Preparation process for halogenated dihydroxybenzene compounds

Abstract

The present disclosure relates to the preparation of halogenated dihydroxybenzene compounds with high yield, selectivity, and purity. These compounds are useful, inter alia, for the synthesis of cannabinoids and cannabinoid-like compounds.

Description

[Technical Field]

[0001] The subject matter described herein relates to the preparation of halogenated dihydroxybenzenes by novel synthetic routes to improve purity and yield and reduce the cost and environmental impact of preparing these useful compounds. [Background technology]

[0002] Dihydroxybenzene compounds are a type of compound known as phenols. These compounds are ubiquitous in nature and modern chemicals. Many are useful both on their own and as building blocks for other compounds. For example, one such compound is olivetol. Olivetol (also known as 5-pentylresorcinol or 5-pentyl-1,3-benzenediol, 5-n-amylresorcinol, and 3,5-dihydroxyamylbenzene) is a naturally occurring phenolic compound.

[0003] While these compounds are useful, improved syntheses utilizing them are always needed. Therefore, derivatives of dihydroxybenzenes, which introduce new chemical handles, are one of the most useful types of compounds. However, the presence of a hydroxy group on the benzene ring can lead to undesired side reactions, necessitating the use of protecting groups.

[0004] Furthermore, reported syntheses of some desirable derivatives require expensive and / or toxic reagents and may produce by-products. Thus, the reactions and the by-products they produce can be cost prohibitive. Furthermore, it would be desirable to reduce the environmental burden created by many of these reactions.

[0005] Therefore, there is a need for efficient, scalable, low-cost, and environmentally friendly synthetic methods for preparing halogenated alkyl-substituted dihydroxybenzenes. The subject matter described herein addresses these unmet needs. Summary of the Invention

[0006] In certain aspects, the subject matter described herein is a method for preparing a compound of formula I, comprising: [ka] During the ceremony, R1 is 、 Branched or linear C 1~12 is alkyl, R2 and R3 each independently represent a halogen, -C(O)OC 1~6 and hydrogen, and at least one of R2 and R3 is halogen; Structure: (wherein, R 1’ is a branched or linear C 1~12 alkyl, and R 2’ and R 3’ are hydrogen and -C(O)OC, respectively. 1~6 independently selected from the group consisting of alkyl and halogen; 2’ and R 3’ wherein at least one of is hydrogen, [ka] HX, where X is a halide, in the presence of an organic sulfoxide; The contacting is at a temperature of about 0°C to about 100°C, A compound of formula I is prepared.

[0007] In certain aspects, the subject matter described herein relates to a method of preparing a compound of formula I: [ka] During the ceremony, R1 is 、 Branched or linear C 1~12 is alkyl, R2 and R3 are each a halogen; The method is: structure: [ka] selectively halogenating a compound of formula I' having the formula: contacting the mixture with HX, where X is a halide, in the presence of an organic sulfoxide; In the formula, R 1’ is a branched or linear C 1~12 is alkyl, R 2’ and R 3’ are hydrogen and The contacting is at a temperature of about 0°C to about 100°C, A compound of formula I is prepared.

[0008] These and other aspects are described fully herein. [Brief explanation of the drawings]

[0009] [Figure 1] shows the structures of some compounds produced in the process for preparing 4,6-dibromo-olivetol ("DBO"). [Figure 2] HPLC trace of DBO is shown, showing the levels of specific impurities. (HPLC method: Column: waters XBridge Shield RP18 3.5 μm, 3.0 x 150 mm, PN: 186003041, Column temperature 35 °C, MPA: 0.05% (v / v) acetic acid / acetonitrile 95 / 5 (v / v) in water, MPB: methanol, UV wavelength 225 nm, flow rate 0.7 mL / min. MPB gradient: 0 min MPA 40%, 19 min MPA 5%, 21 min MPA 5%, 21.1 min MPA 40%, 25 min MPA 40%) [Figure 3A-3B] Data are presented showing that temperature and reactant species have a dominant effect on the formation of 4,6-DBO (product) measured at the end of 6 hours under reaction conditions. [Figure 4A-4B] 1 presents data showing that the volume of reactant species and ethyl acetate have a dominant effect on the formation of 4-MBO measured at the end of 6 hours under reaction conditions. [Figure 5A-5B] 1 presents data showing that the volume of reacting species and ethyl acetate have a dominant effect on the formation of 2,4-DBO measured at the end of 6 hours under reaction conditions. [Figures 6A-6B] 1 presents data showing that temperature, reactants, and volume of ethyl acetate have dominant effects on the formation of 2,4,6-TBO measured at the end of 6 hours under reaction conditions. [Figure 7] HPLC trace of DBO is shown, showing the levels of specific impurities. (HPLC method: Column: waters XBridge Shield RP18 3.5 μm, 3.0 x 150 mm, PN: 186003041, Column temperature 35 °C, MPA: 0.05% (v / v) acetic acid / acetonitrile 95 / 5 (v / v) in water, MPB: methanol, UV wavelength 225 nm, flow rate 0.7 mL / min. MPB gradient: 0 min MPA 40%, 19 min MPA 5%, 21 min MPA 5%, 21.1 min MPA 40%, 25 min MPA 40%) [Figure 8] GC analysis of the product of Example 13 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0010] Disclosed herein is an efficient synthetic route for producing halogenated dihydroxybenzenes with improved purity, efficiency, and safety, reduced volume, low energy costs, and reduced environmental impact. It has now been discovered that the desired halogenated dihydroxybenzenes can be prepared using relatively mild conditions, without the need for cryogenic conditions and the equipment required for such conditions, without the need for special handling and equipment associated with the use of corrosive materials such as diatomic bromine (Br), and / or without toxic solvents such as dichloromethane. Also important for large-scale production is that only one vessel is required for the entire reaction, whereas known methods for producing halogenated olivetol may require two vessels.

[0011] In particular, known synthetic routes for producing halogenated olivetol, such as dibromoolivetol (DBO), generally involve reacting olivetol with diatomic bromine in a solvent such as dichloromethane at −15° C. (See Scheme 1). [ka] Diatomic bromine is acutely toxic and highly corrosive, and requires special care in handling. It also requires low temperatures (-15°C) for the reaction, is unstable, and often undergoes bromine scrambling, resulting in a large volume (V max 48) or more are required, and precise dosages are required, which often exceed the capabilities of existing standard equipment. To overcome these challenges, particularly for producing DBO, and to reduce production costs and environmental impact, the new process described here was developed (see Schemes 2, 3, and 4). Other methods utilizing bromodimethylsulfonium have been shown to produce halogenated arene species. (Majetich G., et al., JOC, 62, 4321-4326 (1997); Song S., et al., Org. Lett. 17, 2886-2889 (2015)). However, among the many scaffolds disclosed, alkylated dihydroxybenzenes are particularly rare.

[0012] The reaction conditions of this disclosure use aqueous HX as the halide source in a suitable co-solvent / oxidation system, such as DMSO and ethyl acetate. The materials and reaction conditions are non-corrosive and safe to handle. Other advantages include increased reaction and workup temperatures, eliminating the need for sub-zero temperatures. Additional benefits include the elimination of dichloromethane, a known carcinogen, from the reaction. Advantageously, the overall yield and impurity profile are significantly improved. Notably, unlike other reactions, there is tunable control over the framework of Formula I, which provides selective halogenation. Another advantage is the substantial reduction or elimination of the amount of bromine scrambling observed in reactions of the type shown in Scheme 1.

[0013] It was not known whether this process could selectively halogenate the skeleton of Formula I in the desired manner. The numbered positions are as follows: [ka] In certain embodiments, the desired product of the methods described herein is a 4,6-dihalogenated compound. The methods described herein have been shown to produce a high percentage of the desired product relative to other halogenated impurities. The structures of certain impurities are as follows: 4-monobromo-olivetol (4-MBO), 2,4-dibromo-olivetol (2,4-DBO), and 2,4,6-tribromo-olivetol (TBO). Another impurity that may be present is 2-MBO. Thus, in certain embodiments, the 2-position of Formula I can be substituted with a halogen as a minor by-product of the synthesis, e.g., a relative formation of 20% or less. The structures of some of these compounds are shown in Figure 1.

[0014] Advantageously, the methods described herein provide for the large-scale preparation of desired compounds of Formula I in high purity, e.g., >99A%, and in excellent yield, e.g., in certain embodiments, greater than about 90%, without the need for the use of corrosive diatomic bromides and toxic dichloromethane.

