Process for the preparation of polycyclic aromatizing agents

Abstract

To provide a method for producing a compound suitable for use as a perfume and / or aroma having an aromatic note of musk.SOLUTION: A process for preparing a compound of formula (I) comprising the steps of: (A) etherifying a phenol derivative to obtain an allyl ether derivative; (B) Claisen rearrangement of the ether from step (A) followed by cyclisation; (C) acetylating or formylating the intermediate from step (B); wherein steps (A) and (B) are carried out in a one pot reaction. Wherein R1, R2, R3 and R4 represent hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, iso-butyl, acetyl, formyl or SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the preparation of compounds of formula (I) which are particularly suitable for use as perfumes. [Background technology]

[0002] Despite the existence of a large number of existing fragrances and aromas, there is still a general demand for more fragrances and aromas in the perfume industry.In particular, there is a demand for fragrances with musky fragrance notes, especially those that can produce other interesting fragrance notes in addition to the musky fragrance notes (in fragrance mixtures), thereby expanding the possibilities for perfumers to create new or original fragrance characteristics.In particular, there is interest in fragrances with musky fragrance notes that can form harmonious combinations with woody and / or floral scents and / or other musky scents.Different olfactory characteristics and notes should preferably be superimposed, thereby creating an overall complex olfactory impression.

[0003] EP 2 641 903 A1 describes a compound represented by formula (I). However, the conventional method for producing the compound requires a very complicated procedure, and the method includes, among other things, three synthesis steps. This method is not only very time-consuming, but also only produces a moderate yield. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] EP 2 641 903 A1 Summary of the Invention [Problem to be solved by the invention]

[0005] It is therefore an object of the present invention to provide a method that overcomes the drawbacks of the prior art, specifically, to provide a simpler and faster method for preparing the compound of formula (I) while maximizing the yield of the compound of formula (I). [Means for solving the problem]

[0006] This object is completely achieved by the claims of the present invention. The present invention comprises the following steps (A) to (C): (A) a step of etherifying a phenol derivative to obtain an allyl ether derivative; (B) Claisen rearrangement of the ether from step (A) followed by cyclization; (C) Acetylation or formylation of the intermediate from step (B). Formula (I): [ka] wherein, for the group of the compound represented by formula (I), R1, R2, R3 and R4 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl or cyano. A method for producing a compound represented by the formula: The present invention relates to a method in which steps (A) and (B) are carried out in a one-pot reaction. DETAILED DESCRIPTION OF THE INVENTION

[0007] The inventors have surprisingly found that the process of the present invention is not only simpler, faster and more cost-effective than previously known processes, but also increases the yield of the compound of formula (I) by more than 70%. This applies in particular to the process described in EP 2 641 903 A1. The increase in yield was particularly surprising in that steps (A) and (B), i.e., the etherification and subsequent Claisen rearrangement and cyclization, are carried out in a one-pot reaction, and therefore the resulting intermediate is not isolated.

[0008] In the present invention, a one-pot reaction is a chemical synthesis characterized by first mixing all necessary reactants and solvents in a vessel, if possible, and then reacting (usually with stirring / mixing and heating or cooling). In some cases, individual components are added solely during the process (preferably via a dropping funnel or other metered addition device). Therefore, a one-pot reaction does not require isolation of intermediates, thereby saving materials, time, and energy. In other words, steps (A) and (B) of the method of the present invention are carried out without isolating the intermediate obtained in step (A).

[0009] The compounds of formula (I) may optionally exist in each case as pure stereoisomers or as mixtures of stereoisomers. In particular, the compounds of formula (I) may exist as enantiomers or mixtures of enantiomers.

[0010] Step (C) is preferably the acetylation of the intermediate from step (B).

[0011] In a preferred embodiment of the present invention, the compound of formula (I) or one, more than one or all of the compounds of formula (I) are, in each case independently of one another, R1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or isobutyl, preferably methyl, ethyl, isopropyl or tert-butyl, and / or R2 is hydrogen, methyl, formyl or acetyl, preferably hydrogen, formyl or acetyl, and / or R3 is hydrogen, methyl, formyl or acetyl, preferably hydrogen, formyl or acetyl, and / or R4 is hydrogen, methyl, formyl or acetyl, preferably hydrogen, formyl or acetyl; This applies.

[0012] In another preferred embodiment of the present invention, the compound of formula (I), or one, more than one or all of the compounds of formula (I) are selected from the group consisting of the following compounds 1 to 3: [ka] are each independently selected from the group consisting of:

[0013] An exemplary sequence of the manufacturing method of the present invention is shown in FIG. 1 below. TIFF2026032210000003.tif119170

[0014] As can be seen in Figure 1, a phenol derivative is first converted to the corresponding allyl ether derivative (Step 1), followed by a Claisen rearrangement and subsequent cyclization (Step 2). The resulting dihydrobenzofuran can then be acetylated or formylated under standard conditions, e.g., via Friedel-Crafts acylation or Vilsmeier-Haack formylation.

