Process

Abstract

There is provided a process for the preparation of a compound of formula (I) comprising the steps of: a) providing styrene, b) converting styrene to a compound of formula (I) in the presence of a catalyst selected from a base or alkaline earth metal salt and acetic acid. # imgabs0 #

Description

Technical Field

[0001] The present invention generally relates to a method for preparing 1-phenylethyl acetate. Background Art

[0002] 1-Phenylethyl acetate (CAS No. 93-92-5), also known as styralyl acetate, is a compound with a strong, bright (radiant), green (leaf, apple), metallic (hazelnut, rhubarb), fruity (plum, apricot), floral (gardenia) fragrance type. For example, the compound can be prepared in two steps by hydrogenating acetophenone to 1-phenylethanol and then acetylating it to 1-phenylethyl acetate.

[0003] Alternatively, styralyl acetate can be obtained from styrene (CAS No. 100-42-5). For example, this transformation can be carried out using a lanthanide salt as a catalyst (Huaxue Shiji 2012, 34, 1151-1152), but the catalyst is rare and thus expensive. In addition, very expensive and non-commercial tungsten-based catalysts (Synth.Comm. 2019, 49, 933-941) or cerium salts (J.Chem.Res. 2003, 5, 270-272) have been reported to be suitable for this method. In both cases, a high catalyst loading is required, and the amount of acetic acid does not provide a safe and effective method.

[0004] There is a need for new or improved methods for preparing styralyl acetate, for example in terms of efficiency and / or sustainability. Summary of the Invention

[0006] According to a first aspect of the present invention, there is provided a method for preparing a compound of formula (I):

[0007]

[0008] Certain embodiments of any aspect of the present invention may provide one or more of the following advantages:

[0009] ● Short synthesis - only one chemical step is required,

[0010] ● Widely available and earth-abundant catalysts,

[0011] ● Low catalyst loading,

[0012] ● No solvent is required,

[0013] ● Fine-tuned amount of acetic acid, resulting in an overall safe process on an industrial scale,

[0014] ● Acetic acid (starting material) that can be obtained as a renewable raw material,

[0015] ● Styrene (starting material), which can be obtained by converting plastic waste as an upcycled starting material,

[0016] ● Recycling of unreacted starting materials (acetic acid and styrene),

[0017] ● High olfactory quality of 1-phenylethyl acetate,

[0018] ● Cost efficiency.

[0019] Details, examples, and preferred embodiments provided herein with respect to any particular one or more of the aspects of the invention will be further described herein, and they are equally applicable to all aspects of the invention. Unless otherwise specified herein or clearly contradicted by the context, the invention encompasses any combination of all possible variations of the embodiments, examples, and preferred embodiments described herein.

[0020] Detailed Description

[0021] The present invention is based on the surprising discovery that the conversion of styrene to 1-phenylethyl acetate can be catalyzed by relatively inexpensive and widely available alkali or alkaline earth metal salts.

[0022] Accordingly, there is provided herein a method for preparing 1-phenylethyl acetate (compound of formula (I)),

[0023]

[0024] The method comprises the following steps:

[0025] a) Providing styrene,

[0026] b) Converting styrene to the compound of formula (I) in the presence of a catalyst and acetic acid,

[0027] wherein the catalyst is selected from alkali or alkaline earth metal salts.

[0028] The method is depicted in Scheme 1.

[0029]

[0030] The catalyst selected from alkali or alkaline earth metal salts is relatively inexpensive and widely available. This represents an improvement over the prior art, in which rare, expensive, and sometimes problematic catalysts (in terms of toxicity or handling safety) have been reported to date.

[0031] When the catalyst is an alkali or alkaline earth metal salt, it is, for example, an alkali or alkaline earth metal halide, or the respective hydrate. For example, it can be selected from alkali or alkaline earth metal chlorides, bromides or iodides, or the respective hydrates. In particular, it can be selected from LiCl, LiBr, LiI, NaBr, MgCl2, MgBr2, MgI2, CaCl2, CaBr2 and CaI2 or the respective hydrates, such as MgBr2(H2O)6 or CaI2(H2O) x .

