WO2020260417A1 - Procédés de préparation de benzoxazines - Google Patents

Procédés de préparation de benzoxazines Download PDF

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Publication number
WO2020260417A1
WO2020260417A1 PCT/EP2020/067748 EP2020067748W WO2020260417A1 WO 2020260417 A1 WO2020260417 A1 WO 2020260417A1 EP 2020067748 W EP2020067748 W EP 2020067748W WO 2020260417 A1 WO2020260417 A1 WO 2020260417A1
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carried out
compound
groups
hydrogen
reaction
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PCT/EP2020/067748
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Sorin Vasile Filip
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Bp Oil International Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10L—FUELS NOT OTHERWISE PROVIDED FOR; NATURAL GAS; SYNTHETIC NATURAL GAS OBTAINED BY PROCESSES NOT COVERED BY SUBCLASSES C10G, C10K; LIQUEFIED PETROLEUM GAS; ADDING MATERIALS TO FUELS OR FIRES TO REDUCE SMOKE OR UNDESIRABLE DEPOSITS OR TO FACILITATE SOOT REMOVAL; FIRELIGHTERS
    • C10L1/00—Liquid carbonaceous fuels
    • C10L1/10—Liquid carbonaceous fuels containing additives
    • C10L1/14—Organic compounds
    • C10L1/22—Organic compounds containing nitrogen
    • C10L1/232—Organic compounds containing nitrogen containing nitrogen in a heterocyclic ring
    • C10L1/233—Organic compounds containing nitrogen containing nitrogen in a heterocyclic ring containing nitrogen and oxygen in the ring, e.g. oxazoles
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10L—FUELS NOT OTHERWISE PROVIDED FOR; NATURAL GAS; SYNTHETIC NATURAL GAS OBTAINED BY PROCESSES NOT COVERED BY SUBCLASSES C10G, C10K; LIQUEFIED PETROLEUM GAS; ADDING MATERIALS TO FUELS OR FIRES TO REDUCE SMOKE OR UNDESIRABLE DEPOSITS OR TO FACILITATE SOOT REMOVAL; FIRELIGHTERS
    • C10L10/00—Use of additives to fuels or fires for particular purposes
    • C10L10/10—Use of additives to fuels or fires for particular purposes for improving the octane number
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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.
  • 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.
  • 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 typically contain a number of additives to improve the properties of the fuel.
  • octane improving additives are 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.
  • TEL tetraethyl lead
  • 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.
  • oxygenates e.g. ethers and alcohols
  • aromatic amines these additives also suffer from various drawbacks.
  • NMA N-methyl aniline
  • 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.
  • 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).
  • Nitrophenols represent useful and relatively cheap starting materials for the preparation of the new class of octane-boosting additives. However, synthesis methods using nitrophenols often proceed via nitroaromatic intermediates. Nitroaromatics can be thermally unstable when isolated, thereby requiring special handling.
  • the new class of octane-boosting additives and similar compounds can be prepared from an aniline-based starting material, using a method which involves protecting the amino group while oxidizing the starting material, to give an amino phenol-based intermediate.
  • the method avoids thermally unstable nitroaromatic starting materials and intermediates. This means that the compounds may be prepared without the need for special handling of any starting materials or intermediates.
  • the present invention provides a method for preparing a compound / having the formula:
  • Ri is hydrogen
  • R 2 , R 3 , 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;
  • R. 6 , R7, Re and R9 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;
  • X is -0-
  • n 0 to 2.
  • the method comprises carrying out the following reaction:
  • q is 1 where PG is a monovalent protecting group, or q is 0 where PG is a divalent protecting group;
  • any -OH or -NH groups in intermediate d may be present in an alkanoylated form.
  • the present invention further provides a process for preparing a fuel for a spark- ignition internal combustion engine.
  • the process comprises:
  • a fuel for a spark-ignition internal combustion engine is also provided.
  • the fuel comprises a compound / of the present invention and a base fuel.
  • the present invention provides a method for preparing a compound f.
  • step (i) of the method the amine group in starting material a is protected with an amine protecting group, while the starting material is oxidised to give an oxidised intermediate d.
  • Step (i) will typically carried out as a series of sub-steps, though it may also be carried out as a single step reaction.
  • step (ii) compound /is formed. Five different routes may be used to carry out step (ii).
  • intermediate d is an N- alkylated intermediate on which ring closing may be carried out to form compound f.
  • the second route involves converting a protecting group in order to form N-alkylated intermediate e and ring closing to form compound f.
  • the third route involves removing a protecting group from intermediate d followed by alkylation to form an alkylated intermediate e and ring closing to form compound f.
  • intermediate d is an O-alkylated intermediate and the route involves removing a protecting group from intermediate d and ring closing to form compound /
  • ring closing is carried out before deprotection of the amine group to form compound f.
  • the method of the present invention comprises the step of purifying the product of step (ii) (‘crude’ compound f) to give a purified form of the compound / Conventional purification methods may be used.
  • the crude compound / may be purified by dissolving the compound in a non-polar solvent, such as heptane, and filtering off the insoluble salts and by-products.
  • the crude compound / may be purified by distillation of the compound, e.g. at reduced pressure.
  • the methods of the present invention are preferably carried out on an industrial scale.
  • the method of preparing the compound /is a batch process the compound /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 /
  • steps (i)-(ii), including any sub-steps thereof, 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.
  • the reactor used to produce compound / preferably has an operating temperature range of at least from 15 to 300 °C and an operating pressure range of at least from 1 mbar to 200 bar.
  • step (i) of the method starting material a is modified, firstly, by introduction of a protecting group on the amine and, secondly, by oxidation to introduce the group -XRio, where X is O.
  • the resulting intermediate d has the following structure:
  • Intermediate d contains an amine protecting group, PG.
  • the amine protecting group may be monovalent in which case q is 1, or it may be divalent in which case q is 0.
  • the amine protecting group is divalent.
  • a wide range of amine protecting groups, PG may be used. Suitable groups must protect the amine whilst allowing oxidation to occur.
  • N-alkylated inter ediate d has the following structure:
  • L is selected from leaving groups and -OH.
  • Suitable leaving groups include:
  • halides e.g. Cl, Br, I
  • substituted aryloxy groups e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl
  • sulfonates e.g. -OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH2CI, phenyl and p-nitrophenyl.
  • Preferred leaving groups are selected from Cl and Br.
  • inter ediate d has the following structure:
  • Intermediate d may also contain a hydroxy protecting group, though it is generally preferred that Rio is H (with, as mentioned herein, the -OH group optionally being present in an alkanoylated form).
  • Hydroxy protecting groups are typically used when the amine protecting group forms an amide with the amine, e.g. where the following compound has been used as an amine protecting agent b (discussed in more detail below):
  • Preferred hydroxy protecting groups may form an alkylated hydroxy group (i.e. -O- alk-).
