A process for making 1-methoxy-4-(3-phenylprop-1-ENYL) benzene

Abstract

There is provided a method of making 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)), wherein the wavy bond indicates an unspecified configuration of the adjacent double bond, comprising the steps of a) preparing a Grignard reagent from (2-haloethyl)benzene and Magnesium, b) reacting the Grignard reagent with 4-methoxybenzaldehyde to form 1-(4- methoxyphenyl)-3-phenylpropan-1-ol (compound of formula (II)), c) dehydrating the compound of formula (II) to provide 1-methoxy-4-(3-phenylprop-1- enyl) benzene (compound of formula (I)), wherein steps a) and b) are carried out in methyl-THF as solvent.

Description

[0001] A PROCESS FOR MAKING 1-METHOXY-4-(3-PHENYLPROP-1-ENYL) BENZENE

[0002] PROCESS

[0003] TECHNICAL FIELD

[0004] The present invention relates generally to a method of making 1-methoxy-4-(3-phenylprop-1- enyl) benzene. It further relates to

[0005] BACKGROUND

[0006] 1-methoxy-4-(3-phenylprop-1-enyl) benzene is a compound capable of releasing fragrant compounds in a controlled manner into the surroundings, a so called fragrance precursor, as described in WO2012 / 085287. By spontaneous air oxidation the compound releases the corresponding fragrant aldehydes.

[0007] The compound can be obtained by a classical Wittig reaction using phenethyltriphenylphosphonium bromide, BuLi (or other strong bases) and 4- methoxybenzaldehyde. However, in this reaction several by-products are formed, which might have a negative impact on the environment and on costs.

[0008] It is therefore desirable to provide a new or improved method of making 1-methoxy-4-(3- phenylprop-1-enyl) benzene.

[0009] SUMMARY

[0010] In accordance with a first aspect of the present invention there is provided a method for making 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)), comprising the steps of a) preparing a Grignard reagent from (2-haloethyl)benzene and Magnesium, b) reacting the Grignard reagent with 4-methoxybenzaldehyde to form 1-(4- methoxyphenyl)-3-phenylpropan-1-ol (compound of formula (II)), c) dehydrating the compound of formula (II) to provide 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)).

[0011] In accordance with a second aspect of the present invention there is provided a method of making 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)), comprising the method described previously, and further comprising a strong base treatment.

[0012] In accordance with a third aspect of the present invention there is provided a method of making a mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)).

[0013] In accordance with a fourth aspect of the present invention there is provided a mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1- methoxy-4-(3-phenylallyl)benzene (compound of formula (III)).

[0014] In accordance with a fifth aspect of the present invention there is provided the use of 1- methoxy-4-(3-phenylallyl)benzene (compound of formula (III)) or the mixture comprising 1- methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3- phenylallyl)benzene (compound of formula (III)) as fragrance precursor for generating the corresponding aldehydes.

[0015] In accordance with a sixth aspect of the present invention there is provided a method for generating a mixture of corresponding fragrant aldehydes, characterized in that the mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1- methoxy-4-(3-phenylallyl)benzene (compound of formula (III)) is exposed to oxygen.

[0016] In accordance with a seventh aspect of the present invention there is provided a perfume composition comprising the mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)). In accordance with an eighth aspect of the present invention there is provided a consumer product comprising the mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)).

[0017] Certain embodiments of any aspect of the present invention may provide one or more of the following advantages:

[0018] • sustainable and environmental friendly manufacturing process;

[0019] • access to a mixture of compounds suitable for use as fragrance precursor, providing a new facette to perfumer’s palette.

[0020] The details, examples and preferences provided in relation to any particular one or more of the stated aspects of the present invention will be further described herein and apply equally to all aspects of the present invention. Any combination of the embodiments, examples and preferences described herein in all possible variations thereof is encompassed by the present invention unless otherwise indicated herein, or otherwise clearly contradicted by context.

[0021] DETAILED DESCRIPTION

[0022] The present invention is based on the surprising finding that the compound of formula (I) can be efficiently provided by the following three step method.

[0023] There is therefore provided herein a method of making 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)), comprising the steps of a) preparing a Grignard reagent from (2-haloethyl)benzene and magnesium, b) reacting the Grignard reagent with 4-methoxybenzaldehyde to form 1-(4- methoxyphenyl)-3-phenylpropan-1-ol (compound of formula (II)), c) dehydrating the compound of formula (II) to provide 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)).

[0024] The the wavy bond of the compound of formula (I) indicates an unspecified configuration of the adjacent double bond. The compound of formula (I) has an E or a Z-configuration, or is a mixture of E- and Z-isomers.

