Preparation method of landiolol hydrochloride intermediate

Abstract

The invention discloses a preparation method of a high-purity landiolol hydrochloride intermediate namely 3-(4-hydroxyphenyl) propionic acid (2, 2-dimethyl-1, 3-dioxolane-4S) methyl ester. The method comprises the following steps: adding a raw material I hydroxyphenylpropionic acid and a raw material II p-toluenesulfonic acid (2, 2-dimethyl-1, 3-dioxolane-4S) methyl ester into a solvent and an inorganic base for reaction, washing the reaction liquid with water, extracting, concentrating, and recrystallizing with the solvent to obtain the high-purity landiolol hydrochloride intermediate 3-(4-hydroxyphenyl) propionic acid (2, 2-dimethyl-1, 3-dioxolane-4S) methyl ester. And column chromatography purification is not needed, the process is stable and controllable, the solvent can be recycled, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and pharmaceutical intermediate technology, and relates to a method for preparing 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester, an intermediate of brandilol hydrochloride. Background Technology

[0002] Landilol hydrochloride, CAS No.: 144481-98-1, Chinese chemical name: [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholino-4-formylamino)ethylamino]propoxy]phenyl]propionate hydrochloride. Structural formula is...

[0003]

[0004] Landilol hydrochloride is a selective β1 receptor blocker that primarily antagonizes β1 receptors in the heart, improving tachycardia-related arrhythmias by inhibiting the increase in stroke rate induced by catecholamines. It is an indispensable emergency drug for perioperative treatment of arrhythmias and for postoperative dynamic monitoring of arrhythmias. However, landilol hydrochloride has a complex chemical structure, a cumbersome preparation process, numerous sensitive groups, and is difficult to control for impurities. 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S)methyl ester is the main fragment and key intermediate in the preparation of landilol hydrochloride; therefore, it is necessary to study a high-purity, industrially suitable preparation method for it.

[0005] Japanese Patent Application Publication No. 5-306281 (publication date: November 19, 1993), compound patent US5013734A, and EP0397031 disclose a method for preparing a landilol hydrochloride intermediate, the synthetic route of which is as follows:

[0006]

[0007] This method involves reacting p-hydroxyphenylpropionic acid with p-toluenesulfonic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester to generate 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester (hereinafter referred to as intermediate 1). This synthetic method has some problems; the reaction product requires purification and separation by column chromatography, resulting in uncontrollable product quality and hindering industrial production.

[0008] The synthetic route in the master's thesis of Shenyang University of Chemical Technology in Chem. Pharm. Bull: 40(6) 1462-1469 (1992) is basically the same as the above route.

[0009]

[0010] This synthesis method has some problems:

[0011] 1. The process is quite complicated, and the first step of the reaction requires a large amount of anhydrous ethanol.

[0012] 2. The phenolic hydroxyl groups on p-hydroxyphenylpropionic acid also readily react with potassium hydroxide to form byproducts.

[0013]

[0014] This byproduct participates in subsequent reactions, generating further byproducts:

[0015]

[0016] This results in unstable quality and low yield of product I (intermediate 1) during production, which is not conducive to industrial production.

[0017] Patent CN200710063716 discloses another route for synthesizing intermediate 1 of landilol hydrochloride. This patent uses S(+)-propane oxide as a raw material to synthesize methyl ester of 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) of landilol hydrochloride according to the following route.

[0018]

[0019] This synthesis method has the following problems:

[0020] 1. The catalyst boron trifluoride diethyl ether used in the synthesis has high reactivity and high toxicity, which is not conducive to industrial production.

[0021] 2. S(+)-epoxychloropropane has relatively low activity, and the reaction time is up to 24 hours.

[0022] 3. The reaction process uses a strong base (potassium hydroxide), which can easily lead to the hydrolysis and degradation of the product.

[0023] Therefore, there is a need for a method to prepare 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester, an intermediate of landilol, which is simple to operate, has a high product yield, low production cost, high product purity, and controllable quality. Summary of the Invention

[0024] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies in the preparation of brandilol hydrochloride intermediate 1, namely 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester, such as poor product purity, numerous byproducts, the need for column chromatography for separation and purification, and low yield, making it unsuitable for industrial production. This invention provides an industrial method for preparing high-purity brandilol hydrochloride intermediates.

[0025] The advantages of the preparation method of this invention are:

[0026] ① The raw materials, solvents, and reagents used in the reaction are all relatively common, readily available, and inexpensive.

[0027] ② It is easy to operate and has a short reaction cycle.

[0028] ③ The reaction product does not require column chromatography purification; high-purity products can be obtained directly by recrystallization. This not only greatly reduces the amount of solvent used but also makes the product quality stable and controllable. It is easy to industrialize and meets the demand for brandylol hydrochloride raw materials, thus having good application prospects.

