Method for manufacturing polycyclic fragrance agents

Abstract

We propose a method for producing a compound represented by formula (I) [wherein, for each group in the compound represented by formula (I), R1, R2, R3 and R4 each independently represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl or cyano], comprising or consisting of the following steps (A) to (C): (A) etherifying a phenol derivative to obtain an allyl ether derivative; (B) subjecting the ether from step (A) to Claisen rearrangement followed by cyclization; and (C) acetylating or formylating the intermediate from step (B), in which steps (A) and (B) are carried out in a one-pot reaction. TIFF2024514789000014.tif4351

Description

Technical Field

[0001] The present invention relates to the production of compounds of formula (I), which are particularly suitable for use as fragrances.

Background Art

[0002] Despite the existence of numerous existing fragrances and aromas, there is still a general demand in the perfume industry for further fragrances and aromas. In particular, there is a demand for fragrances having a musky aromatic note, especially those that can produce other interesting scent notes in addition to the musky aromatic note (in a fragrance mixture), and that can expand the possibilities of new or original aromatic characteristics for fragrance manufacturers. Specifically, there is interest in fragrances having a musky aromatic note that can form a harmonious combination with woody and / or floral scents and / or other musky scents. Different olfactory characteristics and notes should preferably be layered, as they thereby create an overall complex olfactory impression.

[0003] EP 2 641 903 A1 describes compounds of formula (I). However, the conventional production methods thereof require very complex techniques, and the method involves, among other things, a three-step synthesis. This method is not only very time-consuming but also yields only moderate amounts.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Therefore, an object of the present invention is to provide a method for overcoming the shortcomings of the prior art. Specifically, an object of the present invention is to provide a method for maximizing the yield of the compound represented by formula (I) while simultaneously providing a method for producing the compound represented by formula (I) simply and more quickly. [Means for solving the problem]

[0006] This objective is fully achieved by the claims of the present invention. The present invention relates to the following steps (A) to (C): (A) A step of obtaining an allyl ether derivative by etherifying a phenol derivative; (B) Step of performing a Claisen rearrangement and then cyclization of the ether from step (A); (C) Step of acetylating or formylation of the intermediate from step (B) Formula (I), which includes or consists of: [ka] [In the formula, for the groups 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 the compound shown, This describes a method in which steps (A) and (B) are carried out as a one-pot reaction. [Modes for carrying out the invention]

[0007] To our surprise, the inventors found that the method of the present invention is not only simpler, faster, and more cost-effective than conventional methods, but also increases the yield of the compound represented by formula (I) by more than 70%. This is particularly true of the method described in EP 2 641 903 A1. The increase in yield was particularly surprising because steps (A) and (B), namely etherification and the 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 container, and then reacting them (usually with stirring / mixing and heating or cooling). In some cases, individual components may be added exclusively during the operation (preferably via a dropping funnel or other metering / addition device). Thus, a one-pot reaction does not require the 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 the isolation of the intermediate obtained in step (A).

[0009] The compound represented by formula (I) may, depending on the case, exist as a pure stereoisomer or as a mixture of stereoisomers. In particular, the compound represented by formula (I) may exist as an enantiomer or a mixture of enantiomers.

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

[0011] In preferred embodiments of the present invention, for a compound represented by formula (I), or one, two or more, or all of the compounds represented by formula (I), in each case, independently of each other, 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 represented by formula (I), or one, two or all of the compounds represented by formula (I) are the following compounds 1 to 3:

Chemical formula

[0013] An exemplary sequence of the production method of the present invention is shown in FIG. 1 below. TIFF0007843296000003.tif119170

[0014] As can be seen from FIG. 1, the phenol derivative is first converted to the corresponding allyl ether derivative (step 1). Then, Claisen rearrangement and subsequent cyclization follow (step 2). Next, the dihydrobenzofuran thus obtained can be acetylated or formylated under standard conditions, for example, via Friedel-Crafts acylation or Vilsmeier-Haack formylation.

[0015] As already described above, the difference between the method of the present invention and the conventional method is, inter alia, that steps (A) and (B) (corresponding to steps 1 and 2 in the example of FIG. 1) are carried out as a one-pot reaction. Therefore, the isolation of the intermediate from step (A) is no longer necessary, thereby saving materials, time and energy.

