A process for the preparation of 7-ethyl chromanol

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of 7-ethyl chromanol. The 7-ethyl chromanol is prepared by using 7-ethyl indole-3-methyl aldehyde as a starting material, reacting with methyl triphenyl halogenated phosphorus, and then being subjected to borohydride oxidation. The preparation method can effectively avoid the problems of more impurities, difficult purification and low yield caused by Fischer Indole synthesis method in the prior art, and also effectively avoids the use of toxic KCN, improves the operation safety, and simplifies the production operation without the need of reducing pressure fractionation operation for purifying the target product. The preparation process of the 7-ethyl chromanol is simple in operation, the obtained product has high yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing 7-ethylchromol. Background Technology

[0002] Etodolac is a potent nonsteroidal anti-inflammatory drug (NSAID) used to treat rheumatoid arthritis, osteoarthritis, and other conditions. It is characterized by good tolerability, mild side effects, and strong analgesic effect. It also has few gastrointestinal side effects, making it particularly suitable for elderly patients. Developed by AHP Wyeth-Ayesrt in the United States, it was first marketed in the UK in 1985. Its chemical structure is as follows:

[0003]

[0004] 7-Ethylchromol, as a key intermediate in the synthesis of etodoxa acid, directly affects the production, market supply, and quality of this drug. Its chemical structure is as follows:

[0005]

[0006] The main reported methods for preparing 7-ethylchromol are as follows:

[0007] US patents US4062869A and US2006166947A1, and the literature "Synthesis of 7-ethyl-1H-indole" (Jiangsu Chemical Industry, 1993, 21(1), 17-19), "Synthesis of 7-ethylindole" (Chinese Journal of Pharmaceutical Chemistry, 1997, 7(1), 57-59), and "Heterocycles, 2018, 96(1), 67-73) report the use of o-nitroethylbenzene, a byproduct of the industrial production of chloramphenicol intermediate p-nitroethylbenzene, or its downstream intermediate, as raw material. The o-ethylaniline was obtained by reduction with tin powder / hydrochloric acid, then reacted with chloral hydrate and hydroxylamine hydrochloride under acidic conditions to form an oxime acetamide derivative. This derivative was then cyclized in concentrated sulfuric acid to obtain 7-ethylindole ketone, which was then reduced with lithium aluminum hydride to obtain 7-ethylindole. Finally, it was reacted with oxalyl chloride, followed by esterification and reduction with sodium borohydride to obtain:

[0008]

[0009] However, the above process not only has a long synthesis route and is inconvenient to operate, but also has a low overall yield. In addition, the reducing agent used is dangerous and expensive, making it unsuitable for industrial production.

[0010] US Patent US4585877A and the literature “Research on the Synthesis Process of Etodu Acid”. Tianjin Chemical Industry, 2004, 18(5), 22-23; “Synthesis Process of Etodu Acid”. Journal of Chemical Industry and Engineering, 2005, 56(8), 1536-1540. Similarly, using o-nitroethylbenzene as raw material, o-ethylaniline is obtained by reduction with iron powder, and then after diazotization, it is reduced with sodium sulfite (sodium bisulfite or stannous chloride) to obtain o-ethylphenylhydrazine hydrochloride, which is then reacted with 2,3-dihydrofuran in reflux in 1,4-dioxane to obtain:

[0011]

[0012] The Fischer Indole synthesis method is currently the mainstream process for producing 7-ethylchrome alcohol, and it is the simplest and lowest-cost synthesis method available. While the Fischer Indole synthesis method appears clean based solely on the reaction formula, this is not actually the case for the synthesis of 7-ethylchrome alcohol. On the one hand, this technology requires large amounts of environmentally unfriendly or expensive organic solvents such as acetonitrile, DMF, DMAc, and isobutanol, and solvent recovery rates are low. On the other hand, the Fischer rearrangement reaction to form the indole ring requires strong acid catalysis, but strong acids can also catalyze a chain reaction of the indole ring to produce a purplish-black viscous polymer, resulting in many impurities. This leads to low purity of the crude product, complex post-processing, and the 7-ethylchrome alcohol obtained from the reaction separation is a dark (usually brownish-black) viscous gel or oily substance. Methods for separating and purifying this low-purity, dark-colored colloidal substance have been reported, including silica gel column chromatography (see US patents US4585877 and WO9959970) and extraction separation (see WO2005002523), among others. Although silica gel column chromatography can yield high-purity 7-ethylchrome, the use of large amounts of solvent is uneconomical and impractical for industrial production. While extraction separation is currently an effective method for improving the purity of industrial-grade 7-ethylchrome, the purity of crude 7-ethylchrome (typically 60–85%) after separation and purification is still only 95–97%, and the product's color is dark brown (see WO2005002523), which remains unsatisfactory.

