Synthesis method of 2-(1-(3, 3-dimethylcyclohexyl) ethyoxyl)-2-methyl-1-propanol

Abstract

The invention provides a synthesis method of 2-(1-(3, 3-dimethylcyclohexyl) ethyoxyl)-2-methyl-1-propanol, which comprises the following steps: under the action of a base catalyst, reacting 2-substituted 2-methyl propionate with 1-(3, 3-dimethylcyclohexyl) ethanol to obtain an alkyl ester intermediate, and then reducing to obtain the 2-(1-(3, 3-dimethylcyclohexyl) ethyoxyl)-2-methyl-1-propanol. And (2, 3-dimethyl cyclohexyl) ethyoxyl)-2-methyl-1-propanol is used as a raw material. According to the method, 2-substituted 2-methyl propionate is used as an alkylation reagent, compared with epoxy isobutane adopted in a traditional process, a monoalkylated product can be obtained with high selectivity, and the synthesis yield of a target product is remarkably improved.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, and specifically relates to a method for synthesizing 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol by using 1-(3,3-dimethylcyclohexyl)ethanol and 2-halogenated or 2-sulfonate-substituted 2-methylpropionic acid ester as raw materials through alkylation reaction and reduction reaction. Background Art

[0002] Musk was originally an aromatic substance derived from musk animals. It has a deep, warm and lasting aroma and is widely used in perfumes, ointments, cigarettes, cosmetics, detergents and other fields. Natural musk is very scarce and expensive, far from meeting people's growing demand. Scientists have developed a series of artificial musk fragrances, the more famous of which are nitromusk, polycyclic musk, macrocyclic musk, etc. Among them, nitromusk has been basically banned due to its photosensitivity and toxicity problems; polycyclic musk is not easily metabolized and transformed, and has problems such as accumulation and accumulation in the human body. Some developed countries have begun to restrict the addition and use of polycyclic musk; although macrocyclic musk is environmentally friendly and harmless to the human body, its production cost has remained high for a long time, making it difficult to be widely promoted and applied. In 1975, researchers von Fraunberg and Hoffmann from BASF in Germany discovered the first linear musk fragrance Cyclomusk. Since then, a large number of linear musk molecules such as Helvetolide, Romandolide, Serenolide, Edenolide, etc. have been developed and put on the market, leading the popular trend of musk fragrance. The structure of the relevant linear musk is shown below.

[0003]

[0004] Observation of the molecular structures of these linear musks shows that Helvetolide and Serenolide have similar structural units, both containing 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol structure. The current synthesis route of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol is as follows: 1-(3,3-dimethylcyclohexyl)ethanol is used as a raw material, and it is obtained by ring-opening with isobutylene oxide under the action of a Lewis acid catalyst; since the product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol still has a primary alcohol functional group, it is easy to continue to undergo secondary and tertiary ring-opening reactions with isobutylene oxide to obtain a series of polyalkylated by-products, which greatly reduces the yield of the target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol and increases the production cost. The side reaction equation is as follows:

[0005]

[0006] In summary, 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol is a key intermediate for synthesizing linear musk Helvetolide and Serenolide. The main synthesis method at present is to use 1-(3,3-dimethylcyclohexyl)ethanol as a raw material and obtain it by ring-opening reaction with isobutylene oxide. Because the product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol is easy to undergo secondary and tertiary ring-opening reactions with isobutylene oxide under the reaction conditions, the yield is low and the cost is high. In order to prepare linear musk Helvetolide and Serenolide and other products more economically and cheaply, it is necessary to develop a new 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol synthesis route, which has low raw material price and high reaction yield, and can significantly reduce production costs. Summary of the invention

[0007] The purpose of the present invention is to provide a simple synthesis method of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol, using readily available 1-(3,3-dimethylcyclohexyl)ethanol and 2-halogenated or 2-sulfonate-substituted 2-methylpropionic acid ester as raw materials, and obtaining the target product through two steps of alkylation and reduction. The synthesis route of the present invention is novel, and a monoalkylated product can be obtained with high selectivity, without dialkylation and polyalkylation byproducts, and the synthesis yield of the target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol is significantly improved; the method is simple, the conditions are mild, the raw materials are cheap and readily available, and the method has good application value.

