Efficient and Selective Route for the Synthesis of Alkyl 2-Benzoylbenzoates

Abstract

A process for preparing alkyl 2-benzoylbenzoates, comprising reacting a dialkyl phthalate with a Grignard reagent in the presence of an oxygenated solvent, wherein the Grignard reagent may be selected from phenylmagnesium bromide, phenylmagnesium chloride, and phenylmagnesium iodide.

Description

Technical Field

[0001] The present invention relates to a process for preparing alkyl 2-benzoylbenzoate.

Background Art

[0002] Alkyl 2-benzoylbenzoate is typically prepared by a Friedel-Crafts reaction. For example, methyl 2-benzoylbenzoate (M2BB) has conventionally been prepared by a Friedel-Crafts reaction of phthalic anhydride and benzene in the presence of a stoichiometric amount of a Lewis acid, followed by an esterification reaction in a second step. The esterification reaction can occur under acidic conditions using methanol in the presence of a strong acid (Vogel.et.al.Practical Organic Chemistry,5 th Ed.pp 1016). Alternatively, the esterification reaction can occur under basic conditions using iodomethane in the presence of a base (ChemCatChem 2017,9,3989-3996).

[0003] Methyl 2-benzoylbenzoate can also be synthesized via a palladium-catalyzed acylation chemical reaction between benzaldehyde and 2-halomethyl benzoate. However, this chemical reaction requires an expensive transition metal catalyst and a stoichiometric amount of an oxidizing agent (J.Org.Chem.2016,81,6409).

[0004] In addition, methyl 2-benzoylbenzoate may be synthesized by a Suzuki coupling between an activated amide and the corresponding boronic acid (Org.Process Res.Dev.2018,22,1188).

[0005] It would be desirable to develop a process for preparing alkyl 2-benzoylbenzoate that (1) avoids the use of stoichiometric Lewis acids during generation, (2) does not require the use of toxic reagents and strong acids or bases, (3) can prepare alkyl 2-benzoylbenzoate in a single-step operation, and / or (4) can reduce manufacturing costs.

[0006] The present invention provides a process that addresses one or more of the problems associated with existing processes for synthesizing alkyl 2-benzoylbenzoate. SUMMARY OF THE INVENTION

[0007] The present invention relates to a process for preparing alkyl 2-benzoylbenzoate.

[0008] A process comprising reacting a dialkyl phthalate with a Grignard reagent selected from phenylmagnesium bromide, phenylmagnesium chloride, phenylmagnesium iodide, and phenyllithium in the presence of an oxygenated solvent.

[0009] Surprisingly, the selectivity of the reaction for alkyl 2-benzoylbenzoate is very high, and only a small amount of diketone by-product is formed. BRIEF DESCRIPTION OF THE DRAWINGS

[0010]

Figure 1

Figure 2

[0011] As used herein, the terms "a", "an", "the", "at least one", and "one or more" are used interchangeably. The terms "comprise", "include", "contain" and their variations do not have a limiting meaning when these terms appear in the specification and claims. That is, for example, a mixture comprising a polymerization inhibitor can be construed to mean that the mixture contains at least one polymerization inhibitor.

[0012] As used herein, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). For the purposes of the present invention, it should be understood that, consistent with what those skilled in the art would understand, a numerical range is intended to include and support all sub-ranges that may be included within that range. For example, the range of 1 to 100 is intended to convey 1.1 to 100, 1 to 99.99, 1.01 to 99.99, 40 to 6, 1 to 55, etc.

[0013] As used herein, numerical ranges and / or listings of numbers, including such listings in the claims, can be read to include the term "about". In such cases, the term "about" refers to numerical ranges and / or numbers that are substantially the same as those recited herein.

[0014] Unless stated to the contrary or implicit from the context, all parts and percentages are by weight and all test methods are as of the filing date of this application. For the purposes of U.S. patent practice, the contents of any patents, patent applications or publications referred to are necessarily incorporated herein by reference in their entirety, to the extent that the entire contents, particularly with respect to the disclosure of definitions and general knowledge in the art (not in any way inconsistent with the definitions specifically provided in this disclosure), or the corresponding U.S. patent application of the publication, are incorporated by reference in the same manner.