[0015] The subject matter disclosed herein will be described more fully hereinafter. However, many variations and other embodiments of the subject matter disclosed herein will occur to those skilled in the art to which the subject matter relates having the benefit of the teachings presented in the preceding description. Therefore, it should be understood that the subject matter disclosed herein should not be limited to the specific embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all alternatives, modifications, and equivalents. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application, including, but not limited to, defined terms, term usage, described techniques, etc., this application shall prevail. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0016] I. Definition As used herein, the term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 12 carbon atoms (i.e., C1 to C6). 12and having 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), 1 to 5 carbon atoms (i.e., C1-C5 alkyl), or 3 to 5 carbon atoms (i.e., C3-C5 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0017] As used herein, the term "halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo. The term "halide" refers to a halogen or halo in a binary compound with hydrogen.

[0018] As used herein, C 1~6 Alkyl esters are those where the moiety is attached to the phenyl ring at the carbonyl -C(O)OC 1~6 The alkyl group may be represented as "alkyl."

[0019] As used herein, the term "contacting" refers to bringing two or more reagents into contact with one another. Contacting may or may not be facilitated by mixing, stirring, agitation, etc.

[0020] As used herein, the term "selective halogenation" refers to halogenation at specific positions on the aryl ring, e.g., the 4' and 6-positions, such that the yield and purity of the 4-,6-dihalogen compound of Formula I is desired, as disclosed elsewhere herein.

[0021] In structures shown herein where the stereochemistry of a particular chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the invention.

[0022] Additional definitions may be provided herein.

[0023] II.Synthesis method In one aspect, the subject matter described herein is a method for preparing a compound of formula I, comprising: [ka] During the ceremony, R 1は、 Branched or linear C 1~12 is alkyl, R2 and R3 each independently represent a halogen, -C(O)OC 1~6 and hydrogen, and at least one of R2 and R3 is halogen; structure: [ka] (In the formula, R 1’ is a branched or linear C 1~12 alkyl, and R 2’ and R 3’ are hydrogen and -C(O)OC, respectively. 1-6 independently selected from the group consisting of alkyl and halogen; 2’ and R 3’ wherein at least one of is hydrogen, with HX (wherein X is a halide) in the presence of an organic material; The contacting is at a temperature of about 0°C to about 100°C, A compound of formula I is prepared.

[0024] In certain embodiments, the halogen is selected from the group consisting of Br, Cl, F, and I. In certain embodiments, the halogen is selected from the group consisting of Br and Cl. In certain embodiments, the halogen is Br.

[0025] In certain embodiments, HX is selected from the group consisting of HBr, HCl, HF, and HI. In certain embodiments, HX is selected from the group consisting of HBr and HCl. In certain embodiments, HX is HBr. In certain embodiments, HX is an aqueous solution. In certain embodiments, HX is a 10% to 90% aqueous solution. In certain embodiments, HX is a 20% to 80% aqueous solution. In certain embodiments, HX is a 30% to 70% aqueous solution. In certain embodiments, HX is a 40% to 60% aqueous solution. In certain embodiments, HX is a 45% to 55% aqueous solution. In certain embodiments, HX is a 46% to 50% aqueous solution, e.g., a 48% HBr aqueous solution.

[0026] In certain embodiments, HX is present in an amount of about 1.5 to 3.0 molar equivalents. In certain embodiments, HX is present in an amount of about 2.0 to 3.0 molar equivalents. In certain embodiments, HX is present in an amount of about 1.8 to 2.5 molar equivalents. In certain embodiments, HX is present in an amount of about 2.0 to 2.3 molar equivalents. In certain embodiments, HX is present in an amount of about 1.9 molar equivalents, 2.0 molar equivalents, 2.1 molar equivalents, 2.2 molar equivalents, or 2.3 molar equivalents.

[0027] In certain embodiments, R is a linear or branched or straight chain C alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl (including isomers of each). 1~12In certain embodiments, R is a branched or straight chain C alkyl selected from the group consisting of methyl, ethyl, propyl, pentyl, and hexyl (including isomers of each). 1~12 In certain embodiments, R is a straight-chain C alkyl selected from the group consisting of propyl and pentyl. 1~12 In certain embodiments, R is a branched C alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 1~12 It is alkyl.

[0028] In certain embodiments, R 1’ is a linear, branched or straight-chain C alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl (including their respective isomers). 1~12 In certain embodiments, R 1’ is a branched or straight chain C selected from the group consisting of methyl, ethyl, propyl, pentyl, and hexyl (including their isomers). 1~12 In certain embodiments, R 1’ is a linear C alkyl group selected from the group consisting of propyl and pentyl 1~12 In certain embodiments, R 1’ is a branched chain C having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms 1~12 Those skilled in the art will recognize the corresponding nature of the R and R' groups in the starting materials and products of the reaction.

[0029] In all embodiments, R 2’ and R 3’ At least one of R is hydrogen. 2’ and R 3’ The other is hydrogen, -C(O)OC 1~6In certain embodiments, the halogen is selected from the group consisting of an acid ester such as an alkyl, and a halogen. In certain embodiments, the halogen is bromine. In certain embodiments, the halogen is -C(O)OC 1-6 In alkyl, C 1-6 Alkyl is methyl, ethyl, propyl, or butyl. In certain embodiments, C 1~6 Alkyl is methyl, i.e., -C(O)O-Me, or ethyl, i.e., -C(O)O-Et.

[0030] In certain embodiments, the compound of Formula I' is dissolved in a solvent before contacting the compound of Formula I' with HX in the presence of an organic sulfoxide such as DMSO. In certain embodiments, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, acetone, t-butyl methyl ether, ethanol, dichloromethane, n-heptane, toluene, 2-Me-THF, and isopropanol. In certain embodiments, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, and acetone. In certain embodiments, the solvent is ethyl acetate.

[0031] The volume of solvent can be adjusted. As described elsewhere herein, the amount of solvent can affect the formation of the desired compound of Formula I. In certain embodiments, the volume of solvent can be about 5 volumes, 6 volumes, 7 volumes, 8 volumes, 9 volumes, 10 volumes, 11 volumes, 12 volumes, 13 volumes, 14 volumes, 15 volumes, 16 volumes, 17 volumes, 18 volumes, 19 volumes, 20 volumes, 21 volumes, 22 volumes, 23 volumes, 24 volumes, 25 volumes, or more. In certain embodiments, the solvent is present in a range of about 5 volumes to about 25 volumes, or about 9 volumes to about 17 volumes, or about 9.7 volumes to about 16.1 volumes. In certain embodiments, the solvent is ethyl acetate in an amount of at least 15 volumes.

[0032] Without being bound by theory, an organic sulfoxide such as DMSO may act as an oxidizing agent. When performing selective halogenation, the amount of organic sulfoxide such as DMSO may vary. In certain embodiments, the organic sulfoxide such as DMSO is present in an amount of about 1.5 to 5.0 molar equivalents. In certain embodiments, the organic sulfoxide such as DMSO is present in an amount of about 1.8 to 4.5 molar equivalents. In certain embodiments, the organic sulfoxide such as DMSO is present in an amount of about 2.0 to 3.0 molar equivalents. In certain embodiments, the organic sulfoxide such as DMSO is present in an amount of about 1.9 molar equivalents, 2.0 molar equivalents, 2.1 molar equivalents, or 2.2 molar equivalents. The organic sulfoxide may be one known in the art and may be represented by the formula [ka] , where R a and R bは , each independently benzyl, phenyl, alkyl, allyl, aryl. In certain embodiments, the organic sulfoxide is a di-C, such as DMSO. 1~6 Other exemplary organic sulfoxides include: [Table 1]

[0033] In certain embodiments, the contacting is at a temperature of about 0°C to about 100°C, or about 10°C to about 90°C, or about 20°C to about 80°C, or about 30°C to about 70°C, or about 40°C to about 60°C, or about 45°C to about 55°C. In certain embodiments, the contacting is at a temperature of about 0°C to about 20°C, about 20°C to about 25°C, about 25°C to about 30°C, about 30°C to about 35°C, about 35°C to about 40°C, about 40°C to about 45°C, about 45°C to about 50°C, about 50°C to about 55°C, about 55°C to about 60°C, about 60°C to about 65°C, about 65°C to about 70°C, about 70°C to about 75°C, about 75°C to about 80°C, or about 80°C to about 100°C. In certain embodiments, the method does not include any cooling.