[0013] Furthermore, due to the presence of unreacted aldehydes (obtained from the hydrolysis of 2,3-dihydrofuran) and 2,3-dihydrofuran in the system after indole cyclization, the following three byproducts are readily generated, resulting in low purity of the crude product and complex post-processing:

[0014]

[0015] In addition, the use of relatively expensive 2,3-dihydrofuran in the above process increases production costs accordingly.

[0016] Chinese patent applications CN1740153A and CN1740154A and the literature "A New Synthesis Process of 7-Ethylchrome Alcohol" (Journal of Chemical Engineering of Chinese Universities, 2010, 24(1), 127-131) first hydrolyze 2,3-dihydrofuran under acidic conditions to obtain 4-hydroxybutanal, then react it with o-ethylphenylhydrazine salt using a "one-pot method" to generate 4-hydroxybutanal o-ethylphenylhydrazone. Finally, the target product is obtained by Fischer cyclization under concentrated sulfuric acid or ethylene glycol ether solvent conditions, followed by vacuum distillation or recrystallization from cyclohexane.

[0017]

[0018] However, the above process still cannot avoid the defects of the Fischer Indole synthesis method and the use of the expensive 2,3-dihydrofuran.

[0019] Similarly, Chinese patent application CN107522649A and literature Chemical Engineering & Processing: Process Intensification, 121(2017)144-148 employ a microwave-heated tubular continuous flow reaction technology to react phenylhydrazine hydrochloride with 4-hydroxybutyraldehyde, achieving the continuous synthesis of 7-ethylchromol. Although theoretically avoiding the use of strong acids in the Fischer Indole synthesis method, this process has limited batch production and is not suitable for industrial-scale production.

[0020] The literature Heterocycles, 2003, 60(5) 1095-1110 uses 3-ethoxytetrahydrofuran, an active precursor of 2,3-dihydrofuran, as a donor for 4-hydroxybutyraldehyde, but this also cannot avoid the problem of high production costs.

[0021]

[0022] The literature *Journal of Labelled Compounds and Radiopharmaceuticals*, Vol. XIV, No. 3, 1978, 411-425, changes the strategy, introducing a cyano group into 3-substituted-7-ethylindole followed by hydrolysis and reduction to prepare the product.

[0023]

[0024] However, this process uses highly toxic KCN, which poses a significant operational hazard. Furthermore, the cyano-substituted intermediates contain 2-position isomer impurities, resulting in low product purity. Additionally, the carboxylic acid reduction uses expensive and hazardous lithium aluminum hydride, further complicating operational safety and making industrial-scale production difficult.

[0025] In addition, the literature Journal of Medicinal Chemistry, 1976, 19(3), 391-395 describes the design and synthesis of related indoline derivatives using the Reformatsky reaction, but this process also requires the use of expensive and hazardous lithium aluminum hydride.

[0026]

[0027] In addition, the literature *Organic Syntheses*, Coll. Vol. 9, p. 417 (1998); Vol. 74, p. 248 (1997) first protected the 1-position indole hydrogen with tert-butyldimethylchlorosilane (TMDMSCl) under n-butyllithium conditions, then introduced bromine at the 3-position via NBS, followed by Li substitution under n-butyllithium conditions, and then nucleophilic substitution with propylene oxide to deprotect and obtain the relevant derivatives.

[0028]

[0029] However, the above process not only involves many synthesis steps and is cumbersome to operate, but also has a low overall yield. In addition, it requires the repeated use of the hazardous reagent n-butyllithium, which makes the operation less safe and difficult to scale up for industrial production.

[0030] In summary, current methods for preparing 7-ethylchromol suffer from several drawbacks, including high technological risks, cumbersome operations, low yields, and high production costs. Therefore, finding a reaction route suitable for the industrial production of 7-ethylchromol that offers mild reaction conditions, simple operation, high product yield and purity, and low production costs remains a problem that needs to be solved. Summary of the Invention

[0031] To address the problems existing in current 7-ethylchrome alcohol preparation technologies, this invention provides a novel method for preparing 7-ethylchrome alcohol. This method features mild reaction conditions, a simple operation process, and yields a target product with high purity and high yield.