[0008] In order to achieve the above objectives and the above technical effects, the present invention adopts the following technical solutions:

[0009] A method for synthesizing 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol comprises:

[0010] S1, 1-(3,3-dimethylcyclohexyl)ethanol undergoes alkylation reaction with 2-substituted 2-methylpropionic acid ester in the presence of a base catalyst and pyridine as an auxiliary agent to obtain an alkyl ester intermediate;

[0011] S2, the alkyl ester intermediate is reduced under the action of a reducing agent and an optional Lewis acid auxiliary to obtain 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol.

[0012] The reaction route is shown below:

[0013]

[0014] In the present invention, the structure of the 2-substituted 2-methylpropionic acid ester described in S1 is as follows:

[0015]

[0016] Wherein, X can be but not limited to chlorine, bromine, iodine, acetoxy, propionyloxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy; R can be but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, etc.; preferably, the amount of the 2-substituted 2-methylpropionic acid ester is 100-300 mol% of 1-(3,3-dimethylcyclohexyl)ethanol.

[0017] In the present invention, an alkali catalyst is used in S1 to promote the reaction. The alkali catalyst may be, but is not limited to, one or more of metal hydroxides, metal hydrides, carbonates, phosphates, alkyl alcohol salts, and guanidine, preferably potassium carbonate, potassium phosphate, tetramethylguanidine, sodium hydride, sodium hydroxide, and the like; preferably, the amount of the alkali catalyst used is 120-300 mol% of 1-(3,3-dimethylcyclohexyl)ethanol.

[0018] In the present invention, the pyridine auxiliary agent in S1 can be but not limited to pyridine, 3-methylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 4-piperidinylpyridine, etc., preferably 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 4-piperidinylpyridine, etc.; preferably, the auxiliary agent is used in an amount of 0.5-5.0 mol% of 1-(3,3-dimethylcyclohexyl)ethanol.

[0019] In the present invention, a polar aprotic solvent is preferably used in S1, which may be but is not limited to tetrahydrofuran, methyl tert-butyl ether, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyl acetate, ethyl acetate, etc.; preferably, the amount of the solvent is 3.0 to 6.0 times the mass of 1-(3,3-dimethylcyclohexyl)ethanol.

[0020] In the present invention, the reaction time in S1 is 2 to 7 hours; and / or the reaction temperature is 40 to 80°C.

[0021] In the present invention, the reducing agent in S2 can be but not limited to lithium aluminum hydride, sodium borohydride, calcium borohydride, lithium borohydride, diisobutylaluminum hydride, etc., preferably sodium borohydride; preferably, the amount of the reducing agent is 150-300 mol% of the alkyl ester intermediate.

[0022] In the present invention, the Lewis acid auxiliary in S2 can be but not limited to tin octoate, dibutyltin oxide, lithium chloride, zinc chloride, zinc bromide, scandium trifluoromethanesulfonate, etc.; preferably, the Lewis acid auxiliary and sodium borohydride are used in combination, and the amount of the Lewis acid auxiliary is 1-10 mol% of the alkyl ester intermediate.

[0023] In the present invention, a polar aprotic solvent is preferably used in S2, which may be but is not limited to diethyl ether, tetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.; the amount of the solvent is preferably 3.0 to 7.0 times the mass of the alkyl ester intermediate.

[0024] In the present invention, the reaction time in S2 is 2 to 7 hours; and / or the reaction temperature is 30 to 60°C.

[0025] The present invention adopts the above technical solution and has the following positive effects:

[0026] 1. The method adopts a novel synthetic route, can obtain a monoalkylated product with high selectivity, has no dialkylated or polyalkylated by-products, and significantly improves the synthetic yield of the target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol.

