Chemical Process

Abstract

The present invention provides, inter alia, a process for preparing a compound of formula (I) wherein the substituents are as defined in claim 1. JPEG2025515043000048.jpg33159

Description

[Technical field]

[0001] The present invention relates to a novel process for the synthesis of certain α-halonorcamphor compounds, as well as a novel process for forming norcamphor.Such compounds are useful intermediates in the synthesis of herbicidal propynyl-phenyl compounds, which are known, for example from WO 2015 / 197468, and processes for the formation of such compounds or their intermediates are also known. [Background technology]

[0002] The halogenation of norcamphor or its derivatives is known, see, for example, WOODS and ROBERTS, Bromination Rates of Some Norcamphor Derivatives, J. Org. Chem 1957, Vol. 22, p. 1124-6; MCDONALD and TABOR, Molecular Rearrangements, J. Org. Chem 1968, Vol. 33(7), p. 2934-41; and TOBLER et al., The Reaction of Norbornene with t-Butyl Hypochlorite, J. Org. Chem 1964, Vol. 29(10), p. 2834-8.

[0003] Typically, the halogenation of norcamphor is carried out in acetic acid (see, for example, PEREZ et al. Molybdenum(0)-Catalyzed Reductive Dehalogenation of α-Halo Ketones with Phenylsilane, J. Org. Chem 1987, Vol. 52(25), p. 5570-4 or DALTON et al., Bromohydrin Formation in Dimethyl Sulfoxide. V. The Reaction of Norbornene, J. Org. Chem 1972, Vol. 37(3), p. 362-7), however, this often results in overbromination and poor selectivity, necessitating further purification of the product. Although alternative solvents for the halogenation of norcamphor are also known (see, for example, GAUZE et al, Proton Chemical Shifts in Some gem-Difunctional Compounds: 3-endo- and 3-exo-Substituted Norbornanones, J. Phys. Org. Chem. 2006, Vol. 19, p. 376-383, or KOVAL'SKAYA et al. Zhurnal Obshchei Khimii 1992, Vol. 62(4), p. 878-84), they are unsuitable for large-scale production and / or have a high environmental footprint due to yield losses and the need for additional purification of the product. Therefore, such approaches are not ideal for large-scale production, and therefore new, more efficient synthetic methods are desired to avoid the generation of undesired by-products in a more environmentally sustainable manner. Summary of the Invention [Means for solving the problem]

[0004] The present invention provides a selective halogenation process for norcamphor, which (i) significantly limits over-halogenation, and (ii) reduces the need to use excessive amounts of halogenating reagents to achieve complete conversion. Surprisingly, the present inventors have now found that selective halogenation to provide the desired mono-halogenated product, compound of formula (I), can be achieved with the process of the present invention, which can then be converted to the desired propynyl-phenyl herbicidal compound. Such a process allows for process telescoping, which may be more economical, environmentally friendly, and generate less waste. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Therefore, according to the present invention, a compound of formula (I) [ka] (wherein X is a halogen) A process for preparing a compound of formula (I) is provided, the process comprising: Formula (II) [ka] in a suitable reaction medium comprising a halogenating agent and an organic carbonate to obtain a compound of formula (I).

[0006] As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

[0007] As used herein, the terms "hydroxyl" or "hydroxy" refer to an --OH group.

[0008] As used herein, the term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain radical composed solely of carbon and hydrogen atoms, containing no unsaturation, having 1-6 carbon atoms, and attached to the remainder of the molecule by a single bond. C1-C4 alkyl and C1-C2 alkyl should be construed accordingly. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, and 1-dimethylethyl (t-butyl).

[0009] A "C1-C2 alkylene" group refers to the corresponding definition of C1-C2 alkyl, except that such a group is attached to the remainder of the molecule by two single bonds. Examples of C1-C2 alkylene are -CH2- and -CH2CH2-.

[0010] As used herein, the term "C1-C6 alkoxy" refers to any group represented by R a is a C1-C6 alkyl group of the formula -OR a It refers to the group: C1-C4 alkoxy should be construed accordingly. Examples of C1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy and t-butoxy.

[0011] As used herein, the term "C2-C6 alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond that may be in the (E)- or (Z)-configuration, having 2-6 carbon atoms, and attached to the remainder of the molecule by a single bond. C2-C4 alkenyl should be construed accordingly. Examples of C2-C6 alkenyl include, but are not limited to, prop-1-enyl, allyl (prop-2-enyl), and but-1-enyl.

