process

Abstract

Formula (I) [Formula 1] A process for producing a compound represented by JPEG2025541914000010.jpg3343, comprising the steps of: a) providing styrene; b) converting styrene into a compound of formula (I) in the presence of a catalyst and acetic acid; wherein the catalyst is selected from alkali or alkaline earth metal salts, The process is provided, comprising:

Description

[Technical Field]

[0001] Technical Field The present invention relates generally to a process for producing 1-phenylethyl acetate. [Background technology]

[0002] 1-Phenylethyl acetate (CAS number 93-92-5), also known as Gardenol, is a compound with strong, bright, green (leaf, apple), metallic (hazelnut, rhubarb), fruity (plum, apricot), and floral (gardenia) notes. For example, the compound can be prepared in two steps by hydrogenating acetophenone to 1-phenylethanol, followed by acetylation to 1-phenylethyl acetate.

[0003] Alternatively, Gardenol can be obtained from styrene (CAS No. 100-42-5). For example, this transformation can be carried out using lanthanide salts as catalysts (Huaxue Shiji 2012, 34, 1151-1152), but these catalysts are rare and therefore expensive. Also, 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 process. In both cases, high catalyst loadings are required, and the amount of acetic acid does not allow for a safe and efficient process.

[0004] The preparation of Gardenol requires new or improved processes, for example, in terms of efficiency and / or sustainability. Summary of the Invention

[0005] overview According to a first aspect of the present invention, a compound of formula (I) [ka] A process for producing a compound represented by the formula:

[0006] Certain embodiments of any aspect of the present invention may provide one or more of the following advantages: -Short synthesis - only one chemical step is required. -Widely available, earth-abundant catalysts, -Low catalyst load, -No solvent required, - Fine-tuning the amount of acetic acid, leading to an overall safer process on an industrial scale; - acetic acid (starting material) available as a renewable feedstock; -Styrene (starting material) available as an upcycling starting material through the conversion of plastic waste; -Recycling of unreacted starting materials (acetic acid and styrene) -High Gardenol olfactory quality, -Cost-effective.

[0007] The details, examples, and preferences provided with respect to any particular one or more of the described aspects of the invention are further described herein and apply equally to all aspects of the invention. Any combination of the embodiments, examples, and preferences described herein, in all possible variations thereof, is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

[0008] Detailed Description 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 earth alkali metal salts.

[0009] Therefore, the present specification refers to 1-phenylethyl acetate (compound represented by formula (I)) [ka] A process for producing The following steps, a) providing styrene; b) converting styrene into a compound of formula (I) in the presence of a catalyst and acetic acid; wherein the catalyst is selected from alkali or alkaline earth metal salts, The process comprises:

[0010] The method is described in Scheme 1. [ka]

[0011] Catalysts selected from alkali or alkaline earth metal salts are relatively inexpensive and widely available, which is an improvement over the prior art, where rare, expensive, and sometimes problematic catalysts (in terms of toxicity or handling safety) have been reported.

[0012] When the catalyst is an alkali or alkaline earth metal salt, it may be, for example, an alkali or alkaline earth halide, or a hydrate thereof. For example, it may be selected from the group consisting of alkali or alkaline earth chlorides, bromides, or iodides, or a hydrate thereof. In particular, LiCl, LiBr, LiI, NaBr, MgCl, MgBr, MgI, CaCl, CaBr, and CaI, or a hydrate thereof, such as MgBr(H0) or CaI(H0). x It can be selected from the group consisting of:

[0013] The present invention provides a viable synthesis that is sustainable, process- and cost-efficient, particularly for industrialization. Compared to current industrial processes, the present invention offers an alternative by using styrene as a starting material and converting it in a single chemical step. The one-step synthesis of 1-phenylethyl acetate by adding acetic acid across the double bond of styrene is already known in the prior art and uses expensive, high-molecular-weight catalysts that entail additional handling problems. In contrast, the process according to the present invention does not require solvents, uses inexpensive and safe catalysts with low loadings, and therefore generates very limited amounts of waste. The process offers a very high atom economy and generally meets the principles of green chemistry.

[0014] It is advantageous to use commercially available, inexpensive, and earth-abundant alkali or alkaline earth metal salt catalysts at low loadings to promote the reaction. Such catalysts allow good reactivity while limiting styrene loss, thereby reducing atomic waste and process costs. While the formation of 1-phenylethyl acetate is highly reversible, the decomposition of styrene to di-, oligo-, and polymeric forms is not, so a balance between reactivity and limited styrene loss is essential to improve process efficiency.