[0016] In a preferred embodiment of the present invention, the etherification (step A) is carried out using one or more compounds represented by formula (II):

Chemical formula

[0017] The phenol derivative is preferably of formula (III): [Chemical formula] [In the formula, for the groups of the compounds represented by formula (III), 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] is selected from one or more of the compounds represented by. 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 more preferable to use a base in the etherification. This base is preferably selected from the group consisting of potassium carbonate, sodium acetate, potassium acetate, potassium hydrogen carbonate, sodium carbonate and lithium carbonate. It is preferable 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, are carried out at 170°C to 220°C. More preferably, the Claisen rearrangement and subsequent cyclization of the allyl ether derivative from step (A) are carried out at 190°C.

[0021] Preferably, the intermediate from step (B) is distilled before acetylation or formylation. Here, conventional methods well known to those skilled in the art can be considered. An exemplary description thereof can be found, inter alia, in the paragraphs of the examples of the present application.

[0022] In preferred embodiments of the present invention, a solvent is used in 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 compound represented by formula (I) is highly suitable for use as a fragrance and / or aroma, possessing a musky aromatic note. The compound represented by formula (I) is used, for example, in the preparation of (fragrance) articles (e.g., perfume extracts, eau de parfum, eau de toilette, aftershave, eau de cologne, pre-shave products, splash cologne, scented refreshing sheets), as well as in acidic, alkaline, and neutral cleaning agents (e.g., floor cleaners, window cleaners, dish soaps, bathroom and sanitary cleaners, condensed milk, solid and liquid toilet cleaners, powder and foam carpet cleaners), fabric fresheners, ironing aids, liquid detergents, powder detergents, laundry pretreatment agents (e.g., bleaches, fabric softeners and stain removers), fabric softeners, laundry soaps, laundry tablets, disinfectants, surface disinfectants, and in liquid, gel, or solid carrier form, air fresheners, aerosol sprays, waxes and polishes (e.g., furniture polishes, floor waxes, shoe polishes), 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-water). It can be used alone or with other fragrances and / or aromas for fragrance-adding to oil-in-oil-in-water 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, hair removal creams and lotions, aftershave creams and lotions, sunscreen 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), cosmetic products (e.g., eyeshadows, nail polish, makeup, lipsticks, mascaras), as well as candles, lamp oils, incense, insecticides, repellents, and propellants. The initial disclosures of this specification include at least the following aspects: [1] The following steps (A) to (C): (A) A step of obtaining an allyl ether derivative by etherifying a phenol derivative; (B) Step of performing a Claisen rearrangement and then cyclization of the ether from step (A); (C) Step of acetylating or formylation of the intermediate from step (B) Formula (I), which includes or consists of: TIFF0007843296000006.tif6071 [In the formula, for the groups 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 the compound shown, Steps (A) and (B) are carried out as a one-pot reaction. [2] For the compound represented by formula (I), or one, two or more, or all of the compounds represented by formula (I), in each case, independently of each other, 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 The method according to [1], wherein R4 is applied to hydrogen, methyl, formyl, or acetyl, preferably hydrogen, formyl, or acetyl. [3] The compound represented by formula (I), or one, two or more, or all of the compounds represented by formula (I), are compounds 1-3 below: TIFF0007843296000007.tif18976 The method according to [1] or [2], wherein each of the groups consisting of is independently selected. [4] Etherification is expressed by formula (II): TIFF0007843296000008.tif4460 [In the formula, R5 is chlorine, iodine, or bromine.] The method according to any one of [1] to [3], using one or more of the compounds shown in [1]. [5] The method described in [4], wherein R5 is chlorine. [6] Phenol derivatives are given by formula (III): TIFF0007843296000009.tif6764 [In the formula, for each group of the compound represented by formula (III), R1, R2, R3, and R4 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl, or cyano.] A method according to any one of [1] to [5], selected from one or more compounds shown in [1]. [7] The method according to any one of [1] to [6], wherein the phenol derivative is tert-butylphenol. [8] The method according to any one of [1] to [7], wherein the reaction temperature for etherification is 90°C to 130°C. [9] The method according to any of [1] to [8], wherein a base is used in the etherification.

[10] The method according to

[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 Claisen rearrangement of the ether from step (A) and subsequent cyclization are carried out at 170°C to 220°C, according to any of the methods described in [1] to

[10] .

[12] The Claisen rearrangement of the ether from step (A) and subsequent cyclization are carried out at 190°C, as described in

[11] .

[13] The method according to any of [1] to

[12] , wherein the intermediate from step (B) is distilled before acetylation or formylation.

