Preparation method of tergorazan intermediate

Abstract

The invention discloses a preparation method of a tergorazan intermediate, which comprises the following steps: (1) 3, 5-difluorophenol and 3-chloro-1-propanol are dissolved in isopropanol, the molar ratio of the 3-chloro-1-propanol to the 3, 5-difluorophenol is (1-1.5): 1, alkali is added, and heating reflux reaction is performed; (2) 3-bromo-1-propanol is added into the reaction system in the step (1), the molar ratio of the 3-bromo-1-propanol to the 3, 5-difluorophenol is (0.1-0.15): 1, and heating reflux reaction is continued; and (3) after the reaction is finished, filtering and concentrating under reduced pressure to obtain the intermediate compound 3-(3, 5-difluorophenoxy)-1-propanol of the tergorazan. According to the method, dangerous reagents are not used, the industrial production cost can be reduced, the yield is high, and the product purity is high.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing a tegorazan intermediate. Background Technology

[0002] Tegoprazan, also known as tegorason or CJ-12420, is a novel digestive system drug developed by CJ HealthCare in South Korea. It was approved for marketing in South Korea in July 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis. Luoxin Pharmaceutical acquired the rights to develop, manufacture, and commercialize tegoprazan in China, and it was approved for marketing in China in April 2022. It is classified as a Class 1 new chemical drug.

[0003] The CAS number for tegolazan is 942195-55-3. Its chemical name is 4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromogenen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, and its molecular structure is as follows:

[0004]

[0005] The method for preparing the drug tegorazone intermediate compound (2) using compound (1) as an intermediate has been publicly reported in documents such as KR101894091B, CN115109022A, and WO2022016309A. For example, its synthetic route is as follows:

[0006]

[0007] Currently, there are few reported synthetic routes for the preparation of compound (1) (chemical name: 3-(3,5-difluorophenoxy)-1-propanol), which can be roughly summarized into three categories, as embodied in patents KR101894091 B, WO2022016309A, and CN115109022A, as follows:

[0008] (1) Synthetic route 1 disclosed in patent KR101894091 B is shown in the figure below:

[0009]

[0010] The method involves adding 36 kg of NaH and 439 kg of DMF to a reactor and cooling it for later use. Additionally, 116 kg of 3,5-difluorophenol is dissolved in 165 kg of DMF and added dropwise to a reactor below 5°C with stirring. After the addition is complete, 108 kg of 3-chloro-1-propanol is dissolved in 165 kg of DMF and added dropwise to the reactor, and the temperature is raised to 80°C for reaction. After the reaction is complete, the temperature is cooled to 20°C, and 839 kg of diisopropyl ether and 530 kg of purified water are added. 48 kg of concentrated hydrochloric acid is added dropwise, and the mixture is stirred. After separation, a 5% sodium hydroxide aqueous solution is added to the organic layer along with the reaction mixture (29 kg of sodium hydroxide + 579 kg of purified water) and stirred. The organic layer is then separated and concentrated under vacuum to obtain compound (167 kg, 100%).

[0011] The main drawbacks of this method include: NaH (sodium hydride) is a highly reactive and dangerous reagent that reacts violently with water, posing a safety hazard in industrial production.

[0012] (2) Synthetic route 2 disclosed in patent WO2022016309A is shown in the figure below:

[0013]

[0014] The method involves adding NaOH (33.7 g, 842.5 mmol) to a solution of 1-bromo-3,5-difluorobenzene (77.2 g, 400 mmol), Cu(acac)₂ (2.6 g, 10 mmol), and a ligand (5-tert-butyl-quinoline-8-ol, 3.3 g, 16.4 mmol) in 290 g of propylene glycol at ambient temperature. The mixture is stirred and heated to 110–115 °C and refluxed at 110–115 °C for 20–24 hours until complete. The mixture is then cooled to ambient temperature, 270 g of water is added, and the mixture is extracted by adding DCM (270 g). The aqueous layer is separated and further extracted by adding DCM (135 g). The combined organic layers are concentrated to 49.4 g of a light yellow oil (65.7% yield).

[0015] This method uses propylene glycol as a solvent and requires harsh reaction conditions, including reflux at 110-115°C for 20-24 hours. The high-temperature, long-duration reaction consumes a lot of energy and places strict requirements on the equipment, thus limiting the efficiency of large-scale production.