[0025] When compared to the classical Wittig reaction, which is using phenethyltriphenylphosphonium bromide, BuLi and 4-methoxybenzaldehyde, the method of the present invention offers a sustainable and environmental friendly manufacturing process.

[0026] For the classical Wittig reaction in a first step prior to the olefination step the respective ylide needs to be prepared. This requires the alkylation of triphenylphosphine with (2- bromoethyl)benzene and sub-sequent deprotonation of the phosphonium salt with stoichiometric amounts of the strong base BuLi, generating stoichiometric amounts of two sideproducts LiBr and butane. While the bromide anion of LiBr provokes negative effect to the waste water treatment plant and has to be disposed at significant costs, butane is a volatile organic compound (VOC) and causes greenhouse effects to the environment when released to the atmosphere.

[0027] In a second step the ylide is reacted with 4-methoxybenzaldehyde to generate the desired compound of formula (I), and there is also formed triphenylphosphine oxide as undesired byproduct in stoichiometric amounts. Its removal is difficult and costly at industrial scale.

[0028] The method of the present invention is much more environmentally friendly in comparison to the Wittig reaction, as no VOC’s are generated and the by-products, water and magnesium salts, can be treated in a waste water treatment plant. In addition, it is also more cost efficient.

[0029] For example, the (2-haloethyl)benzene can be selected from the group consisting of (2- chloroethyl)benzene and (2-bromoethyl)benzene. In one specific embodiment, step a) of the method of the present invention, the preparation of the Grignard reagent, is carried out in methyl-THF as solvent. For example, the reaction is carried out at a temperature of about 10 - 90 °C, preferably at a temperature between 60 and 85 °C.

[0030] In one specific embodiment, step b) of the method of the present invention, the Grignard reaction, is carried out in methyl-THF as solvent. For example, the reaction is carried out at a temperature between 10 and 100 °C.

[0031] Alternatively, steps a) and b) of the method of the present invention can be carried out in a different solvent, for example in an ether like diethyl ether, THF, glycol ether, cyclopropyl methyl ether, or mixtures thereof, or mixtures of said ether (mixtures) with toluene, xylene and / or decane, for example THF / decane or THF / xylene.

[0032] In another specific embodiment, step c) of the method of the present invention, the dehydrating step, is carried out in methyl-THF as solvent. For example, the reaction is carried out at a temperature of about 80 - 100 °C, preferably of about 85 - 95 °C.

[0033] In one specific embodiment, step a), b) and / or c) of the method of the present invention is carried out in methyl-THF as solvent.

[0034] Typically, the Grignard reaction could be carried out in THF or in a THF / toluene mixture. Compared to THF, methyl-THF, the preferred solvent in step a), b) and / or c) of the present invention, is easier to handle with regard to recovery, drying and recycling.

[0035] For example, THF is miscible with water, thus a considerable amount of it elutes into the aqueous layer during the work-up process, which is problematic regarding recyclability and wastewater load. In contrast to this, methyl-THF has a lower solubility in water, which reduces the wastewater load. Methyl-THF can be easily dried and recycled with a high recovery rate. For example, it can be recovered almost dry from the process and be re-used after a short distillation. The convenient separation of water and methyl-THF is particularly relevant for step b) and / or step c), in which water is involved.

[0036] In one specific embodiment, when using methyl-THF as solvent, the reaction apparatus can be dried during the distillation. This is particularly advantageous, if the method is carried out on industrial scale, as the reactor is dried already during this step. Therefore, it is possible to continue with the next batch of the method without an additional drying step after each batch. Methyl-THF is a greener and safer solvent, obtainable from renewable feedstock, with better toxicological profile than both THF (H351 , carcinogenic category 2) and toluene (H361d, suspected of damaging the unborn child).

[0037] In another specific embodiment, steps a), b) and c), or steps b) and c) are carried out as a one- pot process, for example in methyl-THF as solvent. The one-pot process reduces the work up steps of the intermediates and reduces the number of reactors to be cleaned.

[0038] Methyl-THF as solvent is suitable for both, the Grignard reaction (steps a) and b)) and the dehydration step (step c)). Their performance in one-pot offers an additional advantage by saving time and costs for the workup and set up of a next step, while providing good yields.

[0039] In another specific embodiment, step c) of the method of the present invention, the dehydrating step, is catalysed by methane sulfonic acid.