[0029] This invention provides a method for preparing high-purity brandilol hydrochloride intermediate 1, namely 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester, characterized by comprising the following steps:

[0030] Step 1: Add raw material I (p-hydroxyphenylpropionic acid) and raw material II (p-toluenesulfonic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester) to the reaction solvent and inorganic base, and heat to 90-120℃ to carry out the reaction;

[0031] Step 2: The reaction solution is extracted with water and organic solvent, and the extract is concentrated to obtain the crude product;

[0032] Step 3: Add the crude product to the recrystallization solvent and heat to dissolve. Control the temperature to crystallize and obtain high-purity 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester (intermediate 1).

[0033]

[0034] Preferably, the reaction solvent in step 1 is N,N-dimethylformamide or dimethyl sulfoxide, preferably dimethyl sulfoxide.

[0035] Preferably, the inorganic base used in step 1 is potassium hydroxide or anhydrous potassium carbonate, with anhydrous potassium carbonate being preferred. Comparative experiments show that using anhydrous potassium carbonate can effectively reduce the amount of byproducts in the crude product. It is preferable to use anhydrous potassium carbonate in an amount of 1.0 equivalent to raw material I.

[0036] Preferably, the reaction temperature in step 1 is 90–120°C, more preferably 100–105°C.

[0037] Preferably, the solvent system for recrystallization of the crude product is a mixture of methyl tert-butyl ether and n-heptane, a mixture of ethyl acetate and n-heptane, or a mixture of dichloromethane and n-heptane, with a preference for a mixture of dichloromethane and n-heptane. The preferred ratio of the mixed solvent is dichloromethane to n-heptane = 1:2-3, more preferably 1:2.5, where the ratio is a volume ratio (V / V).

[0038] Preferably, the ratio of recrystallization solvent to crude product is: dichloromethane and n-heptane mixed solvent: crude product = 8.0 to 14.0 times (volume-to-weight ratio, V / W, e.g., solvent volume ml / crude product weight g), preferably 10.5 times.

[0039] Further optimization involves controlling the crystallization temperature during recrystallization to -20 to 25°C, preferably -5 to 5°C. The crystallization time is 1.0 h to 3.0 h, preferably 1.0 to 2.0 h.

[0040] The preparation method of the landilol hydrochloride intermediate 1 disclosed in this invention has the following advantages compared with the prior art:

[0041] (1) The process is simple and the reactants, solvents and reagents are inexpensive and readily available.

[0042] (2) By optimizing the inorganic base, reaction solvent and reaction temperature in step 1, the present invention obtains a crude product with fewer impurities and higher purity. Then, by using an optimized recrystallization solvent system, solvent dosage, crystallization temperature and crystallization time, the crude intermediate 1 is purified, and high-purity intermediate 1 can be obtained stably. This solves the difficulty of column chromatography purification of intermediate 1 and realizes the possibility of large-scale industrial production of intermediate 1.

[0043] (3) The intermediate 1 produced by this invention has high purity, reaching over 99.90%, and the impurity content is all below 0.1%, meeting the requirements of the raw material drug.

[0044] (4) The intermediate 1 produced by the present invention maintains high purity while significantly improving the yield compared with the prior art. Attached Figure Description

[0045] Figure 1 Crude liquid chromatography spectrum of Example 26

[0046] Figure 2 Liquid chromatography profile of the purified product in Example 26 Detailed Implementation Plan

[0047] Terminology Explanation:

[0048] 1. The HPLC method for detecting purity in the examples is as follows:

[0049] Column: C18 (4.6 x 250 mm, 5 μm)

[0050] Wavelength: 220nm

[0051] Flow rate: 1.2 ml / min

[0052] Column temperature: 35℃

[0053] Injection volume: 20 μl

[0054] Solvent: Mobile phase A - Mobile phase B (60:40)

[0055] Mobile phase A: Take 5.44 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000 ml (adjust the pH value to 6.4 with 40% potassium hydroxide solution), mix well and filter.

[0056] Mobile phase B: Acetonitrile

[0057] The specific gradient is as follows:

[0058]

[0059] 2. The maximum single impurity and the purity of the main peak were calculated using the peak area normalization method.

[0060] 3. The proportions of each solvent in the solvent system are volume ratios (V / V).

[0061] 4. The multiple of recrystallization solvent is the volume-to-weight ratio (V / W) of solvent volume to crude product weight, specifically solvent volume (ml) / crude product weight (g).

[0062] 5. The TLC monitoring conditions during the reaction are as follows:

[0063] Monitoring method: TLC method

[0064] Thin-layer plate: GF254

[0065] Glass spotting capillary: 0.5mm

[0066] Developing solvent: Ethyl acetate: Petroleum ether = 1:2

[0067] Reference solution: ethyl acetate solution of SM2 (20 mg / ml);

[0068] Test solution: Take 0.1 ml of reaction solution, add appropriate amount of purified water and ethyl acetate, shake and let stand to separate the layers, take the organic layer;

[0069] Color development method: After development, observe under a UV lamp (254nm);

[0070] Reaction endpoint determination: When the spot of raw material II (SM2) in the test sample basically disappears, the reaction is determined to be complete, Rf product = 0.6, RfSM2 = 0.8.