[0012] As used herein, the term "C2-C6 alkynyl" refers to a straight or branched hydrocarbon chain radical composed solely of carbon and hydrogen atoms, containing at least one triple bond, having 2-6 carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of C3-C6 alkynyl include, but are not limited to, prop-1-ynyl and propargyl (prop-2-ynyl).

[0013] As used herein, the term "C1-C3 alkoxyC1-C3 alkyl-" refers to any of R b is C1-C3 alkyl, and R a is a C1-C3 alkylene group b -OR a - refers to the group.

[0014] As used herein, the term "halogenation reagent" refers to any chemical reagent capable of introducing a halogen atom into a target molecule by forming a carbon-halogen bond.

[0015] As used herein, the term "reaction medium" refers to any solvent or mixture of solvents that is inert under the reaction conditions. Those skilled in the art will appreciate that the reactants and reagents used in the processes of the present invention may also act as solvents.

[0016] As used herein, the term "organic carbonate" refers to any organic reaction medium that contains a carbonate ester functional group -OC(=O)-O- and may be linear or cyclic. Examples of organic carbonates include, but are not limited to, dimethyl carbonate (DMC), diethyl carbonate (DEC), ethylene carbonate (EC), propylene carbonate (PC), butylene carbonate (BC), and glycerol carbonate (GyC).

[0017] The process of the present invention can be carried out in separate process steps, where intermediate compounds can be isolated at each stage. Alternatively, the process can be carried out in a one-step procedure, where the intermediate compounds produced are not isolated. Thus, the process of the present invention can be carried out in a batch or continuous mode.

[0018] The following list is intended to provide a general description of the substituents X, X a , G and R 1 For any one of these substituents, any of the definitions given below may be combined with any of the definitions of any other substituents given below or elsewhere in this document.

[0019] X is a halogen. Preferably, X is chlorine, bromine or iodine. More preferably, X is chlorine or bromine. Most preferably, X is bromine.

[0020] G is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 1 , -C(O)-X a -R 1 and -S(O)2-R 1 Preferably, G is selected from the group consisting of hydrogen, -C(O)-R 1 , -C(O)-X a -R 1 and -S(O)2-R 1 More preferably, G is selected from the group consisting of hydrogen, -C(O)-R 1 and -C(O)-X a -R 1 Even more preferably, G is selected from the group consisting of hydrogen or -C(O)-R 1 Most preferably, G is -C(O)-R 1 It is.

[0021] X a is oxygen or sulfur. Preferably, X a is oxygen.

[0022] R 1 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl and 4-fluorophenyl. 1 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, and phenyl. More preferably, R 1 is selected from the group consisting of C1-C6 alkyl and C2-C6 alkenyl. Even more preferably, R 1 is C1-C6 alkyl.

[0023] The following Scheme 1 illustrates the reaction of the present invention in more detail: The definitions of the substituents are as defined herein.

[0024] Scheme 1: [ka] Step (a) Halogenation: The compound of formula (I) may be represented by the formula (II) [ka] in a suitable reaction medium containing a halogenating agent and an organic carbonate to give a compound of formula (I): [ka] wherein X is as defined herein. The compound can be prepared by obtaining a compound of formula (I).

[0025] Typically, the process described in step (a) is carried out with any halogenating reagent suitable for the preparation of halonorbornones. Preferably, the process described in step (a) is carried out with a halogenating reagent selected from the group consisting of bromine, chlorine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, pyridinium bromide tribromide, copper(II) bromide, sulfuryl chloride and trichloroisocyanuric acid. More preferably, the process described in step (a) is carried out with a halogenating reagent selected from the group consisting of bromine, chlorine, N-bromosuccinimide, N-chlorosuccinimide, pyridinium bromide tribromide, copper(II) bromide, sulfuryl chloride and trichloroisocyanuric acid. Even more preferably, the process described in step (a) is carried out with a halogenating reagent selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide and copper(II) bromide. Even more preferably, the process according to step (a) is carried out with a halogenating reagent selected from bromine or pyridinium bromide tribromide. Most preferably, the process according to step (a) is carried out with a halogenating reagent selected from bromine.

[0026] Typically, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate (or a mixture of organic carbonates). Preferably, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate and glycerol carbonate (and / or mixtures thereof). More preferably, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate and glycerol carbonate (and / or mixtures thereof). Even more preferably, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate and butylene carbonate (and / or mixtures thereof). Even more preferably, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (and / or mixtures thereof). In one embodiment, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate. In another embodiment, the process according to step (a) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is diethyl carbonate.