  • hydroxy protecting groups may be used which form an O-alkylated intermediate d having the structure:
  • L’ is selected from leaving groups and -OH.
  • Suitable leaving groups include: halides (e.g. Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl), and sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH2CI, phenyl and p-nitrophenyl).
  • Preferred leaving groups are selected from Cl and Br.
  • L’ in intermediate d will typically be -OH.
  • step (i) comprises sub-steps, e.g. sub-step (ia) in which a protecting group is added on the amine to form intermediate c, and sub-step (ib) in which intermediate c is converted into oxidised intermediate d:
  • Step (ia) involves reacting starting material a with an amine protecting agent b:
  • each LG is independently selected from leaving groups or both LG groups together form the group -0-C(0)-0- or -0-.
  • the amine protecting agent b will form an amine protecting group, PG, in material c.
  • the amine protecting group may be monovalent in which case q is 1, or it may be divalent in which case q is 0.
  • Amine protecting agents are well-known in the art. Preferred protecting groups agents will form a carbamate (i.e. -NHqC(O)O-) or amide (i.e. -NHqC(O)-) group with an amine.
  • Suitable leaving groups, LG, for use in amine protecting agent b include: halides (e.g. Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl), and sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH 2 CI, phenyl and p-nitrophenyl).
  • halides e.g. Cl, Br, I
  • substituted aryloxy groups e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl
  • sulfonates e.g. -OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH 2 CI, phenyl and p-nitrophenyl.
  • amine protecting agent b preferably has a structure selected from:
  • LG represents a leaving group
  • R’ represents a hydrocarbyl group, e.g. an aryl, alkyl or alkenyl group.
  • each LG is independently selected from leaving groups, or LG and LG together form the group -0-C(0)-C- and -0-.
  • LG are selected from halides (e.g. Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl), and sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF3, -CH2CI, phenyl and p-nitrophenyl), with halides (e.g. Cl or Br) preferred.
  • amine protecting agent b contains two leaving groups, preferably each LG is independently selected from halides (e.g.
  • R’ may be a Ci-2 0 , preferably a Ci-15, and more preferably a Ci-io hydrocarbyl group. Suitable groups include C 1-4 alkyl groups and phenyl groups.
  • Preferred amine protecting agents b where the amine protecting group is monovalent have the structure:
  • amine protecting agent b preferably has a structure selected from:
  • each LG is independently selected from halides (e.g . Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro-substituted aryl groups such as p-nitrophenyl), and sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF3, -CH2CI, phenyl and p-nitrophenyl).
  • each LG is independently selected from halides (e.g. Cl or Br), or one LG (preferably that bonded to the group -C(O)-) is selected from halides (e.g. Cl or Br) while the other LG is selected from substituted aryloxy groups and sulfonates.
  • Amine protecting agent b is preferably used in step (ia) in an amount of from 0.8 to 2.5 molar equivalents, preferably from 1 to 2 molar equivalents, and more preferably from 1.1 to 1.5 molar equivalents as compared to starting material a.
  • Step (ia) is preferably carried out in the presence of a base.
  • Suitable bases may be selected from:
  • inorganic bases preferably from alkali metal hydroxides (e.g. from sodium hydroxide and potassium hydroxide) and alkali metal carbonates (e.g. from sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate); and organic bases, more preferably from nitrogen-containing organic bases, such as from trimethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7- ene.
  • alkali metal hydroxides e.g. from sodium hydroxide and potassium hydroxide
  • alkali metal carbonates e.g. from sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate
  • organic bases more preferably from nitrogen-containing organic bases, such as from trimethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7- ene.
  • Carbonates are preferred for use in step (ia), in particular sodium bicarbonate.
  • the base is preferably used in an amount of from 0.9 to 1.5 molar equivalents, preferably from 1 to 1.3 molar equivalents, and more preferably from 1.05 to 1.2 molar equivalents as compared to starting material a where the amine protecting group is monovalent.
  • the base is preferably used in an amount of from 1.8 to 3 molar equivalents, preferably from 2 to 2.6 molar equivalents, and more preferably from 2.1 to 2.4 molar equivalents as compared to starting material a where the amine protecting group is divalent.
  • This amine protecting agent b may be used to introduce a monovalent or divalent protecting group into the starting material a. Whether a monovalent or divalent protecting group is present in material c will depend on the conditions under which step (ia) is carried out.
  • amine protecting agent b may be desirable to add to the reaction mixture after the base has been added, e.g. dropwise. It may also be desirable to prepare a divalent protecting group, then to hydrolyse it using a base, e.g. a hydroxide base, preferably an alkali metal hydroxide base such as sodium hydroxide.
  • a base e.g. a hydroxide base, preferably an alkali metal hydroxide base such as sodium hydroxide.
  • the base is preferably used in a relative high amount, e.g. from 3 to 6 equivalents as compared to the divalently protected compound.
  • a first amine protecting group may also be converted into a second (or, though less preferred, even a third, and so on) protecting group during step (ia).
  • a first amine protecting group may form an amide (i.e. -NHqC(O)-) which is then subsequently converted to an alkylated amine group (i.e. -NR-alk-), e.g. having a structure as mentioned above preferably in which L is a leaving group.
  • a first amine protecting group may form an alkylated amine group (i.e. -NR-alk-), e.g. having a structure as mentioned above preferably in which L is -OH, which is then subsequently converted to a different alkylated amine group, e.g. by conversion of L into a leaving group.
  • Step (ia) is preferably carried out in the presence of a solvent.
  • the solvent may be a protic or aprotic solvent.
  • Protic solvents may be selected from water, alcohols (e.g. ethanol and methanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • Aprotic solvents may be selected from tetrahydrofuran, diglyme, 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, propionitrile, trichloromethane and dichloroethane.
  • Preferred solvents are aprotic chlorinated solvents, e.g. selected from trichloromethane and dichloroethane, and ether solvents, e.g. selected from dimethyl ether and methyl tert-butyl ether.
  • step (ia) may be carried out in the presence of a catalyst, e.g. acetate- based butylimidazolium ionic liquid immobilised silica-coated magnetic nanoparticles as described in Green Chemistry, 2017, 19(16), 3801-3812, rather than a base.
  • a catalyst e.g. acetate- based butylimidazolium ionic liquid immobilised silica-coated magnetic nanoparticles as described in Green Chemistry, 2017, 19(16), 3801-3812, rather than a base.
  • the reaction is preferably carried out in the absence of a solvent.
  • Step (ia) may be carried out at a temperature of at least 40 °C, for instance a temperature of from 40 to 100 °C, preferably from 50 to 80 °C, and more preferably from 55 to 70 °C.
  • Step (ia) will typically be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar. Step (ia) will generally be carried out for a period of greater than 1 hour, but less than 24 hours.