[0032] The present invention provides a viable synthesis, particularly a viable synthesis for industrialization, which is at the same time highly sustainable, process- and cost-effective. Compared with current industrial methods, the present invention provides an alternative by using styrene as a starting material and converting styrene in a single chemical step. The one-step synthesis of 1-phenylethyl acetate by adding acetic acid to the double bond of styrene is already known in the prior art and uses expensive high molecular weight catalysts and has additional handling problems. In contrast, the method according to the invention does not require any solvent, uses a cheap and safe catalyst at low loadings and thus produces a very limited amount of waste. The method provides a very high atom economy and generally meets the principles of green chemistry.

[0033] It is advantageous to use a low loading of a commercial, cheap and earth-abundant alkali or alkaline earth metal salt catalyst to promote the reaction. Such a catalyst provides good reactivity while limiting the loss of styrene, thereby reducing atomic waste and process costs. The balance between reactivity and limited styrene loss is crucial for improving process efficiency, since the formation of 1-phenylethyl acetate is highly reversible, but the degradation of styrene to dimers, oligomers and polymers is not.

[0034] In one example of the present invention, the catalyst is an alkali or alkaline earth metal bromide or the respective hydrate, such as LiBr, MgBr2, CaBr2 or MgBr2(H2O)6.

[0035] The selection of a suitable catalyst and the adjustment of further reaction parameters should take into account the availability, cost and loading of the catalyst, as well as the potential loss of styrene due to the formation of polystyrene.

[0036] In a further embodiment of the method according to the invention, the catalyst is provided in an amount of 35 mol% or less, 30 mol% or less, 25 mol% or less, 20 mol% or less, 15 mol% or less, 10 mol% or less, 7.5 mol% or less, 5.0 mol% or less, preferably 2.5 mol% or less, 1.0 mol% or less, 0.75 mol% or less, 0.5 mol% or less.

[0037] For example, if the catalyst is an alkali or alkaline earth metal bromide, the amount of the catalyst is about 0.1 - 35 mol%, or 0.5 - 35 mol%, preferably 0.75 - 35 mol%, or 1.0 - 30.0 mol%, more preferably 2.5 - 20.0 mol% or 2.5 - 15.0 mol%, or 5.0 - 10.0 mol%, or about 7.5 mol%.

[0038] In a further embodiment of the process of the invention, the amount of acetic acid is provided in at least 3 styrene equivalents, preferably in at least 7 styrene equivalents, or in at least 10 styrene equivalents.

[0039] Under the conditions of the present invention, the formation of styryl acetate from styrene is reversible. It has been found that a low excess of acetic acid allows the reaction equilibrium to be shifted towards styryl acetate and thus limits the amount of styrene in the reaction mixture and increases the yield of the desired product.

[0040] Furthermore, when the process of the present invention is applied on an industrial scale, it has been found that styrene cannot be heated alone because it shows a very high exothermic decomposition above 51 °C. It has been found that dilution in acetic acid or a mixture of acetic acid and styryl acetate reduces the exothermic decomposition of styrene. With 3 equivalents of acetic acid already in the initial reaction mixture, the reaction can be carried out safely under reflux and the mixture of acetic acid and styrene can be recovered by distillation and then stored without safety concerns. Higher amounts of acetic acid will even better improve the safety of the reaction.

[0041] The amount of acetic acid needs to be balanced against the cost of the unused material that needs to be washed out or recovered.

[0042] In a further embodiment of the process of the invention, the catalyst is provided in an amount of 0.1 - 35 mol% and the acetic acid is provided in an amount of at least 3 styrene equivalents.

[0043] In one example, the process of the present invention can be carried out with 20 mol% of CaCl2 and 20 equivalents of acetic acid.

[0044] In a further example, the process of the present invention can be carried out with 15 mol% of MgCl2 and 10 equivalents of acetic acid.

[0045] In a further example, the process of the present invention can be carried out with 0.75 mol% of MgBr2(H2O)6 and 10 equivalents of acetic acid.

[0046] The conversion of styrene to styrene acetate by the method of the present invention is preferably carried out at elevated temperatures, such as at about 80 °C or higher, such as 100 °C or higher, or at about 110 °C or higher, or at about 120 °C or higher. When the reaction is carried out under pressure, such as in an autoclave, temperatures above 120 °C can be applied.