[0027] 2. Adding a catalytic amount of pyridine as an auxiliary agent in the alkylation reaction can effectively accelerate the reaction; in the ester reduction reaction, the present invention preferably uses cheap sodium borohydride as a reducing agent and Lewis acid as an auxiliary agent to achieve efficient reduction of the ester group under relatively mild conditions. DETAILED DESCRIPTION

[0028] The present invention is described in detail below by examples, but the present invention is not limited to the following examples.

[0029] The main raw material information is as follows:

[0030] 1-(3,3-Dimethylcyclohexyl)ethanol, Apple fragrance, 99%;

[0031] 2-Bromo-2-methylpropionic acid methyl ester, 2-chloro-2-methylpropionic acid methyl ester, AR, Aladdin reagent;

[0032] Ethyl 2-methanesulfonyloxy-2-methylpropionate, Aurora, 99%; Methyl 2-p-toluenesulfonyloxy-2-methylpropionate, isopropyl 2-p-toluenesulfonyloxy-2-methylpropionate, Aldrich, purity 99%;

[0033] Tert-butyl 2-chloro-2-methylpropionate, J&K reagent, purity 98-99%.

[0034] Potassium carbonate, potassium phosphate, sodium hydroxide, sodium hydride, AR, Sinopharm reagent;

[0035] Tetramethylguanidine, 98%, J&K reagent;

[0036] Tetrahydrofuran, ethyl acetate, methyl acetate, N,N-dimethylformamide, AR, Xilong reagent;

[0037] 4-Dimethylaminopyridine, 4-piperidinylpyridine, Alfa Aesar, purity 99%;

[0038] 4-Pyrrolidinylpyridine, Aladdin reagent, purity 99%.

[0039] Sodium borohydride, lithium aluminum hydride, potassium tert-butoxide, Aladdin reagent, purity 99%;

[0040] Lithium chloride, calcium borohydride, diisobutylaluminum hydride (1.5M toluene solution), Anergy reagent, >99%.

[0041] Tin octoate, dibutyltin oxide, zinc chloride, Chinese medicine reagents, purity 98-99%;

[0042] Ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, Anergy reagent, AR.

[0043] The gas chromatography test conditions of the present invention are as follows:

[0044] Instrument model: Agilent 8890B; Chromatographic column: Capillary column HP-5 (30m×0.30mm×0.25μm); Initial temperature 80℃, raised to 100℃ at a rate of 5℃ / min; then raised to 200℃ at a rate of 10℃ / min, maintained for 5.0min. Carrier gas high-purity nitrogen, split ratio 30:1, split flow 42mL / min. Carrier gas saving: 19mL / min, start waiting time 5.0min. Injection temperature 250℃, detector FID, detector temperature 250℃, air flow 350mL / min, hydrogen flow 30mL / min, tail gas flow 60mL / min, injection volume 0.2μL.

[0045] Embodiment 1:

[0046] Synthesis of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester from 1-(3,3-dimethylcyclohexyl)ethanol and 2-bromo-2-methylpropanoic acid methyl ester

[0047] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, tetrahydrofuran (187.5g), 1-(3,3-dimethylcyclohexyl)ethanol (46.88g, 0.3mol) and methyl 2-bromo-2-methylpropionate (54.31g, 0.3mol) were added to the three-necked flask, and the oil bath was turned on to stir the three to mix them evenly. Then, 4-dimethylaminopyridine (0.73g, 0.006mol) and potassium carbonate powder (49.75g, 0.36mol) were added to the reaction solution at one time to obtain a suspended reaction solution. The oil bath was turned on to heat the three-necked flask to 80°C, and the temperature was kept constant. The reaction was stirred rapidly for 4 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0048] After treatment, the reaction solution was filtered to remove the solid powder, and the filtrate was rotary evaporated to remove tetrahydrofuran. Then the crude product was dissolved in ethyl acetate (200 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 74.56 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester with a purity of 98.0% and a yield of 95.0%. High-resolution mass spectrum of the product HRMS-EI M + calcd C 15 H 28 O3:256.2038, found 256.2037.

