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Title:
METHODS FOR PREPARING COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2020/127385
Kind Code:
A1
Abstract:
A method is provided for preparing a compound d having the formula: Formula (I). The method comprises carrying out the following reaction: Formula (i), (ii), (d) where: step (i) is carried out in the presence of a metal catalyst and a hydrogen source; and step (ii) is carried out at a temperature of at least 100 °C and in the presence of the same metal catalyst that was used in step (i) and an aprotic solvent system.

Inventors:
DEELEY JON (GB)
FILIP SORIN (GB)
PRICE GREGORY (GB)
Application Number:
EP2019/085799
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:
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 et al. (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 one-pot reaction:

where: step (i) is carried out in the presence of a metal catalyst and a hydrogen source; and step (ii) is carried out at a temperature of at least 100 °C and in the presence of the same metal catalyst that was used in step (i) and an aprotic solvent system.

2. A method according to claim 1, wherein compound d is an octane-boosting fuel additive having the formula:

where: Rs, 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 as a one-step reaction in which the same reaction materials, and preferably the same reaction conditions, are used in steps (i) and (ii).

4. A method according to any of claims 1 to 3, wherein step (ii) of the reaction is carried out at a temperature of from 100 to 250 °C, preferably from 120 to 200 °C, and more preferably from 130 to 180 °C.

5. A method according to any of claims 1 to 4, wherein the metal catalyst is selected from palladium ( e.g . Pd/C, preferably in the presence of sodium formate), nickel (e.g. in the presence of aluminium such as in Raney nickel or M-SO2/AI2O3), cobalt (e.g. in the presence of aluminium such as in Raney cobalt).

6. A method according to any of claims 1 to 5, wherein the hydrogen source is 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.

7. A method according to any of claims 1 to 6, wherein the aprotic solvent system comprises an aromatic solvent, preferably selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes and anisole.

8. A method according to claim 7, wherein the aromatic solvent is 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.

9. A method according to any of claims 1 to 8, wherein the aprotic solvent system comprises a non-aromatic solvent, preferably selected from heterocyclic solvents such as tetrahydrofuran and 1,4-dioxane.

10. A method according to any of claims 1 to 9, wherein each of the components used in the one-pot reaction, aside from material c, the hydrogen source and solvent systems, are used in amount of up to 0.5 molar equivalents, preferably up to 0.3 molar equivalents, and more preferably up to 0.2 molar equivalents, as compared to material c.

11. A method according to claim 10, wherein no reagents beyond material c and the hydrogen source are used in the one-pot reaction.

12. A method according to any of claims 1 to 11, wherein the one-pot reaction is conducted for a period of greater than 2 hours, and preferably less than 48 hours.

13. A method according to any of claims 1 to 12, wherein the method further comprises preparing material c by carrying out the following reaction:

a b c

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-.

14. A method according to any of claims 1 to 13, 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.

15. A method according to any of claims 1 to 13, wherein the method is a continuous process.

16. A method according to any of claims 1 to 15, wherein the one-pot 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.

17. A compound d having the formula: where: Ri is hydrogen;

III, Its, 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 is obtainable by a method according to any of claims 1 to 16.

18. 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 16; and blending the compound with a base fuel.

19. A fuel for a spark-ignition internal combustion engine, said fuel comprising a compound d according to claim 17 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 in a one-pot method from a nitro alcohol 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;

II I , 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 one-pot reaction:

where: step (i) is carried out in the presence of a metal catalyst and a hydrogen source; and step (ii) is carried out at a temperature of at least 100 °C and in the presence of the same metal catalyst that was used in step (i) and an aprotic solvent system.