[0034] In certain embodiments, the contacting is for a time period of from about 5 minutes to about 24 hours, or from about 30 minutes to about 20 hours, or from about 30 minutes to about 15 hours, or from about 30 minutes to about 10 hours, or from about 30 minutes to about 5 hours, or from about 30 minutes to about 3.5 hours, or from about 1 hour to about 3 hours, or from about 1.5 hours to about 2.5 hours. In certain embodiments, the contacting is for a time period of about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5 hours, about 10 hours, about 15 hours, about 20 hours, about 24 hours, or more.

[0035] In certain embodiments, the method produces a compound of formula I having a purity of greater than about 88 A%, greater than about 90 A%, greater than about 92 A%, greater than about 93 A%, greater than about 94 A%, greater than about 95 A%, greater than about 96 A%, greater than about 97 A%, greater than about 98%, or greater than about 99 A%.

[0036] In certain embodiments, the compound of formula I has one of the following structures, where R2 and R3 are halogen, -C(O)OC 1~6 alkyl, and hydrogen, and at least one of R2 and R3 is halogen: [ka] [ka] [ka]

[0037] In certain embodiments, the compound of formula I is compound 2a: In certain embodiments, the compound of formula I is compound 2b:

[0038] In another aspect, the subject matter is directed to a method of preparing a compound of formula I: [ka] (In the formula, R1 is 、 Branched or linear C 1~12 is alkyl, R2 and R 3は each of which is a halogen) The method is: structure: [ka] (In the formula, R 1’ is a branched or linear C 1~12 is alkyl, R 2’ and R 3’ are each hydrogen, contacting the compound with a first solvent to selectively halogenate the 4- and 6-positions to form a mixture; contacting the mixture with HX, where X is a halide, in the presence of an organic sulfoxide; contacting the mixture with HX is at a temperature of about 0°C to about 100°C; A compound of formula I is prepared.

[0039] In certain embodiments, the selective halogenation process produces a compound of Formula I, which is present in a ratio of at least 10:1 relative to a particular impurity, such as a monohalogenated, trihalogenated, or 2,4-dihalogenated compound. In certain embodiments, the ratio is at least 11:1, at least 12:1, at least 13:1, at least 14:1, at least 15:1, at least 16:1, at least 17:1, at least 18:1, at least 19:1, at least 20:1, at least 21:1, at least 22:1, at least 23:1, at least 24:1, at least 25:1, at least 26:1, at least 27:1, at least 28:1, at least 29:1, at least 30:1, at least 31:1, at least 32:1, at least 33:1, at least 34:1, or at least 35:1. In certain embodiments, the ratio is from about 25:1 to about 35:1. In certain embodiments, the composition comprises 4,6-DBO, 4-MBO, 2,4-DBO and TBO in amounts of about 94%, about 3%, about 1%, and about 1%, respectively.

[0040] In certain embodiments of selective halogenation, the halogen is selected from the group consisting of Br, Cl, F, and I. In certain embodiments, the halogen is selected from the group consisting of Br and Cl. In certain embodiments, the halogen is Br.

[0041] In certain embodiments of selective halogenation, HX is selected from the group consisting of HBr, HCl, HF, and HI. In certain embodiments, HX is selected from the group consisting of HBr and HCl. In certain embodiments, HX is HBr. In certain embodiments, HX is an aqueous solution. In certain embodiments, HX is a 10% to 90% aqueous solution. In certain embodiments, HX is a 20% to 80% aqueous solution. In certain embodiments, HX is a 30% to 70% aqueous solution. In certain embodiments, HX is a 40% to 60% aqueous solution. In certain embodiments, HX is a 45% to 55% aqueous solution. In certain embodiments, HX is a 46% to 50% aqueous solution, e.g., a 48% HBr aqueous solution.

[0042] In certain embodiments of selective halogenation, HX is present in an amount of about 1.5 to 3.0 molar equivalents. In certain embodiments of selective halogenation, HX is present in an amount of about 2.0 to 3.0 molar equivalents. In certain embodiments, HX is present in an amount of about 1.8 to 2.5 molar equivalents. In certain embodiments, HX is present in an amount of about 2.0 to 2.3 molar equivalents. In certain embodiments, HX is present in an amount of about 1.9 molar equivalents, 2.0 molar equivalents, 2.1 molar equivalents, 2.2 molar equivalents, or 2.3 molar equivalents.

[0043] In certain embodiments of selective halogenation, R is a linear or branched or straight chain C alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl (including isomers of each). 1~12 In certain embodiments, R is a branched or straight chain C alkyl selected from the group consisting of methyl, ethyl, propyl, pentyl, and hexyl (including isomers of each). 1~12 In certain embodiments, R is a straight-chain C alkyl selected from the group consisting of propyl and pentyl. 1~12 In certain embodiments, R is a branched C alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 1~12 It is alkyl.

[0044] In certain embodiments of selective halogenation, R 1’ is a linear, branched or straight-chain C alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl (including their respective isomers). 1~12 In certain embodiments, R 1’is a branched or straight chain C selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl (including their isomers). 1~12 In certain embodiments, R 1’ is a branched or straight chain C selected from the group consisting of propyl and pentyl 1~12 In certain embodiments, R 1’ is a branched chain C having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms 1~12 is alkyl 。

[0045] In all embodiments of this aspect, R 2’ and R 3’ are the respective hydrogens to facilitate dihalogenation of the ring.

[0046] In certain embodiments of the selective halogenation, the compound of Formula I' is dissolved in a solvent before contacting the compound of Formula I' with HX in the presence of DMSO. In certain embodiments, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, acetone, t-butyl methyl ether, ethanol, dichloromethane, n-heptane, toluene, 2-Me-THF, and isopropanol. In certain embodiments, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, and acetone. In certain embodiments, the solvent is ethyl acetate.

[0047] In certain selective halogenation embodiments, the first solvent is ethyl acetate in an amount of at least 15 volumes. However, in certain embodiments, the amount of solvent can be 5 volumes, 6 volumes, 7 volumes, 8 volumes, 9 volumes, 10 volumes, 11 volumes, 12 volumes, 13 volumes, 14 volumes, 15 volumes, 16 volumes, 17 volumes, 18 volumes, 19 volumes, 20 volumes, 21 volumes, 22 volumes, 23 volumes, 24 volumes, 25 volumes, or more. In certain embodiments, the solvent is present in a range of about 5 volumes to about 25 volumes, or about 9 volumes to about 17 volumes, or about 9.7 volumes to about 16.1 volumes. In certain embodiments, the solvent is ethyl acetate in an amount of at least 15 volumes.

[0048] When performing selective halogenation, the amount of organic sulfoxide, such as DMSO, can vary. In certain embodiments, the organic sulfoxide, such as DMSO, is present in an amount of about 1.5 to 5.0 molar equivalents. In certain embodiments, the organic sulfoxide, such as DMSO, is present in an amount of about 1.8 to 4.5 molar equivalents. In certain embodiments, the organic sulfoxide, such as DMSO, is present in an amount of about 2.0 to 3.0 molar equivalents. In certain embodiments, the organic sulfoxide, such as DMSO, is present in an amount of about 1.9 molar equivalents, 2.0 molar equivalents, 2.1 molar equivalents, or 2.2 molar equivalents.

[0049] In certain embodiments of selective halogenation, contacting the compound of Formula I' with the solvent and / or contacting the mixture with HX is at a temperature of from about 0°C to about 100°C, or from about 10°C to about 90°C, or from about 20°C to about 80°C, or from about 30°C to about 70°C, or from about 40°C to about 60°C, or from about 45°C to about 55°C. In certain embodiments of the selective halogenation, the contacting is at a temperature of about 0° C. to about 20° C., about 20° C. to about 25° C., about 25° C. to about 30° C., about 30° C. to about 35° C., about 35° C. to about 40° C., about 40° C. to about 45° C., about 45° C. to about 50° C., about 50° C. to about 55° C., about 55° C. to about 60° C., about 60° C. to about 65° C., about 65° C. to about 70° C., about 70° C. to about 75° C., about 75° C. to about 80° C., or about 80° C. to about 100° C. In certain embodiments, the temperature is about 40° C. to about 60° C. In certain embodiments, the method does not include any cooling.

