A process for the preparation of 4-chloro-1-naphthol
By introducing a boric acid group into the synthesis of 4-chloro-1-naphthol to direct the chlorination reaction and using a mild chlorination reagent, a method with high selectivity and high yield of 4-chloro-1-naphthol was achieved, solving the problems of poor selectivity and insufficient environmental friendliness in existing technologies. This method is applicable to the fields of pharmaceuticals, dyes, and fragrances.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANGDONG KANGNUO BIOENGINEERING CO LTD
- Filing Date
- 2026-03-24
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for synthesizing 4-chloro-1-naphthol suffer from poor selectivity, low yield, high cost, and insufficient environmental friendliness, making it difficult to meet the needs of large-scale industrial production.
Using 1-naphthol as a raw material, 4-chloro-1-naphthol was prepared by introducing a boric acid group at the 2-position and then directing the chlorination reaction at the 4-position to avoid the formation of ortho-polychlorinated byproducts. Mild chlorination reagents and catalysts were used.
It improves reaction selectivity and yield, reduces production costs and wastewater volume, is suitable for industrial production, and produces high-purity products applicable to the pharmaceutical, dye, and fragrance industries.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing 4-chloro-1-naphthol, belonging to the field of organic synthesis technology. Background Technology
[0002] 4-Chloro-1-naphthol is an aromatic chlorophenolic compound with significant application value. Its molecular structure contains a naphthalene ring, a phenolic hydroxyl group, and a chlorine atom, combining the stability of aromatic compounds with the reactivity of its functional groups. It is an indispensable key intermediate in the pharmaceutical, dye, and fragrance industries. In the pharmaceutical field, 4-chloro-1-naphthol can be used to synthesize antitumor, anti-inflammatory, and antibacterial drugs. Its phenolic hydroxyl and chlorine atoms can serve as active sites for structural modification, significantly enhancing the bioactivity of the drugs. In the dye field, it can be used as an intermediate for azo dyes and fluorescent dyes, producing dye products with bright colors and good lightfastness. In the fragrance field, it can be used to synthesize novel fragrances with naphthalene and phenolic aromas, widely used in the daily chemical and food additive industries.
[0003] Regarding the synthetic route of 4-chloro-1-naphthol, a search of existing literature and patents revealed relevant reports [Journal of Organic Chemistry, 1978, 43, 2456; CN10238 2341A; Advanced Synthesis and Catalysis, 2022, 364, 2174; Chemistry - An Asian Journal, 2011, 6, 2130] that use 1-naphthol as a raw material and generate 4-chloro-1-naphthol through direct chlorination with chlorine, chlorination with a concentrated hydrochloric acid-hydrogen peroxide system, or chlorination with thionyl chloride. However, existing synthesis methods have significant drawbacks: First, the reaction selectivity is poor. The ortho and para positions of the hydroxyl groups on the naphthalene ring of 1-naphthol are prone to chlorination, easily generating byproducts such as 2-chloro-1-naphthol and 4,6-dichloro-1-naphthol, resulting in a low yield of the target product (usually below 65%). The isomer ratio varies greatly during scale-up, and the process reproducibility is very poor. At the same time, subsequent separation and purification are difficult and costly. Second, the use of chlorination reagents poses safety hazards. Chlorine is a highly toxic gas, making operation difficult. The concentrated hydrochloric acid-hydrogen peroxide system and the thionyl chloride chlorination system are highly corrosive, requiring high-end equipment and easily generating waste acid and wastewater, which puts great pressure on environmental protection and further increases production costs, making it difficult to meet the needs of large-scale industrial production.
[0004] Currently, the synthesis of 4-chloro-1-naphthol still suffers from problems such as poor selectivity, low yield, high cost, and insufficient environmental friendliness, and research on related synthesis methods is relatively scarce. Therefore, developing a method for preparing 4-chloro-1-naphthol that is readily available, has a simple route, high selectivity, high yield, is economical and environmentally friendly, and can be industrialized is of great practical significance and application value for expanding its application scope and promoting the development of related fine chemical industries. Summary of the Invention
[0005] This invention addresses the problems of poor selectivity, numerous byproducts, low yield, high raw material costs, and insufficient environmental friendliness in the synthesis of 4-chloro-1-naphthol in existing technologies. Through in-depth research and exploration, the aim is to provide a highly selective, high-yield, economical, environmentally friendly, and industrially scalable method for preparing 4-chloro-1-naphthol. This invention uses 1-naphthol as the starting material and first introduces a boric acid group at the 2-position to direct the subsequent chlorination reaction at the 4-position, effectively suppressing the formation of ortho- and polychlorinated byproducts. The route is short, highly operable, and yields a high overall yield.