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, a compound d is prepared by carrying out the following one-pot reaction:

The reaction proceeds via a two-step mechanism, in which the nitro group is first reduced to an amine in step (i), thereby allowing ring closing to take place in step (ii). The present invention is based, in part, on the surprising discovery that the same metal catalyst can be used in steps (i) and (ii) of the reaction, thereby enabling the reaction to be carried out in one pot. As is known in the art, one pot reactions are conducted using a method in which the starting material is converted into the target product in a single reactor, i.e. without the removal of any intermediates (in this case intermediate c’) from the reactor. According to the method of the present invention, steps (i) and (ii) of the reaction are carried out in presence of the same metal catalyst. It will be appreciated that metal catalysts are metal -containing catalysts and, as such, they may contain non-metallic elements. At least step (i) is also carried out in the presence of a hydrogen source. At least step (ii) is carried out at a temperature of at least 100 °C and in the presence of an aprotic solvent system.

The reaction is preferably carried out as a one-step reaction in which the same reaction materials, and preferably the same reaction conditions, are used in steps (i) and (ii). Thus, the reaction is preferably carried out as a single step reaction, even though it proceeds via a two-step mechanism. In other, less preferred, embodiments, the reaction may be carried out as a two-step reaction in which a first set of reaction materials and conditions are used to reduce the nitro group in step (i), and a second set of reaction materials and conditions are used to close the ring in step (ii).

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 and the hydrogen source are used in the one-pot reaction. Material c and the hydrogen source are considered to be reagents because they are 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 one-pot reaction, aside from material c, the hydrogen source, and the aprotic solvent system, are used in amount of up to 0.5 molar equivalents, preferably up to 0.3 molar equivalents, and more preferably up to 0.2 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).

Preferably, the one-pot reaction is carried out using material c as the reagent only in the presence of a metal catalyst, hydrogen source and solvent system, i.e. no further reaction materials are used.

Specific reagents and conditions that may be used in a one-step method and a two- step method for preparing the compound d are described in greater detail below.

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 one-pot reaction (‘crude’ compound d ) to give a purified form of the compound d. Conventional purification methods may be used. 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 intermediate d.

In order to produce the compound d on an industrial scale, the one-pot reaction 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 will now be detailed. One-step reaction

In preferred embodiments, the reaction is preferably carried out as a one-step reaction. Thus, the same reaction materials are used in steps (i) and (ii), i.e. steps (i) and (ii) are carried out in the presence of a metal catalyst, a hydrogen source and an aprotic solvent system.

Suitable metal catalysts for use in the one-step reaction include those selected from palladium (e.g. Pd/C), nickel (e.g. in the presence of aluminium such as in Raney nickel or Ni-SiCh/AkCb) and cobalt (e.g. in the presence of aluminium such as in Raney cobalt) catalysts. Nickel catalysts, in particular Ni-SiOi/AkCb, are 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 0.25 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 heterogeneous catalyst reaction.

Heterogeneous catalysis reactions involve the use of a catalyst in a different phase from the reactants. In this embodiment, the reaction is preferably carried out with a solid catalyst in a liquid reagent phase. Thus, 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 one-pot reaction is also 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. 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 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.

The one-step reaction is carried out in the presence of 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. The aprotic solvent system is believed to favour the removal of water from the reaction mixture, particularly at reflux, which encourages the oxidative cyclisation to proceed.

It will be appreciated that an aprotic solvent system is substantially free from any protic solvents, i.e. contains less than 2 % by volume, preferably less than 1 % by volume, and more preferably less than 0.1 % by volume of protic solvents.

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- or 2- methylnaphthalene) and anisole. Mesitylene is particularly suited to the one-pot method of the present invention, delivering high yields of the target compound d. A refinery stream containing a mixture of aromatic compounds with a suitable boiling range (e.g. falling within the range of 100 to 250 °C) may also be used.

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

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.

Where the reaction is carried out as a one-step reaction, the reaction conditions are preferably the same in both steps (i) and (ii), i.e. steps (i) and (ii) are carried out at a temperature of at least 100 °C. In some embodiments, pressure may be required to maintain the solvent system in the liquid phase at a temperature of greater than 100 °C. This may be the case where, for instance, benzene or tetrahydrofuran is used. Suitable pressures may be achieved by carrying out the reaction in the presence of hydrogen gas at the pressures given above, or further pressure may be applied beyond that conferred by the hydrogen gas.

Preferably, steps (i) and (ii) are carried out at a temperature of from 100 to 250 °C, preferably from 120 to 200 °C, and more preferably from 130 to 180 °C. The one-step reaction is preferably carried out under reflux.