  • oxidising agents may be used to convert material c to oxidised intermediate d in step (ib).
  • a mild oxidising agent for instance selected from alkali metal persulfates (e.g . sodium persulfate) and alkali metal peroxymonosulfates (such as potassium peroxymonosulfate) and oxygen gas.
  • Persulfates are particularly suitable for carrying out step (ib), in particular sodium persulfate.
  • the oxidizing agent may be used in an amount of from 0.9 to 3 molar equivalents, preferably from 1 to 2.5 molar equivalents, and more preferably from 1.1 to 2 molar equivalents, as compared to material c. It will be appreciated that, where air is used as the oxidizing agent, the reaction may simply take place in an oxygen environment (e.g. in the presence of air) and, as such, higher molar equivalents of oxygen gas will be used.
  • Suitable catalysts include palladium (such as palladium acetate), ruthenium (such as dichloro(p- cymene)ruthenium(II) dimer) and copper (such as copper (II) triflate or copper (II) acetate) catalysts.
  • the catalyst is selected from palladium or ruthenium catalysts, more preferably from palladium catalysts. Copper catalysts are particularly suited for use with oxygen.
  • the metal catalyst may be used in an amount of up to 0.3 molar equivalents, for instance from 0.005 to 0.2 molar equivalents, preferably from 0.01 to 0.08 molar equivalents, and more preferably from 0.02 to 0.04 molar equivalents, as compared to material c. It has surprisingly been found that the yield of oxidised intermediate d may be enhanced by the use of a low level of metal catalyst.
  • Step (ib) is preferably carried out in the presence of 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 for use in step (ib) may be selected from water, alcohols (e.g. ethanol, methanol and ethylene glycol) and carboxylic acids (e.g. formic acid and acetic acid), preferably from water and carboxylic acids, with acetic acid particularly preferred.
  • alcohols e.g. ethanol, methanol and ethylene glycol
  • carboxylic acids e.g. formic acid and acetic acid
  • intermediate d may have a hydroxy protecting group of formula -CH2CH2OH as Rio.
  • Step (ib) may also be 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.
  • Suitable aprotic solvents for use in step (ib) include aromatic solvents (e.g . selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes, anisole and o-dichlorobenzene) and non aromatic solvents (e.g. selected from heterocyclic solvents (e.g. tetrahydrofuran and 1,4- dioxane), dimethylacetamide, diglyme and organic acid anhydrides (e.g. acetic acid anhydride)).
  • aromatic solvents e.g . selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes, anisole and o-
  • step (ib) is carried out in the presence of a protic solvent, e.g. selected from those listed above, and an aprotic solvent, e.g. selected from those listed above.
  • a protic solvent e.g. selected from those listed above
  • an aprotic solvent e.g. selected from those listed above.
  • step (ib) is carried out in the presence of a carboxylic acid and the corresponding organic acid hydride, for instance acetic acid and acetic acid anhydride.
  • the protic and aprotic solvents are each preferably present in the solvent system in an amount of at least 30 % by weight.
  • Step (ib) may be carried out at a temperature of at least 50 °C, for instance at a temperature of from 50 to 150 °C, preferably from 60 to 120 °C, and more preferably from 70 to 100 °C.
  • step (ii) may be carried out at higher temperatures, e.g. from 130 to 180 °C.
  • Step (ib) will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.
  • Step (ib) may be conducted for a period of greater than 1 hours, preferably greater than 2 hours. Typically, the one-step reaction will be carried out for up to 48 hours.
  • oxidised intermediate d is present in a form in which at least some, and often all, -OH or -NH groups are alkanoylated. This will often happen in instances where a carboxylic acid or an organic acid anhydride is used as a solvent. For instance, if acetic acid and/or acetic acid anhydride are used during oxidation step (ib), then oxidised intermediate d will typically be present in the form of an acetylated compound. For similar reasons, intermediates other than d may also be present in a form in which -OH and/or -NH groups are alkonylated.
  • step (i) is carried out in a single reaction, i.e. without sub-steps.
  • the oxidising agent preferably also serves as the amine protecting agent.
  • step (i) may be carried out in the presence of a diacyl peroxide:
  • each R x is independently selected from a hydrocarbyl groups, e.g. aryl, alkyl or alkenyl groups.
  • each R x is independently selected from a Ci-20, preferably a C2-15, and more preferably a C3-10 hydrocarbyl group.
  • Suitable R x groups include C1-4 alkyl groups and phenyl groups. Typically both R x groups will be the same.
  • the resulting intermediate d will typically have PG as -C(0)R x , q as 1, and Rio as H.
  • the diacyl peroxide may be used in an amount of from 0.5 to 1.5, preferably from 0.8 to 1.2, and more preferably from 0.9 to 1.1 molar equivalents, as compared to starting material a.
  • an alkali metal phosphate may also be present in the reaction mixture, such as dipotassium phosphate. This may be used in an amount of from 0.9 to 1.5, preferably from 1 to 1.3, and more preferably from 1.05 to 1.2 molar equivalents, as compared to starting material a.
  • step (i) is carried out in a single reaction, it may be carried out in the presence of a protic solvent, such as a protic solvent selected from water, alcohols (e.g. methanol, ethanol and 4-methyl -2-pentanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • a protic solvent selected from water, alcohols (e.g. methanol, ethanol and 4-methyl -2-pentanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • a protic solvent selected from water, alcohols (e.g. methanol, ethanol and 4-methyl -2-pentanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • a protic solvent selected from water, alcohols (e.g. methanol, ethanol and 4-methyl -2-pentanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • an alcohol e
  • step (i) is carried out in a single reaction, it may be carried out at a temperature of from 10 to 40 °C, preferably from 15 to 30 °C, and more preferably from 20 to 25 °C. Preferably, the reaction is carried out without heating.
  • the diacyl peroxide may be added dropwise to prevent the temperature from rising too rapidly.
  • step (i) is carried out in a single reaction
  • the reaction may be carried out for a period of greater than 30 minutes.
  • the reaction will be carried out for a period of up to 12 hours, such as for up to 2 hours.
  • Step (ii) formation of target compound f In step (ii) of the method, oxidised intermediate d is converted into a target compound f
  • the method of the present invention may comprise a step of dealkanoylating oxidised intermediate d.
  • Dealkanoylation will typically take place before step (ii), though it may also take place at the end of step (ii). It will be appreciated that dealkanoylation is the removal of any alkanoyl groups from the -OH and -NH groups in intermediate d.
  • Dealkanoylation is preferably carried out in the presence of an acid.
  • Suitable acids include hydrogen halides, in particular hydrogen chloride.
  • the amount of acid that is used will depend, in part, on the number of alkanoylated groups that are present in oxidised intermediate d. However, typically the acid will be used in an amount of from 0.8 to 8 molar equivalents, preferably from 1 to 6 molar equivalents, and more preferably from 2 to 4 molar equivalents, as compared to oxidised intermediate d.