[0071] I. Investigation of Inorganic Base in Crude Intermediate 1 of Synthesis

[0072] Example 1 uses potassium hydroxide to synthesize intermediate 1 crude product

[0073] Add 10.00g of starting material I, 17.23g of starting material II, 3.40g of potassium hydroxide, and 80ml of dimethyl sulfoxide to a 250ml reaction flask. Stir after addition. Turn on the heater and heat the system to 100℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results show the reaction is complete, remove the heater and stop the reaction. After cooling the system to 20-30℃, add 100ml of purified water and 100ml of dichloromethane. Stir for 10-15 minutes and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 30ml each time. After extraction, discard the aqueous phase and combine the organic phases, washing once with 150ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 11.91g of crude intermediate 1 is obtained, with a yield of 70.6%.

[0074] Example 2 uses sodium carbonate to synthesize intermediate 1 crude product

[0075] Add 10.00g of starting material I, 17.23g of starting material II, 6.38g of sodium carbonate, and 80ml of dimethyl sulfoxide to a 250ml reaction flask. Stir after addition. Turn on the heater and heat the system to 100℃ for reaction. Monitor the reaction by TLC after 6 hours. The TLC results show that there are still starting materials remaining. Remove the heater and stop the reaction. After cooling the system to 20-30℃, add 100ml of purified water and 100ml of dichloromethane. Stir for 10-15 minutes and then separate the liquids. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 30ml each time. After extraction, discard the aqueous phase and combine the organic phases. Wash once with 150ml of purified water. Allow to stand and separate the liquids. Concentrate the organic phase until no liquid distills off. 13.87g of crude intermediate 1 is obtained, with a yield of 82.2%.

[0076] Example 3 uses potassium carbonate to synthesize intermediate 1 crude product

[0077] Add 10.00g of starting material I, 17.23g of starting material II, 8.32g of potassium carbonate, and 80ml of dimethyl sulfoxide to a 250ml reaction flask. Stir after addition. Turn on the heater and heat the system to 100℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results show completion, remove the heater and stop the reaction. Cool the system to 200-30℃, add 100ml of purified water, and then add 100ml of dichloromethane. Stir for 10-15 minutes and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 30ml each time. After extraction, discard the aqueous phase, combine the organic phases, and wash once with 150ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 15.18g of crude intermediate 1 is obtained, with a yield of 90.0%.

[0078] Example 4 uses 0.8 equivalents of potassium carbonate to synthesize intermediate 1 crude product.

[0079] Add 20.03g of starting material I, 34.48g of starting material II, 13.31g of potassium carbonate (0.8 equivalent), and 200ml of dimethyl sulfoxide to a 500ml reaction flask. Stir after addition. Turn on the heater and heat the system to 100℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20-30℃, add 200ml of purified water, and then add 200ml of dichloromethane. Stir for 10-15 minutes and then separate the liquid. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 60ml each time. After extraction, discard the aqueous phase and combine the organic phases, washing once with 300ml of purified water. Allow to stand and separate the liquid. Concentrate the organic phase until no liquid distills off. 31.03g of crude intermediate 1 is obtained, with a yield of 91.8%.

[0080] Example 5 uses 0.9 equivalents of potassium carbonate to synthesize intermediate 1 crude product.

[0081] Add 10.00 g of starting material I, 17.29 g of starting material II, 7.49 g of potassium carbonate (0.9 equivalent), and 100 ml of dimethyl sulfoxide to a 250 ml reaction flask. Stir after addition. Turn on the heater and heat the system to 100 °C for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20–30 °C, add 100 ml of purified water, and then add 100 ml of dichloromethane. Stir for 10–15 minutes and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 30 ml each time. After extraction, discard the aqueous phase, combine the organic phases, and wash once with 150 ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 15.92 g of crude intermediate 1 is obtained, with a yield of 91.8%.

[0082] The reaction conditions and HPLC detection results of Examples 1-5 are shown in the table below:

[0083]

[0084] Comparative experimental results show that using potassium hydroxide as the alkali results in more reaction byproducts, a higher maximum single impurity content, and a larger total impurity content, leading to greater pressure on subsequent purification. Using sodium carbonate as the alkali also results in more reaction byproducts, incomplete reaction, and residual raw materials, leading to a lower overall yield. Comparing Examples 3, 4, and 5 reveals that while using a smaller amount of potassium carbonate results in fewer reaction byproducts, there is still a significant amount of residual raw materials. Considering all factors, 1.0 equivalent of potassium carbonate (relative to raw material I) was ultimately chosen as the alkali for the reaction, as it showed better reaction performance.