[0015] As already mentioned above, the method of the present invention differs from the prior art methods in that, inter alia, steps (A) and (B) (corresponding to steps 1 and 2 in the illustration of FIG. 1) are carried out in a one-pot reaction. Therefore, isolation of the intermediate from step (A) is no longer necessary, which saves materials, time and energy.

[0016] In a preferred embodiment of the present invention, the etherification (step A) is carried out by reacting a compound of formula (II): [ka] wherein R5 is chlorine, iodine or bromine. In a more preferred embodiment of the present invention, R5 is chlorine. In other words, in another preferred embodiment, the etherification is carried out using 1-chloro-3-methylbut-2-ene.

[0017] The phenol derivative preferably has the formula (III): [ka] wherein for the group of the compound of formula (III), it applies that in each case R1, R2, R3 and R4 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl or cyano. In another preferred embodiment of the present invention, the aromatic alcohol is tert-butylphenol.

[0018] The etherification is preferably carried out at a reaction temperature of 90° C. to 130° C. In the most preferred embodiment of the present invention, the etherification is carried out at 110° C.

[0019] It is further preferred to use a base in the etherification. The base is preferably selected from the group consisting of potassium carbonate, sodium acetate, potassium acetate, potassium bicarbonate, sodium carbonate and lithium carbonate. It is preferred to use potassium carbonate as the base.

[0020] In a preferred embodiment of the present invention, the Claisen rearrangement and subsequent cyclization of the intermediate from step (A), i.e., the allyl ether derivative, is carried out at 170° C. to 220° C. More preferably, the Claisen rearrangement and subsequent cyclization of the allyl ether derivative from step (A) is carried out at 190° C.

[0021] Preferably, the intermediate from step (B) is distilled before acetylation or formylation. Conventional methods well known to those skilled in the art are contemplated here. Exemplary descriptions in this regard can be found, inter alia, in the Examples section of this application.

[0022] In a preferred embodiment of the present invention, a solvent is used in the etherification. The solvent is preferably selected from the group consisting of tetrahydrofuran, dimethylformamide, methylene chloride, 1,4-dioxane, N-methylpyrrolidone, acetonitrile, cyclohexanone, and mixtures thereof. More preferably, N-methylpyrrolidone is used as the solvent.

[0023] The compounds of formula (I) are highly suitable for use as perfumes and / or aromas with musky fragrant notes. The compounds of formula (I) can be used, for example, for the preparation of (perfumed) articles (e.g. perfume extracts, eau de parfum, eau de toilette, aftershaves, eau de colognes, pre-shave products, splash colognes, scented refreshment sheets), as well as in acidic, alkaline and neutral cleaning agents (e.g. floor cleaners, window cleaners, dishwashing detergents, bathroom and hygiene detergents, refined milk, solid and liquid toilet cleaners, powdered and foamed carpet cleaners), fabric fresheners, ironing aids, liquid detergents, washing powders, laundry pre-treatments (e.g. bleaches, softeners and stain removers), fabric softeners, laundry soaps, laundry tablets, disinfectants, surface disinfectants, and air fresheners in the form of liquids, gels or applied to a solid carrier, aerosol sprays, waxes and polishes (e.g. furniture polish, floor wax, shoe polish), and personal care products (e.g. solid and liquid soaps, shower gels, shampoos, shaving soaps, shaving foams, bath oils, oil-in-water, water-in-oil and water-in-oil formulations). They may be used alone or together with other fragrances and / or aromas in water-in-oil cosmetic emulsions such as skin creams and lotions, face creams and lotions, sunscreen creams and lotions, after-sun creams and lotions, hand creams and lotions, foot creams and lotions, depilatory creams and lotions, after-shave creams and lotions, tanning creams and lotions, hair care products such as hair sprays, hair gels, setting hair lotions, hair conditioners, long-term and semi-long-term hair colorants, hair styling products (e.g., cold wave and hair straighteners), hair tonics, hair creams and lotions, deodorants and antiperspirants (e.g., underarm sprays, roll-ons, deodorant sticks, deodorant creams), decorative cosmetics (e.g., eye shadow, nail polish, makeup, lipstick, mascara), as well as for the fragrance of candles, lamp oil, incense, insecticides, repellents, and propellants.

[0024] The present invention is further characterized by the following examples. [Example]

[0025] Example 1: Synthesis of allyl ether derivatives 1-(7-tert-butyl-2,3,3-trimethyl-2H-benzofuran-5-yl)ethanone (identified as 1 in Figure 1): [ka]

[0026] N-methylpyrrolidone (81.6 g, 0.816 mol), potassium carbonate (27.4 g, 0.193 mol), and tert-butylphenol (25.0 g, 0.165 mol) are first introduced at room temperature with vigorous stirring. The reaction mixture is heated to a bottom temperature of 110° C., and then 1-chloro-3-methylbut-2-ene (29.3 g, 0.249 mol) is metered in over 8 hours. This is followed by a 2-hour post-reaction at the same bottom temperature.

