polyunsaturated alcohol in the presence of a compound of formula R₂-S0₂Hal wherein R₂ is a Ci_-20 hydrocarbyl group, such an Ci-io alkyl group, to form a polyunsaturated sulphonyl ester;

wherein steps (e) and (f) are carried out consecutively in one pot;

(g) converting the polyunsaturated thioester to a polyunsaturated ketone, e.g. compound A or B.

34. A process comprising the following steps:

a-i) treating a polyunsaturated alkyl ester of formula (VI):

wherein R₆ is a C1-C4 alkyl group;

wherein Rs is Ci-₄alkyl; b) converting the epoxide to an aldehyde of formula (X):

optionally;

c) isomerizing the aldehyde of formula (X) to an aldehyde of formula (XI):

d) converting the aldehyde (X) or (XI) into an alcohol; (3Z,6Z,9Z,12Z,15Z)- octadeca-3,6,9,l2,l5-pentaen-l-ol

(e) reacting said alcohol with methanesulphonyl chloride in the presence of a base so as to form

wherein steps (e) and (f) are carried out consecutively in one pot; and g) converting the thioester to compound A or B;

Compound B

Compound A wherein X is CF₃.