[0015] In one example of the present invention, the catalyst is an alkali or alkaline earth bromide or respective hydrate, such as LiBr, MgBr2, CaBr2, or MgBr2(H2O)6. Selection of an appropriate catalyst and adjustment of further reaction parameters should take into account catalyst availability, cost and loading, as well as potential styrene losses due to the formation of polystyrene.

[0016] In further embodiments of the process of the present invention, the catalyst is provided in an amount of not more than 35 mol%, not more than 30 mol%, not more than 25 mol%, not more than 20 mol%, not more than 15 mol%, not more than 10 mol%, not more than 7.5 mol%, not more than 5.0 mol%, preferably not more than 2.5 mol%, not more than 1.0 mol%, not more than 0.75 mol%, not more than 0.5 mol%.

[0017] For example, when the catalyst is an alkali or alkaline earth bromide, the amount of catalyst is about 0.1 to 35 mol%, or 0.5 to 35 mol%, preferably 0.75 to 35 mol%, or 1.0 to 30.0 mol%, more preferably 2.5 to 20.0 mol%, or 2.5 to 15.0 mol%, or 5.0 to 10.0 mol%, or about 7.5 mol%.

[0018] In further embodiments of the process of the present invention, the amount of acetic acid is provided at least 3 equivalents of styrene, preferably at least 7 equivalents of styrene, or at least 10 equivalents of styrene.

[0019] The formation of Gardenol from styrene under the conditions of the present invention is reversible. It has been found that a small excess of acetic acid can push the equilibrium of the reaction toward Gardenol, thus limiting the amount of styrene in the reaction mixture and increasing the yield of the desired product.

[0020] 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 exhibits extremely high exothermic decomposition above 51°C. Dilution in acetic acid or a mixture of acetic acid and Gardenol has been found to reduce the exothermic decomposition of styrene. With three equivalents of acetic acid already in the initial reaction mixture, the reaction can be safely carried out at reflux, and the mixture of acetic acid and styrene can be recovered by distillation and then stored without safety concerns. A higher amount of acetic acid would improve the safety of the reaction even further.

[0021] The amount of acetic acid must be balanced by the cost of unused material that must be washed off or recovered.

[0022] In a further embodiment of the process of the present invention, the catalyst is provided in an amount of 0.1 to 35 mol % and the amount of acetic acid is provided in an amount of at least 3 equivalents of styrene.

[0023] In one example, the process of the present invention can be carried out with 20 mol % CaCl and 20 equivalents of acetic acid. In a further example, the process of the present invention can be carried out with 15 mol % MgCl2 and 10 equivalents of acetic acid. In a further example, the process of the present invention can be carried out with 0.75 mol % MgBr2(H2O)6 and 10 equivalents of acetic acid.

[0024] The conversion of styrene to Gardenol by the process of the present invention is preferably carried out at elevated temperatures, for example, above about 80° C., such as above 100° C., or above about 110° C., or above about 120° C. Temperatures above 120° C. may be applied when the reaction is carried out under pressure, for example, in an autoclave.

[0025] In general, other temperature ranges can be used in the process of the present invention. Lower temperatures may slow the formation of Gardenol but do not improve other reaction outcomes and are therefore less efficient. Higher temperatures require more energy and may increase styrene loss. Reaction times may be affected by other parameters but are generally about 1 to 30 hours, preferably about 3 to 10 hours, e.g., 6 hours.

[0026] In general, other reaction times may be considered for the process of the present invention, however, shorter reaction times may lead to incomplete conversion, while longer reaction times may lead to increased styrene losses.

[0027] 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. Large amounts of water, for example, about 1 equivalent, can already reduce the yield of Gardenol and increase the loss of styrene, but still provide the desired product.

[0028] In a further embodiment, the unconverted styrene and / or unconverted acetic acid can be recycled from the reaction mixture by any suitable purification process, for example, by distillation.

[0029] For example, styrene and acetic acid can be recovered as a mixture by direct distillation of the reaction mixture. The recovered mixture of styrene and acetic acid can be further used as a starting material according to the process of the present invention. As shown in Example 5, the use of the recovered mixture does not have a negative effect on the process of the present invention.

[0030] In a further aspect of the invention, styrene is obtained as an upcycled starting material, for example, as recycled styrene monomer from polystyrene waste, with all atoms of styrene incorporated into the final product, thereby allowing said portion of Gardenol to be derived from upcycled materials. Alternatively, styrene can be obtained by dehydrogenation of ethylbenzene.