[0049] Embodiment 2:

[0050] Synthesis of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester from 1-(3,3-dimethylcyclohexyl)ethanol and 2-bromo-2-methylpropanoic acid methyl ester

[0051] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, tetrahydrofuran (120.3 g), 1-(3,3-dimethylcyclohexyl)ethanol (17.19 g, 0.11 mol) and methyl 2-bromo-2-methylpropionate (59.74 g, 0.33 mol) were added to the three-necked flask. The oil bath was turned on to stir the three to mix them evenly. Then, 4-dimethylaminopyridine (0.67 g, 0.0055 mol) and potassium carbonate powder (30.41 g, 0.22 mol) were added to the reaction solution at one time to obtain a suspended reaction solution. The oil bath was turned on to heat the three-necked flask to 60°C, and the temperature was kept constant. The reaction was stirred rapidly for 7 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0052] After treatment, the reaction solution was filtered to remove the solid powder, the filtrate was rotary evaporated to remove tetrahydrofuran, and then the crude product was dissolved in ethyl acetate (150 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 28.61 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester with a purity of 97.6% and a yield of 99.0%.

[0053] Embodiment 3:

[0054] Synthesis of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester from 1-(3,3-dimethylcyclohexyl)ethanol and 2-bromo-2-methylpropanoic acid methyl ester

[0055] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, tetrahydrofuran (114.9 g), 1-(3,3-dimethylcyclohexyl)ethanol (32.82 g, 0.21 mol) and methyl 2-bromo-2-methylpropionate (41.82 g, 0.23 mol) were added to the three-necked flask, and the oil bath was turned on to stir the three to mix them evenly. Then, 4-dimethylaminopyridine (0.13 g, 0.0011 mol) and potassium tert-butoxide powder (28.28 g, 0.252 mol) were added to the reaction solution at one time to obtain a suspended reaction solution. The oil bath was turned on to heat the three-necked flask to 80°C, and the temperature was kept constant. The reaction was stirred rapidly for 4 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0056] After treatment, the reaction solution was filtered to remove the solid powder, the filtrate was rotary evaporated to remove tetrahydrofuran, and then the obtained crude product was dissolved in ethyl acetate (120 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 53.68 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester with a purity of 98.4% and a yield of 98.1%.

[0057] Embodiment 4:

[0058] Synthesis of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester from 1-(3,3-dimethylcyclohexyl)ethanol and 2-chloro-2-methylpropanoic acid methyl ester

[0059] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, tetrahydrofuran (136.0 g), 1-(3,3-dimethylcyclohexyl)ethanol (45.32 g, 0.29 mol) and methyl 2-chloro-2-methylpropionate (47.53 g, 0.348 mol) were added to the three-necked flask. The oil bath was turned on to stir the three to mix them evenly. Then, 4-pyrrolidinopyridine (0.43 g, 0.0029 mol) and tetramethylguanidine (50.10 g, 0.435 mol) were added to the reaction solution at one time to obtain a clear reaction solution. The oil bath was turned on to heat the three-necked flask to 80°C, and the temperature was kept constant. The reaction was stirred rapidly for 3 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0060] After treatment, the reaction solution was filtered to remove the solid powder, the filtrate was rotary evaporated to remove tetrahydrofuran, and then the crude product was dissolved in ethyl acetate (150 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 73.45 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester with a purity of 98.8% and a yield of 97.6%.