  • dealkanoylation (and thus formation of alkylated intermediate e) may happen in-situ during other reactions in step (ii) and, as such, it will not be necessary to carry out a separate dealkanoylation step.
  • steps (i) and (ii) may be carried out in the same reactor.
  • the method comprises carrying out step (ii) without isolation of oxidised intermediate d following step (i).
  • step (ii) Five main routes are preferred for carrying out step (ii).
  • L and L’ are selected from leaving groups and -OH.
  • Suitable leaving groups include: halides (e.g . Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro- substituted aryl groups such as p-nitrophenyl), and sulfonates (e.g. - OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH2CI, phenyl and p-nitrophenyl).
  • Preferred leaving groups are selected from Cl and Br.
  • L and L’ in intermediate e will typically be OH groups.
  • a first, preferred, route is carried out on an oxidised intermediate d having the following structure:
  • L is as defined in connection with alkylated intermediate e
  • -OH or -NH groups may be in an alkanoylated form.
  • group which acts as the protecting group in step (ii) may be directly converted into the backbone of the heterocyclic ring structure in target compound f.
  • step (ii) is carried out using the conditions described below in connection with the transformation of an N-alkylated intermediate e into target compound /
  • oxidised inter ediate d has the same structure as alkylated intermediate e, and so no steps are required for providing alkylated intermediate e from oxidised intermediate d.
  • a dealkonylatation step is preferably carried out before step (ii) in order to convert oxidised intermediate d into N-alkylated intermediate e, though dealkonylation may also occur in situ during step (ii)
  • the protecting group(s) are converted in sub-step (iia) such that alkylated intermediate e is formed before alkylated intermediate e is transformed into target compound /in sub-step (iib):
  • the second route is preferred for embodiments in which the protecting group forms a cyclic carbamate with the amine, in particular embodiments in which intermediate d has the following structure:
  • -OH group shown above as -XH
  • -XH alkanoylated form
  • L is -OH in N-alkylated intermediate e.
  • Sub-step (iia) of the second route may be carried out in the presence of a base.
  • bases are selected from inorganic bases, for instance from alkali metal hydroxides (e.g . from sodium hydroxide and potassium hydroxide) and alkali metal carbonates (e.g. from sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogen carbonate). Alkali metal hydroxides are particularly suitable.
  • the base may be used in an amount of 0.8 to 5 molar equivalents, preferably from 0.9 to 3 molar equivalents, and more preferably from 1.1 to 2 molar equivalents, as compared to intermediate d.
  • Sub-step (iia) of the second route may be carried out in the presence of a solvent, and preferably a protic solvent.
  • Suitable solvents for use in sub-step (iia) include water, alcohols (e.g. methanol and ethanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • water or methanol is used as the solvent in sub-step (iia).
  • Sub-step (iia) of the second route may be carried out at a temperature of at least 40 °C, for instance at a temperature of from 40 to 150 °C, preferably from 45 to 120 °C, and more preferably from 50 to 100 °C.
  • Sub-step (iia) of the second route will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.
  • Sub-step (iia) in the second route may be conducted for a period of greater than 1 hours, preferably greater than 2 hours. Typically, the reaction will be carried out for up to 12 hours.
  • sub-step (iib) is carried out using the conditions described below in connection with the transformation of an N-alkylated intermediate e into target compound f
  • the protecting group is removed in sub-step (iia’) to form intermediate d which may then be alkylated with an alkylating agent to form alkylated intermediate e in sub-step (iib’) before finally converting alkylated intermediate e into target compound /in sub-step (iic’):
  • the third route is particularly suitable for embodiments in which a monovalent protecting group is present in intermediate d.
  • the compound that forms as alkylated intermediate e is dependent on whether the group -XH or -NH 2 is alkylated during sub-step (b’).
  • a mixture of N- and O-alkylated intermediates may form in which case they may, if desired, be separated using known techniques such as chromatography.
  • Sub-step (a’) of the third route may be carried out in the presence of a base.
  • Preferred bases are selected from inorganic bases, for instance from alkali metal hydroxides (e.g . from sodium hydroxide and potassium hydroxide), alkali metal carbonates (e.g. from sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogen carbonate). Alkali metal hydroxides are particularly suitable.
  • the base may be used in an amount of 0.8 to 5 molar equivalents, preferably from 0.9 to 3 molar equivalents, and more preferably from 1.1 to 2 molar equivalents, as compared to intermediate d.
  • Sub-step (a’) of the third route may be carried out in the presence of a solvent, and preferably a protic solvent system.
  • Suitable solvents for use in sub-step (a) include water, alcohols (e.g. methanol and ethanol) and carboxylic acids (e.g. formic acid and acetic acid).
  • alcohols e.g. methanol and ethanol
  • carboxylic acids e.g. formic acid and acetic acid
  • water or methanol is used as the solvent in sub-step (a).
  • Sub-step (a’) of the third route may be carried out at a temperature of at least 40 °C, for instance at a temperature of from 40 to 150 °C, preferably from 45 to 120 °C, and more preferably from 50 to 100 °C.
  • Sub-step (a’) of the third route will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.
  • Sub-step (a’) of the third route may be conducted for a period of greater than 1 hours, preferably greater than 2 hours. Typically, the reaction will be carried out for up to 12 hours.
  • deprotected intermediate d’ is alkylated with an alkylating agent.
  • the groups -NHRi is alkylated though, as mentioned above, alkylation may also take place on the group -XH.
  • the alkylating agent preferably has the structure:
  • L and L’ are independently selected from OH and leaving groups, or L and L’
  • Suitable leaving groups include: halides (e.g. Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar is selected from nitro-substituted aryl groups such as p-nitrophenyl), and sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH 2 CI, phenyl and p-nitrophenyl).
  • Preferred leaving groups are selected from Cl and Br.
  • Alkylating agent is preferably used in an amount of from 0.5 to 4 molar
  • alkylating agent is preferably used in an amount of from 0.8 to 1 molar equivalents as compared to intermediate d , so as to improve selectivity of the reaction for alkylation at the nitrogen.
  • sub-step (b’) may be conducted in the presence of a solvent selected from aprotic solvents (e.g. tetrahydrofuran, diglyme, acetonitrile, dimethoxyethane, dioxane, N-methyl-2-pyrrolidone,
  • aprotic solvents e.g. tetrahydrofuran, diglyme, acetonitrile, dimethoxyethane, dioxane, N-methyl-2-pyrrolidone
  • aprotic solvents preferably those selected from tetrahydrofuran, diglyme, acetonitrile, dimethylformamide, dimethoxyethane and dioxane.
  • sub-step (b’) may be carried out in the presence of a basic reagent or a catalyst.