[0050] In certain embodiments of selective halogenation, contacting the mixture with HX is for a time period of from about 5 minutes to about 24 hours, or from about 30 minutes to about 20 hours, or from about 30 minutes to about 15 hours, or from about 30 minutes to about 10 hours, or from about 30 minutes to about 5 hours, or from about 30 minutes to about 3.5 hours, or from about 1 hour to about 3 hours, or from about 1.5 hours to about 2.5 hours. In certain embodiments, the contacting is for a time period of about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5 hours, about 10 hours, about 15 hours, about 20 hours, about 24 hours, or more.

[0051] In certain embodiments, the selective halogenation process produces a compound of Formula I having a purity of greater than about 88 A%, greater than about 90 A%, greater than about 92 A%, greater than about 93 A%, greater than about 94 A%, greater than about 95 A%, greater than about 96 A%, greater than about 97 A%, greater than about 98%, or greater than about 99 A%.

[0052] In certain embodiments, the selective halogenation method produces a compound of Formula I selected from the group consisting of: [ka]

[0053] Reaction progress, completion (IPC), and purity can be monitored by HPLC. A representative HPLC of the isolated solid of DBO is shown in Figure 2.

[0054] In certain embodiments, quenching the above method includes, after the contacting step, contacting the reaction mixture containing the compound of Formula I with a buffered quench solution at a pH of about 14. In certain embodiments, the quench solution includes KHPO and NaOH. In certain embodiments, the quench solution is water, KHPO, and about 10%-30% NaOH. In certain embodiments, the buffer includes about 18% NaOH. In certain embodiments, the quench solution is not a NaHCO solution or other solution that results in problematic gas generation.

[0055] In certain embodiments, the above method may further comprise a crystallization process.

[0056] Unlike state-of-the-art methods for preparing dibromo-olivetol, which require gaseous diatomic bromine (Br) at subzero temperatures, Scheme 2 shows a synthetic route for the general procedure for preparing compounds of Formula I using HX in DMSO (or an alternative organic sulfoxide) at temperatures above 0° C. [ka] The general reaction scheme involves charging a dihydroxybenzene such as olivetol, charging a first solvent, charging DMSO (or an alternative organic sulfoxide) and HX, and optionally heating the reaction. The reaction progress was monitored by HPLC.

[0057] In certain embodiments, the methods described herein are directed to preparing 4,6-dibromo-olivetol in high yield with high purity and selectivity. Scheme 3 shows an exemplary route for such synthesis. [ka]

[0058] In certain embodiments, the methods described herein are directed to preparing 4,6-dibromo-olivetol in high yield with high purity and selectivity. Scheme 4 shows an exemplary route for such synthesis, optionally further including purification. [ka]

[0059] The subject matter described herein includes the following specific embodiments. 1. A method for preparing a compound of formula I, comprising: [ka] In the formula, R1 is a branched or linear C 1-12 alkyl, and R2 and R3 are each a halogen, -C(O)OC 1~6 alkyl, and hydrogen, and at least one of R2 and R3 is halogen; The method comprises: structure [ka] having formula I', where R 1’ is a branched or linear C 1~12 alkyl, and R 2’ and R 3’ are halogen and -C(O)OC, respectively. 1~6 alkyl, and hydrogen, wherein R 2’ and R 3’wherein at least one of is hydrogen, with HX, where X is a halide, in the presence of an organic sulfoxide; The contacting is at a temperature of about 0°C to about 100°C, A compound of formula I is prepared. 2. The method of embodiment 1, wherein HX is selected from HBr, HCl, HI, and HF. 3. The method of embodiment 1 or 2, wherein HX is HBr. 4. The method of embodiment 1, 2 or 3, wherein the HBr is aqueous. 5. R1 and R 1’ are the same and each is selected from the group consisting of linear or branched methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. 6. R1 and R 1’ is propyl or pentyl, respectively. 7. R1 and R 1’ are the same, each having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms 1~12 7. The method of embodiment 1, 2, 3, 4, 5 or 6, wherein said alkyl is selected from the group consisting of alkyl. 8. The compound of formula I has the following structure: [ka] (Wherein R1 and R 1’ The method of embodiment 1, 2, 3, 4, 5, 6 or 7, wherein the compound has the following structure: 9. R1 and R 1’ is selected from the group consisting of linear or branched methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. 10. R1 and R 1’ 10. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein each is selected from the group consisting of propyl and pentyl. 11. R1 and R 1’ The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein each is pentyl. 12. The compound of formula I has the following structure: [ka] 12. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein the compound has a purity of greater than about 93A% by HPLC. 13. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein the purity is about 93A% to about 99.5A% by HPLC. 14. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein the purity is about 94A% to about 99.5A%. 15. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the compound of formula I' is selectively dihalogenated at the 4 and 6 positions. 16. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the 4,6-dihalogenated compound of formula I, wherein each of R1 and R2 is halogen, is prepared in a ratio of about 25:1 to about 34:1 relative to the 2,4-dihalogenated impurity compound. 17. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein prior to contacting, the compound of formula I' is contacted with a first solvent to form a mixture. 18. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the first solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, acetone, t-butyl methyl ether, ethanol, dichloromethane, n-heptane, toluene, 2-Me-THF, and isopropanol. 19. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, and acetone. 20. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein the solvent is present from about 9.0 volumes to about 17 volumes. 21. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the solvent is present from about 9.7 volumes to about 16.1 volumes. 22. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the organic sulfoxide is present in an amount of about 2.0 equivalents to about 3.0 equivalents. 23. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein HX is present in an amount of about 2.0 equivalents to about 3.0 equivalents. 24. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the yield is greater than about 82%. 25. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein the yield is about 82% to about 90%. 26. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the yield is greater than about 95%. 27. A method for preparing a compound of formula I, comprising: [ka] (Wherein, R1 is 、 Branched or linear C 1~12 alkyl, and R2 and R3 are each halogen. The method is: structure [ka] (In the formula, R 1’ is a branched or linear C 1~12 alkyl, and R 2’ and R 3’ and each are hydrogen, with a first solvent to selectively halogenate the 4- and 6-positions to form a mixture; contacting the mixture with HX, where X is a halide, in the presence of an organic sulfoxide; The contacting is at a temperature of about 0°C to about 100°C, A compound of formula I is produced. 28. The method of embodiment 27, wherein the compound of formula I is present in a ratio of at least 10:1 to the monohalogenated, trihalogenated, or 2,4-dihalogenated compound. 29. The method of embodiment 27 or 28, wherein the ratio is at least 20:1. 30. The method of embodiment 27, 28 or 29, wherein the ratio is from about 25:1 to about 35:1. 31. The method of embodiment 27, 28, 29 or 30, wherein the halide is Br and HX is HBr. 32. The method of embodiment 27, 28, 29, 30 or 31, wherein the HBr is in an aqueous solution. 33. The method of embodiment 27, 28, 29, 30, 31 or 32, wherein the first solvent is ethyl acetate in an amount of at least 15 volumes. 34. The method of embodiment 27, 28, 29, 30, 31, 32, or 33, wherein the contacting is at a temperature of about 35°C to about 60°C. 35. The method of embodiment 27, 28, 29, 30, 31, 32, 33 or 34, wherein the compound of formula I has a purity of greater than about 99A%. 36.R 1’ The method of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein is propyl or pentyl and the compound of formula I is selected from the group consisting of: [ka] 37. The method of embodiment 1 or 27, further comprising adding aqueous NaOH to the reaction after the contacting time. 38. The method of embodiment 37, wherein the aqueous NaOH is a 10% to 50% (v / v) solution. 39. The method of embodiment 38, wherein the aqueous NaOH is about an 18% (v / v) solution. 40. A composition comprising 4,6-DBO, 4-MBO, 2,4-DBO and TBO in amounts of about 94%, about 3%, about 1%, and about 1%, respectively. 41. Organic sulfoxides have the general formula [ka] wherein each of Ra and Rb is independently selected from the group consisting of benzyl, phenyl, alkyl, aryl, and allyl. 42. At least one of Ra and Rb is C 1~6 42. The method of embodiment 41, wherein the alkyl is alkyl. 43. The method of embodiment 42, wherein the organic sulfoxide is DMSO.

