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Title:
METHODS FOR PREPARING COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2020/127390
Kind Code:
A1
Abstract:
A method is provided for preparing a compound d having the formula (D) The method comprises carrying out the following reaction (c) → (d), where the reaction is carried out at a temperature of at least 100 °C and in the presence of a metal catalyst.

Inventors:
DEELEY JON (GB)
FILIP SORIN (GB)
PRICE GREGORY (GB)
Application Number:
EP2019/085804
Publication Date:
June 25, 2020
Filing Date:
December 17, 2019
Export Citation:
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Assignee:
BP OIL INT (GB)
International Classes:
C07D241/40; C07D243/14; C07D265/36; C07D267/14; C10L1/233; C10L10/10
Domestic Patent References:
WO2019129591A12019-07-04
WO2017137518A12017-08-17
Foreign References:
EP3205701A12017-08-16
US20080064871A12008-03-13
Other References:
TODD EARY C ET AL: "Preparation of substituted 1,2,3,4-tetrahydroquinoxalines and 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepines from catalytic Cp^*Ir hydrogen transfer N-heterocyclization of anilino alcohols", TETRAHEDRON LETTERS, ELSEVIER LTD, AMSTERDAM, NL, vol. 47, no. 38, 18 September 2006 (2006-09-18), pages 6899 - 6902, XP025004893, ISSN: 0040-4039, [retrieved on 20060918], DOI: 10.1016/J.TETLET.2006.07.033
ARTHUR FAIRBOURNE ET AL: "FAIRBOURNE AND TOMS : A NEW SYNTHESIS OF OXAZINES.", JOURNAL OF CHEMICAL SOCIETY 1921, VOL. 119, 1 January 1921 (1921-01-01), pages 2076 - 2078, XP055661186, Retrieved from the Internet [retrieved on 20200123]
FU YING ET AL: "Simple and efficient synthesis of novel N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazines", HETEROCYCLIC COMMUNICATIONS, DE GRUYTER, DE, vol. 18, no. 3, 1 August 2012 (2012-08-01), pages 143 - 146, XP008180796, ISSN: 0793-0283, DOI: 10.1515/HC-2012-0056
Attorney, Agent or Firm:
HILL, Simon Stephen (GB)
Download PDF:
Claims:
Claims:

1. A method for preparing a compound d having the formula:

where: Ri is hydrogen;

III, 1C, R-4, R-5, Rii and R12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

A is a 5- to 10-membered ring, optionally substituted with one or more groups independently selected from alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

X is selected from -O- or -NR10-, where Rio is selected from hydrogen and alkyl groups; and

n is 0 to 2,

said method comprising carrying out the following reaction:

wherein the reaction is carried out at a temperature of at least 100 °C and in the presence of a metal catalyst.

2. The method of Claim 1, wherein compound d is an octane-boosting fuel additive having the formula: where: R7, Rx and R9 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups.

3. A method according to claim 1 or claim 2, wherein the reaction is carried out at a temperature of from 100 to 250 °C.

4. A method according to any of claims 1 to 3, wherein the metal catalyst is selected from palladium, nickel, cobalt, platinum, ruthenium, iridium, rhodium and copper catalysts.

5. A method according to any of claims 1 to 4, wherein each of the components used in the reaction for preparing compound d , aside from any solvent system, are used in amount of up to 0.5 molar equivalents, preferably up to 0.4 molar equivalents, and more preferably up to 0.3 molar equivalents, as compared to material c, and preferably wherein no reagents beyond material c are used in the reaction for preparing compound d.

6. A method according to any of claims 1 to 5, wherein the reaction for preparing compound d may be carried out in the presence of a metal catalyst and a base.

7. A method according to claim 6, wherein:

the metal catalyst is selected from ruthenium and iridium catalysts; and/or the base is selected from inorganic bases, such from alkali metal carbonates and alkali metal alkoxides, and preferably where the base is an alkali metal alkoxide.

8. A method according to any of claims 1 to 5, wherein the reaction for preparing compound d is carried out in the presence of a metal catalyst and, optionally, a solvent system, where preferably no further reaction materials are present.

9. A method according to claim 8, wherein:

the metal catalyst is selected from ruthenium, palladium, rhodium and nickel catalysts, and preferably where the metal catalyst is a nickel catalyst such as Raney nickel; and/or

no solvent system is used, or the solvent system is an aprotic solvent system preferably comprising an aromatic solvent, where the aromatic solvent is selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes and anisole.

10. A method according to any of claims 1 to 5, wherein the reaction for preparing compound d is carried out in the presence of a hydrogen source and an aprotic solvent system.

11. A method according to claim 10, wherein:

the metal catalyst is selected from palladium, nickel, cobalt, platinum, ruthenium, iridium, rhodium, copper and ruthenium catalysts, and preferably is Ni-SiC /AhCb; the hydrogen source is hydrogen gas, preferably at a pressure of from 1 to 50 bar, preferably from 3 to 30 bar, and more preferably from 5 to 15 bar; and/or the aprotic solvent system comprises an aromatic solvent, where the aromatic solvent is selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes and anisole.

12. A method according to any of claims 1 to 5, wherein the reaction for preparing compound d is carried out in the presence of a reaction additive.

13. A method according to claim 12, wherein:

the metal catalyst is selected from palladium, platinum, ruthenium and rhodium catalysts, and preferably from palladium catalysts; and/or

the reaction additive is selected from metal oxides ( e.g . zinc oxide) and inorganic bases (e.g. sodium formate).

14. A method according to any of claims 1 to 13, wherein the method further comprises preparing material c by carrying out the following reaction:

a b ab

I d where: R13 is selected from hydrogen and alkyl groups; and

L is selected from leaving groups and OH and L’ is OH, or L and L’ together form a group selected from -0-C(0)-0- and -0-.

15. A method according to any of claims 1 to 14, wherein the method is a batch process in which the compound d is produced in a batch quantity of greater than 100 kg, preferably greater than 150 kg, and more preferably greater than 200 kg.

16. A method according to any of claims 1 to 14, wherein the method is a continuous process.

17. A method according to any of claims 1 to 16, wherein the reaction is carried out in a reactor having a capacity of at least 500 L, preferably at least 750 L, and more preferably at least 1000 L.

18. A compound d having the formula:

where: Ri is hydrogen;

R2, R3, R4, R5, R11 and R12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

A is a 5- to 10-membered ring, optionally substituted with one or more groups independently selected from alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

X is selected from -O- or -NR10-, where Rio is selected from hydrogen and alkyl groups; and

n is 0 to 2,

wherein the compound d is obtainable by a method according to any of claims 1 to 17.

19. A process for preparing a fuel for a spark-ignition internal combustion engine, said process comprising:

preparing a compound d using a method according to any of claims 1 to 17; and blending the compound with a base fuel.

20. A fuel for a spark-ignition internal combustion engine, said fuel comprising a compound d according to claim 18 and a base fuel.

Description:
METHODS FOR PREPARING COMPOUNDS

Field of the Invention

This invention relates to methods for preparing benzoxazines and similar compounds, including octane-boosting additives for use in a fuel for a spark-ignition internal combustion engine. In particular, the invention relates to methods for preparing octane-boosting additives that are derivatives of benzo[l,4]oxazines and 1,5- benzoxazepines. The invention further relates to methods for preparing fuels for a spark- ignition internal combustion engine comprising the prepared compounds.