[0015] In the process of the present invention, alkyl 2-benzoylbenzoate is prepared by a Grignard reaction as shown in the following formula (I). The dialkyl phthalate reacts with the Grignard reagent in the presence of an oxygenated solvent.

[0016]

Chemical formula

[0017] In the dialkyl phthalate, R and R’ may be the same or different. Preferably, R and R’ are the same as shown in the following formula (II).

[0018]

Chemical formula

[0019] R and R’ may independently be selected from alkyl groups containing 1 to 4 carbon atoms such as, for example, a methyl group, an ethyl group, a propyl group or a tert-butyl group. Preferably, R and R’ are independently selected from a methyl group and an ethyl group. More preferably, both R and R’ are methyl groups, and the product is methyl 2-benoylbenzoate as shown in the following formula (III).

[0020]

Chemical formula

[0021] The Grignard reagent may be selected from phenylmagnesium bromide, phenylmagnesium chloride and phenylmagnesium iodide.

[0022] The Grignard reagent reacts selectively with one of the ester functional groups of the dialkyl phthalate to form the alkyl 2-benzoylbenzoate in an average yield of 60%. When both R and R’ are methyl groups, the single-step reaction is highly selective for methyl 2-benzoylbenzoate (12:1), and only a small amount of by-products (e.g., diketone) are formed. Little excess Grignard reaction was observed in the system with respect to either the newly formed keto-carbonyl functional group or the second ester functional group of dimethyl phthalate.

[0023] The process of the present invention can be carried out without using expensive reagents, additives or ligands, and can provide a significantly improved process yield as compared to the conventional two-step reaction.

[0024] Examples of oxygenated solvents that can be used in the present invention include, but are not limited to, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran and 2-methyltetrahydrofuran.

[0025] The reaction is preferably carried out at an overall concentration of the oxygenated solvent of 0.2 - 1.0 M.

[0026] Preferably, the reaction is carried out at a temperature in the range of -78°C to 150°C. More preferably, the reaction is carried out at a temperature in the range of -40°C to 100°C. Even more preferably, the reaction is carried out at a temperature in the range of 0°C to 40°C. Preferably, the reaction is carried out for at least 1 hour, preferably at least 3 hours and more preferably at least 12 hours.

[0027] The mixing ratio of dialkyl phthalate and Grignard reagent is preferably dialkyl phthalate in the range of 0.90 to 3.0 moles per mole of Grignard reagent, more preferably dialkyl phthalate in the range of 1.0 to 2.75 moles per mole of Grignard reagent, still more preferably dialkyl phthalate in the range of 1.25 to 2.5 moles per mole of Grignard reagent, and even more preferably dialkyl phthalate in the range of 1.4 to 1.6 moles per mole of Grignard reagent.

Example

[0028] The following examples illustrate the present invention but are not intended to limit the scope of the present invention.

[0029] Example 1 A three-necked 250 mL round-bottom flask was charged with dimethyl phthalate (1.0 equivalent) and tetrahydrofuran (concentration 0.2 M) under a nitrogen atmosphere, and phenylmagnesium chloride (1.0 equivalent) was slowly added to the reaction mixture at -78°C. The reaction was maintained at -78°C for 1 hour. After 2 hours, thin-layer chromatography (TLC) and gas chromatography-flame ionization detector (GC-FID) showed mainly starting materials, and the reaction was warmed to 0°C. The reaction was continued at 0°C for an additional 3 hours. TLC indicated product formation, but most was starting material. The reaction was slowly warmed to room temperature and continued for an additional 12 hours. The reaction was then quenched by adding 1N HCl solution to the reaction mixture. Diethyl ether was added and the reaction mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with diethyl ether. The organic layers were combined and dried over MgSO4. The solvent was removed under reduced pressure to give a brownish oil, which was purified by silica gel chromatography (10% - 25% ethyl acetate in hexane) to give the product methyl 2-benzoylbenzoate (yield 49%) and the diketone product (yield 6%).