[0032] The specific technical solution of the present invention is as follows:

[0033] A method for preparing 7-ethylchromol includes the following steps:

[0034] Step 1. Under the protection of an inert gas, SM-2 is first reacted under alkaline conditions, and then SM-1 is added to continue the reaction to obtain compound I-1;

[0035] Step 2. Add compound I-1 to a THF solution of boron reagent and react, then react with hydrogen peroxide under alkaline conditions to obtain compound I;

[0036] The reaction route is as follows:

[0037]

[0038] In SM-2, X is either Br or I.

[0039] Preferably, a method for preparing 7-ethylchromol specifically includes the following steps:

[0040] Step 1. Under inert gas protection and temperature control T1, add alkali / organic solvent A solution to organic solvent A of SM-2 to carry out the reaction, then add SM-1 to the reaction solution, raise the temperature to room temperature and continue the reaction to obtain compound I-1;

[0041] Step 2. Add compound I-1 to a THF solution of boron reagent and react at room temperature until the reactant I-1 is completely reacted. Add an appropriate amount of water and inorganic alkali solution, add hydrogen peroxide at a controlled temperature T2, and continue the reaction at room temperature to obtain compound I.

[0042] Preferably, the inert gas mentioned in step 1 is either nitrogen or argon.

[0043] Preferably, the SM-2 mentioned in step 1 is selected from methyltriphenylphosphine bromide or methyltriphenylphosphine iodide, with methyltriphenylphosphine bromide being more preferred.

[0044] Preferably, the alkali mentioned in step 1 is selected from t-BuOK, KHMDS, and NaHMDS, with KHMDS being the most preferred.

[0045] Preferably, the organic solvent A mentioned in step 1 is selected from one of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and diethyl ether, with tetrahydrofuran being the most preferred.

[0046] Preferably, the molar ratio of compound SM-1 to SM-2 and alkali in step 1 is 1:1.2-2.5:1.2-3.0, more preferably 1:1.5:1.65.

[0047] Preferably, the reaction temperature T in step 1 is -10 to 10°C, more preferably -5 to 0°C.

[0048] In a preferred embodiment, after the reaction in step 1 is completed, a post-processing operation is required. The specific steps are as follows: filtration, pouring the filtrate into purified water, extraction with organic solvent B, combining the organic layers, concentration, drying, and obtaining compound I-1; wherein the organic solvent B is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, preferably dichloromethane.

[0049] Preferably, the boron reagent in step 2 is selected from one of BH3·Me2S, 9-BBN, Sia2BH, and borane-N,N-dimethylaniline, with 9-BBN being the most preferred.

[0050] Preferably, the molar ratio of compound I-1 to boron reagent and hydrogen peroxide in step 2 is 1:1.1-1.5:3.0-6.0, more preferably 1:1.2:4.0.

[0051] Preferably, the inorganic base in step 2 is selected from NaOH and KOH, with NaOH being the preferred choice.

[0052] Preferably, the concentration of the inorganic alkaline solution in step 2 is typically 3 mol / L.

[0053] Preferably, the molar ratio of inorganic alkali to hydrogen peroxide in step 2 is 1 to 1.1:1, more preferably 1.05:1.

[0054] Preferably, the appropriate amount of water mentioned in step 2 is an amount sufficient to quench the remaining boron reagent.

[0055] Preferably, the temperature control T2 in step 2 is -10 to 5°C, more preferably -5 to -2°C.

[0056] In a preferred embodiment, after the reaction in step 2, a post-processing operation is required. The specific steps are as follows: adjust the pH of the solution to 10 with an alkali, then extract with an organic solvent, combine the organic phases, wash with a saturated sodium thiosulfate solution or a saturated sodium sulfite solution, wash with saturated brine, concentrate the organic phase under reduced pressure, and dry to obtain the target product I. The alkali is a commonly used inorganic alkali, such as NaOH, KOH, Na₂CO₃, K₂CO₃, etc.; the organic solvent is selected from one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, preferably dichloromethane.

[0057] The beneficial effects of this invention are:

[0058] This invention provides a novel method for preparing 7-ethylchromol, using 7-ethylindole-3-carboxaldehyde as the starting material, reacting it with SM-2 followed by hydroboration oxidation. This method effectively avoids the problems of high impurities, difficult purification, and low yield associated with the Fischer-Indole synthesis method; it also effectively avoids the use of highly toxic KCN, improving operational safety. Furthermore, the target product does not require vacuum fractionation for purification, simplifying production operations. The 7-ethylchromol preparation process of this invention is simple to operate, yields a product with high yield and purity, and is suitable for industrial production. Detailed Implementation

[0059] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method described herein fall within the scope of protection of the present invention. The boron reagent described in this application is commercially available or can be prepared according to existing technology.