[0016] (3) Synthetic route 3 disclosed in patent CN115109022A is shown in the figure below:

[0017]

[0018] The method involves placing 200 g of 3,5-difluorophenol (1.54 mol), 256 g of 3-bromo-1-propanol (1.84 mol), 318 g of potassium carbonate (2.30 mol), 13 g of potassium iodide (0.08 mol), and 1.2 L of ethanol in a reaction flask, mechanically stirring, heating to 80 °C and refluxing for 5 h, cooling the reaction mixture to room temperature, filtering, and washing the filter cake with 0.5 L of ethanol until the reaction is complete; washing with saturated brine (0.5 L × 2) until the pH is close to neutral, concentrating to obtain a light yellow liquid, and weighing to obtain 280 g of compound of formula (1), with a yield of 96.7% (based on 3,5-difluorophenol).

[0019] This method uses 3-bromo-1-propanol as a raw material, which increases the raw material cost of industrial production and results in poor industrial economics.

[0020] Therefore, it is of great significance to develop a simple, high-yield, low-cost, and industrially suitable method for preparing 3-(3,5-difluorophenoxy)-1-propanol. Summary of the Invention

[0021] In view of this, the purpose of this invention is to provide a method for preparing tegorazan intermediates that does not use hazardous reagents, reduces industrial production costs, and achieves high yield and high product purity.

[0022] To achieve the above objectives, the present invention provides the following technical solution:

[0023] This invention discloses a method for preparing a tagorazan intermediate, which is a compound of formula (1) with the following structural formula:

[0024]

[0025] Specifically, the preparation method of this tagorazan intermediate includes the following steps:

[0026] (1) Dissolve 3,5-difluorophenol and 3-chloro-1-propanol in isopropanol, with a molar ratio of 3-chloro-1-propanol to 3,5-difluorophenol of 1 to 1.5:1, and add alkali and heat to reflux for reaction;

[0027] (2) Add 3-bromo-1-propanol to the reaction system of step (1), the molar ratio of 3-bromo-1-propanol to 3,5-difluorophenol is 0.1 to 0.15:1, and continue to heat and reflux the reaction.

[0028] (3) After the reaction is complete, filter and concentrate under reduced pressure to obtain the intermediate compound 3-(3,5-difluorophenoxy)-1-propanol of tegorazan.

[0029] As a preferred technical solution, the alkali added in step (1) is one of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

[0030] As a further preferred technical solution, the alkali added in step (1) is potassium carbonate, and the molar ratio of potassium carbonate to 3,5-difluorophenol is 4 to 5:1.

[0031] As a preferred technical solution, the temperature of the heating reflux reaction in step (1) is 80-86°C, and the reflux reaction time is 24-30h.

[0032] As a preferred technical solution, the temperature of the heating reflux reaction in step (2) is 80-86°C, and the reflux reaction time is 4-6 hours.

[0033] As a preferred technical solution, the reaction system in step (1) further includes at least one of a phase transfer catalyst and a nucleophilic catalyst.

[0034] Most preferably, the phase transfer catalyst is tetrabutylammonium bromide; and the nucleophilic catalyst is dimethylaminopyridine.

[0035] As a preferred technical solution, the molar ratio of tetrabutylammonium bromide to 3,5-difluorophenol is 0.6 to 0.8:1, and the molar ratio of 4-dimethylaminopyridine to 3,5-difluorophenol is 3 to 4:1.

[0036] As a further preferred technical solution, the temperature of the heating reflux reaction in step (1) is 80-86°C, and the reflux reaction time is 5-8h.

[0037] The beneficial effects of this invention are as follows:

[0038] The beneficial effects of this invention are mainly reflected in multiple dimensions such as safety, economy, efficiency and industrial applicability.

[0039] First, in terms of safety, the highly reactive and dangerous reagent sodium hydride used in traditional processes has been eliminated, and inorganic bases such as potassium carbonate, which are more stable, have been replaced. This has effectively reduced safety hazards in industrial production and improved the controllability of the operation process.

[0040] Secondly, in terms of cost control, the innovative use of inexpensive 3-chloro-1-propanol as the main raw material, with only a small amount of highly active 3-bromo-1-propanol added in the later stage of the reaction to promote the complete reaction, not only significantly reduced the amount of expensive brominating reagents, but also completely consumed the high-priced raw material 3,5-difluorophenol through the step-by-step feeding strategy, avoiding resource waste and significantly reducing the overall raw material cost.

