Preparation method of 7-chloro-2-ethyl-2, 3-dihydrobenzofuran-4-alcohol
Through the amide protection-deprotection strategy and the introduction of aromatic ring negative ions in butyl lithium, react with epoxy derivatives, combined with acidic closed loop and diazotization hydrolysis reaction, 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol was prepared in one pot method, solving the problems of high substrate requirements and insufficient reaction efficiency in the prior art, and achieving the target product preparation with high yield.
Patent Information
- Application Number
- CN202510218435.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-26
- Publication Date
- 2025-05-30
AI Technical Summary
The prior art has problems with high substrate requirements, insufficient reaction efficiency and accuracy in the preparation of 2,3-dihydrobenzofuran compounds, especially the synthesis method of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol has not been fully explored.
The protection-deprotection strategy of amide is adopted to generate aromatic ring negative ions through butyl lithium, react with epoxy derivatives, and synthesize 2,3-dihydrobenzofuran derivative precursors. Then, a closed-loop reaction was carried out under acidic conditions, and the protective group was removed efficiently, and finally the preparation of the target product was achieved through a one-pot method of diazotization and hydrolysis.
The preparation of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol was achieved in a high yield and single configuration based on cheap raw materials, providing a highly efficient synthesis pathway and potential medicinal value.
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Figure CN120058658A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a preparation method of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol. Background Art
[0002] 2,3-Dihydrobenzofuran contains a saturated five-membered oxygen heterocycle fused with a benzene ring. Such natural products widely exist in nature and can be extracted from many medicinal plants. They have excellent biological activities such as anti-inflammatory, antiviral, and anti-tumor. For example, the compound Bglaiastatin with anti-tumor activity comes from the leaves of the tropical plant Milan, and the component with the effects of dispelling wind and dampness and relaxing tendons and activating collaterals comes from the needles of Pinus massoniana. Derivatives obtained from 2,3-dihydrobenzofuran through a series of structural modifications have good biological activities, greatly enriching the types of such compounds as pharmaceutical intermediates. With their unusual structural features and extensive biological activities, they have attracted wide attention from synthetic chemists.
[0003] Currently, there are mainly three categories of preparation methods for 2,3-dihydrobenzofuran compounds: reduction method, intramolecular cyclization reaction, and intermolecular cyclization reaction. Among them, the reduction method has high requirements for substrates, and some functional groups sensitive to transition metals cannot be applied, with large limitations; the intermolecular cyclization reaction has strong designability, but the reaction efficiency and accuracy between molecules are poor. Currently, the method of intramolecular cyclization has become a major mainstream method. In addition, as a 2,3-dihydrobenzofuran derivative, 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol has diverse post-reaction characteristics and has potential excellent physiological activities and medicinal values in the field of drug innovation. Therefore, it is of great significance to explore the synthesis of this compound. Summary of the Invention
[0004] Aiming at the deficiencies of the prior art, the present invention provides a preparation method of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol. The raw materials of the present invention are easily available, the yield is relatively high, and the target product with a single configuration can be obtained.
[0005] The technical solution of the present invention is as follows:
[0006] A preparation method of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, the preparation method is carried out according to the following process:
[0007]
[0008] It includes the following steps:
[0009] (1) Compound 1 is prepared into compound 2 through a nucleophilic substitution reaction under the catalysis of an organic base;
[0010] (2) Compound 2 undergoes an addition reaction under the action of n-butyllithium to obtain Compound 3;
[0011] (3) Compound 3 undergoes a ring-closure reaction under acidic conditions to obtain Compound 4;
[0012] (4) Compound 4 undergoes a diazotization reaction with sodium nitrite and is further hydrolyzed to obtain the 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol.
[0013] Furthermore, in step (1), the specific process of the nucleophilic substitution reaction is as follows: Compound 1 is dissolved in Solvent I, and under the catalysis of an organic base, it undergoes a nucleophilic substitution reaction with pivaloyl chloride to obtain Compound 2.