Background of the Invention

Spark-ignition internal combustion engines are widely used for power, both domestically and in industry. For instance, spark-ignition internal combustion engines are commonly used to power vehicles, such as passenger cars, in the automotive industry.

Fuels for a spark-ignition internal combustion engine (generally gasoline fuels) typically contain a number of additives to improve the properties of the fuel.

One class of fuel additives is octane-improving additives. These additives increase the octane number of the fuel which is desirable for combatting problems associated with pre-ignition, such as knocking. Additisation of a fuel with an octane improver may be carried out by refineries or other suppliers, e.g. fuel terminals or bulk fuel blenders, so that the fuel meets applicable fuel specifications when the base fuel octane number is otherwise too low.

Organometallic compounds, comprising e.g. iron, lead or manganese, are well- known octane improvers, with tetraethyl lead (TEL) having been extensively used as a highly effective octane improver. However, TEL and other organometallic compounds are generally now only used in fuels in small amounts, if at all, as they can be toxic, damaging to the engine and damaging to the environment.

Octane improvers which are not based on metals include oxygenates (e.g. ethers and alcohols) and aromatic amines. However, these additives also suffer from various drawbacks. For instance, N-methyl aniline (NMA), an aromatic amine, must be used at a relatively high treat rate (1.5 to 2 % weight additive / weight base fuel) to have a significant effect on the octane number of the fuel. NMA can also be toxic. Oxygenates give a reduction in energy density in the fuel and, as with NMA, have to be added at high treat rates, potentially causing compatibility problems with fuel storage, fuel lines, seals and other engine components.

Recently, a new class of octane-boosting additive has been discovered. These octane-boosting additives are derivatives of benzo[l,4]oxazines and 1,5-benzoxazepine, and show great promise due to their non-metallic nature, their low oxygenate content, and their efficacy at low treat rates (see WO 2017/137518).

Synthesis routes currently reported in the literature provide various descriptions of how benzoxazines could be prepared on a relatively small scale (hundreds of mg to up to 100 kg scale). For example, US 2008/064871 - which relates to compounds for the treatment or prophylaxis of diseases relating to uric acid, such as gout - discloses the preparation of benzoxazine-derived compounds.

However, such synthesis methods are not viable for preparing the new class of octane-boosting additives on an industrial scale, e.g. from 50 to up to 20,000 tonnes per year, due to the high cost of specialised raw materials, e.g. methylaminophenols, and reagents, e.g. lithium aluminium hydride and dibromoethane, which are required in higher than stoichiometric amounts. Moreover, halogenated reagents can be toxic and produce significant amounts of waste material so would ideally be avoided as reagents on an industrial scale.

Other synthesis methods often involve the use of strong acids. However, strong acids can corrode metallic industrial equipment and so they are not suitable for use as reagents on an industrial scale over long periods of time.

Accordingly, there is a need for methods for synthesising the new class of octane boosting additives that may be implemented on a large scale and which mitigate at least some of the problems highlighted above.

Summary of the Invention

It has now been found that the new class of octane-boosting additives and similar compounds can be prepared from an amino alcohol starting material by using a metal catalyst. Without wishing to be bound by theory, it is believed that the reaction proceeds via a borrowing hydrogen catalysis mechanism, according to which hydrogens are efficiently transferred through the reaction by the catalyst. This means that activation of the alcohol, e.g. by halogenation, is avoided thereby giving a highly efficient synthesis route. Accordingly, the present invention provides a method for preparing a compound d having the formula:

where: Ri is hydrogen;

III, Its, R-4, R-5, Rii and R12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

A is a 5- to 10-membered ring, optionally substituted with one or more groups independently selected from alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

X is selected from -O- or -NR10-, where Rio is selected from hydrogen and alkyl groups; and

n is 0 to 2.

The method comprises carrying out the following reaction:

c d

The reaction is carried out at a temperature of at least 100 °C and in the presence of a metal catalyst.

Also provided is a compound d which is obtainable by a method of the present invention.

The present invention further provides a process for preparing a fuel for a spark- ignition internal combustion engine. The process comprises:

preparing a compound d using a method of the present invention; and blending the compound d with a base fuel.

A fuel for a spark-ignition internal combustion engine is also provided. The fuel comprises a compound d of the present invention and a base fuel.

Detailed Description of the Invention

The present invention provides a method for preparing a compound d. According to the method, the compound d is prepared by carrying out the following reaction:

c d

The reaction is preferably a one-step reaction, i.e. the reaction is preferably carried out using one set of reaction materials, and preferably a single set of conditions.

The reaction is carried out at a temperature of at least 100 °C, such as a temperature of from 100 to 250 °C.

The reaction may be carried out in the presence of a wide range of metal catalysts.

It will be appreciated that metal catalysts are metal -containing catalysts and, as such, they may contain non-metallic elements.

Suitable metal catalysts include those selected from palladium ( e.g . Pd/C, PdO, Pd/AkCb , Pd/C/ZnO or PdCk(PPh3)2), nickel (e.g. in the presence of aluminium such as in Raney nickel or Ni-SiC /AkCb), cobalt (e.g. in the presence of aluminium such as in Raney cobalt), platinum (e.g. Pt/C, PtC , Pt/AhCb, Pt/C/Cu, Pt/C/Fe, PtSiC or Pt/C/V), ruthenium (e.g. Ru/C, RuC , Ru/AkCb, RuCk(PPh3)3, Cp * RuCl(PPli 3 )2, Cp RuCl(COD), (Cp * RuCl)4 or CpRuCl(PPh3)2), iridium (e.g. Ir/C or [CplrCbb), rhodium (e.g. Rh/C, RI12O3, Rh/AkCb, [Rh(COD)Cl]2, (PPh3)3RhCl or RhCl(CO)(PPh3)2) and copper (e.g. in the presence of aluminium such as in Raney Cu, CuO/ZnO, CuO/AkCb/MnO or CuzCnO ) catalysts. As is standard in the art, Cp * represents the ligand 1, 2, 3,4,5- pentamethylcyclopentadienyl, Cp represents the ligand cyclopentadienyl and COD represents the ligand 1,5-cyclooctadiene.

The metal catalyst may be used in an amount of up to 0.5 molar equivalents. The reaction may be carried out as a homogeneous or heterogeneous catalyst reaction. Homogeneous catalysis refers to catalytic reactions where the catalyst is in the same phase as the reactants. Heterogeneous catalysis reactions involve the use of a catalyst in a different phase from the reactants.

The reaction may be carried out in the presence of a base, in the presence of a hydrogen source, or in the presence of a reaction additive.

The reaction may also be carried out in the presence of a solvent system.

Specific conditions that may be used in the reaction for preparing the compound d are described in greater detail below.

An advantage of the present invention is that it does not require the use of reagents in stoichiometric amounts. In preferred embodiments, no reagents beyond material c are used in the reaction. Material c is considered to be a reagent because it is consumed in the course of the reaction. The other components used in the reaction are not considered to be reagents since they are not consumed in the course of the reaction. In embodiments, each of the components used in the reaction for preparing the compound d , aside from material c, any hydrogen source (if used) and any solvent system, are used in amount of up to 0.5 molar equivalents, preferably up to 0.4 molar equivalents, and more preferably up to 0.3 molar equivalents, as compared to material c.

The reaction is preferably carried out in the absence of halogen-containing reagents and acidic reagents, preferably strongly acidic reagents (i.e. compounds which have a pH of less than 5 at 25 °C when present as a 0.01M aqueous solution of said compound).