In some embodiments, the method comprises a pre-heating step which is carried out before step (i). During the pre-heating step, 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. The pre-heating step may be carried out at a temperature of from 40 to 100 °C.

The one-step reaction {i.e. steps (i) and (ii) together) may be conducted for a period of greater than 2 hours, preferably greater than 4 hours. Typically, the one-step reaction will be carried out for up to 24 hours. These values do not include any time periods during which the reaction mixture is pre-heated.

Two-step reaction The reaction may also be carried out as a two-step reaction in which different reaction materials, and preferably different conditions, are used in steps (i) and (ii).

Although different reaction materials may be used in steps (i) and (ii), the same metal catalyst is used throughout. This enables the reaction to be carried out as a one-pot reaction.

Suitable metal catalysts for use in the two-step reaction 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), cobalt (e.g. in the presence of aluminium such as in Raney cobalt). Nickel catalysts, in particular Raney-nickel, and palladium catalysts, in particular Pd/C, are 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 0.25 molar equivalents, and more preferably from 0.05 to 0.2 molar equivalents, as compared to material c.

Typically, all of the catalyst will be added at the beginning of step (i). However, in some embodiments, it may be desirable to add some of the metal catalyst at the beginning of step (i) and the rest of the metal catalyst at a later time in the reaction, e.g. at the beginning of step (ii). In these embodiment, higher quantities of metal catalyst may be used as compared to material c, 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, in step (i) and from 0.005 to 0.3 further molar equivalents, preferably from 0.01 to 0.25 further molar equivalents, and more preferably from 0.05 to 0.2 further molar equivalents, in step (ii).

The reaction is preferably carried out as heterogeneous catalyst reaction.

Heterogeneous catalysis reactions involve the use of a catalyst in a different phase from the reactants. In this embodiment, the reaction is preferably carried out with a solid catalyst in a liquid reagent phase. Thus, 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.

Step (i) of the two-step reaction is also 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. 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 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.

Step (ii) of the two-step reaction may also be carried out in the presence of a hydrogen source, e.g. as described in relation to step (i). For instance, step (ii) may be carried out in the presence of the same hydrogen source as step (i). However, step (ii) may also be carried out in the absence of a hydrogen source. For instance, the reaction chamber may be ventilated to remove any hydrogen gas before step (ii). In this case, step (ii) is preferably carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.

Step (ii) of the two-step reaction is carried out in the presence of 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. The aprotic solvent system is believed to favour the removal of water from the reaction mixture, particularly at reflux, which encourages the oxidative cyclisation to proceed.

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 suited to the one-pot method of the present invention, delivering high yields of the target compound d. A refinery stream containing a mixture of aromatic compounds with a suitable boiling range (e.g. falling within the range of 100 to 250 °C) may also be used.

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 tetrahydrofuran and 1,4-dioxane. The non-aromatic solvent is preferably used in combination with an aromatic solvent.

Step (i) of the two-step reaction is preferably also carried out in the presence of an aprotic solvent system, e.g. as described above in connection with step (ii), as this is believed to give higher yields. However, it may also be carried out in the presence of a protic solvent system, such as aqueous, i.e. water-containing, solvent systems or alcohol solvent systems (e.g. methanol or ethanol).

Where the reaction is carried out as a two-step reaction, the reaction conditions are preferably different in steps (i) and (ii).

Step (ii) is carried out at a temperature of at least 100 °C. As mentioned above, pressure may be required to maintain the solvent system in the liquid phase at a temperature of greater than 100 °C. Suitable pressures may be achieved by carrying out the reaction in the presence of hydrogen gas at the pressures given above, or further pressure may be applied beyond that conferred by the hydrogen gas.

Step (ii) is preferably carried out at a temperature of from 100 to 250 °C, preferably from 120 to 200 °C, and more preferably from 130 to 180 °C. Step (ii) is preferably carried out under reflux.