[0041] Furthermore, improved reaction efficiency is another key advantage. Through a stepwise reaction design using a primary chlorinated derivative followed by a subsequent bromine addition, the reaction time, originally exceeding 65 hours, is reduced to 28-36 hours. Further, by introducing a synergistic dual-catalyst system of tetrabutylammonium bromide and 4-dimethylaminopyridine, the synergistic effect of phase transfer catalysis and nucleophilic catalysis further compresses the reaction time to 9-14 hours, significantly improving production efficiency. Simultaneously, by optimizing reaction conditions (such as temperature, time, and catalyst ratio), this method ensures high yield and high purity of the target product, 3-(3,5-difluorophenoxy)-1-propanol, avoids excessive side reactions, and simplifies post-processing (requiring only filtration and vacuum concentration), making it suitable for large-scale industrial production.

[0042] Finally, this invention uses isopropanol as a solvent, which, compared with DMF and propylene glycol used in traditional processes, has the advantages of low toxicity, easy recovery, and low corrosiveness to equipment, further reducing the requirements for production equipment and environmental treatment costs. In summary, this method achieves a balance between safety, economy, and efficiency through multi-dimensional optimization of material selection, process design, and catalytic system, providing a superior solution for the industrial preparation of tegorazan intermediates. Attached Figure Description

[0043] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided for illustration:

[0044] Figure 1 The 1H NMR spectrum of 3-(3,5-difluorophenoxy)-1-propanol prepared in this invention is shown. Detailed Implementation

[0045] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0046] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0047] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0048] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0049] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0050] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0051] Example 1

[0052] The purpose of this embodiment is to provide a method for preparing a tagorazan intermediate, the structural formula of which is as follows (compound of formula (1)):

[0053]

[0054] The reaction formula for Example 1 is:

[0055]

[0056] Specifically, the preparation method includes the following steps:

[0057] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol and 40.36g (0.43mol) of 3-chloro-1-propanol in sequence; heat to 82-86℃ and reflux for 24h.

[0058] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0059] (3) After the reaction of the raw materials was completed by HPLC, the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered for 10 min; the organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 69.52 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 99.12% and a yield of 97.21%.

[0060] The proton NMR spectrum of the prepared compound of formula (1) is shown below. Figure 1 The NMR data are shown below:

[0061] 1 H NMR (400MHz, DMSO) δ6.84–6.63(m,3H),4.57(t,J=5.1Hz,1H),4.05(t,J=6.3Hz,2H),3.53(q,J=6.1Hz,2H),1.84(p,J=6.3Hz,2H).

[0062] Example 2

[0063] The purpose of this embodiment is to provide a method for preparing a tagorazan intermediate, the structural formula of which is as follows (compound of formula (1)):

[0064]

[0065] The reaction formula for Example 2 is:

[0066]

[0067] Specifically, the preparation method includes the following steps:

[0068] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol and 45.38g (0.48mol) of 3-chloro-1-propanol in sequence; heat to 82-86℃ and reflux for 26h.

[0069] (2) Add 6.40 g of 3-bromopropanol (0.046 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 4 h;

[0070] (3) After the reaction of the raw materials was completed by HPLC, the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out. Then, it was filtered for 10 min. The organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After the concentration was completed, 70.48 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 99.06% and a yield of 98.54%.

[0071] Example 3

[0072] The purpose of this embodiment is to provide a method for preparing a tagorazan intermediate, the structural formula of which is as follows (compound of formula (1)):

[0073]

[0074] The reaction formula for Example 3 is:

[0075]

[0076] Specifically, the preparation method includes the following steps:

[0077] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol and 52.94g (0.56mol) of 3-chloro-1-propanol in sequence; heat to 82-86℃ and reflux for 30h;

[0078] (2) Add 7.90 g of 3-bromopropanol (0.057 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 6 h;

[0079] (3) After the reaction of the raw materials was completed by HPLC, the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out. Then, it was filtered for 10 min. The organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After the concentration was completed, 70.84 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 99.02% and a yield of 99.05%.