[0060] The structure of the 7-ethylchromol compound obtained in this invention is confirmed as follows:

[0061]

[0062] ESI-HRMS (m / z): 190.1232 [M+H] + ; 1 H-NMR (600MHz, DMSO-d6) δ8.04 (s, 1H), 7.45 (dd, J=7.78, 1.02Hz, 1H), 7.08 (t, J=7.21Hz, 1H), 7.02~7.04 (m, 2H), 3 .90(t,J=6.35Hz,2H),3.03(dt,J=6.11,0.68Hz,2H),2.85(q,J=7.58Hz,2H),1.70(s,1H),1.35(t,J=7.60Hz,3H); 13 C-NMR (151MHz, CDCl3) δ135.28,127.10,126.64,122.23,120.54,119.75,116.56,112.54,62.64,28.91,23.95,13.80.

[0063] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0064] Synthesis of Compound I

[0065] Example 1

[0066] Under argon protection and temperature control of -5 to 0℃, a KHMDS / THF solution (16.5 ml, 16.5 mmol) was added to a 30 ml solution of methyltriphenylphosphine bromide (5.36 g, 15 mmol) in THF. After stirring for 1 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the solution was filtered, and the filtrate was poured into purified water (50 ml). The solution was extracted with dichloromethane (30 ml × 3), the organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0067] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of 9-BBN (1.46 g, 12 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M NaOH solution (14 mL, 42 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with NaOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 93.7% and a purity of 98.90%.

[0068] Example 2

[0069] Under argon protection and temperature control of 0–5 °C, t-BuOK / DMF (16.5 mL, 16.5 mmol) was added to DMF (30 mL) containing methyltriphenylphosphine bromide (4.29 g, 12 mmol). After stirring for 1 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the solution was filtered, and the filtrate was added to purified water (50 mL). The solution was extracted with dichloromethane (30 mL × 3), the organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0070] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of 9-BBN (1.34 g, 11 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M KOH solution (14 mL, 42 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with KOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 91.0% and a purity of 98.81%.

[0071] Example 3

[0072] Under nitrogen protection and temperature control of 5–10 °C, a KHMDS / THF solution (16.5 ml, 16.5 mmol) was added to a 30 ml THF solution containing methyltriphenylphosphine bromide (3.93 g, 11 mmol). After stirring for 0.5 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the solution was filtered, and the filtrate was added to purified water (500 ml) and extracted with chloroform (30 ml × 3). The organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0073] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of 9-BBN (1.28 g, 10.5 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M NaOH solution (14 mL, 42 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at a controlled temperature of -10 to -5 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with Na2CO3. The solution was then extracted with chloroform (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 86.1% and a purity of 98.25%.

[0074] Example 4

[0075] Under argon protection and temperature control of -10 to -5℃, a NaHMDS / DMSO solution (16.5 ml, 16.5 mmol) was added to DMSO (30 ml) containing methyltriphenylphosphine bromide (8.93 g, 25 mmol). After stirring for 1 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was added to purified water (50 ml) and extracted with dichloromethane (30 ml × 3). The organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0076] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of 9-BBN (1.83 g, 15 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M NaOH solution (14 mL, 42 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at a controlled temperature of -2 to 5 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with K2CO3. The solution was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 92.6% and a purity of 98.75%.

[0077] Example 5

[0078] Under argon protection and temperature control of -10 to -5℃, t-BuOK / Et2O (16.5 ml, 16.5 mmol) solution was added to Et2O (30 ml) of methyltriphenylphosphine bromide (9.29 g, 26 mmol). After stirring for 1.5 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was added to purified water (50 ml) and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0079] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of 9-BBN (1.95 g, 16 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M NaOH solution (14 mL, 42 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with NaOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 88.2% and a purity of 98.11%.

[0080] Example 6

[0081] Under argon protection and temperature control of 5–10 °C, a KHMDS / THF (12.0 ml, 12 mmol) solution was added to 30 ml of THF containing 6.06 g, 15 mmol of methyltriphenylphosphine iodide. After stirring for 0.5 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the solution was filtered, and the filtrate was added to purified water (50 ml) and extracted with dichloromethane (30 ml × 3). The organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0082] The obtained compound I-1 (10 mmol) was added to a THF (30 mL) solution of BH3·Me2S (0.91 g, 12 mmol). The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3M NaOH solution (10.5 mL, 31.5 mmol) were added. Hydrogen peroxide (ω = 30%, 11.25 mL, 30 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with NaOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 91.5% and a purity of 98.55%.