[0031] In a further embodiment of the invention, the acetic acid is obtained from a renewable resource, for example, from ethanol by oxidative fermentation or by aerobic or anaerobic fermentation of sugars, and all atoms of the acetic acid are incorporated into the final product, thereby allowing said portion of Gardenol to be obtained from a renewable resource. Alternatively, acetic acid can be obtained by carbonylation of methanol or other synthetic methods.

[0032] When the catalyst for the process of the present invention is a halide, such as an alkali halide or an alkaline earth halide, in step b), the addition of a halide atom to the double bond instead of acetate can result in the formation of (1-haloethyl)benzene as a by-product with a yield of up to 2%.These by-products, when their boiling points are close to that of Gardenol, make purification by distillation more difficult, thereby contaminating a significant number of fractions.This reduces the olfactory quality of the product or the yield obtained.

[0033] [ka] In a further embodiment of the process of the invention, when the catalyst is a halide X, acetate is added to the reaction mixture to remove the compound of formula (II). Thus, the process of the invention, in which the catalyst is an alkali or alkaline earth halide or a hydrate thereof, further comprises step c) of removing the by-product (1-haloethyl)benzene formed in process step b) by adding acetate to the reaction mixture. By adding acetate, (1-haloethyl)benzene can be converted to 1-phenylethyl acetate in the same pot in a very short reaction time, for example, within about 30 minutes.

[0034] The reaction mixture thus obtained allows Gardenol to be isolated with the highest level of olfactory purity, which is crucial for its use as a fragrance ingredient.Final purification of Gardenol can be carried out by distillation, if desired.

[0035] For example, acetate can be added to the initial reaction mixture, or alternatively, it can be added at a later stage, for example, after the formation of Gardenol.

[0036] The acetate can be selected from the group consisting of Zn(OAc)2, NaOAc, CuOAc, or the corresponding dihydrate. 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 %.

[0037] For example, when the catalyst for the process of the present invention is a bromide, such as an alkali bromide or alkaline earth bromide, the bromide atom is added to the double bond instead of the acetate atom in step b), resulting in the formation of (1-bromoethyl)benzene (the compound represented by formula (IIa)) as a by-product in a yield of up to 2%. This by-product, whose boiling point is close to that of Gardenol, makes purification by distillation more difficult and thereby contaminates a significant number of fractions. This reduces the olfactory quality of the product or the yield obtained.

[0038] [ka] In a further embodiment of the process of the present invention, when the catalyst is a bromide, acetate is added to the reaction mixture to remove the compound of formula (IIa). Thus, the process of the present invention, in which the catalyst is an alkali or alkaline earth bromide or a hydrate thereof, further comprises step c) of removing the by-product (1-bromoethyl)benzene formed during process step b) by adding acetate to the reaction mixture.

[0039] By adding acetate, (1-bromoethyl)benzene can be converted to 1-phenylethyl acetate in the same pot in a very short reaction time, for example, within about 30 minutes.

[0040] The reaction mixture thus obtained allows Gardenol to be isolated with the highest level of olfactory purity, which is crucial for its use as a fragrance ingredient.Final purification of Gardenol can be carried out by distillation, if desired.

[0041] For example, acetate can be added to the initial reaction mixture, or alternatively, it can be added at a later stage, for example, after the formation of Gardenol. The acetate can be selected from the group consisting of Zn(OAc)2, NaOAc, CuOAc, or the corresponding dihydrate. 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 %.

[0042] example General: Characterization data for 1-phenylethyl acetate: 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. 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. 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). Characterization data correspond to reported values ​​((Eur. J. Org. Chem. 2007, 13, 2073-2077)).

[0043] Example 1: MgBr 2 (H 2 O) 6 &Zn(OAc) 2 (H 2 O) 2 Synthesis of 1-phenylethyl acetate in A solution of MgBr2(HO)6 (2.1 g, 7.2 mmol, 0.0075 equiv.) in acetic acid (577 g, 9.60 mol, 10 equiv.) was heated to reflux. Styrene (100 g, 960 mmol, 1.0 equiv.) was then 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(HO)2 (5.3 g, 24 mmol, 0.025 equiv.) was added portionwise, and the mixture was left stirring 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 (containing 55.3 g of styrene and 546 g of acetic acid). Further distillation afforded 1-phenylethyl acetate (58.7 g, 37% yield, 357 mmol) as a colorless oil.