It may be desirable to purify the compound d before it is used, e.g. as a fuel additive. Thus, in some embodiments, the method of the present invention comprises the step of purifying the product of the reaction (‘crude’ compound d) to give a purified form of the compound d. For instance, the crude compound d may be purified by dissolving the compound in a non-polar solvent, such as heptane, and filtering off the insoluble salts and by-products. Alternatively, the crude compound d may be purified by distillation of the compound, e.g. at reduced pressure. Other conventional purification methods may also be used.

The methods of the present invention are preferably carried out on an industrial scale. For instance, where the method of preparing the compound d is a batch process, the compound d is preferably produced in a batch quantity of greater than 100 kg, preferably greater than 150 kg, and more preferably greater than 200 kg. The method may also be carried out as a continuous process. Preferred continuous processes are carried out for a period of greater than 30 days, and preferably greater than 365 days. The continuous process preferably produces greater than 50 tonnes / day of compound d.

In order to produce the compound d on an industrial scale, the reaction to prepare the compound d and preferably the reaction to prepare material c (described below), may be carried out in reactors having a capacity of at least 500 L, preferably at least 750 L, and more preferably at least 1000 L. It will be appreciated that both reactions may be carried out in the same reactor. The reactor used to produce compound d preferably has an operating temperature range of at least from 100 to 250 °C and an operating pressure range of at least from 1 to 50 bar.

Specific routes by which the compound d may be prepared using a temperature of greater than 100 °C and a metal catalyst will now be detailed.

Reaction in the presence of a basic catalyst

In some embodiments, the reaction for preparing a compound d may be carried out in the presence of a metal catalyst and a base.

The reaction may be carried out in the presence of a range of metal catalysts.

Suitable metal catalysts include ruthenium ( e.g . in the form of RuCk(PPh3)3) and iridium (e.g. [Cp * IrCl2]2) catalysts.

The metal catalyst may be used in an amount of up to 0.3 molar equivalents, for instance from 0.001 to 0.3 molar equivalents, preferably from 0.005 to 0.1 molar equivalents, and more preferably from 0.0075 to 0.075 molar equivalents, as compared to material c.

The reaction is preferably carried out as a homogeneous catalyst reaction. In this embodiment, the reaction is preferably carried out in the liquid phase. Thus, the catalyst is preferably soluble in material c or, if present, the solvent system in which the reaction is conducted.

The reaction is carried out in the presence of a base. Preferred bases include inorganic bases, such as those selected from alkali metal carbonates (e.g. alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate) and alkali metal alkoxides (e.g. alkali metal /c/T-butoxides such as sodium /c/T-but oxide or potassium /c/T-butoxide). In particular, alkali metal oxides are believed to give very high yields of the compound d. The base may be used in an amount of from 0.005 to 0.5 molar equivalents, preferably from 0.01 to 0.3 molar equivalents, and more preferably from 0.05 to 0.2 molar equivalents as compared to material c. It will be appreciated that these quantities mean that the base preferably acts as a catalyst, and is not being used up as a reagent in the reaction.

The reaction may be carried out in the presence of a solvent system, such as an aprotic solvent system. Aprotic solvents are well-known in the art as solvents which are not capable of donating protons. Aprotic solvents do not contain hydrogen atoms directly bound to an atom other than carbon. It will be appreciated that trace amounts ( e.g . less than 5 %, less than 3 % or less than 1 % by volume of the aprotic solvent system) of protic solvents may be present during a reaction in an aprotic solvent, e.g. as a result of the catalyst or base being prepared in a protic solvent such as water.

The aprotic solvent system preferably comprises an aromatic solvent, such as a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl-substituted naphthalenes (i.e. 1- and 2- methylnaphthalene) and anisole.

The aromatic solvent may be present in the aprotic solvent system in an amount of at least 30 %, preferably at least 40 %, and more preferably at least 50 %, by weight. In embodiments, the aromatic solvent is the only solvent that is used, i.e. the aprotic solvent system consists of the aromatic solvent.

The reaction will generally be carried out substantially in the absence of hydrogen gas, e.g. at a level of less than 10 ppm and preferably less than 1 ppm by volume.

Preferably, no further reaction materials (e.g. reagents or catalysts) beyond material c, the metal catalyst, the basic catalyst and, optionally, the solvent system are present.

The reaction is preferably carried out at a temperature of from 100 to 200 °C, preferably from 100 to 180 °C, and more preferably from 100 to 150 °C. In embodiments, the reaction is carried out at around (e.g. at 5 °C above or below) the reflux temperature of the solvent system that is used. The reaction will generally be carried out at just one temperature.

The reaction will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.

The reaction may be conducted for a period of greater than 2 hours, preferably greater than 12 hours. Typically, the reaction will be carried out for up to 48 hours. These values represent the period of time over which the reaction is carried out at a temperature of at least 100 °C.

Reaction without further components

In some particularly preferred embodiments, the reaction for preparing the compound d may be carried out in the presence of a metal catalyst and, optionally, a solvent system.

The reaction will generally be carried out substantially in the absence of hydrogen gas, e.g. at a level of less than 10 ppm and preferably less than 1 ppm by volume.

Preferably, no further reaction materials (e.g. reagents or catalysts) beyond material c, the metal catalyst and, optionally, the solvent system are present.

Suitable metal catalysts include ruthenium (e.g. as RuChCPPt^, Cp * RuCl(PPli3)2, Cp * RuCl(COD), (Cp * RuCl) 4 or CpRuCl(PPh )2), palladium (e.g PdCl 2 (PPh3) 2 ), rhodium (e.g. [Rh(COD)Cl]2, (PPh3)3RhCl or RhCl(CO)(PPh3)2) and nickel (e.g. Raney nickel) catalysts. Nickel catalysts are believed to be particularly suitable, with Raney nickel in particular providing a high yield.

The metal catalyst may be used in an amount of up to 0.3 molar equivalents, for instance from 0.001 to 0.5 molar equivalents, preferably from 0.005 to 0.4 molar equivalents, and more preferably from 0.01 to 0.3 molar equivalents, as compared to material c.

The reaction is preferably carried out as a homogeneous or heterogeneous catalyst reaction. With a homogeneous catalyst reaction, the reaction is preferably carried out in the liquid phase. Thus, the catalyst is preferably soluble in material c or, if present, the solvent system in which the reaction is conducted. With a heterogeneous reaction, the reaction is preferably carried out with a solid catalyst in a liquid reagent phase. The metal catalysts may be supported, e.g. on insoluble media, such as on carbon, alumina or silica. The metal catalyst may be used in the form of a slurry or in the form of a fixed bed catalyst.

The reaction is optionally carried out in the presence of a solvent system.

However, in some embodiments, it is preferred to carry out the reaction using solely material c as the solvent. This system is chemically very efficient and is capable of producing the compound d in large yields.

Solvent systems that may be used include aprotic solvent systems. It will be appreciated that trace amounts (e.g. less than 5 %, less than 3 % or less than 1 % by volume of the aprotic solvent system) of protic solvents may be present during the reaction, e.g. as a result of the catalyst being prepared as a catalyst-in-water slurry.

The aprotic solvent system preferably may comprise an aromatic solvent, such as a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl-substituted naphthalenes and anisole. Mesitylene is particularly suitable, delivering high yields of the compound d.