[0014] Furthermore, Solvent I is selected from any one of dichloromethane and tetrahydrofuran; the concentration of Compound 1 in Solvent I is 0.04 - 0.08 g / mL; the organic base is selected from any one of triethylamine and diisopropylethylamine; the molar ratio of Compound 1 to the organic base is 1:1.8 - 3.0; the molar ratio of Compound 1 to pivaloyl chloride is 1:1.05 - 1.5; the temperature of the nucleophilic substitution reaction is room temperature, and the time is 30 - 60 min.
[0015] Furthermore, in step (2), the addition reaction is specifically as follows: Compound 2 is dissolved in Solvent II, n-butyllithium is added for a preliminary reaction, and then 1,2-epoxybutane is added dropwise for a secondary reaction overnight to obtain Compound 3.
[0016] Furthermore, Solvent II is anhydrous tetrahydrofuran; the concentration of Compound 2 in Solvent II is 0.05 - 0.08 g / mL; the molar ratio of Compound 2 to n-butyllithium is 1:2.2 - 2.8; the molar ratio of Compound 2 to 1,2-epoxybutane is 1:1.2 - 1.6; the temperature of the preliminary reaction is -10 - 0 °C, and the time is 1.5 - 3 h; the temperature of the secondary reaction is 25 - 35 °C.
[0017] Furthermore, in step (3), the ring-closure reaction is specifically as follows: Compound 3 is dissolved in a hydrobromic acid solution and heated for a reaction overnight to obtain Compound 4.
[0018] Furthermore, the mass percentage concentration of the hydrobromic acid solution is 45% - 50%; the concentration of Compound 4 in the hydrobromic acid solution is 0.21 - 0.25 mol / L; the temperature of the reaction is 95 - 105 °C.
[0019] Further, in step (4), the specific reaction process is as follows: Dissolve compound 4 in hydrochloric acid solution, add sodium nitrite at low temperature for diazotization reaction, and then raise the temperature for hydrolysis to obtain compound 5.
[0020] Further, the concentration of the hydrochloric acid solution is 0.4 - 0.6 mol / L; the concentration of compound 4 in the hydrochloric acid solution is 0.03 - 0.05 g / mL; the molar ratio of compound 4 to sodium nitrite is 1:1.05 - 1.1.
[0021] Further, the temperature of the low temperature is -10 - 0 °C, the time of the diazotization reaction is 10 - 30 min; the temperature of the hydrolysis is 95 - 105 °C, and the time is 2 - 3 h.
[0022] The beneficial technical effects of the present invention are as follows:
[0023] Starting from inexpensive raw materials, the present invention first adopts the strategy of protection - deprotection of amide, generates aryl anions with butyllithium, and reacts with various epoxy derivatives to ingeniously and conveniently design and synthesize precursors of 2,3 - dihydrobenzofuran derivatives; then under acidic conditions, intramolecular nucleophilic substitution occurs for ring - closing while efficiently removing the protecting group, thereby obtaining 2,3 - dihydrobenzofuran derivatives with an amino group at the 4 - position; finally, the target product is prepared by a one - pot method using diazotization reaction and hydrolysis reaction. Among them, the generation of aryl anions in step (2) becomes a key step. By introducing different types of epoxy derivatives, it provides an original idea for the preparation of 2,3 - dihydrobenzofuran derivatives with different substitutions at the 2 - position. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 It is a schematic diagram of the reaction process of the present invention.
[0025] Figure 2 It is the 1H - NMR spectrum of 7 - chloro - 2 - ethyl - 2,3 - dihydrobenzofuran - 4 - ol prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION
[0026] The present invention will be specifically described below with reference to the drawings and examples.
[0027] Example 1
[0028] A preparation method of 7 - chloro - 2 - ethyl - 2,3 - dihydrobenzofuran - 4 - ol, the preparation method comprising the following steps:
[0029] (1) Dissolve 10 g (0.063 mol) of 4-chloro-3-methoxyaniline (Compound 1) in 250 mL of dichloromethane, add 11.5 g (0.113 mol) of triethylamine. Cool the reaction solution to 0 °C, slowly add dropwise 7.9 g (0.066 mol) of pivaloyl chloride. After the addition is complete, warm the reaction mixture to room temperature and react for 30 min. After the reaction is complete, quench the reaction with 0.5 mol / L hydrochloric acid solution until weakly acidic, then extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 12 g of a gray solid product, namely Compound 2 N-(4-chloro-3-methoxyphenyl)pivalamide, with a yield of 78% and a content of 95%.