  • Preferred basic reagents include inorganic bases such as alkali metal hydroxides (e.g. selected from sodium hydroxide and potassium hydroxide) or alkali or alkaline earth metal carbonates (e.g. selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and calcium carbonate).
  • alkali metal hydroxides e.g. selected from sodium hydroxide and potassium hydroxide
  • alkali or alkaline earth metal carbonates e.g. selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and calcium carbonate.
  • Preferred basic reagents are alkali or alkaline earth metal carbonates, with potassium carbonate and calcium carbonate particularly preferred.
  • the basic reagent 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 intermediate d.
  • Suitable catalysts for used in sub-step (b’) include acids (e.g. ⁇ -toluene sulfonic acid or sodium hydrogen sulphite), zeolites (e.g. zeolite Y, sodium (faujasite)) and metal catalysts (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 d.
  • sub-step (b’) may also be carried out in the absence of a catalyst, e.g. where the alkylating agent is an epoxide reagent.
  • sub-step (b’) of the first route is generally conducted at a temperature of greater than 40 °C, preferably greater than 60 °C, and more preferably greater than 80 °C. Typically, the reaction will be carried out at a temperature of less than 300 °C. Where the alkylating agent is an epoxide reagent, the reaction is preferably carried out at elevated temperatures (e.g. as above), however it may also be carried out at room temperature e.g. at a temperature at least 15 °C, e.g. from 18 to 30 °C.
  • sub-step (b’) will generally be conducted at a pressure of from 1 to 200 bar.
  • sub-step (b’) will be carried out at ambient pressure, i.e. a pressure of approximately 1 bar.
  • a pressure of from 2 to 200 bar may be used.
  • the reaction may be conducted for a period of greater than 30 minutes, but preferably less than 6 hours, and more preferably less than 4 hours.
  • Examples of preferred conditions for carrying out sub-step (b’) where intermediate d’ is to be alkylated on the group -NHRi are as follows.
  • catalyst zeolite Y, sodium (faujasite), and solvent: ethylene carbonate
  • catalyst / oluene sulfonic acid, and solvent: NMP; or
  • L’ is a halide and L is -XH:
  • catalyst sodium hydrogen sulphite
  • solvent water
  • catalyst Pd/C
  • zinc oxide support zinc oxide support
  • solvent water
  • sub-step (b’) may be 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) and alkali metal carbonates (e.g. selected from sodium bicarbonate, sodium carbonate, potassium
  • a base preferably an inorganic base, such as an alkali metal hydroxide (e.g . selected from sodium hydroxide and potassium hydroxide) and alkali metal carbonates (e.g. selected from sodium bicarbonate, sodium carbonate, potassium
  • Sub-step (b’) 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 intermediate d.
  • sub-step (b’) may be conducted in an aprotic solvent, preferably selected from tetrahydrofuran, diglyme, 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,
  • an aprotic solvent preferably selected from tetrahydrofuran, diglyme, acetonitrile, dimethoxyethane, dioxane, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethylene carbonate, sulfolane, diphenyl ether, acetonitrile, 2-nitropropane, acetone
  • isobutyronitrile methylacetate, methyformate, nitromethane, oxolane and propionitrile, and more preferably from dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, diglyme, ethyl acetate and sulfolane.
  • sub-step (b’) 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 sub-step is carried out under reflux.
  • sub-step (b’) will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.
  • sub-step (b’) may be conducted for a period of greater than 1 hour, but preferably less than 24 hours, and more preferably less than 12 hours.
  • L and L’ in the alkylating agent preferably together form the group -0-C(0)-0-.
  • step (iic’) is carried out using the conditions described below in connection with the transformation of an N- or O-alkylated intermediate e into target compound f.
  • a fourth route is carried out on an O-alkylated intermediate d having the following structure: where: L’ is as defined in connection with alkylated intermediate e; and wherein -OH or -NH groups may be in an alkanoylated form.
  • the protecting group(s) are removed converted in sub-step (iia”) such that alkylated intermediate e is formed before alkylated intermediate e is transformed into target compound /in sub-step (iib”):
  • Preferred intermediates d for use in the fourth method have the structure: where: L’ and R’ are as defined above.
  • Sub-step (iia”) of the fourth route may be carried out in the presence of water.
  • the mixture is heated, e.g. to a temperature of from 30 to 100 °C, preferably from 35 to 80 °C, and more preferably from 40 to 70 °C.
  • an aqueous acid may be used.
  • Suitable acids include hydrogen halides, in particular hydrogen chloride, though a wide range of other acids may also be used.
  • the acid will be used in an amount of from 0.8 to 2 molar equivalents, preferably from 1 to 1.5 molar equivalents, and more preferably from 1.05 to 1.2 molar equivalents, as compared to oxidised intermediate d.
  • Sub-step (iia”) of the fourth route will generally be carried out at ambient pressure, i.e. at a pressure of approximately 1 bar.
  • Sub-step (iia”) in the fourth route may be conducted for a period of greater than 1 hours, preferably greater than 4 hours. Typically, the reaction will be carried out for up to 24 hours.
  • sub-step (iib”) is carried out using the conditions described below in connection with the transformation of an O-alkylated intermediate e into target compound f
  • step (ii) via alkylated intermediate e, once the alkylated intermediate e has been obtained, it is transformed into target compound /
  • alkylated intermediate e is separated from the reaction mixture in which it is prepared by thin film distillation. This ensures that the purity of intermediate e is high prior to the cyclisation step. It also means that intermediate e may be maintained at an elevated temperature (e.g. of from 100 to 200 °C, preferably from 120 to 170 °C, and more preferably from 140 to 160 °C) and added to the reaction mixture for transformation into target compound f. It will be appreciated that, in some instances, the transformation of alkylated intermediate e into target compound / will occur spontaneously on formation of alkylated intermediate e, for instance in embodiments where the alkylated intermediate comprises a leaving group rather as L or L’. However, in order to obtain a good yield of target compound/ it is generally preferred for the conditions to be applied.
  • an elevated temperature e.g. of from 100 to 200 °C, preferably from 120 to 170 °C, and more preferably from 140 to 160 °C
  • the transformation of alkylated intermediate e into target compound / may be conducted in the presence of a hydrogen halide, preferably hydrogen bromide or hydrogen chloride. This is the preferred method for carrying out the transformation where intermediate e is alkylated on the nitrogen.
  • a hydrogen halide is particularly preferred where L or L’ in alkylated intermediate e represents a hydroxy group.
  • the hydrogen halide is preferably in the form of an aqueous solution, e.g.
  • a molar excess of hydrogen halide is preferably used, for instance by using hydrogen halide in an amount of at least 5 molar equivalents, preferably at least 10 molar equivalents, and more preferably at least 15 molar equivalents as compared to intermediate e.
  • the reaction with the hydrogen halide may be conducted at a temperature of greater than 60 °C, preferably greater than 70 °C, and more preferably greater than 80 °C.