[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: 1-naphthol is used as a raw material to react with a deprotonating reagent, followed by reaction with a borate ester, and acidification to generate 1-hydroxynaphth-2-boric acid; then it is reacted with a chlorinating reagent to obtain 4-chloro-1-hydroxynaphth-2-boric acid; finally, it is reacted with an organic base in the presence of copper sulfate to remove boric acid and generate 4-chloro-1-naphthol.
[0007] This invention provides a method for preparing 4-chloro-1-naphthol, comprising the following steps: A. Mix 1-naphthol with a deprotonating agent in an ether solvent, react at low temperature, add borate ester to react, and quench with acid to obtain 1-hydroxynaphth-2-boronic acid; B. Mix 1-hydroxynaphth-2-boronic acid and a chlorinating agent in hexafluoroisopropanol at room temperature to obtain 4-chloro-1-hydroxynaphth-2-boronic acid; C. Mix 4-chloro-1-hydroxynaphth-2-boronic acid, copper sulfate and organic base in ethanol solution and react under heating conditions to obtain 4-chloro-1-naphthol.
[0008] The synthetic route of this invention is represented by the following reaction equation: Further, under preferred conditions, in step A, the deprotonating agent is selected from n-butyllithium (1.6M or 2.5M) or diisopropylaminolithium (2M); the ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or methylcyclopentyl ether; and the borate ester is selected from trimethyl borate or triisopropyl borate.
[0009] Furthermore, under preferred conditions, in step A, the low-temperature condition is -70°C to 0°C.
[0010] Further, under preferred conditions, in step A, the molar ratio of 1-naphthol, deprotonating agent, and borate ester is 1:2-2.5:1-1.5.
[0011] Further, under preferred conditions, in step B, the chlorinating agent is selected from N-chlorosuccinimide (NCS) or 1,3-dichloro-5,5-dimethylhydantoin (DCDMH).
[0012] Further, under preferred conditions, in step B, the molar ratio of 1-hydroxynaphthalene-2-boronic acid to the chlorinating reagent is 1:1-1.2.
[0013] Further, under preferred conditions, in step C, the organic base is selected from diisopropylamine or DBU.
[0014] Furthermore, under preferred conditions, in step C, the heating condition is 70-80℃.
[0015] Further, under preferred conditions, in step C, the molar ratio of 4-chloro-1-hydroxynaphthalene-2-boric acid, copper sulfate, and organic base is 1:0.01-0.02:1-1.2. Compared with the prior art, the present invention has achieved the following technical advancements:
[0016] 1. Using 1-naphthol, which is commercially available and inexpensive, as the starting material, a boric acid group is first introduced at the 2-position so that the chlorination reaction is positioned at the 4-position in the later stage, effectively suppressing the formation of ortho- and polychlorinated byproducts, which is suitable for the needs of large-scale industrial production.
[0017] 2. The three-step reaction route is simple, requiring no high-temperature or high-pressure equipment, and is easy to operate. The second step uses a mild chlorination reagent, avoiding the use of highly toxic chlorine gas and a highly corrosive chlorination system, thus improving operational safety. There are fewer reaction byproducts and less wastewater, which meets the requirements of green chemical development. The third step removes boric acid groups, requiring less catalyst, further reducing production costs and environmental pressure.
[0018] 3. The 4-chloro-1-naphthol prepared by this invention has high purity and stable quality, and can be widely used in the fields of medicine, dyes, and fragrances. It is especially suitable for the synthesis of antitumor drugs and high-end fluorescent dyes that require high purity of intermediates, and has broad application prospects. Specific Implementation
[0019] The present invention will be further illustrated below with specific examples. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention. Example 1
[0020]
[0021] Under nitrogen protection, 1-naphthol (0.1 mol, 14.4 g) was mixed in 100 mL of tetrahydrofuran, cooled to -60 °C, and 100 mL of 2.2 M n-butyllithium solution was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes, and then trimethyl borate (0.12 mol, 12.5 g) was added. The mixture was kept warm and stirred for 1 hour, then slowly heated to 0 °C and reacted for another 2 hours. After the reaction was complete, 1 M hydrochloric acid was added to quench the reaction and adjust the pH to 2. The mixture was extracted twice with 80 mL of ethyl acetate, and the organic layers were combined. The organic layers were washed with 80 mL of saturated brine. After the solvent in the organic layers was evaporated, the crude product n-heptane / MTBE (v / v = 10 / 1) was slurried to obtain 16.2 g of 1-hydroxynaphthalene-2-boric acid, with a yield of 86%. 1 HNMR(400MHz, DMSO-d6+D2O): 8.15 (m, 1H), 8.04 (m, 1H), 7.79-7.65 (m, 2H), 7.50- 7.35 (m, 2H)ppm. Example 2