[0061] Embodiment 5:

[0062] Synthesis of 2-(1-(3,3-dimethylcyclohexyl)ethanol and 2-methanesulfonyloxy-2-methylpropionic acid ethyl ester

[0063] (3,3-Dimethylcyclohexyl)ethoxy)-2-methylpropionic acid ethyl ester

[0064] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, methyl acetate (125.0 g), 1-(3,3-dimethylcyclohexyl)ethanol (25.0 g, 0.16 mol) and ethyl 2-methanesulfonyloxy-2-methylpropionate (40.37 g, 0.192 mol) were added to the three-necked flask, and the oil bath was turned on to stir the three to mix them evenly. Then, 4-piperidylpyridine (0.78 g, 0.0048 mol) and potassium phosphate powder (50.94 g, 0.24 mol) were added to the reaction solution at one time to obtain a suspended reaction solution. The oil bath was turned on to heat the three-necked flask to 60°C, and the temperature was kept constant. The reaction was stirred rapidly for 5 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0065] After treatment, the reaction solution was filtered to remove the solid powder, the filtrate was rotary evaporated to remove methyl acetate, and then the crude product was dissolved in ethyl acetate (200 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 42.95 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid ethyl ester with a purity of 97.2% and a yield of 96.5%.

[0066] Embodiment 6:

[0067] Synthesis of 2-(3,3-dimethylcyclohexyl)ethanol and 2-p-toluenesulfonyloxy-2-methylpropionic acid methyl ester

[0068] (1-(3,3-Dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester

[0069] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, ethyl acetate (121.9 g), 1-(3,3-dimethylcyclohexyl)ethanol (20.31 g, 0.13 mol) and methyl 2-p-toluenesulfonyloxy-2-methylpropionate (38.94 g, 0.143 mol) were added to the three-necked flask. The oil bath was turned on to stir the three to mix them evenly. Then, 4-dimethylaminopyridine (0.32 g, 0.0026 mol) and tetramethylguanidine (19.47 g, 0.169 mol) were added to the reaction solution at one time to obtain a clear reaction solution. The oil bath was turned on to heat the three-necked flask to 80°C, and the temperature was kept constant. The reaction was stirred rapidly for 3 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0070] After post-treatment, the reaction solution was filtered to remove the solid powder, and the solvent ethyl acetate (50 mL) was added, washed twice with dilute hydrochloric acid (20 mL, 2M), saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL) were washed once each. The organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 33.13 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester with a purity of 98.5% and a yield of 97.9%.

[0071] Embodiment 7:

[0072] Synthesis of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid isopropyl ester from 1-(3,3-dimethylcyclohexyl)ethanol and 2-p-toluenesulfonyloxy-2-methylpropionic acid isopropyl ester

[0073] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, tetrahydrofuran (93.8g), 1-(3,3-dimethylcyclohexyl)ethanol (18.75g, 0.12mol) and 2-p-toluenesulfonyloxy-2-methylpropionic acid isopropyl ester (0.132mol) were added to the three-necked flask, and the oil bath was turned on to stir the three to mix them evenly. Then, 4-dimethylaminopyridine (0.15g, 0.0012mol) and sodium hydroxide powder (6.24g, 0.156mol) were added to the reaction solution at one time to obtain a suspended reaction solution. The oil bath was turned on to heat the three-necked flask to 70°C, and the temperature was kept constant. The reaction was stirred rapidly for 3 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0074] After treatment, the reaction solution was filtered to remove the solid powder, the filtrate was rotary evaporated to remove tetrahydrofuran, and then the crude product was dissolved in ethyl acetate (120 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 33.99 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid isopropyl ester with a purity of 96.7% and a yield of 96.3%.