[14] The method according to any one of [1] to

[13] , wherein in the etherification, a solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, methylene chloride, 1,4-dioxane, N-methylpyrrolidone, acetonitrile, cyclohexanone, and mixtures thereof is used.

[15] The method according to

[14] , wherein the solvent is N-methylpyrrolidone.

[0024] The present invention will be further characterized below with reference to examples. [Examples]

[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] First, 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 introduced at room temperature while vigorously stirring. The reaction mixture is heated to a bottom temperature of 110°C, and then 1-chloro-3-methylbuto-2-ene (29.3 g, 0.249 mol) is added by weighing over a period of 8 hours or more. Subsequently, the mixture is reacted again at the same bottom temperature for 2 hours.

[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) were added directly to the reaction solution from Example 1 (one-pot reaction). The mixture was then heated to a bottom temperature of 190°C to remove low-boiling substances by distillation. The reaction was then continued at the same bottom temperature for 8 hours. Subsequently, 100 mL of MTBE was added to the reaction solution at room temperature, the organic phase was washed twice with 100 mL of 10% NaCl, and the mixture was concentrated using a rotary evaporator. The crude product (50.0 g) was distilled using a Kugellohr distillation system.

[0029] Yield: 40.0 g of 7-tert-butyl-2,3,3-trimethyl-2H-benzofuran as colorless oil (97.2% of theoretical value) 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 the turbidity 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 weighed and added at the highest reaction temperature up to 20°C, and the mixture is stirred overnight at the same temperature. Then, 100 g of dichloromethane and water are added to the reaction solution while cooling with ice. The organic phase is neutralized and concentrated. The crude product (39.2 g) is distilled using a Kugellohr distillation system.

[0033] Yield: 36.8 g of 1-(7-tert-butyl-2,3,3-trimethyl-2H-benzofuran-5-yl)ethanone as colorless oil (73.2% of the theoretical value, based on formula 2). 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) A step of obtaining an allyl ether derivative by etherifying a phenol derivative at a temperature of 90°C to 130°C; (B) A step in which the ether from step (A) is subjected to a Claisen rearrangement and then cyclized at a temperature of 170°C to 220°C; and optionally (C) a step of acetylating or formylation of the intermediate from step (B). Formula (I), which includes or consists of: 【Chemistry 1】 [In the formula, R1, R2, R3, and R4 of the group of the compound represented by formula (I) are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl, or cyano.] A method for producing the compound shown, Steps (A) and (B) are carried out as one-pot reactions. The phenol derivative is given by formula (III): 【Chemistry 2】 [In the formula, for each group of the compound represented by formula (III), R1, R2, R3, and R4 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, acetyl, formyl, or cyano.] Selected from one or more compounds shown, Etherification is represented by formula (II): 【Transformation 3】 [In the formula, R5 is chlorine, iodine, or bromine.] A method using one or more of the compounds shown.

2. For the compound represented by formula (I), or one, two or more, or all of the compounds represented by formula (I), in each case, independently of each other, R1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or isobutyl, and / or R2 is hydrogen, methyl, formyl or acetyl, and / or R3 is hydrogen, methyl, formyl or acetyl, and / or The method according to claim 1, wherein R4 is hydrogen, methyl, formyl, or acetyl.

3. The method according to claim 2, wherein R1 is methyl, ethyl, isopropyl, or tert-butyl.

4. The method according to claim 2, wherein R2 is hydrogen, formyl, or acetyl.

5. The method according to claim 2, wherein R3 is hydrogen, formyl, or acetyl.

6. The method according to claim 2, wherein R4 is hydrogen, formyl, or acetyl.

7. The compound represented by formula (I), or one, two or more, or all of the compounds represented by formula (I), are compounds 1 to 3 below: 【Chemistry 4】 The method according to claim 1 or 2, each independently selected from the group consisting of the following.

8. The method according to claim 1, wherein R5 is chlorine.

9. The method according to claim 1, wherein the phenol derivative is tert-butylphenol.

10. The method according to any one of claims 1 to 9, wherein the reaction temperature for etherification is 110°C.

11. The method according to any one of claims 1 to 10, wherein a base is used in the etherification.

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

13. The method according to any one of claims 1 to 12, wherein the Claisen rearrangement and subsequent cyclization of the ether from step (A) is carried out at 190°C.

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

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

16. The method according to claim 15, wherein the solvent is N-methylpyrrolidone.

Images