[0085] II. Investigation of the reaction solvent in the crude intermediate 1

[0086] Raw material I is a highly polar salt, which requires a highly polar solvent. Therefore, methanol, dimethyl sulfoxide, and N,N-dimethylformamide were selected.

[0087] Example 6: N,N-dimethylformamide was used as a solvent to synthesize intermediate 1 (crude product).

[0088] Add 20.00g of starter I, 34.49g of starter II, 16.68g of anhydrous potassium carbonate, and 200ml of N,N-dimethylformamide to a 500ml reaction flask. Stir after addition. Turn on the heater and heat the system to 120℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20-30℃, add 200ml of purified water and 200ml of dichloromethane, and stir for 10-15 minutes. Separate the liquid and aqueous phases. Collect the organic phase. Extract the aqueous phase twice with 60ml of dichloromethane each time. After extraction, discard the aqueous phase and combine the organic phases, washing once with 200ml of purified water. Allow to stand and separate the liquid and aqueous phases. Concentrate the organic phase until no liquid distills off. 22.35g of crude intermediate 1 is obtained, with a yield of 66.2%.

[0089] Example 7: Dimethyl sulfoxide as solvent for the synthesis of intermediate 1 (crude product)

[0090] Add 20.00g of starting material I, 34.49g of starting material II, 16.68g of anhydrous potassium carbonate, and 200ml of dimethyl sulfoxide to a 500ml reaction flask. Stir after addition. Turn on the heater and heat the system to 120℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20-30℃, add 200ml of purified water and 200ml of dichloromethane, stir for 10-15 minutes, and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with 60ml of dichloromethane each time. After extraction, discard the aqueous phase, combine the organic phases, and wash once with 200ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 29.84g of crude intermediate 1 is obtained, with a yield of 88.5%.

[0091] Example 8: Methanol as solvent for the synthesis of intermediate 1 (crude product)

[0092] Add 20.00g of raw material I, 34.49g of raw material II, 16.68g of anhydrous potassium carbonate, and 200ml of methanol to a 500ml reaction flask. After the addition is complete, stir. Turn on the heater and raise the temperature of the system to 80℃ to carry out the reaction. After 4 hours, perform TLC monitoring. The TLC results show that no target point was formed.

[0093] The reaction conditions and HPLC detection results of Examples 6-8 are shown in the table below:

[0094]

[0095] Comparative experimental results show that no target product was formed when methanol was used as the solvent; when N,N-dimethylformamide was used as the solvent, the purity was low, there were more reaction byproducts, and the maximum single impurity content was high, which would lead to greater post-purification pressure and lower overall yield. Therefore, dimethyl sulfoxide, which has better reaction performance, is preferred as the reaction solvent.

[0096] III. Investigation of the reaction temperature in the crude intermediate 1

[0097] Example 9: Crude intermediate 1 synthesized by reaction at 80°C

[0098] Add 20.00g of starter I, 34.24g of starter II, 16.68g of anhydrous potassium carbonate, and 200ml of dimethyl sulfoxide to a 500ml reaction flask. Stir after addition. Turn on the heater and heat the system to 90℃ for reaction. Monitor the reaction by TLC after 4 hours. If TLC results show residual starter, remove the heater and stop the reaction. Cool the system to 20-30℃, add 200ml of purified water and 200ml of dichloromethane, stir for 10-15 minutes, and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 60ml each time. After extraction, discard the aqueous phase, combine the organic phases, and wash once with 200ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 26.83g of crude intermediate 1 is obtained, with a yield of 19.5%.

[0099] Example 10: Synthesis of intermediate 1 (crude product) via reaction at 90°C

[0100] Add 20.00g of starting material I, 34.29g of starting material II, 16.67g of anhydrous potassium carbonate, and 200ml of dimethyl sulfoxide to a 500ml reaction flask. Stir after addition. Turn on the heater and heat the system to 90℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20-30℃, add 200ml of purified water, and then add 200ml of dichloromethane. Stir for 10-15 minutes and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with dichloromethane, 60ml each time. After extraction, discard the aqueous phase, combine the organic phases, and wash once with 200ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 29.83g of crude intermediate 1 is obtained, with a yield of 88.4%.

[0101] Example 11: Intermediate 1 crude product synthesized by reaction at 100℃

[0102] Add 20.00g of starting material I, 34.33g of starting material II, 16.57g of anhydrous potassium carbonate, and 200ml of dimethyl sulfoxide to a 500ml reaction flask. Stir after addition. Turn on the heater and heat the system to 100℃ for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20–30℃, add 200ml of purified water and 200ml of dichloromethane, stir for 10–15 minutes, and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with 60ml of dichloromethane each time. After extraction, discard the aqueous phase, combine the organic phases, and wash once with 200ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 31.05g of crude intermediate 1 is obtained, with a yield of 92.0%.