[0047] Generally, other temperature ranges can also be used for the method of the present invention. Lower temperatures may slow down the formation of styrene acetate without improving any other results of the reaction, and therefore, they are not effective. Higher temperatures require more energy and may increase styrene losses. The reaction time may be affected by other parameters, but is generally about 1 - 30 hours, preferably about 3 - 10 hours, such as 6 hours.

[0048] Generally, other reaction times can also be considered for the method of the present invention. However, shorter reaction times may result in incomplete conversion, while longer reaction times may lead to increased styrene losses.

[0049] The reaction of the present invention can be carried out under anhydrous conditions or in the presence of trace amounts of water. For example, the hydrated form of the catalyst does not significantly affect the reaction. Higher amounts of water, such as about 1 equivalent, may already reduce the yield of styrene acetate and increase styrene losses, although the desired product is still provided.

[0050] In a further embodiment, the unreacted styrene and / or unreacted acetic acid can be recycled from the reaction mixture by any suitable purification method, such as by distillation.

[0051] For example, styrene and acetic acid can be recovered as a mixture by directly distilling the reaction mixture. According to the method of the present invention, the recovered mixture of styrene and acetic acid can be further used as starting materials. As shown in Example 5, using the recovered mixture has no negative impact on the method of the present invention.

[0052] In a further embodiment of the present invention, styrene is obtained as a starting material for upgrading, such as obtained as recycled styrene monomer from polystyrene waste. All atoms of styrene enter into the final product, so that the part of styrene acetate can be obtained from upgraded materials.

[0053] Alternatively, styrene can be obtained by dehydrogenation of ethylbenzene.

[0054] In a further embodiment of the present invention, acetic acid is obtained from renewable resources, such as by oxidative fermentation or by aerobic or anaerobic fermentation of sugars to obtain ethanol. All atoms of acetic acid enter into the final product, so that the part of styrene acetate can be obtained from renewable resources.

[0055] Alternatively, acetic acid can be obtained by carbonylation of methanol or other synthetic methods.

[0056] When the catalyst used in the method of the present invention is a halide, such as an alkali metal halide or an alkaline earth metal halide, in step b), by adding a halide atom instead of an acetate on the double bond, (1-haloethyl)benzene may be formed as a by-product with a yield of up to 2%. These by-products make purification by distillation more difficult when their boiling points are close to that of styralyl acetate, thus contaminating a large amount of fractions. This reduces the olfactory quality of the product or the obtainable yield.

[0057]

[0058] In a further embodiment of the method of the present invention, if the catalyst is a halide X, an acetate is added to the reaction mixture to remove the compound of formula (II). Therefore, the method of the present invention in which the catalyst is an alkali or alkaline earth metal halide or their respective hydrates further includes step c), which eliminates the by-product (1-haloethyl)benzene formed during method step b) by adding an acetate to the reaction mixture.

[0059] By adding an acetate, (1-haloethyl)benzene can be converted to 1-phenylethyl acetate in the same tank within a very short reaction time, such as within about 30 min or less.

[0060] The reaction mixture thus obtained allows the separation of styralyl acetate at the highest olfactory purity level, which is crucial for use as a fragrance ingredient. If desired, final purification of styralyl acetate can be carried out by distillation.

[0061] For example, the acetate can be added to the initial reaction mixture. Alternatively, it can also be added at a later stage, such as after the formation of styralyl acetate.

[0062] The acetate can be selected from Zn(OAc)2, NaOAc, CuOAc or their respective dihydrates.

[0063] The acetate is added to the reaction mixture in an amount of at least 2 mol%, or at least 2.5 mol% or at least 5 mol%.

[0064] For example, when the catalyst used in the method of the present invention is a bromide, such as an alkali metal bromide or an alkaline earth metal bromide, (1-bromoethyl)benzene (the compound of formula (IIa)) may be formed as a by-product with a yield of up to 2% by adding a bromine atom instead of an acetate group to the double bond in step b). Due to its boiling point being close to that of styralyl acetate, this by-product makes purification by distillation more difficult, thus contaminating a large amount of fractions. This reduces the olfactory quality of the product or the obtainable yield.

[0065]

[0066] In a further embodiment of the process according to the invention, if the catalyst is a bromide, an acetate is added to the reaction mixture to remove the compound of formula (IIa). Accordingly, the process according to the invention, wherein the catalyst is an alkali or alkaline earth metal bromide or the respective hydrate, further comprises step c), which eliminates the by-product (1-bromoethyl)benzene formed during process step b) by adding an acetate to the reaction mixture.

