Synthesis method of 1-(2, 6, 6-trimethyl-1, 3-cyclohexadiene-1-yl) ethanone

Abstract

The invention relates to the field of organic synthesis, in particular to a synthetic method of 1-(2, 6, 6-trimethyl-1, 3-cyclohexadiene-1-yl) ethanone, and particularly relates to a synthetic method of 1-(2, 6, 6-trimethyl-1, 3-cyclohexadiene-1-yl) ethanone by taking 4-acetyl-3, 5, 5-trimethylcyclohexene as a raw material and carrying out bromination and elimination steps to synthesize the 1-(2, 6, 6-trimethyl-1, 3-cyclohexadiene-1-yl) ethanone. The method has the advantages of easily available raw materials and high reaction yield, and can be industrially implemented on a large scale.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, and in particular to a method for synthesizing 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone. BACKGROUND

[0002] 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone (hereinafter "the target product") is an intermediate used in the synthesis of a musk perfume product (musk ketone).

[0003]

[0004] The prior art uses bromoiso-propylideneacetone and piperlene as raw materials to obtain the target product through Diels-Alder reaction (D-A reaction) and elimination reaction. For example, Ayyar et al, Chem. Comm. 1973, p161, gives the following reaction route (R is methyl, and formula (III) is the target product of the present application).

[0005]

[0006] However, this method is only suitable for laboratory scale synthesis. Bromoiso-propylideneacetone (compound (I-2) in the above formula) needs to have a bromine atom attached at a specific position, and the synthesis reaction is difficult to carry out, so it is difficult to obtain in large quantities, making the method of the prior art not suitable for industrial application. There is an urgent need for a method for synthesizing the target product that can be implemented on an industrial scale. SUMMARY

[0007] The present inventors have found, through extensive research, that 4-acetyl-3,5,5-trimethylcyclohexene (hereinafter "AC3TMC") can be used as a raw material to synthesize the target product 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone through bromination and elimination steps. This method uses readily available raw materials, has a high reaction yield, and can be implemented on a large scale, thus completing the present application.

[0008]

[0009] Therefore, the present application relates to a method for synthesizing 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone, characterized in that it comprises the following steps:

[0010] (1) brominating the 3-position of 4-acetyl-3,5,5-trimethylcyclohexene;

[0011] (2) removing HBr through an elimination reaction.

[0012] The method of the present application has high stereoselectivity, and can significantly improve the reaction yield. As can be seen from the example part of the present application, even at an industrial scale of several hundred kg, very high yield can be achieved, which is fundamentally impossible for the synthesis method of the prior art. DETAILED DESCRIPTION

[0013] In one embodiment, the bromination of step (1) is carried out using N-bromosuccinimide (abbreviated as NBS). NBS is a commonly used bromination reagent in the art, and its mechanism and conditions for bromination are well known in the art, for example, the reaction is carried out at 40°C in a solvent such as toluene. The reaction mechanism of NBS bromination determines that it is prone to bromination at the allyl position, so when (3S,4R)-AC3TMC is subjected to bromination, the 3-position at the allyl position with an electron-donating group tends to undergo bromination, and the positional selectivity of the reaction is high.

[0014] In the case of using NBS for bromination, the reaction raw material AC3TMC preferably has a trans configuration at the 3- and 4-positions, i.e., the structure of the substance is (3S,4R)-4-acetyl-3,5,5-trimethylcyclohexene (abbreviated as (3S,4R)-AC3TMC) or (3R,4S)-4-acetyl-3,5,5-trimethylcyclohexene (abbreviated as (3R,4S)-AC3TMC). This is because NBS bromination generally does not change the chemical configuration of the reaction site, so the trans configuration of the reaction raw material will determine that the bromine atom at the 3-position and the hydrogen atom at the 4-position after the bromination reaction are still in the trans position, thereby in the subsequent step (2), i.e., the elimination step, the trans elimination method known in the art (such as E2 elimination reaction in the presence of a base) can be used to remove HBr. According to the Zaitsev rule, the bromine atom at the 3-position tends to eliminate with the hydrogen atom at the 4-position, so the reaction selectivity is high.

[0015]

[0016] The present application is precisely through the aforementioned ingeniously designed reaction route, and simultaneously using two reaction steps with high selectivity, that the overall reaction yield is high, and can be implemented on a large scale.