[0103] Example 12 Synthesis of crude intermediate 1 at 105°C

[0104] Add 150.00 g of starter I, 258.48 g of starter II, 124.76 g of anhydrous potassium carbonate, and 900 ml of dimethyl sulfoxide to a 2000 ml reaction flask. Stir after addition. Turn on the heater and heat the system to 105 °C for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. Cool the system to 20–30 °C, add 1500 ml of purified water, and then add 1200 ml of dichloromethane. Stir for 10–15 minutes and then separate the liquid phases. Collect the organic phase. Extract the aqueous phase twice with 450 ml of dichloromethane each time. After extraction, discard the aqueous phase and combine the organic phases. Wash once with 750 ml of purified water. Allow to stand and separate the liquid phases. Concentrate the organic phase until no liquid distills off. 230.26 g of crude product was obtained, with a yield of 91.0%.

[0105] The reaction conditions and HPLC detection results of Examples 7 and 9-12 are compared in the table below:

[0106]

[0107]

[0108] Comparing the above experimental results, the reaction time at 80℃ was relatively long, and the materials were difficult to react completely. The higher the temperature, the shorter the reaction time and the less material remained. Although no residue of raw material II was detected by HPLC at 120℃, the unknown single impurity increased, and the product color became darker. Therefore, 100-105℃ was selected as the preferred temperature range.

[0109] In summary, the preferred conditions for preparing crude intermediate 1 are as follows:

[0110] 1. The inorganic base used in the reaction is anhydrous potassium carbonate, and the amount used is 1.0 times the number of moles of raw material I.

[0111] 2. The reaction solvent is N,N-dimethylformamide or dimethyl sulfoxide, preferably dimethyl sulfoxide.

[0112] 3. The reaction temperature is 90-120℃, preferably 100-105℃.

[0113] IV. Investigation of Recrystallization Solvent Systems

[0114] Example 13

[0115] 20.03 g of the crude intermediate 1 prepared in Example 10, 60 ml of methyl tert-butyl ether, and 80 ml of n-heptane were added to a 250 ml reaction flask and stirred. Heating was initiated, and the system was heated to 70 °C to dissolve the solid. The system was then cooled to 0 °C and crystallized for 1.0 h. The crystals were filtered and dried to obtain 16.84 g of an off-white solid, with a yield of 84.0%.

[0116] Example 14

[0117] 20.00 g of crude intermediate 1 from Example 10, 40 ml of methyl tert-butyl ether, and 80 ml of n-heptane were added to a 250 ml reaction flask and stirred. Heating was initiated, and the system was heated to 70 °C until dissolved. The system was then cooled to 0 °C and crystallized for 1.0 h. The crystals were filtered and dried to obtain 17.46 g of an off-white solid, with a yield of 87.3%.

[0118] Example 15

[0119] 20.00 g of crude intermediate 1 from Example 10, 40 ml of methyl tert-butyl ether, and 40 ml of n-heptane were added to a 250 ml reaction flask and stirred. Heating was initiated, and the system was heated to 60 °C to dissolve completely. The system was then cooled to 0 °C and crystallized for 1.0 h. The crystals were filtered and dried to obtain 12.04 g of an off-white solid, with a yield of 60.0%.

[0120] Example 16

[0121] 10.00 g of crude intermediate 1 from Example 10, 20 ml of ethyl acetate, and 40 ml of n-heptane were added to a 250 ml reaction flask and stirred. Heating was initiated, and the system was heated to 60 °C until dissolved. The system was then cooled to 0 °C and crystallized for 1.0 h. The crystals were filtered and dried to obtain 5.15 g of an off-white solid, with a yield of 50.2%.

[0122] Example 17

[0123] 10.00 g of crude intermediate 1 from Example 10, 12 ml of ethyl acetate, and 48 ml of n-heptane were added to a 250 ml reaction flask and stirred. Heating was initiated, and the system was heated to 60 °C until dissolved. The system was then cooled to 0 °C and crystallized for 1.0 h. The crystals were filtered and dried to obtain 6.99 g of an off-white solid, with a yield of 69.9%.

[0124] Example 18

[0125] 10.00 g of crude intermediate 1 from Example 10 and 20 ml of dichloromethane were added to a 250 ml reaction flask and stirred until dissolved. 40 ml of n-heptane was added dropwise, and a white solid precipitated. Crystallization was allowed to occur at room temperature (25°C) for 1.0 h. The crystals were filtered and dried to obtain 5.92 g of an off-white solid, with a yield of 59.2%.

[0126] The recrystallization conditions and HPLC detection results of Examples 13-18 are shown in the table below:

[0127]

[0128] Comparative experimental results showed that mixed solvents of methyl tert-butyl ether and n-heptane, ethyl acetate and n-heptane, and dichloromethane and n-heptane could all effectively purify the crude intermediate 1, replacing column chromatography for purification. The purification effect of the dichloromethane and n-heptane mixture was significantly higher than that of the methyl tert-butyl ether and n-heptane mixtures and the ethyl acetate and n-heptane mixtures. Therefore, the dichloromethane and n-heptane mixture is the preferred recrystallization solvent.