[0030] Example 2 A 250 mL three-necked round-bottom flask was charged with dimethyl phthalate (1.0 equiv) and tetrahydrofuran (0.2 M concentration) under a nitrogen atmosphere, and phenylmagnesium bromide (1.0 equiv) was slowly added to the reaction mixture at -78 °C. The reaction was held at -78 °C for 1 h. After 2 h, TLC and GC-FID showed mainly starting materials, and the reaction was warmed to 0 °C. The reaction was continued at 0 °C for an additional 3 h. TLC showed product formation, but most was still starting material. The reaction was slowly warmed to 40 °C and continued for an additional 12 h. The reaction was then quenched by adding 1 N HCl solution to the reaction mixture. Diethyl ether was added and the reaction mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was washed further with diethyl ether. The organic layers were combined and dried over MgSO4. The solvent was removed under reduced pressure to give a brownish oil, which was purified by silica gel chromatography (10% - 25% ethyl acetate in hexane) to give the product methyl 2-benzoylbenzoate (60% yield) and the diketone product (5% yield).

[0031] Example 3 Various experiments were carried out using the same techniques as described above in Examples 1 and 2 to test the Grignard reaction conditions with dimethyl phthalate. These experiments are summarized in Table 1 below. Representative GC-FID data of dimethyl phthalate reacted with phenylmagnesium bromide after 16 h are shown in Figure 1.

[0032] [Table 1]

[0033] Example 4 Phenylmagnesium bromide (45 ml, 135 mmol, 1.05 eq) was added dropwise over 30 minutes to a solution of dimethyl phthalate (25.0 g, 128.8 mmol, 1 eq) in THF (600 ml, 0.2 M) under a nitrogen atmosphere at 0 °C. The reaction was slowly warmed to room temperature and then gently heated to 40 °C and continued for 12 hours. Reaction aliquots were taken at 6-hour and 12-hour intervals and the results are shown in Table 2 below. After 12 hours, the reaction was quenched with 1 N HCl solution and the organic layer was isolated from the aqueous layer. The organic layer was concentrated, the concentrated material was diluted with diethyl ether, and hexane (3X) was added and the product was left to stand ( 1 See Figure 2 for 1H NMR). On the other hand, the aqueous layer was analyzed by UPLC method, which showed that a very small amount of organic compound had leached onto the aqueous layer.

[0034]

Table 2

[0035] Example 5 A 1000 ml round-bottom flask equipped with an overhead stirrer, an ice bath, an addition funnel, and a dry nitrogen inlet was charged with dimethyl phthalate (100 g, 0.51 mol) and cooled to -10 °C. Phenylmagnesium bromide (16 wt% solution of 250 g, 0.22 mol) was added to the addition funnel. While maintaining the reactor temperature at -10 °C, phenylmagnesium bromide was added from the addition funnel to the chilled dimethyl phthalate over 75 minutes. The content of the reaction mixture was stirred at -10 °C for 30 minutes. During this period, the addition funnel was charged with an aqueous hydrochloric acid solution (12 wt% solution of 247 g). After holding for 30 minutes, the hydrochloric acid solution was added from the addition funnel to the reaction mixture at -10 °C over 30 minutes. The contents of the reactor were warmed to ambient temperature and the organic layer was separated by a separating funnel. The organic layer was anhydrous sodium sulfate dried and 13 analyzed by 13C-NMR spectroscopy. The selectivity for methyl 2-benzoylbenzoate was 93.5%.

Claims

1. A method for preparing an alkyl 2-benzoylbenzoate, comprising reacting a dialkyl phthalate with a Grignard reagent in the presence of an oxygen-containing solvent selected from diethyl ether, tert-butyl methyl ether, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran, wherein the Grignard reagent is selected from phenylmagnesium bromide, phenylmagnesium chloride, and phenylmagnesium iodide.

2. The method according to claim 1, wherein the dialkyl phthalate is selected from dimethyl phthalate, diethyl phthalate, dipropyl phthalate, and bi-tert-butyl phthalate.

3. The method according to claim 2, wherein the dialkyl phthalate is selected from dimethyl phthalate.

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out at a temperature in the range of -78°C to 150°C.

5. The method according to claim 4, wherein the reaction is carried out at a temperature in the range of -40°C to 100°C.

6. The method according to any one of claims 1 to 5, wherein the dialkyl phthalate is present in an amount in the range of 0.9 to 3.0 moles of the dialkyl phthalate per mole of the Grignard reagent.

7. The method according to any one of claims 1 to 6, wherein the reaction is carried out for at least 1 hour.

8. The method according to claim 7, wherein the reaction is carried out for at least 12 hours. ​

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