However, step (i) is preferably carried out at a lower temperature than step (ii). For instance, step (i) may be carried out at a temperature of from 10 to 100 °C, preferably 15 to 80 °C, and more preferably from 20 to 60 °C.

The two-step reaction (i.e. steps (i) and (ii) together) may be conducted for a period of greater than 2 hours, preferably greater than 10 hours. Step (i) is preferably carried out for a period of greater than 1 hour. Step (ii) is preferably carried out for a period of greater than 8 hours. Typically, the two-step reaction (i.e. steps (i) and (ii) together) will be carried out for up to 48 hours.

Preparation of material c

Material c, the starting material for the one-pot reaction, may be prepared by carrying out the following reaction: a b c 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-.

Ri 3 is preferably selected from hydrogen, methyl and ethyl, and more preferably is hydrogen.

Where L is selected from leaving groups, 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). Preferred leaving groups are selected from halides and sulfonates, and more preferably from Cl and Br.

Preferably, L is selected from leaving groups and L’ is OH, or L and L’ together form the group -0-C(0)-0-. More preferably, L and L’ together form the group -O-C(O)- 0

In a first method for preparing material c, the alkylating agent b may be used in an amount of from 0.5 to 8 molar equivalents, preferably from 0.8 to 5 molar equivalents, and more preferably from 1 to 3 molar equivalents, as compared to starting material a.

In the first method for preparing material c, the reaction may be carried out in the presence of a catalyst, e.g. a catalyst selected from an acid (e.g. p-toluene sulfonic acid or sodium hydrogen sulphite), a zeolite (e.g. zeolite Y, sodium (faujasite)) or a metal catalyst (e.g. a palladium catalyst, preferably used with a zinc oxide support).

The catalyst may be used in an amount of less than 1 molar equivalent, preferably less than 0.5 molar equivalents, and more preferably less than 0.1 molar equivalents as compared to starting material a.

In the first method for preparing material c, the reaction may be carried out in the presence of a base (e.g. an inorganic base, such as an alkali metal carbonate or an alkali metal hydroxide, such as potassium carbonate or sodium hydroxide). 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.

It will be appreciated that both a base and a catalyst may be used in the first method for preparing material c.

In the first method for preparing material c, the reaction may be carried out in the presence of a solvent selected from aprotic solvents ( e.g . 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 preferably from N-methyl-2-pyrrolidone and dimethylformamide.

In the first method for preparing material c, the reaction to prepare material c may be carried out at a temperature of greater than 40 °C, preferably greater than 50 °C, and more preferably at a temperature of from 60 to 350 °C. In some instances, the reaction is carried out under reflux.

In the first method for preparing material c, the reaction to prepare material c will generally be carried out at ambient pressure, i.e. approximately 1 bar, though higher pressures may be used.

In the first method for preparing material c, the reaction to prepare material c may be conducted for a period of greater than 30 minutes, but preferably less than 6 hours, and more preferably less than 4 hours.

The first method for preparing material c is particularly suitable for alkylating agents in which L is selected from leaving groups and L’ is OH.

In a second, and preferred, method for preparing material c, the reaction is preferably carried out in the presence of a solvent. The solvent is preferably a protic solvent. 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.

Suitable protic solvents 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 C n H2n+iOH, 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). Preferably, the protic solvent is an alcohol, preferably cyclohexanol or 4-methyl -2-pentanol, and more preferably 4-methyl -2 -pentanol.

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, the reaction 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, the reaction 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 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.

In the second method for preparing material c, the reaction may also be carried out in the absence of a solvent. However, this is less preferred since material c requires special handling when not used in a solvent.

In the second method for preparing material c, the reaction 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.

In the second method for preparing material c, the alkylating agent b will generally 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 material c that is obtained.

In the second method for preparing material c, the reaction will generally be carried out in the absence of a metal catalyst.

In the second method for preparing material c, the reaction may 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.

In the second method for preparing material c, the reaction will generally be carried out at ambient pressure, i.e. approximately 1 bar.

In the second method for preparing material c, the reaction may be conducted for a period of greater than 4 hours, but preferably less than 48 hours.

The second method for preparing material c is particularly suitable for alkylating agents in which 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.