[0027] Typically, this step can be carried out at a temperature between -20°C and 150°C, preferably between 0°C and 100°C, more preferably between 20°C and 85°C, even more preferably between 60°C and 80°C.

[0028] A person skilled in the art will appreciate that compounds of formula (I) may exist as the following exo isomer (Ia) or endo isomer (Ib); [ka] It will be understood that the present invention includes processes for preparing all such isomers and mixtures thereof in all proportions.

[0029] Scheme 2: [ka] Step (b) Oxidation: The compound of formula (II) may be represented by the formula (III) [ka] with an oxidizing agent in a suitable reaction medium containing an organic carbonate to give a compound of formula (II).

[0030] Typically, the process described in step (b) is carried out with any oxidation reagent suitable for the preparation of norbornone, including, but not limited to, hypohalites such as sodium hypobromite (NaBrO), sodium hypochlorite (NaClO) and potassium hypochlorite (KClO), and halogenides such as sodium bromite (NaBrO2), sodium chlorite (NaClO2), and magnesium chlorite (Mg(ClO2)2) in the presence of a suitable catalyst.

[0031] Preferably, the process described in step (b) is carried out with an oxidizing reagent, wherein the oxidizing reagent is a hypohalite salt. More preferably, the process described in step (b) is carried out with an oxidizing reagent, wherein the oxidizing reagent is selected from the group consisting of sodium hypobromite (NaBrO), sodium hypochlorite (NaClO) and potassium hypochlorite (KClO). Most preferably, the process described in step (b) is carried out with an oxidizing reagent selected from sodium hypochlorite (NaClO).

[0032] Suitable catalysts that can be used in the process described in step (b) include, but are not limited to, Bronsted acids such as trifluoroacetic acid, acetic acid, propionic acid, hydrochloric acid and sulfuric acid; 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-acetamido-TEMPO, 4-carboxy-TEMPO, 4-amino-TEMPO, 4-phosphonoxy-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-hydroxy-TEMPO, 4-oxy-TEMPO, 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl ... Nitroxyl groups such as bamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl and 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxyl, 1-methyl-2-azaadamantane-N-oxyl, 2-azaadamantane-N-oxyl 9-azabicyclo[3.3.1]nonane-N-oxyl; and ruthenium-oxide reagents such as Ru / Al2O3, tetrapropylammonium perruthenate, tetrapropylammonium perruthenate / N-methylmorpholine-N-oxide, and RuCl2(PPh3)3 / TEMPO.

[0033] The amount of the catalyst is typically 0.05 to 50 mol % (based on the compound of formula (III)), preferably 0.1 to 30 mol %, more preferably 0.5 to 15 mol %.

[0034] Preferably, the process described in step (b) is carried out in a suitable reaction medium further comprising a Bronsted acid. More preferably, the process described in step (b) is carried out in a suitable reaction medium further comprising an acid selected from the group consisting of acetic acid, hydrochloric acid and sulfuric acid. Most preferably, the process described in step (b) is carried out in a suitable reaction medium further comprising sulfuric acid.

[0035] In a preferred embodiment, in the process described in step (b), the oxidation reagent is a hypohalite and the suitable reaction medium further comprises a Bronsted acid. Preferably, in the process described in step (b), the oxidation reagent is selected from the group consisting of sodium hypobromite (NaBrO), sodium hypochlorite (NaClO) and potassium hypochlorite (KClO), and the reaction medium further comprises an acid selected from the group consisting of acetic acid, hydrochloric acid and sulfuric acid. Most preferably, in the process described in step (b), the oxidation reagent is sodium hypochlorite (NaClO) and the suitable reaction medium further comprises sulfuric acid.

[0036] Typically, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate (or a mixture of organic carbonates). Preferably, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate and glycerol carbonate (and / or mixtures thereof). More preferably, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate and glycerol carbonate (and / or mixtures thereof). Even more preferably, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate and butylene carbonate (and / or mixtures thereof). Even more preferably, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (and / or mixtures thereof). In one embodiment, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate. In another embodiment, the process according to step (b) is carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is diethyl carbonate.