[0040] In general, the dehydrating step can be catalyzed by any acid. Typically, one would choose a relatively cheap acid, for example, aqueous HOI, sulfuric acid, supported and heterogenous acids, p-toluene sulfonic acid, or others. However, to use aqueous HOI or the other acids mentioned above, glass-lined equipment is required to avoid corrosion. On industrial scale, stainless steel reactors are much more advantageous. The use of methane sulfonic acid (MsOH) as catalyst for the dehydration step allows to perform this step in both glass-lined and stainless steel reactors.

[0041] In another specific embodiment, steps a), b) and c), or steps b) and c) are carried out as a one- pot process using methyl-THF as solvent, and methane sulfonic acid (MsOH) as catalyst for step c) of the method of the present invention, the dehydrating step.

[0042] In a further embodiment the obtained compound of formula (I) is further treated with a strong base with a pKbof about 1 or lower, to cause a shift of the double bond, thereby forming a compound of formula (III). The compound of formula (III) has a double bond with an unspecified configuration, as indicated by the adjacent wavy bond. The compound of formula (III) has an E or a Z-configuration, or is a mixture of E- and Z-isomers.

[0043] For example, the base is KOH or an aq. KOH solution. Alternatively, the base can be any other strong base with a pKbof about 1 or lower, for example any hydroxide of alkali metals and alkaline earth metals, or others selected from the group consisting of metal alkoxides.

[0044] For example, the reaction is carried out at a temperature of about 100 - 150 °C, preferably of about 130 - 140 °C.

[0045] If the compound of formula (I) is treated with a weak base with a pKbof about 3.5 or higher, for example Na2CO3, no isomerization occurs.

[0046] Furthermore, acidic treatment of the compound of formula (I) was found to cause isomerization along with degradation.

[0047] By applying the additional step of strong base treatment to the method of the present invention, there is provided a method of making 1-methoxy-4-(3-phenylallyl) benzene (compound of formula (III)).

[0048] In a further aspect, there is provided the compound of formula (III). The compound of formula (III) might also act as a fragrance precursor, similar to the compound of formula (I). The compound of formula (III) is able to release the corresponding fragrant aldehydes which might be different than the aldehydes released by the compound of formula (I). Therefore, there is provided the use of the compound of formula (III) as a fragrance precursor.

[0049] By applying the additional step of strong base treatment to the method of the present invention, there is also provided a method of making a mixture comprising of 1-methoxy-4-(3-phenylprop- 1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl) benzene (compound of formula (III)).

[0050] In a further aspect, there is provided the mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl) benzene (compound of formula (III)). For example, said mixture might release four different corresponding fragrant aldehydes by oxidative cleavage. Therefore, there is provided the use of the mixture comprising 1-methoxy- 4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3- phenylallyl)benzene (compound of formula (III)) as a fragrance precursor.

[0051] The ratio of the released corresponding fragrant aldehydes can be adjusted by the ratio of the compound of formula (I) and the compound of formula (III). The ratio can be defined by the reaction time and base concentration of the strong base treatment.

[0052] For example, the ratio of the compound of formula (I) and the compound of formula (III) is between 99.9: 0.1 and 50:50, for example between 99.5:0.5 and 57:43, or between 65:35 and 60:40.

[0053] In a further aspect, there is provided the use of the compound of formula (III) as fragrance precursor for generating the corresponding fragrant aldehydes.

[0054] There is also provided the use of the mixture comprising the compound of formula (I) and the compound of formula (III) as fragrance precursor for generating the corresponding fragrant aldehydes.

[0055] In a further aspect, there is provided a method for generating a mixture of corresponding fragrant aldehydes, characterized in that the compound of formula (III) or the mixture comprising the compound of formula (I) and the compound of formula (III) is exposed to oxygen.

[0056] In a further aspect, there is provided a perfume composition comprising the compound of formula (III) or the mixture comprising the compound of formula (I) and the compound of formula (III).

[0057] Said perfume composition may comprise the compound of formula (III) or the mixture comprising the compound of formula (I) and the compound of formula (III) alone, or in combination with known odorant molecules selected from the extensive range of natural products, and synthetic molecules currently available, such as essential oils, alcohols, aldehydes and ketones, ethers and acetals, esters and lactones, macrocycles and heterocycles, and / or in admixture with one or more ingredients or excipients conventionally used in conjunction with odorants in perfume compositions, for example, carrier materials, stabilizers, and other auxiliary agents commonly used in the art. The perfume composition may comprise further precursors possessing a different chemical structure.

[0058] In a further aspect, there is provided a consumer product comprising the compound of formula (III) or the mixture comprising the compound of formula (I) and the compound of formula (III), and a consumer product base.