In a third method for preparing material c, the reaction is carried out in the presence of a trihydrocarbyl phosphine (e.g. a triaryl phosphine or a trialkyl phosphine, such as triphenyl phosphine or tributyl phosphine), and an azo compound (e.g. a dialkyl azodi carboxyl ate, such as diisopropyl azodicarboxylate). This reaction is known as a Mitsunobu reaction.

The trihydrocarbyl phosphine (e.g. triaryl phosphine or trialkyl phosphine) will typically be used in an amount of from 0.8 to 4 molar equivalents, preferably from 0.9 to 2 molar equivalents, and more preferably from 1 to 1.5 molar equivalents as compared to starting material a. The azo compound (e.g. dialkyl azodicarboxylate) will typically be used in an amount of from 0.8 to 1.25 molar equivalents as compared to the triaryl phosphine or trialkyl phosphine (or other trihydrocarbyl phosphine).

However, in some embodiments, the third method for preparing material c may be carried out as a catalytic Mitsunobu reaction. In these embodiments, a metal catalyst may be used to enable the azo compound to also be used in catalytic amounts, e.g. from 0.01 to 0.5 molar equivalents, and preferably from 0.025 to 0.3 molar equivalents, and more preferably from 0.05 to 0.2 molar equivalents as compared to starting material a.

Suitable metal catalysts include iron catalysts (e.g. iron phthalocyanine). The metal catalyst is preferably used in combination with a molecular sieve (e.g. a zeolite, preferably having a pore size of 5 A). The metal catalyst may be used in an amount of from 0.01 to 0.5 molar equivalents, and preferably from 0.025 to 0.3 molar equivalents, and more preferably from 0.05 to 0.2 molar equivalents as compared to starting material a.

Where a catalytic Mitsunobu reaction is carried out, the azo compound preferably has an aromatic group, e.g. a 3,5-dichlorophenyl group, directly bonded to one of the nitrogen atoms in the azo group. The other nitrogen of the azo group is preferably bonded to an alkyl carboxylate group, e.g. -CCbEt.

In the third method for preparing material c, a silane may be present such as phenyl silane. The silane will typically be used in an amount of from 0.8 to 3 molar equivalents, preferably from 0.9 to 2 molar equivalents, and more preferably from 1 to 1.5 molar equivalents as compared to starting material a. The use of a silane is particularly preferred where a catalytic Mitsunobu reaction is carried out.

In the third method for preparing material c, the reaction is preferably conducted in the presence of 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 tetrahydrofuran, acetonitrile, dimethoxyethane and dioxane.

In the third method for preparing material c, the alkylating agent b will generally be used in an amount of from 0.75 to 2 molar equivalents, preferably from 0.8 to 1.5 molar equivalents, and more preferably from 0.9 to 1.2 molar equivalents, as compared to starting material a. In the third method for preparing material c, the reaction is typically conducted at ambient temperature, temperature, i.e. at a temperature of from 15 to 25 °C. Higher temperatures may also be used, e.g. up to 80 °C, particularly where the reaction is a catalytic Mitsunobu reaction.

In the third method for preparing material c, the reaction is preferably conducted at ambient pressure, i.e. at a pressure of approximately 1 bar.

In the third method for preparing material c, the reaction will typically be conducted for a period of greater than 15 minutes, but less than 4 hours, and more preferably less than 2 hours. Catalytic Mitsunobu reactions may be carried out for longer, e.g. up to 24 or even 48 hours.

The third method for preparing material c is suitable for embodiments in which L and U are both OH and X is -0-.

In a fourth method for preparing material c, the reaction may be carried out using borrowing hydrogen catalysis.