[0037] In a preferred embodiment, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate. Preferably, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate and glycerol carbonate (and / or mixtures thereof). More preferably, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate and glycerol carbonate (and / or mixtures thereof). Even more preferably, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate and butylene carbonate (and / or mixtures thereof). Even more preferably, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (and / or mixtures thereof). In one embodiment, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate. In another embodiment, both processes described in steps (a) and (b) are carried out in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is diethyl carbonate.

[0038] Typically, this step can be carried out at a temperature between -20°C and 120°C, preferably between -10°C and 80°C, more preferably between 0°C and 50°C, even more preferably between 10°C and 30°C.

[0039] Those skilled in the art will appreciate that compounds of formula (III) may exist as the following exo isomer (IIIa) or endo isomer (IIIb); [ka] It will be understood that the present invention encompasses the process for the oxidation of all such isomers and mixtures thereof in all proportions to the corresponding compound (II).

[0040] Scheme 3: [ka] Step (c) Hydrolysis: The compound of formula (III) may be represented by the formula (IV) [ka] It can be prepared by hydrolysis of the compound of formula (I).

[0041] The hydrolysis can be carried out using methods known to those skilled in the art. The hydrolysis is typically carried out using suitable conditions including, but not limited to, basic conditions (such as aqueous sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or acidic conditions (such as aqueous sulfuric acid). Preferably, the process described in step (c) is carried out under basic conditions. More preferably, the process described in step (c) is carried out with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Even more preferably, the process described in step (c) is carried out with sodium hydroxide.

[0042] Typically, the process described in step (c) is carried out in the absence of an additional solvent (one skilled in the art would understand that the compound of formula (IV) may act as a solvent) or in the absence of an additional solvent such as, but not limited to, water, acetic acid, propionic acid, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, 3-methyl-1-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethan, ethyl ether ... Preferably, the process according to step (c) is carried out in the presence of a solvent or mixture of solvents such as dimethyl carbonate, diethoxymethane, dipropoxymethane, 1,3-dioxolane, ethyl acetate, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate, glycerol carbonate, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or a derivative thereof, such as 1,4-dicyanobenzene), 1,4-dioxane or sulfolane. Preferably, the process according to step (c) is carried out in the absence of an additional solvent or in the presence of a solvent or mixture of solvents selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, dimethyl carbonate, diethyl carbonate, acetonitrile, tetrahydrofuran and methyltetrahydrofuran. Preferably, the process described in step (c) is carried out in the absence of an additional solvent or in the presence of a solvent or mixture of solvents selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, tetrahydrofuran and methyltetrahydrofuran.

[0043] One skilled in the art will appreciate that the choice of solvent for the process described in step (c) will depend on whether basic or acidic conditions are used.

[0044] Typically, this step can be carried out at a temperature between -20°C and 120°C, preferably between -10°C and 80°C, more preferably between 0°C and 50°C, even more preferably between 10°C and 30°C.

[0045] A person skilled in the art will appreciate that compounds of formula (IV) may exist as the following exo isomer (IVa) or endo isomer (IVb); [ka] It will be understood that the present invention encompasses the process for hydrolyzing all such isomers and mixtures thereof in all proportions to the corresponding compound (III).

[0046] Scheme 4: [ka] Step (d) Oxyformylation: The compound of formula (IV) may be represented by the formula (V) [ka] can be prepared by oxyformylation of the compound of formula:

[0047] Formylation can be carried out using a suitable formylating reagent, such as formic acid.

[0048] Typically, the process described in step (d) is carried out in the absence of an additional solvent (a person skilled in the art will appreciate that the compound of formula (V) or the formylation reagent may act as the solvent) or in the presence of a solvent or mixture of solvents such as, but not limited to, water, acetic acid, propionic acid, methanol, ethanol, propanol, isopropanol, butanol, 3-methyl-1-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, cyclopentyl methyl ether, ethyl acetate, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, diphenyl carbonate, glycerol carbonate, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or a derivative thereof, such as 1,4-dicyanobenzene), 1,4-dioxane or sulfolane. Preferably, the process described in step (d) is carried out in the absence of an additional solvent or in the presence of a solvent or mixture of solvents selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, butanol, dimethyl carbonate, diethyl carbonate, acetonitrile, tetrahydrofuran and methyltetrahydrofuran.

[0049] Typically, this step can be carried out at a temperature between 50°C and 120°C, preferably between 70°C and 100°C.

[0050] Those skilled in the art will appreciate that compounds of formula (IV) can exist as exo isomers (IVa) or endo isomers (IVb). The present invention encompasses processes for the preparation of all such isomers and mixtures thereof in all proportions from compound (V).