[0017] (3S,4R)-AC3TMC is a commonly used intermediate in the synthesis of δ-damascones, and it is relatively easy for a flavor synthesis technician to obtain (3S,4R)-AC3TMC, so the reaction raw material used in the present application is preferably (3S,4R)-AC3TMC. The product obtained after NBS bromination of this substance is (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene.

[0018]

[0019] EXAMPLE

[0020] The following examples are intended to illustrate but not limit the scope of the present application.

[0021] The starting reactant used in the example, (3S,4R)-AC3TMC, was synthesized and characterized by the method of Part A of US Patent 4334098A Example 11 (Note: the product obtained in said Part A is 1-α-acetyl-2-β,6,6-trimethyl-3-cyclohexene, which is identical in structure to (3S,4R)-AC3TMC), and was distilled under high vacuum (<5 mmHg).

[0022] The sources of other reagents used in the example: Toluene: Merck, Germany, purity 99.9%; NBS: Merck, Germany, purity 99%; Sodium carbonate: Arlond Biotech Co., Ltd., purity 99.5%; Calcium sulfate: Arlond Biotech Co., Ltd., purity 97%; N,N-dimethylformamide: Arlond Biotech Co., Ltd., purity 99.5%.

[0023] The structure of the product obtained in each step of the example was determined by the following GC-MS method: Instrument model: Agilent 8860-5977C GC-MS; Chromatographic column: HP-5MS (5% phenyl methyl polysiloxane capillary column); Injection port temperature: 250°C; Carrier gas: High-purity helium (purity > 99.999%); Carrier gas flow rate: 1.0 mL / min; Injection volume: 0.1 μL; Temperature rising program: initial temperature 60°C (hold for 3 min), rise at 10°C / min to 160°C, rise at 5°C / min to 190°C, rise at 10°C / min to 260°C (hold for 10 min); Ion source: Electron impact ion source (EI); Ionization energy: 70 eV; Source temperature: 230°C; Scan mode: Full scan mode (Full Scan); Scan range: m / z 30-500; Data acquisition mode: Positive ion mode (Positive lon Mode); Split ratio: 50:1; Solvent delay time: 4.0 min.

[0024] The purity of the product obtained in each step of the example was determined by the following gas chromatography method: Agilent 8860 gas chromatograph, HP-5 chromatographic column, 70°C for 2 min, rise at 10°C / min to 160°C, then rise at 20°C / min to 210°C, hold at 210°C for 18 min. The purity was determined by gas chromatography peak area normalization method, which is a commonly used method for determining purity in the fragrance industry.

[0025] Other instruments used in the examples include flasks, filter funnels, thermometers, rotary evaporators, etc., which are all conventional commercially available instruments for organic synthesis experiments.

[0026] Example 1

[0027] (1) Bromination reaction

[0028] Into a 1000ml four-necked flask equipped with a thermometer, mechanical stirring and a reflux condenser, 250g of (3S,4R)-AC3TMC and 500g of toluene were added. After purging with nitrogen, the temperature was raised to 40°C while stirring. NBS was added in batches, about 30g each time, with an increase of about 10°C each time. The next batch was added after the temperature returned to 40°C. A total of 278g was added. After the addition was complete, the reaction was carried out at 40°C for 2h. The reaction solution was washed with water until it was neutral, dried, and rotary evaporated to obtain 420g of the crude intermediate. The purity of (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene in the crude intermediate was 83.4% and the yield was 95% as determined by the aforementioned gas chromatography method and peak area normalization method.

[0029] The mass spectrum of the substance obtained by bromination reaction showed a molecular ion peak (m / z 244) and its bromine isotope peak (m / z 266) with a ratio of about 1:1, indicating that the molecule contains one bromine. In addition, the mass spectrum also showed a debromination fragment peak (m / z 165), a methyl ketone characteristic peak (m / z 43), and a characteristic fragment peak of a trimethyl-substituted cyclohexadiene (m / z 121). Combined with the reaction type and route of the raw material and the bromination reaction, it can be confirmed that the main component of the substance obtained by bromination reaction is (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene.