[0030] (2) Dissolve 11 g (0.046 mol) of N-(4-chloro-3-methoxyphenyl)pivalamide (Compound 2) in 220 mL of anhydrous tetrahydrofuran. Under nitrogen protection, cool the reaction solution to -10 °C, slowly add dropwise 40 mL of a n-butyllithium solution (2.5 mol / L). After the addition is complete, stir at -10 °C for 1.5 h. Maintain the temperature at -10 °C and continue to add dropwise 4.0 g (0.055 mol) of 1,2-epoxybutane. After the addition is complete, warm the reaction mixture to 30 °C and react overnight. After the reaction is complete, quench the reaction with an aqueous ammonium chloride solution, extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Use dichloromethane / methanol (20 / 1, V / V) as the eluent, purify by column chromatography, and rotary evaporate and concentrate to obtain 5.7 g of a yellow solid product, namely Compound 3 N-(4-chloro-2-(2-hydroxybutyl)-3-methoxyphenyl)pivalamide, with a yield of 40% and a content of 95%.
[0031] (3) Dissolve 4.5 g (0.014 mol) of N-(4-chloro-2-(2-hydroxybutyl)-3-methoxyphenyl)pivalamide (Compound 3) in 64 mL of an aqueous hydrobromic acid solution with a mass fraction of 45%. React in a sealed tank at 95 °C overnight. After the reaction is complete, quench with a saturated aqueous sodium bicarbonate solution, adjust the pH to about 7-8, extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Use petroleum ether / ethyl acetate (8 / 1) as the eluent, purify by column chromatography, and rotary evaporate and concentrate to obtain 1.9 g of a brown oily product, namely Compound 4 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-amine, with a yield of 67% and a content of 97%.
[0032] (4) Dissolve 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-amine (1.9 g, 9.6 mmol) in hydrochloric acid solution (62 mL, 0.40 mol / L). Cool the reaction solution to -10 °C, add sodium nitrite (0.69 g, 10.1 mmol), stir for 30 min, then heat up to 95 °C and react for 3 h. After complete reaction, dilute with water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and then concentrate. Use petroleum ether / ethyl acetate (5 / 1, V / V) as the eluent, purify by column chromatography, rotary evaporate and concentrate to obtain 0.48 g of a brown oily product, namely 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, with a yield of 24% and a content of 96%.
[0033] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.62 (s, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 4.80 (ddt, J = 9.1, 7.8, 6.4 Hz, 1H), 3.22 (dd, J = 15.7, 9.1 Hz, 1H), 2.76 (dd, J = 15.7, 7.7 Hz, 1H), 1.79–1.62 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).
[0034] Example 2
[0035] A preparation method of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, the preparation method comprising the following steps:
[0036] (1) Dissolve compound 1, 4-chloro-3-methoxyaniline (10 g, 0.063 mol) in dichloromethane (125 mL), add diisopropylethylamine (16.3 g, 0.126 mol), cool the reaction solution to 0 °C, slowly dropwise add pivaloyl chloride (9.1 g, 0.076 mol), after dropping, heat up to room temperature and react for 40 min. After complete reaction, quench with 0.5 mol / L hydrochloric acid solution to weak acidity, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and then concentrate to obtain 13 g of a gray solid product, namely compound 2, N-(4-chloro-3-methoxyphenyl)pivalamide, with a yield of 85% and a content of 95%.
[0037] (2) Dissolve N-(4-chloro-3-methoxyphenyl)pivalamide (11 g, 0.046 mol) in anhydrous tetrahydrofuran (158 mL). Under nitrogen protection, cool the reaction solution to -5°C, and slowly add n-butyllithium solution (44 mL, 2.5 mol / L). After the addition is complete, stir at -5°C for 2 h, keep the temperature at -5°C and continue to add 1,2-epoxybutane (4.6 g, 0.064 mol). After the addition is complete, raise the temperature to 35°C and react overnight. After the reaction is complete, quench the reaction with an aqueous ammonium chloride solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and then concentrate. Use dichloromethane / methanol (20 / 1, V / V) as the eluent, purify by column chromatography, and rotary evaporate and concentrate to obtain 6.0 g of a yellow solid product, namely compound 3 N-(4-chloro-2-(2-hydroxybutyl)-3-methoxyphenyl)pivalamide, with a yield of 42% and a content of 95%.