[0027] Example 2: Synthesis of dihydrobenzofuran 7-tert-butyl-2,3,3-trimethyl-2H-benzofuran (identified as 2 in Figure 1): [ka]

[0028] N-methylpyrrolidone (52.5 g, 0.087 mol) and acetic acid (5.2 g, 0.087 mol) are added directly to the reaction solution from Example 1 (one-pot reaction). The mixture is then heated to a bottom temperature of 190 °C and low boilers are distilled off. This is followed by a post-reaction at the same bottom temperature for 8 hours. 100 mL of MTBE is then added to the reaction solution at room temperature, and the organic phase is washed twice with 100 mL of 10% NaCl and concentrated on a rotary evaporator. The crude product (50.0 g) is distilled on a Kugelrohr distillation system.

[0029] Yield: 40.0 g of 7-tert-butyl-2,3,3-trimethyl-2H-benzofuran as a colorless oil (97.2% of theory) Boiling point: 110℃ / 0.8mbar

[0030] GC evaluation (20m DB-1, inner diameter 0.2μm / 60-9-240℃ cold feed system)

[0031] Example 3: Synthesis of Compound 1 1-(7-tert-butyl-2,3,3-trimethyl-2H-benzofuran-5-yl)ethanone (identified as compound 1 in Figure 1) [ka]

[0032] Acetyl chloride (13.3 g, 0.170 mol) is added dropwise to a suspension of dichloromethane (85 g) and aluminum chloride (25.6 g, 0.192 mol) while cooling. The distillate from Example 2 (40.0 g, 0.160 mol) is metered in at a maximum reaction temperature of 20° C., and the mixture is stirred overnight at the same temperature. Then, while cooling with ice, 100 g of dichloromethane and water are added to the reaction solution. The organic phase is neutralized and concentrated. The crude product (39.2 g) is distilled in a Kugelrohr distillation system.

[0033] Yield: 36.8 g of 1-(7-tert-butyl-2,3,3-trimethyl-2H-benzofuran-5-yl)ethanone as a colorless oil (73.2% of theory, based on formula 2 used) Boiling point: 140℃ / 0.8mbar

[0034] GC evaluation (20m DB-1, inner diameter 0.2μm / 60-9-240℃ cold feed system)

Claims

1. The following steps (A) to (C): (A) a step of etherifying a phenol derivative to obtain an allyl ether derivative; (B) subjecting the ether from step (A) to Claisen rearrangement followed by cyclization; (C) Acetylation or formylation of the intermediate from step (B). Formula (I): 【Chemistry 1】 wherein, for the group of the compound represented by formula (I), R1, R2, R3 and R4 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl or cyano. A method for producing a compound represented by the formula: The method wherein steps (A) and (B) are carried out in a one-pot reaction.

2. for a compound of formula (I), or for one, more than one or all of the compounds of formula (I), in each case independently of one another: R1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or isobutyl, preferably methyl, ethyl, isopropyl or tert-butyl, and / or R2 is hydrogen, methyl, formyl or acetyl, preferably hydrogen, formyl or acetyl, and / or R3 is hydrogen, methyl, formyl or acetyl, preferably hydrogen, formyl or acetyl, and / or 2. The process according to claim 1, wherein R4 is hydrogen, methyl, formyl or acetyl, preferably hydrogen, formyl or acetyl.

3. The compound of formula (I), or one, two or more or all of the compounds of formula (I), may be selected from the group consisting of the following compounds 1 to 3: 【Chemistry 2】 3. The method of claim 1 or 2, wherein each of the hydroxyl groups is independently selected from the group consisting of:

4. Etherification is carried out according to formula (II): 【Transformation 3】 wherein R5 is chlorine, iodine or bromine. The method according to any one of claims 1 to 3, which is carried out using one or more compounds represented by the formula:

5. 5. The method of claim 4, wherein R5 is chlorine.

6. The phenol derivative has the formula (III): 【Chemistry 4】 wherein for the group of compounds of formula (III), it applies that in each case R1, R2, R3 and R4 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl or cyano. The method according to any one of claims 1 to 5, wherein the compound is selected from one or more of the compounds represented by the formula:

7. The method according to any one of claims 1 to 6, wherein the phenol derivative is tert-butylphenol.

8. The method according to any one of claims 1 to 7, wherein the reaction temperature for the etherification is 90°C to 130°C.

9. The method according to any one of claims 1 to 8, wherein a base is used in the etherification.

10. 11. The method of claim 10, wherein the base is selected from the group consisting of potassium carbonate, sodium acetate, potassium acetate, potassium bicarbonate, sodium carbonate, and lithium carbonate.

11. The process according to any one of claims 1 to 10, wherein the Claisen rearrangement of the ether from step (A) and subsequent cyclization is carried out at 170°C to 220°C.

12. 12. The method of claim 11, wherein the Claisen rearrangement of the ether from step (A) and subsequent cyclization is carried out at 190°C.

13. The process according to any one of claims 1 to 12, wherein the intermediate from step (B) is distilled before acetylation or formylation.

14. The method according to any one of claims 1 to 13, wherein the etherification uses a solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, methylene chloride, 1,4-dioxane, N-methylpyrrolidone, acetonitrile, cyclohexanone, and mixtures thereof.

15. The method of claim 14, wherein the solvent is N-methylpyrrolidone.

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