[0060] The present invention is further described in the following non-limiting examples. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only. [Example]

[0061] Example 1: Method A In this process, olivetol (uncorrected for % water) was dissolved in ethyl acetate (22 mL / g) and aqueous 48% HBr (2.1 equiv.) and DMSO (2.1 equiv.) were added for 1 h at 60° C. This procedure gave a high level of the impurity 2,4,6-tribromo-olivetol (TBO) in the reaction (18.7%), with a moderate yield of DBO (65%).

[0062] Subsequently, several reaction parameters were systematically tested. These included the amount of solvent, HX equivalents, reaction temperature, and a review of the impurity profile. Advantageously, it was found that certain parameters could be adjusted to provide the desired compound of Formula I in high purity and high yield.

[0063] Example 2: Method B This process involved reducing the level of trihalogen compounds. The reaction temperature was lowered to approximately 30°C (Method B, Table 1). Results showed that the reaction was complete in 6 hours at 30-40°C. The TBO impurity was found to be 0.7A% by IPC. The reaction was isolated in 87% yield and 99.8A% by following the saturated NaHCO3 quench method (see Example 6). The TBO level was reduced to 0.1A%. These modified conditions resulted in a significant improvement. The results are summarized in Table 1. [Table 2]

[0064] Example 3: Solvent volume test This process included reducing the reaction volume. To study the effect of reducing the reaction volume, an experiment was conducted using 15 volumes of solvent (ethyl acetate). The results of Experiment 5 (Table 2) showed that the reaction was slow to complete at 35 °C with 2.1 equivalents of HBr, even after 7 h, due to 3.5% of 4-MBO remaining. Raising the reaction temperature to 50 °C led to completion when 2.2 or 2.3 equivalents of HBr were used. Because 2.3 equivalents of HBr produced a smaller amount of the impurity 4-MBO (0.6 A%), these conditions were selected for further modification. The conditions of Experiment 13 were used to evaluate workup procedures and subsequent scale-up. The results are shown in Table 2. [Table 3]

[0065] Further reductions in solvent volume were tested. The amount of ethyl acetate was reduced to 10 volumes (Table 3, Run 6). Using the optimized reaction conditions for 22 volumes of ethyl acetate (2.3 equivalents of HBr, 50 °C), it was found that the reaction did not proceed efficiently when 10 volumes of solvent were used. After 7 hours, the reaction yielded 89.0 A% DBO and 7.0 A% 4-MBO. Increasing the temperature, reaction time, and equivalents of HBr (Table 3, Runs 9 and 17) restored some of the DBO yield, but the amount of 4-MBO remained above 1.0%. The data indicate that using 10 volumes of ethyl acetate slowed the reaction. Based on testing, 15 volumes of solvent was selected as the lowest concentration the reaction conditions could tolerate without sacrificing DBO yield and purity. The results are shown in Table 3. [Table 4]

[0066] Example 4: Solvent Screening After testing several process variables, such as solvent volume, temperature, time, and equivalent amount of HX (e.g., HBr), several solvents were screened to analyze which solvents performed as well as or better than ethyl acetate. The solvent screening was performed according to the following procedure.

[0067] Olivetol (1 g, corrected for water %) and solvent (15 volumes) were charged to a 40 mL vial. To this solution, DMSO (2.3 equivalents) and 48% HBr (2.3 equivalents) were added dropwise. The reaction was heated to 50 °C, and aliquots were taken for analysis at 2, 6, and 22 hours. The reaction progress was monitored by HPLC. The results of the solvent screening are summarized in Table 4. [Table 5]

[0068] The data show that four solvents, ethyl acetate, isopropyl acetate, acetonitrile, and acetone, each provided ≥89A% DBO after 6 hours. Detailed impurity results are shown in Table 5. [Table 6]

[0069] Overall, a favorable impurity profile was obtained using ethyl acetate (4-MBO NMT 1.0A%). Testing also showed that isopropyl acetate produced a good impurity profile.

[0070] Example 5: Post-processing and separation Olivetol (10.0 g), ethyl acetate (220 mL), 48% HBr (19.7 g), and DMSO (9.1 g) were placed in a 500 mL reactor and heated to 60 °C. The reaction was sampled for completion after 1 h at 60 °C (0.4% MBO, 4.1% 2,4-DBO, 0.8% TBO). The solution was then distilled to a 5-pot volume. To this solution, n-heptane (300 mL) and water (20 mL) were added to the reactor. The solution was biphasic and free of solids. The mixture was distilled to a 20-pot volume. During the distillation, a slurry of crystalline solids formed. The mixture was cooled to 20 °C and held for 100 min, after which the solid was isolated by filtration through a filter paper. The solid was washed with room-temperature n-heptane (30 g) and dried overnight under vacuum at 40 °C. The isolated yield was 15.4 g (82%), KF 1988.7 ppm, and total purity by HPLC was 99.2%.

[0071] The above procedure was repeated as described in Method A. After workup, 27.2A% TBO was formed in 65% yield with a purity of 72.6%. See Table 1, Method A.

[0072] Example 6: Reaction quench study To further improve the method, the workup and separation procedures were modified in the workup of experiment 17, as described below.

[0073] Run 17 was processed according to the following modified buffer quench procedure. A buffer solution was prepared in a separate container by combining water (4.55 S (S denotes scale factor)), KHPO (1.45 S), and 30% NaOH (1.11 S) and mixing until dissolved. The pH of the buffer solution was 14.

[0074] Upon completion, the reaction solution was cooled to room temperature and the buffer was transferred to the reaction mixture. The solution was stirred for 30 minutes, then the phases were separated. The aqueous layer (pH 5-6) was discarded. The organic phase was distilled to 5 volumes under vacuum at 45°C. Heptane (2 x 10 volumes) was charged to the reactor, and after each addition the solution was distilled to 10 volumes under reduced pressure.

[0075] The distillation apparatus was replaced with a condenser. The reaction was heated to 50°C and water (2 volumes) was added dropwise. Stirring was continued at 50°C for an additional hour, after which the reaction was cooled to 20°C and stirred for an additional 2 hours. The slurry was filtered and rinsed with heptane (2.5 volumes). The wet cake was dried overnight at 40°C. The product yield was 16.2 g (92%) (KF = 0.2%; purity = 99.1 A%, major impurity 4-MBO 0.62 A%, ROI 0.7%). The reaction was carried out using 10 g of Olivetol (KF 6.3%). Reaction V min is the volume, V max is 23 volume.

[0076] Experiment 10 used NaHCO as the quenching solution 3を Experiment 10 was worked up according to the following procedure. After the reaction was complete, the reaction mixture was cooled to room temperature. Saturated NaHCO3 solution (5 g / mL) was added to the reaction mixture and stirred for 30 minutes, then the phases were separated (gentle outgassing of CO2 gas was observed). The aqueous phase was discarded (pH ~ 5). The organic phase was washed with water and distilled under vacuum to 5 volumes, then heptane (2 x 15 volumes) was charged to the reactor and distilled to 15 volumes after each addition.

[0077] The distillation apparatus was removed and replaced with a condenser. The reaction was heated to 50°C and water (2 volumes) was added dropwise. Stirring was continued at 50°C for an additional hour, after which the reaction was cooled to 20°C and stirred for an additional 2 hours. The slurry was filtered and rinsed with heptane (2 volumes). The wet cake was dried overnight at 40°C. The product yield was 7.3 g (87%) of DBO (KF = 0.1%, purity = 99.1 A%, major impurity 4-MBO = 0.7 A%). The reaction was carried out using 5 g of Olivetol (KF = 10.5%). Reaction V min is the volume, V max is 20 volume.

[0078] Both methods gave excellent results, and although it is desirable to avoid this method for large-scale manufacturing, the modified buffer quench was chosen for scale-up, as the NaHCO quench reaction resulted in CO gas evolution.

[0079] Example 7: Scale-up study The process was scaled up to 10 g and 2 x 40 g batches. Results showed that the process was reproducible, yielding excellent purity of DBO with a yield range of 87-92% (Table 6). The solvent exchange distillation volume and wet cake wash volume were found to affect the yield.

[0080] Experiment 20 was performed in a 250 mL ungraded jacketed flask, making it difficult to measure the solvent volumes during the solvent exchanges (first distillation: 5 volumes, second distillation: 10 volumes, third distillation: 10 volumes). Note that measurement error may have occurred.