The aromatic solvent may be present in the aprotic solvent system in an amount of at least 30 %, preferably at least 40 %, and more preferably at least 50 %, by weight. In preferred embodiments, the aromatic solvent is the only solvent that is used, i.e. the aprotic solvent system consists of the aromatic solvent.

The aprotic solvent system may comprise a non-aromatic solvent. Preferred non aromatic solvents are selected from heterocyclic solvents, such as from N-methyl-2- pyrrolidone, tetrahydrofuran and 1,4-dioxane. Other suitable aprotic non-aromatic solvents include dimethylacetamide. The non-aromatic solvent may be used alone or in

combination with an aromatic solvent.

The solvent system may be used in an amount of up to 10 volume equivalents, for instance from 1 to 10 volume equivalents, preferably from 1.5 to 5 volume equivalents, and more preferably from 2 to 3 volume equivalents, as compared to material c.

The reaction is preferably carried out at a temperature of from 100 to 200 °C, preferably from 115 to 180 °C, and more preferably from 130 to 160 °C. The reaction will generally be carried out at just one temperature.

The reaction will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.

The reaction may be conducted for a period of greater than 2 hours, preferably greater than 10 hours, for instance greater than 20. Typically, the reaction will be carried out for up to 30 hours. These values represent the period of time over which the reaction is out at a temperature of at least 100 °C.

Reaction in the presence of hydrogen

In some preferred embodiments, the reaction for preparing the compound d may be carried out in the presence of a metal catalyst, a hydrogen source and an aprotic solvent system.

The reaction may be carried out in the presence of a wide range of metal catalysts. Suitable metal catalysts include those selected from palladium (e.g. Pd/C, PdO, Pd/AhCb , Pd/C/ZnO or PdCk(PPh3)2), nickel (e.g. in the presence of aluminium such as in Raney nickel or Ni-SiC /AhCb), cobalt (e.g. in the presence of aluminium such as in Raney cobalt), platinum (e.g. Pt/C, Pt/AkCb, Pt/C/Cu, Pt/C/Fe, PtSiCh or Pt/C/V), ruthenium (e.g. Ru/C or Ru/AkCb), iridium (e.g. Ir/C), rhodium (e.g. Rh/C, Rh/AkCb, [Rh(COD)Cl]2, (PPh3)3RhCl or RhCl(CO)(PPh3)2), copper (e.g. in the presence of aluminium such as in Raney Cu, CuO/ZnO, CuO/AkCb/MnO or CuzCnO ) and ruthenium (e.g. Cp * RuCl(PPh3)2, Cp RuCl(COD), (Cp * RuCl) 4 or CpRuCl(PPh3)2) catalysts. Nickel catalysts, in particular Ni-SiC /AkCb, are particularly suitable since these catalysts are believed to give high yields of the compound d.

The metal catalyst may be used in an amount of up to 0.5 molar equivalents, for instance from 0.005 to 0.3 molar equivalents, preferably from 0.01 to 0.25 molar equivalents, and more preferably from 0.05 to 0.2 molar equivalents, as compared to material c.

The reaction is preferably carried out as a heterogeneous catalyst reaction. In this embodiment, the reaction is preferably carried out with a solid catalyst in a liquid reagent phase. Thus, preferred metal catalysts are supported, e.g. on insoluble media, such as on carbon, alumina or silica. The metal catalyst may be used in the form of a slurry or in the form of a fixed bed catalyst.

The reaction is carried out in the presence of a hydrogen source. The hydrogen source is preferably hydrogen gas, for instance at a pressure of from 1 to 50 bar, preferably from 3 to 30 bar, and more preferably from 5 to 15 bar. Though less preferred, hydrogen transfer reagents could also be used as the hydrogen source, e.g. formic acid, sodium formate or ammonium formate.

The reaction is carried out in the presence of an aprotic solvent system. It will be appreciated that trace amounts (e.g. less than 5 %, less than 3 % or less than 1 % by volume of the aprotic solvent system) of protic solvents may be present during the reaction, e.g. as a result of the catalyst being prepared as a catalyst-in-water slurry.

The aprotic solvent system preferably comprises an aromatic solvent, such as a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl-substituted naphthalenes and anisole. Mesitylene is particularly suitable, delivering high yields of the compound d.

The aromatic solvent may be present in the aprotic solvent system in an amount of at least 30 %, preferably at least 40 %, and more preferably at least 50 %, by weight. In embodiments, the aromatic solvent is the only solvent that is used, i.e. the aprotic solvent system consists of the aromatic solvent.

The aprotic solvent system may also comprise a non-aromatic solvent. Preferred non-aromatic solvents are selected from heterocyclic solvents, such as from N-methyl-2- pyrrolidone, tetrahydrofuran and 1,4-dioxane. Other suitable aprotic non-aromatic solvents include dimethylacetamide. The non-aromatic solvent is preferably used in combination with an aromatic solvent.

Preferably, no further reaction materials ( e.g . reagents or catalysts) beyond material c, the metal catalyst, the hydrogen source and, optionally, the aprotic solvent system are present.

The reaction is preferably carried out at a temperature of at a temperature of from 100 to 250 °C, preferably from 130 to 230 °C, and more preferably from 150 to 200 °C.

The reaction will generally be carried out at just one temperature. However, in some embodiments, the reaction may be brought up to temperature over a period of up to 3 hours, preferably up to 2 hours, and more preferably up to 1.5 hours. For instance, the reaction may be carried out at a temperature of from 40 to 100 °C for a period of to 3 hours, preferably up to 2 hours, and more preferably up to 1.5 hours, before the reaction is taken up to full temperature.

The reaction may be conducted for a period of greater than 2 hours, preferably greater than 4 hours. Typically, the reaction will be carried out for up to 24 hours. These values represent the period of time over which the reaction is out at a temperature of at least 100 °C.

Reaction in the presence of a reaction additive

In some embodiments, the reaction may be carried out in the presence of a metal catalyst and a reaction additive.

Suitable metal catalysts include those selected from palladium (e.g. Pd/C or PdO), platinum (e.g. Pt/C or PtO?), ruthenium (e.g. Ru/C or RuC ) and rhodium (e.g. Rh/C or RI12O3) catalysts. Palladium catalysts are particularly suitable, since they are believed to give the compound d in high yields.

The metal catalyst may be used in an amount of up to 0.3 molar equivalents, for instance from 0.005 to 0.3 molar equivalents, preferably from 0.01 to 0.25 molar equivalents, and more preferably from 0.03 to 0.15 molar equivalents, as compared to material c. The reaction is preferably carried out as a heterogeneous catalyst reaction. In this embodiment, the reaction is preferably carried out with a solid catalyst in a liquid reagent phase. Thus, preferred metal catalysts are supported, e.g. on insoluble media, such as on carbon, alumina or silica. The metal catalyst may be used in the form of a slurry or in the form of a fixed bed catalyst.

The reaction is carried out in the presence of a reaction additive. Suitable reaction additives include metal oxides and inorganic basis. Preferred metal oxides include zinc oxide. Preferred inorganic bases include such as alkali metal hydroxides, alkali metal carbonates (including alkali metal hydrogen carbonates), alkali metal phosphates and alkali metal formates. Sodium or potassium will typically be used as the alkali metal. Preferred inorganic bases include sodium formate. Metal oxides such as zinc oxide are preferred when an aqueous solvent system is used, whereas alkali metal bases such as sodium formate are preferred for use with aprotic solvent systems.