[0075] Embodiment 8:

[0076] Synthesis of tert-butyl 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionate from 1-(3,3-dimethylcyclohexyl)ethanol and tert-butyl 2-chloro-2-methylpropionate

[0077] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an oil bath. After nitrogen replacement, N,N-dimethylformamide (164.1 g), 1-(3,3-dimethylcyclohexyl)ethanol (32.82 g, 0.21 mol) and tert-butyl 2-chloro-2-methylpropionate (48.77 g, 0.273 mol) were added to the three-necked flask, and the oil bath was turned on to stir the three to mix them evenly. Then, 4-pyrrolidinopyridine (0.62 g, 0.0042 mol) and sodium hydride powder (60 wt%, dispersed in mineral oil, 12.6 g, 0.315 mol) were added to the reaction solution at one time to obtain a suspended reaction solution. The oil bath was turned on to heat the three-necked flask to 40°C, and the temperature was kept constant. The reaction was stirred rapidly for 2 hours. Sampling and GC analysis showed that the reactant 1-(3,3-dimethylcyclohexyl)ethanol was completely consumed.

[0078] After treatment, the reaction solution was filtered to remove the solid powder, the filtrate was rotary evaporated to remove N,N-dimethylformamide, and then the crude product was dissolved in ethyl acetate (200 mL), washed twice with dilute hydrochloric acid (20 mL, 2M), washed once with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate and separated by reduced pressure distillation to obtain 63.38 g of the target intermediate 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid tert-butyl ester with a purity of 98.1% and a yield of 99.2%.

[0079] Embodiment 9:

[0080] Preparation of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol by reduction of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester with sodium borohydride

[0081] At room temperature, a 500mL three-necked flask equipped with a magnetic stirrer was placed in an ice-water bath. After nitrogen replacement, tetrahydrofuran (164.1g), 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester (41.02g, 0.16mol) and tin octanoate (1.3g, 0.0032mol) were added to the three-necked flask, and stirring was started to fully mix the three. After stirring and cooling in an ice-water bath for 20 minutes, sodium borohydride (9.08g, 0.24mol) was slowly added to the reaction solution in batches to obtain a suspended reaction solution. The ice-water bath was removed, the temperature was raised to 60°C and maintained at a constant temperature, and the reaction was carried out for 3 hours under rapid stirring. Sampling and GC analysis showed that the raw material 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester completely disappeared.

[0082] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incompletely reacted sodium borohydride, and the solvent tetrahydrofuran was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (150 mL), washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by reduced pressure distillation. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 36.84 g was obtained by distillation separation with a purity of 97.2% and a yield of 98.0%. High-resolution mass spectrum of the product HRMS-EI M + calcd C 14 H 28 O2:228.2089,found228.2088.

[0083] Embodiment 10:

[0084] Preparation of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol by reduction of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester with sodium borohydride

[0085] At room temperature, place a 500mL three-necked flask equipped with a magnetic stirrer in an ice-water bath. After nitrogen replacement, add tetrahydrofuran (179.5g), 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester (25.64g, 0.10mol) and tin octanoate (1.22g, 0.003mol) to the three-necked flask, start stirring to fully mix the three, stir and cool in an ice-water bath for 20 minutes, and then slowly add sodium borohydride (11.35g, 0.30mol) to the reaction solution in batches to obtain a suspended reaction solution. Remove the ice-water bath, raise the temperature to 50°C and maintain a constant temperature, and react for 3 hours under rapid stirring. Sampling, GC analysis, the raw material 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester completely disappeared.

[0086] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incomplete reaction of sodium borohydride, and the solvent tetrahydrofuran was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (120 mL), and washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 23.05 g was obtained by distillation separation with a purity of 98.1% and a yield of 99.0%.

[0087] Embodiment 11:

[0088] Reduction of tert-butyl 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoate with lithium aluminum hydride to prepare 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol

[0089] At room temperature, place a 500mL three-necked flask equipped with a magnetic stirrer in an ice-water bath. After nitrogen replacement, add ether (131.3g) and tert-butyl 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionate (32.83g, 0.11mol) to the three-necked flask, start stirring to mix the two thoroughly, stir and cool in an ice-water bath for 20 minutes, and then slowly add lithium aluminum hydride (6.26g, 0.165mol) to the reaction solution in batches to obtain a suspended reaction solution. Remove the ice-water bath, raise the temperature to 30°C and maintain a constant temperature, and react for 3 hours under rapid stirring. Sampling, GC analysis, the raw material tert-butyl 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionate completely disappeared.