The borrowing hydrogen reaction is carried out in the presence of a metal catalyst. A wide range of metal catalysts may be used, including 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-SiCh/AhCb), cobalt (e.g. in the presence of aluminium such as in Raney cobalt), platinum (e.g. Pt/C, PtCh, Pt/AkCb, Pt/C/Cu, Pt/C/Fe, PtSi02 or Pt/C/V), ruthenium (e.g. Ru/C, Ru02, RU/AI2O3, RuCk(PPh3)3, Cp * RuCl(PPh3)2, Cp * RuCl(COD), (Cp * RuCl) 4 or CpRuCl(PPh )2), iridium (e.g Ir/C or [Cp * IrCl 2 ] 2 ), rhodium (e.g Rh/C, Rh 2 0 3 , Rh/Al 2 0 3 , [Rh(COD)Cl] 2 , (PPh )3RhCl or RhCl(CO)(PPh )2) and copper (e.g. in the presence of aluminium such as in Raney Cu, CuO/ZnO,

CuO/AkCb/MnO or CuzCnCh) 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, for instance from 0.01 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 starting material a.

In the fourth method for preparing material c, the reaction may be carried out in the presence of a solvent system which may be protic or aprotic. 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 system, 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. Mesitylene is particularly suitable.

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. Other suitable aprotic non-aromatic solvents include dimethylacetamide. The non-aromatic solvent may be used alone or in

combination with an aromatic solvent.

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.

In the fourth method for preparing material c, the borrowing hydrogen reaction may be carried out in the presence of: (1) a base, (2) in the absence of further components, (3) a hydrogen source, or (4) in the presence of a reaction additive.

(1) Where 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 /er/-butoxides such as sodium / / -but oxide or potassium /er/-butoxide). In particular, alkali metal oxides are believed to give very high yields of the compound c.

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 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.

Reactions in the presence of a base are preferably carried out in aprotic solvent systems.

(2) Where the reaction is carried out in the absence of further components, a solvent system may optionally be present, but no further reaction components. Preferred solvent systems are aprotic solvent systems.

(3) Where 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.

Reactions in the presence of a hydrogen source are preferably carried out in the presence of an aprotic solvent system.

(4) Where 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 starting material a and alkylating agent b. 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.

Reactions in the presence of a reaction additive may be carried out in a protic or aprotic solvent system, though aprotic solvent systems are generally preferred.

In the fourth method for preparing material c, the reaction is carried out at a temperature of at least 100 °C, such as a temperature of from 100 to 250 °C, preferably from 110 to 225 °C, and more preferably from 120 to 200 °C. In the fourth method for preparing material c, the reaction will typically carried out at ambient pressure, i.e. at a pressure of approximately 1 bar, unless the reaction is carried out in the presence of hydrogen gas.

In the fourth method for preparing material c, 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 96 hours.

The fourth method for preparing material c is particularly suitable for embodiments in which L and L’ are both OH and X is -NRio-.

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, 1C, R 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>, material c and intermediate c’ from which the compound d is prepared.

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. Advantageously, no more than two, preferably no more than one, and preferably none of R2, R3, R4, Rs, R11 and R12 are selected from a group other than hydrogen. It is preferred that at least one of R2 and R3 is hydrogen, and more preferred that both of R2 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 5 , R 11 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 -NR 10 -, 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, R 3 , 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, R 3 , R4, Rs, Rs, R7, Rs, R 9 , R11 and R12, and preferably at least one of R 6, 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, R 3 , R4, Rs, Rs, R7, Rs, R 9 , 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, R 6 , R7, Rs, R9, R11 and R12 are selected from a group other than hydrogen. Preferably, one or two of R2, R3, R4, Rs, R 6 , 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, R 6 , 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, R 5 , 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 R7 and Rs is a methyl group and the remainder of R2, R3, R4, Rs, Rs, 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 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 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 a structure in accordance with that of the 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 : Screening work for one-step reduction and cvclisation using Pd/C catalyst

Screening work was carried out to determine whether a one-pot synthesis of the compounds d described herein was viable. The following compound was used as material c :

The following conditions were shown to give a compound d , an octane-boosting fuel additive, having the following formula:

at good yield for further investigation:

H 2 Temperature Yield compound d

Catalyst Additive Solvent

(bar) (°C) (%) Example 2: Investigating further metal -catalysts for one-step reduction and cvclisation

Following the successful results obtained using Pd/C, experiments were conducted using different nickel and cobalt catalysts. The compound used as material c in Example 1 was also used in these experiments. Two nickel catalysts were tested: Raney-Ni and Ni- SiCE/AhCh. A cobalt catalyst was also tested: Raney-cobalt.