  • the reaction with the hydrogen halide may be conducted at ambient pressure, i.e. approximately 1 bar.
  • the reaction with the hydrogen halide may be conducted for a period of greater than 1 hour, preferably greater than 2 hours, but preferably less than 5 hours.
  • the reaction with the hydrogen halide is preferably quenched using a base, for instance using an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) or aqueous ammonia.
  • a base for instance using an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) or aqueous ammonia.
  • an alkali metal hydroxide e.g. sodium hydroxide or potassium hydroxide
  • aqueous ammonia e.g. sodium hydroxide or potassium hydroxide
  • the transformation of alkylated intermediate e into target compound / may be carried out in the presence of a base.
  • the base may be selected from:
  • inorganic bases preferably from alkali metal hydroxides (e.g. from sodium hydroxide and potassium hydroxide) and alkali metal carbonates (e.g. from sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate), and more preferably from alkali metal hydroxides such as sodium hydroxide; and organic bases, more preferably from nitrogen-containing organic bases, such as from trimethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7- ene.
  • alkali metal hydroxides e.g. from sodium hydroxide and potassium hydroxide
  • alkali metal carbonates e.g. from sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate
  • alkali metal hydroxides such as sodium hydroxide
  • organic bases more preferably from nitrogen-containing organic bases, such as from trimethylamine, diisopropylethylamine and l,8-diazabicyclo[5.4.0]und
  • 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 intermediate e.
  • the transformation of alkylated intermediate e into target compound / may be carried out in the presence of an inorganic base and:
  • an aprotic solvent preferably selected from tetrahydrofuran, diglyme, acetonitrile, dimethoxyethane, dioxane, N-methyl-2-pyrrolidone, dimethylformamide,
  • a chlorinated solvent preferably selected from trichloromethane and
  • a phase-transfer reagent preferably a quaternary ammonium salt such as a tetraalkylammonium halide salt, e.g. butyltriethylammonium chloride, is preferably used with the chlorinated solvent.
  • a phase-transfer reagent preferably a quaternary ammonium salt such as a tetraalkylammonium halide salt, e.g. butyltriethylammonium chloride, is preferably used with the chlorinated solvent.
  • the transformation of alkylated intermediate e into target compound / may be carried out in the presence of an organic base and an aprotic solvent, preferably selected from tetrahydrofuran, diglyme, 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, diglyme, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate and sulf
  • alkylated intermediate e into target compound / is carried out in the presence of a base
  • it may be carried out at a temperature of greater than 40 °C, preferably greater than 50 °C, and more preferably greater than 60 °C.
  • the reaction is carried out under reflux.
  • the transformation is carried out in the presence of a base, it may be conducted for a period of greater than 30 minutes, but preferably less than 10 hours, and more preferably less than 8 hours.
  • the transformation of alkylated intermediate e into target compound / may be conducted in the presence of a trihydrocarbyl phosphine (e.g . a triaryl phosphine or a trialkyl phosphine, such as triphenyl phosphine or tributyl phosphine), and preferably also an azo compound (e.g. a dialkyl azodi carboxyl ate, such as diisopropyl azodi carboxyl ate).
  • a trihydrocarbyl phosphine e.g a triaryl phosphine or a trialkyl phosphine, such as triphenyl phosphine or tributyl phosphine
  • an azo compound e.g. a dialkyl azodi carboxyl ate, such as diisopropyl azodi carboxyl ate.
  • the trihydrocarbyl phosphine e.g. triaryl phosphine or trialkyl phosphine
  • the trihydrocarbyl 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 intermediate e.
  • the azo compound e.g. a dialkyl azodi carboxyl ate, 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.
  • the reaction may be carried out as a catalytic Mitsunobu reaction.
  • 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 intermediate e.
  • 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 intermediate e.
  • 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.
  • 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 intermediate e.
  • the use of a silane is particularly preferred where a catalytic Mitsunobu reaction is carried out.
  • the transformation of alkylated intermediate e into target compound / is preferably conducted in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, diglyme, 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.
  • an aprotic solvent preferably selected from tetrahydrofuran, diglyme, acet
  • the transformation of alkylated intermediate e into target compound / is typically conducted at ambient 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.
  • the transformation is preferably conducted at ambient pressure, i.e. at a pressure of approximately 1 bar.
  • the transformation 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.
  • intermediate e is alkylated on the oxygen
  • transformation of alkylated intermediate e into target compound / is preferably conducted in the presence of a metal catalyst.
  • 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-SiCh/AhCb), cobalt (e.g. in the presence of aluminium such as in Raney cobalt), platinum (e.g. Pt/C, PtC , Pt/AkCb, Pt/C/Cu, Pt/C/Fe, PtSiC or Pt/C/V), ruthenium (e.g.
  • Cp * represents the ligand 1, 2, 3,4,5- pentamethylcyclopentadienyl
  • Cp represents the ligand cyclopentadienyl
  • COD represents the ligand 1,5-cyclooctadiene.
  • the metal catalyst may be used in an amount of up to 0.5 molar equivalents as compared to intermediate e, for instance from 0.001 to 0.5, preferably from 0.005 to 0.4, and more preferably from 0.01 to 0.3 equivalents as compared to intermediate e.
  • the reaction is preferably carried out at a temperature of at least 100 °C, such as a temperature of from 100 to 250 °C.
  • O-alkylated intermediate e into target compound /in the presence of a metal catalyst may be carried out in the further presence of: (1) a basic catalyst; (2) no further components; (3) a hydrogen source, or (4) a reaction additive.
  • Particularly suitable metal catalysts where a basic catalyst is used include ruthenium (e.g. in the form of RuCh(PPh 3 ) 3 ) and iridium (e.g. [CplrCl?/) catalysts.
  • Preferred basic catalysts include inorganic bases, such as those selected from alkali metal carbonates (e.g. alkali metal carbonates such as sodium carbonate, sodium
  • alkali metal alkoxides e.g. alkali metal /c/V-butoxides such as sodium /c/V-butoxide or potassium /c/V-butoxide. Alkali metal oxides are believed to give very high yields.
  • 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 intermediate e.
  • the reaction may be carried out in the presence of a solvent system, such as an aprotic solvent system.
  • a solvent system such as an aprotic solvent system.
  • trace amounts e.g. less than 5 %, less than 3 % or less than 1 % by volume of the aprotic solvent system
  • protic solvents may be present, 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 (e.g. a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl-substituted naphthalenes (i.e. 1- and 2-methyl naphthalene) and anisole).
  • aromatic solvent e.g. a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl-substituted naphthalenes (i.e. 1- and 2-methyl naphthalene) 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.
  • the aromatic solvent is the only solvent that
  • 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.
  • reaction materials e.g. reagents or catalysts
  • 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.