[0081] Run 21 was performed in a 1 L graduated cylindrical jack reactor, allowing for easy measurement of the solvent volume during the solvent exchanges (first distillation 5 volumes, second distillation 10 volumes, third distillation 10 volumes). The isolated yield of DBO was 87%.

[0082] Run 22 was conducted in a graduated 1 L cylindrical jack reactor (5 volumes for the first distillation, 5 volumes for the second distillation, and 10 volumes for the third distillation). The yield of isolated DBO was 90%. The only difference between Runs 21 and 22 was the volume of the second solvent exchange. Run 21 used a 10-volume distillation, while Run 22 used a 5-volume distillation. The lower yield in Run 21 may be due to an incomplete solvent exchange. DBO is highly soluble in ethyl acetate, resulting in a lower yield in Run 21. Based on the data from Run 22, 5 volumes is recommended for the second distillation for future scale-up. The data are shown in Table 6. [Table 7]

[0083] Run 23 was a scale-up to 40 g of starting material that was performed to overcome salt formation observed during the quench procedure.

[0084] In Experiment 23-A, Olivetol (40 g, uncorrected for water %) and solvent (15 vol) were placed in a 1-liter reactor. DMSO (2.3 equiv.) was added to the solution, and 48% HBr (2.3 equiv.) was charged in a controlled manner. The reaction was heated to 50°C with stirring, and aliquots were taken for HPLC analysis at 0.5, 1, 1.5, and 2 hours. The HPLC results are shown in Table 7. [Table 8]

[0085] At the end of the 2-hour period, the reaction mixture was cooled to 20°C. An HPLC sample was collected. A buffer solution consisting of 30% NaOH, dipotassium hydrogen phosphate, and deionized water in amounts of 1.11 equivalents, 1.45 equivalents, and 4.55 equivalents, respectively, was used to quench the bromination reaction. The pH of the buffer was measured to be 12.74. As previously recommended, buffer was added to bring the reaction mixture to a final pH of 5.68. The reaction mixture was distilled under vacuum to 5 L / kg. The solution appeared biphasic. Next, 10 L / kg of n-heptane was added to the biphasic solution, and the reaction mixture was again distilled under vacuum to 5 L / kg. An additional addition of heptane was added to the reaction mixture and distilled under vacuum to 10 L / kg. A slurry of solids was observed. The solution was cooled to 50°C, and water was added. The solids in the solution instantly crystallized, and the mixture was aged (under stirring) for 1 hour. The solution was then cooled to 20°C and filtered. The solids were isolated on the filter paper. The solid cake was washed with 3 L / kg heptane and the isolated solid was dried under vacuum at 45° C. overnight.

[0086] The addition of the buffer solution caused the temperature of the reaction mixture to increase by 4°C. Cooling the reaction mixture to 20°C resulted in significant salt formation in the aqueous phase of the (quenched) reaction mixture. To address the salt formation issue, deionized water was selected to be added to the reaction mixture with stirring until the salt appeared to dissolve. The remaining unit operations, consisting of solvent exchange distillation, crystallization, and filtration, were carried out according to conventional procedures.

[0087] In Run 23-B, the reaction was carried out under the same conditions as described above for Run 23-A and sampled for LC as shown in Table 8, except that in Run 23-B, a buffer consisting of 30% NaOH was used. The final amount of 30% NaOH used was 2.75 equivalents to achieve a pH of 5.68, compared to Run 23-A, which used 1.11 equivalents. No salt formation was observed when 30% NaOH was used. [Table 9]

[0088] Runs 23-A and 23-B showed products of acceptable quality and yield (Table 8), indicating that the adjusted parameters overcame salt formation in Run 23-A. Thus, the process can be completed without substantial salt formation.

[0089] Experiment 24 was performed to determine the DBO product and impurity generation profile: the effect of temperature holds at various stages of the HBr addition. (i) Determine the DBO product and impurity generation profile during a programmed HBr addition over 30 minutes, (ii) the effect of holding at 20 °C for 2 hours after HBr addition, and (iii) after a 2 hour hold at 20 °C, heat the reaction mixture to 50 °C. In this experiment, Olivetol (6 g, uncorrected for water %) and solvent (15 vol) were placed in a 100 mL reactor. DMSO (2.3 equiv.) was added to the solution, and 48% HBr (2.3 equiv.) was charged in a controlled manner. The reaction was heated to 50° C. with stirring, and aliquots were taken for HPLC analysis at 0.5 and 1 hour during HBr addition at 20° C., 0.5, 1, 1.5, and 2 hours after HBr addition at 20° C., and 0.5, 1, 1.5, 2, 2.5, 5, and 24 hours after HBr addition at 50° C. The HPLC results are shown in Table 9. [Table 10]

[0090] The results show that the bromination reaction begins almost instantly after HBr addition. The kinetics of olivetol bromination are slow during HBr addition at 20°C. However, once complete HBr addition is achieved, olivetol is consumed, and the reaction is found to be highly selective for the formation of 4,6-dibromoolivetol (4,6-DBO). A maximum of 4,6-DBO was formed at the end of 1.5 hours at a reaction temperature of 50°C. The reaction was allowed to proceed for 24 hours at 50°C. This extended period resulted in an increase in 2,4-DBO and TBO levels and a steady decrease in 4,6-DBO. 4-MBO levels reached a maximum at 1.5 hours and then steadily decreased.

[0091] Example 8: General synthetic procedure for preparing 4,6-dibromo-olivetol 1. Description of the process for preparing DBO: All changes are based on the corrected weight of Olivetol. Equip a 1 L jacketed reactor with a mechanical stirrer, condenser, thermocouple, and nitrogen atmosphere. Set the jacket temperature to 20-25°C. Add Olivetol (40g, 1 equivalent, KF 6.3%, corrected weight 37.48g). Add ethyl acetate (562 mL, 15 volumes) and stir at room temperature. Add dimethyl sulfoxide (DMSO, 37.4 g, 2.3 equivalents). Aqueous 48% hydrobromic acid 1 (80.6 g, 2.3 eq) is added dropwise over 10 minutes. 2 hours at 50-52°C 2 Heat. · Remaining 4MBO IPC ≤ 1%.

[0092] 2. Post-processing Cool the reaction mixture to 25°C. In a second appropriately sized reaction vessel, add water (43 mL, 4.55 S) 4 ), dipotassium hydrogen phosphate (13.6 g, 1.45 S), and 30% NaOH (6.3 g, 1.11 S) in a buffer solution 3This solution is exothermic (60°C) and is prepared in advance (1 hour) and cooled to approximately 25°C. Add the buffer to the reaction mixture and stir for 30 minutes. No exotherm was observed upon addition of the buffer. Bottom water phase 5 Remove. Set up the still and distill down to 5 vol (200 mL) under vacuum. 6 . Add heptane (375 ml, 10 volumes) and add 5 volumes 7 Distill until Add heptane (375 ml, 10 vol) and add 10 vol 8 Distill until ·Remove the distillation condenser and replace it with a water condenser. The solution was heated to 50°C, water (75 mL, 2 volumes) was added dropwise, and the mixture was stirred for 1 hour. 9 Stir. Cool to 20°C and stir for 2 hours. · Slurry filtration 10 Then rinse with 3 vol of heptane (110 mL). Dry the wet cake at 40°C for at least 12 hours under vacuum at 0-200 mbar until LOD ≤ 0.5%. ·DBO was obtained as a white crystalline solid in 90% yield (63.5 g) and HPLC purity of 99.73 A%. Reaction is V min =5 and V max =23. Things to keep in mind: 1. The addition of HBr is slightly exothermic (max 4°C). 2. Typical reaction time is 1 h. IPC sample preparation: Take an aliquot of 6 μL dissolved in 1 mL of acetonitrile-water (7:3) mixture. 3. Preparation of buffer solution is exothermic (approximately 50°C), prepare solution at least 1 hour before use. 4. Use Olivetol (corrected for water %) as a scale factor. 5. Ensure that a clear and rapid phase separation is observed and that all of the aqueous phase has been removed (otherwise the ROI of the separated DBO will be higher). The pH of the aqueous phase is 5-6. 6. Set the jacket temperature to 50°C, apply a vacuum of 20-25Hg, and distill with ethyl acetate at approximately 26°C. 7. Because DBO is highly soluble in ethyl acetate, the solvent is distilled at 26-29°C, and complete solvent exchange is important. 8. The solvent is distilled at 38-41°C. 9. Easily stirrable slurry. 10. Filtration is rapid.