[0059] The consumer product for example is selected from fine fragrance, personal care products (body care products, hair care products, cosmetic products) fabric care products, home care products and air care products. As used herein, "consumer product base" means a composition for use as a consumer product to fulfill specific actions, such as cleaning, softening, and caring or the like. The consumer product might further comprise enzymes.

[0060] Alternatively, the compound of formula (I) can be prepared by the following three step synthesis: In the first step, 1-(4-methoxyphenyl)ethan-1-one and benzaldehyde are reacted in the presence of a base, for example KOH or NaOH, or an acid to form the corresponding chaicone derivative, which is then hydrogenated to 1-(4-methoxyphenyl)-3-phenylpropan-1-ol (compound of formula (II)) using either heterogenous or homogenous catalysts (e.g. CuCrO3, Ni-Raney, Ru-MACHO-BH or Ru(PPh3)3Cl2). The so formed secondary alcohol is further dehydrated to the compound of formula (I).

[0061] This approach is even more environmental friendly and sustainable as water is the only byproduct and the process does not use stoichiometric amounts of any metal.

[0062] The compound of formula (I) or the mixture comprising the compound of formula (I) and the compound of formula (III) is a fragrance precursor and can be used in many perfume compositions and / or consumer products. When used in textile care products, for example in detergents and / or fabric softeners, said fragrance precursor shows an increased resistance to be washed out. Its precursor effect, which is the released odour over time, can be perceived after one or more washes, for example three washes with a detergent and / or fabric softener, in which the fragrance precursor is not incorporated, for example with an unperfumed detergent base. In addition, the effect of the fragrance precursor can also be perceived after drying in a tumble dryer at different conditions. Therefore, the compound of formula (I) or the mixture comprising the compound of formula (I) and the compound of formula (III) is a fragrance precursor providing an extraordinary long- lasting effect over time, also after neutral wash and / or tumble drying.

[0063] The invention is now further described with reference to the following non-limiting examples. These examples are for the purpose of illustration only and it is understood that variations and modifications can be made by one skilled in the art.

[0064] EXAMPLES

[0065] Example 1 : Method of making 1-methoxy-4-(3-phenylprop-1-enyl) benzene a) A 4000 mL multi-necked flask fitted with a reaction column, head of column, condenser and dropping funnel is charged with 16 g 2-Phenylethyl chloride, 160 g MeTHF, 58 g Mg and 1 g Iodine. The mixture is stirred slowly and heated smoothly until 30°C. Then heating is stopped and the evolution of the reaction is observed. The mixture becomes colorless, and the reaction temperature evolution starts to increase. After the reaction is initiated, a solution of 320 g 2- Phenylethyl chloride in 400 g MeTHF is added dropwise during 6 h. 40 g MeTHF are added to clean the pipe. Then the reaction is heated for 30 minutes at reflux and the heating is stopped. b) 288 g of anisaldehyde are added dropwise to the reaction mixture of step a) during 3h. 80 g MeTHF are added to clean the pipe. The reaction mixture is then stirred for 30 minutes at 20- 25°C. 400 g of water are added dropwise during 1 ,5h and allowing to increase the temperature to 30°C. The formation of solids is observed. Then 20 g acetic acid are introduced dropwise for 1 ,5h allowing to increase the temperature up to 40°C. 400 g water are added during 10 min. The mixture is heated at 45°C for 1h and the stirring is stopped. Water is decanted. A solution of 40 g Na2CO3in 400 g water is added, and the mixture is heated at 45°C for 30 min. Water is decanted. c) 7.2 g methanesulfonic acid are added to the reaction mixture of step b, the mixture is heated at reflux and azeotropic distillation of Me-THF / water is performed to separate the water in a Dean-Stark / until all alcohol intermediate becomes dehydrated (GC control). The aq. phase is decanted. The organic phase from the dean-stark is returned to the reaction flask. Then a solution of 24 g Na2CO3and 360 g water is charged and the reaction mixture is stirred at 50°C for 30 min. The aq. phase is decanted and the org. phase is evaporated by distillation leading to 405 g of 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound (I), purity of 90%). Example 2: One-pot method of making 1-methoxy-4-(3-phenylprop-1-enyl) benzene