[0067] By adding an acetate, (1-bromoethyl)benzene can be converted into 1-phenylethyl acetate in the same vessel in a very short reaction time, for example in about 30 min or less.

[0068] The reaction mixture thus obtained allows the isolation of styralyl acetate at the highest olfactory purity level, which is crucial for use as a fragrance ingredient. If desired, final purification of styralyl acetate can be carried out by distillation.

[0069] For example, the acetate can be added to the initial reaction mixture. Alternatively, it can also be added at a later stage, for example after the formation of styralyl acetate.

[0070] The acetate may be selected from Zn(OAc)2, NaOAc, CuOAc or the respective dihydrates.

[0071] The acetate is added to the reaction mixture in an amount of at least 2 mol%, or at least 2.5 mol% or at least 5 mol%. Examples

[0072] Overview:

[0073] Characterization data of 1-phenylethyl acetate:

[0074] 1H NMR (CDCl3, 500 MHz) δ 7.37 - 7.26 (m, 5H), 5.88 (q, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.53 (d, J = 6.6 Hz, 3H) ppm.

[0075] 13C NMR (CDCl3, 125 MHz) δ 170.3 (s), 141.6 (s), 128.5 (2d), 127.8 (d), 126.1 (2d), 72.3 (d), 22.2 (q), 21.3 (q) ppm.

[0076] MS (EI): 164 (M+·, 18), 122 (92), 107 (40), 105 (85), 104 (100), 103 (31), 79 (29), 78 (31), 77 (48), 51 (29), 43 (88).

[0077] The characterization data corresponds to the reported values (Eur. J. Org. Chem. 2007, 13, 2073 - 2077).

[0078] Example 1: Synthesis of 1 - phenylethyl acetate using MgBr2(H2O)6 and Zn(OAc)2(H2O)2

[0079] A solution of MgBr2(H2O)6 (2.1 g, 7.2 mmol, 0.0075 eq) in acetic acid (577 g, 9.60 mol, 10 eq) was heated to reflux. Then, styrene (100 g, 960 mmol, 1.0 eq) was added dropwise over 20 min. The resulting reaction mixture was stirred at reflux for 7 h and then cooled to 90 °C. At this temperature, Zn(OAc)2(H2O)2 (5.3 g, 24 mmol, 0.025 eq) was added in portions, and the mixture was stirred at 90 °C for 30 min. Direct distillation of the reaction medium allowed the recovery of 601.3 g of a mixture of unreacted acetic acid and styrene (which contained 55.3 g of styrene and 546 g of acetic acid). Further distillation gave 1 - phenylethyl acetate (58.7 g, 37% yield, 357 mmol) as a colorless oil.

[0080] Example 2: Synthesis of 1 - phenylethyl acetate using MgCl2

[0081] A solution of MgCl2 (6.9 g, 72 mmol, 0.15 eq) in acetic acid (288 g, 4.80 mol, 10 eq) was heated to reflux. Then, styrene (50 g, 480 mmol, 1.0 eq) was added dropwise over 20 min. The resulting reaction mixture was stirred at reflux for 8 h. Direct distillation of the reaction medium allowed the recovery of 276.4 g of a mixture of unreacted acetic acid and styrene (which contained 28.6 g of styrene and 247.8 g of acetic acid). The residue was then diluted with MTBE and water, the phases were separated, and the organic layer was further washed with water (2x), 10 wt% Na2CO3, and brine. The combined organic layers were dried over MgSO4 and filtered. Removal of the solvent gave a yellow liquid, which upon distillation gave 1 - phenylethyl acetate (23.34 g, 30% yield, 142 mmol) as a colorless oil.

[0082] Example 3: Synthesis of 1 - phenylethyl acetate using CaCl2

[0083] A solution of CaCl2 (2.70 g, 24.4 mmol, 0.2 eq) and styrene (12.7 g, 122 mmol, 1.0 eq) in acetic acid (146 g, 2.44 mol, 20 eq) was heated to 110 °C and stirred for 15 h. Direct distillation of the reaction medium allowed the recovery of 142.8 g of a mixture of unreacted acetic acid and styrene (which contained 5.3 g of styrene and 137.5 g of acetic acid). The residue was then diluted with MTBE and water, the phases were separated, and the organic layer was further washed with water (2x), 10 wt% Na2CO3, and brine. The combined organic layers were dried over MgSO4 and filtered. Removal of the solvent gave a colorless liquid which, upon distillation, gave 1-phenylethyl acetate (8.6 g, 43% yield, 53 mmol) as a colorless oil.