[0093] Example 9: Stress response Using the optimized reaction conditions described in Examples 7 and 8, the effect of reaction time on the impurity profile was investigated. The results are summarized in Table 10. The reaction was complete in 1 hour (4-MBO NMT 1.0 A%) and continued for an additional 21 hours to observe the impurity profile. After 22 hours, the reaction produced 15.7 A% of TBO impurity, which would be purged during isolation. These results indicate that the reaction is robust and that high-quality material can be isolated even when the reaction time is extended. The results are shown in Table 10. [Table 11]

[0094] Example 10: Further evaluation of modified reaction conditions A series of further experiments were conducted to analyze the amount of ethyl acetate, amount of reactant, HBr addition rate, excess reagent, excess amount, and reaction temperature. The following general sampling / temperature profile was used: ·Maintain reactor temperature at 20℃ when adding HBr Sample Collection #1 After adding HBr, aging was carried out at 20°C for 30 minutes. Sample Collection #2 Heat to reaction temperature for at least 15 minutes Sample Collection #3 Sample #4 after 30 minutes, Sample #5 after 60 minutes, Sample #6 after 120 minutes, Sample #7 after 240 minutes, Sample #8 after 480 minutes constant 1. Stirring speed (700rpm) 2. Reaction time (6 hours) 3. Temperature during HBr addition (20°C) 4. Holding time after HBr addition (30 min) response 4,6-DBO in 1.6 hours 2,4-DBO in 2.6 hours TBO at 3.6 hours 4.Up to 4,6-DBO

[0095] The results are presented in the form of Pareto charts of effects standardized at the 2.365 criterion, and main effect plots illustrate the different species formed in the operational ranges in Table 10 and Figures 3A, 3B, 4A, 4B, 5A, 5B, 6A and 6B. [Table 12]

[0096] Example 11: Scale-up of modified reactions The purpose of this experiment was to investigate the feasibility of a 15 g scale-up experiment under the reaction conditions determined in Example 10. Olivetol (15 g, uncorrected for water %) and solvent (16 volumes) were placed in a 300 mL reactor. DMSO (2.20 equivalents) was added to the solution, and 48% HBr (2.26 equivalents) was charged in a controlled manner. The reaction was heated to 40 °C with stirring, and aliquots were taken for HPLC analysis at 0.5 and 1 hour during the HBr addition at 20 °C, and at 0.5, 1, 2, and 4 hours after the HBr addition at 40 °C. At the end of the 4 hour period, the reaction mixture was cooled to 20 °C. A buffer solution consisting of 2 equivalents of 18% NaOH was added to quench the bromination reaction and bring the solution to a final pH of 5.52. The solution appeared biphasic without salt formation. The reaction mixture was distilled under vacuum to 5 L / kg. Next, 10 L / kg of n-heptane was added to the biphasic solution, and the reaction mixture was again distilled under vacuum to 5 L / kg. Additional heptane was added to the reaction mixture and distilled under vacuum to 10 L / kg. A slurry of solids was observed. The solution was cooled to 50°C, and water was added. The solids in the solution instantly crystallized, and the mixture was aged (under stirring) for 1 hour. The solution was then cooled to 20°C and filtered. The solids were isolated on the filter paper. The solid cake was washed with 3 L / kg heptane, and the isolated solids were dried under vacuum at 45°C overnight. The HPLC results of the dried DBO solids are shown in Table 11 and Figure 2. The yield of the dried DBO solids was found to be 89%. [Table 13]

[0097] Example 13: Purity Profile The purpose of this experiment was to investigate the final impurity of DBO solids in a 15 g scale-up experiment under reaction conditions favoring high TBO formation. Olivetol (15 g, uncorrected for water %) and solvent (16 volumes) were placed in a 300 mL reactor. DMSO (2.35 equivalents) was added to the solution, and 48% HBr (2.40 equivalents) was charged in a controlled manner. The reaction was heated to 46 °C with stirring, and aliquots were taken at 0.5 and 1 hour for HPLC analysis during the HBr addition at 20 °C. After the HBr addition, samples were taken at 0.5, 1, 2, and 4 hours at 46 °C. At the end of the 4 hour period, the reaction mixture was cooled to 20 °C. A buffer solution consisting of 2 equivalents of 18% NaOH was used to quench the bromination reaction and bring the solution to a final pH in the range of 5-6. The solution appeared biphasic without salt formation. The reaction mixture was distilled under vacuum to 5 L / kg. Next, 10 L / kg of n-heptane was added to the biphasic solution, and the reaction mixture was again distilled under vacuum to 5 L / kg. Additional heptane was added to the reaction mixture and distilled under vacuum to 10 L / kg. A slurry of solids was observed. The solution was cooled to 50°C, and water was added. The solids in the solution instantly crystallized, and the mixture was aged (under stirring) for 1 hour. The solution was then cooled to 20°C and filtered. The solids were isolated on the filter paper. The solid cake was washed with 3 L / kg heptane, and the isolated solid was dried under vacuum at 45°C overnight. The HPLC results of the dried DBO solid are shown in Table 12 and Figure 7. The yield was found to be 90.6%. [Table 14]

[0098] GC analysis of the process stream before and after solvent-swap (replacing ethyl acetate with heptane) distillation showed evidence of ethanol and acetic acid, which are by-products of ethyl acetate hydrolysis. DMS is also present as a by-product of DMSO. An example of the GC analysis is shown in Figure 8.

[0099] Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

[0100] When an amount, concentration, or other value or parameter is given as either a range, a preferred range, or a list of upper and lower preferred values, this should be understood to specifically disclose all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether the ranges are separately disclosed. When a range of numerical values ​​is recited herein, unless otherwise stated, it is intended that the range include its endpoints, and all integers and fractions within the range. It is not intended that the scope of the invention be limited to the specific values ​​recited when defining the range.

[0101] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject belongs, as defined in Singleton et al. (1994) Dictionary of Microbiology and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY, and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5 th Ed., Garland Publishing, New York.

[0102] The disclosures of all cited references, including publications, patents, and patent applications, are expressly incorporated herein by reference in their entirety.

[0103] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context otherwise requires. It is understood that the embodiments described herein include embodiments "consisting of" and / or "consisting essentially of."

[0104] As used herein, the term "about" when referring to a value is meant to encompass variations from the specified amount, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate for practicing the disclosed methods or using the disclosed compositions.