[0129] V. Investigation on the proportion and amount of recrystallization solvent

[0130] Example 19

[0131] 10.00 g of crude intermediate 1 from Example 10 and 20 ml of dichloromethane were added to a 250 ml reaction flask and stirred until dissolved. 60 ml of n-heptane was added dropwise, and a white solid precipitated. Crystallization was allowed to occur at room temperature (25°C) for 1.0 h. The crystals were filtered and dried to obtain 7.36 g of an off-white solid, with a yield of 73.6%.

[0132] Example 20

[0133] 10.00 g of crude intermediate 1 from Example 10 and 30 ml of dichloromethane were added to a 250 ml reaction flask and stirred until dissolved. 75 ml of n-heptane was added dropwise, and a white solid precipitated. Crystallization was allowed to occur at room temperature (25°C) for 1.0 h. The crystals were filtered and dried to obtain 6.78 g of an off-white solid, with a yield of 67.8%.

[0134] Example 21

[0135] 10.00 g of crude intermediate 1 from Example 10 and 40 ml of dichloromethane were added to a 250 ml reaction flask and stirred until dissolved. 100 ml of n-heptane was added dropwise, and a white solid precipitated. Crystallization was allowed to occur at room temperature (25°C) for 1.0 h. The solid was filtered and dried to obtain 5.14 g of an off-white solid, with a yield of 51.4%.

[0136] The recrystallization conditions and HPLC detection results of Examples 18-21 are shown in the table below:

[0137]

[0138] By comparing experimental results, the effect of varying dichloromethane to n-heptane ratios in the dichloromethane and n-heptane mixed system was investigated. As shown in Example 18, a higher dichloromethane ratio resulted in a lower purification yield. As shown in Example 19, reducing the dichloromethane ratio improved the yield but led to poorer purification and higher impurity content. As shown in Example 20, by reducing the dichloromethane ratio in the mixed solvent while appropriately increasing the overall solvent volume, the maximum single impurity unexpectedly decreased to 0.02%, the main peak purity reached 99.96%, and the purification yield was also high. Compared to Example 20, Example 21 increased the solvent volume, but the purification effect was not significantly improved, and the yield decreased, which was not conducive to production requirements. In conclusion, the optimal parameters for recrystallization solvent ratio were determined to be dichloromethane:n-heptane = 1:2.5 (V / V) and a volume of 10.5 times (V / W).

[0139] VI. Investigation of Crystallization Temperature

[0140] Example 22

[0141] 10.00 g of crude intermediate 1 from Example 10 and 30 ml of dichloromethane were added to a 250 ml reaction flask and stirred until dissolved. 75 ml of n-heptane was added dropwise, resulting in the precipitation of a white solid. The mixture was cooled to -5 to 5 °C (0 ± 5 °C) and allowed to crystallize for 1.0 h. After filtration and drying, 7.81 g of an off-white solid was obtained, with a yield of 78.1%.

[0142] Example 23

[0143] 10.00 g of crude intermediate 1 from Example 10 and 30 ml of dichloromethane were added to a 250 ml reaction flask and stirred until dissolved. 75 ml of n-heptane was added dropwise, resulting in the precipitation of a white solid. The mixture was cooled to -20 to -10 °C (-15 ± 5 °C) and allowed to crystallize for 1.0 h. The crystals were filtered and dried to obtain 8.03 g of an off-white solid, with a yield of 80.3%.

[0144] The recrystallization conditions and HPLC detection results of Examples 20 and 22-23 are compared in the table below:

[0145]

[0146] Comparing the experimental results, good purification effects can be obtained by crystallization at temperatures ranging from -20℃ to room temperature of 25℃. Lowering the crystallization temperature can improve the purification yield. However, compared with Example 22, the yield of Example 23 is similar and there is no significant improvement, but the purification effect is worse. Furthermore, since the crystallization temperature of Example 23 is too low, the energy consumption required for refrigeration in industrial production is relatively large. Taking all factors into consideration, crystallization at -5℃ to 5℃ is selected.

[0147] VII. Investigation of Crystallization Time

[0148] Example 24

[0149] The procedure was the same as in Example 22, but the temperature was lowered to -5 to 5°C (0±5°C) for 2.0 h to allow crystallization. After filtration and drying, 7.88 g of a white solid was obtained, with a yield of 78.8%.

[0150] Example 25

[0151] The procedure was the same as in Example 22, but the temperature was lowered to -5 to 5°C (0±5°C) for crystallization for 3.0 h. After filtration and drying, 7.91 g of an off-white solid was obtained, with a yield of 79.1%.