[0051] In a preferred embodiment of the process described in step (d), the excess of formylating reagent, preferably formic acid, is distilled off upon completion of the reaction.

[0052] Those skilled in the art will appreciate that the temperature of the process of the present invention can vary in each of steps (a), (b), (c) and (d). Furthermore, this variability in temperature may also reflect the choice of solvent used. Similarly, those skilled in the art will also appreciate that the pressure of the process of the present invention can vary in each of steps (a), (b), (c) and (d), depending on the choice of solvent and temperature used. Typically, the process of the present invention is carried out at a pressure of 1-20 bar.

[0053] Preferably, the process of the present invention is carried out under an inert atmosphere such as nitrogen or argon.

[0054] Those skilled in the art will appreciate that process steps (a), (b) and (c) can be carried out in separate process steps, where intermediate compounds can be isolated at each stage. Alternatively, process steps (a), (b) and (c) can be carried out in a telescoping manner, where intermediate compounds produced are not isolated. Thus, the process of the present invention can be carried out in a batch, semi-batch or continuous mode.

[0055] Those skilled in the art will appreciate that steps (a), (b), (c) and (d) can equally be represented in a single scheme, see Scheme 5 or Scheme 6 below. Scheme 5: [ka] Scheme 6: [ka]

[0056] In a preferred embodiment of the present invention, the compound of formula (I) [ka] (wherein X is bromine). A process for preparing a compound of formula (I) is provided, the process comprising: Formula (II) [ka] with a halogenating reagent selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide and copper (II) bromide (preferably bromine or pyridinium bromide tribromide, most preferably bromine) in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate) to obtain a compound of formula (I).

[0057] In a preferred embodiment of the present invention, the compound of formula (I) [ka] (wherein X is bromine). A process for preparing a compound of formula (I) is provided, the process comprising: (i) Formula (III) [ka] with an oxidation reagent, where the oxidation reagent is a hypohalite (preferably sodium hypobromite (NaBrO), sodium hypochlorite (NaClO) or potassium hypochlorite (KClO), more preferably sodium hypochlorite (NaClO)), in a suitable reaction medium comprising an organic carbonate, where the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate), and the suitable reaction medium further comprises a Brønsted acid (preferably acetic acid, hydrochloric acid or sulfuric acid, more preferably sulfuric acid), to produce a compound of formula (II): [ka] obtaining a compound of formula (I); (ii) reacting the compound of formula (II) with a halogenating reagent selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide and copper(II) bromide (preferably bromine or pyridinium bromide tribromide, most preferably bromine) in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate) to obtain the compound of formula (I). Includes.

[0058] In a further preferred embodiment of the present invention, [ka] (wherein X is bromine). A process for preparing a compound of formula (I) is provided, the process comprising: (i) Formula (IV) [ka] to hydrolyze a compound of formula (III) [ka] under basic conditions (preferably with aqueous sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, more preferably with aqueous sodium hydroxide); (ii) reacting the compound of formula (III) with an oxidation reagent, wherein the oxidation reagent is a hypohalite (preferably sodium hypobromite (NaBrO), sodium hypochlorite (NaClO) or potassium hypochlorite (KClO), more preferably sodium hypochlorite (NaClO)), in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate), and the suitable reaction medium further comprises a Brønsted acid (preferably acetic acid, hydrochloric acid or sulfuric acid, more preferably sulfuric acid), to produce a compound of formula (II): [ka] obtaining a compound of formula (I); (iii) reacting the compound of formula (II) with a halogenating reagent selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide and copper(II) bromide (preferably bromine or pyridinium bromide tribromide, most preferably bromine) in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate) to obtain the compound of formula (I). Includes.

[0059] In a further preferred embodiment of the present invention, [ka] (wherein X is bromine). A process for preparing a compound of formula (I) is provided, the process comprising: (i) Formula (V) [ka] with formic acid to give a compound of formula (IV) [ka] obtaining a compound of formula (I); (ii) hydrolyzing the compound of formula (IV) to obtain a compound of formula (III) [ka] under basic conditions (preferably with sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, more preferably with sodium hydroxide); (iii) reacting the compound of formula (III) with an oxidation reagent, wherein the oxidation reagent is a hypohalite (preferably sodium hypobromite (NaBrO), sodium hypochlorite (NaClO) or potassium hypochlorite (KClO), more preferably sodium hypochlorite (NaClO)), in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate), and the suitable reaction medium further comprises a Brønsted acid (preferably acetic acid, hydrochloric acid or sulfuric acid, more preferably sulfuric acid), to produce a compound of formula (II): [ka] obtaining a compound of formula (I); (iv) reacting the compound of formula (II) with a halogenating reagent selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide and copper(II) bromide (preferably bromine or pyridinium bromide tribromide, most preferably bromine) in a suitable reaction medium comprising an organic carbonate, wherein the organic carbonate is dimethyl carbonate or diethyl carbonate (preferably dimethyl carbonate) to obtain the compound of formula (I). Includes.