[0038] (3) Dissolve N-(4-chloro-2-(2-hydroxybutyl)-3-methoxyphenyl)pivalamide (4.5 g, 0.014 mol) in an aqueous hydrobromic acid solution with a mass fraction of 48% (60 mL), and carry out the reaction in a sealed tank at 100°C overnight. After the reaction is complete, quench with a saturated aqueous sodium bicarbonate solution, adjust the pH to about 7-8, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and then concentrate. Use petroleum ether / ethyl acetate (8 / 1) as the eluent, purify by column chromatography, and rotary evaporate and concentrate to obtain 1.8 g of a brown oily product, namely compound 4 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-amine, with a yield of 64% and a content of 97%.
[0039] (4) Dissolve 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-amine (1.9 g, 9.6 mmol) in an aqueous hydrochloric acid solution (48 mL, 0.5 mol / L), cool the reaction solution to -5°C, add sodium nitrite (0.71 g, 10.4 mmol), stir for 20 min, then raise the temperature to 100°C and react for 2.5 h. After the reaction is complete, dilute with water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and then concentrate. Use petroleum ether / ethyl acetate (5 / 1, V / V) as the eluent, purify by column chromatography, and rotary evaporate and concentrate to obtain 0.52 g of a brown oily product, namely 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, with a yield of 27% and a content of 96%.
[0040] Example 3
[0041] A preparation method of 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, the preparation method comprising the following steps:
[0042] (1) Dissolve 1 4-chloro-3-methoxyaniline (10 g, 0.063 mol) in tetrahydrofuran (170 mL), add triethylamine (19 g, 0.189 mol), cool the reaction solution to 0 °C, slowly add tert-pentanoyl chloride (11.3 g, 0.095 mol) dropwise. After the addition is complete, warm the reaction mixture to room temperature and react for 60 min. After the reaction is complete, quench the reaction with 0.5 mol / L hydrochloric acid solution until it is weakly acidic, then extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 11 g of a gray solid product, namely compound 2 N-(4-chloro-3-methoxyphenyl)pivalamide, with a yield of 79% and a content of 95%.
[0043] (2) Dissolve N-(4-chloro-3-methoxyphenyl)pivalamide (11 g, 0.046 mol) in anhydrous tetrahydrofuran (138 mL). Under nitrogen protection, cool the reaction solution to 0 °C and slowly add n-butyllithium solution (52 mL, 2.5 mol / L) dropwise. After the addition is complete, stir at 0 °C for 3 h. Keep the temperature at 0 °C and continue to add 1,2-epoxybutane (5.3 g, 0.074 mol) dropwise. After the addition is complete, warm the reaction mixture to 35 °C and react overnight. After the reaction is complete, quench the reaction with aqueous ammonium chloride solution, extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Use dichloromethane / methanol (20 / 1, V / V) as the eluent, purify by column chromatography, and concentrate by rotary evaporation to obtain 6.8 g of a yellow solid product, namely compound 3 N-(4-chloro-2-(2-hydroxybutyl)-3-methoxyphenyl)pivalamide, with a yield of 48% and a content of 95%.
[0044] (3) Dissolve N-(4-chloro-2-(2-hydroxybutyl)-3-methoxyphenyl)pivalamide (4.5 g, 0.014 mol) in an aqueous solution of hydrobromic acid with a mass fraction of 50% (56 mL), and react in a sealed tank at 105 °C overnight. After the reaction is complete, quench the reaction with saturated aqueous sodium bicarbonate solution, adjust the pH to about 7 - 8, extract with ethyl acetate. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Use petroleum ether / ethyl acetate (8 / 1) as the eluent, purify by column chromatography, and concentrate by rotary evaporation to obtain 2.1 g of a brown oily product, namely compound 4 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-amine, with a yield of 74% and a content of 97%.