[0084] Example 4: Recycling experiment - Synthesis of 1-phenylethyl acetate with CaCl2 using recycled acetic acid and styrene recovered from Example 3

[0085] To a mixture of 128.48 g of recycled acetic acid and styrene (which contained 4.73 g of styrene and 123.75 g of acetic acid) was added CaCl2 (2.70 g, 24.4 mmol, 0.2 eq), fresh styrene (8.0 g, 77 mmol, 0.63 eq), and acetic acid (23 g, 0.38 mol, 3.2 eq). The resulting solution was heated to 110 °C and stirred for 15 h. Direct distillation of the reaction medium allowed the recovery of 135.6 g of a mixture of unreacted acetic acid and styrene (which contained 12.7 g of styrene and 131.4 g of acetic acid). The residue was then diluted with MTBE and water, the phases were separated, and the organic layer was further washed with water (2x), 10 wt% Na2CO3, and brine. The combined organic layers were dried over MgSO4 and filtered. Removal of the solvent gave a colorless liquid which, upon distillation, gave 1-phenylethyl acetate (9.02 g, 45% yield, 55 mmol) as a colorless oil.

[0086] Example 5: Screening of reaction conditions:

[0087]

[0088] Table 1

[0089]

[0090]

[0091] Table 1 shows the results of screening different catalysts and reaction conditions, varying the catalyst and its amount, the amount of acetic acid, the reaction time, and the temperature. The reaction conditions were not optimized. It can be seen that the reaction of the present invention can be carried out with a catalyst selected from alkali or alkaline earth metal salts to obtain a good yield of styrene acetate while minimizing the loss of styrene. Other metal catalysts that do not belong to alkali or alkaline earth metal salts proved to be less efficient (entries 18, 20 - 22) and / or led to an increase in styrene loss (entries 17 - 19). The sulfonic acid catalysts 2-naphthalenesulfonic acid (2-NSA) and p-toluenesulfonic acid (pTSA) of entries 1 - 4 are comparative examples.

Claims

1. A method for preparing a compound of formula (I), The method comprises the following steps: a) Providing styrene, b) In the presence of a catalyst and acetic acid, converting styrene into a compound of formula (I), wherein the catalyst is selected from alkali or alkaline earth metal salts.

2. The method according to claim 1, wherein the alkali or alkaline earth metal salt is an alkali or alkaline earth metal halide or its respective hydrate.

3. The method according to claim 1 or 2, wherein the alkali or alkaline earth metal salt is selected from LiCl, LiBr, LiI, NaBr, MgCl2, MgBr2, MgI2, CaCl2, CaBr2 and CaI2.

4. The method according to claims 1 to 3, wherein the alkali or alkaline earth metal salt is an alkali or alkaline earth metal bromide or its respective hydrate.

5. The method according to any one of the preceding claims, wherein the catalyst is provided in an amount of 35 mol% or less.

6. The method according to any one of the preceding claims, wherein the acetic acid is provided in an amount of at least 3 styrene equivalents.

7. The method according to any one of the preceding claims, wherein the unreacted styrene is recycled from the reaction mixture by any suitable purification method.

8. The method according to any one of the preceding claims, wherein the unreacted acetic acid is recycled from the reaction mixture by any suitable purification method.

9. The method according to any one of the preceding claims, wherein the styrene is obtained as a starting material for upgrading.

10. The method according to any one of the preceding claims, wherein the acetic acid is obtained from renewable resources.

11. The method according to claim 2, further comprising step c), which is to eliminate the by-product (1-haloethyl)benzene formed during the method step b) by adding an acetate to the reaction mixture.

12. The method according to claim 11, wherein the acetate is selected from Zn(OAc)2, NaOAc, CuOAc or their respective dihydrates.

13. The method according to claim 11 or 12, wherein the acetate is added in an amount of at least 2 mol%.

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