[0060] In a further embodiment of the invention, the process comprises reacting a compound of formula (I) with a compound of formula (VI) [ka] (In the formula, G is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 1 , -C(O)-X a -R 1 and -S(O)2-R 1 selected from the group consisting of; X a is oxygen or sulfur; and R 1 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl, and 4-fluorophenyl. The method further comprises the step of converting the compound of formula (I) into

[0061] In a preferred embodiment of the invention, the process comprises reacting a compound of formula (I) with a compound of formula (VI) [ka] (In the formula, G is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, C1-C3 alkyl-, -C(O)-R 1 , -C(O)-X a -R 1 and -S(O)2-R 1 selected from the group consisting of; X a is oxygen or sulfur; and R 1 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, phenyl, and 4-fluorophenyl. wherein the process further comprises the steps described on page 54 of WO 2015 / 197468.

[0062] Preferably, the process comprises reacting a compound of formula (I) with a compound of formula (VI) [ka] (Wherein, G is hydrogen or -C(O)-R 1 (Preferably, G is -C(O)-R 1 ) and; X a is oxygen; and R 1 is C1-C6 alkyl and C2-C6 alkenyl (preferably, R 1 is C1-C6 alkyl) wherein the process further comprises the steps described on page 54 of WO 2015 / 197468. EXAMPLES

[0063] The following examples further illustrate the invention but do not limit it. Those skilled in the art will immediately recognize appropriate variations from these procedures, both with respect to reactants and reaction conditions and techniques.

[0064] The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triplet triplet, q = quartet, quin = quintet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, T i = internal temperature, MH + = molecular weight of molecular cation, M = molar amount, Q 1 H NMR=quantitative 1 H nuclear magnetic resonance, RT = room temperature, UFLC = ultra-performance liquid chromatography.

[0065] 1 1 H NMR spectra were recorded at 400 MHz unless otherwise noted and chemical shifts are reported in ppm.

[0066] Some chemical yields were accurately calculated using quantitative 1H NMR and 1,3,5-trimethoxybenzene or caffeine as internal standards.

[0067] The conversion was followed by gas chromatography with an Agilent GC Model 6850 analysis using an Agilent 19091U-211 column (DB-1701 spec). The instrument detector FID was operated with hydrogen at 300° C. The method was 40° C., hold for 2 min, 20° C. / min to 300° C., hold for 2 min at 300° C. for a total time of 19 min.

[0068] Example 1 - Preparation of norbornane-2-yl formate from norbornene [ka] To a 1.5 L double mantle reactor equipped with an overhead stirrer, reflux condenser, and heated dropping funnel was added technical formic acid (88 wt%) (577 g, 11.0 mol, 3.5 equiv.) and T int The temperature was set at 90 °C. Once at temperature, molten norbornene (300 g, 3.1 mol, 1.0 equiv) was added dropwise over 2 h. After addition, the reaction was stirred at this temperature for an additional 2 h and the excess formic acid was distilled off under reduced pressure to give the product (386 g, 95% purity) as a colorless to pale yellow oil, corresponding to an isolated yield of 83%. The product contained 3% norbornan-2-ol, the target product in the next step.

[0069] The distillate, which contains about 10% by weight of product along with the recovered formic acid, can be reused in subsequent batches.Furthermore, the amount of product in the distillate can be reduced by using a distillation column.

[0070] Product purity was quantitatively determined using 1,3,5-trimethoxybenzene as an internal standard. 1 Determined using 1 H NMR. 1 H,NMR(400MHz,CDCl3)δ ppm:7.98(s,1H),4.71(m,1H),2.33(m,2H),1.80-1.70(m,1H),1.60-1.40(m,4H),1.20-0.95(m,3H).