[0152] The recrystallization conditions and HPLC detection results of Examples 22 and 24-25 are compared in the table below:

[0153]

[0154] By comparing the experimental results, it was found that extending the crystallization time did not significantly improve the purity, but the yield increased slightly. However, after 2.0 h, the yield did not increase significantly. Considering all factors, crystallization time of 1.0 h to 2.0 h is sufficient for industrial production.

[0155] In summary, the preferred recrystallization conditions are as follows:

[0156] The preferred recrystallization solvent system is dichloromethane:n-heptane = 1:2.5 (V / V), the preferred amount of recrystallization solvent is 10.5 times (volume-to-weight ratio V / W, i.e., solvent volume ml / crude product weight g), the crystallization temperature is -5~5℃, and the crystallization time is 1.0-2.0h.

[0157] Example 26 Large-scale experiment

[0158] Add 300.00 g of raw material I, 517.03 g of raw material II, 249.54 g of anhydrous potassium carbonate, and 1800 ml of dimethyl sulfoxide to a 5000 ml reaction flask. Stir after addition. Turn on the heater and heat the system to 105 °C for reaction. Monitor the reaction by TLC after 4 hours. Once the TLC results indicate completion, remove the heater and stop the reaction. After cooling the system to 20–30 °C, transfer the reaction solution to a 10 L reaction flask, add 3000 ml of purified water, and then add 2400 ml of dichloromethane. Stir for 10–15 minutes and then separate the liquid. Collect the organic phase. Extract the aqueous phase twice with 900 ml of dichloromethane each time. After extraction, discard the aqueous phase and combine the organic phases, washing once with 1500 ml of purified water. Allow to stand and separate the liquid. Concentrate the organic phase until no liquid distills off. 470.66 g of crude product was obtained, with a yield of 93.0%.

[0159] 400.00 g of crude intermediate 1 from Example 26 and 1200 ml of dichloromethane were added to a 5000 ml reaction flask and stirred until dissolved. 3000 ml of n-heptane was added dropwise, and a white solid precipitated. The mixture was cooled to (0±5a) and allowed to crystallize for 1.0 h. The solution was filtered and dried to obtain 317.2 g of purified intermediate 1, a white solid, with a yield of 79.3%.

[0160] The crude liquid chromatography spectrum of Example 26 is attached. Figure 1 The liquid chromatography spectrum of the refined product is attached. Figure 2 The details of impurities are shown in the table below.

[0161]

[0162] It can be seen that the preparation method of the present invention can obtain high-purity methyl 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) ester of landilol while achieving a good yield.

[0163] VIII. Comparative Examples

[0164] Comparative Example 1

[0165] Following the synthetic route in the literature Chem. Pharm. Bull: 40(6) 1462-1469 (1992), the master's thesis of Shenyang University of Chemical Technology, intermediate 1 was synthesized.

[0166] 100.00 g of p-hydroxyphenylpropionic acid was added to 200 ml of anhydrous ethanol and stirred until dissolved. A KOH ethanol solution (33.7 g KOH dissolved in 700 ml ethanol) was added dropwise, resulting in the precipitation of a white solid. After the addition was complete, the mixture was stirred at room temperature for 2.0 h, filtered, and dried to obtain 82.13 g of a white solid, with a yield of 66.8%.

[0167] Add the product from the previous step to a 1L three-necked flask, add 100.10g of starting material 1 and 500ml of dimethyl sulfoxide, stir, heat to 100℃, and maintain the temperature for 4.0h. Monitor the reaction for completion by TLC, then cool to 20-30℃. Transfer the reaction solution to a beaker containing 500ml of ice water and stir. Add 500ml of ethyl acetate for extraction, and separate the liquid. Extract the aqueous phase with 300ml of ethyl acetate twice. Combine the organic phases and wash successively with saturated sodium bicarbonate, purified water, and saturated sodium chloride aqueous solution. Dry, filter, and concentrate the organic phase. Add 200ml of n-heptane and 200ml of methyl tert-butyl ether to the concentrate, heat until dissolved, and cool to 0℃ to crystallize for 2h. Filter and dry to obtain 61.19g of off-white solid, yield 62.4%. The overall yield of the two steps is 41.7%.

[0168] The results of the comparative HPLC detection are shown in the table below:

[0169]

[0170] This process has the following problems:

[0171] 1. Intermediate 1 needs to be synthesized in two steps, and the synthesis process is long and complicated.

[0172] 2. Liquid chromatography results showed that the product quality was poor, with a large number of byproducts and high content.

[0173] 3. The total yield of the two steps is 41.7%, which is about 30% lower than that of this process.

[0174] Comparative Example 2

[0175] Intermediate 1 was synthesized according to the preparation methods of the intermediates of landilol hydrochloride disclosed in Japanese Patent Application Publication No. 5-306281 (publication date: November 19, 1993), Compound Patent US5013734A, and EP0397031.