[0044] Example 2: MgCl 2 Synthesis of 1-phenylethyl acetate in A solution of MgCl2 (6.9 g, 72 mmol, 0.15 equiv.) in acetic acid (288 g, 4.80 mol, 10 equiv.) was heated to reflux. Styrene (50 g, 480 mmol, 1.0 equiv.) was then 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 (containing 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, after distillation, gave 1-phenylethyl acetate (23.34 g, 30% yield, 142 mmol) as a colorless oil.

[0045] Example 3: CaCl 2 Synthesis of 1-phenylethyl acetate in A solution of CaCl2 (2.70 g, 24.4 mmol, 0.2 equiv.) and styrene (12.7 g, 122 mmol, 1.0 equiv.) in acetic acid (146 g, 2.44 mol, 20 equiv.) 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 (containing 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 washed with additional water (2x), 10 wt% Na2CO3, and brine. The combined organic layers were dried over MgSO4 and filtered. Removal of the solvent yielded a colorless liquid, which, after distillation, gave 1-phenylethyl acetate (8.6 g, 43% yield, 53 mmol) as a colorless oil.

[0046] Example 4: Recycle Experiment - CaCl using recycled acetic acid and styrene recovered from Example 3 2 Synthesis of 1-phenylethyl acetate in To 128.48 g of the recycled acetic acid and styrene mixture (containing 4.73 g of styrene and 123.75 g of acetic acid), CaCl2 (2.70 g, 24.4 mmol, 0.2 equiv.), fresh styrene (8.0 g, 77 mmol, 0.63 equiv.), and acetic acid (23 g, 0.38 mol, 3.2 equiv.) were added. The resulting solution was heated to 110 °C and left stirring for 15 h. Direct distillation of the reaction medium allowed the recovery of 135.6 g of the unreacted acetic acid and styrene mixture (containing 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 after distillation gave 1-phenylethyl acetate (9.02 g, 45% yield, 55 mmol) as a colorless oil.

[0047] Example 5: Screening of reaction conditions: [ka] [Table 1]

[0048] Table 1 shows the results of screening various catalysts and reaction conditions, varying the catalyst and its amount, the amount of acetic acid, and the reaction time and 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 good yields of Gardenol while minimizing styrene loss. Other metal catalysts not belonging to the alkali or alkaline earth metal salt group proved less efficient (entries 18, 20-22) and / or led to increased styrene loss (entries 17-19). The sulfonic acid catalysts 2-naphthylsulfonic acid (2-NSA) and p-toluenesulfonic acid (pTSA) in entries 1-4 are comparative examples.

Claims

1. Formula (I) 【Chemistry 1】 A process for producing a compound represented by the formula: a) providing styrene; b) converting styrene into a compound of formula (I) in the presence of a catalyst and acetic acid; wherein the catalyst is selected from alkali or alkaline earth metal salts, The process comprising:

2. 2. The process of claim 1, wherein the alkali or alkaline earth metal salt is an alkali or alkaline earth halide, or a hydrate thereof.

3. Alkali or alkaline earth metal salts include LiCl, LiBr, LiI, NaBr, MgCl 2 , MgBr 2 , MgI 2 , CaCl 2 , CaBr 2 , and CaI 2 3. The process of claim 1 or 2, selected from the group consisting of:

4. 4. The process of any one of claims 1 to 3, wherein the alkali or alkaline earth metal salt is an alkali or alkaline earth bromide or a hydrate thereof.

5. 10. The process of any preceding claim, wherein the catalyst is provided in an amount of 35 mol % or less.

6. 10. The process of any preceding claim, wherein the acetic acid is provided in at least 3 equivalents of styrene.

7. 10. The process of any preceding claim, wherein unconverted styrene is recycled from the reaction mixture by any suitable purification process.

8. 10. The process of any preceding claim, wherein unconverted acetic acid is recycled from the reaction mixture by any suitable purification process.

9. 10. The process of any of the preceding claims, wherein styrene is obtained as an upcycled starting material.

10. 10. The process of any preceding claim, wherein the acetic acid is obtained from a renewable resource.

11. 3. The process of claim 2, further comprising step c) of removing the by-product (1-haloethyl)benzene formed during process step b) by adding acetate to the reaction mixture.

12. Acetate is Zn(OAc) 2 12. The process of claim 11, wherein the hydrate is selected from the group consisting of NaOAc, CuOAc or the corresponding dihydrates.

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

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