[0071] Example 2 - Preparation of norbornan-2-ol from norbornan-2-yl formate [ka] To a 1 L double mantle reactor equipped with an overhead stirrer, reflux condenser, internal pH probe, and dropping funnel was added crude norbornan-2-yl formate (110 g, 0.8 mol, 1.0 equiv.). To this mixture was added 10% aqueous NaOH (324 g, 0.88 mol, 1.1 equiv.) in a 10% ethanol solution. int= 25°C over 2 hours. Cooling is required to maintain this temperature, however, the reaction proceeds equally well at higher temperatures and cooling can be omitted. If the reaction mass becomes difficult to stir, additional amounts of water can be added. After complete addition, the reaction mixture is further stirred for 1 hour at 25°C. Then 10% aqueous HCl (15.0 g, 0.04 mol, 0.05 eq) is added dropwise to set pH = 8. Once pH is reached, 264 g dimethyl carbonate is added in one portion. The phases are separated and the organic layer is washed with 1 x 50 g water.

[0072] The product is obtained as approximately a 20% by weight solution in DMC (359 g, 86% isolated yield).

[0073] For analytical purposes, a small sample is concentrated under reduced pressure. The purity of the product is quantitatively determined using 1,3,5-trimethoxybenzene as an internal standard. 1 Using 1 H NMR it was determined to be 92%. 1 H,NMR(400MHz,CDCl3)δ ppm:3.75(m,1H),2.25(m,1H),2.12(m,1H),1.66(m,2H),1.56(m,1H),1.50-1.35(m,2H),1.29(m,1H),1.12(m,1H),1.95-0.95(m,2H). Note: The reaction can be carried out by adding norbornane-2-yl formate to 10% aqueous NaOH.

[0074] Example 3 - Preparation of norbornan-2-one from norbornan-2-ol [ka] To a 1.5 L double mantle reactor equipped with an overhead stirrer, reflux condenser, and dropping funnel was added a solution of 23 wt% (in DMC) norbornol (350 g, 0.73 mol, 1.0 equiv.) followed by 10% aqueous sulfuric acid (139 g, 0.14 mol, 0.2 equiv.). To this mixture was added approximately 10 wt% aqueous NaOCl (553 g, 0.77 mol, 1.05 equiv.) in T int = 25°C over 2 hours. Cooling is required to maintain the reaction temperature. After completion, the reaction is further stirred at 25°C for 1 hour. The phases are then separated and the organic layer is used directly in the subsequent step.

[0075] The product content was quantitatively determined using 1,3,5-trimethoxybenzene as an internal standard. 1 26 wt % (solution in DMC) determined using H NMR. This product was directly subjected to subsequent bromination.

[0076] Typical product purity for this method is quantitative using 1,3,5-trimethoxybenzene as an internal standard. 1 Using H NMR, it was determined to be in the range of 90%-95%. 1 H,NMR(400MHz,CDCl3)δ ppm:2.65(m,1H),2.59(m,1H),2.05(m,1H),1.85-1.70(m,4H),1.58-1.38(m,3H).

[0077] If necessary, a higher concentration of aqueous NaOCl solution can be used to improve the process volumetric yield.

[0078] Example 4 - Preparation of 3-bromonorbornan-2-one from norbornan-2-one [ka] A 0.5 L double mantle reactor equipped with an overhead stirrer, reflux condenser, off-gas scrubber, and dropping funnel was charged with a 26 wt % (in DMC) solution of norbornan-2-one (150 g, 0.35 mol, 1.00 equiv.) and T int The temperature is set to 75°C. Neat bromine (57 g, 0.35 mol, 1.00 equiv.) is then added dropwise over 2 h. Gas evolution is observable with each drop of bromine added. Conversion is monitored by GC. Additional bromine (1.6 g, 0.01 mol, 0.03 equiv.) is added to ensure complete conversion of unreacted starting material. After bromine addition is complete, the reaction is further stirred at 75°C for 1 h, then cooled to 25°C and purged with argon to remove residual HBr. The solution is washed with 1x20 g of 10% aqueous NaHSO3, the phases are separated and the organic solvent is removed under reduced pressure to give the product as a brown liquid (68 g, 89% isolated yield). Product purity is quantitatively determined using 1,3,5-trimethoxybenzene as an internal standard. 1 Using 1 H NMR it was determined to be 88%.