[0030] (2) Elimination reaction

[0031] Into a 1000ml four-necked flask equipped with a thermometer, mechanical stirring, and a distillation head, 65.1g of sodium carbonate, 105.2g of calcium sulfate, and 350g of solvent N,N-dimethylformamide were added. The temperature was raised to 120°C while stirring. The crude intermediate obtained by bromination reaction (main component: (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene) was added dropwise, and the dropwise addition lasted for about 4h. After the dropwise addition was completed, the reaction was carried out at constant temperature for 2h. The reaction solution was filtered and washed with water until it was neutral to obtain 242g of crude 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone. The purity of 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone in the crude product was 91% and the yield was 94% as determined by the aforementioned gas chromatography method and peak area normalization method.

[0032] The inventors synthesized 1 -(2,6,6-trimethyl-1,3-cyclohexadien-1 - yl)ethanone (referred to as "1 -acetyl-2,6,6-trimethylcyclohexa-1,3-diene (8)" in the literature) according to the method of the literature (Ayyar et al, Synthesis of δ-Damascone [trans-1 -(2,6,6-trimethylcyclohex-3-enyl)but-2-en-1 -one] and β-Damascenone [trans-1 -(2,6,6-trimethylcyclohexa-1,3-dienyl)but-2-en-1 -one. 1975. DOI: 10.1039 / p19750001727) and purified it as a standard. By comparing the standard with the substance obtained from the elimination reaction by the aforementioned GC-MS method, both had the same molecular ion peak (m / z 164), methyl ketone characteristic peak (m / z 43) and characteristic fragment peak of trimethyl-substituted cyclohexadiene (m / z 121 ), and the same retention time. In combination with the reaction type and route of the raw material and the elimination reaction, it was sufficient to determine that the main component of the substance obtained from the elimination reaction was 1 -(2,6,6-trimethyl-1,3-cyclohexadien-1 - yl)ethanone.

[0033] The crude 1 -(2,6,6-trimethyl-1,3-cyclohexadien-1 -yl)ethanone was distilled under high vacuum (<5 mmHg) to obtain 1 -(2,6,6-trimethyl-1,3-cyclohexadien-1 - yl)ethanone product 209 g. The total yield of the two-step reaction was 89%.

[0034] Example 2

[0035] (1) Bromination reaction

[0036] In a 1 m 3 A stainless steel reaction kettle was charged with 250 kg of (3S,4R)-AC3TMC, 500 kg of toluene, and after purging with nitrogen, the temperature was raised to 40°C with stirring; NBS was added in batches, about 30 kg each time, and the temperature was increased by about 10°C each time, and the next batch was added after the temperature returned to 40°C, and a total of 278 kg was added. After the addition was complete, the reaction was carried out at 40°C for 2 h. The reaction liquid was washed with water until it was neutral, dried, and rotary evaporated to obtain 430 kg of crude intermediate. The purity of (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene in the obtained (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene was 80.5% by the aforementioned gas chromatography method and peak area normalization method, and the yield was 93.9%. The characterization of the obtained (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene was the same as in Example 1.

[0037] (2) Elimination reaction

[0038] In 1 m 3 A stainless steel reactor was charged with sodium carbonate 65.1 kg, calcium sulfate 105.2 kg, solvent N,N-dimethylformamide 350 kg, and stirred to reach 120°C. The crude intermediate obtained from the bromination reaction (main component: (3R,4R)-3-bromo-4-acetyl-3,5,5-trimethylcyclohexene) 430 kg was added dropwise over a period of about 8 h. After the addition was completed, the reaction was maintained at constant temperature for 2 h. The reaction solution was filtered and washed with water until neutral to obtain 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone crude product 235 kg. The purity of 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone was determined to be 92.4% by the gas chromatography method described above and the yield was 93.6%. The characterization of the obtained 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone was the same as in Example 1.

[0039] The crude 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone was distilled under high vacuum (<5 mm Hg) to obtain 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone product 205 kg. The overall yield of the two-step reaction was 87.9%.

Claims

1. A method of synthesizing 1-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)ethanone, characterized in that comprising the steps of: (1) bromination at the 3-position of 4-acetyl-3,5,5-trimethylcyclohexene; (2) removal of HBr by elimination.

2. The process of claim 1 wherein the bromination of step (1) is carried out using N-bromosuccinimide.

3. The process of claim 2 wherein the 4-acetyl-3,5,5-trimethylcyclohexene has a trans configuration at the 3- and 4-positions.

4. The process of claim 3 wherein the 4-acetyl-3,5,5-trimethylcyclohexene is (3S,4R)-4-acetyl-3,5,5-trimethylcyclohexene.

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