[0066] The reactor was flushed with nitrogen and charged with 19 g (792 mmol) magnesium turnings and 45 g THF. One crystal of iodine was added and the reaction mixture was heated to reflux. The heating was stopped and 102 g (720 mmol) (2-chloroethyl)benzene in 62 g THF and 260g toluene was added dropwise. A constant reflux was maintained by the heat of the reaction. After the addition, the dark, metallic and homogenious solution was stirred for 60 minutes without heating. Then the reagent was cooled to 10 °C and 100 g (720 mmol) 4- methoxybenzaldehyde in 156 g toluene was added dropwise in 60 minutes at 10-15 °C. The mixture was stirred for 1h at room temperature, 500 g HCI 2M was added, and the mixture was stirred for 20 minutes. The temperature rose to 45 °C. Then the aqueous layer was removed, and 1 g (13 mmol) p-TSOH was added to the organic layer. The reaction mass was heated to reflux over a Dean-Stark water separator. The reaction mixture was refluxed for 2 h, cooled to room temperature and washed once with 250 g water. The layers were separated and the organic layer concentrated in vacuum to give 169 g crude 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound (I)). Distillation over a 20 cm Vigreux columngave 133 g (593 mmol) of 1- methoxy-4-(3-phenylprop-1-enyl) benzene (mainly the E-isomer) as a colourless liquid (82% yield).

[0067] Example 3: Method of making a mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene and 1-methoxy-4-(3-phenylallyl)benzene

[0068] 3.6 g KOH (50 % in water) is added to the material prepared as described in Example 1 in Me- THF. The organic phase is heated under reflux and water is removed by azeotropic distillation of Me-THF / water using a Dean-Stark. Me-THF is removed by distillation under vacuum yieldingthe crude product containing a mixture of compound (I) and compound (II). Distillation from 170 to 250°C at 1 mbar provides 384 g of a mixture of (1-methoxy-4-(3-phenylprop-1-enyl) benzene (83%) and 1-methoxy-4-(3-phenylallyl)benzene (15%).

[0069] Example 4: Olfactive assessment

[0070] The compounds of formula (I) and (II) and their mixture were olfactively assessed on blotter (5% in EtOH after 24h). The odour of compound of formula (I) is described as floral, aldehydic, anisic like, and honey, linden blossom. The compound of formula (III) does have a similar odour with a stronger anisic aspect. The mixture of the two compounds is described as green (honey) and powdery floral (mimosa, aubepine). The compounds of formula (I) and (II) and their mixture are useful fragrance ingredients, providing different aspects to the perfumer’s palette.

Claims

Claims1. A method of making 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula(I)),wherein the wavy bond indicates an unspecified configuration of the adjacent double bond, comprising the steps of a) preparing a Grignard reagent from (2-haloethyl)benzene and Magnesium, b) reacting the Grignard reagent with 4-methoxybenzaldehyde to form 1-(4- methoxyphenyl)-3-phenylpropan-1-ol (compound of formula (II)),c) dehydrating the compound of formula (II) to provide 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)); wherein steps a) and b) are carried out in methyl-THF as solvent.

2. The method according to claim 1 , wherein the (2-haloethyl)benzene is selected from the group consisting of (2-chloroethyl)benzene and (2-bromoethyl)benzene.

3. The method according to claim 1 or claim 2, wherein step c) is carried out in methyl-THF as solvent.

4. The method according to any one of the previous claims, wherein steps a), b) and c), or steps b) and c) are carried out as a one-pot process.

5. The method according to any one of the previous claims, wherein step c) is catalysed by methane sulfonic acid.

6. The method according to any one of the previous claims, wherein the compound of formula (I) is further treated with a strong base to cause a shift of the double bond, thereby forming a compound of formula (III)wherein the wavy bond indicates an unspecified configuration of the adjacent double bond.

7. The method according to claim 6, wherein the treatment with the strong base is providing a mixture consisting of the compound of formula (I) and the compound of formula (III).

8. A method of making 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)), comprising the method according to any of claim 1 through 5, and further comprising a strong basic treatment.

9. A method of making a mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)), comprising the method according to any of claim 1 through 5, and further comprising a strong base treatment.

10. A mixture comprising 1-methoxy-4-(3-phenylprop-1-enyl) benzene (compound of formula (I)) and 1-methoxy-4-(3-phenylallyl)benzene (compound of formula (III)).

11. The mixture according to claim 10, wherein the ratio of the compound of formula (I) and the compound of formula (III) is between 99.9 : 0.1 and 50 : 50, for example between 99.5 : 0.5 and 57 : 43, or between 65 : 35 and 60 : 40.

12. Use of the compound of formula (III)or a mixture according to claim 10, as fragrance precursor for generating the corresponding fragrant aldehydes.

13. A method for generating a mixture of corresponding fragrant aldehydes, characterized in that the compound of formula (III) or a mixture according to claim 10 is exposed to oxygen.

14. A perfume composition comprising the mixture according to claim 10.

15. A consumer product comprising the mixture according to claim 10 or the perfume composition according to claim 14, and a consumer product base.

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