[0079] The crude product was then int Further purification by overhead distillation at =80°C and 2 mbar pressure affords the target material as a colourless oil. 1 H,NMR(400MHz,CDCl3)δ ppm:3.83(d,J=3.2Hz,1H),2.79(m,1H),2.72(m,1H),2.29(m,1H),1.98(m,1H),1.80(m,1H),1.65-1.40(m,3H).

[0080] 1 From H NMR coupling constant analysis and dihedral angle estimation, the product is mainly an exo isomer (compared to an endo isomer, compound of formula (Ib-I)), which has a bromine atom located at the equatorial position, as shown in the following formula (Ia-I): [ka] It has been shown that the compound can be obtained as follows:

[0081] The general reaction conditions for the solvent comparisons given in Table 1 below are based on the process described in Example 4.

[0082] All experiments were carried out on a scale of 2.5-10.0 g norbornan-2-one.

[0083] A solution of norbornan-2-one (1.00 equiv.) in a solvent (as listed in the table below) is heated to Ti=75-80° C., at which point bromine (1.05-1.10 equiv.) is added over 1-2 h. The reaction is stirred for an additional hour and then a sample is taken for GC analysis.

[0084] [Table 1]

[0085] The analysis was carried out by gas chromatography, but in all cases only three signals were analyzed - the starting material, norbornan-2-one (SM), 3-bromonorbornan-2-one (product) and the perbrominated by-product, 3,3-dibromonorbornan-2-one, formula (VII). [ka] Compounds (by-products).

[0086] Although not included in Table 1, reactions in alkane solvents (methylcyclohexane, heptane, and cyclohexane) show more impurities including bromination of the reaction solvent.

[0087] In Table 1, reactivity is expressed as % product / (% product+% starting material)×100.

[0088] In Table 1, selectivity is expressed as % product / (% product+% by-product)×100.

[0089] In Table 1, selectivity is linked to reactivity with a comparative S / R (selectivity / reactivity) parameter expressed as % product / (% starting material+% by-product).

[0090] The above results demonstrate that the organic carbonate solvents used in the process of the present invention achieve high selectivity (reduction in by-products) and conversion to the desired products.

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, X is a halogen.) A method for preparing the compound: Formula (II) 【Chemistry 2】 A method comprising the step of reacting a compound in a suitable reaction medium containing a halogenating reagent and an organic carbonate to obtain a compound of formula (I).

2. The method according to claim 1, wherein X is chlorine or bromine.

3. The method according to claim 1 or claim 2, wherein X is bromine.

4. The method according to claim 1, wherein the halogenating reagent is selected from the group consisting of bromine, chlorine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, pyridinium bromide tripromide, copper(II) bromide, sulfuryl chloride, and trichloroisocyanuric acid.

5. The method according to claim 3, wherein the halogenating reagent is selected from the group consisting of bromine, N-bromosuccinimide, pyridinium bromide tribromide, and copper(II) bromide.

6. The method according to claim 3, wherein the halogenating reagent is bromine.

7. The compound of formula (II) is of formula (III) 【Transformation 3】 The method according to claim 1 or 2, prepared by a reaction of the compound and an oxidizing reagent in a suitable reaction medium containing an organic carbonate.

8. The method according to claim 7, wherein the oxidizing reagent is sodium hypochlorite.

9. The method according to claim 8, wherein the reaction medium further comprises sulfuric acid.

10. The method according to claim 1 or 2, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, butylene carbonate, and glycerol carbonate.

11. The method according to claim 1 or 2, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate and diethyl carbonate.

12. The method according to claim 1 or 2, wherein the intermediate compound of formula (II) and / or (III) is not isolated.

13. The compound of formula (III) is: (i) Equation (IV) 【Chemistry 4】 The compound is reacted with formic acid to produce formula (V). 【Transformation 5】 Steps to obtain the compound; and (ii) A step of hydrolyzing the compound of formula (V) to the compound of formula (III). The method according to claim 7, which is prepared by...

14. The method according to claim 13, wherein the hydrolysis step is carried out with sodium hydroxide.

15. The above method involves compound (I) of formula (VI) 【Transformation 6】 (wherein, G is hydrogen, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 3 alkoxy C 1 ~C 3 alkyl-, -C(O)-R 1 , -C(O)-X a -R 1 and -S(O) 2 -R 1 is selected from the group consisting of; X a is oxygen or sulfur; and R 1 C 1 ~C 6 Alkyl, C 2 ~C 6 (Selected from the group consisting of alkenyls, phenyls, and 4-fluorophenyls) The method according to claim 1 or 2, further comprising the step of converting to a compound.

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