[0083] Example 7

[0084] Under argon protection and temperature control of -10 to -5℃, a KHMDS / THF (30 ml, 30 mmol) solution was added to a THF (30 ml) solution containing methyltriphenylphosphine bromide (5.36 g, 15 mmol). After stirring for 1 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the solution was filtered, and the filtrate was added to purified water (60 ml) and extracted with methyl tert-butyl ether (30 ml × 3). The organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0085] The obtained compound I-1 (10 mmol) was added to a THF (30 mL) solution of Sia2BH (6.82 g, 12 mmol). The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3M NaOH solution (21 mL, 63 mmol) were added. Hydrogen peroxide (ω = 30%, 22.5 mL, 60 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with NaOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 92.2% and a purity of 98.68%.

[0086] Example 8

[0087] Under argon protection and temperature control of -5 to 0℃, a KHMDS / THF solution (16.5 ml, 16.5 mmol) was added to a 30 ml solution of methyltriphenylphosphine bromide (5.36 g, 15 mmol) in THF. After stirring for 1 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the solution was filtered, and the filtrate was poured into purified water (50 ml). The solution was extracted with dichloromethane (30 ml × 3), the organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0088] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of borane-N,N-dimethylaniline (1.63 g, 12 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M NaOH solution (13.3 mL, 40 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with NaOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 92.5% and a purity of 98.72%.

[0089] Example 9

[0090] Under argon protection and controlled temperature of -5 to 0℃, a KHMDS / THF solution (16.5 ml, 16.5 mmol) was added to a 30 ml solution of methyltriphenylphosphine bromide (5.36 g, 15 mmol) in THF. After stirring for 1 h, SM-1 (1.73 g, 10 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was detected to be complete, the reaction solution was poured into purified water (50 ml), extracted with dichloromethane (30 ml × 3), the organic phases were combined, concentrated, and dried to obtain compound I-1. The obtained compound I-1 can be directly used in the next reaction.

[0091] The obtained compound I-1 (10 mmol) was added to a 30 mL solution of borane-N,N-dimethylaniline (1.63 g, 12 mmol) in THF. The reaction was carried out at room temperature until the reactant I-1 was completely reacted. Then, an appropriate amount of water and 3 M NaOH solution (14.7 mL, 44 mmol) were added. Hydrogen peroxide (ω = 30%, 15 mL, 40 mmol) was added at -5 to -2 °C. The reaction was continued at room temperature until the reaction was completed. The pH of the solution was adjusted to 10 with NaOH. Then, the solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium thiosulfate solution (30 mL × 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and dried to obtain the target product I with a yield of 93.1% and a purity of 98.80%.

Claims

1. A method for preparing 7-ethylchromol, the reaction route of which is as follows: ； In SM-2, X is either Br or I. Specifically, the following steps are included: Step 1. Under inert gas protection and temperature control T1, add a solution of alkali organic solvent A to organic solvent A of SM-2 to carry out the reaction, then add SM-1 to the reaction solution, raise the temperature to room temperature and continue the reaction to obtain compound I-1; Step 2. Add compound I-1 to a THF solution of boron reagent and react at room temperature until the reactant I-1 is completely reacted. Add an appropriate amount of water and inorganic alkali solution, add hydrogen peroxide at a controlled temperature T2, and continue the reaction at room temperature to obtain compound I. The alkali mentioned in step 1 is selected from one of t-BuOK, KHMDS, and NaHMDS; The reaction temperature T1 mentioned in step 1 is -10~10℃; The boron reagent mentioned in step 2 is selected from one of BH3·Me2S, 9-BBN, Sia2BH, and borane-N,N-dimethylaniline; The inorganic base mentioned in step 2 is selected from NaOH and KOH.

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound SM-1 to SM-2 and alkali in step 1 is 1:1.2~2.5:1.2~3.

0.

3. The method according to claim 1, characterized in that, The organic solvent A mentioned in step 1 is selected from one of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and diethyl ether.

4. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of compound I-1 to boron reagent and hydrogen peroxide is 1:1.1~1.5:3.0~6.

0.

5. The method according to claim 1, characterized in that, The molar ratio of inorganic alkali to hydrogen peroxide in step 2 is 1~1.1:1.

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