The reaction additive may be used in an amount of up to 5 molar equivalents, for instance from 0.1 to 5 molar equivalents, preferably from 0.5 to 4 molar equivalents, and more preferably from 1 to 3 molar equivalents, as compared to material c. It will be appreciated that the reaction additive may be used in over-stoichiometric amounts and will typically be consumed in the reaction as a reagent.

The reaction may be carried out in the presence of a protic or an aprotic solvent system, though aprotic solvent systems are generally preferred. It will be appreciated that trace amounts (e.g. less than 5 %, less than 3 % or less than 1 % by volume of the aprotic solvent system) of protic solvents may be present during the reaction, e.g. as a result of the catalyst or reaction additive being prepared in a protic solvent such as water.

Protic solvents are well-known in the art as solvents which are capable of donating protons. Protic solvents typically contain hydrogen atoms directly bound to a nitrogen or an oxygen.

Protic solvent systems include aqueous, i.e. water-containing, solvent systems. In some embodiments, the aqueous solvent system may contain only water. In other embodiments, a mixture of water and an alcohol (e.g. te/7-butanol) or ether (e.g.

dimethoxyethane) may be used.

The aprotic solvent system preferably comprises an aromatic solvent, such as a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl-substituted naphthalenes and anisole. The aromatic solvent may be present in the aprotic solvent system in an amount of at least 30 %, preferably at least 40 %, and more preferably at least 50 %, by weight. In embodiments, the aromatic solvent is the only solvent that is used, i.e. the aprotic solvent system consists of the aromatic solvent.

The aprotic solvent system may comprise a non-aromatic solvent. Preferred non aromatic solvents are selected from heterocyclic solvents, such as from N-methyl-2- pyrrolidone, tetrahydrofuran and 1,4-dioxane. The non-aromatic solvent may be used alone or in combination with an aromatic solvent.

In some embodiments, an aromatic aprotic solvent, e.g. as described above, may be used in combination with a protic solvent, e.g. as described above. Toluene and tert- butanol may be used together.

The reaction will generally be carried out substantially in the absence of hydrogen gas, e.g. at a level of less than 10 ppm and preferably less than 1 ppm by volume.

Preferably, no further reaction materials (e.g. reagents or catalysts) beyond material c, the metal catalyst, the reaction additive and, optionally, the solvent system are present.

The reaction is preferably carried out at a temperature of at a temperature of from 105 to 200 °C, preferably from 110 to 180 °C, and more preferably from 120 to 160 °C. The reaction will generally be carried out at just one temperature.

The reaction will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.

The reaction may be conducted for a period of greater than 6 hours, preferably greater than 12 hours. Typically, the reaction will be carried out for up to 136 hours.

These values represent the period of time over which the reaction is out at a temperature of at least 100 °C.

Preparation of material c

Material c, the starting material for the reaction to produce the compound d, may be prepared by carrying out the following reaction: a b c where: R13 is selected from hydrogen and alkyl groups; and

one L is OH and the other L is selected leaving groups, or both L groups together form the group -0-C(0)-0- or -0-.

The reaction for preparing material c is preferably conducted using reagent b in an amount of from 0.5 to 4 molar equivalents, preferably from 0.7 to 3 molar equivalents, and more preferably from 0.8 to 2 molar equivalents as compared to starting material a.

The reaction for preparing material c is preferably conducted in the presence of a base, preferably an inorganic base, such as an alkali metal hydroxide ( e.g . selected from sodium hydroxide and potassium hydroxide) or an alkali metal carbonate (e.g. selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate). The method is preferably conducted in the presence of an alkali metal carbonate, preferably selected from sodium carbonate or potassium carbonate.

The base is preferably used in an amount of from 0.8 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, and more preferably from 1.05 to 2.5 molar equivalents as compared to starting material a.

The reaction for preparing material c may be conducted in an aprotic solvent, preferably selected from tetrahydrofuran, acetonitrile, dimethoxyethane, dioxane, N- methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethylene carbonate, sulfolane, diphenyl ether, acetonitrile, 2-nitropropane, acetone, butan- 2-one, butylformate, ethyl acetate, isobutyronitrile, methylacetate, methyformate, nitromethane, oxolane and propionitrile, and more preferably from dimethylformamide, N- methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate and sulfolane.

The reaction for preparing material c may be carried out at a temperature of greater than 40 °C, preferably greater than 50 °C, and more preferably greater than 60 °C. In some instances, the reaction is carried out under reflux. The reaction will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.

The reaction may be conducted for a period of greater than 1 hour, but preferably less than 24 hours, and more preferably less than 12 hours.

Substituent R13 of starting material a is selected from hydrogen and alkyl groups. Preferably, R13 is selected from hydrogen, methyl, ethyl, propyl and butyl, preferably from hydrogen and methyl, and more preferably is methyl.

During the reaction to prepare material c, a leaving group L is lost from alkylating agent b. One L is OH and the other L is selected from leaving groups, or both L groups together form the group -0-C(0)-0- or -0-, a group which effectively provides two leaving groups. Preferably, one L is OH and the other L is independently selected from: halides (e.g. Cl, Br, I), sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, - CF3, -CH2CI, phenyl and p-nitrophenyl) and substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl), more preferably from halides and sulfonates, and most preferably from Cl and Br.

Alternatively, and preferably, material c may be prepared by carrying out the following reaction:

c

where: R 13 is selected from hydrogen and alkyl groups; and

L is selected from leaving groups and OH and L’ is OH, or L and L’ together form a group selected frocm -0-C(0)-0- and -0-; and Step (i) is preferably carried out in the presence of a solvent. The solvent is preferably a protic solvent. Suitable protic solvents for use in step (i) include water and alcohols. The alcohol may be selected from Ci-io alcohols, preferably from C3-8 alcohols, and more preferably from C5-6 alcohols. Preferred alcohols have the formula CnThn+iOH , though polyols such as diols and triols may also be used and have the formula C n H2 n+ 2- m(OH)m with m preferably selected from 2 or 3 (e.g. ethylene or propylene glycol).

Preferably, the protic solvent is an alcohol, more preferably cyclohexanol or 4-methyl-2- pentanol.

In some embodiments, it may be desirable to use a mixture of solvents, e.g. a mixture of two or more of the protic solvents described above. This can be useful where it is desirable to carry the reaction in a specific solvent boiling range. For instance, step (i) may be carried out in the presence of two or more alcohols selected from C3-8 alcohols, and more preferably from C5-6 alcohols. In particular embodiments, step (i) is carried out in the presence of a mixture of isomers, e.g. a mixture of 4-methyl-2-pentanol and cyclohexanol.

Where a mixture of solvents is used, each solvent is preferably present in an amount of at least 10 %, and preferably at least 15 % by total weight of the solvent system. For instance, a mixture of 70 to 90 % 4-methyl -2-pentanol and 10 to 30 % cyclohexanol may be used.

The solvent may be used in step (i) in an amount of from 1.5 to 8 g, preferably from 2 to 6 g, and more preferably from 2.5 to 4.0 g of solvent per g of starting material a.

Step (i) may also be carried out in the absence of a solvent. However, this embodiment is less preferred since intermediate ab requires special handling when not used in a solvent.