[0080] Comparative Example 1

[0081] Based on Example 1 above, this comparative example observes the influence of specific factors on the reaction results. This example provides a method for preparing a tegorazan intermediate (the same compound of formula (1) in Example 1), and its reaction formula is as follows:

[0082]

[0083] The specific steps include:

[0084] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol and 40.36g (0.43mol) of 3-chloro-1-propanol in sequence; heat to 82-86℃ and reflux for 24h; HPLC analysis shows that 5.82% of 3,5-difluorophenol remains.

[0085] The reaction time was extended to 30 h, and HPLC analysis showed that 3,5-difluorophenol remained at 3.7%.

[0086] The reaction time was extended to 65 h, and HPLC analysis showed that 0.65% of 3,5-difluorophenol remained.

[0087] (2) After reacting for 65 h, the reactants were cooled to 25 °C, filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out. Then, the mixture was filtered for 10 min. The organic phase was concentrated under reduced pressure at 45 °C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 61.32 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 82.55% and a yield of 85.74%.

[0088] The experimental results show that, by changing only the variable of "whether or not to add 3-bromopropanol" (while keeping other conditions such as the amount of 3-chloro-1-propanol and reaction temperature the same as in Example 1), the phenol residue remained at 0.65% after 65 hours of reaction, with a yield of only 85.74%, demonstrating that the reactivity of chloropropanol was severely insufficient. The reaction kinetic curves show a strong resistance zone from 24 to 65 hours (residue decreased from 5.82% to 0.65%), highlighting the extremely high energy barrier in the later stages of the reaction, directly leading to low production efficiency and raw material waste.

[0089] Comparative Example 2

[0090] Based on Example 1 above, this comparative example observes the influence of specific factors on the reaction results. This example provides a method for preparing a tegorazan intermediate (the same compound of formula (1) in Example 1), and its reaction formula is as follows:

[0091]

[0092] The specific steps include:

[0093] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol and 59.77g (0.43mol) of 3-bromo-1-propanol in sequence; heat to 82-86℃ and reflux for 5h.

[0094] (2) After the reaction of the raw materials was completed by HPLC, the temperature was lowered to 25°C. The mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out. Then, it was filtered for 10 min. The organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 68.84 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 99.06% and a yield of 96.25%.

[0095] The experimental results show that simply replacing "3-chloro-1-propanol + supplemented 3-bromopropanol" with "single 3-bromo-1-propanol" while keeping other conditions unchanged results in a faster reaction but higher raw material costs.

[0096] As can be seen from the comparison between Examples 1-3 and Comparative Examples 1 and 2, the present invention (Examples 1-3) uses inexpensive 3-chloro-1-propanol instead of expensive 3-bromo-1-propanol. Only after the reaction process slows down is an appropriate amount of 3-bromo-1-propanol added to advance the reaction, completely consuming the expensive raw material 3,5-difluorophenol. The reaction time, which originally required more than 65 hours, is shortened to 28-36 hours. This reduces the raw material cost while maintaining the reaction efficiency, and the product yield and purity can both reach a high level.

[0097] Example 4

[0098] The purpose of this embodiment is to provide a method for preparing a tagorazan intermediate, the structural formula of which is as follows (compound of formula (1)):

[0099]

[0100] Based on the aforementioned Examples 1-3, the inventors intend to further accelerate the reaction in step (1), shorten the reaction time in step (1), and effectively control the reaction cost by optimizing the reaction conditions, as follows:

[0101] The reaction formula for Example 4 is:

[0102]

[0103] Specifically, the preparation method includes the following steps:

[0104] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol, 85.45g (0.26mol) of tetrabutylammonium bromide and 181.21g (1.48mol) of 4-dimethylaminopyridine in sequence; heat to 82-86℃ and reflux for 8h;

[0105] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0106] (3) After the reaction of the raw materials was completed by HPLC, the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out. Then, it was filtered for 10 min. The organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After the concentration was completed, 71.14 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 99.08% and a yield of 99.47%.

[0107] In the aforementioned Comparative Examples 1 and 2, the inventors found that if inexpensive but inert chloropropanol (such as Comparative Example 1) is used, it takes 65 hours to consume the raw material phenol down to 0.65% residue, with a yield of only 85.74%; if highly active bromopropanol (Comparative Example 2) is used, although it can be completed in 5 hours, the raw material cost increases dramatically.