  • 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, and preferably greater than 12 hours. Typically, the reaction will be carried out for up to 48 hours.
  • the transformation of alkylated intermediate e into target compound / 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.
  • reaction materials e.g. reagents or catalysts
  • the metal catalyst and, optionally, the solvent system are present.
  • Suitable metal catalysts include ruthenium (e.g. as RuCh(PPh3)3, Cp * RuCl(PPh3)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.
  • reaction is optionally carried out in the presence of a solvent system.
  • 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, napththalene, methyl-substituted naphthalenes and anisole.
  • aromatic solvent such as a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, napththalene, methyl-substituted naphthalenes and anisole.
  • Mesitylene is particularly suitable, delivering high yields of the target compound f.
  • 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.
  • 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 and diglyme.
  • 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 intermediate e.
  • 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 ambient pressure, i.e. at a pressure of approximately 1 bar, though in some instances lower pressures may be preferred (e.g. less than 0.5 bar or 0.1 bar), for instance where the reaction is carried out as a reactive distillation reaction. These reactions are described below in greater detail.
  • the reaction may be conducted for a period of greater than 2 hours, . 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.
  • the transformation of O-alkylated intermediate e into target compound / may be carried out in the presence of a nickel catalyst (e.g. Ra-Ni) at about 150 °C (e.g. from 130 to 170 °C, preferably from 140 to 160 °C), e.g. for a period of from 2 to 5 hours.
  • a nickel catalyst e.g. Ra-Ni
  • These conditions provide excellent conversion and selectivity.
  • the conditions of this very specific embodiment are particularly suitable where the reaction is carried out under reactive distillation ( e.g . under a vacuum, for instance of up to 100 mbar, such as from 1 to 10, preferably 2 to 8, more preferably 4 to 6 mbar), preferably in which intermediate e is continuously fed to the reactor which contains the catalyst and the product is continuously distilled.
  • intermediate e is preferably used in a neat form ( i.e . without a solvent other than target compound /which may act as a solvent once formed).
  • the catalyst is preferably in the form of a slurry or fixed bed, e.g. with tubular set up and/or a high catalyst surface area (e.g. due to
  • the transformation of alkylated intermediate e into target compound / 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.
  • 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 /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, (PPhs/RhCl 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(PPli3)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 target compound f.
  • the reaction is preferably carried out as a heterogeneous catalyst reaction.
  • Heterogeneous catalysis reactions involve the use of a catalyst in a different phase from the reactants.
  • the reaction is preferably carried out with a solid catalyst in a liquid reagent phase.
  • 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.
  • hydrogen transfer reagents may 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.
  • 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 target compound f.
  • 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.
  • 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 and diglyme.
  • the non-aromatic solvent is preferably used in combination with an aromatic solvent.
  • reaction materials e.g. reagents or catalysts
  • the metal catalyst e.g. 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.
  • the transformation of alkylated intermediate e into target compound / 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 RJ1 2 O 3 ) catalysts. Palladium catalysts are particularly suitable, since they are believed to give the target compound /in high yields.
  • Suitable reaction additives include metal oxides and inorganic bases.
  • 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 intermediate e. 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.
  • the aqueous solvent system may contain only water.
  • dimethoxyethane may be used.
  • Suitable aprotic solvent systems preferably comprise an aromatic solvent (e.g. a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes and anisole) or a non aromatic solvent (e.g. N-methyl-2-pyrrolidone, tetrahydrofuran and 1,4-dioxane).
  • aromatic solvent e.g. a solvent selected from toluene, benzene, xylenes, trimethyl benzenes such as mesitylene, diphenyl ether, naphthalene, methyl -substituted naphthalenes and anisole
  • non aromatic solvent e.g. N-methyl-2-pyrrolidone, tetrahydrofuran and 1,4-dioxane
  • an aromatic aprotic solvent e.g. as described above, may be used in combination with a protic solvent, e.g. as described above.
  • 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.
  • reaction materials e.g. reagents or catalysts
  • 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.
  • a fifth route for carrying out step (ii) proceeds via the following route:
  • Each Y is independently selected from leaving groups, and preferably from: halides (e.g. Cl, Br, I), substituted aryloxy groups (e.g. -O-Ar, where Ar selected from nitro- substituted aryl groups such as / nitrophenyl) and sulfonates (e.g. -OSO2A, where A is selected from tolyl, methyl, -CF 3 , -CH2CI, phenyl and /2-nitrophenyl), more preferably from halides, and still more preferably from Cl and Br.
  • at least one and, more preferably, each Y is Br. This is particularly the case where the base is an alkali metal hydroxide.
  • step (iia’”) is preferably conducted in the presence of a catalyst, e.g. a tetrabutylammonium halide as mentioned below.
  • any -OH and -NH groups may be in an alkanoylated form.
  • R’ is as defined previously.
  • Step (iia”’) may be conducted in the presence of a base selected from alkali metal hydroxides and alkali metal carbonates.
  • a base selected from alkali metal hydroxides and alkali metal carbonates.
  • the use of alkali metal hydroxides is particularly preferred.
  • the alkali metal hydroxide may be selected from sodium hydroxide and potassium hydroxide.
  • Sodium hydroxide is particularly preferred.
  • the carbonate base may be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and caesium carbonate. Caesium carbonate is preferred.
  • Caesium carbonate is preferred.
  • Sodium hydroxide and caesium carbonate are particularly preferred, since they reduce the formation of a dimer by-product.
  • the base is used in step (iia’”) an amount of at least 2 molar equivalents as compared to intermediate d.
  • the base is used in an amount of from 2 to 12 molar equivalents, preferably from 3 to 10 molar equivalents, and more preferably from 4 to 8 molar equivalents as compared to intermediate d.
  • the alkylating agent is preferably used in step (iia”’) an amount of from 1 to 20 molar equivalents, preferably from 2 to 15 molar requivalents, and more preferably from 4 to 10 molar equivalents as compared to intermediate d.
  • Step (iia”’) is preferably conducted in the presence of a solvent selected from methyl isobutyl ketone and acetonitrile. Acetonitrile is particularly preferred.
  • the solvent is used in an amount of at least 10 ml / 1 g of intermediate d.
  • step (iia”’) is conducted in the presence of a catalyst, preferably a tetrabutylammonium halide, and more preferably tetrabutylammonium bromide.
  • a catalyst preferably a tetrabutylammonium halide, and more preferably tetrabutylammonium bromide.
  • 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 intermediate d.
  • Step (iia”’) may be conducted at a temperature of from 10 to 150 °C.
  • the reaction is preferably conducted at an elevated temperature, e.g. at a temperature of at least 30 °C, preferably at least 50 °C, and more preferably at least 60 °C.
  • the reaction in step (iia”’) may be conducted under reflux. Elevated temperatures are preferred to reduce by-product formation.