A solution of material c (1.97 g, 10 mmol, 0.05 M) in THF/toluene (200 mL, 1 : 1) was passed through a catalyst bed at 135 °C, 2 bar Eh and at a rate of 1 mL/min. After approximately 6 to 8 hours of continuous circulation of the eluent stream, GC analysis indicated complete conversion of material c. Complete conversion of material c was observed, with the compound d produced in each of the experiments. Higher yields were obtained when Raney-Ni and Raney-Co were used.

Example 3: One-step reduction and cvclisation using mesityl ene solvent

Further experiments were conducted using different nickel catalysts in a mesitylene solvent system. The compound used as material c in Example 1 was also used in these experiments. Two nickel catalysts were tested: Raney-Ni (slurry form in water) and Ni(65 wt%)/Si02/Ah03 (20 mg, 10 mol%).

The catalyst was added to an argon flushed stainless steel autoclave (300 mL). To this was added material c (394 mg, 2.0 mmol) followed by mesitylene (10 mL). The autoclave was sealed, charged to 7 bar with hydrogen and heated to 50 °C for 1 hour before raising the temperature to 170 °C. The reaction was held at this temperature for 20 hours, before cooling to room temperature and sampling for UPLC (MeCN) analysis. LC analysis indicated complete conversion of material c to give 83% and 87 % yield of the compound d for the Raney-Ni and Ni-SiCE/AhCh catalysts, respectively.

Example 4: Investigating two-step reduction and cvclisation using a variety of conditions

Further one-pot experiments were conducted to investigate the use of different reaction materials and conditions in steps (i) and (ii). The compound used as material c in Example 1 was used in these experiments.

The following reaction materials and conditions were used: t4 one-step reaction, but in which different reaction conditions were used in steps (i) and (ii)

Where the solvent was changed between steps (i) and (ii), the original solvent was removed by distillation. Where hydrogen was removed following step (i), this was carried out by simply venting the reaction environment.

Compound d was produced in each of the experiments. Thus, it can be seen that the reaction can be carried out using a protic solvent and relative low temperature in step (i), and in the absence of a hydrogen source in step (ii). The best yields were, however, obtained when an aprotic solvent, in particular mesitylene, was used in both steps (i) and

(ii). Improved yields were also obtained when extra catalyst was added in step (ii).

Example 5: Preparation of material c using the first method

The following material c was prepared:

using the first method described herein. 2-nitrophenol was used as starting material a and 2-bromoethanol was used as reagent b.

Specifically, a mixture of starting material a (10 g, 72 mmol), reagent b (4 eq) and K 2 CO 3 (2.0 eq) was refluxed in MeCN (75 ml) for 4 hours, the organic solvent was evaporated, the residue was partitioned between diethyl ether and water, the organic layer was separated, washed with water, dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (1 : 1 ethyl acetate/hexane) and afforded 10.2 g (77 % yield) of material c as a yellow oil.

Example 6: Preparation of material c using the second method

The following material c was prepared:

using the second method described herein. 4-methyl -2-nitrophenol was used as starting material a and ethylene carbonate was used as reagent b.

Starting material a (100 g, 0.653 mol), reagent b (1 eq) and potassium carbonate (0.04 eq) 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 material c.

In a further experiment, starting material a (1 g, 6.53 mmol), reagent b (1 eq) and potassium carbonate (0.04 eq) were heated at 135 °C in ethylene glycol (10 mL) for 44 hours. HPLC analysis of the reaction confirmed 89% conversion and 87% selectivity for material c.

Comparative Example A: Cyclisation reaction with no catalyst

An experiment was conducted to determine whether cyclisation of a reduced form of material c (‘the intermediate’) could be carried out in the absence of a metal catalyst. The following compound was used as the intermediate:

To a Schlenk flask under N2 was added the intermediate (0.167 g, 1 mmol), KOTlu (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 only trace amounts of the compound d had formed.

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.