[0176] Add 20.00 g of p-hydroxyphenylpropionic acid, 11.31 g of anhydrous potassium carbonate, 20 g of potassium iodide, and 80 ml of dimethyl sulfoxide to a 500 ml three-necked flask and stir. Heat to 100 °C and stir for 30 min. Add raw material 1, maintain the temperature at 100 °C for 15 h, and after the reaction is complete, cool to 20-30 °C. Transfer the reaction solution to a beaker containing 450 ml of purified water, add 450 ml of ethyl acetate and stir. Allow to stand and separate the layers. Extract the aqueous phase with 450 ml of ethyl acetate, allow to stand and separate the layers, combine the organic phases, and wash successively with saturated sodium bicarbonate, purified water, and saturated sodium chloride aqueous solution. Dry, filter, and concentrate the organic phase to obtain 22.37 g of yellow oil. TLC shows spots with many impurities in the oil.

[0177] Crude product recrystallization attempt: 40 ml of n-heptane and 40 ml of methyl tert-butyl ether were added to the concentrate and heated until dissolved. The temperature was then lowered to 43°C, resulting in two phases: an oil phase and a liquid phase. After stirring for 3 hours, no solid precipitated. The reaction solution was concentrated and loaded onto silica gel for column chromatography purification. The eluent was petroleum ether → petroleum ether:ethyl acetate = 1:10 → petroleum ether:ethyl acetate = 1:5. 13.94 g of the target product was collected, with a total yield of 36.8%. TLC showed a small amount of impurities in the product.

[0178] This process has the following problems:

[0179] 1. During the synthesis process, the product quality is poor and there are many by-products, making it impossible to carry out recrystallization purification.

[0180] 2. When purification was performed by column chromatography, the final amount of intermediate 1 was 13.94 g, with a yield of only 36.8%.

[0181] 3. Purification using column chromatography is not suitable for large-scale industrial production.

[0182] In summary, the existing embodiments involve cumbersome procedures, long processing times, high byproduct content, low product yield, and low product purity. In contrast, the preparation method of the present invention is simple to operate, takes less time, has low byproduct content, and achieves higher product yield and purity, representing a significant technological advancement.

Claims

1. A method for preparing high-purity 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester, an intermediate of brandilolol hydrochloride, characterized in that... Includes the following steps: Step 1: Add raw material I, p-hydroxyphenylpropionic acid, and raw material II, p-toluenesulfonic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester, to the reaction solvent and inorganic base, and heat to 90-120℃ to carry out the reaction; Step 2: The reaction solution is extracted with water and organic solvent, and the extract is concentrated to obtain the crude product; Step 3: Add the crude product to the recrystallization solvent and heat to dissolve. Control the temperature to crystallize and obtain high-purity 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester.

2. The preparation method according to claim 1, characterized in that, The inorganic base used in step 1 is selected from potassium hydroxide or anhydrous potassium carbonate, preferably anhydrous potassium carbonate, and more preferably anhydrous potassium carbonate in an amount of 1.0 equivalent relative to raw material I.

3. The preparation method according to claim 1, characterized in that, The reaction solvent in step 1 is N,N-dimethylformamide or dimethyl sulfoxide, preferably dimethyl sulfoxide.

4. The preparation method according to claim 1, characterized in that, The reaction temperature in step 1 is 90–120°C, preferably 100–105°C.

5. The preparation method according to claim 1, characterized in that, The solvent used for recrystallization in step 3 is a mixture of methyl tert-butyl ether and n-heptane, a mixture of ethyl acetate and n-heptane, or a mixture of dichloromethane and n-heptane, preferably a mixture of dichloromethane and n-heptane.

6. The preparation method according to claim 1, characterized in that, In step 3, the recrystallization solvent is a mixture of dichloromethane and n-heptane, with a ratio of dichloromethane:n-heptane = 1:2-3, preferably 1:2.5, where the ratio is a volume ratio.

7. The preparation method according to claim 1, characterized in that, In step 3, the ratio of recrystallization solvent to crude product is: dichloromethane and n-heptane mixed solvent: crude product = 8.0 to 14.0 times, preferably 10.5 times, where the multiple is the volume-weight ratio.

8. The preparation method according to claim 1, characterized in that, The recrystallization temperature of intermediate I in step 3 is -20℃ to 25℃, preferably -5℃ to 5℃.

9. The preparation method according to claim 1, characterized in that, The recrystallization time of intermediate I is 1.0h to 3.0h, preferably 1.0h to 2.0h.

10. The preparation method according to claim 1, characterized in that, In step 3, the recrystallization solvent is a mixed solvent of dichloromethane and n-heptane in a volume ratio of 1:2.5, and the amount used is 10.5 times the volume weight ratio of the crude product. Crystallization is carried out at -5 to 5℃ for 1.0 h to 2.0 h.

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