  • step (iia”’) is an alkali metal hydroxide
  • the reaction is preferably conducted at a temperature of from 15 to 40 °C, preferably from 20 to 35 °C and more preferably from 22 to 30 °C.
  • reaction in step (iia”’) may be carried out for at least 12 hours, and preferably at least 15 hours.
  • Step (iia”’) is preferably conducted at ambient pressure, i.e. a pressure of approximately 1 bar.
  • step (iia”’) may be carried out using one set of reagents and under one set of conditions, in some embodiments a second set of reagents / conditions (e.g. a second base or a different, preferably aprotic, solvent) may be used to encourage ring closing.
  • a second set of reagents / conditions e.g. a second base or a different, preferably aprotic, solvent
  • step (iib’) of the method the nitrogen group of intermediate e is deprotected, thereby forming product f
  • step (iib”’) is preferably carried out in an aqueous solution, preferably comprising an acid or a base, and more preferably comprising a base.
  • the base is preferably selected from inorganic bases, such as from alkali metal bases, preferably from alkali metal hydroxides, and more preferably is sodium hydroxide.
  • the base is preferably used in step (iib”’) in a molar excess as compared to intermediate e.
  • the base may be used in an amount of at least twice, and preferably at least three time the molar quantity of intermediate e. This is believed to help to remove the dimer by-product.
  • the acid is preferably selected from inorganic acids, and more preferably is hydrochloric acid.
  • Step (iib”’) may conducted at an elevated temperature, e.g. at a temperature of at least 30 °C, preferably at least 50 °C, and more preferably at least 60 °C.
  • the reaction in step (iib”’) may be conducted under reflux.
  • reaction in step (iib”’) may be carried out for at least 12 hours, and preferably at least 15 hours.
  • Step (iib”’) is preferably conducted at ambient pressure, i.e. a pressure of approximately 1 bar.
  • step (iia”’) is carried out in the presence of a base (e.g. sodium hydroxide) and a solvent (e.g. acetonitrile) and step (iib”’) is carried out in the presence of an aqueous base (e.g. sodium hydroxide).
  • a base e.g. sodium hydroxide
  • a solvent e.g. acetonitrile
  • R-4, R5, R11 and R12 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;
  • Rfdon R 7 , Re and R 9 are each independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, secondary amine and tertiary amine groups;
  • X is -0-
  • n 0 to 2.
  • 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.
  • 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.
  • 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.
  • 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 R7 and Rx. 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.
  • 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.
  • 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.
  • only one of R2, R3, R4, Rs, Rs, R7, Rs, R9, R11 and R12 is selected from a group other than hydrogen.
  • R 2 and R 3 are hydrogen, and more preferred that both of R 2 and R 3 are hydrogen.
  • 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.
  • 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, Rxs, R7, Rs, R9, R11 and R12 are hydrogen.
  • n may be 0, 1 or 2, though it is preferred that n is 0 or 1, more preferably 0.
  • Octane-boosting additives that may be prepared using the method of the present invention include:
  • Preferred octane-boosting additives include:
  • octane-boosting additive Particularly preferred is the octane-boosting additive:
  • a mixture of compounds / may be used in a fuel composition.
  • a fuel composition may comprise a mixture of:
  • references to alkyl groups include different isomers of the alkyl group.
  • references to propyl groups embrace n-propyl and i-propyl groups
  • references to butyl embrace n-butyl, isobutyl, sec-butyl and tert-butyl groups.
  • the present invention provides compounds / which are obtainable by a method of the present invention.
  • 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:
  • a fuel for a spark-ignition internal combustion engine comprises a compound / and preferably an octane-boosting fuel additive, obtainable and preferably obtained by a method of the present invention, and a base fuel.
  • Gasoline fuels are typically used in spark- ignition internal combustion engines.
  • 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.
  • suitable liquid fuels include hydrocarbon fuels, oxygenate fuels and combinations thereof.
  • the fuel composition may contain the compound /in an amount of up to 20 %, preferably from 0.1 % to 10 %, and more preferably from 0.2 % to 5 % weight compound / / weight base fuel. Even more preferably, the fuel composition contains the compound /in an amount of from 0.25 % to 2 %, and even more preferably still from 0.3 % to 1 % weight compound / / weight base fuel. It will be appreciated that, when more than compound having a structure falling within that of compound /is used, these values refer to the total amount of compounds /in the fuel.
  • the fuel compositions may comprise at least one other further fuel additive.
  • additives examples 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.
  • 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 /
  • 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.
  • Example 1 step (0. sub-step - amine protection
  • intermediate cl, toluene (60 g) plus water (30 g) and sodium hydroxide (2.2 eq) were stirred overnight at 55 °C. Further sodium hydroxide (1 eq) was added and the reaction mixture stirred for a further 24 hours at 78 °C to give intermediate c2 (84.5 % yield).
  • Example 3 step (i) as a single step - simultaneous amine protection and oxidation
  • Example 4 step (iil first route - direct cvclising
  • Oxidised intermediate d2 was directly cyclised as outlined in Example 4.
  • compound d2 was in a form in which the -OH and -NH groups are acetylated, it was dealkanoylated before cyclising by adding combining d2 (2.5 g) with water (3.3 g) and 37 % HC1 (1 ml). The reaction mixture was heated to around 80 °C for approximately 2.5 hours to give the dealkanoylated form of compound d2.
  • compound d2 was in a form in which the -NH group is benzoylated
  • it was dealkanoylated before cyclising by adding combining d2 (5.0 g) with water (10 g) and 37 % HC1 (10 g).
  • the reaction mixture was refluxed at 100 °C for 2.5 hours, after which further water (10 g) was added and the reaction stirred for a further 1 hour to give the dealkanoylated form of compound d2.
  • Example 5 step (iil second route - protecting group conversion and ring closing
  • Example 6 step (ii) third route - protecting group removal alkylation and ring closing
  • Example 8 Example 7: step fourth route - protecting group removal and ring closing
  • Example 8 step ring closing for first to fourth routes
  • catalyst was added to an argon flushed stainless steel autoclave (300 mL). To this was added intermediate e (0.33 g, 2.0 mmol) followed by mesitylene (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 UPLC (MeCN) analysis.
  • intermediate e 0.33 g, 2.0 mmol
  • mesitylene 10 mL
  • Example 9 step fifth route - ring closing and protecting group removal

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Abstract

L'invention concerne un procédé de préparation d'un composé, le procédé consistant à mettre en œuvre la réaction suivante : formule (i) ; formule (ii) dans lesquelles : R10 représente hydrogène ou un groupe de protection hydroxy ; PG est un groupe de protection amine ; et q est 1 ; PG étant un groupe de protection monovalent, ou q est 0 ; PG représentant un groupe de protection divalent ; les groupes -XH ou-NH dans le composé d pouvant être présents sous une forme alcanoylée.
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