Step (i) of the present invention is preferably carried out in the presence of a base. Suitable bases may be selected from:

inorganic bases, e.g. alkali metal hydroxides (such as sodium hydroxide and potassium hydroxides), alkali metal alkoxides (e.g. alkali metal /er/-butoxides such as sodium / <3/7 -but oxide or potassium /cvV-butoxide), and alkali metal carbonates (such as sodium hydrogencarbonate, sodium carbonate, potassium

hydrogencarbonate and potassium carbonate), and

organic bases, e.g. nitrogen-containing organic bases, such as from tetra -n- butylammonium fluoride, trimethylamine, diisopropyl ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine and 4-dimethylaminopyridine. The base is preferably an inorganic base and more preferably is a carbonate, in particular potassium carbonate.

The base may be used in an amount of from 0.005 to 0.3 molar equivalents, preferably from 0.01 to 0.1 molar equivalents, and more preferably from 0.03 to 0.06 molar equivalents as compared to starting material a. It will be appreciated that these quantities mean that the base preferably acts as a catalyst, and is not being used up as a reagent in the reaction.

During step (i), starting material a is alkylated using alkylating agent b. Alkylating agent b contains the groups L and IL

In some embodiments, L is selected from leaving groups and OH and L’ is OH. Suitable leaving groups include: halides ( e.g . Cl, Br, I), sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF3, -CH2CI, phenyl and p-nitrophenyl) and substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl). In these embodiments, preferred leaving groups are selected from halides and sulfonates, and more preferably from Cl and Br.

In preferred embodiments, however, L and L’ together form a group selected from - 0-C(0)-0- and -0-. These embodiments are preferred since they are halogen-free.

Particularly preferred alkylating agents b are those in which L and L’ together form the group -0-C(0)-0-, i.e. organic carbonates, such as ethylene carbonate.

Generally, the alkylating agent b may be used in an amount of from 0.8 to 1.3 molar equivalents, preferably from 0.9 to 1.1 molar equivalents, and more preferably from 1 to 1.02 molar equivalents, as compared to starting material a. Thus, the alkylating agent may be used effectively in just a stoichiometric or slightly over stoichiometric amount.

This is believed to improve the purity of the intermediate ab that is obtained.

Generally, step (i) of the reaction will be carried out in the absence of a metal catalyst. However, in some embodiments, the metal catalyst that is preferably used in step (ii) may be present for the reaction in step (i). This enables the two-step reaction to take place continuously. Suitable metal catalysts are described below in the section relating to step (ii). In these embodiments, it is generally preferred that an organic base (described above) be used as the base in step (i) since they have good solubility in the reaction mixture thereby allowing a homogenous liquid phase to be passed over a catalyst. A hydrogen source (e.g. as described below) may also be used in step (i) where a metal catalyst is present. Step (i) will typically be carried out at a temperature of at least 100 °C, for instance at a temperature of from 100 to 180 °C, preferably from 110 to 160 °C, and more preferably at a temperature of from 120 to 150 °C. In some instances, the reaction is carried out under reflux.

Step (i) will generally be carried out at ambient pressure, i.e. approximately 1 bar.

The reaction may be conducted for a period of greater than 4 hours, but preferably less than 48 hours.

Once intermediate ab has been prepared, it is reduced in step (ii) to form material c. Preferably, the reaction mixture from step (i) is used in its crude form in step (ii), i.e. no materials are removed from the reaction mixture before step (ii) commences. This means that steps (i) and (ii) may be carried out as a one-pot, but two-step, reaction

In embodiments where step (i) is carried out in the presence of a solvent, step (ii) is preferably carried out in the presence of the same solvent. Suitable solvents are described above.

It may be desirable to add a further solvent in step (ii). This solvent will generally be different from the solvent used in step (i), though of course the solvent from step (i) is still present in step (ii).

The further solvent is preferably a protic solvent, e.g. selected from water, alcohols and carboxylic acids. The alcohol may be selected from Ci- 6 alcohols, preferably from Ci-4 alcohols, and more preferably from C1-2 alcohols. Preferred alcohols have the formula C n H n+i OH, though polyols such as diols and triols may also be used and have the formula C n H2n+2-m(OH)m with m preferably selected from 2 or 3 (e.g. ethylene or propylene glycol). The carboxylic acid may be selected from Ci- 6 carboxylic acids, preferably from C1-4 carboxylic acids, and more preferably from C1-2 carboxylic acids. Preferred carboxylic acids have the formula C n Th n+i COOH. Carboxylic acids tend to be used where zinc or iron is present in the reaction mixture. Preferably, the further solvent is an alcohol, most preferably methanol.

Where a further solvent is added, it may be used added in a ratio of further solvent : solvent from step (i) of from 1 :5 to 5: 1, preferably from 1 :3 to 3: 1, and more preferably from 1 :2 to 2: 1, by volume.

As mentioned above, step (i) may also be carried out in the absence of a solvent, in which case step (ii) is carried out in the presence of a solvent, and preferably a protic solvent, e.g. selected from water, alcohols and carboxylic acids. The alcohol may be selected from Ci- 6 alcohols, preferably from Ci-4 alcohols, and more preferably from C1-2 alcohols. Preferred alcohols have the formula C n Ph n+i OH, though polyols such as diols and triols may also be used and have the formula C n H2n+2-m(OH) m with m preferably selected from 2 or 3 ( e.g . ethylene or propylene glycol). The carboxylic acid may be selected from Ci- 6 carboxylic acids, preferably from C1-4 carboxylic acids, and more preferably from C1-2 carboxylic acids. Preferred carboxylic acids have the formula C n f iCOOH. Carboxylic acids tend to be used where zinc or iron is present in the reaction mixture. Preferably, the protic solvent is an alcohol, most preferably methanol.

Step (ii) of the reaction is preferably carried out in the presence of a metal catalyst and a hydrogen source. Suitable metal catalysts for use in step (ii) are hydrogenation catalysts and include those selected from palladium (e.g. Pd/C), nickel (e.g. in the presence of aluminium such as in Raney nickel or Ni-SiC /AkCb) and rhodium (e.g. Rh/C) catalysts. Raney nickel and Pd/C catalysts are preferred, with Pd/C particularly preferred.

The metal catalyst may be used in an amount of up to 0.3 molar equivalents, for instance from 0.005 to 0.3 molar equivalents, preferably from 0.01 to 0.1 molar equivalents, and more preferably from 0.002 to 0.005 molar equivalents, as compared to starting material a.

The hydrogen source that is used in step (ii) is preferably hydrogen gas, for instance at a pressure of from 1 to 50 bar, preferably from 2 to 20 bar, and more preferably from 2.5 to 10 bar. Surprisingly, it has been found that excellent yields may be achieved even when hydrogen gas is used in step (ii) at a pressure of from just 2.5 to 4 bar.

Though less preferred, hydrogen transfer reagents could also be used as the hydrogen source, e.g. formic acid, sodium formate or ammonium formate. Hydrogen transfer reagents generate hydrogen gas in-situ. Hydrogen transfer reagents may be used in combination with hydrogen gas, or as the sole hydrogen source. Hydrogen transfer reagents are preferably used in combination with palladium catalysts, such as Pd/C.

Hydrogen transfer reagents may be used in an amount of up to 5 molar equivalents, for instance from 0.1 to 5 molar equivalents, preferably from 0.5 to 4 molar equivalents, and more preferably from 1 to 3 molar equivalents, as compared to starting material a.