[0108] A comparison of Example 4 and Example 1 shows that this example further added tetrabutylammonium bromide and 4-dimethylaminopyridine to the reaction system. Utilizing the catalytic effect of tetrabutylammonium bromide and 4-dimethylaminopyridine, the reaction rate was further increased, shortening the reaction time from 28–36 h to 9–14 h. Specifically, in this example, by combining the synergistic effect of a dual catalyst (TBAB / DMAP) with a staged haloalcohol feeding strategy, 100% conversion of phenol was achieved within 13 hours, with a yield of 99.47%, even exceeding the high-cost scheme of Comparative Example 2. The significance of this experimental result lies in the fact that while ensuring a high yield of the target product, it significantly improved reaction efficiency, shortened the production cycle, and reduced time costs. It provides a better process scheme for the industrial production of tegorazan intermediates, demonstrating the key role of catalysts in optimizing organic synthesis reactions, and also providing a reference for optimizing conditions in similar etherification reactions.

[0109] Comparative Example 3

[0110] This comparative example, based on Example 4 above and using Example 4 as a control, only adds 4-dimethylaminopyridine (DMAP) and does not include tetrabutylammonium bromide (TBAB). The aim is to verify the effect of the phase transfer catalyst on the experimental results. The reaction formula for this comparative example is:

[0111]

[0112] The specific preparation method is as follows:

[0113] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol and 181.21g (1.48mol) of 4-dimethylaminopyridine in sequence; heat to 82-86℃ and reflux for 8h;

[0114] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0115] (3) HPLC analysis showed that 2.2% of 3,5-difluorophenol remained; the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered again for 10 min; the organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 53.95 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 95.56% and a yield of 75.44%.

[0116] The experimental results show that, in the absence of a phase transfer catalyst (without TBAB), the phenol residue is as high as 2.2%, and the yield drops sharply to 75.44%. Due to the lack of TBAB, solid potassium carbonate cannot be effectively dispersed in isopropanol, resulting in limited solid-liquid mass transfer and a reduced probability of contact between phenoxy anions and chloropropanol. Even with subsequent bromine supplementation, the initial mass transfer bottleneck could not be overcome, proving that TBAB is a key "bridge" for resolving heterogeneous reactions.

[0117] Comparative Example 4

[0118] This comparative example, based on Example 4 above and using Example 4 as a control, adds only tetrabutylammonium bromide (TBAB) and excludes 4-dimethylaminopyridine (DMAP) to verify the effect of nucleophilic catalysts on experimental results. The reaction formula for this comparative example is:

[0119]

[0120] The specific preparation method is as follows:

[0121] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol and 85.45g (0.26mol) of tetrabutylammonium bromide in sequence; heat to 82-86℃ and reflux for 8h;

[0122] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0123] (3) HPLC analysis showed that 1.85% of 3,5-difluorophenol remained; the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered again for 10 min; the organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 56.26 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 95.72% and a yield of 78.67%.

[0124] The experimental results show that, under conditions lacking a nucleophilic catalyst (without DMAP), after 8 hours of reaction, the phenol residue was 1.85%, and the yield was 78.67%. Without DMAP, the nucleophilicity of the phenolic hydroxyl group was insufficient, making it difficult to efficiently attack the carbon center of chloropropanol, thus the etherification rate became the rate-determining step. Although TBAB improved mass transfer, it could not enhance the intrinsic reactivity, causing the reaction to stall in the intermediate stage.

[0125] Comparative Example 5

[0126] Based on Example 4 above, this comparative example further adjusted the ratio of nucleophilic catalyst and phase transfer catalyst added in step (1) to observe the effect of the ratio (molar ratio) of tetrabutylammonium bromide and 4-dimethylaminopyridine catalyst on the experimental results. Groups 1-6 were set up, and their reaction conditions were the same as in Example 4, only the ratio of nucleophilic catalyst and phase transfer catalyst was adjusted. The experimental design and experimental results are shown in Table 1:

[0127] Table 1. Experimental conditions and reaction results for groups 1-6

[0128]