[0105] When a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value between the upper and lower limits of that range, and at any other stated or intervening value within that stated range, is included to the tenth of the unit of the lower limit. The upper and lower limits of these smaller ranges, which may independently be included in smaller ranges, are also included, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[0106] Many modifications and other embodiments of what is described herein will come to mind to one skilled in the art to which the subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the subject matter is not to be limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in practicing the subject matter described herein. The present disclosure is in no way limited to solely the methods and materials described. The present invention includes the following aspects. [Section 1] A method for preparing a compound of formula I, comprising: [C1] JPEG0007776991000041.jpg78165 During the ceremony, R 1 is a branched or linear C 1~12 is alkyl, R 2 and R 3 are each independently a halogen, -C(O)OC 1~6 alkyl, and hydrogen; R 2 and R 3 at least one of is a halogen, and the method further comprises: structure: [C2] JPEG0007776991000042.jpg83169 (In the formula, R 1’ is a branched or linear C 1~12 is alkyl, R 2’ and R 3’ are each independently a halogen, -C(O)OC 1~6 alkyl, and hydrogen; R 2’ and R 3’ wherein at least one of is hydrogen, HX, where X is a halide, in the presence of an organic sulfoxide; the contacting is at a temperature of about 0°C to about 100°C; The method wherein the compound of formula I is prepared. [Section 2] Item 1. The method of item 1, wherein HX is selected from HBr, HCl, HI, and HF. [Section 3] Item 3. The method according to item 2, wherein HX is HBr. [Section 4] Item 3. The method of item 3, wherein the HBr is aqueous. [Section 5] R 1 and R 1’ are the same and each is selected from the group consisting of linear or branched methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. [Section 6] R 1 and R 1’ Item 6. The method according to Item 5, wherein each of the groups is propyl or pentyl. [Section 7] R 1 and R 1’ are identical, each having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; 1~12 Item 1, the method of claim 1, wherein the alkyl is selected from the group consisting of alkyl. [Section 8] The compound of formula I is a compound having the structure: [C3] JPEG0007776991000043.jpg81169 In the formula, R 1 and R 1’ The method according to item 1, wherein [Section 9] R 1 and R 1’ and each is selected from the group consisting of straight-chain or branched methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. [Section 10] R 1 and R 1’ and each is selected from the group consisting of propyl and pentyl. [Section 11] R 1 and R 1’ and each is pentyl. [Section 12] The compound of formula I is a compound having the structure: [C4] TIFF0007776991000044.tif67164 12. The method of claim 11, wherein the compound has a purity of greater than about 93A% by HPLC. [Section 13] Item 13. The method according to Item 12, wherein the purity is about 93A% to about 99.5A% by HPLC. [Section 14] Item 14. The method according to Item 13, wherein the purity is about 94 A% to about 99.5 A%. [Section 15] Item 1, wherein the compound of formula I' is selectively dihalogenated at the 4- and 6-positions. [Section 16] Formula I (wherein, R 1 and R 2 and each of which is a halogen) is prepared in a ratio of about 25:1 to about 34:1 to the 2,4-dihalogenated impurity compound. [Section 17] Item 10. The method of claim 1, wherein, prior to said contacting, said compound of formula I' is contacted with a first solvent to form a mixture. [Section 18] Item 18. The method of item 17, wherein the first solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, acetone, t-butyl methyl ether, ethanol, dichloromethane, n-heptane, toluene, 2-Me-THF, and isopropanol. [Section 19] Item 19. The method of item 18, wherein the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, and acetone. [Section 20] Item 18. The method according to Item 17, wherein the solvent is present in an amount of about 9.0 volumes to about 17 volumes. [Section 21] Item 21. The method according to Item 20, wherein the solvent is present in an amount of about 9.7 volumes to about 16.1 volumes. [Section 22] Item 10. The method of claim 1, wherein the organic sulfoxide is present in an amount of about 2.0 equivalents to about 3.0 equivalents. [Section 23] Item 23. The method of item 22, wherein the HX is present in an amount of about 2.0 equivalents to about 3.0 equivalents. [Section 24] Item 1, wherein the yield is greater than about 82%. [Section 25] Item 25. The method according to Item 24, wherein the yield is about 82% to about 90%. [Section 26] Item 1, wherein the yield is greater than about 95%. [Section 27] A method for preparing a compound of formula I, comprising: [5] JPEG0007776991000045.jpg82169 During the ceremony, R 1 is a branched or linear C 1~12 is alkyl, R 2 and R 3 are halogens, The method comprises: structure: [6] JPEG0007776991000046.jpg82169 (In the formula, R 1’ is a branched or linear C 1~12 is alkyl, R 2’ and R 3’ and each is a halogen, selectively halogenating at the 4- and 6-positions by contacting with a first solvent to form a mixture; contacting the mixture with HX, where X is a halide, in the presence of an organic sulfoxide; the contacting is at a temperature of about 0°C to about 100°C; The method wherein the compound of formula I is prepared. [Section 28] 28. The method of claim 27, wherein the compound of formula I is present in a ratio of at least 10:1 to the monohalogenated, trihalogenated, or 2,4-dihalogenated compound. [Section 29] 29. The method of claim 28, wherein the ratio is at least 20:1. [Section 30] Item 29. The method according to Item 28, wherein the ratio is about 25:1 to about 35:1. [Section 31] 28. The method of claim 27, wherein the halide is Br and HX is HBr. [Section 32] 32. The method of claim 31, wherein the HBr is in an aqueous solution. [Section 33] 28. The method of claim 27, wherein the first solvent is ethyl acetate in an amount of at least 15 volumes. [Section 34] Item 28. The method according to Item 27, wherein the contacting is carried out at a temperature of about 35°C to about 60°C. [Section 35] 28. The method of claim 27, wherein the compound of formula I has a purity of greater than about 99A%. [Section 36] R 1’ is propyl or pentyl, and the compound of formula I is selected from the group consisting of: [7] JPEG0007776991000047.jpg134169 [Section 37] 28. The method of claim 1 or 27, further comprising adding aqueous NaOH to the reaction after said contacting for said period of time. [Section 38] Item 38. The method of item 37, wherein the aqueous NaOH is a 10% to 50% (v / v) solution. [Section 39] 39. The method of claim 38, wherein the aqueous NaOH is about an 18% (v / v) solution. [Section 40] A composition comprising 4,6-DBO, 4-MBO, 2,4-DBO and TBO in amounts of about 94%, about 3%, about 1%, and about 1%, respectively. [Section 41] The organic sulfoxide is represented by the general formula [8] JPEG0007776991000048.jpg2832 Item 28. The method according to item 1 or 27, wherein Ra and Rb are each independently selected from the group consisting of benzyl, phenyl, alkyl, aryl and allyl. [Section 42] At least one of Ra and Rb is C 1~6 Item 42. The method according to item 41, wherein the alkyl is alkyl. [Section 43] 43. The method of claim 42, wherein the organic sulfoxide is DMSO.

Claims

1. A method for preparing a compound of formula I, comprising: 【Chemistry 1】 During the ceremony, R １ is a branched or linear C １～１２ is alkyl, R ２ and R ３ are halogens, The method comprises: structure: 【Chemistry 2】 (In the formula, R １’ is a branched or linear C １～１２ is alkyl, R ２’ and R ３’ are each independently a halogen, —C(O)OC １～６ alkyl, and hydrogen; R ２’ and R ３’ wherein at least one of is hydrogen HX, where X is a halide, in the presence of an organic sulfoxide; the contacting is at a temperature of from 30°C to 55°C; The compound of formula I is prepared, and The method wherein said compound of formula I' is selectively dihalogenated at the 4- and 6-positions.

2. 2. The method of claim 1, wherein HX is selected from HBr, HCl, HI, and HF.

3. R １ and R １’ are the same and each is selected from the group consisting of straight chain or branched methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

4. The compound of formula I is a compound having the structure: 【Transformation 3】 In the formula, R １ and R １’ The method of claim 1 , wherein

5. R １ and R １’ 5. The method of claim 4, wherein each of is selected from the group consisting of straight chain or branched methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

6. The compound of formula I is a compound having the structure: 【Chemistry 4】 6. The method of claim 5, wherein the compound has a purity of greater than 93 A% by HPLC.

7. 10. The method of claim 1, wherein prior to said contacting, said compound of Formula I' is contacted with a first solvent to form a mixture.

8. 8. The method of claim 7, wherein the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, acetonitrile, and acetone.

9. 10. The method of claim 1, wherein the organic sulfoxide is present in an amount of from 2.0 equivalents to 3.0 equivalents.

10. 10. The method of claim 9, wherein the HX is present in an amount of 2.0 to 3.0 equivalents.

11. 10. The method of claim 1, wherein the yield is greater than 82%.

12. A method for preparing a compound of formula I, comprising: 【Transformation 5】 During the ceremony, R １ is a branched or linear C １～１２ is alkyl, R ２ and R ３ are halogens, The method comprises: structure: 【Transformation 6】 (In the formula, R １’ is a branched or linear C １～１２ is alkyl, R ２’ and R ３’ and each are hydrogen, selectively halogenating at the 4- and 6-positions by contacting with a first solvent to form a mixture; contacting the mixture with HX, where X is a halide, in the presence of an organic sulfoxide; the contacting is at a temperature of from 30°C to 55°C; A method wherein the compound of formula I is prepared.

13. 13. The method of claim 12, wherein the compound of formula I is present in a molar ratio of at least 10:1 to the monohalogenated, trihalogenated, or 2,4-dihalogenated compound.

14. 13. The method of claim 12, wherein the halide is Br and HX is HBr.

15. R １’ is propyl or pentyl, and the compound of formula I is selected from the group consisting of: 【Transformation 7】

16. A composition comprising 4,6-DBO, 4-MBO, 2,4-DBO and TBO in amounts of 94% (HPLC A%), 3% (HPLC A%), 1% (HPLC A%) and 1% (HPLC A%), respectively.

17. The organic sulfoxide is represented by the general formula 【Transformation 8】 13. The method of claim 1 or 12, wherein R a and R b are each independently selected from the group consisting of benzyl, phenyl, alkyl, aryl, and allyl.

18. 18. The method of claim 17, wherein the organic sulfoxide is DMSO.

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