[0090] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incomplete reaction of lithium aluminum hydride, and the solvent ether was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (150 mL), and washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 25.22 g was obtained by distillation separation with a purity of 98.9% and a yield of 99.3%.

[0091] Embodiment 12:

[0092] Reduction of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester with calcium borohydride to prepare 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol

[0093] At room temperature, place a 500mL three-necked flask equipped with a magnetic stirrer in an ice-water bath. After nitrogen replacement, add tetrahydrofuran (100.0g), 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester (33.33g, 0.13mol) and dibutyltin oxide (0.32g, 0.0013mol) to the three-necked flask, and stir to mix the three thoroughly to obtain a colorless clear solution. After stirring and cooling in an ice-water bath for 20 minutes, calcium borohydride (0.195mol) was slowly added to the reaction solution in batches to obtain a suspended reaction solution. Remove the ice-water bath, raise the temperature to 50°C and maintain a constant temperature, and react for 3 hours under rapid stirring. Sampling, GC analysis, the raw material 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester completely disappeared.

[0094] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incomplete reaction of calcium borohydride, and the solvent tetrahydrofuran was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (150 mL), and washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 29.9 g was obtained by distillation separation with a purity of 98.7% and a yield of 99.4%.

[0095] Embodiment 13:

[0096] Reduction of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid ethyl ester with lithium borohydride to prepare 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol

[0097] At room temperature, place a 500mL three-necked flask equipped with a magnetic stirrer in an ice-water bath. After nitrogen replacement, add tetrahydrofuran (89.2g) and 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid ethyl ester (29.74g, 0.11mol) to the three-necked flask, and stir to mix the two thoroughly. After stirring and cooling in an ice-water bath for 20 minutes, lithium borohydride (4.79g, 0.22mol) was added to the reaction solution in batches and slowly to obtain a suspended reaction solution. Remove the ice-water bath, raise the temperature to 40°C and maintain a constant temperature, and react for 3 hours under rapid stirring. Sampling, GC analysis, the raw material 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid ethyl ester completely disappeared.

[0098] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incomplete reaction of lithium borohydride, and the solvent tetrahydrofuran was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (120 mL), and washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 25.51 g was obtained by distillation separation with a purity of 97.8% and a yield of 99.3%.

[0099] Embodiment 14:

[0100] Preparation of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol by reduction of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid isopropyl ester with sodium borohydride

[0101] At room temperature, place a 500mL three-necked flask equipped with a magnetic stirrer in an ice-water bath. After nitrogen replacement, add tetrahydrofuran (91.0g), 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid isopropyl ester (22.75g, 0.08mol) and zinc chloride (0.55g, 0.004mol) to the three-necked flask, and stir to mix the three thoroughly. After stirring and cooling in an ice-water bath for 20 minutes, sodium borohydride (9.08g, 0.24mol) was slowly added to the reaction solution in batches to obtain a suspended reaction solution. Remove the ice-water bath, raise the temperature to 40°C and maintain a constant temperature, and react for 3 hours under rapid stirring. Sampling, GC analysis, the raw material 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid isopropyl ester completely disappeared.

[0102] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incomplete reaction of sodium borohydride, and the solvent tetrahydrofuran was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (100 mL), and washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 18.47 g was obtained by distillation separation with a purity of 98.2% and a yield of 99.3%.