[0129] The experimental results above show that when the molar ratio of TBAB to DMAP is 0.26:1.48 (Example 4), the reaction time is the shortest (13 h) and the yield is the highest (99.47%), indicating that the synergistic effect of phase transfer catalysis and nucleophilic catalysis is optimal at this ratio. When the amount of a single catalyst is insufficient (groups 5-1 and 5-3), the phase transfer efficiency or nucleophilic catalytic ability decreases, leading to a longer reaction time, increased feed residue, and a lower yield. Conversely, when the amount of a single catalyst is excessive (groups 5-2 and 5-4), the reaction is inhibited due to increased solution viscosity or excessive complexation, also resulting in a decrease in efficiency. When the total amount of both catalysts is insufficient (group 5-5) or excessive (group 5-6), the reaction time is significantly prolonged, further verifying that a specific ratio of the two catalysts is required to achieve efficient synergy. This result clarifies the optimal ratio range of TBAB and DMAP, providing a key basis for the precise control of catalyst dosage in industrial production, and also demonstrating the importance of "ratio compatibility" for reaction efficiency in multi-catalyst systems.

[0130] Comparative Example 6

[0131] The purpose of this embodiment is to test the effect of the type of phase transfer catalyst on the reaction process, specifically including:

[0132] Group 6-1 uses tetrabutylammonium chloride as a phase transfer catalyst instead of tetrabutylammonium bromide (TBAB), and its reaction formula is as follows:

[0133]

[0134] The reaction steps are as follows:

[0135] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; then add 230.90g of potassium carbonate.

[0136] 1.67 mol of 3,5-difluorophenol (50.00 g, 0.38 mol), 40.36 g of 3-chloro-1-propanol (0.43 mol), 72.28 g of tetrabutylammonium chloride (0.26 mol), and 181.21 g of 4-dimethylaminopyridine (1.48 mol) were added. The mixture was heated to 82-86 °C and refluxed for 8 hours.

[0137] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0138] (3) HPLC analysis showed that 1.53% of 3,5-difluorophenol remained. The filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered for 10 min. The organic phase was concentrated under reduced pressure at 45 °C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 57.95 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 95.91% and a yield of 81.06%.

[0139] Group 6-2 uses tetrabutylphosphine bromide as a phase transfer catalyst instead of tetrabutylammonium bromide (TBAB), and the reaction formula is as follows:

[0140]

[0141] The reaction steps are as follows:

[0142] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol, 88.14g (0.26mol) of tetrabutylphosphine bromide and 181.21g (1.48mol) of 4-dimethylaminopyridine in sequence; heat to 82-86℃ and reflux for 8h;

[0143] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0144] (3) HPLC analysis showed that 1.45% of 3,5-difluorophenol remained. The filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered for 10 min. The organic phase was concentrated under reduced pressure at 45 °C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 60.96 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 95.99% and a yield of 85.23%.

[0145] Group 6-3 uses hexadecyltrimethylammonium bromide as a phase transfer catalyst instead of tetrabutylammonium bromide (TBAB), and the reaction formula is as follows:

[0146]

[0147] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol, 94.76g (0.26mol) of hexadecyltrimethylammonium bromide and 181.21g (1.48mol) of 4-dimethylaminopyridine in sequence; heat to 82-86℃ and reflux for 8h;

[0148] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0149] (3) HPLC analysis showed that 1.66% of 3,5-difluorophenol remained. The filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered for 10 min. The organic phase was concentrated under reduced pressure at 45 °C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 60.31 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 95.78% and a yield of 84.32%.

[0150] In this comparative example, tetrabutylammonium chloride, tetrabutylphosphine bromide, and hexadecyltrimethylammonium bromide were used to replace TBAB, respectively, to investigate the effect of the type of phase transfer catalyst on the reaction. The results showed that the yields of the three catalysts were 81.06%, 85.23%, and 84.32%, respectively, all lower than the 99.47% of Example 4, and the residual feedstock in each exceeded 1.45%. This indicates that TBAB has the best effect in promoting phase transfer efficiency and increasing ion migration rate, while other quaternary ammonium salt or phosphate salt catalysts exhibit decreased catalytic activity due to structural differences.

[0151] Comparative Example 7

[0152] The purpose of this embodiment is to test the effect of the type of nucleophilic catalyst on the reaction process, specifically including:

[0153] Group 7-1 uses pyridine as a nucleophilic catalyst to replace 4-dimethylaminopyridine (DMAP), and its reaction formula is as follows:

[0154]

[0155] The reaction process is as follows:

[0156] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol, 85.45g (0.26mol) of tetrabutylammonium bromide and 116.92g (1.48mol) of pyridine in sequence; heat to 82-86℃ and reflux for 8h;

[0157] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0158] (3) HPLC analysis showed that 0.32% of 3,5-difluorophenol remained; the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered again for 10 min; the organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 65.88 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 97.12% and a yield of 92.11%.