In preferred embodiments, step (ii) of the reaction is preferably carried out in the presence of activated charcoal. The use of activated charcoal is believed to increase both conversion and selectivity. The activated charcoal is preferably an acid washed activated charcoal. The activated charcoal is preferably a steam activated charcoal. An example of an acid washed, steam activated charcoal is Norit® SX Ultra.

The activated charcoal may be used in an amount of from 0.5 to 10 %, preferably from 1 to 8 % by weight, and more preferably from 2 to 5 % by weight of starting material a.

Step (ii) of the reaction may be carried out at a temperature of at least 20 °C, for instance at a temperature of from 20 to 120 °C, preferably from 30 to 100 °C, and more preferably from 40 to 80 °C.

Step (ii) may be carried out for a period of greater than 1.5 hours, but preferably less than 12 hours.

Once step (ii) is complete, material c may be isolated by precipitation and separation of precipitated material c.

Compound d

Compounds d that are prepared using the methods of the present invention have the following formula:

where: Ri is hydrogen;

R.2, 1C, it ! , i s, Rii and R12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

A is a 5- to 10-membered ring, optionally substituted with one or more groups independently selected from alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

X is selected from -O- or -NR10-, where Rio is selected from hydrogen and alkyl groups; and

n is 0 to 2.

Preferred substituents for the compound are described below. It will be appreciated that the preferred substitution patterns also apply to the starting material a, reagent Z>, and material c from which the compound d is prepared. In some embodiments, R2, R3, R4, R5, R11 and R12 are each independently selected from hydrogen and alkyl groups, and preferably from hydrogen, methyl, ethyl, propyl and butyl groups. More preferably, R2, R3, R4, Rs, R11 and R12 are each independently selected from hydrogen, methyl and ethyl, and even more preferably from hydrogen and methyl.

Advantageously, no more than two, preferably no more than one, and preferably none of R 2 , R 3 , R 4 , Rs, R 11 and R 12 are selected from a group other than hydrogen. It is preferred that at least one of R 2 and R 3 is hydrogen, and more preferred that both of R 2 and R 3 are hydrogen.

In some embodiments, A is an optionally substituted 5- to 10-membered unsaturated ring ( e.g . it may be an aromatic ring system) whilst, in other embodiments, A is an optionally substituted saturated ring.

One or more of the ring members in A may be a heteroatom, e.g. selected from O, N and S, though preferably no more than two and more preferably no more than one of the ring atoms is a heteroatom. It will be appreciated that two carbon atoms are present between the groups X and NR10 so, though these are part of the 5- to 10-membered ring, they cannot represent heteroatoms. Preferably, any heteroatoms that are present in the 5- to 10-membered ring are not located next to either of the two carbon atoms that are present between the groups X and NR10.

Suitable optionally substituted rings include aromatic rings such benzene and naphthalene; heteroaromatic rings such as pyridine, pyrazine, pyrimidine, pyrrole and furan; carbocyclic rings such as cyclohexane and cylopentane; and heterocyclic rings such as piperidine, tetrahydrofuran and tetrahydropyran.

In some embodiments, A may be optionally substituted with one or more groups independently selected from alkyl and alkoxy groups, preferably from methyl, ethyl, propyl, butyl, methoxy, ethoxy and propoxy groups, more preferably from methyl, ethyl and methoxy, and even more preferably from methyl and methoxy.

Advantageously, A is substituted with one or two groups as described above, with all remaining substituents on the 5- to 10-membered ring being hydrogen. It is believed that the presence of at least one group other than hydrogen may improve the solubility of the compound d in a fuel.

Preferably, X is -O- or -NR10-, where Rio is selected from hydrogen, methyl, ethyl, propyl and butyl groups, and preferably from hydrogen, methyl and ethyl groups. More preferably, Rio is hydrogen. In preferred embodiments, X is -O-. n may be 0, 1 or 2, though it is preferred that n is 0 or 1, more preferably 0.

In particularly preferred embodiments, the compound d is an octane-boosting fuel additive having the following formula:

where: Ri is hydrogen;

II I , Its, R- 4 , R S , Rii and R 12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

Rf„ R 7 , Re and R 9 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;

X is selected from -O- or -NR10-, where Rio is selected from hydrogen and alkyl groups; and

n is 0 or 1.

In some embodiments, R2, R3, R4, Rs, R11 and R12 are each independently selected from hydrogen and alkyl groups, and preferably from hydrogen, methyl, ethyl, propyl and butyl groups. More preferably, R2, R3, R4, Rs, R11 and R12 are each independently selected from hydrogen, methyl and ethyl, and even more preferably from hydrogen and methyl.

In some embodiments, R 6 , R 7 , Rs and R 9 are each independently selected from hydrogen, alkyl and alkoxy groups, and preferably from hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy and propoxy groups. More preferably, R 6 , R 7 , Rs and R 9 are each independently selected from hydrogen, methyl, ethyl and methoxy, and even more preferably from hydrogen, methyl and methoxy.

Advantageously, at least one of R2, R3, R4, Rs, Rs, R7, Rs, R9, R11 and R12, and preferably at least one of R 5 , R 7 , Rs and R 9 , is selected from a group other than hydrogen. More preferably, at least one of R 7 and Rs is selected from a group other than hydrogen. Alternatively stated, the octane-boosting additive may be substituted in at least one of the positions represented by R2, R3, R4, Rs, Rs, R7, Rs, R9, R11 and R12, preferably in at least one of the positions represented by R 6 , R 7 , Rs and R 9 , and more preferably in at least one of the positions represented by R 7 and Rs. It is believed that the presence of at least one group other than hydrogen may improve the solubility of the octane-boosting additives in a fuel.

Also advantageously, no more than five, preferably no more than three, and more preferably no more than two, of R2, R3, R4, Rs, R6, R7, Rx, R9, R11 and R12 are selected from a group other than hydrogen. Preferably, one or two of R2, R3, R4, Rs, R6, R7, Rs, R9, R 11 and R 12 are selected from a group other than hydrogen. In some embodiments, only one of R2, R3, R4, Rs, Rs, R7, Rs, R9, R11 and R12 is selected from a group other than hydrogen.

It is also preferred that at least one of R 2 and R 3 is hydrogen, and more preferred that both of R 2 and R 3 are hydrogen.

In preferred embodiments, at least one of R 4 , Rs, R 7 and Rs is selected from methyl, ethyl, propyl and butyl groups and the remainder of R2, R3, R4, Rs, R6, R7, Rs, R9, R11 and R 12 are hydrogen. More preferably, at least one of R 7 and Rs are selected from methyl, ethyl, propyl and butyl groups and the remainder of R2, R3, R4, Rs, R6, R7, Rs, R9, R11 and R 12 are hydrogen.

In further preferred embodiments, at least one of R 4 , Rs, R 7 and Rs is a methyl group and the remainder of R2, R3, R4, Rs, Rs, R7, Rs, R9, R11 and R12 are hydrogen. More preferably, at least one of R 7 and Rs is a methyl group and the remainder of R 2 , R 3 , R 4 , Rs, R 6 , R7, Rs, R9, R11 and R12 are hydrogen.

Preferably, X is -O- or -NR10-, where Rio is selected from hydrogen, methyl, ethyl, propyl and butyl groups, and preferably from hydrogen, methyl and ethyl groups. More preferably, Rio is hydrogen. In preferred embodiments, X is -0-.

n may be 0 or 1, though it is preferred that n is 0.