[0103] Embodiment 15:

[0104] Reduction of 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropanoic acid methyl ester with diisobutylaluminum hydride to prepare 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol

[0105] At room temperature, place a 500mL three-necked flask equipped with a magnetic stirrer in an ice-water bath. After nitrogen replacement, add methyl tert-butyl ether (141.0g), 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester (28.20g, 0.11mol) and lithium chloride (0.47g, 0.011mol) to the three-necked flask, and stir to mix the three thoroughly. After stirring and cooling in an ice-water bath for 20 minutes, diisobutylaluminum hydride (0.23mol, 1.5M toluene solution) was added to the reaction solution in batches and slowly to obtain a suspended reaction solution. Remove the ice-water bath, raise the temperature to 30°C and maintain a constant temperature, and react for 3 hours under rapid stirring. Sampling, GC analysis, the raw material 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methylpropionic acid methyl ester completely disappeared.

[0106] After treatment, excess methanol (10 mL) was added to the reaction solution to quench the incomplete reaction of diisobutylaluminum hydride, and the solvent methyl tert-butyl ether was removed by rotary evaporation. The crude product was then dissolved in ethyl acetate (150 mL), and washed once with deionized water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation under reduced pressure. The target product 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol 25.48 g was obtained by distillation separation with a purity of 97.2% and a yield of 98.6%.

[0107] It is easy to understand that the above embodiments are only examples for clear explanation and do not mean that the present invention is limited thereto. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from this are still within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol, comprising the following steps: S1, using 2-substituted 2-methylpropionic acid ester as an alkylating agent and reacting with 1-(3,3-dimethylcyclohexyl)ethanol to obtain an alkyl ester intermediate; S2, the alkyl ester intermediate is reduced to give 2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-methyl-1-propanol; Wherein, X is selected from chlorine, bromine, iodine, acetoxy, propionyloxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy; R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl.

2. The method according to claim 1, characterized in that The amount of the 2-substituted 2-methylpropionic acid ester in S1 is 100-300 mol% of 1-(3,3-dimethylcyclohexyl)ethanol.

3. The method according to any one of claims 1 to 2, characterized in that: In S1, an alkali catalyst is used, and the alkali catalyst includes one or more of metal hydroxides, metal hydrides, carbonates, phosphates, alkyl alcohol salts, and guanidine, preferably one or more of potassium carbonate, potassium phosphate, tetramethylguanidine, sodium hydride, and sodium hydroxide; preferably, the amount of the alkali catalyst is 120-300 mol% of 1-(3,3-dimethylcyclohexyl)ethanol.

4. The method according to claims 1-3, characterized in that: The pyridine auxiliary agent used in S1 includes one or more of pyridine, 3-methylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, and 4-piperidinylpyridine, preferably one or more of 4-dimethylaminopyridine, 4-pyrrolidinopyridine, and 4-piperidinylpyridine; preferably, the auxiliary agent is used in an amount of 0.5-5.0 mol% of 1-(3,3-dimethylcyclohexyl)ethanol.

5. The method according to any one of claims 1 to 4, characterized in that: The reaction time in S1 is 2 to 7 hours; and / or the reaction temperature is 40 to 80°C.

6. The method according to claims 1-5, characterized in that: The solvent in S1 is selected from tetrahydrofuran, methyl tert-butyl ether, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyl acetate, and ethyl acetate.

7. The method according to claim 1, characterized in that The reducing agent in S2 includes one or more of lithium aluminum hydride, lithium borohydride, sodium borohydride, calcium borohydride, and diisobutylaluminum hydride; preferably, the amount of the reducing agent is 150-300 mol% of the alkyl ester intermediate.

8. The method according to claim 1, characterized in that The Lewis acid auxiliary agent is optionally used in S2, including one or more of tin octoate, dibutyltin oxide, lithium chloride, zinc chloride, zinc bromide, and scandium trifluoromethanesulfonate; preferably, the Lewis acid auxiliary agent is used in an amount of 1-10 mol% of the alkyl ester intermediate.

9. The method according to any one of claims 1 and 7-8, characterized in that: The solvent in S2 includes diethyl ether, tetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

10. The method according to any one of claims 1 and 7-9, characterized in that: The reaction time in S2 is 2 to 7 hours; and / or the reaction temperature is 30 to 60°C.

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