[0045] (4) 7-Chloro-2-ethyl-2,3-dihydrobenzofuran-4-amine (1.9 g, 9.6 mmol) was dissolved in an aqueous solution of hydrochloric acid (38 mL, 0.6 mol / L), the reaction solution was cooled to 0°C, sodium nitrite (0.73 g, 10.6 mmol) was added, stirred for 10 min, and then heated to 105°C for 2 h. After the reaction was complete, the solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Petroleum ether / ethyl acetate (5 / 1, V / V) was used as the eluent, and the solution was purified by column chromatography and concentrated by rotary evaporation to obtain 0.49 g of a brown oily product, namely 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, with a yield of 26% and a content of 96%.
[0046] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.
Claims
1. A method for preparing 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol, characterized in that: The preparation method is carried out according to the following process: The steps include: (1) Compound 1 undergoes a nucleophilic substitution reaction under the catalysis of an organic base to obtain compound 2; (2) Compound 2 undergoes an addition reaction under the action of n-butyl lithium to obtain compound 3; (3) Compound 3 undergoes a ring-closing reaction under acidic conditions to obtain compound 4; (4) Compound 4 is subjected to diazotization reaction with sodium nitrite, and then further hydrolyzed to obtain the 7-chloro-2-ethyl-2,3-dihydrobenzofuran-4-ol.
2. The preparation method according to claim 1, characterized in that: In step (1), the specific process of the nucleophilic substitution reaction is: dissolving compound 1 in solvent I, and reacting with t-valeryl chloride under the catalysis of an organic base to undergo a nucleophilic substitution reaction to obtain compound 2.
3. The preparation method according to claim 2, characterized in that: The solvent I is selected from any one of dichloromethane and tetrahydrofuran; the concentration of the compound 1 in the solvent I is 0.04-0.08 g / mL; the organic base is selected from any one of triethylamine and diisopropylethylamine; the molar ratio of the compound 1 to the organic base is 1:1.8-3.0; the molar ratio of the compound 1 to t-valeryl chloride is 1:1.05-1.5; the temperature of the nucleophilic substitution reaction is room temperature, and the time is 30-60 min.
4. The preparation method according to claim 1, characterized in that: In step (2), the addition reaction is specifically as follows: dissolving compound 2 in solvent II, adding n-butyl lithium for a preliminary reaction, and then adding 1,2-butylene oxide dropwise for a secondary reaction overnight to obtain compound 3.
5. The preparation method according to claim 4, characterized in that: The solvent II is anhydrous tetrahydrofuran; the concentration of the compound 2 in the solvent II is 0.05-0.08 g / mL; the molar ratio of the compound 2 to n-butyl lithium is 1:2.2-2.8; the molar ratio of the compound 2 to 1,2-butylene oxide is 1:1.2-1.6; the temperature of the preliminary reaction is -10-0°C, and the time is 1.5-3h; the temperature of the secondary reaction is 25-35°C.
6. The preparation method according to claim 1, characterized in that: In step (3), the ring-closing reaction is specifically as follows: dissolving compound 3 in a hydrobromic acid solution, heating the reaction overnight, and obtaining compound 4.
7. The preparation method according to claim 6, characterized in that: The mass percentage concentration of the hydrobromic acid solution is 45% to 50%; the concentration of the compound 4 in the hydrobromic acid solution is 0.21 to 0.25 mol / L; and the reaction temperature is 95 to 105°C.
8. The preparation method according to claim 1, characterized in that: In step (4), the specific reaction process is: dissolving compound 4 in a hydrochloric acid solution, adding sodium nitrite at low temperature to carry out a diazotization reaction, and then heating to hydrolyze to obtain compound 5.
9. The preparation method according to claim 8, characterized in that: The concentration of the hydrochloric acid solution is 0.4-0.6 mol / L; the concentration of the compound 4 in the hydrochloric acid solution is 0.03-0.05 g / mL; the molar ratio of the compound 4 to sodium nitrite is 1:1.05-1.
1.
10. The preparation method according to claim 8, characterized in that: The low temperature is -10 to 0°C, the diazotization reaction time is 10 to 30 minutes; the hydrolysis temperature is 95 to 105°C, and the time is 2 to 3 hours.