Octane-boosting additives that may be used in the present invention include:

Preferred octane-boosting additives include:

Particularly preferred is the octane-boosting additive:

A mixture of compounds d may be used in a fuel composition. For instance, a fuel composition may comprise a mixture of: It will be appreciated that references to alkyl groups include different isomers of the alkyl group. For instance, references to propyl groups embrace n-propyl and i-propyl groups, and references to butyl embrace n-butyl, isobutyl, sec-butyl and tert-butyl groups. Additive and fuel compositions

The present invention provides compounds d which are obtainable by a method of the present invention. Preferably, the compounds d are obtained by a method of the present invention.

The present invention also provides a process for preparing a fuel for a spark- ignition internal combustion engine, said process comprising:

preparing a compound d , and preferably an octane-boosting fuel additive, using a method of the present invention; and

blending the compound with a base fuel.

A fuel for a spark-ignition internal combustion engine is also provided. The fuel comprises a compound d , and preferably an octane-boosting fuel additive, obtainable and preferably obtained by a method of the present invention, and a base fuel.

Gasoline fuels (including those containing oxygenates) are typically used in spark- ignition internal combustion engines. Commensurately, the fuel composition that may be prepared according to the process of the present invention may be a gasoline fuel composition.

The fuel composition may comprise a major amount {i.e. greater than 50 % by weight) of liquid fuel (“base fuel”) and a minor amount {i.e. less than 50 % by weight) of fuel additive composition. Examples of suitable liquid fuels include hydrocarbon fuels, oxygenate fuels and combinations thereof.

The fuel composition may contain the compound d in an amount of up to 20 %, preferably from 0.1 % to 10 %, and more preferably from 0.2 % to 5 % weight compound d / weight base fuel. Even more preferably, the fuel composition contains the compound d in an amount of from 0.25 % to 2 %, and even more preferably still from 0.3 % to 1 % weight compound d / weight base fuel. It will be appreciated that, when more than one compound having a structure falling within that of compound d is used, these values refer to the total amount of compounds d in the fuel.

The fuel compositions may comprise at least one other further fuel additive.

Examples of such other additives that may be present in the fuel compositions include detergents, friction modifiers/anti-wear additives, corrosion inhibitors, combustion modifiers, anti-oxidants, valve seat recession additives, dehazers/demulsifiers, dyes, markers, odorants, anti-static agents, anti-microbial agents, and lubricity improvers.

Further octane improvers may also be used in the fuel composition, i.e. octane improvers which do not have the structure of compound d.

The fuel compositions are used in a spark-ignition internal combustion engine. Examples of spark-ignition internal combustion engines include direct injection spark- ignition engines and port fuel injection spark-ignition engines. The spark-ignition internal combustion engine may be used in automotive applications, e.g. in a vehicle such as a passenger car.

The invention will now be described with reference to the following non-limiting examples.

Examples

Example 1 : Cydisation of material c using a homogenous catalyst and a basic catalyst

Cyclisation was carried out under a variety of conditions using the following compounds as material c (the compounds d obtained, which are octane-boosting fuel additives, are also shown):

As a general procedure, material c (0.167 g, 1 mmol), a metal catalyst, a base, and a solvent system (2.5 mL) were added to a Schlenk flask under N2. The mixture was heated to reflux under N2 before cooling to room temperature and sampling for EIPLC analysis. The yields of compound d obtained under different conditions are shown in the following table:

A scaled-up experiment was conducted in which 20 g (0.112 mmol) of material c2 was distilled in the presence of [Cp * IrCh]2 (1 mol%), KO*Bu (10 mol%) and a toluene solvent, at a temperature of approximately 117 °C and a pressure of approximately 2.5 bar, for approximately 72 hours to give compound d2 in a yield of 67 %.

Example 2: Cvclisation of material c using homogenous and heterogeneous catalysts without further components

Further cyclisation reactions in the presence of a homogenous catalyst but in the absence of a base, hydrogen or other reaction components were carried out under a variety of conditions. As a general procedure, a mixture of compound c2 and the catalyst were heated, optionally in the presence of a solvent, to the specified temperature. Heating was continued, before cooling to room temperature and sampling for UPLC analysis.

The yields of compound d2 obtained under different conditions are shown in the following table:

Further experiments were carried out using a heterogeneous catalyst. As a general procedure, a mixture of compound c2, Raney Ni (50% in water) and mesitylene was heated. The crude reaction mixture was analysed by HPLC to determine conversion and selectivity.

The yields of compound d2 obtained under different conditions are shown in the following table:

Example 3: Cvclisation of material c using a heterogeneous catalyst system and hydrogen Cyclisation in the presence of a heterogeneous catalyst was carried out under a variety of conditions. Compound c2 was used as material c.

As a general procedure, catalyst was added to an argon flushed stainless steel autoclave (300 mL). To this was added material c2 (0.33 g, 2.0 mmol) followed by mesityl ene (10 mL). The autoclave was sealed, charged to 7 bar with hydrogen and heated to 170 °C, except in the cases of Experiments xxxii, xxxiii and xxxiv where the temperature was raised to 210 °C. The reaction was held at this temperature for 20 hours, before cooling to room temperature and sampling for EIPLC (MeCN) analysis.

The yields of d2 obtained under different conditions are shown in the following table:

Example 4: Cvclisation of material c using a heterogeneous catalyst system and a reaction additive

Further cyclisation reactions in the presence of a heterogeneous catalyst but in the absence of hydrogen and, instead, in the presence of a reaction additive were carried out under a variety of conditions. As a general procedure, compound c2, the reaction additive and the catalyst were heated in a solvent to the specified temperature. The reaction was monitored by UPLC. The yields of compound d2 obtained under different conditions are shown in the following table:

Comparative Example A: Cvclisation reaction with no catalyst

An experiment was conducted to determine whether cyclisation of material c could be carried out in the absence of a metal catalyst. The following compound was used as material c: To a Schlenk flask under N2 was added the material c (0.167 g, 1 mmol), KOTJu (11 mg, 10 mol%) and xylene (2.5 mL). The mixture was heated to reflux under N2 for 24 hours and cooled to room temperature. Analysis of the reaction mixture by GC indicated that trace amounts, if any, of the compound d had formed.

Example 5: One-pot synthesis of material c from starting material a

Starting material a (100 g, 0.653 mol), ethylene carbonate (1 eq) and potassium carbonate (0.04 equiv) were heated at reflux (137 °C) in 4-methyl-2-pentanol (400 mL) for 37 hours. HPLC analysis of the reaction mixture confirmed 92% conversion and 89% selectivity for intermediate ab.

The crude reaction mixture was diluted 1 : 1 (w/w) with methanol before

commencing hydrogenation under 7 bar Fb, using Pd/C 5% (0.06 eq) at 70 °C. Full conversion was achieved after 2 hours. The reaction mixture was filtered at 65 °C (no product crystallized at this temperature) to isolate the catalyst. Material c was isolated by partial removal of solvent, crystallisation (under ambient conditions) and filtration. The product was obtained at a purity of greater than 97 %.

Further recrystallized from toluene (12 volumes) was carried out to achieve greater than 99 % purity.

The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as“40 mm” is intended to mean“about 40 mm”.

Every document cited herein, including any cross referenced or related patent or application, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it alone, or in any combination with any other reference or references, teaches, suggests or discloses any such invention. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope and spirit of this invention.