[0022]
[0023] Under nitrogen protection, 1-naphthol (0.1 mol, 14.4 g) was mixed in 100 mL of THF, cooled to -60 °C, and 110 mL of LDA (2 M) solution was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes, and then trimethyl borate (0.12 mol, 12.5 g) was added. The mixture was kept warm and stirred for 1 hour, then slowly heated to 0 °C and continued to react for 2 hours. After the reaction was complete, 1 M hydrochloric acid was added to quench the reaction and adjust the pH to 2. The mixture was extracted twice with 80 mL of ethyl acetate, and the organic layers were combined. The organic layers were washed with 80 mL of saturated brine. After the solvent in the organic layers was evaporated, the crude product n-heptane / MTBE (v / v=10 / 1) was slurried to obtain 15.4 g of 1-hydroxynaphthyl-2-boric acid, with a yield of 82%. Example 3
[0024]
[0025] Under nitrogen protection, 1-hydroxynaphthalene-2-boric acid (0.1 mol, 18.8 g) and NCS (0.11 mol, 14.7 g) were mixed in 200 mL of hexafluoroisopropanol and reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the crude product was dissolved in 22 mL of methanol. Then, 105 mL of 0.1 M hydrochloric acid aqueous solution was added and stirred until precipitation occurred. The product was filtered and dried to obtain 20.9 g of 4-chloro-1-hydroxynaphthalene-2-boric acid, with a yield of 94%. 1 HNMR(400MHz, DMSO-d6+D2O): 8.26(m, 1H), 8.11(m, 1H), 7.72 (m, 1H), 7.63(m,1H), 7.49(m,1H) ppm. Example 4
[0026]
[0027] Under nitrogen protection, 1-hydroxynaphthalene-2-boric acid (0.1 mol, 18.8 g) and DCDMH (0.11 mol, 21.7 g) were mixed in 200 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the crude product was dissolved in 22 mL of methanol. Then, 105 mL of 0.1 M hydrochloric acid aqueous solution was added and stirred until precipitation occurred. The product was filtered and dried to obtain 18.7 g of 4-chloro-1-hydroxynaphthalene-2-boric acid, with a yield of 84%. Example 5
[0028]
[0029] 4-Chloro-1-hydroxynaphthyl-2-boronic acid (0.1 mol, 22.2 g), copper sulfate (1.5 mmol, 0.24 g), and diisopropylamine (0.11 mol, 11.1 g) were mixed in 150 mL of ethanol (90%), heated to 75 °C, and reacted openly for 5 hours. After cooling to room temperature, 100 mL of water was added, followed by extraction twice with 100 mL of dichloromethane. The organic layers were combined and concentrated. The crude product was simply washed with silica gel, using hexane / ethyl acetate as eluent (v / v = 10 / 1) to give 15.9 g of 4-chloro-1-naphthol, with a yield of 89% and an HPLC purity of 99.6%. 1 HNMR (400 MHz, CDCl3): 8.22 (m, 2H), 7.64 (m, 1H), 7.57 (m, 1H), 7.42 (d, 1H), 6.75 (d, 1H), 5.23 (s, 1H) ppm.
[0030] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A method for preparing 4-chloro-1-naphthol, characterized in that, Includes the following steps: A. Mix 1-naphthol with a deprotonating agent in an ether solvent, react at low temperature, add borate ester to react, and quench with acid to obtain 1-hydroxynaphth-2-boronic acid; B. Mix 1-hydroxynaphth-2-boronic acid and a chlorinating agent in hexafluoroisopropanol at room temperature to obtain 4-chloro-1-hydroxynaphth-2-boronic acid; C. Mix 4-chloro-1-hydroxynaphth-2-boronic acid, copper sulfate and organic base in ethanol solution and react under heating conditions to obtain 4-chloro-1-naphthol.
2. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step A, the deprotonating agent is selected from n-butyllithium or diisopropylaminolithium; the ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or methylcyclopentyl ether; and the borate ester is selected from trimethyl borate or triisopropyl borate.
3. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step A, the low temperature condition is -70°C to 0°C.
4. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step A, the molar ratio of 1-naphthol, deprotonating agent and borate ester is 1:2-2.5:1-1.
5.
5. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step B, the chlorinating agent is selected from N-chlorosuccinimide or 1,3-dichloro-5,5-dimethylhydantoin.
6. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step B, the molar ratio of 1-hydroxynaphthalene-2-boronic acid to the chlorinating reagent is 1:1-1.
2.
7. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step C, the organic base is selected from diisopropylamine or DBU.
8. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step C, the heating condition is 70-80℃.
9. The method for preparing 4-chloro-1-naphthol according to claim 1, characterized in that: In step C, the molar ratio of 4-chloro-1-hydroxynaphthalene-2-boric acid, copper sulfate, and organic base is 1:0.01-0.02:1-1.2.