[0159] Group 7-2 uses pyridine as a nucleophilic catalyst to replace 4-dimethylaminopyridine (DMAP), and its reaction formula is as follows:

[0160]

[0161] The reaction process is as follows:

[0162] (1) Add 230.55g of isopropanol to a 2000mL three-necked flask and start stirring; add 230.90g (1.67mol) of potassium carbonate, 50.00g (0.38mol) of 3,5-difluorophenol, 40.36g (0.43mol) of 3-chloro-1-propanol, 85.45g (0.26mol) of tetrabutylammonium bromide and 158.36g (1.48mol) of 2,6-dimethylpyridine in sequence; heat to 82-86℃ and reflux for 8h;

[0163] (2) Add 5.30 g of 3-bromopropanol (0.038 mol) to the reaction system of step (1) and continue to reflux at 82-86 °C for 5 h;

[0164] (3) HPLC analysis showed that 0.48% of 3,5-difluorophenol remained; the temperature was lowered to 25°C; the mixture was filtered, and the filter cake was washed with 19.60 g of isopropanol until no liquid flowed out, and then filtered again for 10 min; the organic phase was concentrated under reduced pressure at 45°C and a vacuum of -0.09 MPa until no obvious droplets flowed out. After concentration, 65.00 g of white solid 3-(3,5-difluorophenoxy)-1-propanol was obtained with a purity of 96.96% and a yield of 90.88%.

[0165] The results of this comparative experiment show that replacing DMAP with pyridine or 2,6-dimethylpyridine as a nucleophilic catalyst reduced the yield to 92.11% and 90.88%, respectively. Although the feed residue was low (0.32%-0.48%), it was still inferior to the synergistic effect of DMAP. This indicates that the dimethylamino structure of DMAP can more efficiently activate phenolic hydroxyl groups and enhance nucleophilic attack ability, while ordinary pyridine or substituted pyridine cannot achieve the same catalytic efficiency due to electronic effects or steric hindrance. This further verifies the unique advantages of DMAP as a nucleophilic catalyst.

[0166] The embodiments described above are merely preferred embodiments for fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A method for preparing a tegorazan intermediate, characterized in that: Includes the following steps: (1) Dissolve 3,5-difluorophenol and 3-chloro-1-propanol in isopropanol, with a molar ratio of 3-chloro-1-propanol to 3,5-difluorophenol of 1 to 1.5:1, and add alkali and heat to reflux for reaction; (2) Add 3-bromo-1-propanol to the reaction system of step (1), the molar ratio of 3-bromo-1-propanol to 3,5-difluorophenol is 0.1 to 0.15:1, and continue to heat and reflux the reaction. (3) After the reaction is complete, filter and concentrate under reduced pressure to obtain the intermediate compound 3-(3,5-difluorophenoxy)-1-propanol of tegorazan.

2. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: The alkali added in step (1) is one of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

3. The method for preparing the tegorazan intermediate according to claim 2, characterized in that: The alkali added in step (1) is potassium carbonate, and the molar ratio of potassium carbonate to 3,5-difluorophenol is 4 to 5:

1.

4. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: In step (1), the temperature of the reflux reaction is 80-86°C, and the reflux reaction time is 24-30 h.

5. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: In step (2), the temperature of the reflux reaction is 80-86°C, and the reflux reaction time is 4-6 hours.

6. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: The reaction system in step (1) also includes at least one of a phase transfer catalyst and a nucleophilic catalyst.

7. The method for preparing the tegorazan intermediate according to claim 6, characterized in that: The phase transfer catalyst is tetrabutylammonium bromide; the nucleophilic catalyst is dimethylaminopyridine.

8. The method for preparing the tegorazan intermediate according to claim 7, characterized in that: The molar ratio of tetrabutylammonium bromide to 3,5-difluorophenol is 0.6 to 0.8:1, and the molar ratio of 4-dimethylaminopyridine to 3,5-difluorophenol is 3 to 4:

1.

9. The method for preparing the tegorazan intermediate according to any one of claims 6-8, characterized in that: In step (1), the temperature of the reflux reaction is 80-86°C, and the reflux reaction time is 5-8 hours.

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